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Fibroblast growth factor receptor 3 (FGFR3) transmembrane mutation in Crouzon syndrome with acanthosis nigricans

Nature Genetics volume 11, pages 462–464 (1995)Cite this article

Abstract

Crouzon syndrome, an autosomal dominant condition characterized by craniosynostosis, ocular proptosis and midface hypoplasia, is associated with mutations in fibroblast growth factor receptor 2 (FGFR2) (refs 1–3). For example, we have identified 10 different mutations in the FGFR2 extracellular immunoglobulin III (Iglll) domain in 50% (16/32) of our Crouzon syndrome patients2,4,5. All mutations described so far for other craniosynos-totic syndromes with associated limb anomalies — Jackson–Weiss2,4, Pfeiffer6–9, and Apert10,11 — also occur in the extracellular domain of FGFR2, as well as FGFR1 for Pfeiffer syndrome. In contrast, only FGFR3 mutations have been reported in dwarfing conditions — achondroplasia12–14, thanatophoric dyspla-sia15,16, and hypochondroplasia17. For achondroplasia, greater than 99% of mutations occur in the FGFR3 transmembrane domain12–14,18,19. We now report the unexpected observation of a FGFR3 transmembrane domain mutation, Ala391Glu, in three unrelated families with Crouzon syndrome and acanthosis nigricans, a specific skin disorder of hyperkeratosis and hyperpigmentation. The association of non–dwarfing and even non–skeletal conditions with FGFR3 mutations reveals the potential for a wide range of FGFR pleiotropic effects as well as locus heterogeneity in Crouzon syndrome. Our study underscores the biologic complexity of the FGFR gene family.

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Authors and Affiliations

  1. Departments of Pediatrics, Medicine and Surgery, Center for Medical Genetics, The Johns Hopkins School of Medicine, 600 N. Wolfe Street, Baltimore, Maryland, 21287–3914, USA

    Gregory A. Meyers, Kelly A. Przylepa & Ethylin Wang Jabs

  2. The Ronald O. Perelman Department of Dermatology, Department of Cell Biology, New York University School of Medicine, New York, NY, 10016, USA

    Seth J. Orlow

  3. Craniofacial Center at the Center for Children, Medical City Dallas Hospital, Dallas, Texas, 75230, USA

    Ian R. Munro

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  1. Gregory A. Meyers
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  4. Kelly A. Przylepa
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  5. Ethylin Wang Jabs
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Meyers, G., Orlow, S., Munro, I. et al. Fibroblast growth factor receptor 3 (FGFR3) transmembrane mutation in Crouzon syndrome with acanthosis nigricans. Nat Genet 11, 462–464 (1995). https://doi.org/10.1038/ng1295-462

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