Hypochondroplasia: Molecular Analysis of the Fibroblast Growth Factor Receptor 3 Gene

Abstract

Hypochondroplasia is an autosomal-dominant, human skeletal dysplasia with features similar to, but milder than those found in achondroplasia. Although thought to be relatively common, a comprehensive determination of its incidence and prevalence has not been published. It is thought that many mildly affected individuals do not seek medical intervention and may be difficult to distinguish from individuals with short stature but without skeletal dyspla~ia.~ Most cases of hypochondroplasia occur sporadically as a result of new mutations. The diagnosis is difficult to make in infancy and is usually made in early childhood with the majority of cases being diagnosed between one and five years of age.2.4 Many cases are first referred for endocrinologic evaluation of short ~t a t u r e .~ The diagnosis of hypochondroplasia is based on clinical and radiographic findings. Affected individuals have short stature with disproportionately short limbs. The average heights of adults are 146.1 cm in males and 137.6 cm in females4 Faces and hands tend to be normal, although macrocephaly is observed in more than 50% of affected individual^.^.^ Limitation of elbow extension, varus deformity of the lower extremities, and lumbar lordosis are observed frequently, but are usually not as severe as seen in achondroplasia. Spinal stenosis, a common problem in achondroplasia, is

FGFR3 mutation frequency in 324 cases from the International Skeletal Dysplasia Registry

“…Incomplete screening may explain the 70% detection rate for FGFR3 mutations in HCH It has been reported that about 30% of HCH cases do not have a mutation in FGFR3 (Prinos et al 1995;Bellus et al 1996;Rousseau et al 1996a,b,c;Fofanova et al 1998;Prinster et al 1998;Ramaswami et al 1998). We found that p.Asn540Lys, p.Gly380Arg, and p.Lys650Gln mutations in FGFR3 together account for about 90% of the cases.…”

Differential Activation of Cysteine-Substitution Mutants of Fibroblast Growth Factor Receptor 3 Is Determined by Cysteine Localization

“…Mutations in the proximal tyrosine kinase domain (N540K) give rise to an even milder disorder called hypochondroplasia. (13) The most severe of these syndromes is the neonatal, lethal TDII (K650E), which is caused by a mutation in the kinase activation loop. (14) It is intriguing that the cysteine substitutions at residues 370 -371 and 373 lead to the lethal TDI and the nearby G375C mutation results in the less severe achondroplasia.…”

Hypochondroplasia in a Child With 1620c>G (Asn540lys) Mutation in FGFR3

“…1620C>A and 1620C>G mutations which lead to Asn540Lys aminoacid substitution are detected in approximately 50-70% of affected individuals (4). Codon 540 in exon 13 is a major hotspot (7). The other mutations of this gene account for fewer than 2% of HCP patients (8).…”