• Klinefelter syndrome = male hypogonadism in a person with at least 2 X chromosomes + 1 or more Y chromosomes.
• It is a common cause of male hypogonadism.
• Most patients have: 47,XXY
• Main cause:
  meiotic nondisjunction of sex chromosomes.
• Maternal and paternal nondisjunction contribute about equally.
• About 15% are mosaics, such as:
  • 46,XY/47,XXY
  • 47,XXY/48,XXXY
• Presence of a 46,XY cell line usually produces a milder phenotype.

Clinical Features

• The most consistent finding is hypogonadism.
• Typical body habitus:
  • increased leg length
  • elongated appearance
• Common physical features:
  • ↓ facial hair
  • ↓ body hair
  • ↓ pubic hair
  • gynecomastia
  • markedly small testes
• Testicular atrophy causes:
  • ↓ testosterone
  • ↑ FSH
• Fertility is uncommon.
• Infertility results from:
  impaired spermatogenesis → severe oligospermia or azoospermia.
• Rare fertile patients are usually mosaics with many 46,XY cells.
• Testicular histology:
  • seminiferous tubules become hyalinized
  • tubules may appear as ghostlike structures
  • Leydig cells appear prominent due to hyperplasia or loss of surrounding tubules
• Cognitive function ranges from average to below average.
• A mild verbal-skill deficit may occur.
• Associated conditions include:
  • type 2 diabetes
  • metabolic syndrome
  • insulin resistance
  • congenital heart disease
  • mitral valve prolapse
• Risk of extragonadal germ-cell tumors is increased about 20–30 times, especially:
  • mediastinal teratomas
• Other increased risks:
  • breast cancer
  • autoimmune disease such as systemic lupus erythematosus
• Physical findings may vary greatly, but hypogonadism remains the most consistent feature.

KEY CONCEPT

• Klinefelter syndrome = male + extra X chromosome, usually 47,XXY.
• Nondisjunction → extra X → testicular atrophy → ↓ testosterone + ↑ FSH.
• Major features:
  small testes + infertility + gynecomastia + reduced body hair + tall/elongated habitus.
• Mosaic cases with 46,XY cells are usually milder.

CONCEPTUAL EXAMPLES

• Extra X chromosome → abnormal testicular development → ↓ spermatogenesis → infertility.
• Testicular failure → ↓ testosterone → reduced male secondary sexual features.
• ↓ testicular function → loss of negative feedback → ↑ FSH.
• 46,XY/47,XXY mosaicism → more normal XY cells → milder clinical features.