Genotype phenotype correlation in achondroplasia and hypochondroplasia

Abstract

R ecent studies of the fibroblast growth factor receptor 3 (FGFR3) gene have established that achondroplasia and hypochondroplasia are allelic disorders of different mutations.To determine whether the genotype could be distinguished on the basis of the phenotype, we analysed height, arm span, and skeletal radiographs from 23 patients with achondroplasia and the G380R mutation of FGFR3 and eight with hypochondroplasia and the N540K mutation. Both conditions share the classical pathological features of micromelic short stature, reduced or unchanged interpedicular distances in the lumbar spine, disproportionately long fibulae, and squared and shortened pelvic ilia. These were significantly more severe in the G380R patients than in the N540K patients.Our About 60% of patients with HCH have been reported to have an asparagine-to-lysine substitution at residue 540 (N540K) of FGFR3. 10,11 Although the genotypic background of the remaining cases of HCH has not been clarified, the N540K substitution seems to be responsible for a significant proportion of cases of this condition. 12-14In spite of a long history of observations suggesting allelism between ACH and HCH, 15 it has been claimed that the clinical and radiological features of ACH and HCH overlap. 16,17 We have compared the phenotype of genotyped populations to clarify whether or not each of these two genotypes has a distinctive phenotype. Patients and MethodsBlood samples were collected from patients clinically diagnosed as having ACH and HCH, and the FGFR3 genotype was determined as previously described. 18 There were 23 patients with ACH and the G380R substitution, 11 boys and 12 girls with a mean age of 10.0 years (5 to 18). Of the eight HCH patients with the N540K substitution, there were five boys and three girls with a mean age of 11.6 years (7 to 18), all of whom had sporadic mutations. We also assessed 30 genetically normal individuals as a control group. There were 17 boys and 13 girls with a mean age of 11.1 years (3 to 17). We analysed height, arm span and skeletal radiographs. Height was evaluated by the height standard deviation score which was obtained from standard growth curves for the Japanese population. Arm span was examined by calculating the span to height ratio percentage.We studied three of the pathological features of ACH and HCH. [19][20][21] We assessed the ratio of the interpedicular distances at the first and fourth lumbar vertebrae (L1/L4 ratio, Fig. 1a) irrespective of whether they were reduced or not.We also determined the ratio of the length of the fibula to that of the tibia (F/T ratio, Fig. 1b) to ascertain whether the

Novel FGFR3 mutations creating cysteine residues in the extracellular domain of the receptor cause achondroplasia or severe forms of hypochondroplasia

“…In some patients, the clinical features are very subtle making the diagnosis of HCH difficult in those cases. 1,2 Genetically, those diseases are allelic and have been shown to be associated with recurrent mutations in the FGFR3 gene encoding one member of the FGFR subfamily of tyrosine kinase (TK) receptors. 3 -5 The four FGFR (1 -4) members share a common organisation comprising three extracellular immunoglobulin-like loops (Ig I -III), one hydrophobic transmembrane (TM) domain and two cytoplasmic TK sub-domains TK1 and TK2 responsible for the catalytic activity.…”

New proposed clinico‐radiologic and molecular criteria in hypochondroplasia: FGFR 3 gene mutations are not the only cause of hypochondroplasia

“…HCH is a relatively mild form of skeletal dysplasia, characterized by significant variability and heterogeneity in its clinical, radiological, and genetic manifestations, leading to controversies regarding its diagnosis [Matsui et al, 1998;Prinster et al, 1998;Lemyre et al, 1999]. A number of authors have proposed specific criteria for the diagnosis of HCH.…”

“…The grading system has been made for objective expression for clinical features which can be subjective [Wynne-Davies, 1970] (Table II). Radiologic parameters were: (1) fibula/tibia ratio; (2) anteroposterior (AP) L1/L4 interpedicular distance ratio; (3) lateral (lat) L1/L4 pedicle length ratio; (4) humerus/radius length ratio; (5) femur/tibia length ratio; and (6) pelvic index (interteardrop distance divided by the largest width of the pelvis) [Matsui et al, 1998]. Forty-nine patients of ACH were included for the study only to provide clinical and radiological comparison to the main HCH study group.…”

“…Radiologic characteristics consist of rhizo- [Grigelioniene et al, 2000] or mesomelic [Beals, 1969] shortening of the long bones with mild metaphyseal flare, decreased inferior lumbar interpedicular distances, short inferior lumbar pedicles, coxa breva, and squared shortened ilia. Matsui et al [1998] previously reported genotype-phenotype correlations in HCH and ACH in Japanese patients, and concluded that more severe manifestations are associated with FGFR3 G380R mutations producing ACH and milder manifestations are associated with FGFR3 N540K mutations producing HCH. Mild ACH, however, may have phenotypic overlap with severe HCH [Wynne-Davies et al, 1981;Matsui et al, 1998;Ross et al, 2003].…”

“…Matsui et al [1998] previously reported genotype-phenotype correlations in HCH and ACH in Japanese patients, and concluded that more severe manifestations are associated with FGFR3 G380R mutations producing ACH and milder manifestations are associated with FGFR3 N540K mutations producing HCH. Mild ACH, however, may have phenotypic overlap with severe HCH [Wynne-Davies et al, 1981;Matsui et al, 1998;Ross et al, 2003].…”