Familial multiplicity of estrogen insensitivity associated with a loss-of-function ESR1 mutation

Context: Estrogens influence many physiological processes in mammals, including reproduction. Estrogen peripheral actions are mainly mediated through estrogen receptors (ERs) a and b, encoded by ESR1 and ESR2 genes, respectively. Objective: The study's aim was to describe a family in which 3 members presented with estrogen insensitivity. Design and Setting: Clinical evaluation and genetic and mutational analysis were performed in an academic medical center. Patients and Interventions: 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. Results: Hormonal evaluation revealed extremely high plasma 17b-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 ERa revealed strongly reduced transcriptional activity and the inability to securely anchor the activating hormone, estradiol, compared with wild-type ERa. A group of other potential ER activating ligands were tested, but none overcame the estrogen insensitivity in these patients. Conclusion: Description and analysis of this family of patients with mutant ERa provide additional clinical findings toward identification and characterization of what was previously thought to be a highly rare clinical condition.