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COL1A1/2-Related Osteogenesis Imperfecta

Synonyms: Brittle Bone Disease, OI. Includes: Classic Non-Deforming OI with Blue Sclerae, Perinatally Lethal OI, Progressively Deforming OI, Common Variable OI with Normal Sclerae

, MD, , MS, CGC, and , MD.

Author Information
, MD
Executive Director, Marshfield Clinic Research Foundation
Marshfield, Wisconsin
, MS, CGC
Legacy Center for Maternal Fetal Medicine
Portland, Oregon
, MD
Medical College of Wisconsin
Milwaukee, Wisconsin

Initial Posting: ; Last Update: February 14, 2013.

Summary

Disease characteristics. COL1A1/2-related osteogenesis imperfecta (OI) is characterized by fractures with minimal or absent trauma, variable dentinogenesis imperfecta (DI), and, in adult years, hearing loss. The clinical features of COL1A1/2-related OI represent a continuum ranging from perinatal lethality to individuals with severe skeletal deformities, mobility impairments, and very short stature to nearly asymptomatic individuals with a mild predisposition to fractures, normal dentition, normal stature, and normal life span. Fractures can occur in any bone, but are most common in the extremities. DI is characterized by grey or brown teeth that may appear translucent and wear down and break easily. COL1A1/2-related OI has been classified into four types (I, II, III, and IV) based on clinical presentation and radiographic findings. This classification system can be helpful in providing information about prognosis and management for a given individual. The four OI types are now referred to as follows:

  • OI type I: classic non-deforming OI with blue sclerae
  • OI type II: perinatally lethal OI
  • OI type III: progressively deforming OI
  • OI type IV: common variable OI with normal sclerae

Diagnosis/testing. The diagnosis of COL1A1/2-related OI is based on:

  • Family history, a history of fractures, and characteristic physical findings;
  • Radiographic findings (fractures of varying ages and stages of healing, wormian bones, "codfish" vertebrae, and osteopenia); and
  • Molecular genetic testing of COL1A1 and COL1A2 and/or biochemical analysis of type 1 collagen.

Biochemical testing (i.e., analysis of the structure and quantity of type I collagen synthesized in vitro by cultured dermal fibroblasts) detects abnormalities in 98% of individuals with historically classified OI type II, about 90% with OI type I, about 84% with OI type III, and about 84% with OI type IV. Molecular genetic testing of COL1A1 and COL1A2 detects abnormalities in more than 90% of individuals with historically classified OI types I, II, III, or IV.

Management. Treatment of manifestations: Ideally, management is by a multidisciplinary team including specialists in the medical management of OI, orthopedics, rehabilitation medicine, pediatric dentistry, and otology/otolaryngology. Parents/other caregivers must practice safe handling techniques. Mainstays of treatment include: bracing of limbs; orthotics to stabilize lax joints; promotion of appropriate physical activity; muscle strengthening; pain management; and physical and occupational therapy to maximize bone stability, improve mobility, prevent contractures, and prevent head and spinal deformity. Mobility devices are used as needed. Fractures are treated with: intramedullary rodding when indicated to provide anatomic positioning of limbs; as short a period of immobility as is practical; small and lightweight casts; and physical therapy as soon as casts are removed. Progressive scoliosis in severe OI does not respond well to conservative or surgical management. Dental care strives to maintain both primary and permanent dentition, a functional bite or occlusion, optimal gingival health, and overall appearance. Conductive hearing loss may be improved with middle ear surgery; later-onset sensorineural hearing loss is treated in the same manner as it is when caused by other conditions.

Prevention of secondary complications: During general anesthesia proper positioning on the operating room table and use of cushioning such as egg crate foam can help avoid fractures.

Surveillance: Twice-yearly dental visits beginning in early childhood or even infancy for those with DI or at risk for DI. Hearing evaluation at three- to five-year intervals perhaps beginning as early as age five years until hearing loss is identified, then as indicated based on the nature and degree of hearing loss and associated interventions.

Therapies under investigation: The role of treatment with bisphosphonates in changing the natural history of OI is incompletely understood. The Cochrane database contains a detailed meta-analysis of available data and as of the most recent update, bisphosphonate therapy did not appear to reduce fracture incidence but it did impact bone density and adult height. Oral alendronate treatment for two years in children with OI significantly decreased bone turnover and increased spine areal bone mineral density (BMD) but was not associated with improved fracture outcomes. Similarly, risedronate increased BMD and reduced first and recurrent clinical fractures in children with OI. Furthermore, human growth hormone therapy as an adjunct to bisphosphonate therapy correlated with improved linear growth and increased BMD.

Genetic counseling. COL1A1/2-related OI is inherited in an autosomal dominant manner. The proportion of cases caused by a de novo COL1A1 or COL1A2 mutation varies by the severity of disease: approximately 60% of cases of classic non-deforming OI with blue sclerae or common variable OI with normal sclerae, virtually 100% of perinatally lethal OI, and close to 100% of progressively deforming OI are de novo. Gonadal mosaicism may be present in 3%-5% of cases. Each child of an individual with a dominantly inherited form of COL1A1/2-related OI has a 50% chance of inheriting the mutation and of developing some manifestations of OI. Prenatal testing in at-risk pregnancies can be performed by molecular genetic testing if the COL1A1 or COL1A2 mutation has been identified in an affected relative. Ultrasound examination performed in a center with experience in diagnosing OI can be valuable in the prenatal diagnosis of the lethal form and most severe forms prior to 20 weeks' gestation; milder forms may be detected later in pregnancy if fractures or deformities occur.

Diagnosis

COL1A1/2-related osteogenesis imperfecta (OI) is a group of disorders characterized by fractures with minimal or absent trauma, variable dentinogenesis imperfecta (DI), and late-onset hearing loss; however, it is now apparent that the clinical features of COL1A1/2-related OI represent a continuum ranging from perinatal lethality to near-absence of symptoms. The pathogenetic approach to osteogenesis imperfecta has changed with the recent identification of several genes which, when mutated, cause OI. Mutations in all of the recently identified genes (except for the gene which causes OI type V) cause recessively inherited OI. The clinical classification is distinct from the genetic diagnosis, as the recessively inherited forms typically present similarly to the more severe COL1A1/2-related perinatally lethal OI and progressively deforming OI. In time, this clinical classification will be revised; however, there is currently no clear consensus as to the clinical distinctions between the overlapping dominantly and recessively inherited phenotypes. The milder classic non-deforming OI and common variable OI with normal sclerae are caused by mutations in COL1A1 or COL1A2

The clinical diagnosis of COL1A1/2-related osteogenesis imperfecta (OI) depends on the presence of a number of features (see Table 1). No "diagnostic criteria" exist for types of OI. Features of OI include the following:

  • Fractures with minimal or no trauma in the absence of other factors, such as abuse or other known disorders of bone
  • Short stature or stature shorter than predicted based on stature of unaffected family members, often with bone deformity
  • Blue / grey sclera hue
  • Dentinogenesis imperfecta (DI)
  • Progressive, post-pubertal hearing loss
  • Ligamentous laxity and other signs of connective tissue abnormality
  • Family history of OI, usually consistent with autosomal dominant inheritance

Table 1. Clinical Features of COL1A1/2-Related Osteogenesis Imperfecta by Type

TypeInheritanceSeverityFracturesBone DeformityStatureDIScleraeHearing Loss
Classic non-deforming OI with blue scleraeADMildFew to 100UncommonNormal or slightly short for familyRareBluePresent in about 50%
Perinatally lethal OIADPerinatal lethalMultiple fracture of ribs, minimal calvarial mineralization, platyspondyly, marked compression of long bonesSevereSeverely short stature+Dark blue
Progressively deforming OI ADSevereThin ribs, platyspondyly, thin gracile bones with many fractures, "popcorn" epiphyses commonModerate to severeVery short+BlueFrequent
Common variable OI with normal scleraeADModerate to mildMultipleMild to moderateVariably short stature+/-Normal to greySome

Radiographic features of OI change with age. The major findings include the following (Table 2):

  • Fractures of varying ages and stages of healing, often of the long bones but may also involve ribs and skull. Metaphyseal fractures characteristic of child abuse can be seen in a small number of children with OI.
  • "Codfish" vertebrae, which are the consequence of spinal compression fractures, seen more commonly in the adult
  • Wormian bones, defined as "sutural bones which are 6 mm by 4 mm (in diameter) or larger, in excess of ten in number, with a tendency to arrangement in a mosaic pattern" [Cremin et al 1982]. Wormian bones are suggestive of but not pathognomic for OI.
  • Protrusio acetabuli in which the socket of the hip joint is too deep and the acetabulum bulges into the cavity of the pelvis causing intrapelvic protrusion of the acetabulum.
  • Osteopenia or osteoporosis detected by dual energy x-ray absorptiometry (DEXA). Bone density can be normal, especially in OI type I, as DEXA measures mineral content rather than collagen content [Deodhar & Woolf 1994, Paterson & Mole 1994, Cepollaro et al 1999, Lund et al 1999].

    Note: (1) A major determinant of bone density may be the individual’s ability to ambulate. (2) Bone density standards for children under age two years have been determined after sampling very small populations (often <10 persons), thus reliability is an issue (3) Bone density standards for children are based on height; corrections for short stature of severely affected individuals may need to be made. Bone density is not typically measured in children before age two years because of their inability to lie still, though this may be accomplished with patience in sleeping infants. It is not useful to compare bone density in individuals with OI to standards of individuals without OI, but it is useful to follow the bone density of an individual with OI over time.

Table 2. Radiographic Findings of COL1A1/2-Related Osteogenesis Imperfecta by Type

TypeSeveritySkullBackExtremitiesOther
Classic non-deforming OI with blue scleraeMildWormian bonesCodfish vertebrae (adults)Thin corticesOsteopenia
Perinatally lethal OIPerinatal lethalUndermineralization; plaques of calcificationPlatyspondylySeverely deformed; broad, crumpled, bent femursSmall beaded ribs; findings are pathognomonic
Progressively deforming OI SevereWormian bonesCodfish vertebrae; kyphoscoliosisFlared metaphyses ("popcorn"-like appearance [childhood]), bowing, thin corticesThin ribs, severe osteoporosis
Common variable OI with normal scleraeIntermediate± Wormian bonesCodfish vertebraeThin corticesProtrusio acetabuli in a subset

An algorithm for the diagnosis of OI has been published; see Basel & Steiner [2009], Figure 1.

Figure 1

Figure

Figure 1. Recommended testing algorithm for evaluation of osteogenesis imperfecta

Basel & Steiner [2009]. Reprinted with permission from Macmillan Publishers Ltd.

Testing

Biochemical

  • Serum concentrations of vitamin D, calcium, phosphorous, and alkaline phosphatase are typically normal; however, the latter may be elevated acutely in response to fracture.
  • Analysis of type 1 collagen synthesized in vitro by culturing dermal fibroblasts obtained from a small skin biopsy shows the structure and quantity of the collagen. The sensitivity of biochemical testing is approximately 90% in individuals with clinically confirmed OI [Wenstrup et al 1990; Byers PH, personal communication]. Biochemical analysis is helpful in separating individuals with quantitative defects (classic non-deforming OI) from those with qualitative defects (perinatally lethal OI, progressively deforming OI, and common variable OI with normal sclerae).

    The limitation of biochemical analysis is that it will not identify some quantitative defects of type 1 procollagen, variants that alter sequences in some coding regions of COL1A1/COL1A2 [van Dijk et al 2011].

Molecular Genetic Testing

Genes. COL1A1 and COL1A2 are the genes in which mutations are known to cause COL1A1- and COL1A2-related OI. They encode the two chains pro α1(I) and pro α2(I), respectively, of type I procollagen.

Clinical testing

Table 3. Summary of Molecular Genetic Testing Used in COL1A1/2-Related Osteogenesis Imperfecta

Gene 1% of COL1A1/COL1A2-Related OI Attributed to Mutations in This GeneTest MethodMutations Detected 2
COL1A1~5%-70% 3Sequence analysisSequence variants (>95%) 4, 5
Deletion / duplication analysis 6Exonic or whole-gene deletions (1%-2%) 7
COL1A2~5%-30 1Sequence analysisSequence variants (>95%) 4, 5
Deletion / duplication analysis 6Exonic or whole-gene deletions (1%-2%) 7

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. Byers P, personal communication

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5. Sequence analysis of COL1A1 and COL1A2 cDNA to detect mutations in the coding sequence and sequence analysis of COL1A1 and COL1A2 genomic DNA to detect mutations that alter either sequence or stability of mRNA identify close to 100% of mutations in these two genes.

6. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

7. van Dijk et al [2010] and Table A. Genes and Databases, HGMD

Testing Strategy for a Proband

To confirm/establish the diagnosis in a proband. An approach to the molecular diagnosis of OI has been published [van Dijk et al 2012] See Figure 2.

Figure 2

Figure

Figure 2. Preferred diagnostic flow in OI

The approach to diagnosis is designed to maximize the likelihood that causative variants will be identified in all affected individuals or assign those without causative variants to research pools. (more...)

The sensitivity for identifying COL1A1/2- related OI by molecular genetic testing is similar to the sensitivity of analysis of the structure and quantity of type 1 collagen in cultured fibroblasts from a skin biopsy, but current diagnostic algorithms favor molecular genetic testing as the first-line test for laboratory confirmation of COL1A1/2- related OI [van Dijk et al 2011].

In an individual with suspected OI, the suggested diagnostic work flow is as follows:

1.

Perform sequence analysis of COL1A1/2 (may require follow-up studies to determine whether a variant is causative).

2.

If no disease causing mutation is found by sequence analysis of COL1A1/2 then deletion/duplication analysis (which detects an additional 1-2% of disease causing mutations) can be pursued.

3.

If no causative COL1A1/2 variant is found, re-review clinical data. With clear evidence of moderate to severe OI, further analysis should proceed to screening for the non-COL1A1/2-related genetic disorders (see Differential Diagnosis).

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation(s) in the family.

Clinical Description

Natural History

The severity of COL1A1/2-related osteogenesis imperfecta (OI) ranges from perinatal lethality to individuals with severe skeletal deformities, mobility impairments, and very short stature to nearly asymptomatic individuals with a mild predisposition to fractures, normal stature, and normal life span. Although COL1A1/2-related OI comprises the largest proportion of OI, recent classifications based on molecular genetic findings have identified additional types of OI (see Differential Diagnosis)

COL1A1/2 related OI is classified into four types based on clinical presentation, radiographic features, family history, and natural history [Sillence et al 1979]. An update of the Sillence classification was recently proposed and has gained some acceptance (see Emery & Rimoin [2012]). Although this classification of COL1A1/2-related OI into types is helpful in providing information about prognosis and management of a given individual, the features of different types of COL1A1/2-related OI overlap and it is not always easy to categorize the extent of the clinical disorder. It is helpful to remember that the severity of clinical and radiographic features lies on a continuum and that the "types" are defined using characteristics that appear to form clinical "nodes." Interfamilial variability is apparent among individuals with the same OI type and intrafamilial variability is apparent among individuals with the same mutation. Nonetheless, it is reasonable to continue to think of COL1A1/2-related OI in terms of these types in order to provide information about the expected natural history of the disorder.

Classic non-deforming OI with blue sclerae (previously OI type I) is characterized by blue sclerae and normal stature. A small proportion of infants with OI type I have femoral bowing at birth. The first fractures may occur at birth or with diapering. More often, the first fractures occur when the infant begins to walk and, more importantly, to fall. Fractures generally occur at a rate of a few to several per year and then decrease in frequency after puberty. Fracture frequency often increases again in adulthood, especially in postmenopausal women and men beyond the fifth decade [Paterson et al 1984]. Affected individuals may have anywhere from a few fractures to more than 100, but the fractures usually heal normally with no resulting deformity.

Most affected individuals have normal or near normal stature, but may be shorter than other members of their families.

Joint hypermobility predisposes to a number of minor co-morbidities. The primary clinical concern is early-onset degenerative joint disease due to poor alignment of articular surfaces.

In their classification of OI, Sillence et al [1979] designated a subset of classic non-deforming OI with dentinogenesis imperfecta (DI) (OI type IB). In DI, morbidity results not from dental decay but rather from premature wearing down of the teeth, which interferes with chewing. DI can be a significant cosmetic concern. Dental eruption in classic non-deforming OI can sometimes occur early.

Progressive hearing loss occurs in about 50% of adults with classic non-deforming OI, beginning as a conductive hearing loss but with an additional sensorineural hearing loss component in time.

Perinatally lethal OI (previously OI type II). Abnormalities characteristic of perinatally lethal OI are evident at birth. Weight and length are small for gestational age. The sclerae are dark blue and connective tissue is extremely fragile. The skull is large for the body size and soft to palpation. Callus formation on the ribs may be palpable. Extremities are short and bowed. Hips are usually flexed and abducted in a "frog-leg" position. Although some fetuses with perinatally lethal die in utero or are spontaneously aborted, more typically infants die in the immediate perinatal period. More than 60% of affected infants die on the first day; 80% die within the first week; survival beyond one year is exceedingly rare and usually involves intensive support such as continuous assisted ventilation [Byers et al 1988]. Death usually results from pulmonary insufficiency related to the small thorax, rib fractures, or flail chest because of lack of stable ribs. Those who survive the first few days of life may not be able to take in sufficient calories because of respiratory distress.

Histologic evaluation of bone from infants with perinatally lethal OI shows marked reduction in collagen in secondary trabeculae and cortical bone [Horton et al 1980]. Cortical bone is hypercellular with large osteocytes. Trabeculae contain woven bone with large immature osteoblasts [Cole et al 1992, Cole & Dalgleish 1995].

Progressively deforming OI (previously OI type III). The diagnosis of progressively deforming OI is readily apparent at birth. Fractures in the newborn period, simply with handling of the infant, are common. In some affected infants, the number and severity of rib fractures lead to death from pulmonary failure in the first few weeks or months of life.

Infants who survive this period generally fare well, although most do not walk without assistance and usually use a wheel chair or other assistance for mobility because of severe bone fragility and marked bone deformity. Affected individuals have as many as 200 fractures and progressive deformity even in the absence of fracture. Progressively deforming OI is often difficult to manage orthopedically, even with intramedullary rod placement.

Growth is extremely slow and adults with progressively deforming OI are among the shortest individuals known, with some having adult stature of less than one meter (three feet).

Intellect is normal unless there have been intracerebral hemorrhages (extremely rare and apparently isolated to a particular genotype). Faqeih et al [2009] published a report identifying increased risk for intracranial hemorrhage in a “small number” of individuals who were identified to have mutations affecting exon 49 of COL1A2, which codes for the most carboxy-terminal part of the triple-helical domain of the collagen type I alpha 2 chain. They concluded that this mutation appeared to increase the risk for abnormal limb development and intracranial bleeding.

Even within progressively deforming OI, considerable heterogeneity is observed at the clinical level. Some individuals have normal-appearing teeth and facial appearance while others have DI and a large head and enlarged ventricles that reflect the soft calvarium. Relative macrocephaly and barrel chest deformity are observed. Usually sclerae are blue in infancy but lighten with age. Hearing loss generally begins in the teenage years. As molecular testing of this subgroup further differentiates those with COL1A1/2-related OI from the recessive forms, the clinical profile of this heterogeneous group will become more refined.

Basilar impression, an abnormality of the craniovertebral junction caused by descent of the skull on the cervical spine, is common. Basilar impression is characterized by invagination of the margins of the foramen magnum upward into the skull, resulting in protrusion of the odontoid process into the foramen magnum. Basilar impression may progress to brain stem compression, obstructive hydrocephalus, or syringomyelia because of direct mechanical blockage of normal CSF flow [Charnas & Marini 1993, Sillence 1994, Hayes et al 1999]. Symptoms of basilar impression become apparent with neck flexion. Findings include posterior skull pain, C2 sensory deficit, tingling in the fourth and fifth digits, and numbness in the medial forearm. When swimming, affected individuals may perceive that water temperature differs below and above the umbilicus. Lhermitte's sign (tingling on neck flexion) can be demonstrated at any stage. Basilar impression can cause headache with coughing, trigeminal neuralgia, loss of function of the extremities, or parasthesias. At its most severe levels of involvement, sleep apnea and death can occur.

Common variable OI with normal sclerae (previously OI type IV) is characterized by mild short stature, DI, adult-onset hearing loss, and normal-to-grey sclerae. This is the most variable form of OI, ranging in severity from moderately severe to so mild that it may be difficult to make the diagnosis.

Stature is variable and may vary markedly within the family. DI is common but may be mild. Sclerae are typically light blue or gray at birth but quickly lighten to near normal. Hearing loss occurs in some. Basilar impression can occur.

Other Considerations

Facial features. Infants and children with OI are often described as having a triangular-shaped face. The skull is relatively large compared to body size.

Other skeletal problems. Individuals with OI may also have scoliosis, early onset arthritis, non- inflammatory arthralgias and myofascial pain.

Skin. Easy bruising is a frequent observation in OI. This is believed to be caused by microvascular fragility and poor microstructural support of the connective tissues.

Hearing loss. Mixed conductive and sensorineural hearing loss afflicts the majority of adults with OI. Childhood onset hearing loss affects approximately 7% of affected children between ages five and nine years; progressive postpubertal hearing loss is more typical. The initial conductive hearing loss results from fractures of the bones of the middle ear with contracture and scarring of the incus. With age, sensorineural hearing loss compounds the preexisting conductive element. Fixation of the stapes is not unlike otosclerosis and surgical techniques such as stapedotomy used to treat otosclerosis have shown similar success in treating hearing loss in OI [Van der Rijt & Cremers 2003, Kuurila et al 2004, Doi et al 2007]. Bisphosphonate therapy has not been shown to influence hearing loss.

Gastrointestinal. Although complaints of constipation are common in adults with OI who are mobile in wheelchairs, it is not clear if this is a complication of OI itself or of the mode of transport. Bowel obstruction can occur as a result of protrusio acetabuli [Lee et al 1995], but appears to be uncommon.

Cardiovascular. Mitral valve prolapse and aortic dilatation have been reported [McKusick 1972]. Aortic and mitral regurgitation have also been reported [Stein & Kloster 1977, Hortop et al 1986, Vetter et al 1989]. A minority of individuals with OI have a slightly larger than normal aortic root diameter, but the risk of progression or dissection is not increased [Hortop et al 1986]. A recent case report and literature review presented six documented cases to date of individuals who have OI and developed an aortic dissection [McNeeley et al 2012]. Both arterial and/or aortic dissection have been reported in OI; it remains unclear if they occur more commonly in individuals with OI than in the general population.

Development. Cognition is expected to be normal but gross motor development may be hindered by joint hypermobility and progressive deformity due to recurrent fractures.

Functional limitations. Individuals with OI may experience other functional limitations, although these will be highly dependent on the specific physical manifestations of OI.

Life expectancy. The severely affected neonates with perinatally lethal OI typically do not survive, with a significant proportion of infants dying within the first 48 hours. Aggressive life support can prolong survival but ultimately the most severe forms remain perinatally lethal. Life expectancy for classic non-deforming OI and common variable OI is normal. Progressively deforming OI is highly variable and life expectancy may be shortened by the presence of severe kyphoscoliosis with attendant restrictive pulmonary disease resulting in cardiac insufficiency.

Pregnancy. Fertility is normal in OI. Pregnancy in women with OI, especially those with progressively deforming OI, can be complicated because of a small pelvis, which may necessitate delivery by cesarean section. The mode of delivery of infants with OI has been examined to determine if the frequency of complications is higher with vaginal or cesarean section delivery. No difference in the frequency of complications was found. A higher than expected frequency of non-vertex presentations has been noted [Cubert et al 2001]. The role of pregnancy in later fractures, loss of bone mineralization, progression of hearing loss, or any other physical consideration has not been examined in detail.

For most women who have OI, pregnancy is uncomplicated. Joint laxity may increase, as it does with unaffected women, and reduce mobility in small, moderately affected women. Bleeding is probably not more common than usual and complications of vaginal tearing during delivery are not common. Women with OI who are very small require pre-term cesarean section because of respiratory compromise. It is uncertain whether post-partum pelvic relaxation is more common than usual.

Genotype-Phenotype Correlations

In general a clear genotype-phenotype correlation does not exist. General rules for genotype phenotype correlations in COL1A1/2-related OI have been published [Ben Amor et al 2011], but there are exceptions to these rules. It is important to keep these exceptions in mind in providing genetic counseling, particularly in the prenatal setting. Genotyping can be helpful in distinguishing classic non-deforming OI from all other types of OI.

The most common type of COL1 mutation in OI affects the triple helix domain of the COL1A1/2 chains. Glycine to serine substitutions may lead to a more severe phenotype in COL1A1 than a similar change in COL1A2. Substitutions by arginine, aspartate, glutamate, and valine beyond the first 200 amino acid residues of COL1A1 are usually lethal but may have a variable outcome in COL1A2 [Ben Amor et al 2011].

Classic non-deforming OI almost always results from a mutation in one COL1A1 allele that introduces premature termination codons and decreases the stability of mRNA. These mutations may occur by codon changes, by frame shifts, and by splice mutations that result in use of cryptic splice sites and frame shifts. The type I collagen molecule contains two pro α1(I) chains and a single α2(I) chain. If the number of available pro α1(I) chains decreases, the amount of the trimer manufactured is diminished because no more than one pro α2(I) chain can be accommodated per molecule.

Perinatally lethal OI, progressively deforming OI, and common variable OI all result from mutations that alter the structure of either pro α1(I) or pro α2(I) chains. This causes a dominant negative effect whereby the abnormal protein is integrated into the triple helix and collagen fibril, which in turn undergoes continual remodeling, thus resulting in significantly compromised structural integrity of the bone matrix.

The most common mutations result in substitution of another amino acid for glycine in the triple helical domain of either chain; serine, arginine, cysteine, and tryptophan result from substitutions in the first position of the glycine codon and alanine, valine, glutamic acid, and aspartic acid result from substitutions in the second position of the glycine codon.

  • Substitutions in the pro α1(I) chain by arginine, valine, glutamic acid, aspartic acid, and tryptophan are almost always lethal if they occur in the carboxyl-terminal 70% of the triple helix, and have a non-lethal but still moderately severe phenotype if they occur in the remainder of the chain.
  • For the smaller side-chain residues (serine, alanine, and cysteine), the phenotypes are more variable and appear to reflect some characteristics of the stability profile of the triple helix that are not yet fully recognized.
  • Much more variability occurs with mutations that affect glycine residues in the pro α 2(I) chain, even with the large side-chain residues; therefore, it is more difficult to determine the genotype-phenotype relationship.

The other common mutations affect splice sites. Mutations that lead to exon skipping in the pro α1(I) chain beyond exon 14 and in the pro α2(I) chain beyond exon 25 are generally lethal. The phenotypes resulting from mutations in the upstream region are more variable and may lead to significant joint hypermobility.

A relatively small number of mutations that alter amino acid sequences in the carboxyl-terminal regions of both chains have been identified. These domains are used for chain association and mutations have the capacity to destroy this property or lead to abnormalities in chain association. The phenotypic effects of mutations that affect this domain appear to be milder when they result in exclusion rather than inclusion of the chain.

Somatic mosaicism for dominant mutations has been recognized in perinatally lethal OI, progressively deforming OI, and common variable OI. The phenotype of the individual with somatic mosaicism can range from no identifiable characteristics of OI to one of the mild forms.

  • Individuals with somatic mosaicism for mutations that result in non-lethal forms of OI generally have no phenotypic features of OI, even when the mutation is present in a majority of somatic cells.
  • Somatic mosaicism for mutations that result in lethal OI can produce a mild OI phenotype if the mutation is present in the majority of somatic cells; otherwise, the mosaicism is generally asymptomatic.

Penetrance

The penetrance in individuals heterozygous for a COL1A1 or COL1A2 mutation is 100%, although expression may vary considerably, even in the same family.

Nomenclature

Previously used nomenclature:

  • Classic non-deforming OI with blue sclerae: osteogenesis imperfecta type I
  • Perinatally lethal OI: osteogenesis imperfecta type II
  • Progressively deforming OI: osteogenesisi type III
  • Common variable OI with normal sclerae: osteogenesis imperfecta type IV

The classification scheme of "OI congenita" and "OI tarda" was discarded because fractures at birth can be noted in mild OI and infants with severe OI may not have fractures at birth.

In classifications of genetic conditions, OI may be considered a skeletal dysplasia, a connective tissue disorder, a disorder of collagen or extracellular matrix, or a disorder of bone fragility.

Prevalence

Considering all types, OI has a prevalence of approximately 6-7:100,000. The two mildest forms, classic non-deforming OI and common variable OI, account for considerably more than half of all OI. OI is found in all racial and ethnic groups. The most recent estimates of prevalence come from Finland, where OI is thought to affect about 1:15,000 individuals [Kuurila et al 2002]. If the same prevalence is assumed for the US, an estimated 18,000 people in the US would be affected. The incidence of the various subtypes includes all causes of OI, both-collagen related and the autosomal recessive subtypes.

  • Classic non-deforming OI has a prevalence of approximately 3-4:100,000. Sillence et al [1979] reported an incidence in Australia of 3.5 in 100,000.
  • Perinatally lethal OI has an incidence of about 1-2:100,000. Sillence et al [1979] reported an incidence in Australia of 1.6 per 100,000, translating to an approximate prevalence of 1:20,000 in those who survive early-childhood mortality. Perinatally lethal OI is often not considered in prevalence data because of early lethality. Increasingly, perinatally lethal OI is recognized in utero as a consequence of early screening by ultrasound examination with resultant elective termination of pregnancy. This has resulted in a reduced incidence in affected live births in developed countries.
  • Progressively deforming OI has a prevalence of 1-2:100,000. Sillence et al [1979] reported an incidence in Australia of 1.6 per 100,000 for progressively deforming OI.
  • Sillence et al [1979] believed common variable OI to be uncommon. Since then it has been recognized to be a relatively common form of OI, probably about as common as classic non-deforming OI.

Differential Diagnosis

COL1A1/2-Related Osteogenesis Imperfecta (OI)

The primary differential diagnosis for individuals with features of COL1A1/2-related OI are autosomal recessive subtypes of OI and those subtypes of OI in which specific mutations have not yet been identified. Tables 4 and 5 summarize the clinical and radiographic features of these subtypes of OI.

Table 4. Clinical Features of OI by Type

Type 1InheritanceSeverityFracturesBone DeformityStatureDIScleraeHearing Loss
OI with calcification in interosseous membranesADModerateMultiple with hypertrophic callusModerateVariableNoNormalNo
OI type VIUncertainModerateMultipleRhizomelic shorteningMild short statureNoNormalNo
OI types VII-XIARSevere to moderateMultipleYesvariableNoNormalNo

1. Previous nomenclature for type is used.

Table 5. Radiographic Findings of Osteogenesis Imperfecta by Type

Type 1SeveritySkullBackExtremitiesOther
OI with calcification in interosseous membranesIntermediate?Wormian bones?Hypertrophic callus, usually of the femurs; mineralization of the interosseus membrane in the forearm
OI type VIIntermediate?Wormian bones?Similar to common variable OI
OI types VII-XISevere to intermediate?Wormian bones?Similar to perinatally lethal OI and progressively deforming OIRhizomelic shortening

1. Previous nomenclature for type is used.

Histomorphometric evaluation of iliac crest bone from individuals with OI with calcification in interosseous membranes, type VI, and type VII OI shows maintained lamellar structure, reduced cortical width and cancellous bone volume, and increased bone remodeling [Rauch et al 2000]. The distinction of OI type VI from common variable OI and OI with calcification in interosseous membranes rests in part on a characteristic "fish scale" appearance under polarized light.

OI with calcification in interosseous membranes (previously OI type V). This group was initially thought to have either progressively severe OI or common variable OI because of short stature and fractures. Sclerae were generally white. Two features distinguish OI with calcification in interosseous membranes:

  • Striking hypertrophic callus formation, usually at the site of fractures and often in the femoral shaft; and
  • Calcification of the interosseous membrane between the ulna and the radius that leads to the inability to fully supinate and pronate the forearm

OI with calcification in interosseous membranes accounts for about 5% of OI. OI with calcification in interosseous membranes has recently been found to be caused by mutations in the 5’ UTR of IFITM5.

OI type VI. The clinical features of OI type VI are similar to those of common variable OI. The defining features of OI with calcification in interosseous membranes are absent. OI type VI accounts for about 5% of OI. Mutations in SERPINF1 are believed to be causative.

OI type VII is distinguished by rhizomelic shortening of all limbs. OI type VII has been found to date only in a Native Canadian population. It is inherited in an autosomal recessive manner. OI type VII maps to a 4.5-Mb region on the short arm of chromosome 3. Mutations in CRTAP are causative

OI type VIII is a lethal/severe OI with a phenotype that overlaps that of perinatally lethal OI or progressively deforming OI with severe osteoporosis, shortened long bones, and a soft skull with wide open fontanel. However, individuals with OI type VIII typically have white sclerae, a round face, and a short barrel-shaped chest. Mutations in LEPRE1 are causative.

OI type IX is an autosomal recessive, severe form of OI. Mutations in PPIB are causative.

OI type X is an autosomal recessive form of OI characterized by multiple bone deformities and fractures, generalized osteopenia, dentinogenesis imperfecta, and blue sclerae. Mutations in SERPINH1 are causative.

OI type XI is an autosomal recessive form of OI. Affected individuals may have joint contractures. Mutations in FKBP10 can cause OI type XI.

All Forms of OI

The differential diagnosis of OI depends largely on the age at which the individual is assessed [Plotkin 2004]. Clinical features that help to differentiate OI from other conditions include characteristic triangular facies, blue sclerae, joint hypermobility, dental abnormalities, and, in adults, hearing loss.

In Utero

Early prenatal ultrasound examination or radiographic findings may lead to a consideration of hypophosphatasia, thanatophoric dysplasia, campomelic dysplasia, and achondrogenesis as well as perinatally lethal OI. In some cases, either biochemical or molecular testing can be a useful adjunct.

Hypophosphatasia is characterized by defective mineralization of bone and/or teeth in the presence of low activity of serum and bone alkaline phosphatase. Clinical features range from stillbirth without mineralized bone at the severe end to pathologic fractures of the lower extremities in later adulthood at the mild end. At least six clinical forms are currently recognized based on age at diagnosis and severity of features, including:

  • Perinatal (lethal) hypophosphatasia characterized by respiratory insufficiency and hypercalcemia;
  • Perinatal (benign) hypophosphatasia with prenatal skeletal manifestations that slowly resolve into the milder childhood or adult form;
  • Infantile hypophosphatasia with onset between birth and age six months of rickets without elevated serum alkaline phosphatase activity;
  • Childhood hypophosphatasia that ranges from low bone mineral density for age with unexplained fractures to rickets;
  • Adult hypophosphatasia characterized by early loss of adult dentition and stress fractures and pseudofractures of the lower extremities in middle age; and
  • Odontohypophosphatasia characterized by premature exfoliation of primary teeth and/or severe dental caries as an isolated finding or as part of the above forms of hypophosphatasia.

Recurrence of perinatal and infantile hypophosphatasia may reliably be identified by prenatal ultrasound examination. Undermineralization, small thoracic cavity, shortened long bones, and bowing are typical features of autosomal recessive and severe hypophosphatasia. Long bone bowing has been reported prenatally in affected sibs and in children of individuals with childhood or adult hypophosphatasia, but the finding is not diagnostic of hypophosphatasia.

Thanatophoric dysplasia is a neonatal lethal short-limbed dwarfing condition. Ultrasound findings in the first trimester include shortening of the long bones, possibly visible as early as 12-14 weeks' gestation; in a few case reports, increased nuchal translucency and/or reverse flow in the ductus venosus have been observed. In the second and third trimester, ultrasound shows growth deficiency with limb length below the fifth centile recognizable by 20 weeks' gestation, well-ossified spine and skull, platyspondyly, ventriculomegaly, narrow chest cavity with short ribs, polyhydramnios, and bowed femurs (TD type I), cloverleaf skull (kleeblattschaedel) (often in TD type II; occasionally in TD type I) and/or relative macrocephaly. Up to 99% of mutations causing thanatophoric dysplasia type I and more than 99% of mutations causing thanatophoric dysplasia type II can be identified through molecular genetic testing of FGFR3.

Campomelic dysplasia (CD) is a skeletal dysplasia characterized by distinctive facies, Pierre Robin sequence with cleft palate, shortening and bowing of long bones, and club feet. Other findings include laryngotracheomalacia with respiratory compromise and ambiguous genitalia or normal female external genitalia in most individuals with a 46,XY karyotype. Many affected infants die in the neonatal period; additional problems identified in long-term survivors include short stature, cervical spine instability with cord compression, progressive scoliosis, and hearing impairment.

Prenatal ultrasound examination may identify skeletal findings such as increased nuchal translucency, micrognathia, short bowed limbs, and hypoplastic scapulae that raise the possibility of CD in a fetus not known to be at increased risk.

Achondrogenesis type 1B includes extremely short limbs with short fingers and toes, hypoplasia of the thorax, protuberant abdomen, and hydropic fetal appearance caused by the abundance of soft tissue relative to the short skeleton. The face is flat, the neck is short, and the soft tissue of the neck may be thickened. SLC26A2 is the only gene known to be associated with this disorder.

Infancy and Childhood

Non-accidental trauma (child abuse). OI needs to be distinguished from child physical abuse/non-accidental trauma. The prevalence of physical abuse is much greater than the prevalence of OI, and on rare occasion it can occur in a child with OI. Patient history, family history, physical examination, radiographic imaging, and the clinical course all contribute to the distinction of OI from child abuse. The overlap in clinical features includes multiple or recurrent fractures, fractures that do not match the history of trauma, and the finding of fractures of varying ages and at different stages of healing [Carty 1988, Ablin et al 1990, Steiner et al 1996, Ablin & Sane 1997, Marlowe et al 2002].

The continued occurrence of fractures in a child who has been removed from a possibly abusive situation lends support to the possibility of OI. Metaphyseal and rib fractures, thought to be virtually pathognomonic for child abuse, can occur in OI. The presence or absence of blue sclerae is unreliable in distinguishing OI from child abuse because blue sclerae are often found in unaffected normal infants until about age 18 months; children with OI type IV may not have blue sclerae.

Family history is often unrevealing; families suspected of possible child abuse often provide an unverified family history of frequent fractures; conversely, the family history of individuals with OI often does not reveal any other affected individuals because of a de novo mutation in the proband or the presence of a mild phenotype in relatives.

Laboratory testing (biochemical studies or molecular genetic testing of COL1A1 and COL1A2) often is not needed, and in some cases the time required to perform such testing can delay proper disposition of child abuse cases [Steiner et al 1996]. Marlowe and colleagues suggest: “Given the inability to identify all children with OI by clinical examination in situations of suspected NAI, laboratory testing for OI (and other genetic predispositions for fractures) is a valuable adjunct in discerning the basis for fractures and may identify a small group of children with previously undiagnosed OI” [Marlowe et al 2002].

Bruck syndrome (OMIM 259450) [Viljoen et al 1989, McPherson & Clemens 1997] is an autosomal recessive condition characterized by bone fragility, congenital joint contractures, clubfeet, normal or blue sclerae, and wormian bones. Some cases result from defects in the lysyl hydroxylase that hydroxylates the amino-terminal lysyl residues involved in crosslink formation [Bank et al 1999]. More recently, investigators have identified mutations in additional genes as causative of Bruck syndrome, and there is significant overlap in both the clinical features and the genetic causes of Bruck syndrome and OI.

Osteoporosis pseudoglioma syndrome (OMIM 259770) includes bone fragility and fractures, other skeletal deformities, pseudoglioma with blindness in infancy, and other anomalies. It is caused by mutations in the gene encoding the lipoprotein receptor-related protein 5 [Gong et al 1996, Gong et al 2001].

Cole-Carpenter syndrome (OMIM 112240) is characterized by bone deformities, multiple fractures, ocular proptosis, shallow orbits, orbital craniosynostosis, frontal bossing, and hydrocephalus [Cole & Carpenter 1987].

Hadju-Cheney syndrome (OMIM 102500) is characterized by short stature, failure to thrive, conductive hearing loss, dysmorphic features, early tooth loss, genitourinary anomalies, osteopenia, pathologic fractures, wormian bones, failure of suture ossification, basilar impression, vertebral abnormalities, kyphoscoliosis, cervical instability, joint laxity, dislocation of the radial head, long bowed fibulae, pseudoclubbing, short distal digits, acroosteolysis, and hirsutism.

Gerodermia osteodysplastica (OMIM 231070) is characterized by dwarfism, lax skin, osteoporosis, wormian bones, fractures, vertebral compression, dysmorphic facies.

Idiopathic juvenile osteoporosis (IJO) typically presents in pre-adolescents with fractures and osteoporosis. The fracture susceptibility and osteoporosis usually resolve spontaneously with puberty. The etiology of IJO is unknown.

Dentiogenesis imperfecta. DI can occur separately from OI as an isolated familial condition as a result of mutations in DSPP on chromosome 4 [Rajpar et al 2002].

Other. Levin et al [1985] reported three families with apparent OI who had unusual skeletal lesions including multilocular radiolucent and radiopaque lesions of the maxilla and mandible (OMIM 166260). Coarse trabeculae and diffuse osteopenia were also noted. Jones & Baughman [1993] reported multiple idiopathic mandibular bone cysts in an individual with OI. Nishimura et al [1996] reported a fragile bone syndrome in two individuals with craniognathic fibroosseous lesions and abnormal remodeling of the tubular bones.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with COL1A1/2-related osteogenesis imperfecta (OI), the following evaluations are recommended:

  • Physical examination to assess deformities and presence of joint laxity
  • Hearing assessed through formal audiology
  • Screening for basilar impression, best performed by CT and/or MRI scanning with views across the base of the skull. There is no universal agreement on when screening for basilar impression should be done; currently, it is recommended on the basis of concerning signs or symptoms on annual physical examination or on reported symptoms by the affected individual.
  • Cervical spine flexion and extension radiographs, obtained when children are able to cooperate with the examination or prior to participating in sporting activities in more mildly affected individuals
  • Dental evaluation by age two to three years for all children with OI and at the time that teeth erupt in those with DI or at risk for DI
  • Medical genetics consultation

Treatment of Manifestations

Management focuses on supportive therapy to minimize fractures and maximize function, minimize disability, foster independence, and maintain overall health [Marini & Gerber 1997]. Ideally, OI is managed by a multidisciplinary team including specialists in the medical management of OI, orthopedics, rehabilitation medicine, pediatric dentistry, and otology/otolaryngology.

Supportive therapy is individualized depending on the severity, the degree of impairment, and the age of the affected individual. Considerable support from medical personnel is generally required by parents caring for infants with perinatally lethal OI.

Physical medicine treatment

  • Parents and other caregivers should be instructed in safe handling techniques. These are mostly common sense practices in order to relieve stress on a single point. For example: lift an affected infant by bracing the torso, neck and lower body; avoid any situation where increased pressure is placed on a single point on any long bone; when assisting an affected child in standing up, do not pull excessively on an extended arm but bend down and brace a greater surface area (such as placing a hand behind the back and pulling gently from the front (using the arm) while applying pressure from the rear); avoid sudden acceleration/deceleration movements; and avoid throwing a child in the air. Older children should not ride on amusement park rides. Caregivers should avoid recreating the circumstances of a fracture, as it is likely to happen again.
  • The use of bracing to try to stabilize progressively deforming limbs depends in part on the subtype of OI. Progressively deforming OI has proven to be progressive despite external or internal bracing. The use of internal rods or braces to support and stabilize deforming limbs is more successful in the milder subtypes of OI and is guided by the expertise of the managing orthopedist.
  • Orthotics to support ankle instability are used in toddlers with delayed walking secondary to joint hypermobility and in other affected individuals who suffer recurrent subluxations of their ankle joints.
  • Physical activity serves a number of purposes. It provides gravitational stressors required for bone growth and remodeling. The muscles supporting joints are strengthened by activity and as an overall benefit, improved joint stability aides in overall well-being as pain levels are reduced and mobility is increased. Physical activity can be self-directed or coordinated through the services of a physical therapist. Each affected individual’s needs are unique and thus both physical and occupational therapy should be initiated for increased stability of bone, improved mobility, prevention of contractures, prevention of head and spinal deformity, aerobic fitness, and muscle strengthening
  • Mobility devices, such as scooters and chairs for children, and modified automobiles for adults should be considered.
  • Some individuals with OI experience chronic daily pain associated with both fractures and non-specific myofascial pain associated with the generalized connective tissue disorder. Pain management plays an important role in the management of OI. Some affected individuals do well with minimal analgesics, but many benefit from a multidisciplinary pain management service. Analgesics can be used to control pain from fractures.

Orthopedic treatment. Fractures are treated as they would be in unaffected children and adults with attention to the following:

  • The period of immobility in children with OI should be shortened as much as is practical.
  • Casts should be small and lightweight.
  • Physical therapy should begin as soon as the cast is removed to promote mobility and enhance muscle strength and bone mass.
  • At this time, intramedullary rodding remains a mainstay of orthopedic care to provide anatomic positioning of limbs that permits more normal function.

Progressive spinal deformities are particularly difficult to treat because of the poor quality of bone in severely affected children. Progressive scoliosis in severe OI does not respond to conservative management and response to surgical intervention may be limited.

Pharmacologic treatment. Bisphosphonates, analogs of pyrophosphate that decrease bone resorption, are being evaluated in both uncontrolled and controlled trials to assess the extent to which they can increase bone mass and bone strength and improve function in children with OI. These studies are still ongoing. Bisphosphonates have been used most extensively in severely affected children with OI; they may be useful in adults with OI as well [Adami et al 2003].

The role of treatment with bisphosphonates in changing the natural history of OI is incompletely understood. The Cochrane Collaboration is an international network which assembles reviews on various management strategies based on randomized controlled clinical trials within its database in order to improve the practice of evidence-based medicine. As of the Cochrane Collaboration’s most recent update of the OI review, bisphosphonate therapy did not appear to reduce fracture incidence but it did impact bone density and adult height [Phillipi et al 2008; click here for full text].

An open-label trial of cyclical intravenous pamidronate (bisphosphonate) was reported by Glorieux et al [1998], and the effects of relatively long-term use in adults by Astrom & Soderhall [2002] and Zeitlin et al [2003]. Falk et al [2003] replicated the study of Glorieux et al [1998] in children over age 22 months, but did report one child with fracture non-union following treatment with pamidronate. No randomized placebo-controlled clinical trial of pamidronate has been published. Bisphosphonate treatment has produced improvements in bone histomorphometry, increased bone mineral density (BMD), decreased some biochemical markers of bone resorption, and possibly reduced fracture risk. In addition, some investigators have reported decreased bone pain in young, but not older, children following treatment.

Pamidronate use is invasive and inconvenient, typically requiring intravenous infusions every three months four hours a day for three days and has real and potential complications. Recently, pamidronate has been offered even to very young children with OI, but complications including transient asymptomatic hypocalcemia [Plotkin et al 2000] and symptomatic hypocalcemia [Chien et al 2002] have been noted. The long-term consequences of lowering bone turnover in children with OI are unknown, but may include delayed bone union after fracture or osteotomy.

A randomized controlled clinical trial using the oral bisphosphonate alendronate was recently completed and the results published. Ward and colleagues found that treatment with oral alendronate for two years in children with OI significantly decreased bone turnover and increased spine areal BMD but was not associated with improved fracture outcomes [Ward et al 2011]. In a second study with a different oral bisphosphonate, Bishop and colleagues found that oral risedronate increased areal BMD and reduced first and recurrent clinical fractures in children with OI [Bishop et al 2010]. There have not been additional large placebo-controlled trials of IV bisphosphonates, and it is unlikely that additional large randomized placebo controlled studies comparing bisphosphonates with placebo to determine the impact of these agents in altering the natural history of OI will be conducted.

Zoledronic acid, a newer bisphosphonate with a longer half life, greater potency, and more convenient dosing, is being studied in children with OI. A study comparing pamidronate to zoledronic acid was completed; to date, the results have not been published.

Basilar impression. Criteria for surgical intervention are not well defined. If surgery is undertaken, it should be done in a center experienced in the procedures used.

Dental treatment. The goals are the maintenance of both primary and permanent dentition, functional bite or occlusion, optimal gingival health, and overall appearance. Pediatric dentists are the most knowledgeable about DI in children. Some consensus exists that early dental restorative coverage of the primary molars and (if possible) aesthetic coverage of the upper anterior teeth is optimal. Plastic polymers are sometimes used to coat teeth. As anxiety can be an issue with children, pre-medication for anxiolysis (e.g., nitrous oxide analgesia or midazolam) can be used for treatment in a clinic setting.

If warranted, orthodontic treatment can be initiated, but care must be taken in the use of orthodontic appliances because of the brittleness of the teeth.

Dental restorations in adults may best be done by a general dentist knowledgeable about OI or a specialist in prosthetic dentistry.

Hearing loss. Surgical repair of the middle-ear bones and creation of a prosthetic incus can improve unaided hearing.

Later hearing loss appears to have a significant sensorineural component that does not respond to middle ear surgery. Cochlear implantation has been used in a small number of individuals; outcome data are limited.

Management of lethal OI. It is appropriate to offer parents the option of allowing the infant to expire without attempting interventions such as assisted ventilation.

Other therapies. Early trials of anabolic steroids, sodium fluoride, testosterone, vitamins C and D, flavinoids, and calcitonin showed minimal or no improvement in bone formation, or too small a sample size was utilized for meaningful conclusions [reviewed in Byers & Steiner 1992].

Prevention of Secondary Complications

Special attention should be paid to anesthesia concerns including proper positioning on the operating room table, for which egg crate foam is recommended.

Surveillance

The following are appropriate:

  • Dental examinations twice a year for those with DI or at risk for DI
  • Hearing evaluation at three- to five-year intervals perhaps beginning as early as age five years until hearing loss is identified, then as indicated based on the nature and degree of hearing loss and associated interventions

Agents/Circumstances to Avoid

Contact sports should be avoided.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Women with OI who have significant skeletal deformity and short stature should be followed during pregnancy by a high-risk prenatal care center.

Delivery of an infant with OI by cesarean section or by vagina has about the same rate of complications for each type of OI. Delivery of an infant with OI by cesarean section is more frequent than in the general population because a non-vertex presentation cannot be corrected by external manipulation.

Therapies Under Investigation

Human growth hormone has been evaluated as an adjunctive therapy in conjunction with bisphosphonates in a randomized controlled study. In this study, growth hormone therapy was reported to correlate with improved linear growth and increased BMD [Antoniazzi et al 2010]. An additional study presented similar results in 26 children with moderate to severe OI when growth hormone was used in isolation [Marini et al 2003].

Bone marrow transplantation (BMT) to introduce normal mesenchymal stem cells that have the capacity to differentiate into normal osteoblasts as well as transplanted mesenchymal stromal cells which produce factors that stimulate endogenous bone growth in individuals with OI has been evaluated in a pilot clinical trial. Preliminary data was promising and a clinical to evaluate this treatment further has recently concluded [Otsuru et al 2012, www.clinicaltrials.gov].

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Classic non-deforming osteogenesis imperfecta (OI), perinatally lethal OI, progressively deforming OI, and common variable OI caused by COL1A1 or COL1A2 mutations are inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Many individuals diagnosed with the milder forms of OI (classic non-deforming and some probands with common variable OI) have an affected parent.
  • The proportion of cases caused by de novo mutations varies by the severity of disease. Approximately 60% of individuals with mild OI have de novo mutations; virtually 100% of individuals with progressively deforming or perinatally lethal OI have de novo mutations.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include clinical examination of the parents and molecular genetic testing if the mutation in the proband has been identified.

Sibs of a proband

Offspring of a proband. Each child of an individual with a dominantly inherited form of OI has a 50% chance of inheriting the mutation.

Other family members. The risk to other family members depends on the status of the proband's parents. If a parent is affected, his or her family members are at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has clinical evidence of the disorder, it is likely that the proband has a de novo mutation or that one parent has germline mosaicism with or without somatic mosaicism. Other explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

High-risk pregnancies

  • Molecular genetic testing. Analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at about ten to 12 weeks' gestation is possible if the disease-causing allele of an affected family member has been identified.
  • Biochemical analysis of collagen from fetal cells obtained by CVS at about ten to 12 weeks' gestation has been reported. An abnormality of collagen from cultured cells of an affected family member must be identified before this technique can be used for prenatal testing. Note: Biochemical analysis of collagen from amniocytes is not useful because amniocytes do not produce type I collagen.

    Note: Classic non-deforming cannot be identified prenatally even with CVS cells because the proportion of type I procollagen produced by normal cells is reduced compared to control cells and resembles type I procollagen production from individuals with OI; thus, false positive test results can be an issue.
  • Prenatal ultrasound examination performed in a center with experience in diagnosing OI, done at the appropriate gestational age, can be a valuable tool in the prenatal diagnosis of OI. Normally, ultrasound examination detects only the lethal and most severe forms of OI prior to 20 weeks' gestation; milder forms may be detected later in pregnancy when fractures or deformity occur:
    • Perinatally lethal OI. The bony abnormalities can first be seen by ultrasound examination by about 13 to 14 weeks' gestation. By 16 weeks, femoral length is typically two or more weeks delayed, calvarial mineralization is essentially absent, and ribs generally have identified fractures.
    • Progressively deforming OI. Limb length generally begins to fall below the growth curve at about 17 to 18 weeks' gestation; serial ultrasound examinations are required to confirm the trend.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Low-risk pregnancies. Routine prenatal ultrasound examination may identify a fetus not known to be at risk for COL1A1/2-related OI with findings suggestive of OI (perinatally lethal OI or progressively deforming OI) including reduced echogenicity of fetal bones, bowed, crumpled femurs, beaded ribs, evidence of fractures, and markedly diminished calvarial mineralization. As a part of the evaluation of such findings, molecular genetic testing of COL1A1 or COL1A2 may be considered; however, inability to identify a mutation does not eliminate the diagnosis of OI in the fetus.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • National Library of Medicine Genetics Home Reference
  • Osteogenesis Imperfecta Foundation
    804 West Diamond Avenue
    Suite 210
    Gaithersburg MD 20878
    Phone: 800-981-2663 (toll-free); 301-947-0083
    Fax: 301-947-0456
    Email: bonelink@oif.org
  • Brittle Bone Society (BBS)
    Grant-Paterson House
    30 Guthrie Street
    Dundee DD1 5BS
    United Kingdom
    Phone: 08000 282459 (Toll-free Helpline); 01382 204446
    Fax: 01382 206771
    Email: contact@brittlebone.org
  • Children's Brittle Bone Foundation (CBBF)
    7701 95th Street
    Pleasant Prairie WI 53158
    Phone: 866-694-2223 (toll-free)
    Fax: 262-947-0724
    Email: info@cbbf.org
  • OI Registry
    Osteogenesis Imperfecta Foundation
    804 West Diamond Avenue
    Suite 210
    Gaithersburg MD 20878
    Phone: 443-923-9180
    Fax: 443-923-2710
    Email: oiregistrymanager@kennedykrieger.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. COL1A1/2-Related Osteogenesis Imperfecta: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for COL1A1/2-Related Osteogenesis Imperfecta (View All in OMIM)

120150COLLAGEN, TYPE I, ALPHA-1; COL1A1
120160COLLAGEN, TYPE I, ALPHA-2; COL1A2
166200OSTEOGENESIS IMPERFECTA, TYPE I
166210OSTEOGENESIS IMPERFECTA, TYPE II
166220OSTEOGENESIS IMPERFECTA, TYPE IV
259420OSTEOGENESIS IMPERFECTA, TYPE III

Molecular Genetic Pathogenesis

This review focuses on OI caused by mutations in either COL1A1 or COL1A2. These two genes encode the α 1 and α 2 chains of collagen type I. Collagen type I is a heterotrimer consisting of two α 1 chains and one α 2 chain. It is initially synthesized as a pro α chain with a propeptide at each end (N-propeptide and C-propeptide). The propeptides are necessary for pro α chain association and triple helix formation that starts at the carboxy-terminal propeptide and extends to the aminoterminal propeptide.

COL1A1

Normal allelic variants. COL1A1 is 18 kilobases in size and is composed of 52 exons (NM_000088.3).

Pathologic allelic variants. In the vast majority of instances, classic non-deforming OI results from mutations in COL1A1 that result in premature termination codons. The majority of these mutations are deletions or insertions of a small number of nucleotides, a number not divisible by three, in the coding sequences of exons throughout the gene. These mutations (single-codon changes that introduce premature termination codons) and some splice-site mutations that lead to exclusive use of cryptic sites and generation of out-of-frame transcripts all lead to premature termination codons. The presence of a premature termination codon that is separated by one or more introns in the gene leads to marked instability of the mRNA derived from the mutant allele. As a consequence, the amount of COL1A1 mRNA is reduced to half the normal amount, with no compensation by the other allele.

The majority of mutations in COL1A1 that result in perinatally lethal OI, progressively deforming OI, and common variable OI result in substitutions for glycine within the triple helical domain of the pro α chain. The pro α chains consist of an amino-terminal propeptide, a triple helical segment of 1014 amino acids in which glycine is in every third position and prolines preceding glycine residues are generally hydroxylated, as are some lysyl residues in the Y-position of the Gly-X-Y triplet. Glycine, the smallest amino acid, must be in the third position to allow proper chain folding to occur. When substituted, the propagation of the triple helix is delayed, additional post-translation modification occurs, and some of the assembled trimers are never secreted. The consequence of these mutations is that a diminished amount of type I procollagen is secreted and some of the protein in the matrix has an abnormal structure. The clinical consequence appears to result from the position of the substituted glycine, the chain in which the substitution occurs, and the nature of the substituting amino acid.

Perinatally lethal OI, progressively deforming OI, and common variable OI can also result from short deletions or duplications of single amino acids or Gly-X-Y triplets and from exon-skipping events within COL1A1. The relationship between genotype and phenotype is complex, although it appears that mutations closer to the 5' end of the coding sequence that affects the amino-terminal ends of the triple helical domains are likely to have milder clinical phenotypes. This is probably the reflection of chain association occurring at the carboxyl-terminal end of the chain so that a small part of the molecule is affected. Much is still to be learned about the final pathways of molecular pathogenesis.

The mutations in most families are unique; only a few recurrent mutations (mostly CpG dinucleotides) are seen in more than one family.

Normal gene product. COL1A1 encodes the1464-amino acid pro α 1 chains of type I collagen whose triple helix comprises two α 1 chains and one α 2 chain. Type I is a fibril-forming collagen found in most connective tissues and is abundant in bone, cornea, dermis, and tendon.

Abnormal gene product. Classic non-deforming OI is generally characterized by decreased production of type I procollagen. With a reduction in the COL1A1 mRNA, an obligatory decrease in the production of type I procollagen occurs, although the protein produced is structurally normal. The diminished amount of type I collagen in bone appears to reduce the amount of bone that can be made and leads to brittle bones.

The two general outcomes of mutations in COL1A1 are either a decrease in the amount of type I procollagen produced or the production of some abnormal type I procollagen molecules.

COL1A2

Normal allelic variants. COL1A2 spans approximately 38 kb and comprises 52 exons (NM_000089.3).

Pathologic allelic variants. The majority of mutations in COL1A2 that result in perinatally lethal OI, progressively deforming OI, and common variable OI result in substitutions for glycine within the triple helical domain of the pro α chain. The pro α chains consist of an amino-terminal propeptide, a triple helical segment of 1014 amino acids in which glycine is in every third position and prolines preceding glycine residues are generally hydroxylated as are some lysyl residues in the Y-position of the Gly-X-Y triplet. Glycine, the smallest amino acid, must be in the third position to allow proper chain folding to occur. When substituted, the propagation of the triple helix is delayed, additional post-translation modification occurs, and some of the assembled trimers are never secreted. The consequence of these mutations is that a diminished amount of type I procollagen is secreted and some of the protein in the matrix has an abnormal structure. The clinical consequence appears to result from the position of the substituted glycine, the chain in which the substitution occurs, and the nature of the substituting amino acid. Perinatally lethal OI, progressively deforming OI, and common variable OI can also result from short deletions or duplications of single amino acids or Gly-X-Y triplets and from exon-skipping events within COL1A2. The relationship between genotype and phenotype is complex, although it appears that mutations closer to the 5' end of the coding sequence that affect the amino-terminal ends of the triple helical domains are likely to have milder clinical phenotypes. This is probably the reflection of chain association occurring at the carboxyl-terminal end of the chain so that a small part of the molecule is affected. Much is still to be learned about the final pathways of molecular pathogenesis.

The mutations in most families are unique; only a few recurrent mutations (mostly CpG dinucleotides) are seen in more than one family.

Normal gene product: COL1A2 encodes the 1366-amino acid pro α 2 chain of type 1 collagen whose triple helix comprises two α 1 chains and one α 2 chain. Type 1 is a fibril-forming collagen found in most connective tissues and is abundant in bone, cornea, dermis, and tendon

Abnormal gene product: The general outcome of mutations in COL1A2 is the production of some abnormal type I procollagen molecules.

References

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Suggested Reading

  1. Byers PH. Disorders of collagen biosynthesis and structure. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill. Chap 205. Available online. Accessed 9-23-13.

Chapter Notes

Author Notes

Dr. Steiner is a pediatrician, clinical geneticist, and clinical biochemical geneticist. He specializes in inherited metabolic diseases and osteogenesis imperfecta. Dr. Steiner runs an OI clinic at Shriners Hospital in Portland for evaluation of children with OI.

Linked Clinical Research Centers

A joint initiative from the OI Foundation and the Children’s Brittle Bone Foundation, the Linked Clinical Research Center (LCRC) is a nationwide network designed to provide the highest quality of standardized medical care for people living with osteogenesis imperfecta.

The first five hospitals participating in the LCRC:

  • Baylor Medical Center (Houston, TX)
  • Kennedy Krieger Institute (Baltimore, MD)
  • Oregon Health & Science University/Portland Shriners (Portland, OR)
  • Shriners Hospital for Children (Chicago, IL)
  • Shriners Hospital for Children (Montreal, Quebec)

Author History

Jessica Adsit, MS, CGC (2013-present)
Donald Basel, MD, MCW (2013-present)
Peter H Byers, MD; University of Washington Health Sciences Center (2003-2013)
Melanie G Pepin, MS, CGC; University of Washington Health Sciences Center (2003-2013)
Robert D Steiner, MD (2003-present)

Revision History

  • 14 February 2013 (me) Comprehensive update posted live
  • 28 January 2005 (me) Review posted to live Web site
  • 14 June 2003 (rs) Original submission
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