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Hypochondroplasia

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 itnerpedicular distances; short, broad femoral neck; and squared, shortened ilia. The skeletal features are very similar to achondroplasia but usually tend to be milder. Medical complications common to achondroplasia (e.g., spinal stenosis, tibial bowing, obstructive apnea) occur less frequently in hypochondroplasia but deficits in mental capacity and/or function may be more prevalent. Children usually present as toddlers or school-age children with failure to grow; with age, limb disproportion and other features become more prominent.

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 the age of three years, as skeletal disproportion tends to be mild and many of the radiographic features are subtle during infancy. DNA-based testing is available and about 70% of affected individuals are heterozygous for a mutation in the FGFR3 gene. However, it is clear that locus heterogeneity exists because mutations in other as-yet-unidentified genes can result in similar, if not identical, phenotypes.

Management.  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 mental deficiencies are addressed with special educational programs.

Genetic counseling. Hypochondroplasia is inherited in an autosomal dominant manner. It is assumed that the majority of new cases result from spontaneous mutations and that the unaffected parents of a child with hypochondroplasia have an extremely low risk (<0.01%) of having another affected child. An individual with hypochondroplasia who has a partner of average stature has 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 the high incidence of genetic heterogeneity and 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 1965 , Beals 1969 , Dorst 1969 , Walker et al 1971 , Kozlowski 1973 , Frydman et al 1974 , Specht & Daentl 1975 , Newman & Dunbar 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]. 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 most common clinical features of hypochondroplasia:

• 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 mental retardation
• Learning disabilities
• Adult-onset osteoarthritis

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

GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information. —ED.

Gene.   FGFR3 is the only gene known to be associated with hypochondroplasia; however, genetic heterogeneity is suspected. The actual proportion of locus heterogeneity in hypochondroplasia remains in question as a result of the inability of the current molecular assays to detect all possible FGFR3 mutations.

Other loci

• 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 were identified within introns of the IGF1 gene (12q23) that 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 the IGF1 gene.
• 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.

Molecular genetic testing: Clinical uses

• Confirmatory diagnostic testing
• Prenatal diagnosis

Molecular genetic testing: Clinical methods

• Targeted mutation analysis.  Two FGFR3 mutations (C1620A and C1620G) result in a lysine-for-asparagine substitution at codon 540 (N540K) in exon 10 and have been shown to cause hypochondroplasia [Bellus et al 1995 , Prinos et al 1995]. In studies in which a diagnosis was established by physical and radiologic criteria, 72% (133/184) of probands with hypochondroplasia were found to be heterozygous for the FGFR3 N540K mutation [Prinos et al 1995 , Bellus et al 1996 , Rousseau et al 1996 , Prinster et al 1998 , Ramaswami et al 1998 , Fofanova et al 1998]. The relative frequencies of the FGFR3 C1620A and C1620G mutations were 70% and 30%, respectively.

  Note: Mild achondroplasia caused by FGFR3 G380R mutations and severe hypochondroplasia caused by FGFR3 N540K mutations may have similar presentations and are easily confused. Therefore, it is important to test for both FGFR3 N540K and G380R (G1138A and G1138C) mutations when DNA testing is requested for hypochondroplasia.

• Sequence analysis of select exons.  Sequence analysis of FGFR3 exons 9, 10, 13, and 15 detects other rare FGFR3 mutations that account for fewer than 2% of FGFR3 mutations associated with hypochondroplasia. These include: A1619C: N540T [Deutz-Terlouw et al 1998], A1619G: N540S [Mortier et al 2000], A1612G: I538V [Grigelioniene et al 1998], A983T: N328I [Winterpacht et al 2000], and G1650T/C: K650N and A1948C: K650Q [Bellus et al 2000]. Sequence analysis of exon 10 (which allows detection of the G380R mutation associated with achondroplasia) is included because of the clinical overlap between mild achondroplasia and severe hypochondroplasia.

Table 1 summarizes molecular genetic testing for this disorder.

Table 1. Molecular Genetic Testing Used in Hypochondroplasia Test Method Mutations Detected Mutation Detection Rate Test Availability Targeted mutation analysis  1 N540K (C1620A) 49% Clinical N540K (C1620G) 21% Sequence analysis of select exons Mutations in FGFR3 exons 9, 10, 13, and 15 80%

1. Based on testing of 188 individuals with hypochondroplasia

Interpretation of test results.  For issues to consider in interpretation of sequence analysis results, click here.

Genetically Related Disorders

The other phenotypes associated with mutations in the FGFR3 gene:

• Thanatophoric dysplasia
• Achondroplasia . It should be noted that mild cases of achondroplasia caused by FGFR3 G380R mutations and severe cases of hypochondroplasia caused by FGFR3 N540K mutations may have very similar clinical presentations and are thus easily confused. Therefore, it is important to test for both FGFR3 N540K and G380R (G1138A and G1138C) mutations when DNA testing is requested for hypochondroplasia.
• FGFR-related craniosynostosis

Clinical Description

Natural History

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 failure to grow. 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., midface hypoplasia, frontal bossing) are not generally seen. Head size may be large without significant disproportion. Multiple suture craniosynostosis has been reported in one case [Angle et al 1998]. 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].

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." 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]. Some investigators have reported the absence of a pubertal growth spurt [Appan et al 1990 , Bridges et al 1991]. 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]. Joint pain, back pain, and other symptoms of osteoarthritis may occur later in life.

The incidence of mental retardation 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 and Patton 1991]. It is difficult to determine whether these discrepancies result from sampling bias and/or genetic heterogeneity. It is clear that more studies with rigorous diagnostic criteria are required to resolve this issue. The authors' preliminary studies [Bellus & Francomano, unpublished results] suggest that individuals with FGFR3 N540K mutations may have an increased incidence of mild-to-moderate mental retardation or learning disabilities.

Genotype-Phenotype Correlations

Genotype-phenotype correlations are beginning to appear in hypochondroplasia but are complicated by the lack of universal acceptance of a set of diagnostic clinical criteria.

• As one would expect, no difference exists in phenotype between the C1620A and C1620G mutations as they both result in identical mutant proteins. In general, it appears that the phenotypes of individuals diagnosed with hypochondroplasia who have FGFR3 N540K mutations (C1620A and C1620G) have more severe manifestations than those with hypochrondroplasia who do not have these mutations [Rousseau et al 1996 , Ramaswami et al 1998 , Prinster et al 1998]. Currently, however, there is no consensus as to which specific clinical features distinguish FGFR3 N540K hypochondroplasia from hypochondroplasia caused by other FGFR3 mutations or from non- FGFR3 hypochondroplasia.
• Rousseau et al (1996) studied 29 individuals with hypochondroplasia and found that 21 (72%) had FGFR3 N540K while three families without this mutation were not linked to FGFR3, supporting locus heterogeneity. Affected individuals who showed exclusion of linkage to 4p16.3 demonstrated milder radiographic findings (i.e., normal hands and long bones without metaphyseal flaring). Prinster et al (1998) studied 18 individuals with hypochondroplasia and found that nine had FGFR3 N540K mutations. No significant differences in height or body proportions were noted between the two groups. Brachydactyly, although present in equal proportions in both groups, was noted to be generally more severe in individuals with N540K mutations. Ramaswami et al (1998) screened 65 children with hypochondroplasia and found that 28 (43%) were heterozygous for FGFR3 N540K mutations. Individuals with these mutations were noted to be more disproportionate with regard to sitting height and subischial leg length than those without the mutation. More recently, Ramaswami et al (1999) have reported that children with FGFR3 N540K mutations respond to growth hormone therapy with disproportionate elongation of the trunk versus the limbs.
• The K650N and K650Q mutations are associated with a slightly milder skeletal phenotype than N540K mutations. Bellus et al (2000) reported six individuals with K650N or K650Q mutations who had a significantly lower average height deficit than 36 individuals with N540 mutations. 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 N540S mutations. 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.

Hypochondroplasia-achondroplasia compound heterozygotes (FGFR3 N540K - G380R) have been reported [McKusick et al 1973 , Sommer et al 1987 , Bellus et al 1995 , Huggins et al 1997 , Flynn & Pauli 2003]. The skeletal phenotype is more severe than typically found in achondroplasia, but unlike homozygous achondroplasia, is compatible with survival. 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 K540N FGFR3 mutation, and had severe short stature with both rhizomelic and mesomelic shortening of the limbs.

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).

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 disorder 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) are associated with advanced paternal age. Simplex cases of hypochondroplasia caused by the FGFR3 N540K 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 G380R mutation, while both N540K mutations 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 achondroplasia
• Mild forms of metaphyseal chondrodysplasias
• Mild forms of mesomelic dwarfism
• Mild forms of spondylo-epiphyseal-metaphyseal dysplasias
• Leri-Weill dyschondrosteosis
• Pseudohypoparathyroidism and pseudopseudohypoparathyroidism
• Short stature caused by disturbances in the growth hormone axis
• Constitutive short stature

Management

Evaluations at Initial Diagnosis to Establish the Extent of Disease

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 (1995) should be considered in children with hypochondroplasia who exhibit more severe phenotypic features. These recommendations include but are not limited to the following:

• 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 if needed
• Screening developmental assessment
• MRI or CT examination of the foramen magnum if findings suggest severe hypotonia or spinal cord compression
• History for evidence of sleep apnea, with formal sleep study if suggestive
• 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

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.

Prevention of Secondary Complications

• 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 mental retardation 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 if suggestive.
• MRI or CT examination of the foramen magnum is indicated if there is evidence of severe hypotonia or spinal cord compression.
• 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.

Therapies Under Investigation

Trials of growth hormone therapy in hypochondroplasia have shown mixed results. Several reports indicate that some individuals respond well with increased proportional height velocity, others respond with increased disproportionate growth, and some do not respond [Appan et al 1990 , Mullis et al 1991 , Bridges et al 1991]. These differences in individual responses may result 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). While a response to growth hormone has been sustained in some individuals for as long as six years [Bridges & Brook 1994], data about final adult height in these individuals are not yet available and the ultimate success of this approach remains uncertain. Meyer et a l (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. Kanazawa et al (2003) also reported a response to growth hormone among children with hypochondroplasia. Growth hormone therapy is still considered experimental and controversial.

Surgical limb lengthening procedures have been used to treat achondroplasia and hypochondroplasia for over ten 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]. 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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory. —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 normal 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 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 upon 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 below).
• 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 mutations causing hypochondroplasia and achondroplasia and in whom the hypochondroplasia results from an FGFR3 N540K mutation have a severe skeletal phenotype with fthe potential for serious disability [McKusick et al 1973 , Sommer et al 1987 , Huggins et al 1997].

  • 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

  Therefore, it is not possible to provide information about prognosis for all at-risk offspring.

Other family members of a proband.  The risk to other family members depends upon the status of the proband's parents. If a parent is found to be 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. In fact, 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 mental retardation 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 undisclosed adoption could also be explored.

Family planning.  The optimal time for determination of genetic risk and availability of prenatal testing is before pregnancy.

DNA banking.  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. DNA banking is particularly relevant in situations in which the sensitivity of currently available testing is less than 100%. See DNA Banking for a list of laboratories offering this service.

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 15-18 weeks' gestation or chorionic villus sampling (CVS) at about 10-12 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 in 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 most centers would consider 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 N540K and G380R mutation analysis) via amniocentesis may be helpful in ruling out lethal forms of skeletal dysplasia and establishing a more favorable prognosis for the fetus.

Molecular Genetics

Information in the Molecular Genetics tables may differ from that in the text; tables may contain more recent information. —ED.

Normal allelic variants: For a detailed discussion, see the GeneReviews entry for achondroplasia .

Pathologic allelic variants: A recurrent mutation (C1620A: N540K) 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 (C1620G: N540K) was reported [Prinos et al 1995 , Bellus et al 1996] (Prinos et al refer to the mutations as C1659A and C1659G). 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 , Matsui et al 1998 , Prinster et al 1998 , Ramaswami et al 1998 , Fofanova et al 1998]. Several other FGFR3 mutations, A1619C: N540T [Deutz-Terlouw et al 1998], A1619G: N540S [Mortier et al 2000], A1612G: I538V [Grigelioniene et al 1998], A983T: N328I [Winterpacht et al 2000], G1650T/C: K650N, and A1948C: K650Q [Bellus et al 2000] have been proposed as the cause of a small number of cases of hypochondroplasia. (For more information, see Genomic Databases table above.)

Normal gene product: Fibroblast growth factor receptor 3. The FGFR3 gene product is a receptor tyrosine kinase and is a member of the fibroblast growth factor receptor family. This family comprises four related genes in mammals (FGFRs 1-4) 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 exon 13 FGFR3 mutations (N540K, N540T, and I538V) on FGFR3 function have not yet been established. However, several other FGFR3 mutations associated with other, more severe skeletal dysplasias including achondroplasia (G380R and G375C), thanatophoric dysplasia type 1 (R248C), thanatophoric dysplasia type 2 (K650E) and SADDAN (K650N) 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 the K650N hypochondroplasia mutation [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 the FGFR3 gene 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].

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