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 patients^2,4,5. All mutations described so far for other craniosynos-totic syndromes with associated limb anomalies — Jackson–Weiss^2,4, Pfeiffer^6–9, and Apert^10,11 — 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 — achondroplasia^12–14, thanatophoric dyspla-sia^15,16, and hypochondroplasia¹⁷. For achondroplasia, greater than 99% of mutations occur in the FGFR3 transmembrane domain^{12–14,18,19}. 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.