Klinefelter Syndrome

Klinefelter syndrome is a chromosomal aneuploidy characterized by the presence of 1 or more extra X chromosomes in a male karyotype, most commonly leading to karyotype 47,XXY. Klinefelter syndrome is associated with decreased levels of testosterone and is the most common cause of congenital hypogonadism. Symptoms are often not noticed until adolescence or adulthood. Individuals with this condition tend to present as tall, phenotypic men with small testes, decreased body hair, gynecomastia, and infertility. Treatment consists of life-long testosterone replacement therapy.

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Epidemiology and Genetics


  • Incidence: approximately 1 in 600 male births
  • Only diagnosed in approximately 25% of adult men with the condition


  • Karyotype: 2 or more X chromosomes with at least 1 predominantly inactive X chromosome (Barr body) present
    • 47,XXY: most common, karyotype in about 80% of cases
    • 48,XXXY: less common
    • 48,XXYY: less common (additional Y chromosome)
  • Etiology:
    • Most commonly due to meiotic nondisjunction of the sex chromosomes in parental germ cells
      • In meiosis I: Paired homologous chromosomes fail to separate.
      • In meiosis II: Paired sister chromatids fail to separate.
    • May also occur due to mitotic nondisjunction in the developing zygote
    • Origin of nondisjunction may be either maternal or paternal.
  • Risk factor: advanced maternal age

Clinical Presentation

Clinical phenotype

  • Outer appearance:
    • Male phenotype
    • Tall with disproportionately long extremities
    • Eunuchoid features (both male and female features)
    • Classically slender build, but may have abdominal obesity with “pear-shaped” body habitus
    • Gynecomastia (due to ↓ levels of testosterone and ↑ estrogen)
    • Decreased facial/body/pubic hair
    • Decreased muscle mass/growth
    • Small, firm testes
  • Cognition/intelligence:
    • IQ (intelligence quotient) may be normal or mildly reduced.
    • Educational difficulties, especially with language-related functions
    • Symptoms may be more severe with increasing number of X chromosomes present in karyotype.
  • Behavioral abnormalities:
    • Increased risk of psychological disorders
    • Tendency toward poor social adjustments, but normal adult relationships
  • Sex development/fertility:
    • Delayed puberty
    • Hypergonadotropic hypogonadism
      • Primary testicular failure → ↓ testosterone
      • Fibrosis of seminiferous tubules within the testes and loss of function of Sertoli cells (site of spermatogenesis)
      • ↓ Testosterone and lack of testes’ ability to respond to luteinizing hormone (LH) and follicle-stimulating hormone (FSH) → lack of feedback inhibition in pituitary gland → ↑ LH and FSH levels 
    • Infertility due to oligospermia (reduced number of sperm in semen) or azoospermia (absence of sperm in semen)

Associated conditions

  • Cardiac abnormalities: mitral valve prolapse
  • Malignancies:
    • Increased risk of breast cancer (due to ↑ estrogen and ↓ levels of testosterone)
    • Increased risk of testicular cancer
  • Osteoporosis in adulthood

Diagnosis and Management


  • History and clinical examination
  • Genetic testing: Karyotyping confirms the diagnosis.
  • Labs show: ↓ testosterone level and ↑ LH and FSH levels
  • Infertility screening should also be done; typically shows low sperm count.


  • Testosterone replacement therapy (life-long): improves facial/body hair growth, strength/muscle size, libido, and energy level
  • Fertility treatment if children desired: Genetic counseling is warranted as there is a slightly increased risk of chromosomal abnormalities in offspring.

Clinical Relevance

Differential diagnoses

The following conditions are differential diagnoses of Klinefelter syndrome:

  • Kallmann syndrome: a genetic condition that causes hypogonadotropic hypogonadism due to gonadotropin-releasing hormone (GnRH) deficiency. Men and women are both affected. Men may present with delayed puberty, decreased testosterone levels, and small testes. However, an absent or decreased sense of smell is pathognomonic. Unlike in Klinefelter syndrome, LH and FSH levels are elevated. Genetic testing confirms the diagnosis.
  • Fragile X syndrome: an X-linked dominant condition affecting men more commonly than women. Affected persons are usually tall with long, narrow faces and large ears. Abnormally large testes are noted after puberty, unlike the small testes seen in Klinefelter syndrome. Developmental delays are common. Genetic testing confirms the diagnosis. 
  • Marfan syndrome: an autosomal dominant connective tissue disorder that affects both men and women. Affected persons are usually tall with long arms and legs and arachnodactyly (abnormally long, slender fingers and toes). Associated with cardiovascular complications, musculoskeletal abnormalities, and lens dislocation/vision impairment. Marfan syndrome does not cause hypogonadism or cognitive disabilities. Genetic testing confirms the diagnosis.

Related condition

The following condition is related to Klinefelter syndrome as it also causes gonadal insufficiency due to a chromosomal abnormality:

Turner syndrome: a chromosomal abnormality disorder affecting only women. Karyotype is 45,X0 instead of XX. Causes delayed puberty and primary hypergonadotropic hypogonadism (ovarian failure) in women. Affected women are characterized by short stature, widely spaced nipples, and webbed neck. Genetic testing confirms the diagnosis. Management includes hormone replacement therapy and fertility treatments if desired.


  1. Wattendorf, Daniel J., & Muenke, Maximilian. (2005). Klinefelter Syndrome. Am Fam Physician.72(11):2259–2262.
  2. Smith, C.M., & Bremner, W.J.(1998). Klinefelter Syndrome. Arch Intern Med. 158(12):1309–14. doi: 10.1001/archinte.158.12.1309.
  3. Defendi, Germaine L. Klinefelter Syndrome. Medscape. Retrieved November 23, 2020, from https://img.medscape.com/pi/iphone/medscapeapp/html/A945649-business.html

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