Malformations of Cortical Development in Patients With Midline Facial Defects and Ocular Hypertelorism Silvyo David Arau ´ jo Giffoni, M.D., Fernando Cendes, M.D., Ph.D., Marcelo Valente, M.D., Ph.D., Vera Lucia Gil-da-Silva-Lopes, M.D., Ph.D. Objectives: We studied the neuroimaging and neurophysiological aspects of 17 patients with midline facial defects with ocular hypertelorism (MFDH). Methods: The investigation protocol included a previous semistructured questionnaire about family history; gestational, neonatal, and postnatal development; and dysmorphologic and neurologic evaluation. Recognized monogenic disorders and individuals with other well-known conditions were excluded. All patients had high resolution magnetic resonance imaging (MRI) with multiplanar reconstruction (MPR) and routine electroencephalograms (EEGs). Results: We detected abnormalities in five patients whose MRIs had been previously reported as normal. MRI showed central nervous system (CNS) structural abnormalities in all patients, which included commissural alterations in 16/17 (94%), malformations of cortical development in 10/17 (58%), distur- bances of neural tube closure in 7/17 (42%), and posterior fossa anomalies in 6/17 (35%). Some patients had more than one type of malformation occurring at different stages of the embryonary process. EEGs showed epileptiform activity in 4/17 (24%) and background abnormalities in 5/17 (29%) of patients. Conclusion: This study clearly demonstrated the presence of structural and functional neurologic alterations related to MFDH. Therefore, the CNS anomalies cannot be considered incidental findings but an intrinsic part of this condition, which could be related to environmental effects and/or genetic mutations. These findings would provide a basis for future investigations on MFDH and should also be considered when planning rehabilitation. KEY WORDS: cortical malformations, frontonasal dysplasia, midline cleft The term ‘‘midline facial defects with hypertelorism’’ has been known by many synonyms over the years, most frequently frontonasal dysplasia (Sedano et al., 1970) and frontonasal malformation (Sedano and Gorlin, 1988). Recently, the term ‘‘midline facial defects with ocular hypertelorism’’ (MFDH) was proposed, which seems to be appropriate in light of the current knowledge and the integration of several specialties that follow this condition (Gil-da-Silva-Lopes and Maciel-Guerra, 2007). These defects make up a rare group of disorders, characterized by hypertelorism and some degree of bifid nose. Widow’s peak, cranium bifidum occultum, and cleft lip and palate have also been described (Sedano et al., 1970). Clinical and etiologic heterogeneity have been recognized since the first review (DeMyer, 1967). Common central nervous system (CNS) anomalies, including frontal en- cephalocele, Chiari malformation, and corpus callosum anomalies, have been described (Naidich et al., 1988); isolated reports of lipomas and hamartomas were also mentioned (Meguid, 1983; Pascual-Castroviejo et al., 1985; Henneken et al., 1986; Pai et al., 1987). The pathogenesis of these defects is still incompletely understood. It has been postulated that they may occur by impairment of the normal development of frontonasal process involving vascular etiology and abnormalities of the neural crest cells (Sedano and Gorlin, 1988; Gil-da- Silva-Lopes and Maciel-Guerra, 2007) while another theory suggests that MFDH could be caused by twinning of the frontonasal process (Machin, 1996). Environmental etiol- ogy was experimentally documented (Darab et al., 1987) and clinically suspected in 1/3 of 31 persons investigated (Gil-da-Silva-Lopes and Maciel-Guerra, 2007). MFDH represent a developmental field defect (Opitz, 1982; Martinez-Frı ´as, 1995) caused by inadequate devel- Dr. Giffoni is postgraduate student, Department of Medical Genetics, Faculdade de Cie ˆncias Me ´dicas, Universidade Estadual de Campinas (UNICAMP), Campinas-SP, Brazil. Dr. Cendes is Associated Professor, Department of Neurology, Faculdade de Cie ˆncias Me ´dicas, Universidade Estadual de Campinas (UNICAMP), Campinas-SP, Brazil. Dr. Valente is Professor, Department of Radiology, Instituto da Crianc ¸a, Universidade de Sa ˜o Paulo (USP), Sa ˜ o Paulo-SP, Brazil. Dr. Gil-da-Silva-Lopes is Associated Professor, Department of Medical Genetics, Faculdade de Cie ˆncias Me ´dicas, Universidade Estadual de Campinas (UNICAMP), Campinas-SP, Brazil. Submitted August 2008; Accepted October 2009. Address correspondence to: Dr. Vera Lu ´cia Gil-da-Silva-Lopes, Departamento de Gene ´tica Me ´dica, FCM – UNICAMP, Rua Tessa ´ lia Vieira de Camargo, 126, CEP: 13084-971, Campinas, SP – Brazil. E-mail vlopes@fcm.unicamp.br. DOI: 10.1597/08-167.1 343