Snapshot A 30-year-old man presents to the physician with his wife with concerns that they have been unable to get pregnant after trying for the past year. The patient's wife has undergone a female infertility workup with no positive results. On physical examination, the man has scant hair in the axilla and pubic areas, small and firm testes, and the finding seen in the image. Karyotype testing is performed and reveals the presence of an extra X chromosome. Overview Introduction Overview Klinefelter syndrome is a sex chromosome disorder that is a common underlying cause of hypogonadism in men Epidemiology incidence 1 to 2.5 per 1000 men only 25-50% of Klinefelter syndrome patients are diagnosed during their lifetimes risk factors advanced maternal age Pathophysiology pathophysiology male child is born with an extra, inactivated X chromosome karyotype 47,XXY nondisjunction during cell division prevents X chromosome from being distributed normally dysgenesis of seminiferous tubules results in primary testicular failure with ↓ androgen production Presentation Symptoms infertility signs of androgen deficiency gynecomastia breast development at puberty sexual dysfunction osteoporosis Physical exam female hair distribution gynecomastia long extremities tall stature small, firm testes Studies Karyotype karyotype 47,XXY provides a definitive diagnosis generally only recommended in prepubertal or pubertal boys, or men with clinical signs of Klinefelter syndrome who are seeking fertility treatment Serum hormone levels ↑ FSH and LH ↓ testosterone ↑ estradiol due to ↑ expression of aromatase Differential Double Y males (47,XYY) key distinguishing factor phenotypically normal with intact fertility Fragile X syndrome key distinguishing factor enlarged testes Marfan syndrome key distinguishing factor intact fertility Treatment Medical androgen (testosterone) replacement therapy indications promote development of normal male secondary sex characteristics Lifestyle speech and behavioral therapy indications improve speech impairments and psychosocial problems Complications ↑ risk of breast cancer incidence up to 50-fold ↑ incidence of male breast cancer compared to the normal population