The most common sex chromosome aneuploidy, Klinefelter syndrome (KS), is associated with primary gonadal failure and increased morbidity and mortality from cardiometabolic disorders in adulthood. Children with KS also have a high prevalence of metabolic syndrome (MetS). To assess the relationship of gonadal and cardiometabolic function in children with KS, we evaluated serum hormones (gonadotropins, inhibin B (INHB), anti-mullerian hormone (AMH), total testosterone (TT)), and features of MetS (waist circumference, fasting lipid panel, fasting blood glucose (FBG), and blood pressure) in 93 prepubertal boys with KS age 4–12 years (mean 7.7 ± 2.5 years). The cohort was grouped by age and tanner stage, and biomarkers were compared to normal ranges. 80% of this prepubertal cohort had ≥1 feature of metabolic syndrome (MetS) and 11% had ≥3 features of MetS. Risk of MetS was independent of age and body mass index. Sertoli cell dysfunction was common with 18% having an INHB below the normal range. A low INHB was associated with higher FBG, triglycerides, and LDL and lower HDL (p<0.05). An INHB <50 ng/dl yielded a sensitivity of 83% and a specificity of 79% for having ≥3 features of MetS. INHB and AMH positively correlated with each other (p<0.001), and high AMH was protective of MetS. TT was below the lower limit of normal in 49% of subjects, with mean values significantly lower than expected (3.3 ng/dl versus 4.9 ng/dl, p<0.0001), however no convincing relationship between TT and MetS was seen. In conclusion, gonadal and cardiometabolic dysfunction are prevalent in prepubertal boys with KS. Although the relationship of testosterone deficiency and MetS is well known, this study is the first to report an association between impaired sertoli cell function and cardiometabolic risk.

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