Endocrine Abstracts

Background: We describe a patient with 46XX ovotesticular difference of sex development (DSD) due to 46XX/69XXY gonadal mixoploidy, also an NR5A1 variant, who developed severe early-onset obesity and subsequently a pathogenic MC4R variant was identified.

Case Presentation: A term Caucasian baby weighing 3.64kg with non-consanguineous parents presented with atypical genitalia (Prader Stage 2-3) with clitoromegaly, perineal urethral opening, normal vaginal opening, bilateral inguinal herniae and masses palpable in the labio-scrotal folds. Pelvic ultrasound identified a normal uterus and indeterminate gonads in the labio-scrotal folds. Adrenal androgens were within female normal range: DHEAS 8.8umol/l (0.86-16.5) and testosterone 2.5nmol/l (1.7-5.6nmol/l). However, values in the male range were found for AMH (280.2pmol/l; 390-1300pmol/l) and inhibin (149ng/l; 128-300ng/l). Blood karyotype was 46XX and CGH array normal. DSD-panel genetic testing identified a novel heterozygous variant c.389C>T in NR5A1 (nuclear receptor subfamily-5). This was not considered clinically significant as at a different location to NR5A1 variants previously associated with 46XX and 46XY DSD and also identified in the patient’s father. Female sex of rearing was agreed following multidisciplinary team (MDT) and family discussion, and inguinal herniae repair surgery was planned. At laparoscopy a bipolar right gonad was noted and biopsied; histological examination demonstrating both ovarian tissue and seminiferous tubules and karyotyping identified 46XX/69XXY mixoploidy. Further studies confirmed one X chromosome was maternally derived, the other X and Y chromosomes paternally derived. The left gonad was normal ovary, karyotype 46XX. Developmental progress was normal and general health excellent except for escalating weight gain and hyperphagia from the age of 2 years. Aged 4, weight was 115.6kg (>99.6thcentile), height 115.6 cm (>99.6thcentile) and BMI 25.5kg/m² (BMI-SDS +4.2). A targeted gene panel for early-onset obesity identified a pathogenic MC4R heterozygous variant c.105C>A, p.(Tyr35*). She is receiving intensive weight management MDT input.

Discussion: 46,XX/69,XXY gonadal mixoploidy is extremely rare, previous cases having male phenotype with either normal testicular development, undervilirisation or ovotesticular DSD. This in combination with a pathogenic MC4R variant causing hyperphagia and severe obesity is unique and previously unreported. This case highlights the importance of expert MDT management in complex cases and the role of dedicated gene panels.