Mechanism of Disease Map for Klinefelter Syndrome

Overview

• Discussing etiology, pathophysiology, manifestations, and pharmacology of Klinefelter syndrome.
• Core feature: presence of a Barr body (inactivated X chromosome).

Etiology

• Karyotype: 47XXY (normal male: XY).
• Rare cases: 48XXXY or 48XXYY.
• Caused by non-disjunction of sex chromosomes during meiosis.
  • Example: non-disjunction in meiosis II of female chromosomes.
• Advanced maternal age is the biggest risk factor.

Pathophysiology

• Extra X chromosome leads to testicular dysgenesis.
• Testicular dysgenesis causes hormonal imbalances: high FSH and high LH.
  • Seminiferous tubule dysgenesis: loss of Sertoli cells → low inhibin → high FSH.
  • Leydig cell dysgenesis: low testosterone → high LH (due to lack of feedback inhibition).
  • Increased conversion of testosterone to estrogen exacerbates low testosterone state.

Clinical Manifestations

• Hypoandrogenism features:
  • Eunuchoid habitus: tall, slim, long extremities.
  • Gynecomastia (breast development in men).
  • Decreased facial and body hair.
  • Testicular atrophy.
  • Decreased fertility and libido.
  • Azoospermia (low or no sperm count).
  • Possible micropenis (not always the case).
  • Osteoporosis in adulthood.
• Neurocognitive and psychiatric features:
  • Problems with executive functioning, memory, intelligence (worsened with more X chromosomes).
  • Language impairment and poor social skills.
• Other medical conditions:
  • Mitral valve prolapse.
  • Metabolic syndrome.
  • Increased risk of breast and testicular cancer.

Diagnosis

• Clinical diagnosis based on hormonal imbalances and symptoms.
• Confirmatory tests:
  • Karyotyping.
  • Histology (testicle biopsy): fibrosis in seminiferous tubules, Leydig cell hyperplasia.

Pharmacology

• Treatment: lifelong testosterone replacement to combat hypoandrogenism symptoms.