Endocrine manifestations of Luscan–Lumish syndrome associated with a novel SETD2 frameshift variant

Abstract

Abstract Luscan–Lumish syndrome is a rare autosomal-dominant disorder caused by pathogenic SET domain-containing protein 2 (SETD2) variants, classically associated with postnatal overgrowth, obesity, developmental delay, seizures, and Chiari I malformation; endocrine manifestations remain poorly characterized. We report a 47-year-old woman with a novel SETD2 frameshift variant (c.4451_4454del, p.Lys1486Argfs*28) presenting with severe obesity (body mass index 62.9 kg/m2), hypogonadotropic hypogonadism, hyperprolactinemia, and neurodevelopmental manifestations. She underwent rapid weight gain of 60 pounds during adolescence without reported dietary or activity changes, accompanied by hirsutism and secondary amenorrhea. Laboratory evaluation revealed low gonadotropins (luteinizing hormone 0.3 IU/L; reference 1.9-12.5 IU/L, follicular; follicle-stimulating hormone 0.5 IU/L; reference 2.5-10.2 IU/L, follicular), low estradiol (26.4-48 pg/mL [96.9-176.2 pmol/L]; reference 30-400 pg/mL [110.1-1468.4 pmol/L]), and hyperprolactinemia (140 ng/mL [140 µg/L]; reference 4-25 ng/mL [4-25 µg/L]). Despite decades of evaluation, a unifying diagnosis was not established until genetic testing identified the pathogenic SETD2 variant. This case expands the endocrine phenotype of Luscan–Lumish syndrome to include hypogonadotropic hypogonadism and hyperprolactinemia associated with a pituitary microadenoma, highlighting the importance of genetic evaluation in patients with rapid-onset severe obesity and multisystem disease.