MON-143 - A Case of Mixed Gonadal Dysgenesis

Background: Mixed gonadal dysgenesis (MGD) is a rare disorder of sex development, with a prevalence of 6 per 100000 newborn males. It is characterized by asymmetric gonadal development and 45X/46XY mosaicism. It is associated with a high burden of comorbidities, including diabetes, thyroid disorders, obesity, hypertension, and osteoporosis (1).

Clinical

Case: A 74-year-old male with a longstanding history of infertility, hypertension, prediabetes was seen for evaluation of osteoporosis (lowest femoral T-score -2.6, L1-4 T score -2.4). He reported delayed puberty, lifelong paucity of facial and body hair growth, and a diagnosis of azoospermia, noted in his 30s. He denied vision changes, headaches, anosmia, fractures, liver cirrhosis, or diabetes. Infertility was previously attributed to an idiopathic cause with low testosterone levels on prior labs; no additional workup was conducted. He was treated with testosterone injections, which he stopped shortly thereafter due to nipple tenderness. Prolactin levels were slightly elevated at the time; a brain MRI did not reveal a pituitary gland abnormality. On physical exam, the patient had a normal male phenotype, 175 cm tall, BMI 23.78 kg/m2, sparse facial and body hair, a normal penis, male-pattern pubic hair, and bilateral soft, small testes (3-4 mL). At presentation in our clinic, his fasting lab results were as follows: total testosterone (by liquid chromatography/mass spectrometry) and bioavailable testosterone were low (49 ng/dL and 19.3 ng/dL, respectively), sex hormone binding globulin was normal (40 nmol/L), LH and FSH were elevated (65.9 mIU/mL and 104 mIU/mL respectively), prolactin was normal. Results confirmed primary hypogonadism. Karyotype analysis of peripheral blood revealed 45,X/46,XY mosaicism (10% loss of Y chromosome), consistent with MGD. He was started on testosterone gel, which he tolerated well with improvements in overall energy, mood, and normalization of testosterone levels.

Conclusion: This case demonstrates that MGD symptoms can be subtle and easily overlooked due to an apparently normal male phenotype. Our patient's delayed diagnosis likely contributed to his osteoporosis, hypertension, and prediabetes. Timely attention to signs of delayed or incomplete pubertal development, including cytogenetic analysis, is crucial for early diagnosis. Given MGD's association with multiple comorbidities, similar to Turner syndrome, additional health screenings are warranted. Testosterone replacement remains the gold standard for patients with MGD and primary hypogonadism, supporting bone health, secondary sex characteristics, and quality of life.

References:
1. Berglund A, Gravholt CH, Stochholm K: Morbidity in Males With 45,X/46,XY Resembles the Morbidity Pattern in Turner Syndrome: A National Population-Based Study The Journal of Clinical Endocrinology & Metabolism, 2025, 110, 2556–2564.

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