title: Familial Multiplicity of Estrogen Insensitivity Associated With a Loss-of-Function ESR1 Mutation.
abstract: Estrogens influence many physiological processes in mammals, including reproduction. Estrogen peripheral actions are mainly mediated through estrogen receptors (ERs) α and β, encoded by ESR1 and ESR2 genes, respectively.
  
  
  
  The study's aim was to describe a family in which 3 members presented with estrogen insensitivity.
  
  
  
  Clinical evaluation and genetic and mutational analysis were performed in an academic medical center.
  
  
  
  An ESR1 mutation was identified in 2 sisters and 1 brother, originating from a consanguineous Algerian family, who did not enter puberty and presented with delayed bone maturation consistent with estrogen insensitivity. The 2 sisters had enlarged multicystic ovaries. Hormonal evaluation as well as genetic and mutational analysis were performed.
  
  
  
  Hormonal evaluation revealed extremely high plasma 17β-estradiol (>50-fold normal range) associated with elevated gonadotropin levels (greater than threefold normal range), highly suggestive of estrogen resistance. The 3 affected patients carried a homozygous mutation of a highly conserved arginine 394 for which histidine was substituted through an autosomal recessive mode of transmission. Structural and functional analysis of the mutant ERα revealed strongly reduced transcriptional activity and the inability to securely anchor the activating hormone, estradiol, compared with wild-type ERα. A group of other potential ER activating ligands were tested, but none overcame the estrogen insensitivity in these patients.
  
  
  
  Description and analysis of this family of patients with mutant ERα provide additional clinical findings toward identification and characterization of what was previously thought to be a highly rare clinical condition.
authors.affiliation: INSERM 1185, Faculté de Médecine Paris Sud, Université Paris-Saclay, 94270 Le Kremlin-Bicêtre, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Bernard
authors.affiliation: Service de Pédiatrie, Hôpital Nafissa Hamoud, Alger, 16040 Algeria.
authors.forename: Sakina
authors.initials: S
authors.lastname: Kherra
authors.affiliation: INSERM 1185, Faculté de Médecine Paris Sud, Université Paris-Saclay, 94270 Le Kremlin-Bicêtre, France.|Service de Génétique Moléculaire, Pharmacogénétique et Hormonologie, and.
authors.forename: Bruno
authors.initials: B
authors.lastname: Francou
authors.affiliation: INSERM 1185, Faculté de Médecine Paris Sud, Université Paris-Saclay, 94270 Le Kremlin-Bicêtre, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Fagart
authors.affiliation: INSERM 1185, Faculté de Médecine Paris Sud, Université Paris-Saclay, 94270 Le Kremlin-Bicêtre, France.
authors.forename: Say
authors.initials: S
authors.lastname: Viengchareun
authors.affiliation: Laboratoire d'Hormonologie, Pôle de Biologie Médicale et Pathologie, site Saint-Antoine, Hôpitaux Universitaires Est Parisien, Assistance Publique-Hôpitaux de Paris, 75012 Paris, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Guéchot
authors.affiliation: Service de Pédiatrie, Hôpital de Bab El Oued, Alger, 16040 Algeria.
authors.forename: Asmahane
authors.initials: A
authors.lastname: Ladjouze
authors.affiliation: INSERM 1185, Faculté de Médecine Paris Sud, Université Paris-Saclay, 94270 Le Kremlin-Bicêtre, France.|Service de Génétique Moléculaire, Pharmacogénétique et Hormonologie, and.
authors.forename: Anne
authors.initials: A
authors.lastname: Guiochon-Mantel
authors.affiliation: Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, Durham, North Carolina 27709.
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Korach
authors.affiliation: INSERM 1185, Faculté de Médecine Paris Sud, Université Paris-Saclay, 94270 Le Kremlin-Bicêtre, France.
authors.forename: Nadine
authors.initials: N
authors.lastname: Binart
authors.affiliation: INSERM 1185, Faculté de Médecine Paris Sud, Université Paris-Saclay, 94270 Le Kremlin-Bicêtre, France.|Service d'Endocrinologie et Maladies de la Reproduction, Centre Hospitalier Universitaire de Bicêtre, Hôpitaux Universitaires Paris-Sud, Assistance Publique-Hôpitaux de Paris, 94270 Le Kremlin-Bicêtre, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Lombès
authors.affiliation: Service d'Endocrinologie et Maladies de la Reproduction, Hôpital Saint-Antoine, Assistance Publique-Hôpitaux de Paris, 75012 Paris, France; and.|INSERM 933, Université Pierre et Marie Curie, 75011 Paris, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Christin-Maitre
mesh_terms: D000293:Adolescent; D000328:Adult; D015415:Biomarkers / Q000032:analysis; D004351:Drug Resistance / Q000235:genetics*; D047628:Estrogen Receptor alpha / Q000235:genetics* / Q000378:metabolism*; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D011379:Prognosis; D011485:Protein Binding; D012741:Sexual Maturation / Q000235:genetics*; D015533:Transcriptional Activation; D055815:Young Adult
chemical_list: D015415:Biomarkers; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D004967:Estrogens