Otopalatodigital syndrome type 2 in two siblings with a novel filamin A 629G>T mutation: clinical, pathological, and molecular findings.

Otopalatodigital syndrome type 2 (OPD2) is an uncommon X-linked condition characterized by dysmorphic facies, a skeletal dysplasia affecting the axial and appendicular skeleton and extraskeletal anomalies including malformations of the brain, heart, genitourinary system, and intestines. Missense mutations of the FLNA gene, which encodes for the protein filamin A, have recently been shown to cause OPD2 and the allelic syndromes otopalatodigital type 1, Melnick-Needles, and frontometaphyseal dysplasia. Collectively these conditions constitute the otopalatodigital spectrum disorders. We report on two sibs affected by OPD2. The diagnosis was achieved at autopsy of a macerated male stillborn with typical external and skeletal findings of OPD2. A subsequent pregnancy was terminated due to ultrasonographic findings resembling those observed in the previous sibling. Histopathological studies revealed osseus sclerosis and do not support the previously reported membranous ossification defect observed in this condition. Mutation analysis demonstrated a novel mutation, 629G>T, in FLNA that had arisen de novo in the mother. This missense mutation predicts the substitution C210F within the second calponin homology domain of the actin-binding domain of filamin A. The identical substitution has been recently identified in an analogous amino-acid position within the actin binding domain of beta-spectrin leading to hereditary spherocytosis. The observation that phenylalanine is normally present in the same position in other proteins (utrophin, dystrophin) but leads to disease when present in filamin A implies that the function and/or structure of these actin binding domains are not entirely equivalent.