Cortical brain malformations: effect of clinical, neuroradiological, and modern genetic classification.

Background: Malformations of cortical development (MCDs) are a major source of handicap. Much progress in understanding the genetic causes has been made recently. The number of affected children in whom a molecularly confirmed diagnosis can be made is unclear.

Objective: To evaluate the etiology of MCDs in children and the effect of a combined radiological, clinical, and syndrome classification.

Design: A case series of 113 children with a radiological diagnosis of MCD from January 1, 1992, to January 1, 2006.

Setting: The Erasmus Medical Center-Sophia Children's Hospital, a secondary and tertiary referral center.

Patients: Patients with MCD underwent a complete radiological, clinical, and neurological assessment and testing for known genes involved in the pathogenesis of MCD as appropriate for their phenotype.

Results: We established an etiological diagnosis in 45 of 113 cases (40%). For 21 patients (19%), this included molecular and/or genetic confirmation (Miller-Dieker syndrome; LIS1, DCX, FLNA, EIF2AK3, or KIAA1279 mutations; or an inborn error of metabolism). In 17 (15%), a syndrome with an unknown genetic defect was diagnosed. In 7 patients (6%), we found evidence of a gestational insult. Of the remaining 68 patients, 34 probably have a yet-unknown genetic disorder based on the presence of multiple congenital anomalies (15 patients), a family history with multiple affected persons (12 patients), or consanguineous parents (7 patients).

Conclusions: In our cohort, combining diagnostic molecular testing with clinical, radiological, and genetic classification; syndrome identification; and family study provided a diagnosis in 40% of the cases of MCD. This contributes to the possibility of prenatal diagnosis and improved patient treatment and disease management.