Apert and Crouzon syndromes—Cognitive development, brain abnormalities, and molecular aspects

Abstract

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 development 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). © 2016 Wiley Periodicals, Inc.

NEGR1 and FGFR2 cooperatively regulate cortical development and core behaviours related to autism disorders in mice

“…Moreover, gene-association studies have also implicated FGFR2 as a candidate gene in ASD ( Wentz et al , 2014 ; Coci et al , 2017 ). Interestingly, FGFR2 mutations are causative of syndromic intellectual disabilities, such as Crouzon syndrome ( Fernandes et al , 2016 ) and Apert syndrome whose patients may also suffer from ASD ( Morey-Canellas et al , 2003 ; Koca, 2016 ). Finally, alterations in ERK and AKT signalling have been widely implicated in schizophrenia and intellectual disability ( Hirayama-Kurogi et al , 2017 ; Wang et al , 2017 a ), and both an increase ( Kalkman, 2012 ; Faridar et al , 2014 ; Pucilowska et al , 2015 ; Onore et al , 2017 ) as well as a decrease of ERK or AKT signalling ( Satoh et al , 2011 ; Nicolini et al , 2015 ; Yufune et al , 2015 ) have been described in ASD.…”

Integration of Brain and Skull in Prenatal Mouse Models of Apert and Crouzon Syndromes

“…Cognitive effects in craniosynostosis conditions vary widely- from normal to severe- and surgery can have its own effects on long-term outcome (Blank, 1959; Lefebvre et al, 1959; Kapp-Simon et al, 1993, 2007; Renier et al, 1996; Kapp-Simon, 1998; Yacubian-Fernandes et al, 2004, 2005; Becker et al, 2005; Da Costa et al, 2006; Hashim et al, 2014; Fernandes et al, 2016), but there is currently no clear understanding of the relationship between IQ, genetics and brain malformations in these syndromes (Fernandes et al, 2016). Because the gross morphology of the brain mirrors the shape of the skull in craniosynostosis conditions, it is widely assumed that abnormal brain shape is a response to constraints on skull growth caused by premature suture closure.…”

Clinical Findings of 2-Months-Old Baby With Apert Syndrome: A Rare Case Report

“…Craniosynostosis happened because of mutation in gene fibroblast growth factor receptors (FGFR2) which can also happen in other diseases like Crouzon Syndrome, Pfeiffer Syndrome, Beare-Stevenson Syndrome, and Jackson-Weiss Syndrome. 1,3,4 Craniosynostosis can be the only abnormalities who are present, or accompanied by other. AS is a rare autosomal dominant disorder which more than 98% cases happened in de novo mutation.…”