Klinefelter Syndrome: A Wide Range of Clinical Findings

WHAT IS IT?

• Klinefelter syndrome is also known as XXY syndrome
  • Present in 1 in 500 to 1 in 1000 newborn males
• A sex chromosome abnormality that involves the presence of two or more X chromosomes and one Y chromosome
  • Majority are 47,XXY karyotype
  • Remaining cases are 48, XXXY or mosaic 46,XY/47,XXY
• Prenatally, usually no obvious physical features detectable on ultrasound
• In infancy, possible minor findings:
  • Hypospadias and small or undescended testes
• Clinical features may be subtle and often a diagnosis is not made until adolescence, adulthood, or not at all:
  • Tall stature
  • Small and atrophic testes
  • Gynecomastia (excess breast tissue)
  • Evidence of androgen deficiency such as decreased body hair
  • Increased risk for breast cancer and autoimmune disorders (e.g. lupus)
• Intellectual development:
  • Individuals who have a 47,XXY karyotype usually have normal intelligence
  • Starting in childhood, educational support may be needed to address learning disabilities, delayed speech and language development
  • Individuals who have more than two X chromosomes are likely to have more severe symptoms
• Treatment:
  • Testosterone replacement is available and is usually started in early puberty
    • Treatment should be under the care of an endocrinologist and ideally with the collaboration of a multidisciplinary team
    • Recent data suggest treatment early in childhood may have a positive impact on neurodevelopment and social behaviors
  • Removal of excess breast tissue is an option for cosmetic reasons and to reduce the risk for breast cancer
  • Fertility treatment now available using assisted reproductive technology (ART), including testicular sperm extraction with intercytoplasmic sperm injection (TESE-ICSI)
  • Academic educational support to assist with language-based learning disabilities (LLD) and motor planning issues

CAUSE:

Klinefelter syndrome is a condition caused by an abnormal karyotype (2 or more X chromosomes and one Y chromosome) that is present at the time of conception. It usually is the result of non-disjunction during meiosis and is either of maternal (55%) or paternal (45%) origin. It is a sporadic condition, not inherited.

KEY POINTS:

• ACOG requires all women be offered prenatal screening (biochemical/cfDNA) or invasive testing (amniocentesis; CVS) to detect an increased risk or to diagnose aneuploidy, respectively
• Currently, the only way to prenatally diagnose Klinefelter syndrome is through invasive testing (amniocentesis or CVS)
• Klinefelter syndrome is now included on some cfDNA screening tests
  Invasive testing is necessary to confirm any positive result on screening using cfDNA
• If there is a history of Klinefelter syndrome, refer for genetic counseling

Learn More – Primary Sources:

NIH GARD –Klinefelter syndrome

NICHD – Klinefelter syndrome

US NLM – Genetics Home Reference: Klinefelter syndrome

Management of Klinefelter syndrome During Transition

Neurodevelopmental outcome of prenatally diagnosed boys with 47,XXY (Klinefelter syndrome) and the potential influence of early hormonal therapy

Oxandrolone Treatment Results in an Increased Risk of Gonadarche in Prepubertal Boys With Klinefelter Syndrome

Locate a Genetic Counselor or Genetics Services:

Genetic Services Locator-ACMG

Genetic Services Locator-NSGC

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