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, 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 intellectual disability

• 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

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 IGF1 (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 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 uses

• Confirmatory diagnostic testing

• Prenatal diagnosis

Clinical testing

• 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. Summary of Molecular Genetic Testing Used in Hypochondroplasia

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
FGFR3	Targeted mutation analysis 1	N540K (C1620A)	49%	Clinical
		N540K (C1620G)	21%
	Sequence analysis of select exons	Mutations in exons 9, 10, 13, and 15	80%

Test Availability refers to availability in the GeneTests Laboratory Directory. 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.

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

2. 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 FGFR3:

• 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

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 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 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 intellectual disability 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 1999, 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.

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 [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 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 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 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. 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.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

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 Molecular Genetics).

• 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 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

• 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 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. 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 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 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 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. See for a list of laboratories offering DNA banking.

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 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.

Literature Cited

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Author History

Arthur S Aylsworth, MD, FACMG; University of North Carolina (1999-2005)
Gary A Bellus, MD, PhD; University of Colorado Health Sciences Center (1999-2005)
Clair A Francomano, MD (2005-present)
Thaddeus E Kelly, MD, PhD; University of Virginia Hospital (1999-2005)

Revision History

• 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