SAT-236 - Diagnostic Pathways Across the Lifespan in Klinefelter Syndrome: From Prenatal Detection to Pubertal Presentation

Background
Klinefelter syndrome (KS) is the most common sex chromosome aneuploidy in males, with an estimated prevalence of approximately 1 in 650 male births. Despite its frequency, most affected individuals remain undiagnosed, often illustrated by the “iceberg” phenomenon in which only a minority of affected individuals are clinically recognized. Clinical manifestations vary across the lifespan and may include cryptorchidism, neurodevelopmental or learning difficulties, pubertal abnormalities such as small testes or gynecomastia, and adult infertility or hypogonadism. These heterogenous presentations may lead to diagnosis in different clinical contexts. We describe three cases illustrating distinct diagnostic pathways to KS identification.
Methods
Descriptive review of three patients evaluated in a pediatric endocrinology outpatient clinic. Clinical features, hormonal profiles, and cytogenetic findings were analyzed.
Results
Case 1: A 16-year-old male was referred for reduced testicular volume. Examination revealed testes measuring 4 mL without gynecomastia. Laboratory evaluation demonstrated hypergonadotroic hypogonadism (FSH 49 mIU/mL, LH 23 mIU/mL) with preserved total testosterone. Karyotype confirmed 47,XXY . The patient was part of a spontaneous twin pregnancy; similar clinical findings in his twin brother prompted endocrine evaluation, leading to the diagnosis of KS.
Case 2: A 10-year-old patient with prenatal diagnosis of KS was evaluated during routine endocrine follow-up. History included left cryptorchidism and autoimmune hypothyroidism. Examination showed prepubertal genitalia with testicular volume of 4 mL and no gynecomastia. Hormonal evaluation demonstrated elevated gonadotropins (FSH 26 mIU/mL, LH 5.74 mIU/mL) with normal total testosterone. Cytogenetic analysis confirmed 47,XXY.
Case 3: A 13-year-old boy presented with gynecomastia. Examination demonstrated gynecomastia, testes measuring 3 mL, and eunuchoid body proportions. Laboratory evaluation showed elevated gonadotropins (FSH 33 mIU/mL, LH 21 mIU/mL) with normal total testosterone. Karyotype confirmed 47,XXY.
Conclusions
Clinical manifestations of KS vary across the lifespan and may lead to diagnosis in different clinical contexts. Klinefelter syndrome may be identified through diverse diagnostic pathways, including prenatal detection with longitudinal endocrine follow-up and evaluation prompted by pubertal abnormalities. Recognition of key clinical contexts such as reduced testicular volume, gynecomastia, or family-triggered assessment may facilitate earlier diagnosis. Increased clinical awareness is essential to reduce underdiagnosis and optimize timely endocrine and reproductive management.

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