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.

Figure 1

Panel A: Capal bone fusion (capitate-hamate) in an individual with Muenke syndrome (black arrow). Panel B: Broad thumbs and clindodactyly in an individual with Muenke syndrome (black arrow).

Figure 2

Composite audiogram showing mean (±SD) hearing threshold conduction (AC; 250 Hz–8000 Hz) and bone conduction (BC; 250 Hz–8000 Hz) for better hearing ear. Data represent averaged hearing thresholds on 18 individuals with Muenke syndrome from four facilities. Image adapted from Muenke Lab National Institutes of Health Muenke syndrome study (Doherty et al., 2007).