Perinatal presentation of Klinefelter syndrome and variants: take-home lessons for the urologist

Abstract Background Klinefelter syndrome (KS) is a sex chromosome disorder usually diagnosed in adulthood during work-up for infertility or hypogonadism. Perinatal diagnoses are uncommon. Case presentation We report two newborn cases of KS with associated hypospadias and bilateral cryptorchidism suspected on prenatal genetic testing triggered by ambiguous genital appearance on prenatal ultrasound. Management is presented and the relevant literature on the prenatal and prepubertal presentation and management of KS is summarized. Conclusions Klinefelter syndrome can be suspected prenatally in patients with increased nuchal translucency or ambiguous genitalia. Cell-free DNA can establish prenatal diagnosis with good sensitivity and specificity. Early diagnosis allows for early initiation of multidisciplinary care, focused counseling, lifestyle modification, early androgen replacement, and cryopreservation during late puberty or early adulthood. Testosterone treatment during infancy was linked to improved phenotypic features of KS and better cognitive and behavioral outcomes.