OR15-4 Long-Term Follow-Up of a Female with a Mutation in the Estrogen Receptor Alpha (ESR1) Gene

We previously reported the first female with a mutation in the ESR1 gene encoding estrogen receptor-α (ER-α), which dramatically reduced estrogen signaling in vitro. She presented at 17(9/12) years with absent breast development, markedly elevated serum estradiol and estrone levels, modestly high gonadotropins, and multicystic ovaries by ultrasound. The natural history of estrogen insensitivity in women is unknown. The purpose of this report is to present: 1) the neuroendocrine phenotype; 2) studies to identify a ligand to stimulate the mutant receptor; and 3) the effect of targeted treatment. We now provide long-term clinical follow up and a detailed hormonal analysis of the patient at age 23(4/12) years. On no treatment, serum FSH and LH were drawn every 10 minutes for 8 hours, and estradiol and estrone levels were measured every hour during the study. Various compounds that are potential for treatment were used in transient transfection assays to determine if estrogen signaling could be induced. A personalized medicine approach was tailored to our patient, in which she received increasing doses of diethylstilbestrol (DES) with the primary endpoints being increased vaginal discharge and breast development. Follow up exams, labs, pelvic ultrasounds, DXA, and bone age X-rays were completed at various intervals up to age 23(4/12) years. The Bioethics Board approved this treatment. During the frequent sampling study, E2 was 604 pg/mL, E1 was 596 pg/mL, FSH was 10.0+/-0.1 IU/L (mean+/-SE), and LH was 6.7+/-0.2 IU/L. There were 3 pulses in 8 hr with an LH pulse amplitude of 2.3+/-0.5 IU/L. Although DES was shown to successfully transactivate the mutant ESR1in vitro, both in HEK293 cells and in her lymphoblastoid cells, the patient had no clinical response. After 2.5 years of treatment with increasing doses of DES, there was no vaginal discharge and breasts remained at Tanner 1. At 23(4/12) years, LH, FSH and E2 were unchanged. A vaginal maturation index showed a predominance of parabasal cells consistent with a lack of estrogen effect. Ultrasound showed bilateral ovarian cysts. At chronologic age 23(4/12) years, her bone age was 17 years and the epiphysis remained open in the ulnar bone. DXA revealed a Z-score of -2.9 at the femoral neck and -4.5 at the lumbar spine. Our findings in this severely estrogen insensitive female indicate elevated gonadotropins with normal amplitude and low frequency LH pulse dynamics in the presence of markedly increased estrogens. Treatment with DES, which stimulated estrogen signaling in vitro, did not induce secondary sexual characteristics in our patient. She remains hypoestrogenic despite the presence of ovarian cysts with a hypoestrogenic vaginal smear, absent breast development, and low bone mineral mass. Future studies will be directed towards further identification of other potential signaling mechanisms and activators of this mutant receptor.