Hypochondroplasia

A number sign (#) is used with this entry because of evidence that hypochondroplasia can be caused by mutation in the gene for fibroblast growth factor receptor-3 (FGFR3; 134934), located on 4p, which is consistently mutated in achondroplasia (ACH; 100800). Not all patients with presumed hypochondroplasia have demonstrable mutations in the FGFR3 gene, suggesting genetic heterogeneity.

Description

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).

Nomenclature

Lamy and Maroteaux (1961) suggested the term hypochondroplasia.

Clinical Features

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.

Inheritance

Beals (1969) described 5 kindreds with clear evidence of autosomal dominant inheritance. Both father-to-daughter and mother-to-daughter transmission have been reported.

Diagnosis

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.

Molecular Genetics

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.

By using microarray-based next-generation sequencing to study a Chinese woman with hypochondroplasia, Wang et al. (2013) identified a G342C mutation (134934.0036) in the extracellular IgIII loop of FGFR3. The mutation was also found in the woman's fetus when ultrasound scan detected a short femur and dwarfism. Wang et al. (2013) concluded that the sequencing procedure enabled a correct diagnosis, distinguishing HCH from other skeletal dysplasias.

Heterogeneity

Mullis et al. (1991) reported findings suggesting that some cases of hypochondroplasia are caused by a defect in insulin-like growth factor I (IGF1; 147440). They studied 20 children with short stature attributed to hypochondroplasia by radiologic and clinical criteria who were undergoing treatment with recombinant human growth hormone. The frequency of a particular heterozygous pattern of restriction fragments was significantly higher in children with hypochondroplasia than in the control groups. The hypochondroplastic children whose response to r-hGH treatment was characterized by a proportionate increase in both spinal and subischial leg length were all heterozygous for 2 coinherited IGF1 RFLP alleles. Those children whose response was characterized by accentuation of the body disproportion by r-hGH treatment were all homozygous for these alleles. Studies of 5 families containing heterozygous children demonstrated strong linkage (lod score = 3.311 at 0 recombination) of the IGF1 locus to this subgroup of hypochondroplasia. An allele at each of 2 RFLP loci were in strong linkage disequilibrium with this trait.

Stoilov et al. (1995) found the G380R mutation in the FGFR3 gene (134934.0001) in 21 of 23 achondroplasia patients but in none of 8 hypochondroplasia patients studied. Furthermore, linkage studies in a 3-generation family with hypochondroplasia showed discordant segregation with markers in the 4p16.3 region where the achondroplasia locus is situated, suggesting that at least some cases of hypochondroplasia are caused by mutations in a gene other than FGFR3.

Genetic heterogeneity of hypochondroplasia seemed to be evident in the patients reported by Flynn and Pauli (2003), who were thought to be double heterozygotes for mutations at the FGFR3 locus and another unidentified locus. The female probands were dichorionic, diamniotic twins born to a mother with achondroplasia and a father with hypochondroplasia. Mutation of the FGFR3 gene was not identified in the father by either molecular testing for the common hypochondroplasia mutation or by sequencing of the FGFR3 gene.