Villanueva, CarineJacobson-Dickman, ElkaXu, ChengManouvrier, SylvieDwyer, Andrew A.Sykiotis, Gerasimos P.Beenken, AndrewLiu, YangTommiska, JohannaHu, YouliTiosano, DovGerard, MarionLeger, JulianeDrouin-Garraud, ValérieLefebvre, HervéPolak, MichelCarel, Jean-ClaudePhan-Hug, FranziskaHauschild, MichaelPlummer, LaceyRey, Jean-PierreRaivio, TaneliBouloux, PierreSidis, YisraelMohammadi, Moosade Roux, NicolasPitteloud, Nelly2016-06-142014Villanueva, C., E. Jacobson-Dickman, C. Xu, S. Manouvrier, A. A. Dwyer, G. P. Sykiotis, A. Beenken, et al. 2014. “Congenital hypogonadotropic hypogonadism with split hand/foot malformation: a clinical entity with a high frequency of FGFR1 mutations.” Genetics in medicine : official journal of the American College of Medical Genetics 17 (8): 651-659. doi:10.1038/gim.2014.166. http://dx.doi.org/10.1038/gim.2014.166.1098-3600http://nrs.harvard.edu/urn-3:HUL.InstRepos:27320294Purpose Congenital hypogonadotropic hypogonadism (CHH) and split hand/foot malformation (SHFM) are two rare genetic conditions. Here we report a clinical entity comprising CHH and SHFM. Methods: We identified patients with CHH and SHFM through international collaboration. Probands and available family members underwent phenotyping and screening for FGFR1 mutations. The impact of identified mutations was assessed by sequence- and structure-based predictions, and/or functional assays. Results: We identified 8 probands with CHH with (n=3, Kallmann Syndrome) or without anosmia (n=5) and SHFM, 7 of whom (88%) harbor FGFR1 mutations: one individual is homozygous for p.V429E; six individuals are heterozygous for p.G348R, p.G485R, p.Q594*, p.E670A, p.V688L, and p.L712P. All mutations were predicted to be loss-of-function by in silico analysis. Probands with FGFR1 mutations have severe GnRH deficiency (absent puberty and/or cryptorchidism and/or micropenis). SHFM in both hands and feet was only observed in the patient with the homozygous p.V429E mutation; V429 maps to the FRS2α binding domain of FGFR1, and functional studies of the p.V429E mutation demonstrated that it decreased recruitment and phosphorylation of FRS2α to FG FR 1 , thereby resulting in reduced MAPK signaling. Conclusion: FGFR1 should be prioritized for genetic testing in patients with CHH and SHFM, because the likelihood of a mutation increases from 10% in the general CHH population to 88%.en-UScongenital hypogonadotropic hypogonadismsplit hand/foot malformationfibroblast growth factor receptor 1FGF receptor substrate 2αJournal Article2016-06-1410.1038/gim.2014.166