RF34 | PMON19 Biallelic Variants in the INHA Gene Are the Cause of Gonadal Dysgenesis, Primary Amenorrhea and Absence of Puberty in the Setting of Hypergonadotropic Hypogonadism

BACKGROUND: Hypergonadotropic hypogonadism can be caused by congenital or acquired causes. These can range from chromosomal abnormalities, enzymatic defects or mutations that cause gonadotropin resistance, trauma, chemotherapy, infections etc. It is uncommon in females other than in Turner syndrome and not all the genetic etiologies are known. CLINICAL CASE: A 15 10/12 year old female with primary amenorrhea and absent pubertal development presented with FSH and LH levels of 35.24 mIU/mL and 14.38 mIU/mL, respectively and non-pubertal estradiol levels of 4 pg/mL consistent with hypergonadotropic hypogonadism. Her evaluation showed a normal 46,XX female karyotype and no evidence of hyperandrogenism or thyroid dysfunction. Ultrasound showed no evidence of ovaries and a rudimentary uterus measuring 0.9 cm×1.4 cm×1.2 cm with a delayed bone age of 12 years. Family history was positive for mother having delayed puberty with menarche at 16.5 years of age. Patient was started on hormone replacement therapy with transdermal estrogen. Four months after treatment she developed breast buds and vaginal discharge. After 1.5 years, the uterus measurements were 5.7 cm x3.7 cm x2.2 cm although no ovarian tissue or follicles were identified on MRI. Her biochemical profile also showed decreases in FSH (3.48 mIU/mL) and LH (0.99 mIU/mL) and an increase in estradiol (38pg/mL). Exome sequencing was performed and revealed biallelic missense variants c.766C>T, p.(Pro256Ser) and c.1036G>C p.(Gly346Arg) in exon 2 of the INHA (NM_002191) gene. Both variants are rare in the human population, seen in a heterozygous state with a global allele frequency (gnomADv2.1) of 0 and 0.00002790 (rs780833794), respectively, and predicted to be damaging by bioinformatic tools. INHA, a member of the transforming growth factor-β (TGF-β) superfamily, encodes the alpha subunit of glycoprotein hormones inhibin A and B. Studies in animal models indicate that inhibin A negatively regulates follicle stimulating hormone (FSH) secretion by suppressing FSHR expression and plays a crucial role in ovarian steroid hormone production, follicular development, proliferation and apoptosis of granulosa cells, and oocyte maturation. Heterozygous pathogenic variants in the INHA gene have been reported in patients with primary ovarian insufficiency (POI) and secondary amenorrhea(1), while our patient with biallelic variants in INHA is affected by gonadal dysgenesis, primary amenorrhea, absence of puberty, a more severe POI phenotype. CONCLUSION: To our knowledge, this is the first case of biallelic mutations in INHA gene leading to a severe phenotype (gonadal dysgenesis, primary amenorrhea and absence of puberty) compared to heterozygous mutations that lead to POI with secondary amenorrhea. (1)References: Marozzi A, Porta C, et al. 2002. Mutation analysis of the inhibin alpha gene in a cohort of Italian women affected by ovarian failure. Human Reproduction Vol. 17 No.7 1741-1745 Presentation: Monday, June 13, 2022 12:30 p.m. - 12:35 p.m., Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.