Endocrine Abstracts

JOINT2787

Introduction: Ovarian dysgenesis (OD) is a major cause of hypergonadotropic hypogonadism and premature ovarian insufficiency (POI) in adolescent females. X chromosome numerical or structural abnormalities have historically been the most frequent congenital etiology of this condition. More recently, additional pathogenetic mechanisms have been identified, including Fragile X premutation and mutations in genes involved in meiosis, DNA damage repair, and homologous chromosome recombination.

PSMC3IP: is a novel candidate gene associated with autosomal recessive OD, playing a crucial role in homologous chromosome pairing and recombination during meiosis.

Case Report: A 13-year, 6-month-old adolescent girl, the firstborn of apparently non-consanguineous parents, was referred for evaluation due to short stature, delayed pubertal development (Tanner stage PH1 B1), and primary amenorrhea. Psychomotor development was normal. Baseline biochemical tests, thyroid function, and celiac serology were unremarkable. However, FSH levels were repeatedly elevated, while estradiol, AMH, and testosterone levels were low or undetectable. LH levels were in the high-normal range. IGF-1 levels were low (108 ng/ml, < -2 SD), and bone age was delayed by more than three years. Karyotype analysis (50 metaphases) revealed a normal 46XX pattern, and FISH analysis did not detect Yp11.3 sequences. Due to short stature, GH stimulation tests (arginine and clonidine after estradiol priming) were performed, showing low GH peaks (6.83 ng/ml and 2.32 ng/ml, respectively), confirming GH deficiency. Brain MRI revealed diffuse pituitary gland enlargement without focal lesions. Ophthalmological evaluation was normal. Consequently, rhGH therapy was initiated at age 14 and is currently ongoing. Further investigation of POI through pelvic ultrasound revealed marked uterine and ovarian hypoplasia. Autoantibodies against adrenal and ovarian tissues were undetectable. Genetic testing, including SNP microarray and Fragile X (FMR1) analysis, did not reveal CGG repeat expansion nor significant chromosomal rearrangements. Whole-exome sequencing identified a homozygous likely pathogenic variant (Class IV) in PSMC3IP (c.429_430del; p.Arg143Serfs*5). At 14 years and 6 months, estradiol replacement therapy was initiated and is ongoing.

Discussion: Only a few cases of autosomal recessive OD due to PSMC3IP variants have been reported to date. This case highlights the role of meiotic arrest in OD pathogenesis and supports the observation that distal (C-terminal) pathogenic variants in PSMC3IP are preferentially associated with OD. Additionally, the unique co-occurrence of pituitary hyperplasia and GH deficiency expands the clinical spectrum of this novel genetic condition.