Abstract 2: Androgen Insensitivity in Klinefelter syndrome: A rare cause of genital ambiguity

Background: The etiologies for ambiguous genitalia with palpable gonads include gonadal dysgenesis, congenital adrenal hyperplasia, androgen biosynthetic defects or androgen insensitivity. Klinefelter syndrome (1 in 500-1000 live male births) classically presents with hypergonadotropichypogonadism, infertility and neurocognitive deficits in adult men, and less frequently as isolated hypospadias and micropenis in infants. Klinefelter syndrome rarely can present with ambiguous genitalia. We detail a child with Klinefelter syndrome and associated androgen insensitivity presenting with genital ambiguity. Case Details: 3 year 5 months old child (DOB: 6/5/19), reared as male, presented with complaints of ambiguous genitalia and small-sized penis since birth. He was passing urine from a normally located urethralopening. Although gonads were noticed in the scrotum since birth, there was bifid scrotum. There was no history of hypoglycemia, salt-wasting crises or hyperpigmentation. Child was born out of non-consanguineous marriage, by cesarean delivery, at term, with a birth weight of 2.6 kg. Child had attained developmental milestones appropriate for age. On examination, Ht:92 cm (-1.96 Z), Wt:13kg (-1.33 Z), BP: 85/54mmhg (SBP: 50th centile, DBP: 90th centile), MPH:162.5 cm, US:LS:0.7, Arm Span: 89 cm. On examination, he had bilateral symmetric external genitalia with palpable gonads in the labio-scrotal folds. The labioscrotal folds were non-fused, but rugosity and pigmentation were present. Phallic length was 1.8 cm with a single urethral opening at the tip of phallus. EMS score was 6 and AG ratio was 0.5. Evaluation revealed Na:138, K:4.3, Cortisol:13.5 mcg/dl, LH: 0.862 mIU/ml, FSH:2.4 mIU/ml, Testosterone: 507 ng/dl. Post-hCG stimulation Testosterone/Dihydrotestosterone ratio was 12.43, while Testosterone/Androstenedione ratio was 22.96. Karyotype was 47,XXY. Genetic analysis revealed a pathogenic variant in the androgen receptor c.2495G>A (p.Arg832Gln), suggestive of androgen insensitivitysyndrome. Discussion: There have been isolated case reports of genital ambiguity in Klinefelter syndrome with associated AIS. The mechanisms suggested to explain genital ambiguity in Klinefelter syndrome include parental origin of the X chromosome, skewed inactivation of the X chromosome, CAG repeat polymorphism, double dosage of DAX-1 gene and androgen insensitivity. Although rare, it remains paramount to recognize Klinefelter syndrome as a cause of genital ambiguity. Genotypic-phenotypic discordance in Klinefelter syndrome should especially alert the clinician to look for associated androgen insensitivity as one of the mechanisms.