ESPE Abstracts

Background: Variants in the estrogen receptor α (ESR1) have previously been described in male and female patients presenting with estrogen resistance. Estrogen resistance is characterized by delayed bone-age, early-onset osteoporosis, delayed puberty and multicystic ovaries in women. So far, no clinical consequences of variants in the estrogen receptor β (ESR2) have been reported in 46,XX patients, although ESR2 variants have previously been implicated in 46,XY DSD patients. Here we describe the first case of a 16-year old woman with complete lack of estrogen action, indicated through absent breast development, primary amenorrhea and osteoporosis. Additionally, she presented with dysgenetic gonads, which has not been observed in ESR1 deficient patients.

Methods: The genomic DNA of the patient was analyzed using whole exome sequencing (WES) We could exclude variants in other genes related to 46,XX DSD, in genes up- and downstream of the estrogen receptors and in genes implicated in premature ovarian failure. We performed functional transactivation studies using wild type and variant ESR2 in ovarian, bone and breast cell lines and 3D molecular models of the wild type and variant ESR2 were created.

Results: A heterozygous missense variant of a highly conserved amino acid (AA) was identified in ESR2 (c.941A>G, p.Lys314Arg). The Lys314 was shown by the 3D model to be part of the co-factor binding site and its substitution with an Arg leads to a disrupted interaction between ESR2 and its co-factor NCOA1. The functional transactivation studies showed that the variant in ESR2 leads to a disrupted estradiol-dependent signaling in the three cell lines. In the pre-granulosa cell system, the mutant ESR2 completely lost its function and has a dominant negative effect, suggesting that ESR2 is necessary for ovarian development.

Conclusion: We describe the first case of complete ovarian dysgenesis in a woman due to a loss-of-function variant of the ESR2. This suggests that ESR1 is not sufficient by itself to advance ovarian development and that ESR2 is necessary for human ovarian determination. It remains to be established, whether estrogen resistance due to milder defects in ESR2 might account for unexplained cases of ovarian failure or infertility.