Clinical and molecular diagnosis of the skeletal dysplasias associated with mutations in the gene encoding Fibroblast Growth Factor Receptor 3 (FGFR3) in Portugal.

Mutations in the gene that encodes Fibroblast Growth Factor Receptor 3 (FGFR3) are associated with Achondroplasia (MIM 100800), Hypochondroplasia (MIM 146000), Muenke Syndrome (MIM 602849), Thanatophoric Dysplasia (MIM 187600, MIM 187601) and Lacrimo-Auriculo-Dento-Digital Syndrome (MIM 149730).Here we report a clinical and molecular study in a large cohort of 125 Portuguese patients with these skeletal disorders. The identification of the P250R mutation allowed the confirmation of the Muenke Syndrome in 9 out of the 52 cases referred. Two known mutations were found in the Thanatophoric Dysplasia referred cases. No mutations were identified in the LADD syndrome patient. In Achondroplasia and Hypochondroplasia, genetic heterogeneity was present amongst the 70 clinically diagnosed patients with 5 different mutations identified. As in other studies, complex phenotypic heterogeneity amongst patients carrying the same gene defect was observed. In several cases, the new amino acids encoded, as a consequence of mutations, were related to the severity of patients' phenotype. The presence of 10 misdiagnosed cases emphasizes the importance of performing mutation analysis of the hotspot regions responsible for both dysplasias (Ach and Hch). For patients with an unquestionable clinical diagnosis, lacking the most common mutations, a complete screening of FGFR3 is necessary.