FIBROBLAST-GROWTH-FACTOR-RECEPTOR-3 (FGFR3) TRANSMEMBRANE MUTATION IN CROUZON-SYNDROME WITH ACANTHOSIS NIGRICANS

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. © 1995 Nature Publishing Group.