Klinefelter’s syndrome

Klinefelter’s syndrome, which not uncommonly presents in adult life rather than at adolescence. This syndrome is characterised by dysgenesis of the seminiferous tubules and is a common cause of primary hypogonadism and male infertility. Karyotype analysis of unselected newborns has estimated an incidence of 1 per 800 to 1000 males, the most common human chromosomal abnormality.

Patients are phenotypically male with testes of usually < 3cm in length and azoospermia. Gynaecomastia is also common. Karyotype analysis typically demonstrates the 47, XXY karyotype. Patients show poor to normal virilization at puberty and tend to have a tall stature due to disproportionately long legs.
Testosterone levels vary but are usually decreased and gonadotrophins are raised – particularly FSH. Plasma estradiol levels are usually normal or elevated, similarly SHBG.

Undescended testes are 3 times as common as in normal boys. Prepubertal studies indicate that children with the 47, XXY Karyotype have lower birth weights, smaller mean head circumferences, a slightly increased risk of congenital anomalies, height percentiles that increase with age, a lower verbal IQ than normal boys and poor motor and muscle tone.
Associated abnormalities include an increased frequency of diabetes mellitus; 19% of patients have been reported to have impaired glucose tolerance and 8% to be diabetic. 47 XXY patients with gynaecomastia also have an increased predisposition to cancer of the breast. In addition, 20-50% of boys 8 years or older with primary mediastinal germ cell tumours have Klinefelter’s syndrome.
25% of adults with Klinefelter’s have osteoporosis, although this is uncommon in patients on testosterone replacement. Chronic lung disease and varicose veins are also thought to be more common.

It seems that normal complements of germ cells are present in these patients in early foetal life but during late gestation and early infancy there is a dramatic loss of spermatogonia. In adult patients, spermatogenesis may rarely be present but most fertile patients have proved to have sex chromosome mosaicism (46, XY/47 XXY) and often lack the features which distinguish them from typical patients with Klinefelter’s syndrome. The technique of intracytoplasmic sperm injection (ICSI) has been used with some success in this group of patients – however, there is also an increased risk of trisomy 21 in children of patients with Klinefelter’s syndrome.

The mainstay of treatment is testosterone replacement. Patients diagnosed pre-pubertally may be given small doses of testosterone intramuscularly (e.g. 50mg im monthly) to initiate puberty and avoid the psychological and physical consequences of hypogonadism. The dose may be gradually increased (100mg im, monthly) once bone age has advanced to allow full growth potential to be realised. Once the final height has been reached an adult replacement dose of testosterone, e.g. 250mg im 3 weekly. Alternatively testosterone patches or the newer gels or buccal preparations may be used in adults.