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Congenital hypogonadotropic hypogonadism with split hand/foot malformation: a clinical entity with a high frequency of FGFR1 mutations.

Authors: Villanueva, C  Jacobson-Dickman, E  Xu, C  Manouvrier, S  Dwyer, AA  Sykiotis, GP  Beenken, A  Liu, Y  Tommiska, J  Hu, Y  Tiosano, D  Gerard, M  Leger, J  Drouin-Garraud, V  Lefebvre, H  Polak, M  Carel, JC  Phan-Hug, F  Hauschild, M  Plummer, L  Rey, JP  Raivio, T  Bouloux, P  Sidis, Y  Mohammadi, M  De Roux, N  Pitteloud, N 
Citation: Villanueva C, etal., Genet Med. 2015 Aug;17(8):651-9. doi: 10.1038/gim.2014.166. Epub 2014 Nov 13.
Pubmed: (View Article at PubMed) PMID:25394172
DOI: Full-text: DOI:10.1038/gim.2014.166

PURPOSE: Congenital hypogonadotropic hypogonadism (CHH) and split hand/foot malformation (SHFM) are two rare genetic conditions. Here we report a clinical entity comprising the two. 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 eight probands with CHH with (n = 3; Kallmann syndrome) or without anosmia (n = 5) and SHFM, seven of whom (88%) harbor FGFR1 mutations. Of these seven, one individual is homozygous for p.V429E and six individuals are heterozygous for p.G348R, p.G485R, p.Q594*, p.E670A, p.V688L, or p.L712P. All mutations were predicted by in silico analysis to cause loss of function. Probands with FGFR1 mutations have severe gonadotropin-releasing hormone deficiency (absent puberty and/or cryptorchidism and/or micropenis). SHFM in both hands and feet was observed only in the patient with the homozygous p.V429E mutation; V429 maps to the fibroblast growth factor receptor substrate 2alpha binding domain of FGFR1, and functional studies of the p.V429E mutation demonstrated that it decreased recruitment and phosphorylation of fibroblast growth factor receptor substrate 2alpha to FGFR1, thereby resulting in reduced mitogen-activated protein kinase 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% in these patients.

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RGD Object Information
RGD ID: 11098154
Created: 2016-06-08
Species: All species
Last Modified: 2016-06-08
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.