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Klinefelter Syndrome (KS) affects 1 in 500 male conceptions and is therefore the most common sex chromosome abnormality.  It results in small testes, testosterone deficiency, infertility and often in swelling of glandular breast tissue (gynecomastia).  The first report in 9 patients, by HF Klinefelter Jr, EC Reifenstein Jr and F Albright in 1942, was followed by the discovery of an extra X chromosome as the cause of KS by PA Jacobs and JA Strong in 1959.  More than two thirds of KS patients have the 47, XXY karyotype, few present with more than 2 X chromosomes or with mosaicism, having a normal XY and another abnormal XXY cell line.  Testicular biopsy shows hyalinized and fibrotic seminiferous tubules, with few, if any, areas of sperm production.  Seminiferous tubules normally comprise 85% of the testicular volume, and degenerative changes, such as fibrosis and hyalinization of the seminiferous tubules are the cause of testicular atrophy, which is invariably present in KS.

The chromosomal abnormality in KS is caused by an error in the division process in the production of gametes, where sperm or ovum contain an extra X chromosome, in addition to the normal X or Y chromosome.  Advanced maternal age may be associated with these division errors in KS.

Whereas a smear of the buccal mucosal membranes can show sex chromatin (Barr bodies), representing the extra X chromosome in KS men, a chromosome analysis, performed in peripheral blood cells will usually confirm the diagnosis of KS, define the number of X chromosomes and provide information about the presence of mosaicism.   In the untreated adult KS patient, testosterone levels are usually low or below normal, with elevated LH.

The diagnosis of KS is frequently made by prenatal genetic testing.   In infancy the KS boy may present with a small penis, hypospadia or undescended testes.  At school-age the child may show behavioral problems or learning disabilities.  The adolescent may have tall stature, excessive growth of the lower extremities and delayed puberty, eunuchoidal features and small testes usually remaining at a volume of 2-3 mL.   Testosterone production reaches a plateau after age 14 years and may never reach the midnormal adult range, in spite of high levels of LH stimulation.  Adult KS patients have decreased bone mineral density, which could be caused by testosterone deficiency.  Many adult KS men are first diagnosed during an infertility evaluation, when testicular atrophy and absence of sperm in the ejaculate are noticed.  KS patients have a high incidence of learning disabilities with decreased verbal IQ, but usually normal intellectual performance.  Language skills can be impaired, patients may be aggressive, being not inclined to participate in social activities and having a tendency to depression.

 KS can be complicated by mild adult-onset diabetes mellitus with insulin resistance, by hypothyroidism, by varicose veins of the lower extremities which can cause venous ulcers, by thinning of the surface of the teeth (taurodontism), which can cause early decay, by breast cancer that may develop in middle age, by leukemia and Hodgkin and non-Hodgkin lymphoma, and in the young by gonadal or extragonadal germinal cell tumors, frequently located in the mediastinum.  Cerebrovascular accidents are more common in KS than in men with a normal 46, XY karyotype.

It is desirable to establish the diagnosis of KS as early as possible. This will direct the observation of parents to learning disabilities and behavioral abnormalities, which require remedial action.  Attention should be paid to the possibility of complications, and screening tests should be ordered.   In adolescence testosterone replacement should be initiated, as soon as gonadotropin levels increase above normal.  Testosterone doses must be advanced over years with yearly increments, imitating the increase in testosterone production that occurs during normal puberty.  Testosterone not only will advance virilization and support development of adequate bone mineralization, it also can improve fatigue, muscle strength, academic performance and further social adjustment.

 In earlier years KS was thought to be invariably associated with antisocial behavior and mental retardation.  This impression was prompted by institutionalized patients, whose findings served for earlier reports.  Clinical experience with a wider segment of the population and decades of follow-up of KS men provide much more positive information.  Early diagnosis, observation and remedial action for emotional and behavioral abnormalities and timely treatment with testosterone can modulate the clinical course of KS and permit patients to live a full life as contributing members of our society.


    Wolfram E. Nolten



Editor’s Note: Dr. Nolten has given us a broad overview of Klinefelter Syndrome.  In the preceding article, he referred to medical, educational, and psychological problems that may be related to this disorder.  Dr. Nolten was a founding member of AAKSIS and was also on its Board of Directors until the time of his death in January 2009.