Phenotype and Genotype Study in a Case of Frontometaphyseal Dysplasia 1

Frontometaphyseal dysplasia 1 (FMD1) is a rare X-linked craniofacial syndrome belonging in the otopalatodigital spectrum of disorders. Here we present a case with severe FMD1 that was caused by a mutation in the FLNA gene located on Xq28.

A diagnosis for FMD1 was clinically set for a 22-year-old male who presented with cranial hyperostosis with marked supraorbital ridge, hypertelorism, progressive mixed hearing loss, partial anodontia, scoliosis, generalized skeletal dysplasia, and muscle atrophy. The patient's two older brothers had also severe FMD1 manifestations with generalized skeletal dysplasia, cranial hyperostosis, progressive hearing loss, and scoliosis, while their mother and maternal grandmother had some less prominent FMD1 signs. Total DNA was extracted from blood samples of the patient, his brothers, and his parents.

DNA sequencing of all 48 exons of the FLNA gene revealed a single-point mutation (3476A>C) in exon 22. The missense mutation changes an Asp codon into an Ala codon in amino acid position 1159. The patient's two brothers had the same mutation, while their mother was a heterozygous carrier having both the mutant allele and the normal allele.

The clinical diagnosis for FMD1 was confirmed by genetic analysis. It is evident that the FLNA gene product filamin A plays a critical developmental role in morphogenesis of several tissues being a cytoskeleton component, since mutations in its gene cause multiple manifestations and diverse disorders of the otopalatodigital spectrum.