Klinefelter Syndrome: More Than Hypogonadism

The challenges that a physician has to face in the management of KS may even emerge during intrauterine life, as the diagnosis is often established by prenatal screening, a situation requiring thorough genetic counselling of the parents. The recent introduction of non-invasive prenatal screening is anticipated to increase the number of couples seeking counselling and it is largely admitted that their decision whether to abort or not relies heavily on the information received during counselling [117118119]. The termination rate in KS pregnancies varies from 11.6% to 87.5% in different countries. In certain societies, the way research has changed our understanding of the natural history and prognosis of this condition has led to a significant decrease in the rate of termination [119,120]; whereas in other societies it still remains high, depending on local traditions, religious beliefs and legislation [121].

Subsequently, the management of KS children warrants the collaboration of a multidisciplinary team consisting of pediatric endocrinologists as well as developmental and behavioural specialists, in order to ameliorate the developmental defects of early life [56]. In addition, an initial echocardiographic study should be offered in order to reveal congenital cardiovascular abnormalities [68]. As the boy transits to adulthood, follow-up should be conveyed to a specialized team consisting of adult endocrinologists/andrologists, cardiologists and occasionally psychologists to aid in facing the challenges of adult life.

In the presence of hypogonadism, TRT remains the medical treatment of choice until robust evidence and feasible therapies are found to compensate for the genetic defects of KS. Although there is evidence that TRT in KS is not as effective as in 46,XY hypogonadal males, at least regarding body proportions and BMD [70,102], the association of hypogonadism with both increased morbidity and mortality is well established and should be addressed accordingly [122,123]. Besides, many of the anticipated benefits of TRT such as improvement in energy level/stamina, attention span, mood, measures of cardiometabolic health and general well-being are also observed in young KS patients [124,125]. Moreover, it has been demonstrated that early TRT may have a beneficial effect on KS boys’ developmental and behavioural issues without serious adverse effects [126,127]; however it should be stressed that TRT is not a “cure” for the neurodevelopmental deficits of KS that may exist due to the possible effects of the extra X chromosome on brain development [117]. In contrast, there is concern about the negative impact TRT might have on the risk of comorbidities prevalent among patients with KS, such as venous thromboembolism and obstructive sleep apnea [128,129]. Since specific data regarding therapeutic targets are not available for KS patients, the general guidelines on TRT should be employed [130]; however, randomized controlled trials are needed to evaluate the efficacy of TRT on different aspects of the syndrome, to determine optimal dose regimens and to assess the suitability of the available testosterone formulations for different subgroups of KS patients [117].

As TRT would suppress any spermatogenesis, the option and chances of TESE should be discussed with the patient before initiation of TRT. If paternity is desired by a patient who is already on TRT this therapy has to be suspended for at least 6 months to allow spermatogenesis to recover [131].

There are no universally accepted guidelines on the follow-up of KS patients. Apart from TRT that should be monitored according to current guidelines for hypogonadism, including T, PSA and hematocrit evaluation [132], patients should be followed up for their related comorbidities. Regarding CV morbidity, the initial evaluation has been proposed to include risk assessment for MetS and thromboembolic disease as well as echocardiography focused on systolic and diastolic dysfunction. The subsequent follow-up should be based on the relevant findings [68]. Concerning screening for related malignancies, the level of absolute risk of breast cancer does not justify regular examination with mammography, but warrants monthly breast self-examination and periodic physical examination by a specialized physician [84], while a recent Italian consensus [133] suggests bi-annual chest X-ray to address the risk for extragonadal germ cell tumours. The same consensus proposes bi-annual assessment of BMD and 25OH-vitamin D status to address the risk of osteoporosis.

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