Hypochondroplasia and acanthosis nigricans: a new syndrome due to the p.Lys650Thr mutation in the fibroblast growth factor receptor 3 gene?

Abstract

Background: Hypochondroplasia (HCH) is a skeletal dysplasia inherited in an autosomal dominant manner due, in most cases, to mutations in the fibroblast growth factor receptor 3 (FGFR3). Acanthosis nigricans (AN) is a velvety and papillomatous pigmented hyperkeratosis of the skin, which has been recognized in some genetic disorders more severe than HCH involving the FGFR3 gene. Objective and design: After initial study of the proband, who had been consulted for short stature and who also presented AN, the study was extended to the patient's mother and to 12 additional family members. Methods: Clinical, biochemical and radiological studies were performed on the family. In addition, exons 11 and 13 of FGFR3 were analyzed. Results: The proband and ten relatives presented HCH plus AN and the analysis of FGFR3 showed the p.Lys650Thr mutation. The members with normal phenotypes were non-carriers of the mutation. Conclusion: This is the first report of a large pedigree with the clinical phenotype of HCH plus AN due to a FGFR3 mutation, p.Lys650Thr. This finding demonstrates the coexistence of both conditions due to the same mutation and it might represent a true complex, which should be further established by searching for AN in mild HCH patients or for HCH in patients with AN.

Cracking the Molecular Origin of Intrinsic Tyrosine Kinase Activity through Analysis of Pathogenic Gain-of-Function Mutations

“…The Lys650Asn and Lys650Gln mutations lead to hypochondroplasia (HCH), a mild form of dwarfism (Bellus et al, 1995; Bellus et al, 2000). The Lys650Thr mutation causes an even milder form of HCH (Berk et al, 2007; Castro-Feijoo et al, 2008). In vitro autophosphorylation assays have shown that these mutations confer different degrees of ligand-independent activation on FGFR kinase, and that the degree of aberrant activation correlates with the clinical severity of the dwarfism syndromes caused by the mutations (Bellus et al, 2000).…”

Acanthosis Nigricans and Insulin Sensitivity in Patients with Achondroplasia and Hypochodroplasia due to FGFR3 Mutations

“…Recently, familial AN without any obvious skeletal abnormality has been reported in association with a mutation in FGFR3 (p.K650T) (3). Interestingly, the same mutation has also been found in a family with hypochondroplasia (HCH) and extensive AN (4). There have been only two reported cases of AN in patients with ACH without SADDAN (5,6) and one in a patient with mild osteochondrodysplasia (p.K650Q) (7).…”

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

“…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). However, familial cases who were not linked to FGFR3 have been reported that support a genetically heterogeneous condition (9,10).…”