 |
|
|
The Agency for Healthcare Research and Quality (AHRQ), through its Evidence-Based Practice Centers (EPCs), sponsors the development of evidence reports and technology assessments to assist public- and private-sector organizations in their efforts to improve the quality of health care in the United States. The reports and assessments provide organizations with comprehensive, science-based information on common, costly medical conditions and new health care technologies. The EPCs systematically review the relevant scientific literature on topics assigned to them by AHRQ and conduct additional analyses when appropriate prior to developing their reports and assessments.
To bring the broadest range of experts into the development of evidence reports and health technology assessments, AHRQ encourages the EPCs to form partnerships and enter into collaborations with other medical and research organizations. The EPCs work with these partner organizations to ensure that the evidence reports and technology assessments they produce will become building blocks for health care quality improvement projects throughout the Nation. The reports undergo peer review prior to their release.
AHRQ expects that the EPC evidence reports and technology assessments will inform individual health plans, providers, and purchasers as well as the health care system as a whole by providing important information to help improve health care quality.
We welcome written comments on this evidence report. They may be sent to: Director, Center for Practice and Technology Assessment, Agency for Healthcare Research and Quality, 6010 Executive Blvd., Suite 300, Rockville, MD 20852.
Carolyn M. Clancy, M.D.
Director
Agency for Healthcare Research and Quality
Jean Slutsky, P.A., M.S.P.H.
Acting Director, Center for Practice and Technology Assessment
Agency for Healthcare Research and Quality
The authors of this report are responsible for its content. Statements in the report should not be construed as endorsement by the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services of a particular drug, device, test, treatment, or other clinical service.
Objectives. The evidence report provides a systematic review of the scientific evidence to answer three questions of whether short stature in a child 1) due to a medically determinable cause or 2) due to skeletal dysplasia may be associated with disability, and 3) whether decreasing growth velocity in a child with a chronic disease may serve as an indicator of severity of the disease.
Search Strategy. Systematic searches were performed for relevant articles in MEDLINE® from 1966 through February 2001, with updates through October 2001. Additional studies were identified from other databases, reference lists of review and primary articles, and from domain experts.
Selection Criteria. Eligibility criteria for study inclusion included: primary articles reporting original data on at least 10 children; in studies of children with short stature, data on association between height and functional ability or limitation; in studies of children with chronic diseases, association between a measure of severity of disease and either height or height velocity. Studies could be cross-sectional or longitudinal, prospective or retrospective, comparative or not.
Main Results. A total of 13,537 English language citations were reviewed. Of these, 825 articles were reviewed for inclusion. For Question 1, 31 studies met inclusion criteria; for Question 2, 31 studies; and for Question 3, 53 studies. Detailed data extraction was performed on these 115 studies.
Based on the reviewed articles, no severe functional limitations were found in children with short stature due to isolated short stature, growth hormone deficiency, multiple hormone deficiency, Turner syndrome, or Russell-Silver syndrome. The studies reviewed focused on intelligence, academic achievement, behavior, visual-motor perception, and psychomotor development. In each of these categories, children with short stature either had testing that was not significantly different from the controls or from the population mean, or if the testing were significantly poorer, it was generally within 1 standard deviation (SD) of the population mean.
Based on the articles reviewed, children with skeletal dysplasias were not at increased risk of having severe impairments in intelligence, academic achievement, or psychological outcome. There was an increased risk for delay in achievement of motor skills in children with achondroplasia and osteogenesis imperfecta, and decreased ambulation, range of motion and mobility in children with more severe forms of osteogenesis imperfecta. The results for hearing impairment, respiratory dysfunction and spinal curvature appear to indicate an increased risk for impairment in these three areas, but the studies were limited in the number of children evaluated and how the samples were selected.
The evidence from four conditions (congenital heart disease, juvenile rheumatoid arthritis, Crohn's disease and human immunodeficiency virus (HIV) infection) appear to indicate that a sustained decrease in linear growth velocity can be used as a marker of the severity of these underlying conditions. Evidence is less clear for astham, atopic dermatits, diabetes, ß-thalassemia, and chronic kidney disease. There was only one study each for sickle cell disease, congenital adrenal hyperplasia and cerebral palsy so it is difficult to draw conclusions for these conditions. No study addressed whether the process of having a decreasing height velocity was likely to be disabling.
Conclusions. No severe functional limitations were found in children with short stature due to growth hormone deficiency, multi-hormone deficiency, Turner syndrome, Russell-Silver syndrome or isolated short stature. These children generally scored within 1 SD of the population mean. Children with skeletal dysplasias were not at increased risk of having severe impairments in intelligence, academic achievement, or psychological outcome. Sustained decrease in linear growth velocity has been shown to be associated with the severity of congenital heart disease, juvenile rheumatoid arthritis, Crohn's disease, and HIV.
The Social Security Administration (SSA) requested that the Agency for Healthcare Research and Quality (AHRQ), through its Evidence-based Practice Center (EPC) program, provide a systematic review of the scientific evidence about whether short stature in a child due to a medically determinable cause may be associated with disability, whether skeletal dysplasias in a child may be considered a disability, and whether decreasing growth velocity in a child with a chronic disease may serve as an indicator of severity of the disease. The population of interest includes children age 17 years or younger, both male and female, of all racial, ethnic and socioeconomic groupings.
The evidence report was prepared to assist SSA in updating its Listing of Impairments and revising its disability policy, as may be appropriate.
There are multiple causes of short stature. The most common causes are familial short stature (FSS) and constitutional growth delay (CGD). FSS occurs when a child has height below the third percentile due to a genetic tendency to short stature in his or her family. Children with FSS typically reach adult height consistent with their family background. CGD occurs when a child is shorter than would be expected by her or his genetic background and no determinable medical cause of the short stature can be found. Often children with CGD experience a delayed onset of pubertal development and usually obtain normal or near normal adult height. Neither FSS nor CGD is considered to be due to medically determinable causes in most cases. Since it can be difficult to differentiate between these two conditions, the term isolated short stature (ISS), is often used interchangeably for both FSS and CGD.
Medically determinable causes of short stature include abnormalities in the growth hormone axis such as decreased growth hormone production and diminished response to growth hormone. Other endocrine abnormalities such as hypothyroidism and Cushing disease may lead to short stature and a variety of genetic disorders including chromosomal disorders, metabolic disorders and single gene disorders can also result in short stature.
Skeletal dysplasias are genetic disorders that result in abnormal formation of part or all of the skeleton. Not all skeletal dysplasia will result in short stature. The skeletal dysplasias most likely to lead to short stature are those that involve formation and growth of the long bones and/or the spine.
The presence of a chronic disease in a child has long been known to be a risk factor for decreased growth to a varying degree. However, the underlying cause of the decreased growth has not been determined in all chronic diseases.
The following key questions were refined by the EPC Evidence Review Team and technical experts from those posed by the SSA.
Question 1. Is short stature (height < the 5th percentile) as a result of a medically determinable impairment associated with severe functional limitations, according to, but not limited to, SSA's definition of disability?
Question 2. What is the evidence that short stature (height < 5th percentile) due to a skeletal dysplasia is disabling according to, but not limited to, SSA's definition of disability? If so, are children disabled by virtue of their size or other features of their conditions?
Question 3. What is the evidence that a sustained decrease in linear growth velocity can be used as a marker of severity of an underlying disease? Is such a process likely to be disabling?
A range of definitions of short stature among children exists. In general, short stature has been defined as a height less than the 3rd percentile. This corresponds to a value of 1.9 standard deviations below the mean height (which is commonly rounded up to 2.0). However, many studies use a variety of definitions including height less than the 5th and 10th percentiles (corresponding to 1.65 and 1.3 standard deviations below the mean, respectively). The total number of children who have short stature due to either a medically determinable cause or a skeletal dysplasia as opposed to familial short stature has not been reported. However, by definition, approximately 2.2 million American children have short stature. (US Census, 2001)
Systematic searches were performed for full journal articles of original data. The primary search for the literature review consisted of a MEDLINE® search from 1966 through February 2001, with updates through October 2001. Supplemental searches were also performed in ERIC, PsycInfo, Healthstar and EMBASE. Additional studies were identified from reference lists of review and primary articles, and from domain experts.
Development of the search strategies was an iterative process that included input from domain experts. Keywords from known relevant studies were used to refine and focus the final search strategies used.
Including studies found from other sources, a total of 13,537 English language citations were reviewed. Screening of the abstracts and titles identified 825 articles potentially useful to address the three report questions. A set of minimum inclusion criteria were used in this initial screening: primary articles reporting original data on at least 10 children that provided primary or secondary evaluation of growth failure and had a primary or secondary outcome of a potential functional limitation. Studies could be cross-sectional or longitudinal, prospective or retrospective, comparative or not.
A total of 825 studies were retrieved for careful evaluation. Detailed examination of these articles identified 31 studies that met inclusion criteria for Question 1, 31 studies for Question 2, and 53 studies for Question 3. Detailed data extraction was performed on these 115 studies.
Question 1. Is short stature (height < the 5th percentile) as a result of a medically determinable impairment associated with severe functional limitations, according to, but not limited to, SSA's definition of disability?
We reviewed 31 papers that provided information on functional abilities among children with short stature due to medically determinable impairments. A number of these papers provided analyses from the same samples of children. One study reported on different outcomes in two separate papers. Therefore, 24 papers from 23 studies are summarized here. Few studies explicitly examined functional impairment, per se. Data are reported on the association of short stature with academic achievement, intelligence, visual-motor skills, psychomotor development, and teacher-graded behavior.
Fifteen of the 23 studies were prospective cross-sectional studies; seven were prospective longitudinal studies; and one was a retrospective longitudinal study. Two were of good quality, eleven were of fair quality, and nine were of poor quality. One study was of fair quality in its analysis of intelligence, but of poor quality in its analysis of academic achievement.
Based on the reviewed articles, no severe functional limitations were found in children with short stature due to growth hormone deficiency, multi-hormone deficiency, Turner syndrome, Russell-Silver syndrome or isolated short stature. These specific causes of short stature were chosen because they allowed us to isolate the effect of short stature and thus enable us to determine if there was an increased risk for disability related problems just due to short stature. The articles focused on intelligence, academic achievement, behavior, visual-motor perception, and psychomotor development. In each of these categories, children with short stature either had testing that was not significantly different from the controls or from the population mean, or if the testing were significantly poorer it was still for the most part within one standard deviation (SD) of the population mean.
Association of short stature with academic achievement. Eleven studies evaluated academic achievement in approximately 996 children with short stature as a result of a medically determinable impairment. Five of the studies found that children with short stature had academic achievement scores at or above the population norm. The other six studies found scores below the population norm but the great majority was still within one SD of the mean. These results imply that children with short stature do not have enough difficulties with academic achievement to qualify as a disability. A major limitation in five of the studies was the exclusion of children with a low intelligence quotient (IQ).
Association of sort stature with intelligence. Twenty-one studies evaluated IQ in approximately 1,156 children with short stature as a result of a medically determinable impairment. Fifteen studies found short stature children to have IQs at or above the population mean, while the remaining studies reported IQs for the most part less then one SD below the mean. Three of the studies that found IQs at or above the mean excluded children with low IQs. The studies were limited by the IQ exclusion and also by an absence of a control population in many of the studies. Future studies are required to better delineate this question.
Association of short stature with visual-motor skills. Only three studies involving 81 patients could be found that evaluated visual-motor perception in children with short stature. All three found significantly lower visual-motor skills in the evaluated children. These studies, however, were limited by their reporting of the data. Furthermore, it is not clear how a decrease in visual-motor skill can be correlated with the SSA definition of disability. Future studies are needed to evaluate disabilities caused by functional limitations in visual-motor skills.
Association of short stature with Psychomotor development. Only one poor quality study evaluated 14 children with short stature due to Russell-Silver syndrome for psychomotor development by the Denver Developmental Screening Test. These children were found to have delays in meeting their developmental landmarks. However, the value of this finding in relation to disability is questionable since the children did eventually meet their developmental landmarks (e.g., walking). Future studies are needed to determine the significance of these findings.
Association of short stature with behavior. Teacher-based evaluation of behavior in children with short stature was reported in five studies involving 274 children. In general, behavior in the children with short stature was not significantly different from the controls. Exceptions to this were increased hyperactivity reported in one study, increased locus of control in another study, and general increased behavior problems in a third study. It is difficult to extrapolate behavior in general from these studies since they tended to use different tests, and the test results do not always overlap. In addition, sub-group results were not given for each study. Furthermore, the value of behavioral impairments for determining a child's level of disability is questionable. Further studies are needed that evaluate large groups of non-selected short stature children, use the same behavior-based test, compare results to matched controls, and determine likelihood of disability.
Question 2. What is the evidence that short stature (height < 5th percentile) due to a skeletal dysplasia is disabling according to, but not limited to, SSA's definition of disability? If so, are children disabled by virtue of their size or other features of their conditions?
There were 31 papers from 25 study groups that provided information on functional abilities among children with short stature due to skeletal dysplasia. Of the studies, 22 were prospective cross-sectional studies; five were prospective longitudinal studies; 2 were retrospective longitudinal; and 2 were retrospective cross-sectional. One was of good quality, 16 were of fair quality, and 12 were of poor quality. One study was of good quality in its analysis of academic achievement, but of fair quality in its analysis of ambulation and mobility. One study was of fair quality in its analysis of neuromuscular function and range of motion, but of poor quality in its analysis of ambulation and mobility.
Based on the articles reviewed, children with skeletal dysplasias were not at increased risk of having severe impairments in intelligence, academic achievement, or psychological outcome. There was an increased risk for delay in achievement of motor skills in children with achondroplasia and osteogenesis imperfecta, and decreased ambulation, range of motion and mobility in children with more severe forms of osteogenesis imperfecta. The results for hearing impairment, respiratory dysfunction and spinal curvature appear to indicate an increased risk for impairment in these three areas, but the studies were limited in the number of children evaluated and how the samples were selected, thus making it difficult to arrive at a definitive conclusion in these areas.
Association with academic achievement. Three studies examined academic achievement among 84 children with achondroplasia or osteogenesis imperfecta. In two studies, achondroplasia patients scored lower than control groups, yet remained in the normal range. Further studies on this issue are needed to evaluate a larger population of children with achondroplasia, osteogenesis imperfecta and other types of skeletal dysplasias.
Association with intelligence. Five studies with 116 children evaluated intelligence in children with achondroplasia, osteogenesis imperfecta and other skeletal dysplasias. No evidence of significantly impaired intelligence was found in any of the skeletal dysplasias by intelligence testing with all scores either above the population norm or within 0.5 SD of the norm. These studies were generally small for the comparisons made. Further studies on this issue are needed to evaluate a larger population with skeletal-dysplasias clearly defined by up-to-date standards.
Association with psychomotor development. Six studies involving a total of 196 children found generally delayed achievement of psychomotor abilities or development in children with achondroplasia and osteogenesis imperfecta. Each group evaluated was small, used different testing instruments, and had varying ages of subjects. Furthermore, none was followed longitudinally. Clinically useful conclusions about ultimate motor function in children with skeletal dysplasias cannot be made from these studies. Larger, longitudinal studies are needed that test psychomotor functional abilities.
Association with neuromuscular function. From review of the available literature, children with short stature due to various skeletal dysplasias appear to be at risk for neuromuscular abnormalities. Six studies with 185 children evaluated neuromuscular function in children with skeletal dysplasias. The four studies that looked solely at children with achondroplasia found varied abnormalities. The three that measured strength found substantial weakness and hypotonia. Asymmetry, sensory deficits, poor coordination, and seizures were found in frequencies higher than controls or than are expected in the healthy population. All studies highlighted the significant risk of often occult cervical cord compression in these young children. The one paper that evaluated osteogenesis imperfecta found substantial muscle weakness in children who are moderately to severely affected by their disease. The one paper that reviewed other skeletal dysplasias found cervical cord complications in children with Morquio disease. Further studies of children with skeletal dysplasias, especially achondroplasia, are needed to better delineate the extent of neuromuscular impairment.
Association with ambulation and mobility. Of the eight papers considering ambulation and mobility in children (N=345) with short stature due to skeletal dysplasia, all considered children with osteogenesis imperfecta. All found significant impairment in ambulation, with greater impairment, as expected, in patients with more severe disease. Children with the less severe types of osteogenesis imperfecta (tarda, Type I, Type IV) were more likely to attain some walking capability, although a substantial proportion of these children did require assistance. Orthopedic abnormalities such as scoliosis, decreased range of motion, decreased muscle strength and fracture contribute to limitations of ambulation. All of the studies were of small size; although given the rarity of osteogenesis imperfecta, the studies were of reasonable size. Definitions of levels of ambulation were consistent and fairly objective. Studies of ambulation and mobility disabilities are necessary for children with skeletal dysplasias other than osteogenesis imperfecta.
Association with limb range of motion. Two studies evaluated upper and lower range of motion (ROM) abnormalities in children with various types of osteogenesis imperfecta (N=40) and with achondroplasia (N=41). Decreased ROM was found in children with osteogenesis imperfecta, but no such correlation was seen in children with achondroplasia. Decreased lower extremity ROM may impact on ability to independently ambulate. Decreased upper extremity ROM may limit an individual's independence by reducing his or her ability to engage in self-care. Further studies are necessary to better delineate the connection between limb ROM and various skeletal dysplasias.
Association with spinal curvature. Four papers assessed spinal deformities in 209 children with short stature due to skeletal dysplasia. Three studied children with osteogenesis imperfecta, and one studied children with diastrophic dysplasia. A high prevalence of scoliosis was found in children with both conditions. One study also found a high prevalence of pathologic kyphosis. All studies, however, likely represent a selected, perhaps more severe, population of patients followed by academic medical centers. Thus to find prevalence in the general population of individuals with skeletal dysplasias, it will be necessary to evaluate scoliosis and kyphosis in a group of unselected individuals with skeletal dysplasias.
Association with hearing loss. Of the six studies that reported on hearing loss in 151 children with skeletal dysplasia, only three performed objective hearing testing. All papers that reported actual hearing testing in young osteogenesis imperfecta patients reported a sizable proportion with hearing loss, although the prevalence varied due to selection and cohort size differences. Subjective reports of hearing problems in achondroplasia patients were common. However, one study found no difference in self-reported hearing function between children with a mix of skeletal dysplasias, including achondroplasia, and control children. The available literature supports that children with at least some skeletal dysplasias, specifically achondroplasia and osteogenesis imperfecta, are at risk for hearing problems. Further studies with a larger, unselected population of children with skeletal dysplasia are needed to better define the extent, severity and type of hearing loss.
Association of short stature with respiratory dysfunction. Of the four papers evaluating sleep and respiratory dysfunction in 94 children with achondroplasia, all found a high incidence of abnormality, including central hypopnea, central apnea, and obstructive apnea. All four papers, however, reported on small numbers of children. Two of the groups contained patients referred for their respiratory or neurologic symptoms, and therefore may not represent the general achondroplasia population. Further studies that look at larger groups of non-selected achondroplasia patients are needed to define the prevalence of apnea in this population.
Little information on pulmonary function in children with skeletal dysplasia was found. One group found abnormal pulmonary function in a small group of children with achondroplasia, and one found no significant abnormality in a smaller group of children with osteogenesis imperfecta. More data are required before meaningful conclusions can be drawn.
Association of short stature with psychological outcomes. Only one paper was found that adequately studied the association of short stature due to skeletal dysplasia with psychological outcomes. The study found no evidence for increased rates of depression or anxiety in children with skeletal dysplasia. Further studies that evaluate psychological problems such as depression and anxiety are needed to validate these results.
Question 3. What is the evidence that a sustained decrease in linear growth velocity can be used as a marker of severity of an underlying disease? Is such a process likely to be disabling?
We reviewed 53 articles that evaluated whether a sustained decrease in linear growth velocity can be used as a marker of the severity of 12 medical conditions and whether such a process is likely to be disabling. One study separately evaluated children with both asthma and congenital heart disease. The evidence from four conditions—congenital heart disease, Crohn's disease, juvenile rheumatoid arthritis, and human immunodeficiency virus (HIV) infection—appear to indicate that a sustained decrease in linear growth velocity can be used as a marker of the severity of these underlying conditions. Evidence is less clear for asthma, diabetes, β-thalassemia, chronic kidney failure, and atopic dermatitis. There was only one study each for cerebral palsy, sickle cell anemia and congenital adrenal hyperplasia, so it is difficult to draw conclusions for these conditions. None of the studies addressed the question of whether the process of having a decreasing linear growth velocity was likely to be disabling.
Association of severity of asthma. Eleven studies evaluated the association between severity of asthma and height or height velocity in 3,778 children. Overall, the studies did not find a consistent result. Six of the studies found no association between severity of asthma and growth retardation. No study found an association between mild asthma and growth retardation.
Studies were limited by poorly defined samples, limited data and analysis, missing data and, frequently, by the fact that severity of disease was measured by steroid treatment. These studies do not clearly provide evidence that a sustained decrease in linear growth velocity can be used as a marker of severity of asthma or whether a decrease in growth velocity is likely to be disabling. Future well-designed studies are needed.
Congenital heart disease. Six studies evaluated the association between severity of congenital heart diseases and height or height velocity in 1,784 children. Many studies were limited by incomplete data and statistical analysis and some studies were limited because they excluded children with the most severe congenital cardiac defects. Given the limitations, the results do suggest that height and height velocity retardation is seen in children with severe congenital heart defects and may be a marker for more severe disease. Whether the decrease in height or height velocity in itself is disabling is not answered.
Insulin-dependent diabetes mellitus. Eleven studies involving 1,099 children evaluated the relationship between growth retardation and control or severity of insulin dependent diabetes mellitus. Overall, the studies showed mixed results with five studies demonstrating a positive relationship between poor diabetes control or increased severity of disease and decreased growth velocity. Several studies associated growth deceleration with peripubertal onset of illness. Some studies were limited because they did not use a well-defined, objective measure, such as glycohemoglobin (Hgb Alc), to assess severity or control. Some studies were limited by unclear statistical analysis, lack of specific data included or summary results. These studies did not find clear evidence that a sustained decrease in linear growth velocity can be used as a marker of severity of diabetes or whether a decrease in linear growth velocity is in itself disabling. Further prospective, longitudinal studies of the linear growth of children with diabetes mellitus, using objective measure of control like Hgb Alc, are needed to clarify whether a decrease in linear growth velocity may be a marker for severity of disease.
β-Thalassemia. There were three studies involving 295 children that evaluated the relationship between growth retardation and severity of anemia β-thalassemia. One study showed a relationship between increased severity of anemia and reduced height, and one study showed a trend toward increased severity of disease and decreased growth. The studies were limited by incomplete data reporting and by inconsistent definitions of severity. These studies do not show clear evidence that a sustained decrease in linear growth velocity can be used as a marker of the severity of the disease. Prospective longitudinal cohort studies with clear definitions of severity (i.e. hemoglobin levels) and measurements of height velocity may answer the question.
Inflammatory bowel disease. There were three studies involving 660 children that evaluated the relationship between growth retardation and the severity of inflammatory bowel disease. Two studies included only children with Crohn's disease. The other two studies included children with both Crohn's disease and ulcerative colitis. Disease severity was associated with height velocity among children with both Crohn's disease and ulcerative colitis; however, height was not significantly associated with disease severity in any study. There are no data presented to suggest that the process of growth failure is likely to be disabling. Further prospective longitudinal studies that include larger numbers of patients who have ulcerative colitis and Crohn's disease, and that compare both with population standards and with each other, may clarify whether growth retardation is a marker associated with severity of all inflammatory bowel diseases, or is related to one in particular.
Juvenile rheumatoid arthritis. Three studies involving 153 children, evaluated the relationship between growth retardation and the subtypes or severity of juvenile rheumatoid arthritis. All studies indicated an association between decreased growth velocity and increased severity of the disease. One study noted that height velocity normalized after the first year of treatment. The studies were limited in two cases by excluding children with the most severe disease, by incomplete statistical analyses in one, and by poorly defined outcomes in another. With these caveats, the studies suggest that a decrease in linear growth velocity is associated with more severe disease and may serve as a marker of severity of the underlying disease. There are no data reported addressing the question of whether decreased growth velocity is in itself disabling. Future well-designed studies with broad inclusion criteria are needed to clarify the issue.
Chronic kidney disease. Ten studies, involving 684 children, evaluated the relationship between growth retardation and severity of chronic kidney disease. Eight of the studies found a positive relationship between increased severity of kidney failure and decreased height or height velocity. Single studies of sub-populations of children with autosomal recessive polycystic kidney disease (ARPKD) and very young children with chronic kidney disease found no association of disease severity with height velocity. There was conflicting evidence about the role of steroid use in causing growth retardation. Some studies were limited by using a severity marker other than glomerular filtration rate, by small sample sizes, or by incomplete data reporting. Overall, the studies suggest that a decrease in linear growth velocity is associated with the severity of the underlying disease but this finding was not universal. No data were available to assess if a decreased height velocity is in itself disabling. Additional prospective, longitudinal studies that evaluate whether a decrease in linear growth velocity can be used as a marker of severity of underlying kidney disease are needed.
Human immunodeficiency virus infection. There were two studies evaluating the relationship between growth retardation and progression to disease in 60 HIV-positive children. Both studies found that linear growth retardation is a marker for progression to active disease in HIV-positive children and linear growth deceleration may precede the onset of symptoms of active disease. These studies were limited by incomplete data reporting and poorly defined methods, predictors and outcomes. Despite the limitations, the studies do indicate that a sustained decrease in linear growth velocity is a marker for progression from seropositive status to active disease. No data were included that assess whether a decreased linear growth velocity is in itself likely to be disabling. Larger, prospective, longitudinal studies of the relationship between decreasing linear growth velocity and progression of disease could confirm the usefulness of decreased linear growth velocity as a marker for increasing severity of disease.
Atopic dermatitis. Two studies, involving 148 children, evaluated the relationship between growth retardation and severity of atopic dermatitis. The studies reported conflicting results with one study reporting a positive association between increased severity and decreased height and the other study showing no association between increased severity and decreased height or height velocity. In the first study the more severely affected group had higher steroid use and some used systemic steroids. In the second study, those using systemic glucocorticoids were excluded from analysis. This study was also limited by a failure to report complete results and a failure to report statistical analyses. These studies do not clearly provide evidence that a sustained decrease in linear growth velocity is a marker for the severity of the underlying disease. No data were provided that look at whether the process of a decreasing linear growth velocity is in itself disabling. Further prospective longitudinal studies are needed to clarify whether growth velocity is affected by the severity of atopic dermatitis, or whether the apparent effect is related to steroid treatment.
Cerebral palsy. There was only one study with 81 subjects that looked at the relationship between growth retardation and cerebral palsy. The study did not find a significant association between the type of cerebral palsy and decreased growth velocity but cognitive impairment, and non-ambulatory status were associated with decreased growth velocity. This suggests that those more severely affected by both motor and non-motor neurological deficits have decreased growth velocity. This study was limited by the exclusion criteria, which likely excluded the most severely affected children. No data were presented to answer the question about whether the process of having a decreasing linear growth velocity is in itself disabling. Further prospective longitudinal studies of children with varying severity of cerebral palsy are needed to confirm whether a decreasing linear growth velocity is a marker for the severity of the underlying disorder.
Sickle cell disease. There was only one study with 24 subjects that evaluated the association of growth retardation with the severity of sickle cell disease. That study found a positive association between severe sickle cell disease (measured by need for transfusions and the number of crises) and decreased height percentile compared to controls. The study was small and did not explicitly compare less severe sickle cell disease to more severe disease. The study also did not look at height velocity as a predictor of more severe disease. Further prospective longitudinal studies that compare larger numbers of patients with mild, moderate and severe sickle cell disease are needed to determine if a decreasing linear growth velocity can serve as a marker for the severity of the underlying disease.
Congenital adrenal hyperplasia. There was only one study with 9 subjects that looked at the relationship between growth retardation and congenital adrenal hyperplasia. It did not find an association between number of escapes (more severe disease) and decreased growth velocity. The study was limited by its small size and by its reporting of results in graphic form only. There is not clear evidence that a decreasing linear growth velocity can be used as a marker for the underlying severity of congenital adrenal hyperplasia. No data were presented that look at whether the process of a decreasing linear growth velocity is in itself disabling. Further prospective longitudinal studies of larger numbers of patients with congenital adrenal hyperplasia are needed to answer the question of whether decreasing linear growth velocity can be used as a marker for severity of the underlying disease.
There were several limitations encountered in evaluating Questions 1 and 2. Very few studies looked specifically at disability as defined by SSA. Most studies in fact were looking at functional ability such as IQ or academic achievement. Such areas are focused on in the published literature because they allow for acquisition of data that can be compared to published norms. Results from such studies have to be extrapolated to determine if the children evaluated meet the SSA definition of disability. For example, one SSA criterion of disability includes acquiring and using information. Reduced IQ in a child may lead to limitations in acquiring or using information, but there is not a linear relationship between decreased IQ and reduced ability to acquire and use information. Even those studies that evaluated functional impairment, such as those that evaluated inability or limitation of walking, do not necessarily correlate directly with SSA's definitions of disability.
One limitation to evaluating Question 3 relates to difficulties in trying to correlate the severity of disease with decreasing growth velocity. Frequently a report that details height in a specific disorder does not directly correlate this with severity of disease. Also the way in which severity of disease was reported may vary between reports discussing the same disease. The same problem was seen with reporting of growth data, which is given in a variety of different formats (e.g., one-time height, growth velocity, and standard deviation from the mean). This makes it more difficult to determine the overall validity of the results.
Further research is needed to better define the relationships both between short stature and disability and between growth velocity and severity of chronic disease. Research on disability should focus on functional deficits rather than functional ability. Studies that examine physical limitations directly related to short stature are needed. Further prospective longitudinal studies of growth velocity in chronic disease are needed. Studies are needed of children of various ages, including puberty. Studies need to clearly define severity of disease and avoid confounding severity with treatment options.
The Social Security Administration (SSA) of the Department of Health and Human Services requested that the Agency for Healthcare Research and Quality (AHRQ), through its Evidence-based Practice Center (EPC) program, provide the scientific basis for SSA to determine disability claims for children with short stature, with skeletal dysplasias, and with chronic disease in which decreasing growth velocity may be a component. This evidence report is prepared to assist SSA in updating its Listing of Impairments and revising its disability policy, as may be appropriate.
This report summarizes the scientific evidence about whether short stature in a child due to a medically determinable cause may be associated with disability, whether skeletal dysplasias in a child may be considered a disability, and whether decreasing growth velocity in a child with a chronic disease may serve as an indicator of severity of the disease. The population of interest includes children age 17 years or younger, both male and female, of all racial, ethnic and socioeconomic groupings.
A range of definitions of short stature among children exists. In general, short stature has been defined as a height less than the 3rd percentile (Plotnick, 1990). This corresponds to a value of 1.9 standard deviations below the mean height (which is commonly rounded up to 2.0). However, many studies use a variety of definitions including height less than the 5th and 10th percentiles (corresponding to 1.65 and 1.3 standard deviations below the mean, respectively). The total number of children who have short stature due to either a medically determinable cause or a skeletal dysplasia as opposed to familial short stature has not been reported. However, by definition, approximately 2.2 million American children have short stature (US Census, 2001).
There are multiple causes of short stature. The most common causes are familial short stature (FSS) and constitutional growth delay (CGD). FSS occurs when a child has height below the third percentile due to a genetic tendency to short stature in his or her family (Mahoney, 1987). Children with FSS typically reach adult height consistent with their family background. CGD occurs when a child is shorter than would be expected by her or his genetic background and no determinable medical cause of the short stature can be found. Often children with CGD experience a delayed onset of pubertal development and usually obtain normal or near normal adult height (Plotnick, 1990). Neither FSS nor CGD is considered to be due to medically determinable causes in most cases (Attie, 2000). Since it can be difficult to differentiate between these two conditions, the term isolated short stature (ISS), is often used interchangeably for both FSS and CGD.
Medically determinable causes of short stature include abnormalities in the growth hormone axis such as decreased growth hormone production and diminished response to growth hormone. Other endocrine abnormalities such as hypothyroidism and Cushing disease may lead to short stature (Bacon, Spencer, Hopwood, et al., 1990). A variety of genetic disorders including chromosomal disorders, metabolic disorders and single gene disorders can also result in short stature (Bacon, Spencer, Hopwood, et al., 1990).
Skeletal dysplasias are genetic disorders that result in abnormal formation of part or all of the skeleton. Not all skeletal dysplasia will result in short stature. The skeletal dysplasias most likely to lead to short stature are those that involve formation and growth of the long bones and/or the spine. The most common skeletal dysplasias that typically result in short stature include achondroplasia, hypochondroplasia, and osteogenesis imperfecta (Taybi and Lachman, 1996). There are more than 200 described skeletal dysplasias, many of which may lead to short stature, but each of these conditions individually is quite rare (Online Mendelian Inheritance in Man, 2002).
The presence of a chronic disease in a child has long been known to be a risk factor for decreased growth to a varying degree (Plotnick, 1990). However, the underlying cause of the decreased growth has not been determined in all chronic diseases. Diseases that affect a child's nutritional status (inflammatory bowel disease, celiac disease) may lead to a decrease in growth velocity secondary to caloric and general nutritional insufficiency (Kelts, Grand, Shen, et al., 1979;Oliva and Lake, 1996). Other diseases such as asthma, which do not appear to directly affect nutritional status, have also been reported to lead to decreased growth velocity (Abrams, 2001).
The definition of disability in children used for the purposes of this report came from the SSA and was based on a definition passed by Congress in 1996. Under Title XVI, a child under age 18 years will be considered disabled if he or she has a medically determinable physical or mental impairment or combination of impairments that causes marked and severe functional limitations, and that can be expected to cause death or that has lasted or can be expected to last for a continuous period of not less than 12 months (Disability evaluation under Social Security, 1999).
Specific areas of functioning include: 1) acquiring and using information, 2) attending and completing tasks, 3) interacting and relating with others, 4) moving about and manipulating objects, 5) caring for yourself, 6) health and physical well-being. Disability is based on the degree to which the above functions are interfered with. Disability is established if there are marked limitations in at least two areas or there is an extreme limitation in one area of functioning. Where standardized tests of function exist, the regulations define a “marked” degree of functional limitation as more than two but less than three standard deviations below the mean and an “extreme” limitation as three or more standard deviations below the mean. (Disability evaluation under Social Security, 1999).
However, SSA's definition of disability is an administrative one, which is not commonly used by clinicians or researchers. In general, disability is defined differently by different researchers for different diseases. Furthermore, studies of children with short stature frequently focus on differences of ability, rather than on disability per se. Thus, any analysis of the literature to evaluate disability for SSA will be limited by the fact that few studies have primary analyses of disability that correspond to SSA's definition.
The evaluation of the association of short stature due to medically determinable causes with disability is complicated by the fact that it is often hard to distinguish whether the disability is due directly to short stature or to the underlying medical problem. As an example, Turner syndrome, which is caused by the absence of part or all of one X chromosome in a female, results in short stature in the majority of girls affected. These girls often have difficulties in visual-spatial relationships, but these difficulties are believed to be secondary to their genetic defect and not related to their short stature (Ross, Stefanatos, Roeltgen, et al., 1995). Similarly in Down syndrome, which is caused by chromosome 21 trisomy, children generally have short stature; however the significant mental retardation in these children is not thought to be secondary to their stature (Tolmie, 1997).
Evaluation of children with short stature may be done by a variety of medical specialties including endocrinology, gastroenterology, and genetics and depending on the specialty, different evaluations may be done. In general, research done on children with short stature has tended to focus on intelligence and psychological concerns, which fall into the first three areas of functioning discussed above (acquiring and using information, attending and completing tasks, and interacting and relating with others).
Evaluation of disability among children with short stature due to medically determinable causes is limited in that few studies examine disability per se, but instead compare different levels of ability (e.g. cognitive ability). In addition, direct associations between ability and height are often not reported.
Skeletal dysplasias are a relatively heterogeneous group of diseases that cause abnormalities in development of one or more parts of the skeleton. For the most part skeletal dysplasias tend to affect only bony development, specifically metaphyseal or epiphyseal development. However, certain skeletal dysplasias may also have other associated anomalies, such as severe myopia and cleft palate in diastrophic dysplasia, which may impact on a disability evaluation. Most, but not all, skeletal dysplasias will lead to stature below the third percentile. The most common skeletal dysplasias include achondroplasia, hypochondroplasia, osteogenesis imperfecta, and diastrophic dysplasia (Taybi and Lachman, 1996). The research on disability and skeletal dysplasia has tended to focus on structural abnormalities of the bones and short stature and has looked at problems such as difficulties in acquiring and using information, moving about and manipulating objects, caring for self, and health and physical well-being.
Evaluation of disability among children with skeletal dysplasia, as with children with short stature due to medically determinable causes, is limited in that few studies examine disability per se, but instead compare different levels of ability (e.g. cognitive ability). The main exception to this are studies of ambulation and mobility. In addition, direct associations between ability and height and between severity of short stature within a particular skeletal dysplasia are often not reported.
Some chronic diseases (e.g., inflammatory bowel disease, asthma, congenital heart disease) have been associated with poor growth in the affected child. The poor growth may lead to height less than the third percentile in some, or the height may stay within the normal range but with a decreased growth velocity (Mahoney, 1987). Of interest is whether decreased growth velocity can be used as a marker to indicate worsening severity of disease. This question does not directly relate to disability.
Certain chronic diseases, such as diabetes or chronic kidney disease, have clearly defined methods of measuring severity of disease (i.e., HgbA1c and glomerular filtration rate, respectively). However, most chronic diseases have less well-defined measures of severity (e.g., asthma, congenital heart disease, sickle cell anemia). Therefore, different studies use different, non-standard definitions of severity, making comparisons across studies difficult. For some chronic diseases, severity of disease may just be a proxy for different categories or sub-types of the disease (e.g., congenital heart disease, juvenile rheumatoid arthritis). Growth may be affected differently by the different categories of the chronic disease, which may not be associated with the “severity” of the disease.
To properly evaluate the association between chronic disease severity and growth, studies must be longitudinal and measure height velocity. However, much of the research on severity of chronic disease has been cross-sectional. Therefore, height, rather than height velocity, has frequently been analyzed.
This evidence report is based on a systematic review of the literature. A series of teleconferences was held with the science partner representatives from the Social Security Administration (SSA), the American Academy of Pediatrics (AAP), the internal technical experts from the Evidence-based Practice Center (EPC), and a representative of the Disability Law Center to formulate the key questions addressed by this report. A comprehensive search of the medical literature was conducted to identify the evidence available to address the questions.
Detailed information about each study used in the systematic review was abstracted. The results are presented in evidence tables. Information directly pertinent to answer each aspect of the key questions addressed is presented in summary tables within the Results section (Chapter 3). A list of abbreviations is presented in Appendix 2.
The EPC staff, pediatric experts, and representatives of SSA arrived at consensus on three key questions following discussions and between-meeting solicitation of comments from the group members. The key questions were refined to ensure that the answers would be useful to SSA, would be of interest to the technical experts, would be appropriate for literature review, and would likely be available in the literature. The final key questions are:
Is short stature (height < 5th percentile) as a result of a medically determinable impairment associated with severe functional limitations, according to, but not limited to, SSA's definition of disability?
What is the evidence that short stature (height < 5th percentile) due to a skeletal dysplasia is disabling according to, but not limited to, SSA's definition of disability? If so, are children disabled by virtue of their size or other features of their conditions?
What is the evidence that a sustained decrease in linear growth velocity can be used as a marker of severity of an underlying disease? Is such a process likely to be disabling?
For all key questions, the populations of interest are boys and girls under age 18 years who have short stature. Children of all ethnicities, nationalities, racial, and socioeconomic groups were included.
For key questions 1 and 2, short stature was defined as height less than the 5th percentile (or less than -1.67 standard deviations (SD) below the mean) for age. However, given the variability of definitions of short stature in the literature, we accepted definitions of short stature up to the 25th percentile.
For key questions 1 and 2, disability was defined based on SSA definitions published in “Disability Evaluation Under Social Security” (Disability Evaluation Under Social Security, 1999), as discussed in the Introduction. The list of impairments provided by SSA was reviewed to determine the possible disabilities of interest. However, SSA's definition of disability is based on a need to determine an administrative definition to comply with Federal law. Clinicians and researchers, though, use various definitions of ability and disability to care for patients. Thus, very few studies have examined the association between short stature and (SSA-defined) disability, per se. This report therefore focuses on assessments of functional limitations, as defined by study authors. Objective and teacher- or clinician-scored assessments were included. Parent or child determinations of functional ability were excluded.
The primary categories (or causes) of short stature considered included isolated or idiopathic short stature, constitutional growth delay, growth hormone deficiency, multiple hormone deficiency, Russell-Silver syndrome, and Turner syndrome. No predetermined definitions for each of the causes of short stature were used; instead, definitions used by study authors were accepted. Studies that focused on children with Down syndrome were not reviewed as SSA already defines such children as disabled from birth.
The associations between short stature due to medically determinable impairment and functional ability included academic achievement, intelligence, academic advancement, visual motor skills, psychomotor development, and teacher-graded behavioral problems.
The primary skeletal diseases resulting in short stature considered included osteogenesis imperfecta, achondroplasia, diastrophic dysplasia, and other skeletal dysplasias. No predetermined definitions for each skeletal dysplasia were used; instead, definitions used by study authors were accepted.
The associations between short stature due to skeletal dysplasia and functional ability included academic achievement, intelligence, psychomotor development (visual-motor skills, motor development, and motor development patterns), neuromuscular function, ambulation and mobility, limb range of motion, spinal curvature, hearing loss, respiratory dysfunction (sleep apnea and pulmonary function), and psychological outcomes.
Attention was paid to addressing the association between disease severity and decreased linear growth velocity. Thus, only studies that categorized children with chronic diseases by disease severity and that also directly compared height to disease severity were included. Studies that investigated only the association between disease presence and height were not reviewed. No predetermined definitions of disease severity were used; instead definitions used by study authors were accepted. To capture the full range of data available on growth in children with chronic disease, we included both studies that evaluated height velocity as well as height alone.
The review focused on chronic diseases that either are associated with, or may result in, disability, as defined by SSA. We did not review studies that evaluated the association between treatment for chronic disease and height, unless sufficient data were available to answer the primary question. Thus, studies of steroid use for gastrointestinal and most other diseases were generally excluded. For studies of children with asthma, we excluded those that explicitly examined the effect on growth of steroid use. However, we included studies that used medication requirement (including steroids) as a marker of severity, since this was a common method of analysis. Cancer and cardiac diseases requiring surgery were not considered because separating the effect on height of treatment from the underlying disease is not possible.
Systematic searches were performed for full journal articles of original data. The primary search for the literature review consisted of a MEDLINE® search from 1966 through February 2001, with updates through October 2001. Supplemental searches were also performed in ERIC, PsycInfo, Healthstar and Embase. Additional studies were identified from reference lists of review and primary articles, and from domain experts.
Development of the search strategies was an iterative process that included input from domain experts. Keywords from known relevant studies were used to refine and focus the final search strategies used.
Only articles that included human children under age 18 years and that were published in English were included. Case reports, review articles, commentaries, letters, and abstracts were excluded.
Pediatrician domain experts and EPC staff manually screened the titles and abstracts of the search results to identify potentially useful articles to address each of the key questions. A set of minimum inclusion criteria were used in this initial screening: primary articles reporting original data on at least 10 children that provided primary or secondary evaluation of growth failure and had a primary or secondary outcome of a potential functional limitation. Studies could be cross-sectional or longitudinal, prospective or retrospective, comparative or not. Full articles of abstracts found potentially useful were retrieved for more careful evaluation.
Data abstraction forms were developed in an iterative process by EPC staff with the pediatrician experts. The forms were designed to capture information of various aspects of the primary articles. Individual forms were developed for each key question. Forms included study setting, demographics (including such information as age, height, sex, race, and socioeconomic status), eligibility criteria, number of subjects, study design, funding source, relevant measurements and outcomes evaluated, statistical methodology, results, potential biases, and study quality.
Pediatrician domain experts performed all the data abstraction. Abstractors were trained by the EPC staff. As part of the training, each Team Member abstracted three studies in duplicate with the Team Leader and meetings were held to discuss discrepancies. After training, all remaining studies were abstracted by one pediatrician. All abstracted data were reviewed by two members of the EPC staff when data were transferred to evidence and summary tables.
Articles that reported data on the same or overlapping sets of children were grouped together in the evidence and summary tables, or noted to contain duplicate data, to avoid duplication of results. One study author (RHH Engelbert) was contacted by email to clarify the overlap of a number of studies.
Summary tables were created to describe studies reviewed for each topic. The tables describe the strength of the evidence according to four dimensions: study size, study sample applicability, results, and methodological quality. For questions 1 and 2, studies are grouped first by study sample disease type. Within each section, studies are ordered first by methodological quality (best to worst), then by study size (largest to smallest). For question 3, studies are grouped first by methodological quality, then by applicability of study sample to children with the given chronic disease, then by study size.
Methodological quality (also known as internal validity) refers to the design, conduct, and reporting of the clinical study. Because studies with a variety of design types were evaluated, a three-level classification of study quality, used in previous reports, was modified. All studies were graded on the following scale:
Good quality. Least bias. Results are valid. A study that mostly adheres to the commonly held concepts of high quality, including the following: a formal study; prospective design, clear description of the population and setting; proper measurement techniques; appropriate statistical and analytic methods; no reporting errors; no obvious bias.
Fair quality. Susceptible to some bias, but not sufficient to invalidate the results. A study that does not meet all the criteria of category A. It has some deficiencies but none likely to cause major bias.
Poor quality. Significant bias likely that may invalidate the results. A study with serious errors in design or reporting. These studies may have large amounts of missing information or discrepancies in reporting.
In general, studies that reported data relevant to multiple topics of interest were given the same quality rating for each topic; however, some studies were rated differently for different topics, depending on the quality of the data for each topic. For example, a study may have performed a complete and valid statistical analysis of intelligence but may not have performed a statistical analysis of academic achievement. The study may therefore receive a lower quality rating for its analysis of academic achievement than for intelligence.
Applicability (also known as generalizability or external validity) addressed the issue of whether the study sample is sufficiently broad so that the results of the study can be generalized to the population of interest at large. The study population is typically defined by the eligibility criteria. Restrictive eligibility criteria (e.g., single sex, limited range of disease severity) or small sample size may reduce the applicability of a given study.
For questions 1 and 2 the applicability of each study is described by the type of disease causing short stature. The few studies that had particularly restrictive eligibility are noted in each table's footnotes. For certain disability topics (e.g., hearing loss and ambulation) where separate results are reported for different sub-populations of children, columns were added to the tables to describe the populations. For each study, the mean, median, or threshold height (generally expressed in age and sex standard deviations from the mean, or standard deviation score (SDS) were recorded.
For question 3, where all studies within a given table evaluate children with the same (or similar) diseases, a designation for applicability was assigned to each article, according to the following three-level scale:
Study is representative of all children with the given chronic disease. Study sample includes both sexes, the full range of disease severity, a sufficient number of subjects. There are no substantial eligibility restrictions.
Sample is representative of a relevant sub-group of children with the given chronic disease. There were eligibility restrictions that may limit the applicability, such as single sex, disease severity, or co-morbidities.
Sample is representative of a narrow subgroup of children with the given chronic disease. There were substantial eligibility restrictions that limit applicability.
To complement the applicability scale, each table has a column describing the diseases of the study population.
The study (sample) size is used as a measure of the weight of the evidence. In general, large studies provide more precise estimates of prevalence and associations. In addition, large studies are more likely to have wide applicability, depending on eligibility criteria. However, large study size does not guarantee applicability.
The type of results available is determined by each study's design, the purpose of the study, and the question(s) being asked. Therefore, the results presented vary across summary tables. For questions 1 and 2 most summary tables present either the mean test results of a given test or the prevalence of a given condition. When necessary, the test or condition evaluated in each study is included. When available, the results for a control group are also included. Summary tables for question 3 include separate columns for association of disease severity with height and with height velocity. For appropriate topics in questions 1 and for all topics in question 3, associations are described with the following arrows:
Statistically significant positive association between severity of chronic disease and height or height velocity. More severe chronic disease associated with growth retardation. If statistical analysis was not reported, but a large clinical difference in growth based on disease severity was, statistical significance was assumed to be likely. This symbol was used only in studies evaluated for question 3.
Statistically significant negative association between ability and disease causing short stature. This symbol was used only in studies evaluated for visual-motor skills in question 1.
Trend toward positive association between severity of chronic disease and height or height velocity. Some indication that children with more severe chronic disease may be associated with growth retardation. However, association either is not statistically significant or statistical analysis was not reported. This symbol was used only in studies evaluated for question 3.
No association between severity of chronic disease and height or height velocity. This symbol was used only in studies evaluated for question 3.
While literature searches were intended to be comprehensive, they may not have been exhaustive. As noted above, search strategies were limited to focus on studies likely to be relevant. Searches were limited to English language publications. Hand searches of journals were not performed, and review articles and textbook chapters were not systematically searched. However, important studies known to the domain experts and studies found in reference lists were included in the review.
| Author Year | Sample N (Controls) | Mean Height, SDS | Test | Mean Academic Achievement Score | Biasa | Qualityb | |||
|---|---|---|---|---|---|---|---|---|---|
| Math | Reading | Compre-hension | Spelling | ||||||
| Isolated Short Stature or Constitutional Growth Delay | |||||||||
| Downie 1997 | 106(119) | <-2 | BAS | 40[44] | 44[48] |
| |||
| Wilson 1986 | ~350(~6,400) | <-1.6 | WRAT | ~92c |
| ||||
| Stathis 1999 | 113(3,178) | <-2 | PPVT-R | 92[97] | >IQ |
| |||
| Siegel 1994 | 90(90) | -2.8 | WRAT | 96 22%<80d | 102 | 98 | >IQ |
| |
| Kranzler 2000 | 34(29)e | -1.7 | KTEA | 105[121] | 106[115] | 107[114] Totalf | 104[101] | >IQ |
|
| Kranzler 2000 | 27(29)g | -2.7 | KTEA | 107[121] | 104[115] | 106[114] Totalf | 105[101] | >IQ |
|
| Gordon 1984 | 24(23) | <-1.6 | PIAT | 103 | 102 | 102 | Matched |
| |
| Isolated Growth Hormone or Multiple Hormone Deficiency | |||||||||
| Siegel 1986 | 42 | <-2 | WRAT | 85 | 96 | >IQ |
| ||
| Abbott 1982 | 11 | ND | WRAT | 83 | 88 | 85 | No stat |
| |
| Siegel 1994 | 87(90) | -2.7 | WRAT | 99 | 103 | 98 | >IQ |
| |
| Isolated Short Stature or Growth Hormone Deficiency | |||||||||
| Siegel 1998 | 25(25) | -3.1 | WRAT | 102 | 105 | 99 |
| ||
| Turner Syndrome | |||||||||
| Siegel 1998 | 22(25) | -3.3 | WRAT | 90 | 98 | 95 |
| ||
| Ross 1997 | 20 w/GHh | ND | WRAT | 100 | No stat |
| |||
| Ross 1997 | 20 w/o GHi | ND | WRAT | 97 | No stat |
| |||
| Russell-Silver Syndrome | |||||||||
| Lai 1994 | 25 | -2.2 | Nealej | Delay 7 mo | Delay 15 mo | No stat |
| ||
Mean scores in bold were significantly different than normal population; results not in bold not significantly different, except as noted in bias column.
Mean score for normal population for each test is 100, unless otherwise noted in brackets
BAS = British Ability Scales; KTEA = Kaufman Test of Educational Achievement; Neale = Neale analysis of reading ability, British edition; PIAT = Peabody Individual Achievement Test; PPVT-R = Peabody Picture Vocabulary Test-Revised; WRAT = Wide Range Achievement Test
Studies noted with “>IQ” excluded subjects with low intelligence quotient or known mental impairment excluded.
Studies noted with “No stat” did not perform statistical analysis comparing IQ of subjects to normal controls.
Study noted with “Matched” used controls that were matched for IQ among other factors.
See Methods, Summary Tables, Study Quality.
Significant correlation between height and reading and arithmetic subtests of WRAT. WRAT score reported graphically.
Significantly more children with ISS had an arithmetic score less than 80 than controls (7%).
Non-referred subjects, shortest 10% at school.
Control children had math and reading scores of 121 and 115, respectively
Referred to endocrinology clinic for short stature.
Subjects with Turner syndrome, treated with growth hormone
Subjects with Turner syndrome, not treated with growth hormone
Neale assessment of reading ability measured reading competence. No data clearly provided on how arithmetic competence was measured.
Six studies evaluated academic achievement in approximately 744 children with ISS or CGD. Academic achievement was measured with a variety of tests, including the Wide Ranging Achievement Test (WRAT), the Peabody Picture Vocabulary Test - Revised (PPVT-R), the British Ability Scales (BAS), the Kaufman Test of Educational Achievement (KTEA), and Peabody Individual Achievement Test (PIAT). The scores of the children with short stature were all compared to controls. All studies analyzed prospective data. Two were longitudinal, four were cross-sectional. One study was of good quality, one was of fair quality, and four were rated poor quality because they excluded children with low intelligence quotients (IQ) for analyses of cognitive function or analyzed cognitive function despite matching subjects and controls by IQ.
In four prospective, longitudinal papers (Downie, Mulligan, McCaughey, et al., 1996;Downie, Mulligan, Stratford, et al., 1997;Voss, Bailey, Mulligan, et al., 1991; Voss and Mulligan, 1994) children with ISS were tested repeatedly at different ages. In the final analysis (Downie, Mulligan, Stratford, et al., 1997) 106 13 year old children with ISS had significantly lower reading and mathematics attainment scores on BAS than the same aged controls. The scores remained significantly lower than for controls after adjusting for social class. However the absolute difference in scores were within 1 standard deviation (SD) of the average control subjects' scores.
Wilson, Duncan, Dornbusch, et al. (1986) reported on a prospective, longitudinal study of 6,768 adolescents, aged 12 to 17 years old, who were in Cycle III of the National Health Examination Survey from 1966-1970. Approximately 350 of these children had height below the 5th percentile. There was a small but significant correlation between standardized height and WRAT score. Mean WRAT score for different height percentile groups of children rose consistently with height. Similar results were found for the same children when they were 6 to 11 years old.
Stathis, O'Callaghan, Williams, et al. (1999), in a prospective, cross-sectional analysis of 113 4 to 6 year old children with height less than the 3rd percentile, found that receptive vocabulary, measured with PPVT-R, was significantly lower among both boys and girls than among children of normal height. However, the absolute differences in scores were within 1 SD of the mean for normal children. The value of this study is limited, though, since 14 children with PPVT-R scores less than 50, with cerebral palsy, or with other neurological disorders were excluded from the analysis.
In a prospective, cross-sectional study,Siegel, Clopper, Stoppani, et al. (1994) evaluated WRAT-R in 90 children with ISS with a mean age of 11 years old. There were no significant differences between mean reading, spelling, and math scores in the children with ISS and the normal controls. However, significantly more ISS children (22 percent) had a skill deficit in mathematics (score less than 80) compared to both GHD children (10 percent) and normal children (7 percent). The value of this study is limited, though, since children with “known mental impairments” were excluded.
Kranzler, Rosenbloom, Proctor, et al. (2000) evaluated two groups of 6 to 12 year old children with ISS in a prospective, cross-sectional study. One group consisted of 34 children who were identified in local public schools as being in the shortest 10 percent of the class (“non-referred”). The second group consisted of 27 children with ISS who had been referred to pediatric endocrinology because of short stature. Among both groups, children with ISS scored significantly lower than normal height controls on both mathematics and reading KTEA. For both groups, spelling and composite achievement scores were similar to controls. However, mean scores for all groups of children were above standardized norms. The value of this study is limited, though, since children with IQ less than 75 were excluded.
Gordon, Post, Crouthamel, et al. (1984) evaluated 24 6 to 12 year old children with height less than the 5th percentile due to CGD in a prospective, cross-sectional study. The children had normal scores on math, reading recognition, and comprehension PIAT. These scores were not significantly different from controls; however the controls were matched for Full Scale IQ.
Three studies evaluated academic achievement in children with GHD and multiple hormone deficiency (MHD). A total of 140 children were evaluated by WRAT. The test results were either compared to controls or population norms. Two of the studies (Siegel, Clopper, Stoppani, et al., 1994; Siegel and Hopwood, 1986) excluded subjects with low IQ or known mental impairment. All were prospective; one was longitudinal, two were cross-sectional. Two were rated as fair quality; one poor.
Siegel and Hopwood (1986) evaluated 42 children with short stature due to hypopituitarism (28 with isolated GHD and 14 with MHD) and a mean age of 12 years. Academic achievement was evaluated by WRAT and was compared to population norms in a prospective, cross-sectional study. A significant decrease in math scores was found in the hypopituitary children but no difference in reading scores. The children with hypopituitarism had WRAT scores within 1 SD of the mean. Of note, the study excluded one child with hypopituitarism because severe mental retardation prevented using some of the tests.
Eleven children, aged 4 to 18 years old, with short stature due to GHD and/or other pituitary hormone deficiency were evaluated in a longitudinal, prospective study byAbbott, Rotnem, Genel, et al. (1982). Their academic achievement tests (WRAT) were less than the mean but within 1 SD of the mean (except for WRAT arithmetic scores, which were within 1.5 SD of the mean) when compared to population norms.
Siegel, Clopper, Stoppani, et al. (1994) evaluated 87 children with height less than the 3rd percentile either due to GHD and mean age of 11 years. The children were compared to average stature control children matched for age, sex and socioeconomic status in a prospective, cross-sectional study. Academic achievement in the children with short stature tested by the WRAT-R test was not significantly different from the results of the controls. However, children with known mental impairment were excluded from this study.
One study evaluated academic achievement with WRAT in 25 girls with a mean age of 10 years who had either ISS or short stature due to GHD. In a longitudinal, prospective study,Siegel, Clopper, and Stabler (1998) compared the girls with ISS/GHD to a group of girls with short stature due to Turner syndrome and a control group of girls with average stature. The girls with short stature had similar academic achievement testing, measured by WRAT, compared to control girls of average stature and girls with Turner syndrome. These results were from the baseline study for an evaluation of the effects of growth hormone on girls with short stature. The study was of good quality.
Two studies evaluated academic achievement (WRAT) in 62 girls with short stature secondary to Turner syndrome. The test results were compared to population norms or to controls. Both were longitudinal, prospective studies. One was of good quality; one of fair quality.
Siegel, Clopper, and Stabler (1998) tested 22 girls with Turner syndrome with a mean age of 10 years for academic achievement (WRAT). Test scores for the girls with Turner syndrome were not significantly different from control girls of average stature. This was a longitudinal, prospective study.
In a prospective study that was part of a double-blind randomized controlled trial of growth hormone for the treatme nt of Turner syndrome, Ross, Feuillan, Kushner, et al. (1997) evaluated 40 girls with a mean age of 9 years. The study found that girls with Turner syndrome had WRAT scores that were at or just below the population average, whether they received growth hormone or a placebo.
One study evaluated academic achievement in 25 children with Russell-Silver syndrome. Lai, Skuse, Stanhope, et al. (1994) tested children aged 6 to 12 years old with the clinical diagnosis of Russell-Silver syndrome with the Neale analysis of reading and an undefined test of arithmetic competence in a prospective, cross-sectional study. The children with Russell-Silver syndrome were found to have substantial delays in both reading and arithmetic competence. Because of the poor reporting and the lack of statistical analysis, the study was graded poor quality.
Six studies examined academic achievement among children with ISS or CGD. Four found that the short children had significantly lower scores on various tests of academic achievement than normal height children. Two studies found that, overall, short children had similar scores as normal controls. Among all the studies, short children scored either above population norms or within 1 SD of normal scores. One study found that short children were significantly more likely to have a skill deficit (in mathematics) than normal height children even though mean scores were similar. Three of the studies excluded children with low IQ and a fourth matched short children with normal children with similar IQs.
Three studies examined academic achievement among children with GHD or MHD. One found that short children had significantly lower mathematics test scores than normal height controls. All three found that test scores among short children were within 1.5 SD of population means. One study excluded one child with severe mental retardation; another excluded children with low IQs.
A single study examined academic achievement among children with either ISS or GHD. These children scored at or above population means.
Two studies examined academic achievement among children with Turner syndrome. One study found no significant difference between girls with Turner syndrome and controls. Both studies found that girls with Turner syndrome scored within 1 SD of population norms.
One study examined academic achievement among children with Russell-Silver syndrome. These children were found to have substantial delays in both reading and arithmetic competence.
| Author Year | Sample N (Controls) | Mean Height, SDS | Full | Mean IQ Verbal | Performance | Biasa | Qualityb |
|---|---|---|---|---|---|---|---|
| Isolated Short Stature or Constitutional Growth Delay | |||||||
| Downie 1997 | 106 (119) | <-2 | 103d |
| |||
| Wilson 1986 | ~350 (~1800) | <-1.6 | ~93c |
| |||
| Rovet 1985 | 25 | < -2 | 101 | 98 | 102 | No stat |
|
| Siegel 1994 | 90 (90) | -2.8 | 107 | >IQ |
| ||
| 18%<90e | |||||||
| Kranzler 2000 | 34 (29)f | -1.7 | 105 | 104 | 105 Matrices | >IQ |
|
| Kranzler 2000 | 27 (29)g | -2.7 | 103 | 101h | 106 Matrices | >IQ |
|
| Gordon 1984 | 24 (23) | < -1.6 | 108 | 107 | 108 | Matched |
|
| Holmes 1985 | 21 | <-2 | 104 | No stat |
| ||
| McCauley 1987 | 16 | -4.5 | 100 | 108 | >IQ |
| |
| No stat | |||||||
| Isolated Growth Hormone or Multiple Hormone Deficiency | |||||||
| Siegel 1986 | 42 | < -2 | 94 | 94 | >IQ |
| |
| Frisch 1990 | 23 | -2.5 | 115 | 104 | 114 |
| |
| Meyer-Bahlburg 1978 | 13 w/GHD | -3.7 | 101 | No stat |
| ||
| Abbott 1982 | 11 | ND | 88 | 89 | 89 | No stat |
|
| Meyer-Bahlburg 1978 | 9 w/MHD | -4.0 | 102 | No stat |
| ||
| Siegel 1994 | 87 (90) | -2.7 | 110 | >IQ |
| ||
| 9%<90e | |||||||
| Holmes 1985 | 17 | < -2 | 97 |
| |||
| Combined Isolated Short Stature, Constitutional Growth Delay, and Growth Hormone Deficiency | |||||||
| Siegel 1998 | 25 (25) | -3.1 | 105 |
| |||
| Steinhausen 1976 | 32 | -3.7 | 103 | 102 | 103 | No stat |
|
| Pollitt 1964 | 13 | -6.9 | 103 | 103 | 102 |
| |
| Young-Hyman 1986 | 27 | < -2 | 110 | >IQ |
| ||
| Turner Syndrome | |||||||
| Siegel 1998 | 22 (25) | -3.3 | 102 |
| |||
| Ross 1997 | 20 w/ GHi | ND | 98 | 104 | 92 | No stat |
|
| Ross 1997 | 20 w/o GHj | ND | 99 | 102 | 96 | No stat |
|
| Robinson 1983 | 9 (17) | ND | 87 | 93 | 83 |
| |
| McCauley 1987 | 17 | -5.0 | 95 | 91 | >IQ |
| |
| No stat | |||||||
| Holmes 1985 | 9 | < -2 | 103 | No stat |
| ||
| Russell-Silver Syndrome | |||||||
| Lai 1994 | 25 | -2.2 | 86 | 89 | 84 |
| |
| Tanner 1975 | 11 | -2.6 | 103 | No stat |
| ||
| Angehrn 1979 | 9k | -4.4 | 91 | No stat |
| ||
| Combined Isolated Short Stature and Russell-Silver Syndrome | |||||||
| Skuse 1996 | 22 (21) | -2.5 | 96 | 95 | 97 | >IQ |
|
Mean IQ results in bold were significantly different than normal population; results not in bold not significantly different, except as noted.
w/ GHD = Children with growth hormone deficiency; w/MHD = Children with multiple hormone deficiency
Studies noted with “>IQ” excluded subjects with low IQ or known mental impairment excluded. Studies noted with “No stat” did not perform statistical analysis comparing IQ of subjects to normal controls. Study noted with “Matched” used controls that were matched for IQ among other factors.
See Methods, Summary Tables, Study Quality.
Significant correlation between height and IQ. IQ value reported graphically.
Controls had mean IQ of 109
Significantly more children with ISS and with GHD had IQ < 90 than controls (3%).
Non-referred subjects, shortest 10% at school.
Referred to endocrinology clinic for short stature.
Controls had mean verbal IQ of 110
Subjects with Turner syndrome, treated with growth hormone
Subjects with Turner syndrome, not treated with growth hormone
5 additional children who were not tested were “probably of normal intelligence.” No data on 6 other children in study.
Eight studies evaluated intelligence in children with ISS or CGD with approximately 693 subjects. Tests included Wechsler Intelligence Scale for Children (WISC), British Ability Scales (BAS), Kaufman-Brief Intelligence Test (K-BIT), and Slosson Intelligence Test (SIT). Test results were either compared to controls or to population norms. All studies analyzed prospective data. Three were longitudinal; five were cross-sectional. One study was of good quality; two were of fair quality; and five were of poor quality, primarily because of excluding subjects with low IQ or known mental impairment.
In four prospective, longitudinal papers (Downie, Mulligan, McCaughey, et al., 1996; Downie, Mulligan, Stratford, et al., 1997; Voss, Bailey, Mulligan, et al., 1991; Voss and Mulligan, 1994) children with ISS were tested repeatedly at different ages. In the final analysis (Downie, Mulligan, Stratford, et al., 1997) 106 13 year old children with ISS had IQ measured with BAS. Children with short stature had significantly lower IQ than normal height controls, even after adjusting for socioeconomic status. However, mean IQ among study subjects was greater than 100.
Wilson, Duncan, Dornbusch, et al. (1986) reported on a prospective, longitudinal study of 6,768 adolescents, aged 12 to 17 years old, who were in Cycle III of the National Health Examination Survey from 1966-1970. Approximately 350 of these children had height below the 5th percentile. These children had significantly lower IQ scores, measured by WISC, than the general population mean. IQ was significantly correlated with height for all children. However, average WISC scores for short children were within 1 SD of the mean. Similar results were found for the same children when they were 6 to 11 years old.
Rovet, Netley, and MacLeod (1986) evaluated 25 boys with a mean age of 14 years who had ISS in a prospective, cross-sectional study. Verbal, performance and full-scale IQs, measured by WISC, were similar to the population average.
In a prospective, cross-sectional study Siegel, Clopper, Stoppani, et al. (1994) evaluated intelligence with SIT in 90 children with ISS and a mean age of 11 years old. There were no significant differences between mean IQ in the children with ISS and the normal controls. However, significantly more ISS children (18 percent) had an IQ less than 90 than normal children (3 percent). The value of this study is limited, though, since children with “known mental impairments” were excluded.
Kranzler, Rosenbloom, Proctor, et al. (2000) evaluated two groups of 6 to 12 year old children with ISS in a prospective, cross-sectional study. One group consisted of 34 children who were identified in local public schools as being in the shortest 10 percent of the class (“non-referred”). The second group consisted of 27 children with ISS who had been referred to pediatric endocrinology because of short stature. Among both groups, children with ISS had similar composite and matrices IQ measured by K-BIT as normal height controls. Non-referred short children had similar verbal IQ as controls, while referred short children had significantly lower IQ than controls. However, the mean verbal IQs for all groups of children were above 100. The value of this study is limited, though, since children with IQ less than 75 were excluded.
Gordon, Post, Crouthamel, et al. (1984) evaluated 24 6 to 12 year old children with height less than the 5th percentile due to CGD in a prospective, cross-sectional study. The children had above normal scores on full, verbal, and performance IQ by WISC. These scores were not significantly different from controls; however the controls were matched for Full Scale IQ.
Holmes, Karlsson, and Thompson (1985) evaluated 21 children with short stature due to CGD who were age 12 years at the start of a prospective longitudinal study. The verbal IQs, measured by WISC, of these children were slightly above the population mean. No statistical analysis was performed and the study suffered from incomplete reporting.
In a prospective, cross-sectional study, McCauley, Kay, Ito, et al. (1987) evaluated 16 girls with ISS and a mean age of 13 years. These girls had scored at or above the population mean for both verbal and performance IQ measured by WISC. However, children with IQ less than 79 were excluded.
Six studies evaluated intelligence in children with short stature due to GHD or MHD with a total of 202 subjects. The tests used included the WISC and SIT. Test results for children with short stature due to GHD/MHD were either compared to average stature controls or to population norms. All of the studies were prospective. Two were longitudinal; four were cross-sectional. No study was of good quality; four were of fair quality; and two were of poor quality.
Siegel and Hopwood (1986) evaluated 42 children with short stature due to hypopituitarism (28 with isolated GHD and 14 with MHD) and a mean age of 12 years. IQ was evaluated by WISC and was compared to population norms in a prospective, cross-sectional study. Their verbal and performance IQs were significantly less than the population average, but within 1 SD of the population average. Of note, the study excluded one child with hypopituitarism because severe mental retardation prevented using some of the tests.
Frisch, Hausler, Lindenbauer, et al. (1990) evaluated 23 children aged 7 to 16 years old with isolated GHD or MHD who were evaluated by IQ testing with the German language version of WISC in a prospective, cross-sectional study. The children scored statistically higher on full score and performance IQ tests than the population at large. Verbal IQ scores were similar to controls. No correlation was found between standardized height and IQ score.
In a prospective, cross-sectional study, 13 children with short stature due to isolated GHD and nine children wi th MHD were evaluated by Meyer-Bahlburg, Feinman, MacGillivray, et al. (1978) by IQ testing (WISC). The children ranged in age from about 4 to 18 years old. Both groups of children had normal full score IQs.
Eleven children, aged 4 to 18 years old, with short stature due to GHD and/or other pituitary hormone deficiency were evaluated in a longitudinal, prospective study by Abbott, Rotnem, Genel, et al. (1982). The children had verbal, performance and full-scale IQs that were less then the general population mean but within 1 SD of the mean. No statistical analysis was reported. The study found that overall IQ scores were more related to socioeconomic level and specific physical dysfunction, such as eye defects, than to hypopituitarism.
In a prospective, cross-sectional study Siegel, Clopper, Stoppani, et al. (1994) evaluated intelligence with SIT in 87 children with GHD and a mean age of 11 years old. There were no significant differences between mean IQ in the children with GHD and the normal controls. However, significantly more GHD children (9 percent) had an IQ less than 90 than normal children (3 percent). The value of this study is limited, though, since children with “known mental impairments” were excluded.
Holmes, Karlsson, and Thompson (1985) evaluated 17 children with short stature due to GHD who were age 12 years at the start of the study in a prospective longitudinal study. The verbal IQs, measured by WISC, of these children were slightly below the population mean. No statistical analysis was performed and the study suffered from incomplete reporting.
Four studies evaluated intelligence with WISC or SIT in 97 subjects with ISS, CGD and GHD. The test results were compared to controls of average stature or to population norms. One study excluded subjects with low IQ or known mental impairment. All of the studies were prospective. One was longitudinal; three were cross-sectional. One study was of good quality; two were of fair quality; and one was of poor quality.
Siegel, Clopper, and Stabler (1998) evaluated IQ with SIT in 25 girls with a mean age of 10 years who had either ISS or short stature due to GHD. This longitudinal, prospective study, compared the girls with ISS/GHD to a group of girls with short stature due to Turner syndrome and a control group of girls with average stature. These results were from the baseline study for an evaluation of the effects of growth hormone on girls with short stature. No significant difference was found in the IQ of girls with GHD/ISS compared to control girls of average stature.
Steinhausen and Stahnke (1976) reported IQ testing (WISC) in 32 children ranging from 9 to 17 years old with height less than the 3rd percentile due to either hypopituitarism or familial reasons and compared these children to age-matched children of “normal” height. Performance, verbal and full-scale IQ testing scores were similar among these children and controls. This was a prospective, cross-sectional study.
Intelligence testing was performed in 13 children aged 3 to 16 years with short stature due to GHD, CGD, or Turner syndrome by Pollitt and Money (1964) in a prospective, cross-sectional study. Average full-scale, verbal and performance IQ scores (measured by WISC) were normal. Results were all slightly above the population mean (verbal 103, performance 101, full-scale 102). The 2 children who were tested with the Stanford-Binet, revised had IQs (48), which were slightly below the population norm. The study did not find a significant difference in intelligence in children with short stature.
Young-Hyman (1986) evaluated 27 children with ISS, GHD or CGD and a mean age of 12 years in a prospective, cross-sectional study. The full-scale IQs (WISC) were on average above the normal range. However, no statistical analysis was performed and the study excluded children with mental disability or learning problems.
Five studies evaluated intelligence in girls with short stature secondary to Turner syndrome with a total of 97 subjects. Tests used included WISC and SIT. The test results were compared either to controls or to population norms. One study excluded subjects with low IQ or known mental impairment. All studies were prospective. Three were longitudinal; two were cross-sectional. One study was of good quality; two were of fair quality; and two were of poor quality.
Siegel, Clopper, and Stabler (1998) evaluated IQ with SIT in 22 girls with a mean age of 10 years who had Turner syndrome. This longitudinal, prospective study, compared these girls to girls with ISS/GHD and to a control group of girls with average stature. These results were from the baseline study for an evaluation of the effects of growth hormone on girls with short stature. The girls with Turner syndrome had IQ scores that were slightly above the population mean, but slightly less than the scores for the control girls of average height (108).
In a prospective study that was part of a double-blind randomized controlled trial of growth hormone for the treatment of Turner syndrome, Ross, Feuillan, Kushner, et al. (1997) evaluated 40 girls with a mean age of 9 years. The study found that girls with Turner syndrome had IQ scores (measured by WISC) that were similar to the population norm, whether they received growth hormone or a placebo.
Robinson, Bender, Borelli, et al. (1983), in a small prospective, cross-sectional study, evaluated nine girls with Turner syndrome who ranged from 7 to 15 years old. Measured by WISC, the average full-scale and verbal IQs of these girls were significantly below normal, although still within 1 SD of normal mean. The mean verbal IQ was not significantly lower than normal.
McCauley, Kay, Ito, et al. (1987) tested IQ in 17 3 to 16 year old girls with short stature due to Turner syndrome. The girls had somewhat low verbal and performance IQs (measured by WISC) that were within 1 SD of the mean. No statistical analyses were performed in this prospective, cross-sectional study. Children with IQ less than 79 were excluded from the study.
Holmes, Karlsson, and Thompson (1985) evaluated 9 children with Turner syndrome who were age 12 years at the start of a prospective longitudinal study. The verbal IQs, measured by WISC, of these children were slightly above the population mean. No statistical analysis was performed and the study suffered from incomplete reporting.
Three studies evaluated intelligence in children with short stature due to Russell-Silver syndrome with 45 total subjects. The test scores were compared to population norms. Two were prospective; one was retrospective. Two were longitudinal; one was cross-sectional. One study was of fair quality; two were of poor quality.
Lai, Skuse, Stanhope, et al. (1994) evaluated IQ with WISC in 25 children with Russell-Silver syndrome in a prospective, cross-sectional study. The children were 6 to 12 years old and had significantly lower full-scale, verbal, and performance IQs than the general population norm. However, the scores were within 1 SD of the general population mean. The full-scale IQ range was 46–130 with 8 children (32 percent) having IQs less than 70.
A longitudinal, retrospective study by Tanner, Lejarraga, and Cameron (1975) evaluated 39 children with Russell-Silver syndrome aged 1½ to 10 years old in an attempt to understand the natural history of this condition. IQ testing was only available for 11 of the children and the specific test used was not reported. The mean full-scale IQ was slightly above the population mean of 100.
A longitudinal, prospective study by Angehrn, Zachmann, and Prader (1979) evaluated growth and development in 20 children with Russell-Silver syndrome and a mean age of 4 years old. IQs (specific test not reported) were reported for only nine of the children. Six of them had IQs in the normal range (mean of 102) and 3 had IQs less than 86 (85, 83 and 38).
One study evaluated intelligence via WISC in 22 children with either ISS or Russell-Silver syndrome. The test scores were compared to the average stature control group. Skuse and Gilmour (1997) evaluated seven children with Russell-Silver syndrome and 15 with ISS in a prospective, cross-sectional study. The children with short stature had significantly lower average full-scale and performance IQ scores and lower verbal IQ than control children who had mean IQ scores from 105 to 108. However, the mean scores of the short children were within 1 SD of the population mean. The study was graded to be of poor quality because it excluded children with IQ less than 72.
Eight studies evaluated intelligence among children with ISS or CGD. Three studies found that short children had significantly lower IQs than normal controls. All studies found that, overall, short children had IQs that were either above or within 1 SD of population norms. One study found that short children were significantly more likely to have some intelligence deficit (IQ less than 90) even though mean scores were similar. Four studies excluded children with low IQ and one study matched short children with normal height children with similar IQs.
Seven studies evaluated intelligence among children with GHD or MHD. Two studies found that short children had significantly lower IQs than normal controls. All studies found that, overall, short children had IQs that were either above or within 1 SD of population norms. One study found that short children were significantly more likely to have some intelligence deficit (IQ less than 90) even though mean scores were similar. One study excluded one child with severe mental retardation; one excluded children with low IQs.
Four studies evaluated intelligence among children with either ISS, CGD or GHD. None found that short children had significantly lower IQs than normal controls. All found that, overall, short children had IQs that were above population norms. One study excluded children with low IQs.
Five studies evaluated intelligence among girls with Turner syndrome. One small study found that girls with Turner syndrome had significantly lower IQs than normal height controls and that their IQs were, on average, about 1.5 SD below population norms. The remaining studies found that girls with Turner syndrome had IQs that were within 1 SD of population norms. Ones study excluded girls with low IQ.
Three studies evaluated children with Russell-Silver syndrome and one with either Russell-Silver syndrome or ISS. Two studies found that the short children had significantly lower IQs than normal height controls. One excluded children with low IQs. All studies found that children with Russell-Silver syndrome, overall, had IQs within 1.5 SD of population norms.
| Author, Year | Sample N (Controls) | Mean Height | Measure | Results | Qualitya |
|---|---|---|---|---|---|
| Isolated Short Stature | |||||
| Abbott 1982 | 11 | 81–132 cm | Bender Visual Motor | - 2 y 1 mob |
|
| Beery Visual Motor Integration | -3 y 8 mob | ||||
| Young-Hyman 1986 | 27 | ND | Bender Visual Motor | - 2 y 6 mob |
|
| Growth Hormone or Multiple Hormone Deficiency | |||||
| Siegel 1986 | 42 | < -2 SDS | Bender Visual Motor Score < 16th percentile & ≥ 4 brain injury indicators | 26% |
|
Results in bold were significantly different than normal population.
See Methods, Summary Tables, Study Quality.
Discrepancy between chronological age and age equivalence, in years and months.
Eleven children, aged 4 to 18 years old, with short stature due to GHD and/or other pituitary hormone deficiency had Bender Visual Motor Gestalt testing done by Abbott, Rotnem, Genel, et al. (1982) in a longitudinal, prospective study. Visual integration skills were significantly delayed in these children compared to population norms.
Young-Hyman (1986) evaluated 27 children with short stature who had presented to an endocrine clinic in a prospective, cross-sectional study. Perceptual motor skills as assessed by the Bender visual-motor skills were significantly delayed. The tested children had skills rated at 9.2 y compared to their chronological age of 11.8 years. Reporting of the analysis was poor.
Siegel and Hopwood (1986) evaluated Bender visual-motor integration testing in 42 children who were 6 to 16 years old and had short stature due to hypopituitarism. Significant visual-motor integration deficits occurred in one-quarter of the children. This was a prospective, cross-sectional study. Reporting of the analysis was poor.
Three studies evaluated visual-motor skills in children with either ISS, GHD, or MHD. All three found that short children were significantly more likely to a reduction in visual-motor skills. The degree of functional deficit or disability in visual-motor skills was not reported.
| Author Year | Sample N (Controls) | Mean Height, SDS | Measure | Association | Qualitya |
|---|---|---|---|---|---|
| Russell-Silver Syndrome | |||||
| Angehrn 1979 | 14 | -4.4 | DDST | >90th %ile in >50% subjects |
|
DDST = Denver developmental screening test
See Methods, Summary Tables, Study Quality.
One study evaluated psychomotor development among children with Russell-Silver syndrome. This study found that these children tended to be delayed in meeting their early developmental landmarks.
| Author Year | Sample N (Controls) | Mean Height, SDS | Test | Total (Control) | Internalizing (Control) | Externalizing (Control) | School (Control) | Qualitya |
|---|---|---|---|---|---|---|---|---|
| Isolated Short Stature | ||||||||
| Voss 1991b | 140 (140) | RBQ | 29% >9 (21%) Disturbance | 16% >3 (8%) Hyperactivity | ||||
| Voss 1994b | 132 (132) | <-2.0 | RBQ | 6.2 (5.1) | 1.2 (1.0) Conduct | 1.2 (1.2) Emotion | 1.7 (1.1) Activity |
|
| Downie 1997b | 98 (115) | N&S | 17 (14) Locus of control | |||||
| Gordon 1984 | 24 (23) | -1.7 | CBCL | 31 (28) |
| |||
| Kranzler 2000 | 34 (29)c | -1.7 | BASC | 51 (50) | 47 (48) | 47 (46) |
| |
| Kranzler 2000 | 27 (29)d | -2.7 | BASC | 50 (50) | 51 (48) | 50 (46) |
| |
| Growth Hormone Deficient or Constitutional Growth Delay | ||||||||
| Steinhausen 1976 | 32 (32) | -2.0 | HANES | 13 (16) Neuroticism | 11 (12) Extraversion |
| ||
| Isolated Short Stature or Russell-Silver Syndrome | ||||||||
| Skuse 1994 | 17 (15) | -2.5 | CBCL | 49 (42) | NSe | NSe |
| |
Bold = significantly different from control
BASC = Behavior Assessment System for Children; CBCL = Child Behavior Checklist; HANES = Hamburg Neuroticism Extraversion Scale; RBQ = Rutter's Behavior Questionnaire ; N&S = Nowicki and Strickland Locus of control scale; NS = Non-significant
See Methods, Summary Tables, Study Quality.
Voss 1991, Voss 1994, and Downie 1997 included same overall sample of subjects.
Non-referred subjects, shortest 10% at school.
Referred to endocrinology clinic for short stature.
Exact data not reported.
In three prospective, longitudinal papers (Downie, Mulligan, Stratford, et al., 1997; Voss, Bailey, Mulligan, et al., 1991; Voss and Mulligan, 1994) children with ISS were tested repeatedly at different ages. In the first study (Voss, Bailey, Mulligan, et al., 1991) of 140 short children between 7 and 9 years old, 29 percent were found to have a behavior disturbance (defined as total RBQ score greater than 9), which was somewhat higher than among control children (21 percent); the difference was not significant. In these same children, hyperactivity (defined as activity sub-scale score of greater than 3) occurred in significantly more short children than controls (16 percent versus 8 percent). As reported in Voss and Mulligan (1994) for a subset of 132 of the children with short stature, mean behavior scale scores for short children were non-significantly higher than for control children for total behavior, conduct, emotion, and activity, after controlling for socio-economic status. In Downie, Mulligan, Stratford, et al. (1997) 98 of the children were evaluated at age 13 years with N&S. Locus of control score was significantly higher among the children with short stature.
Gordon, Post, Crouthamel, et al. (1984) evaluated 24 children aged 6 to 12 years old with CGD in a prospective, cross-sectional study. Behavior was assessed with CBCL. There was no significant difference in behavior between short stature children and controls.
Kranzler, Rosenbloom, Proctor, et al. (2000) evaluated two groups of 6 to 12 year old children with ISS in a prospective, cross-sectional study. One group consisted of 34 children who were identified in local public schools as being in the shortest 10 percent of the class (“non-referred”). The second group consisted of 27 children with ISS who had been referred to pediatric endocrinology because of short stature. Behavioral functioning was assessed with BASC. Both the referred and non-referred children had behavior functioning scores that were similar to controls.
Steinhausen and Stahnke (1976) evaluated 32 children ranging from 9 to 17 years old with height less than the 3rd percentile due to either hypopituitarism or familial reasons and compared these children to age-matched children of “normal” height. Extraversion and neuroticism were measured with HANES. The children with short stature had similar scores as controls. This was a prospective, cross-sectional study.
Skuse and Gilmour (1997) evaluated 22 children aged 6 to 12 years with Russell-Silver syndrome or ISS in a prospective, cross-sectional study. Among a subset of 17 short children, they had statistically higher total behavior scores, but similar internalizing and externalizing scores compared to controls. However, this was only a preliminary analysis of available data on a subset of the total sample. Reporting of the results was also incomplete.
Three studies evaluated teacher-graded behavior among children with ISS. One study found that short children scored significantly worse in terms of locus of control and that significantly more short children were likely to have hyperactivity than normal height controls. Other tests of behavior were found to be similar among short and normal height children. No study described any functional limitations or disabilities based on behavior.
One study evaluated behavior among children with either GHD or CGD and found that neuroticism and extraversion scores were similar among short children and normal height controls. One study evaluated children with either ISS or Russell-Silver syndrome and found that short children had significantly more total behavior problems than normal height controls. Neither study described any functional limitations or disabilities based on behavior.
| Mean Academic Achievement Score | ||||||||
|---|---|---|---|---|---|---|---|---|
| Author Year | Sample N (Controls) | Test | Math | Reading | Comprehension | Spelling | Biasa | Qualityb |
| Achondroplasia | ||||||||
| Brinkman, 1993 | 30 (30)c | CAS | 49 [55] | 46 [54]d | 51 [55]e | 48 [56]f |
| |
| Thompson, 1999 | 12–15 (17)g | WRAT | 89 [96] | 80 [95]h | 88 [97] | >IQ |
| |
| Osteogenesis Imperfecta | ||||||||
| Alston, 1983 | 40 (40) | Multii | 104 [105]j | 100 [102] | 102 [104] |
| ||
Mean scores in bold were significantly different than normal population; results not in bold not significantly different, except as noted in bias column.
Mean score for normal population for each test is 100, unless otherwise noted in brackets
CAS = Cognitive abilities score, WRAT = Wide range achievement test
Studies noted with “>IQ” excluded subjects with low IQ or known mental impairment excluded. Studies noted with “No stat” did not perform statistical analysis comparing IQ of subjects to normal controls
See Methods, Summary Tables, Study Quality.
30 normal height controls. Also had 30 sibling controls and 30 short stature controls.
Verbal
Reasoning
Total
17 normally developing controls. Also had 19 premature arrested hydrocephalus controls.
Sentence writing
Raven's Progressive Matrices, Primary Reading Test, Wide Span Reading Test, Gapadol Reading Test, Graded Word Spelling Test
Non-verbal Intelligence
Two studies evaluated academic achievement in approximately 43 children with achondroplasia. Academic achievement was measured with either the Cognitive Abilities Score or WRAT. The scores of the children with skeletal dysplasia were compared to controls. Both were prospective cross-sectional studies. Both were of fair quality.
Brinkmann, Schlitt, Zorowka, et al. (1993) performed cognitive testing, including verbal comprehension, arithmetic thinking, and reasoning, on children with achondroplasia. In a prospective, cross-sectional study, 30 subjects with a mean age of 9 years old were compared with 30 of their own siblings, 30 children with short stature not due to skeletal dysplasia. Controls were matched for age, sex, and socioeconomic status. The children with achondroplasia were found to have testing within the normal range, although they did score significantly lower than all three control groups.
Thompson, Hecht, Bohan, et al. (1999) prospectively examined children with a mean age of 7 years old with achondroplasia with WRAT-R, comparing them with normally developing controls in a cross-sectional study. In order to separate out the effect of the common neuroanatomic defect, hydrocephalus, from the effect of the dwarfing condition itself, they were also compared with 19 children born prematurely with low birthweight who had arrested, unshunted hydrocephalus. All results were age-corrected. The different sub-test results of the WRAT-R were reported for between 12 and 15 children with achondroplasia. In general, achondroplasia children had average cognitive abilities within 1 SD of population norms. The three groups had statistically similar in academic achievement. However, the small sample size minimized the possibility of finding statistically significant differences and children with low IQs were excluded.
One study evaluated academic achievement in children with osteogenesis imperfecta. The study was a prospective cross-sectional analysis of good quality. Alston (1979) evaluated 40 children ranging from 5 to 16 years old for nonverbal intellectual ability including reading and spelling. The controls were chosen from the same class or neighborhood as subjects, and were matched for age, sex, and social class. Children with osteogenesis imperfecta had normal scores that were not significantly different than controls.
Three studies examined academic achievement among children with achondroplasia or osteogenesis imperfecta. One found that children with achondroplasia had significantly lower scores on academic achievement tests than normal height children. However, among all the studies, children with skeletal dysplasias scored either above population norms or within 1 SD of normal scores. One of the studies excluded children with low IQ.
| Mean IQ | |||||||
|---|---|---|---|---|---|---|---|
| Author, Year | Sample N (Controls) | Test | Full | Verbal | Performance | Biasa | Qualityb |
| Achondroplasia | |||||||
| Rogers, 1979 | 19c | WISC | 96 | 95 | 100 | No stat |
|
| 15d | BSID/SB | 97 | |||||
| Thompson, 1999 | 16 | WISC | 94 | 101 | >IQ No stat |
| |
| Hecht, 1991 | 13 | BSID | 97 | No stat |
| ||
| Osteogenesis Imperfecta | |||||||
| Reite, 1972 | 12 | WISC | 107 | No stat |
| ||
| Skeletal Dysplasia | |||||||
| Rogers, 1979 | 22e | WISC | 104 | 104 | 103 | No stat |
|
| 12f | BSID/SB | 100 | |||||
| Shurka, 1976 | 7 | WISC | 102 | 103 | 99 | No stat |
|
Mean scores in bold were significantly different than normal population; results not in bold not significantly different, except as noted in bias column.
Mean score for normal population for each test is 100, unless otherwise noted in brackets
IQ = Intelligence quotient, BSID = Bayley Scales of Infant Development, SB = Stanford-Binet Intelligence Scale; WISC = Wechsler Intelligence Scale for Children
Studies noted with “>IQ” excluded subjects with low IQ or known mental impairment excluded. Studies noted with “No stat” did not perform statistical analysis comparing IQ of subjects to normal controls
See Methods, Summary Tables, Study Quality.
School age children
Preschool age children
School age children with skeletal dysplasias other than achondroplasia
Preschool age children with skeletal dysplasias other than achondroplasia
Three studies evaluated intelligence in 63 children with achondroplasia. IQs were measured with either Wechsler Intelligence Scale for Children, Bayley Scales of Infant Development, or the Stanford-Binet Intelligence Scale. The scores of the children with skeletal dysplasia were compared to population norms. All were prospective cross-sectional studies. Two were of fair quality; one was of poor quality.
In a prospective cross-sectional study by Rogers, Perry, and Rosenberg (1979), 34 children aged from 6 months to 15 years with achondroplasia were studied with intelligence testing. The mean IQ scores for both the pre-school and school age children were within the normal range.
Thompson, Hecht, Bohan, et al. (1999) prospectively examined 16 children with a mean age of 7 years old with achondroplasia with intelligence testing in a cross-sectional study. Achondroplasia children had average cognitive abilities within 1 SD of population norms. Of note, though, children with low IQ were excluded from analysis.
In a paper by Hecht, Thompson, Weir, et al. (1991), 13 infants with achondroplasia were evaluated for intelligence in a prospective cross-sectional study. The children with achondroplasia had a mean mental developmental index within the normal range. However, a wide range of scores was obtained. Their results were correlated with ventricular size, degree of cortical atrophy, and neurological and respiratory complications. Three of the infants were also found to have abnormal polysomnograms showing obstructive apnea or hypoxemia. There was a significant correlation between an abnormal polysomnogram and a low test score. They concluded that the mental performance in the children with achondroplasia was average, and that the respiratory complications, not the achondroplasia itself, may contribute to decreased intellectual potential.
One study evaluated intelligence in children with osteogenesis imperfecta. The study was prospective, cross-sectional and of poor quality. Reite, Davis, Solomons, et al. (1972) evaluated 12 6 to 17 year old children with severe osteogenesis imperfecta. The children's mean IQ was somewhat above normal.
Two studies evaluated intelligence in children with a variety of skeletal dysplasias. Both were prospective cross-sectional studies. One was of fair quality; one was of poor quality.
In a prospective cross-sectional study by Rogers, Perry, and Rosenberg (1979), 34 children aged from 6 months to 15 years with skeletal dysplasias other than achondroplasia were studied with intelligence testing. The mean IQ scores for both the pre-school and school age children were within the normal range.
In a small prospective cross-sectional study, Shurka and Laron (1976) measured IQ in 7 children with skeletal dysplasia and a mean age of 14 years old. The children had mean IQs that were within the normal range.
Five studies evaluated intelligence among children with achondroplasia, osteogenesis imperfecta and other skeletal dysplasias. The studies found no evidence of significantly impaired intelligence in the children. The mean IQs were all within 1 SD of population norms. None of the studies performed statistical analyses or reported comparisons with control groups. One study excluded children with low IQ from evaluation.
| Author, Year | Sample N (Controls) | Population | Measure | Results | Qualitya |
|---|---|---|---|---|---|
| Achondroplasia | |||||
| Thompson, 1999 | 13 (12) | All | Beery Visual Motor Integration | 82 [92] |
|
| Judgment of Line Orientation | 85 [100] | ||||
| 12 (17) | Fine Motor Skills (various tests) | No significant difference | |||
| Hecht, 1991 | 13 | Infants | Psychomotor Development Index | 63 (62% < 50)b |
|
Results in bold were significantly different than control; results not in bold were not statistically analyzed.
Results in brackets are those of normal controls.
See Methods, Summary Tables, Study Quality.
Population norm = 100
| Author, Year | Sample N (Controls) | Population | Patterns of Development (%) | Qualitya | ||||
|---|---|---|---|---|---|---|---|---|
| Abnormal Arrested | Delayed Arrested | Normal Arrested | Delayed | Normal | ||||
| Achondroplasia | ||||||||
| Pauli, 1995b | 52 | All | 10% had “disproportionate developmental delays” |
| ||||
| Osteogenesis Imperfecta | ||||||||
| Daly, 1996 | 31 | Congenita B | 19 | 19 | 29 | 29 | 3 |
|
| 15 | Tarda A | 0 | 27 | 7 | 20 | 47 | ||
| 4 | Tarda B | 0 | 0 | 0 | 0 | 100 | ||
| 15 | Type I | 0 | 0 | 7 | 27 | 67 | ||
| 29 | Type III | 21 | 34 | 28 | 17 | 0 | ||
| 7 | Type IV | 0 | 14 | 14 | 43 | 29 | ||
See Methods, Summary Tables, Study Quality.
Five studies evaluated psychomotor development in children with achondroplasia. All were prospective. One was longitudinal; four were cross-sectional. Two were of fair quality; three were of poor quality.
Among the reviewed studies, substantial proportions of children with achondroplasia were found to have delayed and/or abnormal gross, fine, or visual motor development. The one study of children with osteogenesis imperfecta similarly found abnormal patterns of development in the more severely affected patients. All studies are small and used different testing instruments, making comparisons among studies difficult. Two studies (Fowler, Glinski, Reiser, et al., 1997; Pauli, Horton, Glinski, et al., 1995) reported on similar outcomes in samples of children that probably overlapped.
| Author Year | Population | Sample N (Controls) | Outcome | Result | Qualitya | |
|---|---|---|---|---|---|---|
| Achondroplasia | ||||||
| Thompson, 1999 | All | 13 (13) | Gross Motor Arm Coordination score | 73 [93]b |
| |
| Gross Motor Leg Coordination score | 79 [104]b | |||||
| Pauli, 1995 | All | 52 | Weakness by history | 14% |
| |
| 52 | Sensory abnormality by history | 4% | ||||
| 52 | “Abnormality” by history | 42% | ||||
| 52 | Asymmetry by history | 21% | ||||
| 52 | Seizures by history | 8% | ||||
| 44 | Decreased limb tone by exam | 70% | ||||
| 40 | Abnormal arm strength by exam | 32% | ||||
| 40 | Abnormal leg strength by exam | 50% | ||||
| 39 | Decreased truncal tone by exam | 70% | ||||
| Ruiz-Garcia, 1997 | All | 39 | Weakness by exam | 31% (26%)c |
| |
| Sensory deficit by exam | 10% (5%)c | |||||
| Hypotonia by exam | 59% (49%)c | |||||
| Quadriparesis by exam | 15% (13%)c | |||||
| Compressive neural syndrome | 31% | |||||
| Reid, 1988 | All | 26 | Paresis | 42% |
| |
| Osteogenesis Imperfecta | ||||||
| Engelbert, 2001 | Type I | 17 | 4.5 | |||
| Type III | 11 | Arm strength score | 3.5 | |||
| Type IV | 12 | 0=None | 4.5 |
| ||
| Type I | 17 | 5=Normal | 4.8 | |||
| Type III | 11 | Leg strength score | 3.6 | |||
| Type IV | 12 | 3.8 | ||||
| Morquio Disease | ||||||
| Skeletal Dysplasia Group, 1989 | All | 15 | “Known neurological complications” | 33% |
| |
See Methods, Summary Tables, Study Quality.
Significantly lower than controls
Reported results differ in table and text (in parentheses).
Four studies evaluated neuromuscular function in children with achondroplasia. All were prospective. Two were longitudinal; two were cross-sectional. One was of fair quality; three were of poor quality.
Thompson, Hecht, Bohan, et al. (1999) prospectively examined 13 children with achondroplasia who had a mean age of 7 years old for gross motor coordination, comparing them with normal controls in a cross-sectional study. All results were age-corrected. Sample size for gross motor skills were reduced because some children were unable to complete the testing due to fatigue or time constraints. Achondroplasia subjects performed significantly less well in gross motor arm and leg coordination skills than control children.
Pauli, Horton, Glinski, et al. (1995) reported on 52 infants and young children with achondroplasia in a prospective longitudinal study. By history and neurological examination, neurological abnormalities referable to the upper cervical cord were found to be common. Seizures occurred in a small percentage of subjects.
Reid, Pyeritz, Kopits, et al. (1988) conducted a prospective longitudinal evaluation of 26 children less than 7 years old with achondroplasia. Of note, about three-quarters of the subjects were referred to the study because they were symptomatic. By neurological exam, 42 percent had varying forms of paresis, some of these children were asymptomatic. For some, this was the clue to the presence of cervicomedullary compression, in that the children were otherwise asymptomatic. The findings in this study may not be applicable to all children with achondroplasia because the subjects were highly selected.
One study evaluated neuromuscular function in children with osteogenesis imperfecta. The study was of fair quality. Engelbert, Gulmans, Uiterwaal, et al. (2001), in a prospective, cross-sectional study, measured muscle strength in 40 children with osteogenesis imperfecta who had a mean age of 12 years old. Muscle strength of upper and lower extremity muscle groups was measured using standardized criteria using a six point scale. All subjects had some degree of weakness. In children with osteogenesis imperfecta Type I, muscle strength was almost comparable to the healthy population. In children with osteogenesis imperfecta Type III, muscle strength was severely decreased in both upper and lower extremities. In those with osteogenesis imperfecta Type IV, muscle strength was also decreased, particularly in the lower extremities. Of note, the level of ambulation and functional skills regarding mobility correlated highly with muscle strength.
One study evaluated neuromuscular function in children with Morquio disease. The study was of poor quality. In a retrospective cross-sectional review of cervical spine anomalies in all patients on the register of the Skeletal Dysplasia Group (1989), 15 children, between ages 1 and 15 years old, had Morquio disease. All had either hypoplasia or absence of the odontoid. Of these children, 1/3 had known neurological complications related to the odontoid abnormalities. The descriptions of the neurological complications were not reported.
Four papers that reviewed neuromuscular function in children with achondroplasia all found abnormalities. The three that measured strength found substantial weakness and hypotonia. Asymmetry, sensory deficits, poor coordination, and even seizures were found in frequencies higher than either controls or than expected in the healthy population. All highlighted the significant risk of often occult cervical cord compression in these young children. The one paper that evaluated osteogenesis imperfecta also found significant weakness in children who are moderately to severely affected. The one paper that reviewed other skeletal dysplasias found cervical cord complications in children with the mucopolysaccharidosis Morquio disease.
| Ambulation Ability (%) | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Author Year | Sample | Population | Without Assistance | Assistance Needed | Wheelchair | Qualitya | ||||||
| N | C | N | H | Th | C | N | H | Th | ||||
| Osteogenesis Imperfecta | ||||||||||||
| Engelbert, 2000b | 41 | Type I | 59 | 10 | 12 | 0 | 5 | 0 | 7 | 7 | 0e |
|
| 11 | Type III | 0 | 0 | 0 | 0 | 0 | 9 | 27 | 19 | 45e | ||
| 18 | Type IV | 28 | 0 | 0 | 0 | 11 | 6 | 11 | 22 | 22e | ||
| Daly, 1996 | 31 | Congenita B | 13 | 0 | 87 |
| ||||||
| 15 | Tarda A | 60 | 13 | 27 | ||||||||
| 15 | Type I | 93 | 7 | 0 | ||||||||
| 29 | Type III | 3 | 0 | 97 | ||||||||
| 7 | Type IV | 29 | 14 | 57 | ||||||||
| Engelbert, 1999b | 19 | Type I | 53c | 26c | 16c | 5c | c | c | c | c | 0d |
|
| 13 | Type III | 0 | 0 | 31c | 8c | 0 | 0 | c | c | 61d | ||
| 10 | Type IV | 10c | 10c | 10c | 40c | c | c | c | c | 30d | ||
| Alston, 1983 | 40 | All | 38 |
| ||||||||
| Engelbert, 2001b | 17 | Type I | 50f |
| ||||||||
| 11 | Type III | 50f | ||||||||||
| 12 | Type IV | 50f | ||||||||||
| Norimatsu, 1982 | 8 | Congenita | 0 | 62 | 38 |
| ||||||
| 14 | Tarda | 0 | 86 | 14 | ||||||||
| Resultg | Scale | |||||||||||
| Engelbert, 1997b | 16h | Type Ih | Mobility = 31 | PEDI: Median of healthy children ≤ 7.5 y = 50 |
| |||||||
| Self-care = 39 | ||||||||||||
| 8h | Type IIIh | Mobility = 5 | ||||||||||
| Self-care = 31 | ||||||||||||
| 6h | Type IVh | Mobility = 10 | ||||||||||
| Self-care = 37 | ||||||||||||
| 16i | Type Ii | Mobility = 100 | PEDI: Normal healthy children > 7.5 y = 100 | |||||||||
| Self-care = 100 | ||||||||||||
| 6i | Type III i | Mobility = 70 | ||||||||||
| Self-care = 41 | ||||||||||||
| 9i | Type IVi | Mobility = 93 | ||||||||||
| Self-care = 62 | ||||||||||||
| Bleck, 1981 | 12 | Severe Congenita | Ambulation = 0.7 | 0 = None 4 = Community walker |
| |||||||
| Mobility = 3.0 | 0 = None 4 = Travel beyond community | |||||||||||
| Indep = 2.6 | 0 = None 4 = Normal activity | |||||||||||
| ADL = 2.5 | 0 = None possible 4 = Normal ADL | |||||||||||
| 12 | Tarda | Ambulation = 2.8 | 0 = None 4 = Community walker | |||||||||
| Mobility = 3.8 | 0 = None 4 = Travel beyond community | |||||||||||
| Indep = 3.4 | 0 = None 4 = Normal activity | |||||||||||
| ADL = 3.7 | 0 = None possible 4 = Normal ADL | |||||||||||
C = Community walker, N = Neighborhood walker, H = Home walker, Th = Therapy/exercise walker
PEDI = Pediatric Evaluation of Disability Inventory; Indep = Independence, ADL = Activities of daily living
See Methods, Summary Tables, Study Quality.
Likely overlap in subjects among studies by Engelbert
No distinction made between those who require assistance and those who can walk independently
Bottom shufflers, Sit unsupported only, Sit supported only.
Non-walkers
Average child fell into reported category
Engelbert, 1997: Median scores. Bleck, 1981: Mean scores.
Children aged ≤ 7.5 years
Children aged > 7.5 years
Among eight studies, six reported the frequency of different ambulatory abilities. Two studies scored subjects on scales to estimate ambulation and mobility abilities. Four papers by the same authors are likely to have substantial overlap in subjects. Seven were prospective; one was retrospective. Three were longitudinal; five were cross-sectional. One study was of good quality; five were of fair quality; and two were of poor quality.
Engelbert and co-authors reported on ambulation ability on children with osteogenesis imperfecta in four papers with separate, but probably overlapping groups of children. The largest (Engelbert, Uiterwaal, Gulmans, et al., 2000) evaluated 70 children with either Type I, III, or IV osteogenesis imperfecta who had a mean age of 11 years old. Questionnaires were sent to parents of children with “definite” osteogenesis imperfecta in this prospective cross-sectional study. The study attempted to identify predictors of walking ability in the children. They categorized mobility using a nine-level classification of walking ranging from electric wheelchair bound to independent community walking without cane or crutches. By parent report, most children with Type I disease were community walkers without aides. All children were walkers, but a substantial percentage of children were restricted in their walking ability or required assistance for walking. Of children with Type III disease, almost half were wheelchair bound and all walkers required assistance. Of children with Type IV disease, about a quarter were community walkers without aids, half required assistance with walking, and about a quarter were non-walkers. Using univariate analysis, they found that rolling over by age 8 months, sitting without support by 9 months, and getting to sitting or standing position without support by 12 months were all correlated with improved chances of walking. Multivariate analysis, however, showed that the most important predictor is the type of osteogenesis imperfecta, or severity of illness. Developmental milestones added little predictive value. The presence of intermedullary rods and dentinogenesis imperfecta were better indicators than development of worse prognosis for most types.
Daly, Wisbeach, Sanpera, Jr., et al. (1996) aimed to compare the ability of the two popularly used classifications of osteogenesis imperfecta to predict walking and general motor development of the child. Questionnaires were mailed to families of children with osteogenesis imperfecta in a prospective cross-sectional study. Questionnaires were returned for 51 children with a mean age of 7 years old. The children were classified into categories described by Shapiro based on radiographic appearance of bones and history of fractures (Congenita A, Congenita B, Tarda A, and Tarda B) and into categories described by Sillence (I, III, and IV). They correlated the classifications with ultimate progression to walking, either aided or independent. Not all categories had sufficient numbers of children for analysis. Substantial percentages of children with either Congenita B or Tarda A osteogenesis imperfecta, or with Type III or IV disease were either wheelchair bound or required assistance with walking. Only one child with Type I disease required assistance with walking. In addition they found that of those children who could sit by 10 months, 76 percent became walkers. Of those who could not independently sit by 10 months, only 18 percent ultimately walked. They concluded that the Sillence classification, the Shapiro classification and the ability to sit independently by 10 months were all predictors of ultimate ability to walk in children with osteogenesis imperfecta.
In a second report by Engelbert, Beemer, van der, et al. (1999), 42 children with a mean age of 7 years who had osteogenesis imperfecta were followed in a prospective, longitudinal study. Children who had had intramedullary fixation surgery within 6 months or who had any other disability or impairment were excluded. Level of ambulation was measured. At follow-up, half the children with Type I disease were community walkers. All attained at least some degree of walking. Of children with Type III disease, about 40 percent were household or exercise (therapy only) walkers. The rest of the children were wheelchair bound. Of children with Type IV disease, only 10 percent were community walkers. Most children had some walking limitation or required a wheelchair. For all groups of children, it was not clear how many of the children could walk unassisted. Of note, little progression in walking ability occurred over time, particularly in the more severely affected.
In a prospective, cross- sectional study by Alston (1979), 40 children with osteogenesis imperfecta who ranged in age from 5 to 16 years old were evaluated. Type of mobility was examined in an attempt to correlate these with the subject's type of school. Approximately one-third of the children were wheelchair bound. The ambulatory level of the walking children was not reported and the type and severity of osteogenesis imperfecta were not defined for these subjects.
The third study by Engelbert, Gulmans, Uiterwaal, et al. (2001) was a prospective, cross-sectional study of 40 children with osteogenesis imperfecta who had a mean age of 12 years old. The study reported limited data on ambulation ability. Children were categorized by a nine-level classification of walking ability. The mean scores for children with each type of disease were reported. Type I patients had median level of 9 or independent walking. Type III patients had a median level of 2 or capable of at most therapy walking with the aid of crutches or canes. Type IV patients had a median level of 5 or capable of household walking without the use of crutches or canes.
Norimatsu, Mayuzumi, and Takahashi (1982) published a retrospective longitudinal case series of 22 children with osteogenesis imperfecta who were followed for up to 20 years and were between 4 and 22 years at final examination. Walking ability were reported in these patients. Three of the eight children with osteogenesis imperfecta congenita were wheelchair bound; the remainder walked with assistance. Among children with osteogenesis imperfecta tarda, two of 14 were wheelchair bound; the remainder walked with assistance. The low rate of successful walking may have been related to a high prevalence of scoliosis in this sample of children.
In the fourth study by Engelbert, Custers, van der Net, et al. (1997), 61 children with osteogenesis imperfecta were evaluated in a prospective cross-sectional study. Children under age 7.5 years were evaluated separately from those who were between ages 7.5 and 18 years old. Mobility and self-care were evaluated by questionnaires administered to either the parents or children. Younger and older children with Type I osteogenesis imperfecta scored within 2 SD of the test's normal median for mobility. All younger and older children with Type III disease and most with Type IV disease had mobility scores considerably below 2 SD from the median. Younger children with all types of disease and older children with Types I and IV disease scored within 2 SD of the test's normal median for self-care. Only older children with Type III disease were likely to have self-care scores below 2 SD from the normal median.
A study by Bleck (1981) evaluated 24 children with varying degrees of severity of osteogenesis imperfecta who had a mean age of 13 years old at the end of the study. In this prospective longitudinal study children were managed with surgery as needed and orthotics aiming for early weight bearing in order to minimize osteoporosis thereby preventing refracture and deformity. Ambulation and mobility were measured using 5-point scales ranging from no function to no limitation. Those children with the most severe disease (osteogenesis imperfecta congenita) had limitations in activities of daily living, mobility efficiency, and independence and severe limitation in ambulation even after aggressive orthotic management. Those with the mild to moderate osteogenesis imperfecta tarda also had mild limitations in mobility and activities of daily living and moderate limitations in independence and ambulation. Despite the limitations, all 12 with osteogenesis imperfecta tarda attained complete independence in daily living, mobility and ambulation.
The eight papers that evaluated mobility and ambulation in children with skeletal dysplasia all included only children with osteogenesis imperfecta. All found significant impairment in ambulation, with greater impairment, as expected, in the patients with more severe disease. Children with the less severe types of osteogenesis imperfecta (tarda, Type I, and Type IV) were more likely to attain some walking capability, but still with a significant amount of assistance. Few children with congenita or Type III disease had any walking ability without assistance. Orthopedic abnormalities such as scoliosis, decreased range of motion, decreased muscle strength and fracture were found to contribute to limitations of ambulation. Although all the studies are relatively small, they are reasonably sized given the rarity of the disorder. Information regarding ambulation and mobility in children with short stature due to other skeletal dysplasias was not found.
| Author Year | Joint | Scale | Sample N (Controls) | Category | Measure (Range) | Qualitya |
|---|---|---|---|---|---|---|
| Achondroplasia | ||||||
| Bailey, 1971 | Elbow | Angle from full extension | 41 | 0–2 years | 11° (5°–25°) |
|
| 3–12 years | 19° (10°–40°) | |||||
| 13–20 years | 24° (0°–40°) | |||||
| Osteogenesis Imperfecta | ||||||
| Engelbert, 2001 | Arm | 0 = Normal | 17 | Type I | 0.5 |
|
| 4 = Maximally decreased | 11 | Type III | 1.8 | |||
| 12 | Type IV | 1.3 | ||||
| Leg | 17 | Type I | 0 | |||
| 11 | Type III | 3.3 | ||||
| 12 | Type IV | 1.7 | ||||
See Methods, Summary Tables, Study Quality.
One poor quality study evaluated joint range of motion in children with achondroplasia. In a small descriptive paper, Bailey (1971) retrospectively looked at a cross-section of 41 children with achondroplasia, describing upper limb bony abnormalities. The entire study included subjects up to 72 years old. Data are reported for infants to 20 year olds. Nine upper limb abnormalities evaluated. Only two were found frequently in the sample. Almost all children had lack of full elbow extension (93 percent) and some had limited elbow supination (34 percent). Other abnormalities were found infrequently. Degree of elbow flexion deformity worsened with age. Although these orthopedic abnormalities were found, functional limitations were not evaluated. However, “none of the patients volunteered disability from this problem.”
One fair quality study evaluated joint range of motion in children with osteogenesis imperfecta. Engelbert, Gulmans, Uiterwaal, et al. (2001), in a prospective, cross-sectional study, measured motor function, including joint range of motion (ROM) in 40 children with osteogenesis imperfecta who had a mean age of 12 years old. Using standard goniometry, the total ROM in the upper and lower extremities were measured. Measurements were evaluated using the Joint Alignment and Motion Scale, where a score of 0 is normal ROM and a score of 4 is maximally decreased ROM. Subjects with Type I disease all had normal or nearly normal ROM in both arms and legs. Subjects with Type III disease had somewhat limited ROM in upper extremities and substantially limited ROM in lower extremities. Subjects with Type IV disease had somewhat limited ROM in upper and lower extremities. Of note, level of ambulation strongly correlated with joint ROM.
Two studies demonstrate upper and lower ROM abnormalities in children with achondroplasia and with various types of osteogenesis imperfecta. ROM limitation correlated with functional disability in children with osteogenesis imperfecta but not with achondroplasia.
| Author Year | Sample N (Controls) | Population | Scoliosis | Kyphosis | Qualitya | ||
|---|---|---|---|---|---|---|---|
| Cobb Angle | % of Subjects | Cobb Angle | % of Subjects | ||||
| Osteogenesis Imperfecta | |||||||
| Benson, 1978 | 103 | All | 10°–19° | 19 |
| ||
| 20°–49° | 14 | ||||||
| ≥ 50° | 22 | ||||||
| Engelbert, 1998 | 17 | Type I | > 10° | 12 | < 10° or > 40° | 12 |
|
| 16 | Type III | > 10° | 63 | < 10° or > 40° | 75 | ||
| 14 | Type IV | > 10° | 71 | < 10° or > 40° | 29 | ||
| Norimatsu, 1982 | 8 | Congenita | 5°–29° | 13 |
| ||
| 30°–50° | 0 | ||||||
| > 50° | 87 | ||||||
| 14 | Tarda | 5°–29° | 62 | ||||
| 30°–50° | 15 | ||||||
| > 50° | 23 | ||||||
| Diastrophic Dysplasia | |||||||
| Poussa, 1991 | 38 | All | > 15° | 29 |
| ||
See Methods, Summary Tables, Study Quality.
Three studies evaluated spinal curvature in children with osteogenesis imperfecta. One was prospective studies; two were retrospective. Two were longitudinal; one was cross-sectional. Two studies were of fair quality; one was of poor quality.
Benson, Donaldson, and Millar (1978) evaluated children with osteogenesis imperfecta aged 1 month to 16 years in a retrospective longitudinal study. Scoliosis was measured by roentgenographic measurement in 103 children. Different forms of osteogenesis imperfecta were not analyzed separately. Scoliosis of at least 10 degrees was found in 55 percent of the children. Of note, progression of curvature was common. Younger children had less curvature and older children had more. Furthermore, in patients for whom more than one radiograph was available, progression was almost always noted.
Engelbert, Gerver, Breslau-Siderius, et al. (1998) reported a prospective cross-sectional study of 47 children with a mean age of 7 years who had osteogenesis imperfecta and were examined for the presence of spinal deformities. Scoliosis was defined as spinal curvature of greater than 10 degrees. Pathologic kyphosis was defined as curvature of less than 10 degrees or more than 40 degrees. Scoliosis was highly prevalent among children with Types III and IV disease and less prevalent in children with Type I disease. Kyphosis was highly prevalent in children with Type III disease; those with Types I and IV disease were less likely to have kyphosis. Of note, no significant association was found between age and presence of scoliosis or pathological kyphosis. Children with scoliosis were twice as likely to also have pathological kyphosis.
Norimatsu, Mayuzumi, and Takahashi (1982) published a retrospective longitudinal study of 22 children with osteogenesis imperfecta followed over the course of 20 years. Evaluation of the scoliosis was performed by Cobb's method on radiographic examinations. All children had some degree of scoliosis (at least 5 degrees). Most children with osteogenesis congenita had severe scoliosis, while most children with osteogenesis tarda had mild scoliosis. Progression of scoliosis was found with age, and rapid progression occurred once curvature exceeded 50 degrees. However, the data for these findings were not reported. Of note, multiple subjects reported were closely related.
One study evaluated spinal scoliosis in children with diastrophic dysplasia. The study was prospective longitudinal in design and of fair quality. Poussa, Merikanto, Ryoppy, et al. (1991) evaluated 38 children with diastrophic dysplasia, 20 years old or younger. Scoliosis was measured using Cobb's method, and was defined as curvature greater than 15 degrees. Among the whole group, almost a third had scoliosis. Progression of scoliosis was suggested because older subgroups had a higher incidence of scoliosis than younger groups. The mean magnitude of curvature of those with scoliosis was 39 degrees.
Among the four studies reviewed, a high prevalence of scoliosis was found in children with both osteogenesis imperfecta and diastrophic dysplasia. One study also found high prevalence of pathologic kyphosis. None of the papers used control groups for comparison. Although two groups followed their patient longitudinally, progression of spinal deformity was only implied from comparing age groups, as paired measurements were not presented for the majority of subjects. All groups likely represent a selected, perhaps more severe, population of patients followed by academic medical centers.
| Author Year | Sample N (Controls) | Population | Definition | Results | Qualitya |
|---|---|---|---|---|---|
| Achondroplasia | % of Subjects | ||||
| Brinkmann, 1993 | 27 (28, 27)b | All | Parental Report | 63 (18, 19)c |
|
| Ruiz-Garcia, 1997 | 32 | All | Abnormal BAERd | 50% |
|
| Osteogenesis Imperfecta | % of Subjects | ||||
| Kuurila, 2000 | 45 | All | Pure Tone < 20 dB | 7 |
|
| Conductive < 15 dB | |||||
| Cox, 1982 | 15 | All | Pure Tone: | 33 |
|
| < 30 dB at < 1000 Hz | |||||
| < 25 dB at > 2000 Hz | |||||
| Stewart, 1987 | 13 | All | Pure Tone < 30 dB | 15 |
|
| Conductive < 15 dB | |||||
| Skeletal Dysplasia | Score | ||||
| Apasajalo, 1998 | 19 (239) | Achondroplasia | Hearing HRQOL | 95e |
|
| Diastrophic Dysplasia | Hearing HRQOL | 93e | |||
| Cartilage-hair Hypoplasia | Hearing HRQOL | 85e | |||
BAER = Brainstem auditory evoked responses; HRQOL = Health Related Quality of Life
See Methods, Summary Tables, Study Quality.
Short controls and normal controls, respectively
Subgroup of all 13 children with osteogenesis imperfecta
Abnormal defined as deviation from population normals by at least 3 SD.
Score (where 100 is normal)
| Author Year | Sample N (Controls) | Population | % with Sleep Apnea | Qualitya | |||
|---|---|---|---|---|---|---|---|
| Central Hypopnea | Central Apnea | Obstructive Apnea | |||||
| Achondroplasia | |||||||
| Waters, 1993 | 20b | All | 75 |
| |||
| Pauli, 1995 | 35 | All | 40 | 66 | 23 |
| |
| Reid, 1988 | 26 | All | 35 |
| |||
| Hecht, 1991 | 13 | All | 7c | 15 |
| ||
See Methods, Summary Tables, Study Quality.
15 children; 5 adults
Hypoxemia and respiratory acidosis
Two prospective cross-sectional studies evaluated hearing loss in children with achondroplasia. One study was of fair quality; one was of poor quality.
Brinkmann, Schlitt, Zorowka, et al. (1993) evaluated 27 children with achondroplasia with a mean age of 9 years old in a prospective cross-sectional study. The children were compared with 28 children with short stature not due to skeletal dysplasia and 27 normal controls. Controls were matched for age, sex, and socioeconomic status. Hearing deficits were present in 63% of children with achondroplasia as reported by their parents, compared to 18% of short stature controls and 19% of normal controls. Statistical significance of this comparison was not reported. Hearing testing was performed in only some of these patients. Of those reported to have hearing deficits, many had middle ear disease, tympanotstomy tubes, and speech and language delay and difficulty.
Ruiz-Garcia, Tovar-Baudin, Castillo-Ruiz, et al. (1997) prospectively evaluated children with achondroplasia who had a mean age of 4 years old in a cross-sectional study. Children who had prior neurosurgery were excluded. In 32 children hearing was assessed with brainstem auditory evoked response (BAER) testing. Half of the subjects had abnormal BAER studies revealing hearing loss. It was reported that the children had middle ear lesions due to repetitive ear infections.
Three studies evaluated hearing deficits in children with osteogenesis imperfecta. All were prospective cross-sectional studies. One was of fair quality; two were of poor quality.
Kuurila, Grenman, Johansson, et al. (2000) evaluated 45 children with mild to severe osteogenesis imperfecta for hearing loss in a prospective, cross-sectional study. The children had a mean age of 10 years old. All subjects underwent audiometry. Only three of the 45 (7 percent) children were found to have hearing loss. Only two of the children, both with conductive hearing loss, were thought to have hearing loss related to osteogenesis imperfecta. One child had sensorineural deafness in the first year of life thought due to another etiology.
In Cox and Simmons (1982), a prospective, cross-sectional study, 15 children with a mean age of 9 years old with osteogenesis imperfecta had objective audiological evaluation. The children were all from five families. Five of the fifteen children (33 percent) had some degree of hearing loss using a standard definition. All five were characterized as mild conductive loss.
Stewart and O'Reilly (1989) reported on 13 children between 10 and 19 years old with osteogenesis imperfecta. Hearing was tested with audiometry. A prospective cross-sectional examination found that two of the children (15 percent) had hearing loss. One of these two had pure sensorineural hearing loss, which is not considered to be the typical hearing loss of osteogenesis imperfecta, but no other explanation could be found. Of the 11 with no hearing loss, three had abnormal tympanometry possibly suggestive of early conductive hearing loss.
One prospective cross-sectional study evaluated hearing deficits in children with a variety of skeletal dysplasias. The study was of fair quality. Apajasalo, Sintonen, Rautonen, et al. (1998) evaluated 19 adolescent patients (aged 12 to 15 years old) with either achondroplasia, diastrophic dysplasia, or cartilage-hair dysplasia. Hearing function was self-reported on a measure of Health Related Quality of Life, a validated questionnaire tool. They were compared with a large control group of age-matched area students who also completed the questionnaire. There was no difference children with skeletal dysplasias and controls in their self-report of the hearing dimension. No actual hearing testing was performed.
Six studies evaluated hearing loss in children with skeletal dysplasia. Only four performed objective hearing testing. One relied on parental reporting and one was a study of health related quality of life. A large proportion of children with achondroplasia were reported to have hearing problems, either by parental report or by BAER testing. The papers that reported on hearing testing in young patients with osteogenesis imperfeca all reported a sizable proportion with hearing loss, although the prevalence varied due to selection and small sample sizes. One study concluded that hearing quality of life was not different among children with a variety of skeletal dysplasias as normal controls.
Four studies evaluated sleep abnormalities in 94 children with short stature due to skeletal dysplasia. All evaluated patients with achondroplasia and reported the percentage of children with either hypopnea or apnea during sleep. All were prospective. Two were longitudinal; two were cross-sectional. One study was of fair quality; and three were of poor quality.
Waters, Everett, Sillence, et al. (1993) performed overnight sleep studies on 20 patients with achondroplasia to measure and characterize the types of apnea and other respiratory abnormalities in a prospective cross-sectional study. Fifteen of the subjects were aged 1 to 14 years old; five were between 20 to 31 years old. All subjects had at least snoring, implying at least some degree of airway obstruction during sleep. Three-quarters had abnormal frequency of apnea. Of the 15 subjects with apnea, 12 had periodic breathing (called “cyclic apnea” in this paper) and 9 had obstructive apnea. Because the sleep apnea seen in achondroplasia is thought to be due to constriction of the brainstem because of abnormal shape and size of the skull base, they also performed a test of brainstem dysfunction, somatasensory evoked potentials (SEP) in 19. More than half the subjects had normal studies; abnormal results in were found in 42 percent. Abnormal SEP did not correlate with sleep abnormalities, and could not be used to predict the sleep respiratory abnormalities.
Pauli, Horton, Glinski, et al. (1995) evaluated 35 infants and young children with achondroplasia in a prospective longitudinal study. The children were followed for clinical problems attributable to cervicomedullary junction compression. Overnight polysomnography revealed frequent central apnea, central hypopnea, and/or obstructive apnea.
Reid, Pyeritz, Kopits, et al. (1988) conducted a prospective longitudinal evaluation of 26 children under 7 years old with achondroplasia. Three-quarters of the children had been referred to the clinic for various undefined symptoms. History, physical examination, and respiratory evaluation including arterial blood gases, electrocardiogram, echocardiogram, chest radiograph, and multi-channel polysomnography were performed. By history 22 subjects (85 percent) had respiratory abnormality in the preceding 6 months, including pneumonia, loud snoring, cyanotic spells, or apnea. On testing, 85 percent of the subjects had respiratory abnormalities, such as hypoxemia, hypercapnea, pulmonary infiltrates, abnormal right systolic time intervals on echocardiography, right ventricular hypertrophy on electrocardiogram, and apnea. One-third of subjects had obstructive apnea. An unreported number of those with obstructive apnea also had central apnea. The subjects evaluated were highly selected patients, in that most were referred for respiratory and/or neurological symptoms, and the others were followed in a tertiary center.
In a prospective, cross-sectional study, Hecht, Thompson, Weir, et al. (1991) evaluated 13 infants with achondroplasia. Four of the subjects had a history consistent with respiratory dysfunction, including one with tachypnea, two with obstructive apnea, and one with daytime apnea. Three of the infants were also found to have abnormal polysomnograms showing obstructive apnea or hypoxemia with respiratory acidosis. The subjects were a small, selected group, in that five of them were referred for symptoms of the complications they were studying.
Of the four papers evaluating sleep and respiratory dysfunction in children with achondroplasia, all found a high incidence of abnormality, including central hypopnea, central apnea, and obstructive apnea. All four papers, however, reported on small groups; two of which were highly selected samples.
| Author Year | Sample N (Control) | Population | Pulmonary Function % Predicted or mm Hq | Qualitya | ||||
|---|---|---|---|---|---|---|---|---|
| FVC | RV | FEV1 / FVC | P O2 | P CO2 | ||||
| Achondroplasia | ||||||||
| Stokes, 1988 | 24 | All | 72%b |
| ||||
| Osteogenesis Imperfecta | ||||||||
| Falvo, 1973 | 10 | All | 85c | 119c | 99 | 88 | 35 |
|
FVC = Forced vital capacity; FEV1/FVC = Forced expiratory volume in 1 second divided by forced vital capacity; P O2 = Oxygen partial pressure; P CO2 = Carbon dioxide partial pressure; RV = Residual volume
See Methods, Summary Tables, Study Quality.
Significantly lower than population norms
Reduction of FVC and increase in RV were found only in subjects with kyphoscoliosis
One study of fair quality evaluated pulmonary function in children with achondroplasia. Using a prospective, cross-sectional cohort design, Stokes, Pyeritz, Wise, et al. (1988) systematically measured pulmonary function tests in 24 children under age 18 years old with achondroplasia. Mean forced vital capacity for the group of children was significantly lower than predicted values for children with comparable sitting height. Although only a small number of children were included, the sample evaluated was relatively unselected, and probably is broadly representative of the average child with achondroplasia.
One study of fair quality evaluated pulmonary function in children with osteogenesis imperfecta. Falvo, Klain, Krauss, et al. (1973) performed pulmonary function testing on 10 children between ages 4 and 19 years old with osteogenesis imperfecta of varying severity. While it was implied that the data were collected prospectively for a cross-section of patients, the study methodology is unclear. Results were compared with population norms. Vital capacity and residual volume were abnormal only in the four subjects who also had kyphoscoliosis. No patient had severe hypoxemia or hypercapnea. Other parameters of pulmonary function were within normal limits. The number of subjects is small, and no statistical comparisons were reported.
One study found abnormal pulmonary function in a small group of children with achondroplasia. A second study found no significant abnormality in a smaller group of children with osteogenesis imperfecta.
| Author, Year | Sample N (Controls) | Population | Measure | Resultsa | Qualityb |
|---|---|---|---|---|---|
| Skeletal Dysplasia | |||||
| Hunter, 1998 | 55 (37) | Not defined | BDI score (mean) | 6.5 [6.4] |
|
| Moderate to severe depression (%) | 7% [11%] | ||||
| SSTAI score- State (mean) | 27.6 [27.9] | ||||
| SSTAI score- Trait (mean) | 32.5 [31.7] | ||||
BDI = Beck Depression Inventory; SSTAI = Spielberger State-Trait Anxiety Inventory Score
Results of normal controls are in brackets.
See Methods, Summary Tables, Study Quality.
The single study of depression and anxiety among children with skeletal dysplasias found no evidence for increased rates of depression or anxiety.
| Author Year | Generalizabilitya | Sample N | Population | Disease Severity | Heightb,c | Height Velocityb,c | Qualitya |
|---|---|---|---|---|---|---|---|
| Neville 1996 |
| 699 | Asthmatic children | Low potency medications |
|
| |
| High dose inhaled steroids |
| ||||||
| Martin 1981 |
| 315d | Age 10 y | Mild - Severe |
|
| |
| Very severe |
| ||||||
| Age 14 y | Mild - Severe |
| |||||
| Very severe |
| ||||||
| Age 21 y | Mild - Very severe |
| |||||
| McNicol 1970 |
| 226 | Asthmatic children | Frequency of asthma episodes |
|
| |
| Rona 1980 |
| 102 | Asthmatic children | Frequency of asthma episodes |
|
|
|
|
|
| ||||||
| Hauspie 1979 |
| 500 | Class II-IV (Osváth) |
|
| ||
| 607 | Asthmatic boys | CARA vs asthma vs asthma w/eczema |
| ||||
| Steroid requirements |
| ||||||
| Sant' Anna 1996 |
| 514 | Asthmatic children | Mild - Severe |
|
| |
| Spock 1965 |
| 200 | Asthmatic children | Poor - Excellent |
|
| |
| Ferguson 1982 |
| 36 | Short asthmatic children | Mild-Severe |
|
| |
| Cernelc 1975 |
| 337 | Asthmatic children | Pulmonary function |
|
| |
| Klein 1991 |
| 176 | Non-steroid-dependent asthmatic | Mild- Moderate |
|
| |
| Balfour-Lynn 1986 |
| 66 | Asthmatic children | Medications required |
|
|
|
|
| |||||||
CARA = Chronic aspecific respiratory affection
See Methods…
Univariate analysis, unless noted otherwise.
Non-significant trend toward more severe asthma associated with growth retardation (or no statistical analysis)
More severe asthma significantly associated with growth retardation
No association between asthma severity and growth retardation.
Same children at different ages.
Adjusted for parental height, socioeconomic status, and number of siblings.
In a secondary analysis of a prospective longitudinal cohort of 2,915 children with asthma, Neville, McCowan, Thomas, et al. (1996) evaluated height measurements in 699 children aged 3 to 13 years old. Children were grouped based on their medication requirements over the previous year. Only children who required high dose inhaled steroids had a mild decrease in height in comparison to the general local population. Children who required less intense therapy were of equivalent height in comparison to the general local population. Height velocity was not measured.
Martin, Landau, and Phelan (1981) reported on a prospective longitudinal cohort study of 315 children with asthma who were examined at 10, 14 and 21 years of age. Disease severity was based on the frequency and recency of wheezing episodes. Height percentile was compared to that of 62 non-asthmatic children evaluated at the same ages. Children with very severe asthma were significantly more likely to have height less than tenth percentile than non-asthmatic children at 10 and 14 years old, but by 21 years of age, there was no significant difference in the prevalence of height less than tenth percentile between groups. Height velocity was not measured.
Mcnicol, Williams, and Gillam (1970) reported on a prospective longitudinal cohort study of 226 children with asthma and 94 controls at age 10 years. Asthmatic children were grouped as mild, moderate and severe based on number of episodes of asthma by age 10 years and symptoms within 12 months of examination. Children with asthma were evaluated for height and compared to non-asthmatic controls. There was no significant difference in height found between the control group and any group of asthmatic children regardless of degree of severity of asthma. Height velocity was not measured.
In a retrospective cross-sectional study of 102 5 to 11 year old children attending primary school in the United Kingdom, Rona and du (1980) reported on children identified with asthma based on parental report. Severity of disease was graded by number of asthma episodes a year. Height velocity, measured as centimeters gained in the previous 12 months, was lower for both boys and girls with more frequent asthma (3 or more asthma episodes per year) than for children with less frequent asthma, who also had lower height velocity than non-asthmatic controls. However, the difference in height velocities were not statistically significant in unadjusted models or models that adjusted for parental height, social class, and number of siblings. In both unadjusted and adjusted models, children with frequent asthma were significantly shorter (mean of -0.4 SDS) than controls. Children with less frequent asthma were of similar height as controls.
In a retrospective cross-sectional study, Hauspie, Gyenis, Alexander, et al. (1979) reported on two different samples of 3 to 16 year old boys with asthma (500 Hungarian boys in institutional setting and 607 Belgian boys who were a sub-sample of a longitudinal growth study). Among the Hungarian boys, severity of disease was based on Osvath (1976). Belgian boys were categorized as having either chronic aspecific respiratory affection, asthma alone, or asthma with eczema; steroid requirements were also measured. The study found similar results for both groups. Height was retarded in subjects with more severe disease and longer duration of corticotherapy. It is unclear if those with more severe disease had more steroid use. Height velocity was not measured.
Sant'Anna, Sole, and Naspitz (1996) reported a retrospective cross-sectional case series of 514 6 month to 16 year old children with various degrees of asthma. Children were measured upon admission to an asthma/allergy clinic. Asthma severity was based on the International Consensus Report on Diagnosis and Treatment of Asthma (International consensus report on diagnosis and treatment of asthma, 1992). Heights were compared to National Standards for age (National Center for Health Statistics standard) and the number of children with heights less than third percentile were noted. No significant increase in short stature was noted for the asthmatics in this study. Moreover, age, asthma severity, and steroid use had no statistically significant effect on heights of these asthmatic children. Height velocity was not measured.
Spock (1965) reported on a retrospective longitudinal cohort study of 200 children with asthma (initial age 4–12 years old) who had growth parameters followed for at least 4 years. Asthma severity was graded poor to excellent, although the scale was not defined. Height velocity was approximately normal in all groups of children. Children with excellent clinical status had height velocity 9 percent above normal values established by the Child Research Council of the University of Colorado.; Children with good clinical status had height velocity 7 percent above normal, those with fair clinical status had height velocity 2 percent above normal, and those with poor clinical status had height velocity 3 percent below normal. These differences were not statistically different. The study also found that appropriate asthma therapy did not result in a growth spurt, but that steroid therapy dosage and duration was associated with retarded growth in asthmatic children.
Ferguson, Murray, and Tze (1982) evaluated 36 3 to 17 year old asthmatic children with short stature (height less than third percentile) in a prospective longitudinal study. Disease severity was based on wheezing frequency and duration, therapy requirements and duration. No significant association was found between height and severity of asthma. Height velocity was not measured.
Cernelc and Cernelc (1974) reported on a prospective cross-sectional study of 337 asthmatic children. The children's ages were not reported. Asthma severity was based on normal versus abnormal pulmonary function tests. No significant difference in height was found between the two groups of children. Height velocity was not measured.
In a prospective cross-sectional study Klein, Dungy, and Galant (1991) evaluated 176 2 to 15 year old children with non-steroid dependent asthma. Asthma severity was based on hospitalization and medication requirements over the previous year. No significant difference was found between the height and asthma severity. Height velocity was not measured.
Balfour-Lynn (1986) reported on a prospective longitudinal study of 66 2 to 12 year old children who were followed for height from entrance into a pediatric asthma clinic until they reached adult heights. Disease severity was based on medication requirements. No significant difference was found “growth retardation,” although this term was not defined. The proportion of children with height less than the tenth percentile was similar in all groups; no child had height below the third percentile. All children “grew along expected centile lines without appreciable deviation… until age 10 years, regardless of treatment required.”
Among the 11 reviewed studies, the evidence of the association between asthma severity and children's heights were mixed. Four studies found a significant association between the severity of asthma and height; one found a non-significant trend toward an association; and five found no association between asthma severity and height. No study found an association between mild asthma and growth retardation. The three studies that examined the association of asthma severity and height velocity did not find a statistically significant association between the two, although two studies found a possible trend toward slower height velocity with more severe asthma.
Poorly defined samples, limited data and analysis, missing data and varying definitions of disease severity limited these studies. Asthma severity was commonly defined by medication requirements, including steroid treatment. The underlying question of how growth is affected by severity of asthma is not clearly answered by these studies in part due to lack of consistency in defining asthma severity between the studies as well as differences in the treatment of asthma in the studies.
| Author Year | Generalizabilitya | Sample N | Population | Disease Severity | Heightb, c | Height Velocityb, c | Qualitya |
|---|---|---|---|---|---|---|---|
| Levy 1977 |
| 777 | Ventricular septal defect | Severity based on pressure and resistance |
|
| |
| Strangway 1976 |
| 181 | Congenital heart disease, Age 0–2 y | Cyanosis |
|
| |
| Cardiac enlargement |
| ||||||
| Congestive heart failure |
| ||||||
| 387 | Congenital heart disease, Age 2–11 y | Cyanosis |
| ||||
| Cardiac enlargement |
| ||||||
| Congestive heart failure |
| ||||||
| Baum 1980 |
| 26 | Congenital heart disease | Congestive heart failure |
|
| |
| Feldt 1969 |
| 73 | Aortic or pulmonary stenosis | Valvular gradient > 50 mm Hg |
|
| |
| 83 | Tetralogy of Fallot | Various including hemoglobin |
| ||||
| 155 | Ventricular septal defect | Pulmonary vascular pressure |
| ||||
| Cernelc 1975 |
| 22 | Congenital heart disease | Cyanosis |
|
| |
| White 1970 |
| 80 | Congenital heart disease | Cyanosis |
|
| |
See Methods…
Univariate analysis, unless noted otherwise.
Non-significant trend toward more severe cardiac disease associated with growth retardation (or no statistical analysis)
More severe cardiac disease significantly associated with growth retardation
No association between cardiac disease severity and growth retardation.
Levy, Rosenthal, Miettinen, et al. (1978) evaluated 777 children with ventricular septal defect (VSD) with a mean age of 4 years old in a retrospective longitudinal study. Subjects were evaluated for growth and hemodynamic severity based on pulmonary artery pressure and systemic resistance ratio. The study found that children with VSD had subnormal height, regardless of the severity of the defect and that the more severe the hemodynamic disturbance, the shorter the children. Height velocity was not evaluated.
Strangway, Fowler, Cunningham, et al. (1976) evaluated two groups of children with a variety of congenital heart defects in a prospective longitudinal study. The study evaluated 181 infants to age 2 years and 387 children between 2 and 11 years old. Children with additional major congenital lesions or who had undergone corrective cardiac surgery were excluded. The children were classified by the presence of cyanosis, cardiac enlargement, and congestive heart failure. Overall, short stature was uncommon and growth rates were close to normal for both infants and children. Among cyanotic infants, height velocities were significantly delayed compared to those infants without cyanosis. Cyanosis was not associated with height velocity in older children. Cardiac enlargement and congestive heart failure were not significantly associated with height velocity in either infants or children.
In a prospective cross-sectional study Baum, Beck, Kodama, et al. (1980) evaluated 26 children with a variety of acyanotic congenital heart diseases and a mean age of 4 years. Disease severity was based on congestive heart failure (CHF), although this was not defined. The study found that children with acyanotic congenital heart disease with CHF had a significant reduction in height (by 5 to 9 cm) in comparison to children without CHF. Furthermore, half the children with CHF had height less than the fifth percentile, while none of the children without CHF did. Height velocity was not analyzed.
Feldt, Strickler, and Weidman (1969) reported on 311 children of all ages with a variety of congenital heart diseases in a prospective longitudinal study. For children with aortic or pulmonary stenosis, disease severity was based on valvular gradient. For children with tetralogy of Fallot, disease severity was based on cyanosis, hematocrit level, magnitude of shunt, and history of hypoxemia. For children with VSD, disease severity was based on pulmonary vascular pressure. Growth failure was based on both height and weight being more than 2 SD below the mean. Among the 73 children with valvular stenoses, those with pressure gradients above 50 mm Hg were more likely to have “severe growth failure.” Among the 83 children with tetralogy of Fallot, growth failure was not associated with any of the measures of defect severity. Among the 155 children wit VSD, growth failure was not associated with pulmonary vascular pressure. However, no statistical analyses were explicitly reported. Height velocity was not analyzed.
Cernelc and Cernelc (1974) evaluated 22 children with congenital heart disease in a prospective cross-sectional study. The age of the children and the types of heart defects among the children were not reported. Disease severity was based on the presence of cyanosis. The study found that children with cyanotic congenital heart disease were significantly shorter than the general population while those without cyanosis were not significantly different in height than the general population. Height velocity was not analyzed.
White, Jr., Jordan, Fischer, et al. (1971) evaluated 80 12 to 18 year old children with a variety of congenital heart diseases in a prospective cross-sectional study. Children who had undergone total corrective surgery for tetralogy of Fallot were excluded. Disease severity was based on the presence of cyanosis. Of the children with cyanosis, 19 percent had height less than the second percentile compared to only 2 percent of the children without cyanosis. However, no statistical analysis was performed. Height velocity was not analyzed.
Among the reviewed studies, there was general agreement that those children with more severe congenital heart disease were more likely to have growth retardation. One study, however, found no association between height and severity of either tetralogy of Fallot or VSD. Only one study evaluated height velocity and found that reduced height velocity was associated with cyanosis in infants; however, the association was not found in older children. They also found a trend toward reduced height velocity being associated with the presence of CHF. Many studies were limited by incomplete data and statistical analysis and some studies were limited because they excluded children with the most severe congenital heart defects.
| Author Year | Generalizabilitya | Sample N | Population | Disease Severity | Heightb, c | Height Velocityb, c | Qualitya |
|---|---|---|---|---|---|---|---|
| Wise 1992 |
| 122 | Type I DM | Hgb A1c |
|
| |
| Soliman 1996 |
| 45 | Type I DM | Hgb A1c > 10% |
|
| |
| Court 1982 |
| 111 | Diabetes | Glucosuria |
|
|
|
| Izumi 1995 |
| 107 | Type I DM | Hgb A1c |
|
| |
| Salardi 1987 |
| 79 | Type I DM | Hgb A1c |
|
|
|
| Pitukcheewanont 1995 |
| 82 | Type I DM | Hgb A1c |
|
|
|
|
| |||||||
| Arreola 1991 |
| ~198 | Type I DM | Hgb A1c |
|
| |
| Rosenbloom 1982 |
| 142 | Type I DM | Limited joint mobility |
|
| |
| Jivani 1973 |
| 104 | Diabetes | Poor or Good |
|
|
|
| Herber 1988 |
| 67 | Type I DM | Hgb A1c |
|
| |
| Vanelli 1992 |
| 42 | Type I DM pubertal girls | Insulin requirement |
|
| |
DM = Diabetes mellitus; Hgb A1c = Glycosylated hemoglobin
See Methods…
Univariate analysis, unless noted otherwise.
More severe diabetes significantly associated with growth retardation
No association between diabetes severity and growth retardation.
Multivariate analysis adjusting for age of diabetes onset and initial height
Wise, Kolb, and Sauder (1992) evaluated 122 children with Type I diabetes in a prospective longitudinal study over a 5-year period. No data were reported on the age of the children. Height velocity and glycemic control, using Hgb A1c levels, were assessed. A significant linear relationship was seen between Hgb A1c and growth velocity. The most severe growth retardation occurred when Hgb A1c levels were greater than 16 percent. These children had average height velocity 0.07 SDS below the mean. In contrast, Hgb A1c levels less than 8 percent were associated with growth acceleration; average height velocity was 0.10 SDS above the mean. The level of Hgb A1c at which growth suppression occurred was dependent on pubertal status. Children who were prepubertal or in the early stages of puberty were most vulnerable to growth suppression. For these children growth suppression was seen with Hgb A1c greater than 8 percent.
In a prospective longitudinal study Soliman, Ahmed, and Asfour (1996) evaluated 45 children aged 2 to 12 years with Type I diabetes who had height velocity and glycemic control evaluated. Good glycemic control was defined as Hgb A1c less than 10 percent. Children with good glycemic control had significant higher growth velocity (mean +0.75 SDS) than those with poor glycemic control (mean -1.6 SDS).
Court, Parkin, Roberts, et al. (1982) evaluated 121 diabetic children with a mean age of 13 years in a retrospective cross-sectional study. The study implied only that the subjects all had Type I diabetes. Diabetic control was measured by urinary glucose score or by 24-hour urinary glucose excretion. Children whose diabetes was under poor control had average height (-0.96 SDS) that was significantly lower than those under good control (-0.22 SDS). Likewise, average height velocity was significantly lower for children under poor control (-1.22 SDS) than those under good control (-0.61 SDS).
Izumi, Hoshi, Kuno, et al. (1995) evaluated 107 Type I diabetic children with a mean age of 14 years old in a retrospective longitudinal study. Severity of diabetes was based on Hgb A1c levels and were graded mild (less than 10 percent), moderate (10 to 12 percent) and severe (more than 12 percent). The study found no height and diabetic control. Height velocity was not evaluated.
Salardi, Tonioli, Tassoni, et al. (1987) evaluated 79 children ranging in age from 1 to 15 years with Type I diabetes in a prospective longitudinal study. Diabetics control was measured by Hgb A1c levels. Height and height velocity were not associated with diabetic control.
In a retrospective longitudinal cohort study Pitukcheewanont, Alemzadeh, Jacobs, et al. (1995) evaluated 82 children with Type I diabetes with a mean age of 11 years old over a 6-year period. Glycemic control was determined with Hgb A1c levels. There was no association between mean Hgb A1c and height in univariate or multivariate analyses. There was also no association between Hgb A1c and height velocity at any Tanner stage in univariate analysis.
Arreola, Junco, Partida-Hernandez, et al. (1991) reported on a retrospective longitudinal cohort study of about 198 children with Type I diabetes. The children's medical records were examined yearly for five years. They were between 1 and 16 years old in the first year evaluated. The exact number of children included varied from year to year. Diabetic control was based on Hgb A1c levels. Children with poor control (Hgb A1c greater than 11 percent) had significantly lower height velocity (approximately 0.54 cm/month) compared to those with good control (approximately 0.22 cm/month). Overall, there was a significant correlation between Hgb A1c level and height velocity.
Rosenbloom, Silverstein, Lezotte, et al. (1982) performed a prospective longitudinal cohort study of 142 pre-pubertal children with diabetes who had had diabetes for at least 3 years. The study used joint mobility as an indication of severity of microvascular disease. Diabetic children with mild, moderate or severe limitations of joint mobility were significantly more likely to be below the 25th percentile for height than those without limited joint mobility. However, the correlation between Hgb A1c and joint mobility was poor. There were no data on height velocity
Jivani and Rayner (1973) evaluated 104 diabetic children aged between 9 months and 13 years old in a retrospective longitudinal study. Diabetes control was measured good, fair or poor based on ketonuria, glycosuria, serum glucose, and hypoglycemic reactions. Data on subjects with “fair” control were not reported. Height and height velocity were not associated with severity of diabetes.
Herber and Dunsmore (1988) evaluated 67 children with Type I diabetes who had an initial mean age of 11 years and were followed over 3 years in a retrospective longitudinal study. Disease severity was based on Hgb A1c levels. The study found no association between change in height and Hgb A1c. Height velocity was also similar to the general population. The range of diabetes severity was somewhat limited in that, in general, the study population was in good control.
Vanelli, de Fanti, Adinolfi, et al. (1992) evaluated 42 girls with Type I diabetes who became diabetic at the onset of puberty in a prospective longitudinal study. Diabetes severity was insulin requirements. It is likely that the children were stratified into high and low insulin requirement groups post hoc. The children treated with greater amounts of insulin had lower mean Hgb A1c (9 percent) and significantly higher mean peak height velocity (8.5 cm per year) than those treated with less insulin (Hgb A1c 10 percent; peak height velocity 6.9 cm per year).
Among the reviewed studies, there were mixed results correlating severity of diabetes with height and height velocity. Five studies demonstrated a positive relationship between poor diabetes control/increased severity of disease and decreased growth velocity; four studies found no association. Two studies found an association between markers of severity of diabetes and height; three found no association. Several studies associated growth deceleration with peripubertal onset of illness. Some studies were limited because they did not use a well-defined, objective measure like Hgb A1c to assess severity/control. Some studies were limited by unclear statistical analysis, lack of specific data included or summary results.
| Author Year | Generalizabilitya | Sample N | Population | Disease Severity | Heightb, c | Height Velocityb, c | Qualitya |
|---|---|---|---|---|---|---|---|
| Kattamis 1970 |
| 74 | β-thalassaemia | Hemoglobin |
|
| |
| Madeddu 1978 |
| 50 | β-thalassaemia | Hemoglobin |
|
| |
| Constantoulakis 1975 |
| 171 | β-thalassaemia | β-thalassemia severity index |
|
| |
| Hemoglobin |
| ||||||
| Total blood transfusion |
| ||||||
See Methods…
Univariate analysis, unless noted otherwise.
Non-significant trend toward more severe β-thalassemia associated with growth retardation (or no statistical analysis)
More severe β-thalassemia significantly associated with growth retardatio
No association between β-thalassemia severity and growth retardation.
Linear regression model adjusting for age and other variables listed.
In a prospective cross-sectional study, Kattamis, Touliatos, Haidas, et al. (1970) evaluated 74 children aged 1 to 11 years old with homozygous β-thalassemia. Subjects height percentiles were compared in reference to the severity of their anemia. Severity of anemia was determined by pre-transfusion hemoglobin (Hgb) concentration. Children were transfused either when Hgb was at levels greater than 8 mg/dL, between 6 and 8 mg/dL, or below than 6 mg/dL. Children with higher pre-transfusion Hgb were significantly taller (mean height of 56th percentile) than children with moderate Hgb levels (22nd percentile) and lower Hgb (7th percentile). However, the study may have confounded disease severity with treatment options. The children in the moderate anemia group were not followed as regularly and were either of low socioeconomic status or had to travel long distances for transfusion. The children in the severe anemia group mostly were allowed to have their Hgb levels fall below 5 mg/dL before transfusion. Height velocity was not evaluated.
Madeddu, Dore, Marongiu, et al. (1978) evaluated 50 children with homozygous β-thalassemia ages 2 to 13 years old in a prospective cross-sectional study. Severity of disease was based on pre-transfusion Hgb levels. Children with height less than the 3rd percentile had somewhat lower mean Hgb (6.6 g/dL) than taller children (approximately 7.1 g/dL). There was no significant association between Hgb level and height. Height velocity was not evaluated.
In a retrospective longitudinal, Constantoulakis, Panagopoulos, and Augoustaki (1975) evaluated 171 patients aged 7 months to 28 years with homozygous β-thalassemia. A variety of measures were used to determine disease severity. These measures were included in a multiple regression analysis to determine the association between height and the measures. A “severity of disease index” was created that was based on the amount of blood transfused in the previous two years. The regression also included total blood transfused since birth, mean Hgb level of the previous two to four years, and age. Of note is that none of the variables included in the model are independent of other included variables. In the model there was a trend toward lower height percentiles being associated with low Hgb levels and severity of disease index; however, neither was statistically significant in a linear regression controlling for age. Total blood transfused since birth was not associated with height. Height velocity was not evaluated.
Among the three reviewed studies, the evidence of the association between β-thalassemia severity and children's heights was inconclusive. One study found a significant association between pre-transfusion Hgb and height. However, the study may have confounded underlying severity of disease with treatment choices. Another study may have found some evidence of an association between disease severity and height, but the value of their finding is limited by the poor regression technique used. The third study found no association, although a trend may have been indicated.
| Author Year | Generalizabilitya | Sample N | Population | Disease Severity | Heightb, c | Height Velocityb, c | Qualitya |
|---|---|---|---|---|---|---|---|
| Saha 1998 |
| 29 | UC | Disease severity |
|
|
|
| 18 | Crohn's |
|
| ||||
| Griffiths 1993 |
| 100 | Crohn's | Frequency / Chronicity |
|
|
|
| Disease location |
|
| |||||
| Farmer 1979 |
| 513 | Crohn's | Disease location |
|
| |
UC = Ulcerative colitis
See Methods…
Univariate analysis, unless noted otherwise.
Non-significant trend toward more severe inflammatory bowel disease associated with growth retardation (or no statistical analysis)
More severe inflammatory bowel disease significantly associated with growth retardation
No association between inflammatory bowel disease severity and growth retardation.
Linear regression adjusting for corticosteroid use.
Saha, Ruuska, Laippala, et al. (1998) evaluated 47 prepubertal children with a mean age of 7 years old who had either ulcerative colitis or Crohn's disease in a retrospective longitudinal study. The children were followed for the first four years after diagnosis or until they reached age 12 years old. Mean height and height velocity standard deviation scores were calculated at diagnosis and yearly after that. Disease severity was scored based on number of relapses, hospitalizations, surgeries and medications. For both children with ulcerative colitis and Crohn's disease, disease severity was significantly associated with height velocity. Children with more severe disease were the shortest, but the difference in height among children with different disease severity was not statistically significant. Of note, no statistical difference in HVSDS in children receiving or not receiving Prednisone was found.
In a retrospective longitudinal study, Griffiths, Nguyen, Smith, et al. (1993) evaluated 100 prepubertal children with a mean age of 11 years old at initial diagnosis of Crohn's disease who had been followed for at least two years. The study evaluated the relationship between growth velocity, defined as growth in cm/year, and severity of the Crohn's disease, determined by gastrointestinal symptom frequency and chronicity, and disease location. The study found that the severity of gastrointestinal symptoms was the major factor influencing linear growth during the first two years after diagnosis. Height velocity decreased with increasing symptoms. No difference in mean linear growth velocities were found among patients stratified by anatomical localization of disease. Longer term follow-up found that those children who reached maturity by the end of the study achieved their expected height, regardless of disease severity or location. Of note, duration of corticosteroid administration was not a significant predictor of height velocity.
Farmer and Michener (1979) performed a retrospective longitudinal case series study of 513 patients younger than 20 years old who had Crohn's disease. The mean duration of follow-up was almost 8 years. Growth retardation was defined as height less than third percentile on the growth curve for any given age. Short stature occurred at similar frequencies among children diagnosed with Crohn's disease no matter what the pattern of disease: ileocolic (7 percent), colon (8 percent) and small intestine (6 percent). The study did not report whether those with short stature had different complication rates than taller children. Height velocity was not explicitly measured.
All three studies evaluating the relationship between growth retardation and the severity of inflammatory bowel disease included children with Crohn's disease. One study also included children with ulcerative colitis. Severity of inflammatory bowel disease was found to correlate with loss of height velocity in two studies. Crohn's disease location, however, did not correlate with either height or height velocity in two studies. There were no data presented to suggest that the process of growth failure is likely to be disabling.
| Author Year | Generalizabilitya | Sample N | Population | Disease Severity | Heightb, c | Height Velocityb, c | Qualitya |
|---|---|---|---|---|---|---|---|
| Bernstein 1977 |
| 31 | JRA | Systemic vs Other |
|
| |
| Polito 1997 |
| 58 | JRA | Systemic / Polyarticular vs Pauciarticular |
| ||
| Number of affected joints |
|
| |||||
|
| 37 | Systemic or Polyarticular | Total disease flares |
| |||
| Functional class |
| ||||||
| Saha 1999 |
| 64 | JRA | Polyarticular vs Systemic / Pauciarticular |
|
|
|
| Severity Score |
|
| |||||
JRA = Juvenile rheumatoid arthritis
See Methods…
Univariate analysis, unless noted otherwise.
Non-significant trend toward more severe juvenile rheumatoid arthritis associated with growth retardation (or no statistical analysis)
More severe juvenile rheumatoid arthritis significantly associated with growth retardation
No association between juvenile rheumatoid arthritis severity and growth retardation.
Statistical significance not explicitly reported. Implied significance.
Adjusted for sex and duration of disease (implied).
Adjusted for glucocorticoid use and duration of disease (implied).
Bernstein, Stobie, Singsen, et al. (1977) performed a retrospective longitudinal cohort study of 31 children with JRA. At initial evaluation, the children were between 1 and 11 years old and were followed for a mean of 6.6 years. Children with JRA were classified into systemic, polyarticular, and pauciarticular groups according to the mode of onset of their disease. Children with systemic JRA (more severe disease) had significantly lower mean change in height in comparison to children with polyarticular and pauciarticular JRA.
In a retrospective longitudinal study of 58 children with JRA who had a mean age of 6 years old at initial evaluation, Polito, Strano, Olivieri, et al. (1997) evaluated subjects for at least 1 year. The study evaluated height velocity compared to a population standard and measured disease severity based on disease type in all subjects. In children with systemic or polyarticular disease, height velocity was also evaluated based on number of affected joints, the total duration of disease flares, and an undefined functional class. Children with more severe JRA (systemic or polyarticular) were significantly more likely to have a decreased growth velocity when followed over time in comparison to children with less severe JRA (pauciarticular). Among those with either systemic or polyarticular disease, decreased height velocity significantly correlated with duration of flares and with functional class, but not with the number of joints affected. Furthermore, the study concluded that decreased growth velocity was likely secondary to the JRA separate from steroid medication use. Of note, though, since steroid use was an exclusion criteria, those most seriously affected were likely excluded.
Saha, Verronen, Laippala, et al. (1999) conducted a retrospective longitudinal study of 64 prepubertal children diagnosed with juvenile chronic arthritis who were followed from the time of diagnosis for 2 years or until they reached age 12. At initial evaluation, the children had a mean age of 4 years old. Children with the most severe disease were excluded. Disease severity was based on type of disease (pauciarticular, polyarticular, and systemic) and by a severity score based on medication requirements. The paper implied that associations with height and height velocity were adjusted in multivariate analyses. The study found that both height and height velocity were significantly decreased with increased severity of disease type or severity in the first year after diagnosis. However, height severity normalized after this.
All studies indicated an association between decreased growth velocity and increased severity of JRA. One of the studies, however, found that height velocity normalized after the first year of treatment. Two studies excluded children with the most severe disease There were no data reported to address the question of whether decreased growth velocity is in itself disabling.
| Author Year | Generalizabilitya | Sample N | Population | Disease Severity | Heightb, c | Height Velocityb, c | Qualitya |
|---|---|---|---|---|---|---|---|
| Schaefer 1996d |
| 321 | CKD | GFR |
|
| |
| GFR < 25 |
|
| |||||
| Karlberg 1996d |
| 47 | CKD, aged 9 mo-2 y | GFR |
|
| |
| 14 | Infants with CKD |
| |||||
| Konrad 1995d |
| 24 | ARPKD girls | GFR < 60 |
|
| |
| 34 | ARPKD boys | GFR < 60 |
| ||||
| Norman 2000 |
| 60 | CKD | GFR categories |
|
| |
| Rizzoni 1984 |
| 47 | CKD | GFR |
|
|
|
| Tsau 1989 |
| 52 | Nephrotic syndrome | Relapsing vs non-relapsing disease |
|
| |
| Schärer 1999 |
| 33 | Prepubertal nephrotics | No CKIf |
|
| |
| CKIf |
| ||||||
| ESRDf |
| ||||||
|
| 16 | Steroid resistant nephrotics | Serum albumin / protein |
| |||
| Ismaili 2001 |
| 11 | Infants with CKD | GFR < 15 at 6 months |
|
| |
| Claris-Appiani 1989 |
| 17 | Predialysis CKD | Creatinine clearance |
|
|
|
| Tejani 1983 |
| 24 | Focal segmental sclerosis | Steroid resistant vs sensitive |
|
| |
ARPKD = autosomal recessive polycystic kidney disease, CKD = chronic kidney disease, GFR = glomerular filtration rate.
See Methods…
Univariate analysis, unless noted otherwise.
Non-significant trend toward more severe juvenile rheumatoid arthritis associated with growth retardation (or no statistical analysis)
More severe juvenile rheumatoid arthritis significantly associated with growth retardation.
No association between juvenile rheumatoid arthritis severity and growth retardation.
Karlberg, Schaefer, Hennicke, et al. (1996), Schaefer, Wingen, Hennicke, et al. (1996) and Konrad, Zerres, Wuhl, et al. (1995) used subjects from same dataset.
Multivariate analysis. No data on other variables in model.
No CKI = Reached final height without kidney function deterioration (chronic kidney insufficiency).
CKI = Reached final height with serum creatinine > 1.2 mg/dL after age 13.6 years.
ESRD = Developed end stage renal disease before reaching final height.
Adjusted for multiple variables including bone age, blood urea nitrogen, nutrition, and parathyroid hormone.
Three papers reported separate analyses on different sets of subjects from the same overall sample of patients (Karlberg, Schaefer, Hennicke, et al., 1996; Konrad, Zerres, Wuhl, et al., 1995; Schaefer, Wingen, Hennicke, et al., 1996). The largest, by Schaefer, Wingen, Hennicke, et al. (1996) reported on a prospective longitudinal study of 321 children with CKD followed to age 10 years old. Disease severity was based on a measure of kidney function, glomerular filtration rate (GFR). For children in most age groups evaluated, those with lower GFR had lower height velocities. Among children of all ages, those with GFR less than 25 mL/min had significantly lower heights and height velocities compared to children with greater kidney function.
In a subset of children reported in Schaefer, Wingen, Hennicke, et al. (1996), 61 children diagnosed with CKD prior to age 6 months and who were younger than 2 years old were evaluated by Karlberg, Schaefer, Hennicke, et al. (1996) in a prospective longitudinal analysis. In a multivariate analysis, kidney function, measured by GFR, was not associated with height velocity in either infants or young children.
In another subset of patients, Konrad, Zerres, Wuhl, et al. (1995) reported a prospective longitudinal study of 58 prepubertal children with autosomal recessive polycystic kidney disease (ARPKD) who were older than 1 year at initial evaluation. Severity of CKD was measured by GFR. Girls with ARPKD who had GFR less than 60 mL/min/1.73 m2 were significantly shorter than girls with greater kidney function. However, in boys, height was not associated with kidney function. Height velocity was not analyzed.
Norman, Coleman, Macdonald, et al. (2000) performed a prospective cross-sectional study of 60 children with CKD aged 2 to 17 years old. Severity of CKD was defined as mild (GFR 50–75 mL/min/1.73 m2), moderate (GFR 25–50 mL/min/1.73 m2) and severe (GFR less than 25 mL/min/1.73 m2). The study found that those with more severe CKD (moderate and severe) were more likely to be significantly shorter than children with only mild CKD. Height velocity was not analyzed.
Rizzoni, Basso, and Setari (1984), in a retrospective longitudinal study, evaluated 47 children with CKD, from neonate to age 15 years old. CKD severity was measured with GFR. No relationship between GFR and growth velocity or height was found.
Tsau, Chen, and Lee (1989) performed a retrospective longitudinal analysis of 52 children with nephrotic syndrome, with a mean age of 5 years old. The children were categorized into two groups based on clinical course. Those with frequent relapsing, steroid-dependent and steroid-resistant disease were classified as having a less favorable clinical course. Those with occasional relapsing disease or who had not had relapses were classified as having a more favorable course. Growth data were obtained and analyzed up to the age of 15 years old. The study found that children with more severe nephrotic disease had significantly decreased yearly growth velocity in comparison to children with more mild nephrotic syndrome. However, further analysis concluded that the duration of steroid administered per year was found to be the major determinant of growth suppression in nephrotic children.
Scharer, Essigmann, and Schaefer (1999) performed a prospective cross-sectional study of 33 prepubertal children with nephrotic syndrome, who had a mean age of 4 years old. Children were followed for a minimum of 1.2 years. Children were classified by the degree of deterioration of their kidney function during follow-up. Nephrotic children with no or with moderate deterioration of kidney function did not experience reduction of height velocity compared to population norms. Those children who went on to develop end-stage renal disease had significant reduction of height velocity compared to population norms. In a subgroup of 16 children who had steroid resistant nephrotic syndrome, disease severity was determined by serum total protein and albumin levels. Height velocity correlated significantly with total protein and albumin levels, such that those with more severe nephrotic syndrome had lower height velocity.
Ismaili, Schurmans, Wissing, et al. (2001) performed a retrospective longitudinal study of 11 infants with kidney dysplasia and CKD. The authors analyzed kidney function and growth from birth to 4 years of age. Disease severity was based on GFR at 6 months of age, using 15 mL/min as a threshold for severity. Infants with more severe CKD at 6 months had a significantly more severe delay in height compared to those children with less severe CKD.
Claris-Appiani, Bianchi, Bini, et al. (1989) performed a prospective longitudinal cohort study of 17 children with CKD who were aged 1 to 9 years old and were followed for 1 year. Severity of CKD was measured using creatinine clearance. Children with more severe CKD were significantly shorter. However, growth velocity did not correlate with creatinine clearance in multivariate analysis controlling for a variety of factors.
Tejani, Nicastri, Sen, et al. (1983) performed a retrospective longitudinal evaluation of 24 children with nephrotic syndrome and focal segmental glomerular sclerosis (FSGS). The children were between 3 and 19 years old at follow-up. The children were classified based on whether their disease was steroid resistant or steroid sensitive. Sixty-nine percent of children with steroid resistant FSGS had short stature, compared to 12% of children with steroid sensitive disease. The growth retardation was less common in steroid sensitive FSGS despite increased exposure to steroids in these children.
Among the reviewed studies, the majority found a positive relationship between increased severity of CKD and either decreased growth velocity or short stature. However, these findings were not universal. Single studies of sub-populations, such as children with ARPKD and very young children found conflicting evidence. Two studies commented on the use of steroids and how they related to growth. In one study of children with nephrotic syndrome, steroid use was associated with growth retardation. However, the second study, of children with focal segmental sclerosis, found that children whose disease was amenable to steroid use, and therefore received steroids, grew faster than children with steroid resistant disease. Some studies were limited by using a severity marker that was not GFR or by small sample sizes or limited data reporting. No data were available to assess if a decreased height velocity is in itself disabling
| Author Year | General-izabilitya | Sample N | Population | Disease Severity | Heightb, c | Height Velocityb, c | Qualitya |
|---|---|---|---|---|---|---|---|
| Brettler 1990 |
| 36 | Hemophiliac boys with HIV | Progression to AIDS or ARC |
|
| |
| Matarazzo 1994 |
| 24 | Perinatal HIV | Clinical deterioration |
|
|
|
HIV = human immunodeficiency virus; AIDS = acquired immunodeficiency syndrome; ARC = AIDS related complex
See Methods…
Univariate analysis, unless noted otherwise.
Non-significant trend toward more severe HIV disease associated with growth retardation (or no statistical analysis)
More severe HIV disease significantly associated with growth retardation
No association between HIV disease severity and growth retardation.
Multivariate analysis. Included CD4 count and p24 antigenemia and possibly other variables not reported.
Brettler, Forsberg, Bolivar, et al. (1990) evaluated 36 boys with hemophilia A and HIV in a longitudinal study. Data were collected both retrospectively and prospectively. The boys had a median age of 8 years old and were younger than 12.5 years old. Growth failure was defined as a decrease in at least 15 percentile points in height or weight for age for two consecutive years. In a multivariate analysis that controlled for CD4 count and p24 antigenemia, growth failure was found to be the strongest prognostic variable for the progression to acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC). The authors conclude that “growth abnormalities in HIV-infected children without symptoms should be considered as an early sign of progression toward symptomatic disease.”
Matarazzo, Palomba, Lala, et al. (1994) performed a prospective longitudinal cohort study of 24 children who were perinatally infected with HIV who were evaluated for 24 months. Disease severity was based on clinical deterioration; although this was not defined. At both 1 and 2 year follow-up, children who had clinical deterioration were substantially shorter and had substantially lower height velocity than children with stable clinical condition. At follow-up, most children with a stable clinical condition maintained normal growth whereas those with growth reduction showed progression in the severity of the disease. However, statistical analysis was not performed.
Both studies that evaluated growth retardation in children with HIV found that linear growth retardation is a marker for progression to active disease in HIV positive children and that linear growth deceleration may precede the onset of symptoms of active disease. These studies were limited by incomplete reporting of data and poorly defined methods, predictors and outcomes. Despite the limitations, the studies seem to indicate that a sustained decrease in linear growth velocity is a marker for progression from seropositive status to active disease. No data were included that assess whether a decreased linear growth velocity is in itself likely to be disabling.
| Author Year | General-izabilitya | Sample N | Population | Disease Severity | Heightb, c | Height Velocityb, c | Qualitya |
|---|---|---|---|---|---|---|---|
| Massarano 1993 |
| 68 | Eczema | % BSA affected |
|
| |
| >50% vs <50% BSA affected |
| ||||||
| Patel 1988 |
| 80 | Atopic dermatitis | >50% vs <50% BSA affected |
|
|
|
| Asthma vs no asthma |
|
| |||||
BSA = body surface area
See Methods…
Univariate analysis, unless noted otherwise.
More severe atopic dermatitis or eczema significantly associated with growth retardation
No association between atopic dermatitis or eczema severity and growth retardation.
In multivariate analysis controlling for parental height, diet, duration of eczema, treatment and asthma.
| Author Year | Generalizabilitya | Sample N | Population | Disease Severity | Heightb, c | Height Velocityb, c | Qualitya |
|---|---|---|---|---|---|---|---|
| Samson-Fang 1998 |
| 81 | Cerebral palsy | Cognitive impairment |
|
| |
| 72 | Non-ambulatory |
| |||||
| 80 | Type of disease |
| |||||
| Evliyaoglu 1996 |
| 24 | Sickle cell anemia | Severe vs Mild |
|
| |
| Rasat 1995 |
| 9 | Congenital adrenal hyperplasia | Number of escapes from suppression |
|
| |
See Methods…
Univariate analysis, unless noted otherwise.
Non-significant trend toward more severe chronic disease associated with growth retardation (or no statistical analysis)
More severe chronic disease significantly associated with growth retardation
No association between chronic disease severity and growth retardation.
Massarano, Hollis, Devlin, et al. (1993) performed a prospective cross-sectional analysis of 68 children age 2 to 12 years old with atopic eczema. Disease severity was based on percentage of skin affected by eczema. All children had been treated with topical steroids; however those with more than 50% skin involvement were treated with more potent steroids. Both groups had similar asthma and asthma treatment scores. In a multivariate analysis, height was significantly associated with percent of skin affected by eczema. Furthermore, the mean height of those children with more than 50% skin involvement was significantly less those with less skin involvement. Children on systemic steroids were included in the study. There were no data on height velocity.
Patel, Clayton, Addison, et al. (1998) performed a prospective longitudinal study of 80 prepubertal children with atopic dermatitis. The children had a mean age of 5 years old at initial evaluation and were followed over a 2-year period. In one analysis, height severity was based on percentage of skin involvement. Neither height velocity nor height differed between patients with less than 50% skin involvement and those with at least 50% skin involvement. In a secondary analysis, affected children with and without asthma had similar heights and height velocities. Of note, there were also no differences in height or height velocities between children treated with mild potency topical glucocorticoids and those treated with moderate potency ones. Children with systemic steroids were excluded from the study.
The two studies of growth in children with atopic dermatitis reported conflicting results. One study, which included children on systemic steroids, found a positive association between increased severity and decreased height. The other study, which excluded children on systemic steroids, found no association between increased severity and decreased height or height velocity. These studies do not clearly provide evidence that a sustained decrease in linear growth velocity is a marker for the severity of the underlying disease. Further prospective longitudinal studies that evaluate the severity of the dermatitis and the contribution of systemic and topical steroid use and coexisting conditions like asthma are needed to determine whether growth failure is related to severity of illness or to medication treatment or co-morbid medical illness. No data were provided that look at whether the process of a decreasing linear growth velocity is in itself disabling.
The relationship between growth and the severity of three chronic diseases - cerebral palsy, sickle cell anemia, and congenital adrenal hyperplasia - were evaluated in one paper each.
The association of growth and severity of cerebral palsy was evaluated by Samson-Fang and Stevenson (1998) in a retrospective cross-sectional study of good quality. The study included 81 children with cerebral palsy younger than 10 years old. Severity of disease was evaluated in three ways: presence of a cognitive impairment, ambulation ability, and type of cerebral palsy (spastic disease, extra-pyramidal disease, and mixed disease). Cognitive impairment and non-ambulatory status were independently associated with a lower height velocity. Height velocity, however, was not associated with disease type.
The association of growth and severity of sickle cell anemia was evaluated by Evliyaoglu, Kilinc, and Sargin (1996) in a prospective cross-sectional study of fair quality. The study included 24 children with homozygous SS sickle cell anemia with a mean age of 9 years old. Sickle cell patients were classified into two groups: a mild clinical course group who did not require blood transfusions and had no sickle crises; and a severe clinical course group who needed blood transfusions beginning early in life and had suffered from frequent sickle crises. The children with severe sickle cell anemia were significantly shorter than those with mild courses. Height velocity was not analyzed.
The association of growth and severity of congenital adrenal hyperplasia was evaluated by Rasat, Espiner, and Abbott (1995) in a retrospective longitudinal study of poor quality. The study analyzed 9 children with congenital adrenal hyperplasia who had a mean age at initial evaluation of 15 years old and were followed for a median of 14 years. All subjects had been treated with glucocorticoids. Disease severity was expressed as the frequency of biochemical escapes from adrenal suppression. There was no association between final height and number of suppression escapes. Height velocity was not evaluated.
In one study, height velocity was found to be associated with severity of impairments due to cerebral palsy, but not with type of disease. Height was associated with severity of course of sickle cell anemia in a single study. In a small study, no association was found between final height and severity of congenital adrenal hyperplasia. Further studies disease are needed to confirm these results and to more clearly evaluate height velocity and severity of disease. No data were presented to answer the question about whether the process of having a decreasing linear growth velocity is in itself disabling in children with any of these diseases.
In this chapter, we discuss the conclusions resulting from our evaluation of the three questions asked by the Social Security Administration (SSA). We also describe the limitations of the existing studies related to disability and short stature as well as the relationship between chronic disease and decreased growth.
This report summarizes the scientific evidence in regard to three questions attempting to determine if children with short stature are disabled because of their short stature, if children with short stature secondary to a skeletal dysplasia are disabled and if decreased growth velocity can be related to severity of chronic disease.
The results presented in Chapter 3 are based on the screening of 13,537 MEDLINE® citations and the review of 825 full articles.
There were 23 studies that provided information on functional abilities among children with short stature due to medically determinable impairments. Fifteen were prospective cross-sectional studies; seven were prospective longitudinal studies; and one was a retrospective longitudinal study. Two were of good quality, eleven were of fair quality, and nine were of poor quality. One study was of fair quality in its analysis of intelligence, but of poor quality in its analysis of academic achievement.
Based on the reviewed articles, no severe functional limitations were found in children with short stature due to growth hormone deficiency, multi-hormone deficiency, Turner syndrome, Russell-Silver syndrome or isolated short stature. These specific causes of short stature were chosen because they allowed us to isolate the effect of short stature and thus enabled us to determine if there was an increased risk for disability-related problems due just to short stature. The articles focused on intelligence, academic achievement, behavior, visual-motor perception, and psychomotor development. In each of these categories, children with short stature either had testing that was not significantly different from the controls or from the population mean, or if the testing were significantly poorer it was still for the most part within 1 standard deviation (SD) of the population mean.
Eleven studies evaluated the relationship between academic achievement and short stature. Five of the studies found that children with short stature had academic achievement scores at or above the population norm. The other six studies found scores below the population norm but the great majority of subjects were still within 1 SD of the mean. These results imply that children with short stature do not have enough difficulties with academic achievement to qualify as a disability. A major limitation in five of the studies was the exclusion of children with a low intelligence quotient (IQ). Further studies that look at academic achievement in a large unselected population of children with short stature and compares them to matched controls are needed to more clearly delineate this relationship.
Intelligence was evaluated in 21 studies of children with short stature. Fifteen studies found short stature children to have IQs at or above the population mean, while the remaining studies reported IQs for the most part less then 1 SD below the mean. Three of the studies that found IQs at or above the mean excluded children with low IQs. The studies were limited by the IQ exclusion and also by an absence of a control population in many of the studies. Future studies are needed to better delineate this question.
Only three studies could be found that evaluated visual-motor perception in children with short stature. All three found significantly lower visual-motor skills in the evaluated children. These studies, however, were limited by their reporting of the data. Furthermore, it is not clear how a decrease in visual-motor skill can be correlated with the SSA definition of disability. Future studies are needed to evaluate disabilities caused by functional limitations in visual-motor skills.
Only one study evaluated developmental skills in a group of children with short stature. These children, who had Russell-Silver syndrome, were found to have delays in meeting their developmental landmarks. However, the value of this finding in relation to disability is questionable since the children did eventually meet their developmental landmarks (e.g., walking). Future studies are needed to determine the significance of these findings.
Teacher-based evaluation of behavior in children with short stature was reported in seven studies. In general, behavior in the children with short stature was not significantly different from the controls. Exceptions to this were increased hyperactivity reported in one study, increased locus of control in another study, and general increased behavior problems in a third study. It is difficult to extrapolate behavior in general from these studies since they tended to use different tests, and the test results do not always overlap. In addition, sub-group results were not given for each study. Furthermore, the value of behavioral impairments for determining a child's level of disability is questionable. Further studies are needed that evaluate large groups of non-selected short stature children, use the same behavior based test, compare results to matched controls, and determine likelihood of disability.
There were 31 papers from 25 study groups that provided information on functional abilities among children with short stature due to skeletal dysplasia. Of the studies, 22 were prospective cross-sectional studies; five were prospective longitudinal studies; two were retrospective longitudinal; and two were retrospective cross-sectional. One was of good quality, 16 were of fair quality, and 12 were of poor quality. One study was of good quality in its analysis of academic achievement, but of fair quality in its analysis of ambulation and mobility. One study was of fair quality in its analysis of neuromuscular function and range of motion, but of poor quality in its analysis of ambulation and mobility.
Based on the articles reviewed, children with skeletal dysplasias were not at increased risk of having severe impairments in intelligence, academic achievement, or psychological outcome. There was an increased risk for delay in achievement of motor skills in children with achondroplasia and osteogenesis imperfecta, and decreased ambulation, range of motion and mobility in children with more severe forms of osteogenesis imperfecta. The results for hearing impairment, respiratory dysfunction and spinal curvature appear to indicate an increased risk for impairment in these three areas, but the studies were limited in the number of children evaluated and how the samples were selected, thus making it difficult to arrive at a definitive conclusion in these areas.
Three studies examined academic achievement among children with achondroplasia or osteogenesis imperfecta. In two studies, achondroplasia patients scored lower than control groups, yet remained in the normal range. Further studies on this issue are needed to evaluate a larger population of children with achondroplasia, osteogenesis imperfecta and other types of skeletal dysplasias.
Five studies evaluated intelligence in children with achondroplasia, osteogenesis imperfecta and other skeletal dysplasias. No evidence of significantly impaired intelligence was found in any of the skeletal dysplasias by intelligence testing with all scores either above the population norm or within 0.5 SD of the norm. These studies were generally small for the comparisons made. Further studies on this issue are needed to evaluate a larger population with skeletal-dysplasias clearly defined by up-to-date standards.
Six studies found generally delayed achievement of psychomotor abilities or development in children with achondroplasia and osteogenesis imperfecta. Each group evaluated was small, used different testing instruments, and had varying ages of subjects. Furthermore, none was followed longitudinally. Clinically useful conclusions about ultimate motor function in children with skeletal dysplasias cannot be made from these studies. Larger, longitudinal studies are needed that test psychomotor functional abilities.
From review of the available literature, children with short stature due to various skeletal dysplasias appear to be at risk for neuromuscular abnormalities. Six studies evaluated neuromuscular function in children with skeletal dysplasias. The four studies that looked solely at children with achondroplasia found varied abnormalities. The three that measured strength found substantial weakness and hypotonia. Asymmetry, sensory deficits, poor coordination, and seizures were found in frequencies higher than controls or than are expected in the healthy population. All studies highlighted the significant risk of often occult cervical cord compression in these young children. The one paper that evaluated osteogenesis imperfecta found substantial muscle weakness in children who are moderately to severely affected their disease. The one paper that reviewed other skeletal dysplasias found cervical cord complications in children with Morquio disease. Further studies of children with skeletal dysplasias, especially achondroplasia, are needed to better delineate the extent of neuromuscular impairment.
Of the eight papers considering ambulation and mobility in children with short stature due to skeletal dysplasia, all considered children with osteogenesis imperfecta. All found significant impairment in ambulation, with greater impairment, as expected, in patients with more severe disease. Children with the less severe types of osteogenesis imperfecta (tarda, Type I, Type IV) were more likely to attain some walking capability, although a substantial proportion of these children did require assistance. Orthopedic abnormalities such as scoliosis, decreased range of motion, decreased muscle strength and fracture contribute to limitations of ambulation. All of the studies were of small size; although given the rarity of osteogenesis imperfecta, the studies were of reasonable size. Definitions of levels of ambulation were consistent and fairly objective. Studies of ambulation and mobility disabilities are necessary for children with skeletal dysplasias other than osteogenesis imperfecta.
Two studies evaluated upper and lower range of motion (ROM) abnormalities in children with various types of osteogenesis imperfecta and with achondroplasia. Decreased ROM was found in children with osteogenesis imperfecta, but no such correlation was seen in children with achondroplasia. Decreased lower extremity ROM may impact on ability to independently ambulate. Decreased upper extremity ROM may limit an individual's independence by reducing his or her ability to engage in self-care. Further studies are necessary to better delineate the connection between limb ROM and various skeletal dysplasias.
Four papers assessed spinal deformities in children with short stature due to skeletal dysplasia. Three studied children with osteogenesis imperfecta, and one studied children with diastrophic dysplasia. A high prevalence of scoliosis was found in children with both conditions. One study also found a high prevalence of pathologic kyphosis. All studies, however, likely represent a selected, perhaps more severe, population of patients followed by academic medical centers. Thus to find prevalence in the general population of individuals with skeletal dysplasias, it will be necessary to evaluate scoliosis and kyphosis in a group of unselected individuals with skeletal dysplasias.
Of the six studies that reported on hearing loss in children with skeletal dysplasia, only three performed objective hearing testing. All papers that reported actual hearing testing in young osteogenesis imperfecta patients reported a sizable proportion with hearing loss, although the prevalences varied due to selection and cohort size differences. Subjective reports of hearing problems in achondroplasia patients were common. One study did not show a high level of self-report of hearing in patients with a mix of skeletal dysplasias, including achondroplasia. The available literature supports that children with at least some skeletal dysplasias, specifically achondroplasia and osteogenesis imperfecta, are at risk for hearing problems. Further studies with a larger, unselected population of children with skeletal dysplasia are needed to better define the extent, severity and type of hearing loss.
Of the four papers evaluating sleep and respiratory dysfunction in children with achondroplasia, all found a high incidence of abnormality, including central hypopnea, central apnea, and obstructive apnea. All four papers, however, reported on small numbers of children. Two of the groups contained patients referred for their respiratory or neurologic symptoms, and therefore may not represent the general achondroplasia population. Further studies that look at larger groups of non-selected achondroplasia patients are needed to define the prevalence of apnea in this population.
Little information on pulmonary function in children with skeletal dysplasia was found. One group found abnormal pulmonary function in a small group of children with achondroplasia, and one found no significant abnormality in a smaller group of children with osteogenesis imperfecta. More data are required before meaningful conclusions can be drawn.
Only one paper was found that adequately studied the association of short stature due to skeletal dysplasia with psychological outcomes. The study found no evidence for increased rates of depression or anxiety in children with skeletal dysplasia. Further studies that evaluate psychological problems such as depression and anxiety are needed to validate these results.
We reviewed 53 articles that evaluated whether a sustained decrease in linear growth velocity can be used as a marker of the severity of 12 medical conditions and whether such a process is likely to be disabling. Nineteen were prospective longitudinal studies, 19 were retrospective longitudinal studies, 10 were prospective cross-sectional studies, and five were retrospective cross-sectional studies. Four were of good quality, 29 were of fair quality, and 20 were of poor quality. The evidence from four conditions (congenital heart disease, juvenile rheumatoid arthritis, Crohn's disease and (human immunodeficiency virus infection (HIV)) appear to indicate that a sustained decrease in linear growth velocity can be used as a marker of the severity of these underlying conditions. Evidence is less clear for asthama, atopic dermatitis, diabetes, ß-thalassemia, and chronic kidney failure. There was only one study for sickle cell disease, congenital adrenal hyperplasia and cerebral palsy so it is difficult to draw conclusions for these conditions. None of the studies addressed the question of whether the process of having a decreasing linear growth velocity was likely to be disabling.
Eleven studies evaluated the relationship between the severity of asthma and growth retardation. Overall, the studies did not find a consistent result. Six of the studies found no association between severity of asthma and growth retardation. No study found an association between mild asthma and growth retardation.
Studies were limited by poorly defined samples, limited data and analysis, missing data and, frequently, by the fact that severity of disease was measured by steroid treatment. These studies do not clearly provide evidence that a sustained decrease in linear growth velocity can be used as a marker of severity of asthma or whether a decrease in growth velocity is likely to be disabling. Future well-designed studies are needed.
There were six studies that evaluated the relationship between congenital heart disease and growth retardation. Many studies were limited by incomplete data and statistical analysis and some studies were limited because they excluded children with the most severe congenital cardiac defects. Given the limitations, the results do suggest that height and height velocity retardation is seen in children with severe congenital heart defects and may be a marker for more severe disease. Whether the decrease in height or height velocity in itself is disabling is not answered.
Eleven studies evaluated the relationship between growth retardation and control or severity of insulin dependent diabetes mellitus. Overall, the studies showed mixed results with five studies demonstrating a positive relationship between poor diabetes control or increased severity of disease and decreased growth velocity. Several studies associated growth deceleration with peripubertal onset of illness. Some studies were limited because they did not use a well-defined, objective measure, such as glycohemoglobin (Hgb A1c), to assess severity or control. Some studies were limited by unclear statistical analysis, lack of specific data included or summary results. These studies did not find clear evidence that a sustained decrease in linear growth velocity can be used as a marker of severity of diabetes or whether a decrease in linear growth velocity is in itself disabling. Further prospective, longitudinal studies of the linear growth of children with diabetes mellitus, using objective measure of control like Hgb A1c, are needed to clarify whether a decrease in linear growth velocity may be a marker for severity of disease.
There were three studies that evaluated the relationship between growth retardation and severity of anemia in ß-thalassemia. One study showed a relationship between increased severity of anemia and reduced height and one study showed a trend toward increased severity of disease and decreased growth. The studies were limited by incomplete data reporting and by inconsistent definitions of severity. These studies do not show clear evidence that a sustained decrease in linear growth velocity can be used as a marker of the severity of the disease. Prospective longitudinal cohort studies with clear definitions of severity (i.e. hemoglobin levels) and measurements of height velocity may answer the question.
There were three studies evaluating the relationship between growth retardation and the severity of inflammatory bowel disease. Two studies included only children with Crohn's disease. The other two studies included children with both Crohn's disease and ulcerative colitis. Disease severity was associated with height velocity among children with both Crohn's disease and ulcerative colitis; however, height was not significantly associated with disease severity in any study. There are no data presented to suggest that the process of growth failure is likely to be disabling. Further prospective longitudinal studies that include both larger numbers of patients with ulcerative colitis patients and Crohn's disease and that compare both to population standards and to each other may clarify whether growth retardation is a marker associated with severity of all inflammatory bowel diseases, or is related to one in particular.
Three studies evaluated the relationship between growth retardation and the subtypes or severity of juvenile rheumatoid arthritis. All studies indicated an association between decreased growth velocity and increased severity of the disease. One study noted that height velocity normalized after the first year of treatment. The studies were limited in two cases by excluding children with the most severe disease, by incomplete statistical analyses in one, and by poorly defined outcomes in another. With these caveats, the studies suggest that a decrease in linear growth velocity is associated with more severe disease and may serve as a marker of severity of the underlying disease. There are no data reported addressing the question of whether decreased growth velocity is in itself disabling. Future well-designed studies with broad inclusion criteria are needed to clarify the issue.
Ten studies evaluated the relationship between growth retardation and severity of chronic kidney disease. Eight of the studies found a positive relationship between increased severity of kidney failure and decreased height or height velocity. Single studies of sub-populations of children with autosomal recessive polycystic kidney disease (ARPKD) and very young children with chronic kidney disease found no association of disease severity with height velocity. There was conflicting evidence about the role of steroid use in causing growth retardation. Some studies were limited by using a severity marker other than glomerular filtration rate, by small sample sizes, or by incomplete data reporting. Overall, the studies suggest that a decrease in linear growth velocity is associated with the severity of the underlying disease but this finding was not universal. No data were available to assess if a decreased height velocity is in itself disabling. Additional prospective, longitudinal studies that evaluate whether a decrease in linear growth velocity can be used as a marker of severity of underlying kidney disease are needed.
There were two studies evaluating the relationship between growth retardation and progression to disease in HIV positive children. Both studies found that linear growth retardation is a marker for progression to active disease in HIV positive children and linear growth deceleration may precede the onset of symptoms of active disease. These studies were limited by incomplete data reporting and poorly defined methods, predictors and outcomes. Despite the limitations, the studies do indicate that a sustained decrease in linear growth velocity is a marker for progression from seropositive status to active disease. No data were included that assess whether a decreased linear growth velocity is in itself likely to be disabling. Larger, prospective, longitudinal studies of the relationship between decreasing linear growth velocity and progression of disease could confirm the usefulness of decreased linear growth velocity as a marker for increasing severity of disease.
Two studies evaluated the relationship between growth retardation and severity of atopic dermatitis. The studies reported conflicting results with one study reporting a positive association between increased severity and decreased height and the other study showing no association between increased severity and decreased height or height velocity. In the first study the more severely affected group had higher steroid use and some used systemic steroids. In the second study, those using systemic glucocorticoids were excluded from analysis. This study was also limited by a failure to report complete results and a failure to report statistical analyses. These studies do not clearly provide evidence that a sustained decrease in linear growth velocity is a marker for the severity of the underlying disease. No data were provided that look at whether the process of a decreasing linear growth velocity is in itself disabling. Further prospective longitudinal studies are needed to clarify whether growth velocity is affected by the severity of atopic dermatitis, or whether the apparent effect is related to steroid treatment.
There was only one study with 81 subjects that looked at the relationship between growth retardation and cerebral palsy. The study did not find a significant association between the type of cerebral palsy and decreased growth velocity but cognitive impairment and non-ambulatory status were associated with decreased growth velocity. This suggests that those more severely affected by both motor and non-motor neurological deficits have decreased growth velocity. This study was limited by the exclusion criteria, which likely excluded the most severely affected children. No data were presented to answer the question about whether the process of having a decreasing linear growth velocity is in itself disabling. Further prospective longitudinal studies of children with varying severity of cerebral palsy are needed to confirm whether a decreasing linear growth velocity is a marker for the severity of the underlying disorder.
There was only one study with 24 subjects that evaluated the association of growth retardation with the severity of sickle cell disease. That study found a positive association between severe sickle cell disease (measured by need for transfusions and the number of crises) and decreased height percentile compared to controls. The study was small and did not explicitly compare less severe sickle cell disease to more severe disease. The study also did not look at height velocity as a predictor of more severe disease. Further prospective longitudinal studies that compare larger numbers of patients with mild, moderate and severe sickle cell disease are needed to determine if a decreasing linear growth velocity can serve as a marker for the severity of the underlying disease.
There was only one study with 9 subjects that looked at the relationship between growth retardation and congenital adrenal hyperplasia. It did not find an association between number of escapes (more severe disease) and decreased growth velocity. The study was limited by its small size and by its reporting of results in graphic form only. There is not clear evidence that a decreasing linear growth velocity can be used as a marker for the underlying severity of congenital adrenal hyperplasia. No data were presented that look at whether the process of a decreasing linear growth velocity is in itself disabling. Further prospective longitudinal studies of larger numbers of patients with congenital adrenal hyperplasia are needed to answer the question of whether decreasing linear growth velocity can be used as a marker for severity of the underlying disease.
There were several limitations encountered in evaluating Questions 1 and 2. Very few studies looked specifically at disability as defined by SSA. Most studies in fact were looking at functional ability such as IQ or academic achievement. Such areas are focused on in the published literature because they allow for acquisition of data that can be compared to published norms. Results from such studies have to be extrapolated to determine if the children evaluated meet the SSA definition of disability. For example, one SSA criterion of disability includes acquiring and using information. A significantly reduced IQ in a child may lead to such limitations, but there is not a clear relationship between IQ and difficulties in acquiring and using information. Even those studies that evaluated functional impairment, such as those that evaluated inability or limitation of walking, do not necessarily correlate directly with SSA's definitions of disability. A further limitation to evaluation of intellectual function for Questions 1 and 2 is that many relevant articles excluded children with limited IQ. Similar biases due to eligibility criteria and sample choices limit the generalizability of many of the studies.
One limitation to evaluating Question 3 relates to difficulties in trying to correlate the severity of disease with decreasing growth velocity. Frequently a report that details height in a specific disorder does not directly correlate this with severity of disease. Also the way in which severity of disease was reported may vary between reports discussing the same disease. The same problem was seen with the reporting of growth data, which is given in a variety of different formats (e.g., one-time height, growth velocity, and standard deviation from the mean). This makes it more difficult to determine the overall validity of the results.
If the relationship between short stature and disability is to be elucidated, future research is needed. This is true for both short stature caused by medical conditions and skeletal dysplasia. Such research would be most beneficial if it focused on functional deficits (including disability, as defined by the Social Security Administration). Especially helpful would be studies that look at physical limitations related to short stature such as difficulties in using public restrooms due to the height of the toilet or difficulties in climbing stairs. Such studies may need to focus more on more extreme short stature (i.e. 5 to 7 standard deviations below the mean) to see a significant difference. Also studies on short children have tended to focus on functional ability and have not specifically evaluated functional deficits. For example, many studies evaluated intelligence in children with short stature but few have evaluated the proportion of short children who have mental retardation.
To properly answer the question of whether a decreasing growth velocity may indicate worsening severity of disease, prospective, longitudinal studies are needed. Studies should be prospective to minimize bias related to treatment, severity of disease and to allow accurate and consistent measurement of disease severity and growth. Longitudinal studies will allow accurate measurement of growth velocity and avoid using height as a proxy. Studies are also needed of children at various ages including puberty to account for different growth rates at different ages. The severity of disease in such studies needs to be clearly defined. In classifying children by severity of disease, researchers should clearly define the severity categories and use well-established definitions of severity. The severity definitions should not be confounded by treatment or management decisions. Finally other factors that affect height should be controlled for such as parental height, age and socioeconomic status. This is also why growth velocity is the best way to evaluate growth in an individual since it tends to remove the influence of some of these confounding factors, especially parental height.
| # | Search History | Results | Summary |
|---|---|---|---|
| 1 | disab$.af. | 66184 | Disability |
| 2 | Limitation$.af. | 45673 | |
| 3 | Handicap$.af. | 13104 | |
| 4 | Impair$.af. | 152795 | |
| 5 | 1 or 2 or 3 or 4 | 263105 | |
| 6 | exp bone diseases, developmental/ | 36107 | Height, growth disorders and short stature |
| 7 | exp growth disorders/ | 16301 | |
| 8 | exp body height/ | 18639 | |
| 9 | short stature.tw. | 3374 | |
| 10 | 6 or 7 or 8 or 9 | 68793 | |
| 11 | 5 and 10 | 3203 | Questions 1 & 2 |
| 12 | exp *bone diseases, developmental/ | 27528 | Linear growth and linear growth delay |
| 13 | (short stature or skeletal dysplasia).tw. | 3798 | |
| 14 | Growth velocity.tw. | 1257 | |
| 15 | Growth retardation.tw. | 8452 | |
| 16 | Growth delay.tw. | 1306 | |
| 17 | Growth restriction.tw. | 725 | |
| 18 | Height retardation.tw. | 16 | |
| 19 | (height adj6 restrict$).tw. | 54 | |
| 20 | linear velocity.tw. | 160 | |
| 21 | (height adj6 delay).tw. | 89 | |
| 22 | Length delay.tw. | 106 | |
| 23 | (length adj6 retardation).tw. | 145 | |
| 24 | exp growth disorders/ | 16301 | |
| 25 | 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24 | 51939 | |
| 26 | *fetal development/ | 6938 | Excluded diseases/conditions |
| 27 | *pregnancy/ | 21154 | |
| 28 | *facial bones/ | 3492 | |
| 29 | *facies/ | 103 | |
| 30 | *failure to thrive/ | 443 | |
| 31 | *thanatophoric dysplasia/ | 122 | |
| 32 | *fetal growth retardation/ | 3897 | |
| 33 | exp basal cell nevus syndrome/ | 536 | |
| 34 | exp craniofacial dysostosis/ | 3267 | |
| 35 | exp klippel-feil syndrome/ | 469 | |
| 36 | exp synostosis/ | 4073 | |
| 37 | exp funnel chest/ | 828 | |
| 38 | exp gigantism/ | 823 | |
| 39 | exp leg length inequality/ | 1670 | |
| 40 | exp marfan syndrome/ | 2697 | |
| 41 | exp fibrous dysplasia of bone/ | 2313 | |
| 42 | exp hyperostosis, cortical, congenital/ | 353 | |
| 43 | exp hyperostosis frontalis interna/ | 241 | |
| 44 | exp exostoses, multiple hereditary/ | 601 | |
| 45 | exp osteopetrosis/ | 1419 | |
| 46 | exp osteopoikilosis/ | 209 | |
| 47 | exp acquired hyperostosis syndrome/ | 37 | |
| 48 | exp platybasia/ | 278 | |
| 49 | 26 or 27 or 28 or 29 or 30 or 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38 or 39 or 40 or 41 or 42 or 43 or 44 or 45 or 46 or 47 or 48 | 54379 | |
| 50 | 25 not 49 | 32177 | Question 3 |
| 51 | 11 or 50 | 36731 | Questions 1, 2 & 3 |
| 52 | Case Report/ | 964105 | Exclude case reports |
| 53 | 51 not 52 | 22559 | |
| 54 | limit 53 to human | 18613 | Limit to humans and English language |
| 55 | limit 54 to English language | 14258 | |
| 56 | limit 55 to (newborn infant <birth to 1 month> or infant <1 to 23 months> or preschool child <2 to 5 years> or child <6 to 12 years> or adolescence <13 to 18 years>) | 9857 | Limit to children |
| 57 | 55 not 56 | 4401 | |
| 58 | limit 57 to (adult <19 to 44 years> or middle age <45 to 64 years> or “aged <65 and over>” or “aged, <80 and over>”) | 900 | |
| 59 | 55 not 58 | 13358 | |
| 60 | limit 59 to (addresses or bibliography or biography or comment or dictionary or directory or editorial or festschrift or interview or letter or news or periodical index) | 714 | |
| 61 | 59 not 60 | 12644 | |
| # | Search History | Results | Summary |
|---|---|---|---|
| 1 | exp growth | 203509 | Growth/Growth disorders |
| 2 | exp growth disorders | 16301 | |
| 3 | 1 or 2 | 215194 | |
| 4 | exp Heart diseases | 445916 | Growth & Heart disease |
| 5 | 3 and 4 | 9467 | |
| 6 | limit 5 to human, English, and children; Exclude main search results | 667 | |
| 7 | exp Arthritis, rtheumatpid | 44173 | Growth & Arthritis |
| 8 | 3 and 6 | 184 | |
| 9 | limit 8 to human, English, and children; Exclude main search results | 47 | |
| 10 | exp Asthma | 52692 | Growth & Asthma |
| 11 | 2 and 8 | 618 | |
| 12 | limit 11 to human, English, and children; Exclude main search results | 169 | |
| 13 | 6 ro 9 or 12 | 883 | Total |
| AAP | American Academy of Pediatrics |
| ACH | Achondroplasia |
| ADL | Activities of daily living |
| AHRQ | Agency for Healthcare Research and Quality |
| AIDS | Acquired immunodeficiency syndrome |
| ARC | AIDS-related complex |
| ARPKD | Autosomal recessive polycystic kidney disease |
| BAER | Brainstem auditory evoked responses |
| BAS | British Ability Scales |
| BASC | Behavior Assessment System for Children |
| BDI | Beck Depression Inventory |
| BSA | Body surface area |
| BSID | Bayley Scales of Infant Development |
| CARA | Chronic aspecific respiratory affection |
| CAS | Cognitive abilities score |
| CBCL | Child Behavior Checklist |
| CBPC | Child Behavior Problem Checklist |
| CGD | Constitutional growth delay |
| CHD | Congenital heart disease |
| CHF | Congestive heart failure |
| CHIPS | Children's Interpersonal Problem Solving Scale |
| CKD | Chronic kidney disease |
| CKF | Chronic kidney failure |
| CP | Cerebral palsy |
| CPQ | Children's Personality Questionnaire |
| DDST | Denver developmental screening test |
| Dept | Department |
| DM | Diabetes mellitus |
| EPC | Evidence-based Practice Center |
| ESRD | End-stage renal disease |
| FEV1/FVC | Forced expiratory volume in 1 second divided by forced vital capacity |
| FRNS | Focal relapsing nephrotic syndrome |
| FSGS | Focal segmental glomerular sclerosis |
| FSS | Familial short stature |
| FVC | Forced vital capacity |
| GFR | Glomerular filtration rate |
| GH | Growth hormone |
| GHb | Glycohemoglobin |
| GHD | Growth hormone deficiency |
| GVI | Growth velocity index |
| HANES | Hamburg Neuroticism Extraversion Scale |
| Hgb | Hemoglobin |
| Hgb A1c | Hemoglobin A1c (Glycosylated hemoglobin) |
| HIV | Human immunodeficiency virus |
| HRQOL | Health-related quality of life |
| IBD | Inflammatory bowel disease |
| IQ | Intelligence quotient |
| ISS | Isolated short stature |
| IUGR | Intrauterine growth retardation |
| JLO | judgment of line orientation |
| JRA | Juvenile rheumatoid arthritis |
| K-BIT | Kaufman-Brief Intelligence Test |
| KTEA | Kaufman Test of Educational Achievement |
| LPA | Little People of America |
| LPS | Structural Intelligence Test, in German |
| MES | Marburg Scales of Perceived Parental Behavior |
| MHD | Multiple hormone deficiency |
| min | Minutes |
| N&S | Nowicki and Strickland Locus of control scale |
| NCHS | National Center for Health Statistics |
| Neale | Neale analysis of reading ability, British edition |
| NS | Non-significant |
| OI | Osteogenesis imperfecta |
| ORNS | Occasional or no relapsing nephrotic syndrome |
| P CO2 | Carbon dioxide partial pressure |
| P O2 | Oxygen partial pressure |
| PEDI | Pediatric Evaluation of Disability Inventory |
| PIAT | Peabody Individual Achievement Test |
| PKD | Polycystic kidney disease |
| PPVT-R | Peabody Picture Vocabulary Test-Revised |
| RBQ | Rutter's Behavior Questionnaire |
| ROM | Range of motion |
| RR | Relative Risk |
| RSS | Russell-Silver Syndrome |
| RV | Residual volume |
| SB | Stanford-Binet Intelligence Scale |
| SD | Standard deviation |
| SDNS | Steroid dependent nephrotic syndrome |
| SDS | Standard deviation score |
| SEP | Somatosensory evoked potentials |
| SES | Socioeconomic status |
| SIT | Slosson Intelligence Test |
| SRNS | Steroid-resistant nephrotic syndrome |
| SSA | Social Security Administration |
| SSTAI | Spielberger State-Trait Anxiety Inventory Score |
| TS | Turner Syndrome |
| UC | Ulcerative colitis |
| VMI | Visual motor integration |
| VSD | Ventricular septal defect |
| WISC | Wechsler Intelligence Scale for Children |
| WRAT | Wide Range Achievement Test |
The Evidence-based Practice Center staff acknowledges the collaboration of the clinical experts who served on the EPC Technical Expert Panel. The EPC also acknowledges the contributions by those who acted as peer reviewers for the evidence report.
Joseph Lau, MD; EPC/Project Director
Ethan Balk, MD, MPH, Assistant Project Director and Project Leader, Short Stature
Cynthia Cole, MD, MPH, Coordinating Team Leader
Deirdre DeVine, M Litt, Project Manager
Priscilla Chew, MPH, Project Leader, Failure to Thrive
Kimberly Miller, BA, Research Assistant
Chenchen Wang, MD, MSc, Project Leader, Low Birth Weight
Evidence Review Teams, Tufts New England Medical Center
Very Low Birth Weight
Dr. Cynthia Cole, Project Coordinator and Team Leader
Drs. Geoffrey Binney, John Fiascone, James Hagadorn, and Chiwan Kim Patricia Casey, NNP
Short Stature
Dr. Patricia Wheeler, Team Leader
Drs. Barbara Shephard and Karen Bresnahan
Failure To Thrive
Dr. Ellen Perrin, Team Leader
Drs. Stephan Glicken, Nicholas Guerina, Kevin Petit, Robert Sege, MaryAnn Volpe, and Deborah Frank
James Perrin, MD, Pediatric Consultant to the EPC
Social Security Administration (SSA):
Science Partner: Dr. Paul Burgan, MD, PhD; Regina Connell, MS
Agency for Healthcare Research and Quality (AHRQ)
Marian James, PhD, Task Order Officer
Marilee Allen, MD (Very Low Birth Weight)
Professor
Neonatology, Department of Pediatrics
Johns Hopkins University
Baltimore, Maryland
Joseph Hersh, MD (Short Stature)
Louisville, Kentucky
Michael Farrell, MD (Failure to Thrive)
Chief of Staff
Childrens' Hospital Medical Center
Cincinnati, Ohio
Carla Herrerias, BS, MPH
Senior Health Policy Analyst
Department of Practice and Research
American Academy of Pediatrics
Elk Grove Village, Illinois
Disability Law Center, Inc.
Linda Landry, Esq.
Very Low Birth Weight
Deborah Campbell, MD
Hartsdale, New York
Warren N. Rosenfeld, MD
Department of Pediatrics
Winthrop University Hospital
Mineola, New York
Short Stature
Susan Rose, MD
Department of Endocrinology
Childrens' Hospital Medical Center of Cincinnati
Cincinnati, Ohio
Failure to Thrive
William Cochran, MD
Department of Pediatric GI/Nutrition
Geisinger Health System
Danville, Pennsylvania
A. Jay Cohen, MD
The Endocrine Clinic, PC
Memphis, Tennessee
David M. Brown, MD
Professor of Pediatrics
University of Minnesota
Minneapolis, Minnesota
Gilman Grave, MD
Chief, Endocrinology, Nutrition and Growth Branch
Center for Research for Mothers and Children
Bethesda, Maryland
Catherine Y. Spong, MD (for VLBW and Failure to Thrive)
Chief, Pregnancy and Perinatology Branch
Center for Research for Mothers and Children
Bethesda, Maryland
Tonse Raju, MD (for VLBW and Failure to Thrive)
Pregnancy and Perinatology Branch
Center for Research for Mothers and Children
Bethesda, Maryland
Denis Drotar, MD
Professor and Chief
Division of Behavioral Pediatrics and Psychology
Rainbow Babies and Childrens' Hospital
Cleveland, Ohio
Daniel Kessler, MD
Phoenix, Arizona
Free Full text in PMC]Free Full text in PMC]Free Full text in PMC]Free Full text in PMC]
