Fibroblast Growth Factor Receptor-Related Skeletal Disorders

Unique mutations in three human fibroblast growth factor receptors (FGFRI, FGFR2, and FGFR3) have been identified as causing various skeletal disorders that affect the skull (craniosynostosis syndromes) and the growth of the long bones (dwarfism syndromes). Craniosynostosis is the premature fusion of one or more cranial sutures. It is relatively common, with an estimated birth prevalence of 340 per million. More than 90 syndromes are associated with craniosynostosis, and the majority are inherited in an autosomal dominant manner. The best known of these include Crouzon, Jackson-Weiss, Pfeiffer, Apert, and Saethre-Chotzen syndromes. These syndromes have in common premature synostosis of the coronal sutures of the skull, underdevelopment of the midface, some cases having variable abnormalities of the extremities and other organ systems. All are inherited as autosomal dominant traits, most with complete penetrance and variable expressivity. Although viewed clinically as distinct entities, Crouzon, Jackson-Weiss, Pfeiffer, and Apert syndromes have now been shown to be allelic, with alterations in the same gene ( FGFR2 ). Other craniosynostosis syndromes also shown to be caused by FGFR mutations include Beare-Stevenson cutis gyrata syndrome, Crouzon syndrome with acanthosis nigricans, and a craniosynostosis syndrome associated with a unique FGFR3 point mutation. Interestingly, the two former conditions have dermatologic findings, but the first disorder is associated with FGFR2 mutations, whereas the second is secondary to a FGFR3 mutation. In contrast, there are two craniosynostotic conditions with mutations in transcription factors. Craniosynostosis, Boston type, is a result of a mutation in a homeobox gene, MSX2 , and Saethre-Chotzen syndrome has been linked to mutations in the TWIST gene, a basic helix-loophelix transcription factor. It has been suggested that the FGFRs are part of the same signaling pathway as TWIST. These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.