Resident University of Arkansas for Medical Sciences/Arkansas Children's Hospital Little Rock, AR, United States
Disclosure(s):
Lavina Fernandes, MD: No financial relationships to disclose
Background:
Differences of sex development (DSD) in neonates require prompt, systematic evaluation due to broad differential diagnosis and implications for management, sex assignment, and family counseling. Infants with 46,XY DSD may present with similar genital phenotypes despite distinct underlying etiologies.We describe 3 full-term neonates presenting with ambiguous genitalia and 46,XY karyotypes.
Case presentation:
Case 1 presented with multiple congenital anomalies, including macrocephaly and postaxial polydactyly. Undervirilized genitalia, with smooth labioscrotal folds, small phallus, and no palpable gonads. Newborn screen was negative for congenital adrenal hyperplasia (CAH). Imaging showed gonads in the inguinal canals, absent Müllerian structures, and absent posterior pituitary bright spot on brain MRI. Endocrine evaluation confirmed panhypopituitarism. Genetic testing identified a pathogenic GLI2 variant, consistent with a syndromic hypothalamic–pituitary dysfunction.
Case 2 presented with multiple congenital anomalies including micrognathia, cleft palate, and polydactyly. Undervirilized genitalia with small phallic structure, deep midline raphe and no palpable gonads. Imaging confirmed gonads in the inguinal canals and absent Müllerian structures. Hormonal evaluation showed elevated 7-dehydrocholesterol with otherwise normal pituitary function. Trio genome sequencing confirmed Smith-Lemli-Opitz syndrome, a disorder of cholesterol biosynthesis leading to impaired steroidogenesis and undervirilization.
Case 3 presented with undervirilized genitalia, palpable gonads in bifid scrotum with a single urogenital orifice at the base of a small phallic structure. No extragenital anomalies. Imaging confirmed bilateral testis and absent Müllerian structures. Hormonal testing showed elevated anti-mullerian hormone and testosterone levels consistent with mini-puberty. Whole exome sequencing revealed pathogenic Androgen Receptor mutation consistent with X-linked androgen insensitivity syndrome (AIS). This patient lacked dysmorphic features or extragenital anomalies, directing the evaluation toward disorders of androgen action, with androgen insensitivity syndrome identified through endocrine and molecular testing.
Discussion/
Conclusion:
This case series highlights the possibility of significant phenotypic overlap yet etiologic diversity among neonates with 46,XY DSD. A systematic, stepwise diagnostic approach - beginning with careful examination, karyotype confirmation, imaging and followed by targeted hormonal and genetic testing when indicated - is essential to identify underlying pathophysiology, enable timely management of life-threatening endocrinopathies, and guide long-term care.
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