• PMID: 25394172
• Gene Name: FGFR1
• Condition: Congenital hypogonadotropic hypogonadism (CHH)
• Association: 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.
• Mutation: p.V429E, p.G348R, p.G485R, p.Q594*, p.E670A, p.V688L, or p.L712P
• Population size: 8
• Population details: 8 with CHH (3 Kallmann syndrome, 5 without insomnia)
• Sex: Male
• Infertility type: Male infertility
• Other associated phenotypes: Congenital hypogonadotropic hypogonadism (CHH)

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

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.

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 2α 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 2α 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. FAU - Villanueva, Carine AU - Villanueva C AUID- ORCID: 0000000339450431 AD - 1] Unité Mixte de Recherche 1141, Institut National de la Santé et de la Recherche Médicale, Paris, France [2] Université Paris Diderot, Sorbonne Paris Cité, Hôpital Robert Debré, Paris, France. FAU - Jacobson-Dickman, Elka AU - Jacobson-Dickman E AD - 1] Harvard Reproductive Endocrine Sciences Center and the Reproductive Endocrine Unit of the Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA [2] Department of Pediatrics, Division of Pediatric Endocrinology, State University of New York Downstate Medical Center, Brooklyn, New York, USA. FAU - Xu, Cheng AU - Xu C AD - 1] Department of Endocrinology and Diabetes, Shanghai Huashan Hospital, Shanghai, China [2] Department of Endocrinology, Diabetology and Metabolism, Lausanne University Hospital (CHUV), Lausanne, Switzerland [3] Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland. FAU - Manouvrier, Sylvie AU - Manouvrier S AD - Service de Génétique Clinique, Hôpital Jeanne de Flandre, Lille, France. FAU - Dwyer, Andrew A AU - Dwyer AA AD - 1] Harvard Reproductive Endocrine Sciences Center and the Reproductive Endocrine Unit of the Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA [2] Department of Endocrinology, Diabetology and Metabolism, Lausanne University Hospital (CHUV), Lausanne, Switzerland [3] Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland. FAU - Sykiotis, Gerasimos P AU - Sykiotis GP AD - 1] Harvard Reproductive Endocrine Sciences Center and the Reproductive Endocrine Unit of the Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA [2] Department of Endocrinology, Diabetology and Metabolism, Lausanne University Hospital (CHUV), Lausanne, Switzerland [3] Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland. FAU - Beenken, Andrew AU - Beenken A AD - Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York, USA. FAU - Liu, Yang AU - Liu Y AD - Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York, USA. FAU - Tommiska, Johanna AU - Tommiska J AD - Institute of Biomedicine/Physiology, University of Helsinki and Children's Hospital, Helsinki University Central Hospital, Helsinki, Finland. FAU - Hu, Youli AU - Hu Y AD - Centre for Neuroendocrinology, University College London Medical School, London, UK. FAU - Tiosano, Dov AU - Tiosano D AD - 1] Division of Pediatric Endocrinology, Meyer Children's Hospital, Rambam Health Care Campus, Haifa, Israel [2] Bruce Rappaport Faculty of Medicine, Institute of Technology, Haifa, Israel. FAU - Gerard, Marion AU - Gerard M AD - Clinical Genetics, Hôpital Universitaire de la Côte de Nacre, Caen, France. FAU - Leger, Juliane AU - Leger J AD - 1] Unité Mixte de Recherche 1141, Institut National de la Santé et de la Recherche Médicale, Paris, France [2] Université Paris Diderot, Sorbonne Paris Cité, Hôpital Robert Debré, Paris, France [3] Service d'Endocrinologie Diabétologie Pédiatrique et Centre de Référence des Maladies Endocriniennes Rares de la Croissance, Assistance Publique-Hôpitaux de Paris, Hôpital Robert Debré, Paris, France. FAU - Drouin-Garraud, Valérie AU - Drouin-Garraud V AD - Department of Genetics, Rouen University Hospital, Rouen, France. FAU - Lefebvre, Hervé AU - Lefebvre H AD - Department of Endocrinology, University Hospital of Rouen, Institute for Biomedical Research, University of Rouen, Rouen, France. FAU - Polak, Michel AU - Polak M AD - Service d'Endocrinologie Gynécologie Diabétologie Pédiatriques, Hôpital Universitaire Necker Enfants Malades, University Paris Descartes, Paris, France. FAU - Carel, Jean-Claude AU - Carel JC AD - 1] Unité Mixte de Recherche 1141, Institut National de la Santé et de la Recherche Médicale, Paris, France [2] Université Paris Diderot, Sorbonne Paris Cité, Hôpital Robert Debré, Paris, France [3] Service d'Endocrinologie Diabétologie Pédiatrique et Centre de Référence des Maladies Endocriniennes Rares de la Croissance, Assistance Publique-Hôpitaux de Paris, Hôpital Robert Debré, Paris, France. FAU - Phan-Hug, Franziska AU - Phan-Hug F AD - Endocrinology-Diabetology Unit, Department of Pediatrics, Lausanne University Hospital (CHUV), Lausanne, Switzerland. FAU - Hauschild, Michael AU - Hauschild M AUID- ORCID: 0000000219408730 AD - Endocrinology-Diabetology Unit, Department of Pediatrics, Lausanne University Hospital (CHUV), Lausanne, Switzerland. FAU - Plummer, Lacey AU - Plummer L AD - Harvard Reproductive Endocrine Sciences Center and the Reproductive Endocrine Unit of the Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA. FAU - Rey, Jean-Pierre AU - Rey JP AD - 1] Department of Endocrinology, Diabetology and Metabolism, Lausanne University Hospital (CHUV), Lausanne, Switzerland [2] Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland. FAU - Raivio, Taneli AU - Raivio T AUID- ORCID: 0000000284225359 AD - Institute of Biomedicine/Physiology, University of Helsinki and Children's Hospital, Helsinki University Central Hospital, Helsinki, Finland. FAU - Bouloux, Pierre AU - Bouloux P AD - Centre for Neuroendocrinology, University College London Medical School, London, UK. FAU - Sidis, Yisrael AU - Sidis Y AD - 1] Harvard Reproductive Endocrine Sciences Center and the Reproductive Endocrine Unit of the Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA [2] Department of Endocrinology, Diabetology and Metabolism, Lausanne University Hospital (CHUV), Lausanne, Switzerland [3] Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland. FAU - Mohammadi, Moosa AU - Mohammadi M AUID- ORCID: 0000000179588262 AD - Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York, USA. FAU - de Roux, Nicolas AU - de Roux N AD - 1] Unité Mixte de Recherche 1141, Institut National de la Santé et de la Recherche Médicale, Paris, France [2] Université Paris Diderot, Sorbonne Paris Cité, Hôpital Robert Debré, Paris, France [3] Laboratoire de Biochimie, Assistance Publique-Hôpitaux de Paris, Hôpital Robert Debré, Paris, France.