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

Abstract

Fibroblast growth factor receptor 3 (FGFR3) is the only gene known to cause achondroplasia (ACH), hypochondroplasia (HCH), and thanatophoric dysplasia types I and II (TD I and TD II). A second, as yet unidentified, gene also causes HCH. In this study, we used sequencing analysis to determine the frequency of FGFR3 mutations for each phenotype in 324 cases from the International Skeletal Dysplasia Registry (ISDR). Our data suggest that there is a considerable overlap of genotype and phenotype between ACH and HCH. Thus, it is important to test for mutations found in either disorder when ACH or HCH is suspected. Only two of 29 cases with HCH did not have an identified mutation in FGFR3, much less than previously reported. We recommend testing other mutations in FGFR3, instead of just the common HCH mutation, p.Asn540Lys. The mutation frequency for TD I and TD II in the largest series of cases to date are also reported. This study provides valuable information on FGFR3 mutation frequency of four skeletal dysplasias for clinical diagnostic laboratories and clinicians.

Keywords: Achondroplasia; FGFR3; hypochondroplasia; mutation frequency; thanatophoric dysplasia.

Figure 1

Radiographs of a case of achondroplasia with a p.Asn540Lys mutation (R#00-347). (A) Pelvis and femur, age 3 years. Narrow sacrosciatic notches and femoral shortening. (B) AP lower legs, age 3 years. There is distal overgrowth of the fibulae. (C) AP spine, age 3 years, shows platyspondyly and interpediculate narrowing in the lumbar spine. (D) Lateral spine, age 3 years. Note a narrow spinal canal and a wedge vertebrae at L2. (E) PA, left hand, age 3 years. There is significant brachydactyly and brachymetacarpia.

Figure 2

Radiographs of a case of hypochondroplasia with a p.Gly380Arg mutation (R# 92-231A). (A) AP chest and pelvis, age 5 years. The sacrosciatic notch is narrowed, but there is no interpediculate narrowing. (B) AP legs, age 5 years. There is distal fibular overgrowth. (C) AP arm, age 5 years. There is only mild rhizomelic shortening. (D) Lateral lumbar spine, age 12.5 years. There is mild platyspondyly and a narrowed spinal canal. (E) PA left hand, age 5 years. Note the brachydactyly and brachymetacarpia. (F) PA, left hand, age 12.5 years. The brachymetacarpia is less pronounced than at age 5.