Klinefelter Syndrome

Epidemiology and Etiology:

• 2 or more X chromosomes AND one or more Y chromosomes
• 47 XXY (82%)
• Caused by nondisjunction in one of the parents
• Maternal nondisjunction in meosis I (>50%)
• Paternal error (nearly 50%)
1. Paternal nondisjunciton in meosis I
• Mosaicism (15%)
• 47,XXY/46,XY mostly
• Likely due to loss of an X chromosome from a 47,XXY zygote
• Variable phenotype
• Risk factors:
• Advanced maternal age
• 1 in 500 live male births

Common sites:

Gross features:

• Male
• (post-pubertal)
• Small atrophic testes
• May be normal in mosaic
• Normal to small penis
• No beard
• Lack of male-distribution pubic hair
• Gynecomastia maybe (transiently)
• Elongated body
• Long legs; increased length between soles and pubic bone
• Those with more X chromosomes (ex. 48 XXXY or 49 XXXXY):
• More severe phenotype
• Cryptorchidism
• Hypospadias
• More severe testicular hypoplasia
• Skeletal changes
• Prognathism
• Radioulnar synostosis

Histologic features:

• Testicular tubules atrophied maybe
• Replaced by pink, hyaline, collagenous ghosts
• Varying number of tubules involved
• Prominent Leydig cells due to atrophic tubules
• Embryonic-appearing tubules maybe
• Cords of cells without a lumen

Immunophenotype:

Marker:

Sensitivity:

Specificity:

Molecular features:

Other features:

• Rarely diagnosed before puberty
• Clinical features:
• Hypogonadism (manifesting at puberty)
• Lack of deep voice
• Infertility; reduced spermatogenesis
• Rare cases of fertility may be due to undetected 47,XXY/46,XY mosaicism
• ICSI success rate is low
• There may be a slight increased risk (~3%) for a sex chromosome abnormality in the children but numbers are low
• Preimplantation genetic diagnosis is recommended
• IQ lower than normal (but not mental retardation usually)
• Learning difficulty at school is expected
• Lower with extra X’s
• Blood tests:
• FSH elevated (and other gonadotropins)
• Testosterone low
• Estradiol elevated
• Malignancy risk:
• Breast cancer risk elevated (20X above normal male)
• Extragonadal germ cell tumours
• Autoimmune disease elevated risk (similar to females?)
• SLE
• Others
• More severe phenotype with extra X’s

References:

• Robbins & Cotran Pathologic Basis of Disease (2005)
• Gardner RJM, Sutherland GR. Chromosome abnormalities and genetic counseling. Oxford University Press; 2004.
• Nussbaum RL, McInnes RR, Willard HF. Thompson & Thompson Genetics in Medicine: With STUDENT CONSULT Online Access. 7th ed. Saunders; 2007.