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

Abstract

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.

Increased p21 expression in chondrocytes of achondroplasic children independently from the presence of the G380R FGFR3 mutation

“…Another study on 24 Portuguese patients with ACH fi rst sequenced exons 9 and 10, identifying the G380R mutation in 21 cases, a N540K substitution in two, and no mutation after sequencing of the entire gene in one subject. 26 Although no mutation was detected in our patient, we could not exclude the possibility that variations at the transcriptional or posttranscriptional level could alter FGFR3 expression in the affected tissue (i. e., the cartilage); however, the amount of tissue obtained prevented us from performing these analyses.…”

Achondroplasia with 47, xxy karyotype: a case report of the neonatal diagnosis of an extremely unusual association

“…More than 90% of achondroplasia cases are sporadic and there is an association of increased incidence with advancing paternal age at the time of conception of affected individuals, as in this case, suggesting that de novo mutations are of paternal origin [10]. Recently, Almeida et al [12] emphasized the clinical heterogeneity of skeletal dysplasias (achondroplasia and hypochondroplasia) associated with FGFR3 mutations, and the importance of undertaking mutation analysis to confirm the clinical diagnosis and to establish an appropriate prognosis and genetic counseling [12]. …”

Treatment of Varus Deformities of the Lower Limbs in Patients with Achondroplasia and Hypochondroplasia

“…Achondroplasia is caused by mutation in the gene that codes for the fibroblast growth factor receptor type 3 ( FGFR3 ) [5-7]. The abnormality seen in the bone of patients with achondroplasia is failure of enchondral ossification.…”

“…Long bones are short, with wide-appearing diaphysis, mild flaring of metaphyseal-epiphyseal junction, slight shortening of ulna relative to radius, elongated ulnar styloid, elongated distal fibula, short and broad femoral neck and rectangular proximal tibial epiphyses are frequent abnormalities. Hypochondroplasia is caused by mutation in the gene that codes for the FGFR3 [5-7]. Hypochondroplasia cannot be detected at birth and, if mild, may remain undiagnosed throughout the patient’s life.…”