Review Proposes Best Practices for Diagnosing, Treating Klinefelter Syndrome

A paper recently published in Endocrine Reviews presents a comprehensive look at Klinefelter syndrome (KS), a rare disease that poses diagnostic challenges and remains largely misunderstood in the medical community.

The review, by Claus H. Gravholt, MD, PhD, of the Department of Endocrinology and Internal Medicine (MEA) at Aarhus University Hospital in Norrebrogade, Denmark, et al, points out that many patients with KS are misdiagnosed or remain undiagnosed, as there is insufficient insight into the prevalence and causes of different syndrome-associated traits that may impact adversely on prognosis. They write that current attempts at providing guidelines may underestimate morbidity and mortality, and that previous guidelines relied on expert consensus that did not include a broad base of professional working with KS.

The authors write that KS prevalence is estimated to be about 152 cases per 100,000 newborn males, but only 25% of KS patients are accurately diagnosed, and many of these diagnoses are not made until adulthood. KS patients usually have small testes, infertility, hypergonadothropic hypogonadism, and cognitive impairment. “Available data show that diagnosis of KS is often seriously delayed, and frequently a diagnosis is never made, illustrating that new diagnostic avenues should be implemented,” the authors write. “Late diagnosis or non-diagnosis extend to all sex chromosome syndromes.” They go on to call for population-based, neonatal screening, since screening would enable early establishment of appropriate treatment. However, given how rare KS is, it will likely take a long time to “demonstrate associations between early diagnosis, continuous specialized care and improved long-term outcomes,” the authors write.

KS is associated with a lower socio-economic status, which could explain the increased risk of morbidity and mortality. The authors write that KS affects all aspects of socio-economic status, including educational achievement, cohabitation, fatherhood, employment and income. KS is also associated with hypogonadism, which in turn is associated with greater risk of metabolic syndrome, type 2 diabetes, cardiovascular disease, breast cancer, and extragonadal germ cell tumors.

The treatment for both the physical symptoms and the subsequent quality of life measures is testosterone replacement therapy (TRT). However, the authors write that the effects of this therapy have not been rigorously studied. “There is only scant evidence that TRT in infants and boys has positive effects on cognitive and social functions, and no good evidence for this in adolescence or adulthood,” they write.

This review covers a lot of ground, because, as the authors write, men with KS “face a bewildering array of medical, neurocognitive and social problems, which are only beginning to become apparent in recent years.” The authors conclude the review with a number of questions for moving forward: Is the testicular demise inevitable, or is there a possibility for rescuing testicular function, thus possibly avoiding infertility and the need for testosterone substitution? Why is it so difficult to diagnose KS? How detrimental is late diagnosis to the life of KS males? Would early diagnosis improve the lives of males with KS materially?

The authors then write: “It is clear that the current diagnostic approach is not sufficient, and we advocate for the incorporation of diagnostics of sex chromosome abnormalities, including KS, into neonatal screening programs. It is currently not clear which methodology would be most appropriate to use in a neonatal screening program, and therefore the costs of such an intervention is not yet clear.”

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