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Insight Into the Ontogeny of GnRH Neurons From Patients Born Without a Nose.

  • Delaney, Angela1, 2
  • Volochayev, Rita1, 2
  • Meader, Brooke1, 2
  • Lee, Janice3
  • Almpani, Konstantinia3
  • Noukelak, Germaine Y2
  • Henkind, Jennifer4
  • Chalmers, Laura5
  • Law, Jennifer R6
  • Williamson, Kathleen A7
  • Jacobsen, Christina M8
  • Buitrago, Tatiana Pineda9
  • Perez, Orlando10
  • Cho, Chie-Hee11
  • Kaindl, Angela12
  • Rauch, Anita13
  • Steindl, Katharina13
  • Garcia, Jose Elias14
  • Russell, Bianca E15
  • Prasad, Rameshwar16
  • And 26 more
  • 1 Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland.
  • 2 Clinical Research Branch, National Institute of Environmental Health Sciences, Durham, North Carolina.
  • 3 National Institute of Dental and Craniofacial Research, Bethesda, Maryland.
  • 4 Stamford Pediatric Associates, Stamford, Connecticut.
  • 5 Department of Pediatrics, University of Oklahoma College of Medicine, Tulsa, Oklahoma.
  • 6 Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
  • 7 MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh Western General Hospital, Edinburgh, UK.
  • 8 Divisions of Endocrinology and Genetic and Genomics, Boston Children's Hospital, Department of Pediatrics, Harvard Medical School, Boston, Massachusetts.
  • 9 Fundación Hospital Infantil Universitario de San José, Bogotá, Colombia. , (Colombia)
  • 10 Academia Nacional de Medicina de Colombia, Bogotá, Colombia. , (Colombia)
  • 11 Department of Radiology, Charité-University Medicine Berlin, Berlin, Germany. , (Germany)
  • 12 Biology & Neurobiology, Charité-University Medicine Berlin and Berlin Institute of Health, Berlin, Germany. , (Germany)
  • 13 Institute of Medical Genetics and Radiz-Rare Disease Initiative Zurich, Clinical Research Priority Program for Rare Diseases, University of Zurich, Schlieren-Zurich, Switzerland. , (Switzerland)
  • 14 División de Genética, Centro de Investigación Biomédica de Occidente, Instituto Mexicano del Seguro Social, Guadalajara, Mexico. , (Mexico)
  • 15 Department of Pediatrics, Division of Genetics, University of California, Los Angeles, California.
  • 16 Department of Neonatology, IPGME&R and SSKM Hospital, Kolkata, India. , (India)
  • 17 Department of Pediatric and Adolescent Medicine, Haukeland University Hospital, Bergen, Norway. , (Norway)
  • 18 Division of Endocrinology, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah.
  • 19 Harvard Reproductive Endocrine Sciences Center and NICHD Center of Excellence in Translational Research in Fertility and Infertility, Reproductive Endocrine Unit of the Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
  • 20 Department of Craniofacial Surgery, Children's University Hospital of San Jose, Bogotá, Colombia. , (Colombia)
  • 21 Service de Génétique Clinique, CHU Robert Debré, Paris, France. , (France)
  • 22 Department of Plastic and Reconstructive Surgery, Kagoshima City Hospital, Kagoshima, Japan. , (Japan)
  • 23 Department of Pediatrics, University of Kagoshima Hospital, Kagoshima, Japan. , (Japan)
  • 24 Department of Clinical Genetics, Hospital for Rehabilitation of Craniofacial Anomalies (HRCA), University of São Paulo, Bauru, Brazil. , (Brazil)
  • 25 Craniofacial Team, HRCA, University of São Paulo, Bauru, Brazil. , (Brazil)
  • 26 Pediatric and Community Dentistry Sector, HRCA, University of São Paulo, Bauru, Brazil. , (Brazil)
  • 27 William F. Connell School of Nursing, Boston College, Chestnut Hill, Massachusetts.
  • 28 Department of Pediatrics, Cedars Sinai Medical Center, Los Angeles, California.
  • 29 Medical Genetics, MassGeneral Hospital for Children and Harvard Medical School, Boston, Massachusetts.
Published Article
The Journal of Clinical Endocrinology & Metabolism
The Endocrine Society
Publication Date
May 01, 2020
DOI: 10.1210/clinem/dgaa065
PMID: 32034419


The reproductive axis is controlled by a network of gonadotropin-releasing hormone (GnRH) neurons born in the primitive nose that migrate to the hypothalamus alongside axons of the olfactory system. The observation that congenital anosmia (inability to smell) is often associated with GnRH deficiency in humans led to the prevailing view that GnRH neurons depend on olfactory structures to reach the brain, but this hypothesis has not been confirmed. The objective of this work is to determine the potential for normal reproductive function in the setting of completely absent internal and external olfactory structures. We conducted comprehensive phenotyping studies in 11 patients with congenital arhinia. These studies were augmented by review of medical records and study questionnaires in another 40 international patients. All male patients demonstrated clinical and/or biochemical signs of GnRH deficiency, and the 5 men studied in person had no luteinizing hormone (LH) pulses, suggesting absent GnRH activity. The 6 women studied in person also had apulsatile LH profiles, yet 3 had spontaneous breast development and 2 women (studied from afar) had normal breast development and menstrual cycles, suggesting a fully intact reproductive axis. Administration of pulsatile GnRH to 2 GnRH-deficient patients revealed normal pituitary responsiveness but gonadal failure in the male patient. Patients with arhinia teach us that the GnRH neuron, a key gatekeeper of the reproductive axis, is associated with but may not depend on olfactory structures for normal migration and function, and more broadly, illustrate the power of extreme human phenotypes in answering fundamental questions about human embryology. © Published by Oxford University Press on behalf of the Endocrine Society 2020.

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