Peripheral precocious puberty in a 4-month-old infant associated with an ESR1 variant: a case report

Precocious puberty (PP) refers to pubertal onset before 8 years in females and 9 years in males. We present a rare case of a 6-year and 7-month-old Jordanian girl with peripheral PP onset at 4 months of age. Clinical evaluation revealed vaginal spotting, premature thelarche, advanced bone age, and recurrent uterine bleeding requiring multiple transfusions. Imaging demonstrated a progressive cervicovaginal mass and endometrial polyps. Histopathology identified atypical hyperplasia/endometrioid intraepithelial neoplasia. Gonadotropins remained persistently suppressed, excluding central PP. Whole-exome sequencing (WES) identified a heterozygous likely-pathogenic ESR1 missense variant (NM_000125.3; c.1610A > C; p.Tyr537Ser), previously linked to estrogen-independent receptor activation in breast cancer. Tamoxifen produced partial clinical response with subsequent recurrence; the patient is now on combined letrozole-tamoxifen therapy. This case highlights the value of WES in unexplained PP and suggests that gain-of-function ESR1 variants may drive peripheral PP through receptor hypersensitivity.