Impact of genetics on the diagnosis and clinical management of syndromic craniosynostoses

Abstract

Purpose More than 60 different mutations have been identified to be causal in syndromic forms of craniosynostosis. The majority of these mutations occur in the fibroblast growth factor receptor 2 gene (FGFR2). The clinical management of syndromic craniosynostosis varies based on the particular causal mutation. Additionally, the diagnosis of a patient with syndromic craniosynostosis is based on the clinical presentation, signs, and symptoms. The understanding of the hallmark features of particular syndromic forms of craniosynostosis leads to efficient diagnosis, management, and long-term prognosis of patients with syndromic craniosynostoses. Methods A comprehensive literature review was done with respect to the major forms of syndromic craniosynostosis and additional less common FGFR-related forms of syndromic craniosynostosis. Additionally, information and data gathered from studies performed in our own investigative lab (lab of Dr. Muenke) were further analyzed and reviewed. A literature review was also performed with regard to the genetic workup and diagnosis of patients with craniosynostosis. Results Patients with Apert syndrome (craniosynostosis syndrome due to mutations in FGFR2) are most severely affected in terms of intellectual disability, developmental delay, central nervous system anomalies, and limb anomalies. All patients with FGFR-related syndromic craniosynostosis have some degree of hearing loss that requires thorough initial evaluations and subsequent follow-up. Conclusions Patients with syndromic craniosynostosis require management and treatment of issues involving multiple organ systems which span beyond craniosynostosis. Thus, effective care of these patients requires a multidisciplinary approach.

Distinct sets of FGF receptors sculpt excitatory and inhibitory synaptogenesis

“…What are the behavioral, neurological or psychiatric consequences of losing FGFR2b or FGFR1b signaling in humans? Dominant negative mutations and mutations leading to overactivation in FGFR2 and FGFR1 cause craniosynostosis syndromes, dominated by cranial defects, which also include seizures and intellectual disability (Agochukwu et al, 2012;Melville et al, 2010;Stevens et al, 2010a;Williams and Umemori, 2014). Analysis of single-nucleotide polymorphisms in human patients has linked mutations in FGFR2 to susceptibility to schizophrenia (O'Donovan et al, 2009) and bipolar disorder (Wang et al, 2012), and FGFR1 mutations to susceptibility to depression (Gaughran et al, 2006) and schizophrenia (Shi et al, 2011).…”

Syndromic Craniosynostosis: Complexities of Clinical Care

“…The midface demonstrates maxillary hypoplasia with a maxillary arch malpositioned with a superior cant creating an anterior open bite subtending a V-shaped high palate or cleft palate ( Fig. 3 ) [Agochukwu et al, 2012a]. Palate anomalies include cleft, a submucous cleft, or bifid uvula with a frequency of 75% [Peterson and Pruzansky, 1974].…”

“…Palate anomalies include cleft, a submucous cleft, or bifid uvula with a frequency of 75% [Peterson and Pruzansky, 1974]. Airway compromise occurs at many levels from small nostrils, choanal stenosis and thickened secretions with the Class III occlusion, and anterior open bite creating difficulty with oral continence [Agochukwu et al, 2012a]. Cutaneous anomalies are a distinctive trait of the syndromic spectrum varying from severe acne to horizontal creases over the supraorbital rim [Cohen and Kreiborg, 1995].…”

Two cases of Antley-Bixler syndrome caused by mutations in different genes, FGFR2 and POR

“…The incidence of craniosynostosis is ~1:2,500 [1]. Syndromic craniosynostosis are estimated to comprise 15% of all cases and over 180 craniosynostosis syndromes have been identified [2]. Mutations in the fibroblast growth factor receptor 2 gene (FGFR2 ) are associated with various craniosynostosis syndromes, including Apert, Crouzon, Pfeiffer, and Antley-Bixler syndromes (ABS; OMIM #207410, leading to proptosis and airway narrowing is also present in most patients.…”