Klinefelter Syndrome

Background

• Klinefelter syndrome is the most common sex chromosome disorder in males and is characterized by hypergonadotropic hypogonadism and neurodevelopmental deficits.
• It is caused by the addition of ≥ 1 extra X chromosome(s) to the normal 46,XY male karyotype.
  • 47,XXY karyotype is the most common.
  • Karyotypes with > 1 extra X chromosome are generally associated with a more severe phenotype, and mosaicism is typically associated with a less severe phenotype.
• Although phenotype varies widely, the "classic" Klinefelter phenotype includes small testes, tall stature, eunuchoid body habitus, gynecomastia, and sparse body hair.
• Presentation typically varies by age, and often includes:
  • infertility or sexual dysfunction in adults.
  • delayed puberty or gynecomastia in adolescents.
  • language delay, learning disabilities, or behavior problems in prepubertal children.
  • prenatal genetic diagnosis on routine amniocentesis.
• Rarely, Klinefelter syndrome may present with genital abnormalities such as micropenis, but presentation during infancy is uncommon.
• Common complications include metabolic syndrome, diabetes and other endocrine disorders, cardiac dysfunction, psychiatric disorders, osteoporosis, and breast cancer.

Evaluation

• Blood tests
  • In adolescents and adults, measure hormone levels to identify hypergonadotropic hypogonadism (also called primary hypogonadism).
    • Low testosterone on 2 occasions in the morning and after fasting indicates hypogonadism.
    • Elevated follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in the presence of low testosterone suggests primary hypogonadism.
    • Other hormone levels, such as estradiol, sex hormone binding globulin, and inhibin B help support the diagnosis.
  • In prepubertal boys, hormone levels are generally not useful for diagnosis because abnormalities characteristic of Klinefelter syndrome do not occur until at least midpuberty.
• Genetic testing is required for definitive diagnosis.
• Testing to detect and monitor complications should include:
  • Fasting glucose, lipids, and HbA1c.
  • Vitamin D, calcium, and bone densitometry.
  • Thyroid function tests.
• Testing before starting testosterone replacement therapy should include a hematocrit and, in adults, serum prostate-specific antigen (PSA).

Management

• Testosterone replacement therapy is standard treatment for hypogonadism associated with Klinefelter syndrome.
  • Absolute or relative contraindications to testosterone therapy include breast or prostate cancer, erythrocytosis, untreated obstructive sleep apnea, severe lower urinary tract symptoms, uncontrolled heart failure, desire for fertility, myocardial infarction or stroke in the last 6 months, and thrombophilia.
  • In infants and prepubertal children, consider low-dose testosterone to treat micropenis. Do not use testosterone therapy except to treat micropenis (Strong recommendation).
  • In adolescents, testosterone therapy is recommended for delayed puberty or signs and symptoms of hypogonadism associated with low-normal serum testosterone and elevated serum luteinizing hormone (LH) after fertility issues have been addressed. (Strong recommendation)
  • In adults, testosterone therapy is recommended for hypogonadism as diagnosed according to established guidelines, with initiation of treatment after fertility issues have been addressed if possible. (Strong recommendation)
• Perform sperm retrieval and cryopreservation for fertility preservation or to treat infertility in adults who desire current or future paternity (Strong recommendation), and consider it for fertility preservation in adolescents (Weak recommendation).
• Follow-up should include regular monitoring of:
  • Growth and pubertal progression in children.
  • Testosterone levels, hematocrit, lipids, and bone density in adolescents and adults.
  • Treatment response and complications.