Muenke syndrome (FGFR3‐related craniosynostosis): Expansion of the phenotype and review of the literature

Emily S Doherty ,Carol Knightly,R Brian Lowry,Thomas C Hart,Virginia Kimonis,Beth Solomon,Donald W Hadley,H Jeff Kim,Felicitas Lacbawan,Demetrio L Domingo,Fernanda Sarquis Jehee,Maria Rita Passos Bueno,Elaine H Zackai,Brian P Brooks,Christopher Zalewski,Maximilian Muenke,Kenneth N Rosenbaum ,La Donna Immken ,Carmen C Brewer ,Alan Shanske ,Donna M Mcdonald‐Mcginn

doi:10.1002/ajmg.a.32078

Abstract

Muenke syndrome is an autosomal dominant disorder characterized by coronal suture craniosynostosis, hearing loss, developmental delay, carpal and tarsal fusions, and the presence of the Pro250Arg mutation in the FGFR3 gene. Reduced penetrance and variable expressivity contribute to the wide spectrum of clinical findings in Muenke syndrome. To better define the clinical features of this syndrome, we initiated a study of the natural history of Muenke syndrome. To date, we have conducted a standardized evaluation of nine patients with a confirmed Pro250Arg mutation in FGFR3. We reviewed audiograms from an additional 13 patients with Muenke syndrome. A majority of the patients (95%) demonstrated a mild-to-moderate, low frequency sensorineural hearing loss. This pattern of hearing loss was not previously recognized as characteristic of Muenke syndrome. We also report on feeding and swallowing difficulties in children with Muenke syndrome. Combining 312 reported cases of Muenke syndrome with data from the nine NIH patients, we found that females with the Pro250Arg mutation were significantly more likely to be reported with craniosynostosis than males (P < 0.01). Based on our findings, we propose that the clinical management should include audiometric and developmental assessment in addition to standard clinical care and appropriate genetic counseling.

Highlights

Muenke syndrome [OMIM#602849] is defined by the c.749 C > G mutation encoding a Pro250Arg substitution in the fibroblast growth factor receptor 3 (FGFR3) gene encoding the FGFR3 protein [Bellus et al, 1996; Muenke et al, 1997]
Combining 312 reported cases of Muenke syndrome with data from the nine National Institutes of Health (NIH) patients, we found that females with the Pro250Arg mutation were significantly more likely to be reported with craniosynostosis than males (P < 0.01)
The skull phenotype was clearly documented in 312 cases. Combining those cases with the nine NIH patients, some form of craniosynostosis was present in 86%, macrocephaly was present in 3%, and a ‘‘normal’’ examination was present in 11% (Table I)

Summary

Introduction

Muenke syndrome [OMIM#602849] is defined by the c.749 C > G mutation encoding a Pro250Arg substitution in the fibroblast growth factor receptor 3 (FGFR3) gene encoding the FGFR3 protein [Bellus et al, 1996; Muenke et al, 1997]. Clinical diagnosis of Muenke syndrome in these cases may be difficult or impossible without molecular diagnostic testing. Subtle phenotypes such as macrocephaly or minor facial dysmorphisms alone have been reported [Gripp et al, 1998; Sabatino et al, 2004]. Some individuals who are heterozygous for the FGFR3 Pro250Arg mutation may be clinically and radiographically asymptomatic [Robin et al, 1998]. Sex-related expressivity of the mutation has been suggested, based on a more severe phenotype in females [Gripp et al, 1998; Lajeunie et al, 1999]

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Results

Conclusion