SUN-183 Primary Amenorrhea With Tall Stature In a Young Female Due To Novel Estrogen Receptor Alpha Defect

Abstract Disclosure: M.V. Reddy: None. A. Bajpai: None. P. Gupta: None. G. Sri Harsha: None. Background: Estrogen plays an important role in the regulation of reproduction, growth, skeletal maturation, and bone mineralization. Its action is mediated by estrogen receptors (ERs) α and β, encoded by ESR1 and ESR2 genes, respectively, and by membrane receptors. Impaired estrogen effect due to inherited estrogen receptor defect is associated with dramatic impact. To date, only 5 females and 2 males, from 4 families, with loss of ERα function have been reported. Here we describe the first case of Estrogen Resistance Syndrome in a young female from India. Clinical case: A 20-year-old female product of a consanguineous marriage presented with primary amenorrhea and absent breast development. History of intermittent use of estrogen plus progesterone preparations for breast development and attaining menarche for past five years. On examination, she was tall (172 cm, height SDS+3) with stage I breast and stage 4 pubic hair development. She had mild facial acne, a gap between the first and second toes, and crowding of the fourth and fifth toes on both feet. External genital examination revealed mild clitoromegaly with normal urogenital openings.Work-up in view of impaired estrogen and increased androgen effect showed elevated LH (25.9 mU/ml; early follicular phase -1.9-12.5), FSH (40.8 mU/ml; early follicular phase-5-20), Testosterone (99.12 ng/dl; normal 10-75) levels with normal estradiol (55.91 pg/ml, early follicular phase- 22.4-115), androstenedione (6040ng/l, normal 180-2600), 17-hydroxyprogesterone (1.61 ng/dl; normal 0.2-2), AMH (10.76 ng/ml, normal 0.96-13.34) and DHEAS (362.9 mcg/dL; normal 29-781). She had delayed skeletal maturation with a bone age of 13 years and an open knee epiphysis. USG pelvis revealed a small uterus with no endometrial stripe and both ovaries normal size and echo texture with no cyst seen. MRI Pelvis also revealed a hypoplastic uterus and normal-sized ovaries without any cyst. DXA showed a Z score of -2.2 at the spine and -1 at the left femoral neck. The karyotype was normal (46 XX). Delayed puberty and skeletal maturation, tall stature, hypoplastic uterus, 46 XX karyotype with elevated estradiol and FSH levels suggested estradiol resistance. Whole exome sequencing revealed a novel homozygous nonsense variation in the exon1 of ESR1 gene (chr6:g.151808152 C>A) that results in a stop codon and premature truncation of the protein at codon 80 (p.Tyr80Ter) confirming the diagnosis.Conclusion- Our case differs from the previous reports in milder elevation in estradiol levels, absence of ovarian cysts, and digital abnormalities. These discrepancies may be due to compensatory pathways in the setting of impaired ESR1 effect that need further exploration. Presentation: Sunday, July 13, 2025