Evidence map›Paper›PMID 25394172›Full record

ArticleGenetics in medicine : official journal of the American College of Medical Genetics2015

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

Carine Villanueva, Elka Jacobson-Dickman, Cheng Xu, Sylvie Manouvrier, Andrew A Dwyer, Gerasimos P Sykiotis, Andrew Beenken, Yang Liu, Johanna Tommiska, Youli Hu and 17 more

Registry-linked trialOpen access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Genetics in medicine : official journal of the American College of Medical Genetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT01601171 (The Genetics of Neuroendocrine Reproductive Disorders and of the Cleft Lip and/or Palate), which is not on this map. Cited by 31 papers.

0numbers the graph read from it
0cells of the map it votes in
31citing papers in PubMed
2.6field-weighted citation impact, top 10% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

NCT01601171 recruitingnot on this map

The Genetics of Neuroendocrine Reproductive Disorders and of the Cleft Lip and/or Palate

TypeobservationalSponsorCentre Hospitalier Universitaire VaudoisRan2012 to 2030Enrolled2,000ConditionsKallmann Syndrome, Hypogonadotropic Hypogonadism, Hypothalamic Amenorrhea, Polycystic Ovarian Syndrome
3 · Its place in the literature

Who cites it

31 citing papers in PubMed, 73 citations in OpenAlex.

  1. Article
  2. Evidence-based classification of genes implicated in craniosynostosis disorders using the ClinGen curation framework.Genetics in medicine : official journal of the American College of Medical Genetics · 2026
    Article
  3. Article
  4. Article
  5. Review
  6. Review
  7. Review
  8. Article
  9. Frontiers in endocrinology · 2025
    Article
  10. Article
  11. Article
  12. Article
  13. Article
  14. Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences · 2022
    Article
  15. Review
  16. Review
  17. Article
  18. NovelGenes · 2021
    Article
  19. Review
  20. Pathogenic mosaic variants in congenital hypogonadotropic hypogonadism.Genetics in medicine : official journal of the American College of Medical Genetics · 2020
    Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

27 authors at 13 institutions in 7 countries.

Carine Villanueva1] 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.ORCID 0000000339450431
Elka Jacobson-Dickman1] 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.
Cheng Xu1] 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.
Sylvie ManouvrierService de Génétique Clinique, Hôpital Jeanne de Flandre, Lille, France.
Andrew A Dwyer1] 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 Sykiotis1] 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 BeenkenDepartment of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York, USA.
Yang LiuDepartment of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York, USA.
Johanna TommiskaInstitute of Biomedicine/Physiology, University of Helsinki and Children's Hospital, Helsinki University Central Hospital, Helsinki, Finland.
Youli HuCentre for Neuroendocrinology, University College London Medical School, London, UK.
Dov Tiosano1] 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.
Marion GerardClinical Genetics, Hôpital Universitaire de la Côte de Nacre, Caen, France.
Juliane Leger1] 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.
Valérie Drouin-GarraudDepartment of Genetics, Rouen University Hospital, Rouen, France.
Hervé LefebvreDepartment of Endocrinology, University Hospital of Rouen, Institute for Biomedical Research, University of Rouen, Rouen, France.
Michel PolakService d'Endocrinologie Gynécologie Diabétologie Pédiatriques, Hôpital Universitaire Necker Enfants Malades, University Paris Descartes, Paris, France.
Jean-Claude Carel1] 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.
Franziska Phan-HugEndocrinology-Diabetology Unit, Department of Pediatrics, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
Michael HauschildEndocrinology-Diabetology Unit, Department of Pediatrics, Lausanne University Hospital (CHUV), Lausanne, Switzerland.ORCID 0000000219408730
Lacey PlummerHarvard Reproductive Endocrine Sciences Center and the Reproductive Endocrine Unit of the Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
Jean-Pierre Rey1] Department of Endocrinology, Diabetology and Metabolism, Lausanne University Hospital (CHUV), Lausanne, Switzerland [2] Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland.
Taneli RaivioInstitute of Biomedicine/Physiology, University of Helsinki and Children's Hospital, Helsinki University Central Hospital, Helsinki, Finland.ORCID 0000000284225359
Pierre BoulouxCentre for Neuroendocrinology, University College London Medical School, London, UK.
Yisrael Sidis1] 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.
Moosa MohammadiDepartment of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York, USA.ORCID 0000000179588262
Nicolas de Roux1] 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.
Nelly Pitteloud1] 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.
Massachusetts General Hospital · USInserm · FRNew York University · USUniversity of Lausanne · CHUniversité de Rouen Normandie · FRUniversity College London · GBUniversity of Helsinki · FICentre Hospitalier Universitaire de Caen Normandie · FRHôpital Jeanne de Flandre · FRHôpital Necker-Enfants Malades · FRHuashan Hospital · CNRambam Health Care Campus · ILState University of New York · US

Funding

The Genetic Determinants of Human GNRH DeficiencyU54HD028138 · NICHD · MASSACHUSETTS GENERAL HOSPITAL · PI CROWLEY, WILLIAM FRANCIS · 2000 to 2013
$19.9M
MECHANISMS OF FGF RECEPTOR REGULATION AND SIGNALINGR01DE013686 · NIDCR · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · PI MOHAMMADI, MOOSA · 2000 to 2020
$12.3M
Training program in Molecular BiophysicsT32GM088118 · NIGMS · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · PI STOKES, DAVID L. · 2010 to 2019
$1.8M
The role of FGF signaling in neuroendocrine control of reproductionR01HD056264 · NICHD · MASSACHUSETTS GENERAL HOSPITAL · PI PITTELOUD, NELLY · 2008 to 2012
$1.8M
NICHD NIH HHS R01 HD056264NICHD NIH HHS R01HD056264NICHD NIH HHS U54 HD028138NIDCR NIH HHS R01 DE013686NIDCR NIH HHS R01DE013686NIGMS NIH HHS T32 GM088118
6 · The paper itself

Abstract

purposeCongenital hypogonadotropic hypogonadism (CHH) and split hand/foot malformation (SHFM) are two rare genetic conditions. Here we report a clinical entity comprising the two.

methodsWe 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.

resultsWe 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.

conclusionFGFR1 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.

Indexed as

MutationAdaptor Proteins, Signal TransducingAmino Acid SequenceAnimalsConserved SequenceFemaleGenetic Association StudiesHumansHypogonadismLimb Deformities, CongenitalMaleMAP Kinase Signaling SystemMembrane ProteinsMolecular Sequence DataPedigreePhosphorylationAdaptor Proteins, Signal TransducingFGFR1 protein, humanFRS2 protein, humanMembrane ProteinsReceptor, Fibroblast Growth Factor, Type 1

Identifiers

PMID25394172
PMCPMC4430466
OpenAlexW1980056733

What OpenQuestion holds

Textmetadata
LicenceTDM
Read underepoch 390

Registered trials

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.