RESEARCH ARTICLE Apert and Crouzon Syndromes—Cognitive Development, Brain Abnormalities, and Molecular Aspects Marilyse B. L. Fernandes, 1 Luciana P. Maximino, 2 Gimol B. Perosa, 3 Dagma V. M. Abramides, 2 Maria Rita Passos-Bueno, 4 and Adriano Yacubian-Fernandes 2,3 * 1 Hospital de ReabilitaS c~ ao de Anomalias Craniofaciais, USP, Bauru, SP, Brazil 2 Departamento de Fonoaudiologia, FOB-USP, Bauru, SP, Brazil 3 Departamento de Neurologia, Psicologia e Psiquiatria, UNESP, Botucatu, SP, Brazil 4 Instituto de Bioci^ encias, USP, S~ ao Paulo, SP, Brazil Manuscript Received: 14 June 2015; Manuscript Accepted: 13 March 2016 Apert and Crouzon are the most common craniosynostosis syndromes associated with mutations in the fibroblast growth factor receptor 2 (FGFR2) gene. We conducted a study to examine the molecular biology, brain abnormalities, and cognitive devel- opment of individuals with these syndromes. A retrospective longitudinal review of 14 patients with Apert and Crouzon syndromes seen at the outpatient Craniofacial Surgery Hospital for Rehabilitation of Craniofacial Anomalies in Brazil from January 1999 through August 2010 was performed. Patients between 11 and 36 years of age (mean 18.29  5.80), received cognitive evaluations, cerebral magnetic resonance imaging, and molecular DNA analyses. Eight patients with Apert syndrome (AS) had full scale intelligence quotients (FSIQs) that ranged from 47 to 108 (mean 76.9  20.2), and structural brain abnormalities were identified in five of eight patients. Six patients presented with a gain-of-function mutation (p.Ser252Trp) in FGFR2 and FSIQs in those patients ranged from 47 to78 (mean 67.2  10.7). One patient with a gain-of-function mutation (p.Pro253Arg) had a FSIQ of 108 and another patient with an atypical splice mutation (940–2A !G) had a FSIQ of 104. Six patients with Crouzon syndrome had with mutations in exons IIIa and IIIc of FGFR2 and their FSIQs ranged from 82 to 102 (mean 93.5  6.7). These reveal that molecular aspects are another factor that can be considered in studies of global and cognitive development of patients with Apert and Crouzon syndrome (CS). Ó 2016 Wiley Periodicals, Inc. Key words: syndromic craniosynostosis; intellectual function- ing; central nervous system; molecular biology INTRODUCTION Premature fusion of cranial sutures underlies craniosynostosis, which occurs in both nonsyndromic and syndromic forms. Syn- dromic craniosynostosis is usually associated with limb abnormal- ities, dysmorphic facial features, and skull deformity. Mutations in the gene encoding fibroblast growth factor receptor 2 (FGFR2) account for several severe craniosynostosis conditions, including Apert, Pfeiffer, Crouzon, Beare–Stevenson, and Jackson–Weiss syndromes [Bonaventure and El Ghouzzi, 2003; Cunningham et al., 2007]. FGFR2 belongs to a family of four fibroblast growth factor receptors, which contain an extracellular ligand-binding domain, a transmembrane domain, and an intracellular domain with tyrosine kinase activity. Many craniosynostosis disorders have their origins in specific embryological processes, including brain patterning, migration and fusion of tissues in the face, and bone differentiation in the skull vault [Wilkie and Morriss-Kay, 2001]. Extracranial pheno- types such as limb, cardiac, central nervous system, and tracheal malformations are well described [Cunningham et al., 2007]. Conflict of interest: none. Grant sponsor: FAPESP; Grant sponsor: CAPES; Grant sponsor: CNPq.  Correspondence to: Adriano Yacubian-Fernandes, Faculdade de Odontologia de Bauru, FOB-USP, Al. Oct avio Pinheiro Brisola, 9-75, Bauru, SP 17012-901, Brasil. E-mail: yacubian@usp.br Article first published online in Wiley Online Library (wileyonlinelibrary.com): 30 March 2016 DOI 10.1002/ajmg.a.37640 How to Cite this Article: Fernandes MBL, Maximino LP, Perosa GB, Abramides DVM, Passos-Bueno MR, Yacubian-Fernandes A. 2016. Apert and Crouzon syndromes—Cognitive development, brain abnormalities, and molecular aspects. Am J Med Genet Part A 170A:1532–1537. Ó 2016 Wiley Periodicals, Inc. 1532