KLINEFELTER SYNDROME

Klinefelter syndrome is the commonest sex chromosome disorder in males, characterized by presence of extra X chromosome/s, though many of them remain undetected throughout the life.

Incidence of Klinefelter syndrome is ~1:1000 male live­births, being higher in children/adults with mental retardation or psychiatric problems.

Cytogenetically, commonest karyotype is presence of an extra X chromosome (47,XXY), due to meiotic nondisjunction. Advanced maternal age is a risk factor and extra X chromosome is of maternal origin in ~60% cases. Other variants include Mosaicism (46,XY / 47,XXY) or more than one extra X (48, XXXY, 49,XXXXY, etc.).

Clinical spectrum is highly variable, with no well- defined somatic phenotype and many cases are indistinguishable from normal males. Mosaic individuals tend to have milder phenotype and better prognosis. Severity of the disorder increases with increasing number of X chromosomes.

TABLE 11.10: Features of Klinefelter syndrome

• Abnormal development

- Delayed speech and language development

- Scholastic failure and learning disabilities

• BehavioralZpsychological problems

- Shy/passive behavior with social isolation

- Aggressive or anti-social behavior

• Abnormal sexual functions

- Cryptorchidism, micropenis, hypospadias

- Delayed puberty, poor virilization

- Azoospermia and infertility

• Somatic abnormalities

- Tall and thin stature (Eunuchoid features)

- Cranio-facial abnormalities*

*mongoloid slant, epicanthic folds, large mouth, large/malformed ears and flat/wide nasal bridge

Most cases are normal in pre-pubertal period with delayed onset of puberty and gynecomastia being earliest presentation. Other important indicators include:

(a) tall stature with long legs, (b) intellectual disability, (c) behavioral problems, and (d) abnormal sexual deve­lopment, e.g. small testes, micropenis, etc.

Diagnosis needs confirmation by cytogenetic studies, though presence of one or more Barr bodies (normally absent in males) have been used as a screening test.

Gonadal biopsy reveals reduction/absence of germ cells with hyalinization of seminiferous tubules. Gonadotropin levels (FSH/LH) are normal till early puberty, but subsequently, testosterone levels are lower and estradiol levels are higher than the age-related values.

Management includes: (a) early intervention programs for speech/language dysfunction and learning dis­abilities, (b) psychotherapy, and (c) hormone replacement therapy with testosterone enanthate, from 11-12 years onwards to facilitate virilization.

Other important sex chromosome disorders are:

47 XYY male, is a common (1:1,000 live births) but usually an asymptomatic chromosomal defect, with no striking phenotype abnormalities, except relatively tall stature and mild behavioral problems.

Fragile X syndrome is one of the commonest causes of mental retardation in males, characterized by presence of an abnormally fragile site on long arm of X chromosome (usually Xq27.3) due to unstable DNA sequence (allelic expansion of the trinucleotide sequence CGG located in the 5' untranslated region of FMR1 gene). Typical phenotype includes: (a) macrosomia, i.e. large body size,

(b) characteristic facies with long face, macrognathia and prominent ears, (c) macroorchidism, and (d) intellectual disability with stereotyped behavior and speech. Females are less severely affected than males, though present with premature ovarian failure.

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