Abstract
Crouzon syndrome is a dominantly inherited disorder characterized by craniosynostosis and facial dysostosis, caused by mutations in the fibroblast growth factor receptor 2 (FGFR2) gene; it belongs to a class of disorders that mostly arise as de novo mutations and exhibit a near-exclusive paternal origin of mutation and elevated paternal age (“paternal age effect”). However, even if this is the major mode of origin of mutations in paternal age-effect disorders, germline mosaicism may also occur. Here we describe the first molecularly documented evidence of germline and somatic mosaicism for FGFR2 mutation, identified in the mother of a child with Crouzon syndrome caused by a heterozygous c.1007A>G (p.Asp336Gly) substitution. Levels of maternal somatic mosaicism for this mutation, estimated by pyrosequencing, ranged from 3.3% in hair roots to 14.1% in blood. Our observation underlines the importance of parental molecular testing for accurate genetic counseling of the risk of recurrence for Crouzon, and other paternal age-effect syndromes. © 2010 Wiley-Liss, Inc.
Highlights
Crouzon syndrome (OMIM #123500) comprises craniosynostosis, exorbitism, hypertelorism, midface hypoplasia, hooked nose, thin vermilion of the upper lip and mandibular prognathism, leading to dental malocclusion
The clinical features fall within the overlap zone between Pfeiffer and Crouzon syndromes, which are known to overlap at the molecular level [Rutland et al, 1995; Kan et al, 2002]; Crouzon syndrome was favored as the final diagnosis because of the late presentation and the mild craniofacial phenotype
We report on the first molecularly proven case of a somatic and germline mosaicism for a dominant mutation in the fibroblast growth factor receptor 2 (FGFR2) gene
Summary
Crouzon syndrome (OMIM #123500) comprises craniosynostosis, exorbitism, hypertelorism, midface hypoplasia, hooked nose, thin vermilion of the upper lip and mandibular prognathism, leading to dental malocclusion. The limbs are traditionally described as normal, subtle alterations, for example in metacarpophalangeal proportions of the hands, are a consistent finding [Murdoch-Kinch and Ward, 1997]. Crouzon syndrome is caused by over 40 different heterozygous missense mutations in the fibroblast growth factor receptor 2 (FGFR2) gene [reviewed in Passos-Bueno et al, 2008]. How to Cite this Article: Goriely A, Lord H, Lim J, Johnson D, Lester T, Firth HV, Wilkie AOM. Germline and somatic mosaicism for FGFR2 mutation in the mother of a child with Crouzon syndrome: Implications for genetic testing in ‘‘paternal age-effect’’ syndromes. Am J Med Genet Part A 152A:2067–2073
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