Hearing Loss in Syndromic Craniosynostoses: Introduction and Consideration of Mechanisms

Abstract

Purpose There are a number of craniosynostosis syndromes with hearing loss—including Muenke, Apert, Pfeiffer, Crouzon, Beare-Stevenson, Crouzon with acanthosis nigricans, and Jackson-Weiss syndromes—that result from mutations in the fibroblast growth factor receptor (FGFR) genes. Studies of FGFRs and their ligands, fibroblast growth factors (FGFs), have revealed clues to the precise contribution of aberrant FGFR signaling to inner ear morphogenesis and the hearing loss encountered in craniosynostoses. The purpose of this article is to review basic studies of FGFRs with emphasis on their function and expression in the inner ear and surrounding structures. Method A Medline search was performed to find basic science articles regarding FGFR, their ligands, and their expression and relevant mouse models. Additional items searched included clinical descriptions and studies of individuals with FGFR-related craniosynostosis syndromes. Results The FGF signaling pathway is essential for the morphogensis and proper function of the inner ear and auditory sensory epithelium. Conclusion The variable auditory phenotypes seen in individuals with Muenke syndrome may have a genetic basis, likely due to multiple interacting factors in the genetic environment or modifying factors. Further analysis and studies of mouse models of Muenke syndrome, in particular, may provide clues to the specific effects of the defining mutation in FGFR3 in the inner ear not only at birth but also into adulthood. In particular, investigations into these models may give insight into the variable expression and incomplete penetrance of this phenotype.

The Fibroblast Growth Factor signaling pathway

“…By contrast, in the lethal skeletal dysplasia syndrome, Thanatophoric dysplasia, type I or type II, the R248C mutation in the extracellular domain or the K650E mutation in the intracellular domain activates FGFR3 in a ligand independent manner (Figure (d) and (e)). Muenke syndrome (Muenke nonsyndromic coronal craniosynostosis) is an autosomal dominant disorder characterized by synostosis, macrocephaly, midfacial hypoplasia, and hearing loss caused by gain‐of‐function missense mutations in FGFR3 (Table (b)). Mouse models for aberrant osteogenesis, Achondroplasia, and Muenke syndrome have been developed (Table (b)).…”

Obstructive sleep apnoea in children with craniofacial syndromes

“…In many of the craniosynostoses, mutations in fibroblast growth factor receptor genes affect inner ear morphogenesis, causing hearing loss 9 .…”

Baja talla por déficit selectivo e idiopático de hormona de crecimiento asociado al Síndrome de Crouzon

“…16 El síndrome de Pfeiffer presenta una herencia autosómica dominante y puede estar causado por dos tipos de mutaciones: la que afecta al gen FGFR1, situado en el cromosoma 8, o la del gen FGFR2, en el cromosoma 10. 21 Se asocia a turricefalia, sinostosis radio humerales o radio cubitales, de ojos prominentes y muy separados, sus pulgares y dedos son gordos, cortos y anchos. 16 Ocasionalmente, puede presentarse hidrocefalia, junto con protrusión ocular marcada, codos anquilosados y retraso del desarrollo psicomotor.…”