Early-Onset Complete Ovarian Failure and Lack of Puberty in a Woman With Mutated Estrogen Receptor ß (ESR2).

Context: Estrogen resistance due to mutations in the estrogen receptor α gene (ESR1) has been described in men and women and is characterized by osteoporosis, delayed bone age and continuous growth in adulthood, and delayed puberty and multiple ovarian cysts in women. Although mutations in the estrogen receptor ß gene ESR2 were found in 46, XY patients with differences of sex development, no genetic variants of ESR2 were linked to gonadal defects in women. Settings and Patient: Here we describe a 16-year-old female patient who came to our tertiary care hospital with complete lack of estrogen action, as demonstrated by absent breast development, primary amenorrhea, and osteoporosis, resembling patients with ESR1 mutation. However, her gonads were clearly abnormal (streak), a finding not observed in ESR1-deficient patients. Design: To gain insights into the molecular consequences of the ESR2 defect, whole exome sequencing and extensive functional transactivation studies in ovarian, bone, and breast cells were conducted, with or without the natural activator of estrogen receptors, 17ß-estradiol. Results: We identified a loss-of-function heterozygous mutation of a highly conserved residue in ESR2 that disrupts estradiol-dependent signaling and has a dominant negative effect, most likely due to failure to interact with its coactivator, nuclear coactivator 1. Conclusions: This is a report of a loss-of-function mutation in the estrogen receptor ß in a young woman with complete ovarian failure, suggesting that ESR2 is necessary for human ovarian determination and/or maintenance and that ESR1 is not sufficient to sustain ovarian function in humans.

A novel DAX-1 (NR0B1) mutation in a boy with X-linked adrenal hypoplasia congenita.

BACKGROUND: X-linked adrenal hypoplasia congenita (AHC) is caused by mutations in DAX-1 (NR0B1) playing a key role in adrenal and reproductive development. CASE PRESENTATION: Herein we report a 2.5-year-old boy who presented with acute adrenal failure. Family history revealed unexplained death in three brothers of the patient's mother during infancy. Molecular analysis of the DAX-1 gene revealed the presence of a novel hemizygous mutation, c.870C>A in exon 1, leading to the formation of a premature stop codon. The same mutation was identified in the patient's mother. The truncated mutant protein is most likely misfolded, sequestered in the endoplasmic reticulum and therefore cannot bind to and activate its target DNA sequences in the nucleus. CONCLUSIONS: DAX-1 mutation must be considered when diagnosis of primary adrenocortical insufficiency is made, especially if there is a history of unexplained death of maternal male relatives.