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Hypochondroplasia

, MD, PhD, , MD, PhD, , MD, and , MD, PhD.

Author Information
, MD, PhD
Alfred I duPont Hospital for Children
Wilmington, Delaware
, MD, PhD
Department of Pediatrics
University of Colorado Denver
Aurora, Colorado
, MD
Children’s Hospital of Eastern Ontario
Ottawa, Ontario
, MD, PhD
Southern California Permanente Medical Group
Los Angeles, California

Initial Posting: ; Last Update: September 26, 2013.

Summary

Disease characteristics. Hypochondroplasia is a skeletal dysplasia characterized by short stature; stocky build; disproportionately short arms and legs; broad, short hands and feet; mild joint laxity; and macrocephaly. Radiologic features include shortening of long bones with mild metaphyseal flare; narrowing of the inferior lumbar interpedicular distances; short, broad femoral neck; and squared, shortened ilia. The skeletal features are very similar to those seen in achondroplasia but tend to be milder. Medical complications common to achondroplasia (e.g., spinal stenosis, tibial bowing, obstructive apnea) occur less frequently in hypochondroplasia but intellectual disability and epilepsy may be more prevalent. Children usually present as toddlers or school-age children with decreased growth velocity leading to short stature and limb disproportion. Other features also become more prominent over time.

Diagnosis/testing. Hypochondroplasia is diagnosed by the recognition of characteristic clinical and radiologic findings that remain controversial. The diagnosis is difficult to make in children under age three years, as skeletal disproportion tends to be mild and many of the radiographic features are subtle during infancy. DNA-based testing is possible and about 70% of affected individuals are heterozygous for a mutation in FGFR3. However, there is evidence that locus heterogeneity exists, implying that mutations in other as-yet unidentified genes may result in similar, if not identical, phenotypes.

Management. Treatment of manifestations: Management of short stature in hypochondroplasia is influenced by parental expectations and concerns; one approach is to address these concerns rather than trying to treat the child. Laminectomy relieves symptoms of spinal stenosis; about 70% of individuals experience relief of symptoms following decompression without laminectomy. Developmental milestones are followed closely during early childhood so that cognitive impairments are addressed with special educational programs. Epilepsy is treated in the standard fashion.

Surveillance: Height, weight, and head circumference should be monitored using achondroplasia-standardized growth curves. The following should be performed at routine well-child visits: neurologic examination for signs of spinal cord compression, history for evidence of sleep apnea, physical evaluation for emerging leg bowing, and monitoring for social adjustment. MRI or CT examination of the foramen magnum is indicated if there is evidence of severe hypotonia, spinal cord compression, or central sleep apnea.

Pregnancy management: Vaginal deliveries are possible, although for each pregnancy, pelvic outlet capacity should be assessed in relation to fetal head size; epidural or spinal anesthetic can be used, but a consultation with an anesthesiologist prior to delivery is recommended to assess the spinal anatomy; spinal stenosis may be aggravated during pregnancy.

Genetic counseling. Hypochondroplasia is inherited in an autosomal dominant manner. The majority of new cases result from spontaneous mutations and the unaffected parents of a child with hypochondroplasia have an extremely low risk of having another affected child. An individual with hypochondroplasia who has a partner of average stature is at a 50% risk of having a child with hypochondroplasia. If an affected individual's partner also has hypochondroplasia (or another dominant form of skeletal dysplasia), genetic counseling becomes more complicated because of (1) the risk for inheriting two dominantly inherited skeletal dysplasias, (2) the high incidence of genetic heterogeneity, and (3) the lack of medical literature addressing these circumstances. Prenatal molecular genetic testing is available if the mutation(s) in the parent(s) with hypochondroplasia have been identified; however, requests for prenatal testing for conditions such as heterozygous hypochondroplasia are not common.

Diagnosis

Clinical Diagnosis

The clinical and radiologic diagnostic criteria for hypochondroplasia remain controversial for several reasons, including the following:

  • No single radiologic or clinical feature is unique to hypochondroplasia.
  • The expression of many of the established diagnostic features in affected individuals is variable.
  • Locus heterogeneity has been established.

Genetic heterogeneity and lack of agreement on a definitive set of diagnostic criteria have made it difficult to compare data from the many studies reported in the literature [Ravenna 1913, Kozlowski & Bartkowiak 1965, Beals 1969, Dorst 1969, Walker et al 1971, Kozlowski 1973, Frydman et al 1974, Newman & Dunbar 1975, Specht & Daentl 1975, Scott 1976, Glasgow et al 1978, Hall & Spranger 1979, Heselson et al 1979, Oberklaid et al 1979, Wynne-Davies et al 1981, Maroteaux & Falzon 1988, Song et al 2012]. Nevertheless, it is clear that a complete radiographic survey including skull, pelvis, AP and lateral spine, legs, arms, and hands is absolutely necessary to make a clinical diagnosis of hypochondroplasia.

Physical features. The diagnosis of hypochondroplasia should be considered in individuals who have the following:

  • Short stature (adult height 128-165 cm; 2-3 SD below the mean in children)
  • Stocky build
  • Shortening of the proximal (rhizomelia) or middle (mesomelia) segments of the extremities
  • Limitation of elbow extension
  • Broad, short hands and feet (brachydactyly)
  • Generalized, mild joint laxity
  • Large head (macrocephaly) with relatively normal facies

Less common but significant clinical features:

  • Scoliosis
  • Bow legs (genu varum) (usually mild)
  • Lumbar lordosis with protruding abdomen
  • Mild to moderate intellectual disability
  • Learning disabilities
  • Adult-onset osteoarthritis
  • Acanthosis nigricans
  • Temporal lobe epilepsy

Radiologic features. The most common radiologic features of hypochondroplasia:

  • Shortening of long bones with mild metaphyseal flare (especially femora and tibiae)
  • Narrowing of or failure to widen in the inferior lumbar interpedicular distances
  • Mild to moderate brachydactyly
  • Short, broad femoral neck
  • Squared, shortened ilia

Less common but significant radiologic features:

  • Elongation of the distal fibula
  • Shortening (anterior-posterior) of the lumbar pedicles
  • Dorsal concavity of the lumbar vertebral bodies
  • Shortening of the distal ulna
  • Long ulnar styloid (seen only in adults)
  • Prominence of muscle insertions on long bones
  • Shallow "chevron" deformity of distal femur metaphysis
  • Low articulation of sacrum on pelvis with a horizontal orientation
  • Flattened acetabular roof

The clinical and radiologic features above have all been described in hypochondroplasia, but a consensus opinion of which or how many of these features must be present to confirm a clinical diagnosis does not currently exist. The presence of the above listed radiologic criteria for hypochondroplasia varies significantly among affected individuals. Many of these features are not present in affected infants but develop later in life. The mild end of the hypochondroplasia phenotypic spectrum may overlap with “normal” individuals of short stature, making it difficult to establish a definitive clinical diagnosis in these individuals.

Molecular Genetic Testing

Gene. FGFR3 is the only gene in which mutations are known to cause hypochondroplasia and mutations throughout the gene have been described [Heuertz et al 2006]. Genetic heterogeneity is suspected, as only approximately 70% of those individuals with a clinical and radiographic diagnosis of hypochondroplasia have mutations in FGFR3; to date, a true second locus has not been found.

Evidence for locus heterogeneity

  • Using diagnostic criteria based solely on the radiographic finding of decreased interpediculate distance between L1 and L5, Mullis et al [1991] studied 20 children with hypochondroplasia. Two RFLPs identified within introns of IGF1 (12q23) showed a positive LOD score of 3.31 in some families with hypochondroplasia. To date, no further refinement of the genetic locus on 12q23 has been reported and no pathogenetic mutations have been reported in IGF1.
  • It is likely that, in the future, further combined molecular and clinical studies will lead to the discovery of other genetically distinct subtypes of hypochondroplasia.

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in Hypochondroplasia

Gene 1 Test Method Mutations Detected 2 Mutation Detection Frequency by Test Method 3
FGFR3Targeted mutation analysis 4c.1620C>A 5 70% 6
c.1620C>G 530% 5
Sequence analysis Sequence variants 7 (including c.1620C>A and c.1620C>GUnknown 8
Deletion/duplication analysis 9Exonic or whole gene deletion/duplication Unknown, none reported 10

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

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. Mutation panels may vary by laboratory.

5. The two most common mutations, detection frequency based on testing of 188 individuals with hypochondroplasia See also Testing Strategy.

6. In studies in which a diagnosis was established by physical and radiologic criteria, 70% (180/258) of probands with hypochondroplasia were found to be heterozygous for one mutation resulting in c.1620C>A [Prinos et al 1995, Bellus et al 1996, Rousseau et al 1996, Fofanova et al 1998, Prinster et al 1998, Ramaswami et al 1998, Heuertz et al 2006].

7. 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.

8. Heuertz et al [2006] reported 54 FGFR3 mutations detected by sequencing all coding regions in 74 probands with hypochondroplasia (47 [87%] were c.1620C>A ), whereas Song et al [2012], using broader diagnostic criteria for hypochondroplasia to diagnose 58 individuals, found 19 FGFR3 mutations (10 [58%] were c.1620C>A).

9. 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.

10. No deletions or duplications involving FGFR3 have been reported to cause hypochondroplasia. 

Testing Strategy

To confirm/establish the diagnosis in a proband:

Single gene testing. One strategy for molecular diagnosis of a proband suspected of having hypochondroplasia is sequence analysis (or targeted mutations) of FGFR3.

  • Targeted mutation analysis for the two common mutations should be pursued first.
  • Sequence analysis can be performed when the suspicion of hypochondroplasia based on clinical and radiographic grounds is high and targeted mutation analysis for the two common mutations is normal. As mutations have been reported in almost all domains of the protein, analysis should include sequencing of all coding regions. To date, only missense mutations have been described.

Multi-gene panel. Another strategy for molecular diagnosis of a proband suspected of having hypochondroplasia is use of a multi-gene panel.

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

Clinical Description

Natural History

Growth. The most common presenting feature of children with hypochondroplasia is short stature with disproportionate limbs. Birth weight and length are often within the normal range and the disproportion in limb-to-trunk length is often mild and easily overlooked during infancy. Typically, these children present as toddlers or school-age children to pediatricians or pediatric endocrinologists with decreased growth velocity leading to short stature. Some investigators have reported the absence of a pubertal growth spurt [Appan et al 1990, Bridges et al 1991]. Overall height is usually two to three standard deviations below the mean during childhood, and adult heights range from 138 to 165 cm (54" to 65") for men and 128 to 151 cm (50" to 59") for women [Maroteaux & Falzon 1988, Appan et al 1990].

With age, limb disproportion usually becomes more prominent in the legs than the arms. Both rhizomelic [Frydman et al 1974, Specht & Daentl 1975, Maroteaux & Falzon 1988] and mesomelic [Beals 1969, Walker et al 1971] shortening have been reported, although others have reported the predominance of neither [Hall & Spranger 1979]. The hands are relatively short but do not exhibit the "trident" appearance that is typical in achondroplasia. Facial features are usually normal and the classic facial features of achondroplasia (e.g., midfaceretrusion, frontal bossing) are not generally seen. Head size may be large without significant disproportion.

Orthopedics. When children begin to walk, exaggerated lumbar lordosis and mild genu varum (bow legs) are often noted. The genu varum is usually transient and rarely requires surgical intervention. Young children and adults often have a thick, muscular appearance and may be described as "stocky." Joint pain, back pain, and other symptoms of osteoarthritis may occur later in life. Multiple suture craniosynostosis has been reported in one case [Angle et al 1998].

Cognitive development. The incidence of intellectual disability is thought to be higher in hypochondroplasia than in achondroplasia or the general population. This observation has been controversial and several studies have reported conflicting results [Beals 1969, Walker et al 1971, Frydman et al 1974, Specht & Daentl 1975, Hall & Spranger 1979, Wynne-Davies & Patton 1991]. It is unclear whether these discrepancies result from sampling bias, genetic heterogeneity, or both; more studies with rigorous diagnostic criteria are required to resolve this issue. Preliminary studies [Bellus & Francomano, unpublished results] suggest that individuals with the FGFR3 p.Asn540Lys substitution may have an increased incidence of mild-to-moderate intellectual disability or learning disabilities. Eight of 13 Finnish individuals with the FGFR3 p.Asn540Lys substitution had neurocognitive difficulties [Linnankivi et al 2012; see Neurology below].

Endocrinology. Acanthosis nigricans is observed occasionally in children and adults with hypochondroplasia [Leroy et al 2007, Castro-Feijoo et al 2008, Alatzoglou et al 2009, Berk et al 2010, Blomberg et al 2010] and appears to be more prevalent in individuals with specific FGFR3 mutations (i.e., p.Lys650Gln and p.Lys650Thr). The severity of acanthosis nigricans in individuals reported with these mutations is much milder than that observed in SADDAN syndrome (FGFR3 mutation p.Lys650Met). While increased insulin resistance has been reported in one individual with acanthosis nigricans and hypochondroplasia due to a p.Lys650Gln mutation [Blomberg et al 2010], no evidence of insulin resistance was found in an individual with acanthosis nigricans and hypochondroplasia due to a p.Asn540Lys mutation [Alatzoglou et al 2009]. Insulin resistance is also not found in SADDAN syndrome [Bellus et al 1999].

Neurology. Symptoms of spinal stenosis are seen in some adults with hypochondroplasia, but occur much less frequently and tend to be milder than those seen in achondroplasia [Wynne-Davies et al 1981]. Unlike achondroplasia, motor milestones are usually not significantly delayed and symptoms resulting from spinal cord compression (e.g., apnea, neuropathy) are less common [Wynne-Davies et al 1981].

Hulse et al [2012] described a male with hypochondroplasia (p.Asn540Lys) who developed seizures in the neonatal period. EEGs revealed abnormalities in the left temporal lobe region, and brain MRI revealed abnormal orientation of the hippocampal heads. Reference was made to four other reported cases of medial temporal lobe epilepsy related to hypochondroplasia.

Linnankivi et al [2012] assessed neurologic and neuroimaging aspects of 13 Finnish individuals with hypochondroplasia with a confirmed FGFR3 p.Asn540Lys substitution. Eight affected individuals had neurocognitive difficulties, ranging from specific learning disorder (2/13) to mild intellectual disability (5/13) or global developmental delay (1/13). Six of 13 affected individuals had a history of epilepsy. Of eight individuals who underwent head MRI, all had temporal lobe dysgenesis, six had peritrigonal white matter reduction, and four had abnormally shaped lateral ventricles.

Genotype-Phenotype Correlations

Other than p.Asn540Lys, most mutations have not been reported in high enough frequency to make any generalizations about specific genotype/phenotype manifestations.

  • As one would expect, no difference exists in phenotype between the FGFR3 c.1620C>A and c.1620C>G mutations, as they result in identical mutant proteins, p.Asn540Lys. In general, it appears that the phenotypes of individuals diagnosed with hypochondroplasia who have FGFR3 mutations c.1620C>A or c.1620C>G have more severe manifestations than those with hypochrondroplasia who do not have these mutations [Rousseau et al 1996, Prinster et al 1998, Ramaswami et al 1998]. More recently, both Heuertz et al [2006] and Song et al [2012] reported that a p.Tyr278Cys (c.829A>G) mutation resulted in a phenotype that resembled achondroplasia in the newborn period. There is still no consensus as to which specific clinical features distinguish hypochondroplasia due to FGFR3 p.Asn540Lys from hypochondroplasia caused by other FGFR3 mutations or from non- FGFR3-related hypochondroplasia.
  • Fano et al [2005] reported that affected individuals with a head circumference greater than 1.86 standard deviations had a greater likelihood of possessing the p.Asn540Lys mutation.
  • Individuals with p.Lys650Gln or p.Lys650Thr have a higher likelihood of developing acanthosis nigricans (see Endocrinology above).
  • Mutations resulting in p.Lys650Asn and p.Lys650Gln are associated with a slightly milder skeletal phenotype than mutations resulting in p.Asn540Lys. Bellus et al [2000] reported six individuals with p.Lys650Asn or p.Lys650Gly who had a significantly lower average height deficit than 36 individuals with p.Asn540Lys. In addition, the L1:L4 interpediculate distance and fibula/tibia length ratios were closer to normal.
  • Mortier et al [2000] and Thauvin-Robinet et al [2003] reported on families with p.Asn540Lys. The phenotype in both families was relatively mild, with heights overlapping the lower end of the normal range for age, mild disproportion of the limbs, and macrocephaly.

Somatic mosaicism has not been reported in hypochondroplasia.

Penetrance

Because of evidence that the height range in hypochondroplasia may overlap that of the normal population, individuals with hypochondroplasia may not be recognized as having a skeletal dysplasia unless an astute physician recognizes their disproportionate short stature. However, there have been no reports of individuals with an FGFR3 mutation without demonstrable radiographic changes compatible with hypochondroplasia or one of the other phenotypes known to be associated with mutations in this gene (see Genetically Related Disorders).

Anticipation

Genetic anticipation is not known to occur in hypochondroplasia.

Prevalence

No studies attempting to determine the prevalence of FGFR3 and/or non- FGFR3 hypochondroplasia have been published. Ascertainment of cases is problematic as it is thought that many affected individuals present with no symptoms other than short stature and do not seek medical intervention. However, it is generally agreed that hypochondroplasia is a relatively common skeletal dysplasia that may approach the prevalence of achondroplasia (i.e., one in 15,000 - 40,000 live births). In addition, simplex cases (affected individuals with no family history of hypochondroplasia) have been associated with advanced paternal age. Simplex cases of hypochondroplasia caused by the FGFR3 p.Asn540Lys mutation are probably not as common as simplex cases of achondroplasia, given the fact that a transition at a CpG dinucleotide is the most common cause of the achondroplasia-causing p.Gly380Arg change, while both mutations leading to p.Asn540Lys result from transversions not associated with CpG dinucleotides.

Differential Diagnosis

Numerous forms of skeletal dysplasia with disproportionate limbs are recognized and are characterized by clinical and radiologic features that distinguish them from hypochondroplasia and achondroplasia. Many of these disorders are quite rare. The diagnosis of hypochondroplasia is seldom made at birth unless a prior family history exists. Most affected individuals present with short stature as toddlers or young school-age children. Inappropriate diagnoses of hypochondroplasia are often made because the disorder is considered to be relatively common and the radiologic features are variable and may be subtle. The following conditions may be confused with hypochondroplasia:

  • Mild forms of metaphyseal chondrodysplasias
  • Mild forms of mesomelic dwarfism
  • Mild forms of spondylo-epiphyseal-metaphyseal dysplasias
  • Pseudohypoparathyroidism and pseudopseudohypoparathyroidism
  • Short stature caused by disturbances in the growth hormone axis
  • Constitutive short stature

Hypochondroplasia-achondroplasia complex (FGFR3 p.[Asn540Lys];[Gly380Arg]) has been reported [McKusick et al 1973, Sommer et al 1987, Bellus et al 1995, Huggins et al 1999, Flynn & Pauli 2003, Bober et al 2012]. The skeletal phenotype is more severe than typically found in achondroplasia, but unlike homozygous achondroplasia, is not uniformly lethal. Life span however, may be decreased.

Hypochondroplasia-SHOX deletion. Ross et al [2003] described the phenotype in one child with compound heterozygosity for Leri-Weil dyschondrosteosis and hypochondroplasia. This child inherited both a SHOX deletion and the p.Asn540Lys FGFR3 mutation, and had severe short stature with both rhizomelic and mesomelic shortening of the limbs.

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

Evaluation of children with hypochondroplasia usually does not differ significantly from the evaluation of children with normal stature except for genetic counseling issues and dealing with parental concerns about short stature. However, because the phenotype of FGFR3 hypochondroplasia may overlap with that of achondroplasia, recommendations for the management of achondroplasia as outlined by the American Academy of Pediatrics Committee on Genetics [Trotter et al 2005] should be considered in children with hypochondroplasia who exhibit more severe phenotypic features. These recommendations include but are not limited to the following:

  • Medical genetics consultation
  • Measurement of height, weight, and head circumference and plotting on achondroplasia-standardized growth curves
  • Neurologic examination for signs of spinal cord compression, with referral to a pediatric neurologist or neurosurgeon if needed
  • Screening developmental assessment
  • History for evidence of sleep apnea, with formal sleep study if suggestive
  • MRI or CT examination of the foramen magnum if clinical findings of severe hypotonia, spinal cord compression, or central sleep apnea as demonstrated through a sleep study are present
  • Evaluation for thoracic or lumbar gibbus in the presence of truncal weakness
  • Examination for leg bowing, with orthopedic referral if bowing interferes with walking
  • Speech evaluation at diagnosis or by age two years
  • Observation for symptoms suggestive of epilepsy, with referral to a pediatric neurologist when indicated

Treatment of Manifestations

Management of short stature is influenced by parental expectations and concerns. Final adult height in hypochondroplasia is considerably greater than that achieved in achondroplasia and therefore, functional limitations in society (e.g., operating an elevator, driving a car, using an automatic teller machine) are generally less severe or not an issue. One reasonable approach is to address the parents' expectations and prejudices regarding the height of their child rather than attempting to treat the child.

Developmental intervention and special educational input are appropriate, as indicated by deficiencies.

The usual neurosurgical approach to spinal stenosis is laminectomy. Thomeer & van Dijk [2002] determined that about 70% of symptomatic individuals with achondroplasia experienced total relief of symptoms following decompression without laminectomy. The L2-3 level most commonly required decompression.

Making the family aware of support groups, such as the Little People of America Inc. (LPA), can result in assistance with adaptation of the affected individual and the family to short stature through peer support, personal example, and social awareness programs. The LPA offers information on employment, education, disability rights, adoption of children of short stature, medical issues, suitable clothing, adaptive devices, and parenting through local meetings, workshops, seminars, and a national newsletter.

Seizure disorders should be treated in the standard manner.

Prevention of Secondary Complications

The following are appropriate:

  • Standard management of frequent middle ear infections
  • Consideration of surgery if neurologic status is affected by spinal cord compression

Surveillance

Height, weight, and head circumference should be monitored using achondroplasia-standardized growth curves.

Because an increased prevalence of mild-to-moderate intellectual disability and/or learning disabilities in children with hypochondroplasia appears likely, developmental milestones should be followed closely during early childhood and a timely referral to an appropriate professional made if there are any indications of learning difficulties during school-age years.

Neurologic examination for signs of spinal cord compression should be performed at routine well-child visits, with referral to a pediatric neurologist if needed.

History for evidence of sleep apnea should be taken at routine visits, with formal sleep study obtained when indicated.

MRI or CT examination of the foramen magnum is indicated if there is evidence of severe hypotonia, spinal cord compression or central sleep apnea.

Affected individuals should be evaluated for emerging leg bowing at routine visits, with orthopedic referral if bowing interferes with walking.

Social adjustment should be monitored.

Evaluation of Relatives at Risk

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

Pregnancy Management

There is a paucity of literature regarding pregnancy management in women with skeletal dysplasias. However, a number of women with hypochondroplasia have had unremarkable pregnancies and deliveries.

  • In comparison to women who have achondroplasia, vaginal deliveries are possible, although for each pregnancy, pelvic outlet capacity should be assessed in relation to fetal head size.
  • Epidural or spinal anesthetic can be utilized, but a consultation with an anesthesiologist prior to delivery is recommended to assess the spinal anatomy.
  • If present, spinal stenosis may be aggravated during pregnancy due to the normal physiologic changes to the shape of the spine that occur as gestation progresses.

Therapies Under Investigation

Growth hormone therapy. Trials of growth hormone therapy in hypochondroplasia have shown mixed results. These differences in individual responses published prior to gene discovery in 1995 [Appan et al 1990, Bridges et al 1991, Mullis et al 1991, Bridges & Brook 1994] may have resulted from genetic heterogeneity and indicate a need for stratification of affected individuals with regard to genetic etiology (e.g., those with FGFR3 mutations and those without). Meyer et al [2003] emphasized the importance of considering pubertal development in assessing the response to growth hormone stimulation testing. Tanaka et al [2003] reported data suggesting that children with hypochondroplasia may have a greater response to growth hormone therapy than children with achondroplasia.

Pinto et al [2012] treated 19 children with hypochondroplasia (11/19 with confirmed FGFR3 mutations, mean age 9.0+/-3.0 years) with human recombinant growth hormone over a three-year period. Their mean height increased 1.32+/-1.05 standard deviation score (SDS) compared to a historical cohort of 40 untreated individuals with hypochondroplasia. Rothenbuhler et al [2012] treated six children with hypochondroplasia (confirmed FGFR3 p.Asn540Lys substitution, mean age 2.6+/-0.7 years) with human recombinant growth hormone over a six-year period. Their mean height SDS increased by 1.9 during the study period, and trunk/leg disproportion was improved. Since data about final adult height in growth hormone-treated individuals with hypochondroplasia are not available, the ultimate success of this approach remains uncertain. Growth hormone therapy should still be considered experimental and controversial in this condition.

Surgical limb lengthening procedures have been used to treat achondroplasia and hypochondroplasia for more than 15 years. Although the complication rate was high initially, outcomes have steadily improved and significant increases in overall height have been reported [Yasui et al 1997, Lie & Chow 2009]. Nevertheless, the procedure is very invasive and entails considerable disability and discomfort over a long period of time. While some advocate performing the procedure during childhood, many pediatricians, geneticists, and ethicists advocate postponement until adolescence, when the affected individual is able to make an informed decision. Surgical limb lengthening is controversial, but is achieving greater acceptance with fewer complications as larger numbers of operations have been performed.

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

Hypochondroplasia is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • The majority of individuals with hypochondroplasia have parents of average stature and represent simplex occurrences caused by a de novo mutation; however, in some instances, one or both parents have hypochondroplasia.
  • There appears to be a paternal age effect in some simplex occurrences of hypochondroplasia [Walker et al 1971]. It is likely that de novo mutations occur on the paternally derived chromosome during spermatogenesis, as has been shown in achondroplasia [Wilkin et al 1998] and Apert syndrome [Moloney et al 1996].
  • Because the skeletal features of hypochondroplasia are milder than those of achondroplasia and the incidence of disabilities is lower, the reproductive fitness of individuals with hypochondroplasia is most likely greater than that of individuals with achondroplasia. It is likely that the number of families with multiple affected members is higher for hypochondroplasia than for achondroplasia, and that the percentage of cases of hypochondroplasia attributable to de novo mutations is less than the 80% figure stated for achondroplasia.

Sibs of a proband

  • The risk to sibs of the proband depends on the genetic status of the parents.
  • If one parent is affected, the risk is 50%.
  • If both parents have hypochondroplasia or one has hypochondroplasia and the other has a different autosomal dominant skeletal dysplasia, the risk to sibs is more complex (see Offspring of a proband).
  • Germline mosaicism has not been reported for hypochondroplasia and therefore the risk that the sibs of an affected individual born to parents of normal stature would have hypochondroplasia appears to be extremely low (<0.01%).

Offspring of a proband

  • An individual with hypochondroplasia who has a reproductive partner of average stature is at a 50% risk of having a child with hypochondroplasia.
  • When the proband and the proband's reproductive partner are affected with the same or a different skeletal dysplasia, genetic counseling is more complicated. In general, if both members of a couple have a dominantly inherited skeletal dysplasia, each child has a 25% chance of having normal stature, a 25% chance of having the same skeletal dysplasia as the father, a 25% chance of having the same skeletal dysplasia as the mother, and a 25% chance of inheriting a disease-causing mutation from both parents and being at risk for a potentially poor pregnancy outcome.
    • Individuals who are compound heterozygotes for FGFR3 p.[Asn540Lys];[Gly380Arg]), the mutations that cause hypochondroplasia and achondroplasia, respectively or individuals in whom the hypochondroplasia results from FGFR3 p.Asn540Lys have a severe skeletal phenotype with the potential for serious disability [McKusick et al 1973, Sommer et al 1987, Huggins et al 1999].
    • Poor outcomes have been reported for individuals who are compound heterozygotes for achondroplasia and spondyloepiphyseal dysplasia congenita [Young et al 1992, Gunthard et al 1995] or achondroplasia and pseudoachondroplasia [Langer et al 1993].
    • Compound heterozygotes for either achondroplasia and dyschondrosteosis or hypochondroplasia and dyschondrosteosis have phenotypes that do not appear to be more severe than that of either parent [Ross et al 2003].
  • Genetic counseling of couples both of whom have hypochondroplasia is complicated by (1) genetic heterogeneity and (2) lack of information about the phenotypes and prognosis for offspring who inherit a disease-causing mutation from both parents. No reports address the following phenotypes
    • Individuals with hypochondroplasia who are homozygous for FGFR3 mutations or homozygous for non- FGFR3 mutations
    • Individuals who are compound heterozygotes for an FGFR3 mutation and a non- FGFR3 mutation
  • Similarly, the following phenotypes have not been described:
    • Individuals who are compound heterozygotes for a non- FGFR3 mutation causing hypochondroplasia and an FGFR3 mutation causing achondroplasia
    • Individuals who are compound heterozygotes for hypochondroplasia (as a result of either an FGFR3 mutation or a mutation in a different gene) and another dominantly inherited skeletal dysplasia (except individuals who are compound heterozygotes for FGFR3 mutations causing hypochondroplasia and achondroplasia. See above: Individuals who are compound heterozygotes for FGFR3).
    • Therefore, it is not possible to provide information about prognosis for all at-risk offspring.

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

Genetic counseling for hypochondroplasia presents dilemmas relating to ethical and genetic issues. Hypochondroplasia is considered a mild disorder in which the chief physical disability is generally short stature. Many affected individuals do not think of themselves as disabled. However, some parents may consider short stature a significant physical, emotional, and/or social disability. Furthermore, a child with hypochondroplasia may have intellectual disability or a learning disability. An additional issue is genetic heterogeneity (i.e., mutations in more than one gene causing hypochondroplasia), which may result in an inability to predict phenotype or prognosis and/or make diagnosis difficult.

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical 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.

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 pregnancy

  • Molecular genetic testing. A high-risk pregnancy is one in which one parent has hypochondroplasia and the other parent is of normal stature, has hypochondroplasia, or has another dominantly inherited skeletal dysplasia. Prenatal diagnosis for high-risk pregnancies is possible by 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. The mutation in the parent with hypochondroplasia must be identified before prenatal testing can be performed. Similarly, if the other parent has a dominantly inherited skeletal dysplasia, the causative mutation must be identified before prenatal testing is possible.

    Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
  • Fetal ultrasound examination. If the causative mutation for the other disorder present in the couple is not known or if the mutation causing hypochondroplasia cannot be identified, ultrasound examination is the only method of prenatal testing. It is often possible to detect an affected fetus early in the pregnancy if the fetus is at risk of being a compound heterozygote with another dominantly inherited skeletal dysplasia. However, it is currently difficult to detect heterozygous hypochondroplasia or other milder phenotypes using ultrasonography. Signs of disproportionate growth may suggest the diagnosis of hypochondroplasia, but a "normal" third trimester ultrasound examination is not sufficient to rule out a diagnosis of hypochondroplasia. The phenotype of homozygous hypochondroplasia has not yet been described; therefore, no statement can be made regarding prenatal diagnosis of homozygous hypochondroplasia by ultrasound examination.

    If significant macrocephaly is noted, it is appropriate to consider delivery by caesarean section to reduce the risk of potential CNS complications associated with a vaginal delivery.

Requests for prenatal testing for conditions such as heterozygous hypochondroplasia are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although decisions about prenatal testing to be the choice of the parents, careful discussion of these issues is appropriate.

Low-risk pregnancy. A fetus with a de novo FGFR3 mutation causing hypochondroplasia who exhibits short limbs may be detected by routine ultrasound examination late in pregnancy [Jones et al 1990]. DNA-based diagnosis (i.e., FGFR3 p.Asn540Lys and p.Gly380Arg mutation analysis) via amniocentesis may be helpful in ruling out lethal forms of skeletal dysplasia and establishing a more favorable prognosis for 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
  • Human Growth Foundation (HGF)
    997 Glen Cove Avenue
    Suite 5
    Glen Head NY 11545
    Phone: 800-451-6434 (toll-free)
    Fax: 516-671-4055
    Email: hgf1@hgfound.org
  • Little People of America, Inc. (LPA)
    250 El Camino Real
    Suite 201
    Tustin CA 92780
    Phone: 888-572-2001 (toll-free); 714-368-3689
    Fax: 714-368-3367
    Email: info@lpaonline.org
  • MAGIC Foundation
    6645 West North Avenue
    Oak Park IL 60302
    Phone: 800-362-4423 (Toll-free Parent Help Line); 708-383-0808
    Fax: 708-383-0899
    Email: info@magicfoundation.org
  • Medline Plus
  • International Skeletal Dysplasia Registry
    Cedars-Sinai Medical Center
    116 North Robertson Boulevard, 4th floor (UPS, FedEx, DHL, etc)
    Pacific Theatres, 4th Floor, 8700 Beverly Boulevard (USPS regular mail only)
    Los Angeles CA 90048
    Phone: 310-423-9915
    Fax: 310-423-1528

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. Hypochondroplasia: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
FGFR34p16​.3Fibroblast growth factor receptor 3FGFR3 @ LOVDFGFR3

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 Hypochondroplasia (View All in OMIM)

134934FIBROBLAST GROWTH FACTOR RECEPTOR 3; FGFR3
146000HYPOCHONDROPLASIA; HCH

Normal allelic variants. The 4.3-kb cDNA has 19 exons and encodes an 806-residue protein (isoform 1).

Pathologic allelic variants. A recurrent mutation (c.1620C>A, p.Asn540Lys) in exon 13 that encodes the ATP-binding segment of the tyrosine kinase domain was found in eight of 14 individuals with hypochondroplasia and reported first by Bellus et al [1995]. Subsequently, another mutation at the same nucleotide resulting in the same amino acid substitution (c.1620C>G, p.Asn540Lys) was reported [Prinos et al 1995, Bellus et al 1996]. These two mutations account for the majority of over 200 reported cases of hypochondroplasia [Bellus et al 1995, Prinos et al 1995, Bellus et al 1996, Bonaventure et al 1996, Fofanova et al 1998, Matsui et al 1998, Prinster et al 1998, Ramaswami et al 1998]. Several other FGFR3 mutationshave been proposed as the cause of a small number of cases of hypochondroplasia. (For more information, see Table A.)

Table 2. FGFR3 Pathologic Allelic Variants that Cause Hypochondroplasia Discussed in this GeneReview

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid ChangeReference Sequences
c.829A>Gp.Tyr278Cys
c.1612A>Gp.Ile538ValNM_000142​.4
NP_000133​.1
c.1619A>Cp.Asn540Thr
c.1620C>A
(C1659A)
p.Asn540Lys
c.1620C>G
(C1659G)
p.Asn540Lys
c.1950G>Tp.Lys650Asn
c.1948A>Cp.Lys650Gln

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

For more information see Table 3 (pdf).

Normal gene product. Fibroblast growth factor receptor 3 is a receptor tyrosine kinase and ia member of the fibroblast growth factor receptor family. This family comprises four related genes in mammals (FGFR1 - FGFR4) with highly conserved structure. The FGFR genes are all characterized by an extracellular ligand-binding domain consisting of three immunoglobulin (Ig) subdomains, a transmembrane domain, and a split intracellular tyrosine kinase domain [Johnson & Williams 1993]. A stretch of four to eight acidic amino acids termed the acid box (whose function is not known) is found between the first and second Ig domains. Alternative splicing of FGFR transcripts results in several distinct mRNA isoforms that may lack one or more Ig domains, the acid box, or the intracellular tyrosine kinase domain. Some isoforms have regions of alternative sequence within the extracellular Ig domains. Exons eight and nine are alternatively spliced and encode different carboxyl termini of the third Ig domain. Alternative splicing of the FGFR genes is thought to modulate the affinity of the numerous FGFs for the receptor and may control other aspects of receptor-mediated signaling.

Abnormal gene product. The effects of the FGFR3 mutations on FGFR3 function have been shown to result in constitutive activation of the receptor tyrosine kinase [Naski et al 1996, Webster & Donoghue 1996, Webster et al 1996, Thompson et al 1997, Tavormina et al 1999]. It therefore seems likely that the FGFR3 mutations found in hypochondroplasia may result in constitutive activation of the receptor tyrosine kinase, but to a lesser degree than these other mutations. Such appears to be the case in hypochondroplasia resulting from p.Lys650Asn [G Bellus, D Donoghue, M Webster, C Francomano, unpublished results]. The premise that FGFR3 gain-of-function mutations cause skeletal dysplasia is supported by the observation that targeted disruption of FGFR3 in mice results in enhanced growth of long bones and vertebrae, suggesting that FGFR3 normally functions as a negative regulator of bone growth [Colvin et al 1996, Deng et al 1996].

References

Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page Image PubMed.jpg

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Chapter Notes

Author History

Arthur S Aylsworth, MD, FACMG; University of North Carolina (1999-2005)
Gary A Bellus, MD, PhD (1999-2005; 2013-present)
Michael B Bober, MD, PhD (2013-present)
Clair A Francomano, MD; National Institutes of Health (2005-2013)
Thaddeus E Kelly, MD, PhD; University of Virginia Hospital (1999-2005)
Sarah M Nikkel, MD (2013-present)
George E Tiller, MD, PhD (2013-present)

Revision History

  • 26 September 2013 (me) Comprehensive update posted live
  • 12 December 2005 (me) Comprehensive update posted to live Web site
  • 13 February 2003 (me) Comprehensive update posted to live Web site
  • 15 July 1999 (pb) Review posted to live Web site
  • 27 April 1999 (gb) Original submission
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Tests in GTR by Gene

Tests in GTR by Condition

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