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ANZAC Research Institute and Department of Andrology Concord Hospital University of Sydney Sydney, New South Wales 2139, Australia
Address all correspondence and requests for reprints to: Professor D. J. Handelsman, ANZAC Research Institute, Sydney, New South Wales 2139, Australia. E-mail: djh{at}anzac.edu.au.
A century ago it was said that a sound knowledge of syphilis, considered the "great imitator" with manifestations in all body systems, provided a medical education in its own right. It is equally true that understanding the protean manifestations of Klinefelter’s syndrome (KS), the most frequent genetic disorder of male reproductive function, highlights a complete spectrum of men’s health issues. Since its original clinical description in 1942 and the identification of its chromosomal basis in 1959, KS has become a familiar textbook archetype of hypogonadism, and excellent reviews of its clinical, diagnostic, and therapeutic features are available (1).
The cardinal features of KS arise from the failure of germ cells to survive in the aneuploid testis with puberty triggering their extinction instead of the usual proliferation to colonize the seminiferous tubules (2). This causes azoospermia with the hallmark of small, firm testes of less than 4 ml volume, a clinical feature signifying that the germinal epithelium was never or only fleetingly established. This contrasts with testicular damage acquired after spermatogenesis is established in which subsequent seminiferous tubule collapse leaves a soft, flaccid "atrophic" testis. Beyond infertility, however, spermatogenic failure has no direct adverse health effects so the familiar clinical manifestations of KS arise mainly from the accompanying Leydig cell dysfunction. This produces androgen deficiency of variable severity featuring undervirilization, eunuchoidism, and gynecomastia together with suboptimal development of bone, muscle, and psychosexual function. Other clinical features such as the neurobehavioral disabilities and cancer susceptibility have unclear pathogenesis possibly reflecting indirect effects of androgen deficiency, genetic effects of the aneuploidy, and/or ascertainment bias.
Until recently, knowledge of long-term health outcomes for men with KS was largely based on informed deduction from distinctive clinical observations such as rare disease associations (breast cancer, midline germinal tumors), osteoporosis in young men, or the new diagnosis in old men, suggesting unimpaired life expectancy. However, the low prevalence of KS means that even decades of experience in large centers cannot identify long-term health outcomes with reliability. Although formidable undertakings, the largest cross-sectional study comprises fewer than 200 cases (1), whereas the only long-term longitudinal cohort study followed up fewer than 20 boys diagnosed at birth to early adulthood (3). Recent research has made remarkable progress in appraising the lifetime impact of KS on men’s health. Major registry-based studies of lifetime health outcomes among men with KS have recently been published from Denmark (4, 5) and the United Kingdom (6, 7). Comprising 781 and 3518 cases, respectively, of KS, these studies display the power of extensive data from national health systems linking karyotypic diagnosis with lifetime individual heath outcomes, and service use. These population-based studies provide comprehensive and mostly consistent definition of diagnosis (4), mortality (5, 6, 7, 8), and now hospitalization-based morbidity (9) among men with KS.
The first Danish study (4) showed a striking discrepancy between the well-established prevalence of KS from systematic studies of neonates (152 per 100,000 or 1 in 660 male births) and the karyotypic diagnosis of KS among adults (
40 per 100,000), indicating that only approximately 25% of men with KS are ever diagnosed during life and less than 10% before puberty. Remarkably this large discrepancy had escaped notice until recently (10), and the Danish registry linkage data now firmly establish this finding. Systematic underdiagnosis of KS has profound implications, extending beyond the failure to recognize an easily treated but uncommon disorder. One possible reason for the failure to diagnose a readily recognizable archetypal clinical syndrome like KS could be the existence of a common but less conspicuous form such as due to pharmacogenetic variation in androgen receptor sensitivity. This would be analogous to the congenital bilateral absence of the vas deferens, a subtle forme fruste of cystic fibrosis lacking its striking classical pulmonary and gastrointestinal manifestations. Yet tiny testes are virtually universal in KS including among the karyotypic variants (20% of KS cases), which, apart from the rare 46 (3–4% of KS cases) XX variant, share the classical somatic dysmorphic features. More likely the diagnostic gap arises simply from a widespread failure to recognize clinical features of KS, notably undeveloped testes. Given the essentially normal life expectancy and making the mild assumption that palpation of the pathognomonic small firm testes would prompt cytogenetic diagnosis, a striking inference is that most men in the community never undergo a full genital examination by a doctor during their lives. This is a stark contrast with pelvic examination, long a routine for women throughout life. Because this diagnostic gap is identified in countries with effective national health schemes providing ready access to medical care, it is likely that even more cases in which socioeconomic barriers hinder ready access to medical care are missed and that less conspicuous hypogonadism in young men is still more often overlooked.
The second Danish study examined mortality patterns among 781 men with KS, compared with 3803 controls matched for month of birth analyzing the primary and contributing causes of death as recorded on death certificates of the 124 and 491 deaths, respectively. The life expectancy in KS (median 71.4 yr) was significantly, but minimally (2.1 yr), shorter than controls confirming earlier, less robust data (11) and consistent with the contention that prepubertal castration does not shorten life expectancy (12). Among primary causes of death in adults, a significant excess due to infectious, pulmonary, and urinary tract diseases was observed, whereas an excess of neurological and circulatory disease also significantly contributed to deaths. The U.K. study corroborated these findings in a larger study including more than 3000 men with nonmosaic KS, drawing on nearly all U.K. cytogenetic testing laboratories from the 1960s onward. By linking medical records in the central registers of the U.K. National Health Scheme database with death certificates and ICD coding, death rates were analyzed for all-cause (7) and cancer (6) deaths. Among the 461 deaths of men with KS in the U.K. study, there was an excess from many causes including cardiovascular, nervous, respiratory, and renal diseases as well as diabetes, epilepsy, pulmonary embolism, peripheral vascular disease, intestinal ischemia, and femoral fracture but lower death rates from ischemic heart disease and prostate cancer. Cancer deaths were increased overall, mainly due to increases in lung and breast cancers and non-Hodgkins lymphoma.
The similarities between these studies are more important than their differences and, together, they provide robust and comprehensive patterns of causes of death in men with KS. Both confirm increased death rates from a wide range of disorders known or suspected to afflict men with KS (1). The individual age matching in the Danish study offers greater specificity for the age-related death, the major confounder in mortality studies. By contrast, the larger U.K. data offer greater power to detect weaker associations but, lacking age matching and using instead national death rates as a comparator, might miss significant shifts in age profile in which the overall prevalence of disease was similar. Although linkage studies are constrained by the accuracy of both death certificates and ICD coding, random misclassifications tend to nullify genuine relationships rather than creating spurious ones. Hence, to the extent that systematic misclassifications are avoided, the strength of associations may be underestimated with weaker ones missed, but positive associations can be considered reliable. Within these limitations, linkage studies provide illuminating descriptive findings for which causality and mechanisms require elucidation. A key issue stimulated but unresolved by these studies is the need to identify the pathogenic mechanisms involved distinguishing between the causes of death related to the hormonal deficits, which are potentially preventable, from those related to the nonhormonal genetic consequences of the aneuploidy, which may still be palliated.
In the present issue (9), the Danish group extend their linkage studies to morbidity patterns among 832 men with KS, compared with 4033 age-matched controls, using discharge diagnosis after hospitalization as an end point. The study found a wide array of disorders causing more hospitalization in men with KS, reinforcing and extending the observed mortality patterns. The shift in focus to nonfatal outcomes using the softer end point of hospitalization is susceptible to surveillance and recall biases. The latter arises after diagnosis of one major medical disorder, which encourages subsequent reporting of more nonfatal health outcomes. This was neatly circumvented in the Danish morbidity study by observing that similar morbidity patterns were evident even before the KS diagnosis. Nevertheless, health outcomes based on death or hospitalization overlook morbidity among ambulatory men that has profound albeit indirect impact on health. For example, the frequent neurobehavioral disability with prominent dyslexia-like cognitive limitations in KS (13) together with the subtle and insidious effects of chronic androgen deficiency in impeding psychosexual development and virilization have pervasive effects. These culminate in low socioeconomic status with corresponding tobacco, alcohol, and dietary and activity patterns (although not specifically reported in these studies) that may underlie the excess in pulmonary infections, obstructive airways disease, lung cancers, cirrhosis, obesity, diabetes, and neuropsychiatric disorders. Clarification of such mechanisms requires complementary clinical studies obtaining more details of individual clinical features.
Another difficulty in evaluating the impact of chronic androgen deficiency is the uncertain impact of testosterone treatment. The men in the KS cohorts were probably offered standard testosterone treatment, yet because many young men cease testosterone treatment that requires frequent administration and inadequate treatment leads to suboptimal benefits (14), it is most likely the observed outcomes might underestimate somewhat the effects of chronic androgen deficiency consistent with the findings of more frequent fractures of hip, spine, and forearm as well as deaths from hip fracture in the KS cohorts. Similar studies of men with idiopathic hypogonadotropic hypogonadism with equally profound lifelong androgen deficiency but without aneuploidy could provide interesting corroboration of these findings. However, the even lower prevalence of idiopathic hypogonadotropic hypogonadism means that such studies would be feasible only on a multinational basis, and the lack of a convenient tracer equivalent to that provided by karyotypic diagnosis for KS is a further constraint.
These studies shed interesting light on the long-term consequences of androgen deficiency with implications for the escalating use of androgens among older men. Although increased risk of both fatal and nonfatal fractures is well established after orchidectomy, these studies provide the first compelling evidence that hypogonadism is associated with increased risk of fatal and nonfatal fractures. The fewer deaths from prostate cancer provide evidence that lifelong androgen deficiency protects against fatal prostate cancer, reinforcing evidence that 5
-reductase inhibition prevented early-stage prostate cancer in the Prostate Cancer Prevention Trial. The increased frequency of genitourinary infections without change in benign prostate disease raises interesting questions about potential androgen-sensitive mechanisms influencing lower urinary tract function via prostate, bladder, or pelvic nerve mechanisms in parallel with increasing recognition that androgens may also influence peripheral neuromuscular effector mechanisms of erection. The cardiovascular effects are complex, with increased morbidity (9) but reduced deaths (7) from ischemic heart disease but more deaths due to ischemia in peripheral and intestinal arteries and from thromboembolism, highlighting the heterogeneity of androgen effects on cardiovascular disease (15). In concert, these studies provide a reminder that, whereas long-term testosterone treatment for older men may offer improvement in fractures, it also risks increasing risk of death from cardiovascular and prostate cancer, the latter being the pivotal factors in deciding the utility of androgen treatment for older men (16). Ultimately, only rigorous prospective, placebo-controlled clinical trials can establish the net risks and benefits of testosterone treatment for older men (17).
Whereas variations in breast and prostate cancer deaths are consistent with known androgen dependence and excess lung cancer may be related to presumed smoking patterns, the increase in non-Hodgkins lymphoma has no obvious hormonal mechanism highlighting that oncogenic effects of the aneuploidy itself cannot be excluded. Both national studies still had insufficient power to confirm the rare but well-established association between extragonadal midline germ cell cancers and KS (18), with the Danish study finding no midline tumors although despite cases reported in Denmark (19). This vindicates the role of astute clinical observation as well as highlighting the need for even larger linkage studies.
These studies challenge future clinical research to rectify the regrettable gap in current medical practice that permits lifelong but readily correctible hormonal deficits to remain undetected in many men despite well-organized medical care systems and to seek more effective treatment of men with lifelong hypogonadism. Both highlight the need for earlier, more efficient diagnosis either at birth or at least by adolescence, depending on how well early therapeutic intervention rectifies clinical features. The dyslexia-like neurobehavioral cognitive deficits and somatic dysmorphic stigmata of KS stamp an indelible, if ghostly, mark on men predestining a subordinate social niche into which they gravitate. It has long been postulated that some of these stigmata may reflect chronic androgen deficiency so that early treatment might ameliorate social adjustment. Proper evaluation of this hypothesis would require international collaborative studies akin to the large-scale multicenter cancer and cardiovascular studies that are now commonplace. A more accessible goal may be to close the diagnostic gap. As part of a systematic approach to more effective male reproductive health care (20), rectifying the underdiagnosis of KS could be a benchmark to be achieved either by establishing genetic screening for KS at birth or introducing the expectation that standard medical care for young men includes at least one genital examination during late adolescence, a function once fulfilled in some places by routine medical examinations before marriage or military conscription.
Overall the insight provided by linkage data into the effectiveness of current medical practice highlights the power of comprehensive data linkage and sets benchmarks for progress. It also raises the pertinent question, in the spirit of Archie Cochrane, why such data assembly and analysis is not mandated by the self-interest of health systems everywhere.
Footnotes
There are no relevant disclosures for this article.
Abbreviation: KS, Klinefelter’s syndrome.
Received January 24, 2006.
Accepted January 31, 2006.
References
This article has been cited by other articles:
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  D. J. Handelsman Update in Andrology J. Clin. Endocrinol. Metab., December 1, 2007; 92(12): 4505 - 4511. [Abstract] [Full Text] [PDF]
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 A. B. Araujo, V. Kupelian, S. T. Page, D. J. Handelsman, W. J. Bremner, and J. B. McKinlay Sex Steroids and All-Cause and Cause-Specific Mortality in Men Arch Intern Med, June 25, 2007; 167(12): 1252 - 1260. [Abstract] [Full Text] [PDF]
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