In-frame deletion in FLNA causing familial periventricular heterotopia with skeletal dysplasia in males

Periventricular heterotopia (PH) is an etiologically heterogeneous disorder characterized by nodules of neurons ectopically placed along the lateral ventricles. Truncating and missense mutations of the FLNA gene have been identified in almost 100% of families and 26% of sporadic patients with PH. The otopalatodigital syndrome spectrum is caused by distinct FLNA missense mutations or in-frame deletions disrupting the development of craniofacial and long bones. We report on a clinical, neuroimaging, X-ray, and molecular study of a family in which classical bilateral PH appeared as an isolated anatomic feature in the mother and was associated with skeletal abnormalities and facial dysmorphisms in her two sons. Both boys exhibited PH associated with flat face and spatulate finger tips, short broad phalanx and metacarpus, and bowed radius with dislocated wrist joints. All three patients harbored the c.7865_7870del in-frame deletion (p.2622_2623delDK) in the carboxyl-terminal domain (repeat 24) of FLNA. The X-inactivation observed in the mother was skewed towards the mutant allele, resulting in the preferential expression of the wild-type allele. The in-frame deletion in the carboxyl-terminal domain of FLNA caused a phenotype in which PH was associated with skeletal features suggestive of the otopalatodigital syndrome spectrum in boys. There appears to be a continuum among allelic disorders due to FLNA mutations.