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


CONCLUSIONS
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.
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.
Carine
0000000339450431
C
Villanueva
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.
Elka
E
Jacobson-Dickman
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.
Cheng
C
Xu
Service de Génétique Clinique, Hôpital Jeanne de Flandre, Lille, France.
Sylvie
S
Manouvrier
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.
Andrew A
AA
Dwyer
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.
Gerasimos P
GP
Sykiotis
Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York, USA.
Andrew
A
Beenken
Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York, USA.
Yang
Y
Liu
Institute of Biomedicine/Physiology, University of Helsinki and Children's Hospital, Helsinki University Central Hospital, Helsinki, Finland.
Johanna
J
Tommiska
Centre for Neuroendocrinology, University College London Medical School, London, UK.
Youli
Y
Hu
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.
Dov
D
Tiosano
Clinical Genetics, Hôpital Universitaire de la Côte de Nacre, Caen, France.
Marion
M
Gerard
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.
Juliane
J
Leger
Department of Genetics, Rouen University Hospital, Rouen, France.
Valérie
V
Drouin-Garraud
Department of Endocrinology, University Hospital of Rouen, Institute for Biomedical Research, University of Rouen, Rouen, France.
Hervé
H
Lefebvre
Service d'Endocrinologie Gynécologie Diabétologie Pédiatriques, Hôpital Universitaire Necker Enfants Malades, University Paris Descartes, Paris, France.
Michel
M
Polak
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.
Jean-Claude
JC
Carel
Endocrinology-Diabetology Unit, Department of Pediatrics, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
Franziska
F
Phan-Hug
Endocrinology-Diabetology Unit, Department of Pediatrics, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
Michael
0000000219408730
M
Hauschild
Harvard Reproductive Endocrine Sciences Center and the Reproductive Endocrine Unit of the Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
Lacey
L
Plummer
1] Department of Endocrinology, Diabetology and Metabolism, Lausanne University Hospital (CHUV), Lausanne, Switzerland [2] Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland.
Jean-Pierre
JP
Rey
Institute of Biomedicine/Physiology, University of Helsinki and Children's Hospital, Helsinki University Central Hospital, Helsinki, Finland.
Taneli
0000000284225359
T
Raivio
Centre for Neuroendocrinology, University College London Medical School, London, UK.
Pierre
P
Bouloux
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.
Yisrael
Y
Sidis
Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York, USA.
Moosa
0000000179588262
M
Mohammadi
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.
Nicolas
N
de Roux
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.
Nelly
N
Pitteloud
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D017124:Conserved Sequence; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D007006:Hypogonadism / Q000151:congenital* / Q000235:genetics* / Q000378:metabolism; D017880:Limb Deformities, Congenital / Q000235:genetics* / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D010766:Phosphorylation; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics* / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; C106534:FRS2 protein, human; D008565:Membrane Proteins; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1