Genetic basis of potential therapeutic strategies for craniosynostosis

• Published in: American journal of medical genetics. Part A 2010-12, Vol.152A (12), p.3007-3015
• Main Authors: Melville, Heather, Wang, Yingli, Taub, Peter J., Jabs, Ethylin Wang
• Format: Article
• Language: English
• Subjects: Animals; Apert syndrome; Craniosynostoses - diagnosis; Craniosynostoses - genetics; Craniosynostoses - surgery; craniosynostosis; Disease Models, Animal; fibroblast growth factor receptor; Forecasting; Humans; inhibitor; Mutation; Receptors, Fibroblast Growth Factor - genetics; Signal Transduction - genetics; surgery; Syndrome; treatment
• ISSN: 1552-4825; 1552-4833; 1552-4833
• DOI: 10.1002/ajmg.a.33703

Craniosynostosis, the premature fusion of one or more cranial sutures, is a common malformation of the skull that can result in facial deformity and increased intracranial pressure. Syndromic craniosynostosis is present in ∼15% of craniosynostosis patients and often is clinically diagnosed by neurocranial phenotype as well as various other skeletal abnormalities. The most common genetic mutations identified in syndromic craniosynostosis involve the fibroblast growth factor receptor (FGFR) family with other mutations occurring in genes for transcription factors TWIST, MSX2, and GLI3, and other proteins EFNB1, RAB23, RECQL4, and POR, presumed to be involved either upstream or downstream of the FGFR signaling pathway. Both syndromic and nonsyndromic craniosynostosis patients require early diagnosis and intervention. The premature suture fusion can impose pressure on the growing brain and cause continued abnormal postnatal craniofacial development. Currently, treatment options for craniosynostosis are almost exclusively surgical. Serious complications can occur in infants requiring either open or endoscopic repair and therefore the development of nonsurgical techniques is highly desirable although arguably difficult to design and implement. Genetic studies of aberrant signaling caused by mutations underlying craniosynostosis in in vitro calvarial culture and in vivo animal model systems have provided promising targets in designing genetic and pharmacologic strategies for systemic or adjuvant nonsurgical treatment. Here we will review the current literature and provide insights to future possibilities and limitations of therapeutic applications. © 2010 Wiley‐Liss, Inc.