Summary

Klinefelter's syndrome (KS) is the most common sex chromosome aneuploidy in males, with a karyotype of 47,XXY (one extra X chromosome). It is the most common genetic cause of male infertility and hypogonadism. Most cases are undiagnosed until adulthood, often presenting with infertility. Clinical features include tall stature, small firm testes, gynaecomastia, sparse body hair, and learning difficulties. Biochemically, there is hypergonadotrophic hypogonadism (high LH/FSH, low testosterone). Treatment involves testosterone replacement therapy (TRT) to improve secondary sexual characteristics, bone density, and quality of life. Fertility may be possible with testicular sperm extraction (TESE) and ICSI.

Key Facts

• Karyotype: 47,XXY (extra X chromosome)
• Incidence: 1 in 500-1000 male births
• Classic Features: Tall stature, small testes, gynaecomastia, sparse facial hair
• Biochemistry: High LH/FSH (hypergonadotrophic), Low testosterone
• Treatment: Testosterone replacement therapy
• Fertility: Usually infertile; TESE + ICSI may work

Clinical Pearls

"Most Are Undiagnosed": Only 25% of Klinefelter cases are diagnosed, often only when presenting with infertility in adulthood.

"High Gonadotrophins, Low Testosterone": The testes fail (primary hypogonadism), so LH and FSH are high as the pituitary tries to stimulate them. Testosterone remains low.

"Tall with Small Testes": The combination of tall stature with small, firm testes is classic for Klinefelter's.

"Testosterone Helps, But Not Fertility": TRT improves sexual function, bone density, and quality of life, but does NOT restore fertility. Sperm extraction may be possible.

General

• Tall stature (arm span > height in some)
• Eunuchoid proportions (long limbs relative to trunk)

Secondary Sexual Characteristics

• Sparse facial and body hair
• Gynaecomastia (palpate for breast tissue)
• Female-pattern fat distribution

Genitalia

• Small, firm testes (<4mL bilaterally)
• Normal or small phallus

Other

• May have mild intellectual difficulties

With Treatment

• Normal life expectancy (slightly reduced in some studies)
• Good quality of life with TRT
• Fertility possible in some with TESE/ICSI

Without Treatment

• Osteoporosis
• Metabolic complications
• Psychological issues

Key Guidelines

1. Endocrine Society Clinical Practice Guideline: Klinefelter Syndrome
2. European Academy of Andrology Guidelines

Key Evidence

TRT

• Improves bone density, body composition, and quality of life

Fertility

• TESE successful in ~50% of XXY males
• Better outcomes with earlier intervention

What is Klinefelter's Syndrome?

Klinefelter's syndrome is a condition where males are born with an extra X chromosome (XXY instead of XY). It affects about 1 in 600 boys.

What Are the Signs?

• Taller than average
• Smaller testicles
• Breast tissue (gynaecomastia)
• Less facial and body hair than usual
• Difficulty having children (infertility)
• May have learning difficulties

Is There Treatment?

Yes:

• Testosterone treatment can help with energy, muscle mass, bone strength, and sexual development
• Fertility treatment (sperm extraction and IVF) may allow some men with Klinefelter's to have biological children

What About School and Work?

Many people with Klinefelter's live completely normal lives. Some may need extra help at school, particularly with language and reading. With support, most do very well.