ESPE Abstracts (2022) 95 P1-173

ESPE2022 Poster Category 1 Sex Differentiation, Gonads and Gynaecology, and Sex Endocrinology (56 abstracts)

Differences due to the variant type in the inheritance pattern of BMP15 gene-related primary ovarian insufficiency: a girl with a homozygous null BMP15 gene variant

Zehra Yavas Abali 1 , Esra Arslan Ates 2 , Mehmet Eltan 3 , Busra Gurpinar Tosun 3 , Abdullah Bereket 3 , Tulay Guran 3 & Serap Turan 3

1Marmara University, Pendik Research and Training Hospital, Pediatric Endocrinology Unit, Istanbul, Turkey; 2Marmara University, Pendik Research and Training Hospital, Department of Medical Genetics, Istanbul, Turkey; 3Marmara University, School of Medicine, Department of Pediatric Endocrinology and Diabetes, Istanbul, Turkey

Background: Bone morphogenetic protein 15 (BMP15), is an oocyte-specific growth factor, that regulates folliculogenesis and ovulation rate. It is encoded by the BMP15 gene (chromosome Xp11.2), in which heterozygous missense variants in the precursor or mature peptide cause primary ovarian insufficiency (POI) with the dominant-negative effect. BMP15-related ovarian dysgenesis (OD) constitutes 1.5-2.0% of POI. The underlying mechanism still remains elusive and a double dose of BMP15 is required for adequate ovarian reserve. POI due to recently identified homozygous BMP15 variants and the reports of physiological menopause in heterozygous mothers indicate that different mechanisms play a role in the etiology.

Case report: A 17-year-old girl was admitted for the evaluation of amenorrhea. Her healthy parents were 1.5-degree cousins. She was born at term with a birth weight of 3,200 g. She had no history of chronic disease or medication use. Her 42-year-old mother had regular menstrual cycles and her age at menarche was 12-years. Her weight, height, and body mass index at first evaluation were 76.6 kg (2.4 SDS), 164.5 cm (0.3 SDS) and 28.3 kg/m2 (2.2 SDS), respectively. Physical examination was normal except for acanthosis nigricans and hemangioma on the 4 and 5th fingers of the left hand. Her breast was Tanner stage 4 and pubic hair was stage 5. Hypergonadotropic hypogonadism (LH 40.5 mIU/ml, FSH 88.7 mIU/ml, E2 <5.0 pg/mL) was detected in this girl with primary amenorrhea. Sizes of the uterus and left and ovaries on pelvic ultrasonography were, 17x34x55 mm, 10x18 mm, and 10x17 mm, respectively. Urinary ultrasonography revealed a duplicated collecting system. Steroid hormone profile (LCMS/MS) was normal and urinary reducing substance was negative. Echocardiography, audiology, and ophthalmologic examinations were also normal. Chromosome analysis was 46, XX (30 metaphases). Clinical exome sequencing of the patient revealed a novel homozygous ‘null’ BMP15 gene variant (NM_005448, c.610C>T; p.R204*). Segregation analysis confirmed that her mother was heterozygous and her father was hemizygous for this variant.

Conclusion: Our case supports the recent hypothesis that "null" BMP15 gene variants cause POI only in the homozygous state, and this makes the role of isolated BMP15 haploinsufficiency in the etiology of OD controversial. Biallelic BMP15 “null” variants have a recessive inheritance pattern with a “knockout‐like” effect and this mechanism, which has been hypothesized recently, is supported by the present case.

Volume 95

60th Annual ESPE (ESPE 2022)

Rome, Italy
15 Sep 2022 - 17 Sep 2022

European Society for Paediatric Endocrinology 

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