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 Hypogonadism Hypogonadism is a condition characterized by reduced or no sex hormone production by the testes or ovaries. Hypogonadism can result from primary (hypergonadotropic) or secondary (hypogonadotropic) failure. Symptoms include infertility, increased risk of osteoporosis, erectile dysfunction, decreased libido, and regression (or absence) of secondary sexual characteristics. 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 Gynecomastia Gynecomastia is a benign proliferation of male breast glandular ductal tissue, usually bilateral, caused by increased estrogen activity, decreased testosterone activity, or medications. The condition is common and physiological in neonates, adolescent boys, and elderly men. Gynecomastia, and infertility Infertility Infertility is the inability to conceive in the context of regular intercourse. The most common causes of infertility in women are related to ovulatory dysfunction or tubal obstruction, whereas, in men, abnormal sperm is a common cause. Infertility. Treatment consists of life-long testosterone replacement therapy.

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Epidemiology and Genetics

Epidemiology

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

Genetics Genetics Genetics is the study of genes and their functions and behaviors. Basic Terms of Genetics

  • 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 Meiosis The creation of eukaryotic gametes involves a DNA replication phase followed by 2 cellular division stages: meiosis I and meiosis II. Meiosis I separates homologous chromosomes into separate cells (1n, 2c), while meiosis II separates sister chromatids into gametes (1n, 1c). Meiosis I: Paired homologous chromosomes fail to separate.
      • In meiosis Meiosis The creation of eukaryotic gametes involves a DNA replication phase followed by 2 cellular division stages: meiosis I and meiosis II. Meiosis I separates homologous chromosomes into separate cells (1n, 2c), while meiosis II separates sister chromatids into gametes (1n, 1c). 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 Obesity Obesity is a condition associated with excess body weight, specifically with the deposition of excessive adipose tissue. Obesity is considered a global epidemic. Major influences come from the western diet and sedentary lifestyles, but the exact mechanisms likely include a mixture of genetic and environmental factors. 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 Delayed Puberty Delayed puberty (DP) is defined as the lack of testicular growth in boys past the age of 14 and the lack of thelarche in girls past the age of 13. Delayed puberty affects up to 5% of healthy boys and girls, and half of all cases are due to constitutional growth delay. Delayed Puberty
    • Hypergonadotropic hypogonadism Hypogonadism Hypogonadism is a condition characterized by reduced or no sex hormone production by the testes or ovaries. Hypogonadism can result from primary (hypergonadotropic) or secondary (hypogonadotropic) failure. Symptoms include infertility, increased risk of osteoporosis, erectile dysfunction, decreased libido, and regression (or absence) of secondary sexual characteristics. 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 Pituitary gland The pituitary gland, also known as the hypophysis, is considered the "master endocrine gland" because it releases hormones that regulate the activity of multiple major endocrine organs in the body. The gland sits on the sella turcica, just below the hypothalamus, which is the primary regulator of the pituitary gland. 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 Mitral valve prolapse Mitral valve prolapse (MVP) is the most common cardiac valvular defect, and is characterized by bulging of the mitral valve (MV) cusps into the left atrium (LA) during systole. Mitral valve prolapse is most commonly due to idiopathic myxomatous degeneration. Patients are typically asymptomatic. Mitral Valve Prolapse
  • Malignancies:
    • Increased risk of breast cancer Breast cancer Breast cancer is a disease characterized by malignant transformation of the epithelial cells of the breast. Breast cancer is the most common form of cancer and 2nd most common cause of cancer-related death among women. Breast Cancer (due to ↑ estrogen and ↓ levels of testosterone)
    • Increased risk of testicular cancer Testicular cancer Testicular cancer is the most common solid malignancy affecting men 15-35 years of age. Most of the testicular cancers are of the germ cell tumor type, and they can be classified as seminomas and nonseminomas. The most common presentation of testicular cancer is a painless testicular mass. Testicular Cancer
  • Osteoporosis Osteoporosis Osteoporosis refers to a decrease in bone mass and density leading to an increased number of fractures. There are 2 forms of osteoporosis: primary, which is commonly postmenopausal or senile; and secondary, which is a manifestation of immobilization, underlying medical disorders, or long-term use of certain medications. Osteoporosis in adulthood

Diagnosis and Management

Diagnosis

  • 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.

Management

  • 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 Kallmann syndrome Kallmann syndrome (KS), also called olfacto-genital syndrome, is a genetic condition that causes hypogonadotropic hypogonadism due to decreased secretion of gonadotropin-releasing hormone (GnRH) by the hypothalamus. The lack of sex hormones results in impaired pubertal development. Kallmann Syndrome: a genetic condition that causes hypogonadotropic hypogonadism Hypogonadism Hypogonadism is a condition characterized by reduced or no sex hormone production by the testes or ovaries. Hypogonadism can result from primary (hypergonadotropic) or secondary (hypogonadotropic) failure. Symptoms include infertility, increased risk of osteoporosis, erectile dysfunction, decreased libido, and regression (or absence) of secondary sexual characteristics. 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 Fragile X syndrome Fragile X syndrome (FXS), also known as Martin-Bell syndrome, is a genetic condition with X-linked inheritance. Both boys and girls may be affected, but the severity is much worse in boys. Characteristic features include a long face, prominent forehead and chin, large ears, flat feet, and large testes post-puberty for boys. 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 Marfan syndrome Marfan syndrome is a genetic condition with autosomal dominant inheritance. Marfan syndrome affects the elasticity of connective tissues throughout the body, most notably in the cardiovascular, ocular, and musculoskeletal systems. Marfan Syndrome: an autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance connective tissue Connective tissue Connective tissues originate from embryonic mesenchyme and are present throughout the body except inside the brain and spinal cord. The main function of connective tissues is to provide structural support to organs. Connective tissues consist of cells and an extracellular matrix. 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 Marfan syndrome Marfan syndrome is a genetic condition with autosomal dominant inheritance. Marfan syndrome affects the elasticity of connective tissues throughout the body, most notably in the cardiovascular, ocular, and musculoskeletal systems. Marfan Syndrome does not cause hypogonadism Hypogonadism Hypogonadism is a condition characterized by reduced or no sex hormone production by the testes or ovaries. Hypogonadism can result from primary (hypergonadotropic) or secondary (hypogonadotropic) failure. Symptoms include infertility, increased risk of osteoporosis, erectile dysfunction, decreased libido, and regression (or absence) of secondary sexual characteristics. 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 Turner syndrome Turner syndrome is a genetic condition affecting women, in which 1 X chromosome is partly or completely missing. The classic result is the karyotype 45,XO with a female phenotype. Turner syndrome is associated with decreased sex hormone levels and is the most common cause of primary amenorrhea. Turner Syndrome: a chromosomal abnormality disorder affecting only women. Karyotype is 45,X0 instead of XX. Causes delayed puberty and primary hypergonadotropic hypogonadism Hypogonadism Hypogonadism is a condition characterized by reduced or no sex hormone production by the testes or ovaries. Hypogonadism can result from primary (hypergonadotropic) or secondary (hypogonadotropic) failure. Symptoms include infertility, increased risk of osteoporosis, erectile dysfunction, decreased libido, and regression (or absence) of secondary sexual characteristics. 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.

References

  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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