Hypochondroplasia is a autosomal dominant disorder characterized by short-limbed dwarfism, lumbar lordosis, short and broad bones, and caudad narrowing of the interpediculate distance of the lumbar spine. It shows some resemblance to achondroplasia, but is much milder and ... Hypochondroplasia is a autosomal dominant disorder characterized by short-limbed dwarfism, lumbar lordosis, short and broad bones, and caudad narrowing of the interpediculate distance of the lumbar spine. It shows some resemblance to achondroplasia, but is much milder and can be distinguished on clinical and radiographic grounds (Walker et al., 1971).
The diagnosis of hypochondroplasia on clinical and radiologic grounds is often uncertain. Appan et al. (1990) studied growth and growth hormone therapy in 84 patients with hypochondroplasia, which they suggested could be diagnosed on the basis of 'short ... The diagnosis of hypochondroplasia on clinical and radiologic grounds is often uncertain. Appan et al. (1990) studied growth and growth hormone therapy in 84 patients with hypochondroplasia, which they suggested could be diagnosed on the basis of 'short stature with near-normal craniofacies and the invariable radiographic finding of a failure of increase in the interpedicular distance in the lumbar spine from L1 to L5 in the absence of any other gross measurable radiological abnormality.' If one defines hypochondroplasia as an achondroplasia-like disorder with mutation in the FGFR3 gene, i.e., a mild allelic form of achondroplasia, it is likely that use of the above criteria would lead to many false-positive diagnoses when checked against a complete mutation search of the FGFR3 gene.
Beals (1969) reported 5 kindreds segregating hypochondroplasia. He found that the limbs in this disorder are usually short, without rhizomelia, mesomelia, or acromelia, but may have mild metaphyseal flaring. Brachydactyly and mild limitation in elbow extension can be ... Beals (1969) reported 5 kindreds segregating hypochondroplasia. He found that the limbs in this disorder are usually short, without rhizomelia, mesomelia, or acromelia, but may have mild metaphyseal flaring. Brachydactyly and mild limitation in elbow extension can be evident. Spinal manifestations may include anteroposterior shortening of lumbar pedicles. The spinal canal may be narrowed or unchanged caudally. Lumbar lordosis may be evident. Specht and Daentl (1975) reported 6 new cases of hypochondroplasia with moderate rhizomelic shortness of stature and normal craniofacial appearance and hand configuration. Glasgow et al. (1978) described 3 patients with hypochondroplasia. Clues to the diagnosis were abnormality of body proportions with short limbs and lumbar lordosis, but without the extreme short stature or facial features of achondroplasia, and short, stubby hands and feet. Radiologic features included long bones that were shorter than the normal range for age, as well as broader and slightly bowed with mildly flared metaphyses. Vertebral changes consisted of mild tapering of the spinal canal and low articulation of the sacrum on the iliac bones. The pelvis was small with normal flaring of the iliac wings. Two of the patients had a large head with delayed closure of the fontanels. In a review of 39 cases of hypochondroplasia, Hall and Spranger (1979) found that macrocephaly was noted in approximately half of cases. Evidence that hypochondroplasia and achondroplasia are allelic disorders came from the observation of the presumed genetic compound in an offspring of an achondroplastic father and a hypochondroplastic mother (McKusick et al., 1973). Sommer et al. (1987) gave a follow-up on this child at age 14 years. The patient had severe neurologic impairment and increased deep tendon reflexes and clonus. She had very little speech and could not walk. Her mental scale was placed at about 1 year when tested at age 10.
Bellus et al. (1995) demonstrated that a recurrent mutation in the tyrosine kinase domain of FGFR3 was present in 8 of 14 unrelated patients with hypochondroplasia. The mutation caused a C-to-A transversion at nucleotide 1620, resulting in an ... Bellus et al. (1995) demonstrated that a recurrent mutation in the tyrosine kinase domain of FGFR3 was present in 8 of 14 unrelated patients with hypochondroplasia. The mutation caused a C-to-A transversion at nucleotide 1620, resulting in an asn540-to-lys substitution in the proximal tyrosine kinase domain (134934.0010). Thus, hypochondroplasia and achondroplasia are indeed allelic as are also thanatophoric dysplasia type I (e.g., 134934.0004) and type II (e.g., 134934.0005). Since 6 of the 14 patients with hypochondroplasia did not carry the asn540-to-lys mutation, hypochondroplasia may be caused by mutation in some other gene or perhaps by other undetected mutations in FGFR3. Review of the medical records of the hypochondroplasia patients revealed no obvious phenotypic differences between individuals who did or did not have the asn540-to-lys mutation of FGFR3. Rousseau et al. (1996) examined 13 patients with sporadic hypochondroplasia and 16 probands from familial cases. In all sporadic cases and in 8 of 16 familial cases, the N540K mutation of the FGFR3 gene, located on 4p16.3, was found. In 6 familial cases, linkage to 4p16 was excluded; 2 families were uninformative. Clinical comparison showed that patients unlinked to 4p16 generally had a milder phenotype. Prinster et al. (1998) selected 18 patients with a phenotype compatible with hypochondroplasia based on the most common radiologic criteria. The presence of the N540K mutation was verified by restriction enzyme digestions in 9 of the 18 patients. Although similar in phenotype to patients without the mutation, these 9 had the additional feature of relative macrocephaly. Furthermore, the association of the unchanged or narrow interpedicular distance with the fibula longer than the tibia was more common in patients with the N540K mutation. Ramaswami et al. (1998) screened 65 children with hypochondroplasia diagnosed by clinical and radiologic criteria for 2 previously described mutations, 1620C-A (134934.0010) and 1620C-G (134934.0012), in FGFR3; 28 (43%) of the 65 patients were heterozygous for the 1620C-A transversion, resulting in a lys540-to-asn substitution in the tyrosine kinase domain of FGFR3. Children with the common 1620C-A mutation met all the criteria for the diagnosis of HCH with a severe phenotype resembling that of achondroplasia, and disproportionate stature in early childhood. Patients without the 1620C-A mutation were proportionately short and presented at an older age with the same radiologic characteristics as in HCH and the same failure of the puberty growth spurt. The latter group did not come to attention until a mean age of 10.45 years, whereas the group with the 1620C-A mutation had a mean age at diagnosis of 5.8 years. Huggins et al. (1999) reported an 8-month-old girl with achondroplasia/hypochondroplasia whose father had the G380R achondroplasia mutation (134934.0001) in the FGFR3 gene and whose mother had the N450K hypochondroplasia mutation (134934.0010). Chitayat et al. (1999) simultaneously reported an infant boy with achondroplasia/hypochondroplasia whose mother had the G380R mutation and whose father had the N450K mutation. Molecular analysis confirmed the compound heterozygosity of both children, who displayed an intermediate phenotype that was more severe than either condition in the heterozygous state but less severe than homozygous ACH. Mortier et al. (2000) reported a father and daughter with clinical and radiographic features of hypochondroplasia who were heterozygous for an A-to-G transition resulting in the replacement of an asparagine residue at position 540 by a serine residue (134934.0023). They noted the important role of the asn540 site in the tyrosine kinase I domain in the pathogenesis of hypochondroplasia and recommended that, in patients with hypochondroplasia who do not have the common N540K mutation, sequence analysis of the tyrosine kinase I domain of FGFR3 should be performed to exclude other changes in that region. Heuertz et al. (2006) screened 18 exons of the FGFR3 gene in 25 patients with hypochondroplasia and 1 with achondroplasia in whom the common mutations G380R and N540K had been excluded. The authors identified 7 novel missense mutations, 1 in the patient with achondroplasia (S279C; 134934.0030) and 6 in patients with hypochondroplasia (see, e.g., Y278C, 134934.0031 and S84L, 134934.0032); no mutations were detected in the remaining 19 patients who were diagnosed clinically with hypochondroplasia. Heuertz et al. (2006) noted that 4 of the 6 extracellular mutations created additional cysteine residues and were associated with severe phenotypes. Leroy et al. (2007) identified a missense mutation in the FGFR3 gene (134934.0022) in a girl with a mild form of hypochondroplasia who was also diagnosed with acanthosis nigricans at 8 years of age.
The clinical and radiologic diagnostic criteria for hypochondroplasia remain controversial for several reasons, including the following:...
DiagnosisClinical DiagnosisThe 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]. 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 disabilityLearning 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 TestingGene. 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. Evidence for locus heterogeneityUsing 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 (c.1620C>A and c.1620C>G) result in a lysine-for-asparagine substitution at codon 540 (p.Asn540Lys) 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 p.Asn540Lys mutation [Prinos et al 1995, Bellus et al 1996, Rousseau et al 1996, Fofanova et al 1998, Prinster et al 1998, Ramaswami et al 1998]. The relative frequencies of the FGFR3 c.1620C>A and c.1620C>G mutations were 70% and 30%, respectively. Note: Mild achondroplasia caused by FGFR3 p.Gly380Arg mutations and severe hypochondroplasia caused by FGFR3 p.Asn540Lys mutations may have similar presentations and are easily confused. Therefore, it is important to test for both FGFR3 p.Asn540Lys and p.Gly380Arg (c.1138G>A and c.1138G>C) 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: c.1619A>C: p.Asn540Thr [Deutz-Terlouw et al 1998], c.1619A>G: p.Asn540Lys [Mortier et al 2000], c.1612A>G: p.Ile538Val [Grigelioniene et al 1998], c.983A>T: p.Asn328Ile [Winterpacht et al 2000], and c.1650G>T/C: p.Lys650Asn and c.1948A>C: p.Lys650Gln [Bellus et al 2000]. Sequence analysis of exon 10 (which allows detection of the p.Gly380Arg 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 HypochondroplasiaView in own windowGene SymbolTest Method Mutations Detected Mutation Detection Frequency by Test Method 1Test Availability FGFR3Targeted mutation analysis 2 p.Asn540Lys (c.1620C>A) 49% Clinical p.Asn540Lys (c.1620C>G) 21% Sequence analysis of select exonsMutations in exons 9, 10, 13, and 15 80% 1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Based on testing of 188 individuals with hypochondroplasiaInterpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Genetically Related DisordersThe other phenotypes associated with mutations in FGFR3: Thanatophoric dysplasia Achondroplasia. It should be noted that mild cases of achondroplasia caused by FGFR3 p.Gly380Arg mutations and severe cases of hypochondroplasia caused by FGFR3 p.Asn540Lys mutations may have very similar clinical presentations and are thus easily confused. Therefore, it is important to test for both FGFR3 p.Asn540Lys and p.Gly380Arg (c.1138G>A and c.1138G>C) mutations when DNA testing is requested for hypochondroplasia. FGFR-related craniosynostosis
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]....
Natural HistoryThe 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 p.Asn540Lys mutations may have an increased incidence of mild-to-moderate intellectual disability or learning disabilities.
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:...
Differential DiagnosisNumerous 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
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 [AAPCG 1995] should be considered in children with hypochondroplasia who exhibit more severe phenotypic features. These recommendations include but are not limited to the following:...
ManagementEvaluations Following Initial DiagnosisEvaluation 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 [AAPCG 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 ManifestationsManagement 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 ComplicationsThe following are appropriate:Standard management of frequent middle ear infections Consideration of surgery if neurologic status is affected by spinal cord compression SurveillanceHeight, 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. Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationTrials 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, Bridges et al 1991, Mullis 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.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDFGFR34p16.3Fibroblast growth factor receptor 3FGFR3 @ LOVDFGFR3Data 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) View in own window 134934FIBROBLAST GROWTH FACTOR RECEPTOR 3; FGFR3 146000HYPOCHONDROPLASIA; HCHNormal allelic variants. For a detailed discussion, see achondroplasia. 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] (Prinos et al refer to the mutations as c.1659C>A and c.1659C>G). 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, Fofanova et al 1998, Prinster et al 1998, Ramaswami et al 1998]. Several other FGFR3 mutations, c.1619A>C: p.Asn540Thr [Deutz-Terlouw et al 1998], c.1619A>G: p.Asn540Ser [Mortier et al 2000], c.1612A>G: p.Ile538Val [Grigelioniene et al 1998], c.983A>T: p.Asn328Ile [Winterpacht et al 2000], c.1650G>T/C: p.Lys650Asn, and c.1948A>C: p.Lys650Gln [Bellus et al 2000] have been proposed as the cause of a small number of cases of hypochondroplasia. (For more information, see Table A.) Normal gene product. Fibroblast growth factor receptor 3. FGFR3 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 (p.Asn540Lys, p.Asn540Thr, and p.Ile538Val) on FGFR3 function have not yet been established. However, several other FGFR3 mutations associated with other, more severe skeletal dysplasias including achondroplasia (p.Gly380Arg and p.Gly375Cys), thanatophoric dysplasia type 1 (p.Arg248Cys), thanatophoric dysplasia type 2 (p.Lys650Glu) and SADDAN (p.Lys650Asn) 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 p.Lys650Asn 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 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].