Valproic acid embryopathy: Report of two siblings with further expansion of the phenotypic abnormalities and a review of the literature

Fetal Valproate Syndrome (FVS) results from prenatal exposure to valproic a cid (VPA). It is characterized by a distinctive facial appearance, a cluste r of minor and major anomalies, and central nervous system dysfunction. In this study, two siblings who were exposed to monotherapy with VPA are descr ibed with documentation of long-term follow up. Both children had craniofac ial findings, multiple systemic and orthopedic abnormalities, an overgrowth pattern, and developmental deficits. The literature from 1978-2000 is revi ewed. A total of 69 cases that were solely exposed to VPA with adequate phe notypic description were identified. The clinical manifestations of FVS enc ompass a wide spectrum of abnormalities including consistent facial phenoty pe, multiple systemic and orthopedic involvement, central nervous system dy sfunction, and altered physical growth. The facial appearance is characteri zed by a small broad nose, small ears, flat philtrum, a long upper lip with shallow philtrum, and micro/retrognathia. In this review, 62% of the patie nts had musculoskeletal abnormalities, 30% had minor skin defects, 26% had cardiovascular abnormalities, 22% had genital abnormalities, and 16% had pu lmonary abnormalities. Less frequently encountered abnormalities included b rain, eye, kidney, and hearing defects. Neural tube defects were seen in 3% of the sample. Twelve percent of affected children died in infancy and 29% of surviving patients had developmental deficits/mental retardation. Altho ugh 15% of patients had growth retardation, an overgrowth pattern was seen in 9%. The data from this comprehensive review especially the developmental outcome should be added to the teratogenic risk, that arises in associatio n with the use of VPA during pregnancy. (C) 2001 Wiley-Liss, Inc.