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.

Fig. 1

Early drawing (1920) of a child with Apert syndrome. Original illustrations (nos. 506 and 507) are housed in the Walters Collection of the Max Brōdel Archives in the Department of Art as Applied to Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

Fig. 2

Symmetric cutaneous and bony syndactyly in Apert syndrome

Fig. 3

Broad, medially deviated thumbs in a patient with Pfeiffer syndrome (black and white arrows). Photos courtesy of Prof. Dr. H Collmann

Fig. 4

a Carpal bone fusion (capitate–hamate) in a patient with Muenke syndrome (black arrow). b Broad thumbs and clinodactyly in a patient with Muenke syndrome. Photos courtesy of Prof. Dr. H Collmann

Fig. 5

a Cutaneous syndactyly in a patient with Saethre–Chotzen syndrome. b Lateral deviation of the large toes in a patient with Saethre–Chotzen syndrome. c Ear anomalies in a patient with Saethre–Chotzen syndrome. d Duplication of the distal phalanx of the hallux (large toe) in a patient with Saethre–Chotzen syndrome. Photos courtesy of Prof. Dr. H. Collmann

Fig. 6

Proposed genetic workup in a patient with craniosynostosis

Fig. 7

Copper beaten skull in a patient with Saethre–Chotzen syndrome. Photo courtesy of Prof. Dr. H. Collmann