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Mortality in Patients with Klinefelter Syndrome in Britain: A Cohort Study

Section of Epidemiology (A.J.S., C.D.H., M.J.S.), Institute of Cancer Research, Sutton, Surrey SM2 5NG, United Kingdom; Cell and Molecular Genetics Section, Medical Research Council Human Genetics Unit (A.F.W.), Western General Hospital, Edinburgh EH4 2XU, United Kingdom; and Wessex Regional Genetics Laboratory (P.A.J.), Salisbury District Hospital, Salisbury SP2 8BJ, United Kingdom

Address all correspondence and requests for reprints to: Professor A. J. Swerdlow, D.Sc., Section of Epidemiology, Brookes Lawley Building, Institute of Cancer Research, Sutton, Surrey SM2 5NG, United Kingdom. E-mail: anthony.swerdlow{at}icr.ac.uk.

	Abstract

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Context: Klinefelter syndrome is characterized by hypogonadism and infertility, consequent on the presence of extra X chromosome(s). There is limited information about long-term mortality in this syndrome because there have been no large cohort studies.

Objective: Our objective was to investigate mortality in men with Klinefelter syndrome.

Design and Setting: We obtained data about patients diagnosed with Klinefelter syndrome at almost all cytogenetics centers in Britain, as far back as records were available, and conducted a cohort study of their mortality, overall and by karyotype.

Patients: We assessed 3518 patients diagnosed since 1959, followed to mid-2003.

Outcome Measure: The outcome measure was standardized mortality ratio (SMR).

Results: A total of 461 deaths occurred. There was significantly raised mortality overall [SMR, 1.5; 95% confidence interval (CI), 1.4–1.7] and from most major causes of death including cardiovascular disease (SMR, 1.3; 95% CI, 1.1–1.5), nervous system disease (SMR, 2.8; 95% CI, 1.6–4.6), and respiratory disease (SMR, 2.3; 95% CI, 1.8–2.9). Mortality was particularly raised from diabetes (SMR, 5.8; 95% CI, 3.4–9.3), epilepsy (SMR, 7.2; 95% CI, 3.1–14.1), pulmonary embolism (SMR, 5.7; 95% CI, 2.5–11.3), peripheral vascular disease (SMR, 7.9; 95% CI, 2.9–17.2), vascular insufficiency of the intestine (SMR, 12.3; 95% CI, 4.0–28.8), renal disease (SMR, 5.0; 95% CI, 2.0–10.3), and femoral fracture (SMR, 39.4; 95% CI, 4.8–142.3). Mortality from ischemic heart disease was significantly decreased (SMR, 0.7; 95% CI, 0.5–0.9).

Conclusions: Patients diagnosed with Klinefelter syndrome have raised mortality from several specific causes. This may reflect hormonal and genetic mechanisms.

	Introduction

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KLINEFELTER SYNDROME IS a numerical chromosome abnormality in males, characterized by the presence of one or more extra X chromosomes. It occurs in about 1.5 per 1000 of the male population (1). The clinical syndrome was initially described in 1942 (2), and the chromosome constitution was discovered in 1959 (3). Characteristically, the patients have hypogonadism and elevated gonadotropin levels, and various other hormonal and physical abnormalities occur. There has been limited information about long-term mortality risks, however, because of the lack of large cohort (follow-up) studies. The only such published studies have been a cohort of 466 men from a Scottish register (4), later extended to two other centers with a total of 695 men (5), and a cohort of 781 men from Denmark (6). To enable more detailed analyses, based on much larger numbers, we assembled a cohort of cases of Klinefelter syndrome diagnosed in Britain for as long as records are held by the cytogenetics centers in the country and followed up the cohort for mortality, for periods of up to 40 yr. We have previously reported on cancer risks in this cohort (7).

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Discussion References

 
We extracted identification and diagnostic data about all patients with Klinefelter syndrome diagnosed as far back as records had been retained (1959 at earliest), from each cytogenetics laboratory in Britain except two small ones. Appropriate ethics committee agreement was obtained for this. Data for the comparatively rare 46,XX male variant of Klinefelter syndrome were not included in the study because these data have particular potential to include recording and transcription errors from normal males and females. Patients who were recorded as being karyotyped because of cancer were excluded from the study. Identification data about the cohort members were sent to the National Health Service Central Registers (NHSCRs) for England and Wales and for Scotland, which hold records of all NHS patients in their countries and are therefore virtually complete population registers. The registers hold data on deaths, emigrations, and other exits, and therefore the cohort members were flagged on these registers to obtain information on mortality and other losses to follow-up. We were sent death certificates for those who had died. These were coded to the underlying cause of death, using the International Classification of Diseases (ICD) revision employed in Britain at the time of death: ICD7 from 1958–1967, ICD8 from 1968–1978, ICD9 from 1979–1999 in Scotland and 1979–2000 in England and Wales, and ICD10 from 2000 in Scotland and from 2001 in England and Wales. The coding was largely undertaken by the national death coding office, and for the remainder by the authors following the national coding procedures. We then bridge-coded between ICD revisions to give the ICD9 categories shown in the tables. We made an exception for deaths coded under ICD rules to Klinefelter syndrome, which we recoded to the underlying cause that would have applied if Klinefelter had not been written on the certificate; this was done because the purpose of the study was to compare causes of death in Klinefelter patients with the general population, rather than to discover how often certifiers believed Klinefelter to be the cause of other fatal diseases.

For each man in the cohort, we computed person-years of follow-up by 5-yr age group, calendar year, and country (England and Wales vs. Scotland), beginning from the date of cytogenetic diagnosis and ending at June 30, 2003, or the 85th birthday, date of death, or other loss to follow-up, whichever was earliest. Follow-up was censored at age 85 because at older ages than this, national (i.e. expected) mortality rates are not available by 5-yr age group, and the certified cause of death is often inaccurate. We calculated expected cause-specific mortality in the cohort by multiplying the age-, calendar year-, and country-specific person-years at risk in the cohort by the corresponding national mortality rates for men. Standardized mortality ratios (SMRs) were then calculated as the ratio of observed to expected deaths, and 95% confidence intervals (CIs) for the SMRs were calculated assuming a Poisson distribution (8). Tests for trend and for the difference between SMRs were conducted as described by Breslow and Day (8). Significance tests were two-sided. Absolute excess risks were calculated by subtracting the expected from the observed numbers of deaths and dividing by person-years at risk.

We subdivided the subjects for analysis by the number of sex chromosomes, whether mosaicism was present, and if so, the constitution of the non-Klinefelter component. Where information was available for mosaics on the numbers of cells diagnosed with each mosaic component, we designated the subject as mosaic only if more than one cell had been counted with each component. We did not have direct information for the study subjects on whether mosaicism was congenital or acquired, but as a rough proxy for this [because the prevalence of acquired mosaicism rises with age (9)], we conducted separate analyses for mosaics diagnosed before age 45 yr and those diagnosed at older ages.

To assess, as far as possible, whether bias might account for certain of the results, we conducted several subanalyses of risks in subdivisions by birth year, risks omitting follow-up and deaths in the early years after cytogenetic diagnosis, and risks omitting cohort members recorded by the Medical Research Council Human Genetics Unit (MRC HGU).

	Results

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There were 4806 patients with Klinefelter syndrome in the records of the 25 laboratories in the study. The cases had been diagnosed during 1959–2002. At most laboratories, the earliest cases were from the 1960s or early 1970s, depending on when the laboratory was founded and for how long their records had been kept. A total of 1288 cases were not included in the cohort because there was insufficient information for flagging (1224, largely missing date of birth), the year of cytogenetic testing was unknown (24), cytogenetic testing was a consequence of cancer diagnosis (16), cytogenetic testing was conducted after age 85 (two cases), or other reasons (22). The remaining 3518 men were flagged at the NHSCRs and formed the study cohort. The karyotype of most of these men was 47,XXY (3002) or 47,XXY mosaic (320), but 146 had four sex chromosomes, 49 had five sex chromosomes, and one was reported only as Klinefelter syndrome (Table 1). Twenty-two percent had been diagnosed at ages under 15 yr, 62% at 15–44 yr, and 17% at older ages.

The all-cause SMR was 1.5 (95% CI, 1.4–1.7), and there was significantly raised mortality from endocrine and metabolic disease, mental disorders, and diseases of the nervous, circulatory, respiratory, and genitourinary systems as well as from congenital anomalies (Table 2). Within more specific categories there were particularly raised risks of death from diabetes (SMR, 5.8; 95% CI, 3.4–9.3), epilepsy (SMR, 7.2; 95% CI, 3.1–14.1), pulmonary embolism (SMR, 5.7; 95% CI, 2.5–11.3), peripheral vascular disease (SMR, 7.9; 95% CI, 2.9–17.2), vascular insufficiency of the intestine (SMR, 12.3; 95% CI, 4.0–28.8), and cardiovascular congenital anomalies (SMR, 7.3; 95% CI, 2.4–17.1). There was also greatly raised mortality from fractures of the femur (SMR, 39.4; 95% CI, 4.8–142.3), but based on only two deaths. Mortality was significantly raised from cerebrovascular disease (SMR, 2.2; 95% CI, 1.6–3.0) but significantly diminished from ischemic heart disease (SMR, 0.7; 95% CI, 0.5–0.9). When the risk of ischemic heart disease was reanalyzed with female rates as expected (not in the table), the SMR was 1.9 (95% CI, 1.4–2.4). The five deaths coded to the ICD rubric vascular insufficiency of the intestine comprised three whose death certificates stated (superior) mesenteric artery thrombosis, and two stated as small bowel infarction or ischemia. Most of the death certificates coded to cerebrovascular disease did not specify whether the cause was thrombotic or hemorrhagic; of those that stated this, there were six deaths due to subarachnoid hemorrhage, four others due to intracerebral hemorrhage, and nine due to cerebrovascular occlusion or thrombosis. Only five of the 17 death certificates for deaths from diabetes stated the diabetes type; four were type 2, and one was type 1. None of the death certificates for the epilepsy deaths indicated any cause of the epilepsy. The mental disorder deaths were mainly due to drug or alcohol abuse/dependence (seven) or dementia (four). All but two of the nine genitourinary system deaths were from renal causes (SMR, 5.0; 95% CI, 2.0–10.3), mainly stated simply as renal failure. We did not analyze cancer deaths by site of the cancer because we have reported this previously (7): in brief, significantly increased risks of mortality from lung and breast cancers and of non-Hodgkin’s lymphoma and significantly reduced risk of prostate cancer mortality were found (7).

Subcategory analyses for men with 48, and separately 49, sex chromosomes (not in table) were also limited by small numbers, but the all-cause SMRs for these groups were 1.9 [95% CI, 1.2–3.0 (n = 21)] and 3.5 [95% CI, 0.7–10.4 (n = 3)], respectively.

To check for possible bias caused by selective cytogenetic examination of ill people because of their illness, we reanalyzed the above tables omitting events and person-years in the first year after cytogenetic diagnosis and also omitting the first 3 yr after diagnosis (not in table). With the possible exception of deaths from congenital malformation, the results suggested that there was not appreciable bias; the all-cause SMRs were 1.5 for total follow-up, 1.5 omitting the 1st year of follow-up, and 1.4 omitting the first 3 yr. Major causes of death also showed no appreciable trend except, possibly, congenital malformation mortality, for which SMRs were 6.8 (n = 9), 6.6 (n = 6), and 2.7 (n = 2), respectively.

To examine for potential bias, we also conducted analyses in subcategories by year of birth, because there might be greater potential for selective karyotypic diagnosis in those born many years before karyotyping became widely available, and less potential in those born more recently. The analyses did not suggest any material bias: the all-cause SMR was 1.6 (95% CI, 1.4–1.8) for those born before 1940 and 1.4 (95% CI, 1.1–1.7) for patients born later. To check whether bias had been introduced by inclusion in the cohort of cases from the MRC HGU register, which unlike the other registers was research based rather than clinically based, we reanalyzed excluding the MRC HGU subcohort; the results were not materially affected, with an all-cause SMR of 1.6 (95% CI, 1.4–1.8).

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

 
The study showed significantly raised mortality from several causes in a cohort large enough to give relatively stable risk estimates. The possibility of bias as an explanation of the results needs careful consideration, however. Inevitably, the study was based on those cases of Klinefelter syndrome that have come to clinical diagnosis; we estimate that this was less than one third of all cases born, even in recent years (7). Cases reaching diagnosis might be phenotypically or in other ways different from those that do not. From a clinical perspective, however, their mortality is that of relevance, because clinical interest is in risks for cases who are recognized as such, not cases who never reach diagnosis. Because this selection might be greater for cases born long before cytogenetic diagnosis was available, we reanalyzed the data excluding cases born before 1940, but there was no material effect on the results.

Second, cytogenetic diagnosis of Klinefelter syndrome might occur as a consequence of clinical diagnosis or care for an illness, mortality from which would then be artifactually raised within the cohort. This effect is obvious for leukemia, for which the diagnostic work-up often includes cytogenetic examination of the bone marrow, and also occurs for other cancers (7). To minimize such effects, we omitted from the analysis individuals known to have been karyotyped because of cancer. It was not practical to detect directly whether there had been similar referrals for nonmalignant diseases, but to examine whether bias had occurred in this way we analyzed risks omitting the early years after cytogenetic diagnosis, when any referral bias would have had its greatest effect; the lack of change in results in these analyses suggests that such bias was negligible, except perhaps for congenital malformation deaths. For the latter cause, some bias is almost inevitable, because by definition congenital conditions must have been present before karyotyping; the number of such deaths was few (2% of all deaths), however, so the bias to overall mortality will not have been material.

We had to omit from the cohort Klinefelter cases whose date of birth was not recorded and cases whose records were no longer retained by the cytogenetic centers. In both instances, bias is not plausible. Date of birth was recorded (or not) at the time of cytogenetic diagnosis, before follow-up and mortality occurred. Destruction of old records was on the basis of year of karyotyping, not on the basis of the particular diagnosis or follow-up.

Confounding seems unlikely to have affected any of the results except possibly those for congenital malformation mortality, because the only known risk factor for Klinefelter syndrome is older maternal age in cases of maternal origin (10), which as far as we know is not associated with any of the noncongenital causes of death examined in the study. Because patients with Klinefelter syndrome (especially those with four or five sex chromosomes) tend to have a low IQ, it is possible that they might have had consequent lifestyles that affected their risks of cause-specific mortality. We do not have relevant information on the behaviors and environments of patients with Klinefelter syndrome to enable assessment of the extent to which this indirect mechanism, rather than a direct effect of chromosomal constitution, could explain the significant findings in our study.

As is usual good practice in epidemiological studies, we censored risk at age 85 yr, because of the diminishing accuracy of death certificate diagnosis with older age (11, 12). The effect of doing otherwise would have been negligible, however, because ages beyond 85 represented only 0.1% of total person-years and 3% of deaths in the cohort. Although death certification at younger ages is also not perfect, this source of information on cause of death was used for both the cohort and the general population comparison, so should not in principle have led to bias.

In the first analyses of mortality in patients with Klinefelter syndrome, Price et al. (4) noted excesses of deaths from aortic valve disease (three cases) and subarachnoid hemorrhage (three cases). Price’s cohort of 466 patients was from the MRC HGU Register, which is a subset of the present subjects. For aortic valve disease, no additional cases were found in our study beyond those described by Price et al. (4), and indeed one of the cases he described was strictly not codable to aortic valve disease as the underlying cause of death. Mortality from this cause is not significantly raised in our much larger cohort, and it appears in retrospect that Price’s finding was a chance one. By contrast, three additional deaths from subarachnoid hemorrhage were found in our cohort, and there was a significantly raised risk, suggesting that this cause of death may truly be associated.

The raised risk of cerebrovascular disease mortality is only to a minor extent due to the excess of deaths from subarachnoid hemorrhage. Generalized atheroma seems unlikely to be the explanation for the raised risk, in the light of the significantly reduced SMR for ischemic heart disease. Similarly, the highly significant 12-fold risk of mortality from vascular insufficiency of the intestine appears to be a specific association with Klinefelter because it is far greater than the general cardiovascular disease risks. No deaths from this cause were seen in the much smaller Danish cohort (6). There was also a significant excess of mortality from peripheral vascular disease and from pulmonary embolism; a raised incidence of pulmonary embolism has been shown previously (13). It seems possible that the various specific cardiovascular mortality excesses are linked, and might all be thromboembolic, reflecting deficient fibrinolysis in Klinefelter syndrome, as a consequence of the androgen deficiency present in the syndrome (14, 15, 16). The prevalence of chronic leg ulceration is much raised in Klinefelter (13) and has been shown to be associated with elevated activity of plasminogen activator inhibitor-1, levels of which correlate inversely with testosterone levels (17). Interpretation is complicated, however, because Klinefelter patients are sometimes treated with testosterone, but historically patients sometimes discontinued treatment because it entailed injections; we have no information on the extent of use of testosterone in our cohort.

The significantly diminished risk of ischemic heart disease mortality is unlikely to be due to diminished smoking because the cohort showed raised lung cancer risks (7). It is not what would be expected from the hypoandrogenism in Klinefelter patients. We do not have an explanation for the finding.

A raised prevalence of glucose intolerance has been found in clinical series of Klinefelter patients (18, 19), which appears to be a result of insulin resistance (19). The significantly raised mortality from diabetes in our cohort accords with this, although mortality from this cause was much lower in the smaller Danish cohort (6). We found mortality from diabetes similar in 47,XXY and 47,XXY mosaic patients, although based on small numbers in the latter group. This accords with evidence, although again based on small numbers, that abnormal glucose tolerance is also highly prevalent in both groups (20). No deaths from diabetes occurred in men with more than three sex chromosomes, but the confidence interval was wide.

The raised respiratory mortality in our cohort was seen also in the Danish cohort study (6) and is of uncertain interpretation. Respiratory function testing on a clinical series of patients with Klinefelter syndrome has shown a high prevalence of restrictive defects and of decreased functional residual capacity but not of obstructive disease (21). Pneumonia is a diagnosis that has frequently been entered as the underlying cause of death on death certificates by certifiers in the United Kingdom when it may in fact have been the terminal event in deaths due to another cause (22).

Klinefelter syndrome is associated with decreased bone density (23), and corresponding with this there was a highly significantly raised mortality, albeit based on only two deaths, from fractured femur, a condition characteristically related to osteoporosis. The excesses of mortality from genitourinary diseases, epilepsy, and substance abuse do not have obvious explanations. The MRC HGU ascertained some patients with Klinefelter syndrome from mental subnormality and penal institutions (24), but exclusion of MRC HGU patients from the cohort did not diminish the SMRs for epilepsy or mental disorders.

Although numbers were too small to analyze cause-specific mortality in patients with four and five sex chromosomes, the progressively greater all-cause SMRs with greater aneuploidy accords with the more severe phenotypic features noted in such patients (25). The greater mortality in mosaic 47,XXY than in nonmosaic 47,XXY patients is not in the direction that would be expected and we have no explanation for it. (It is possible, although unlikely, of course, that despite its statistical significance, it is a chance finding.) The analyses by age at diagnosis did not suggest an association specific to acquired (or to congenital) mosaicism.

Several potential mechanisms might explain raised mortality from specific diseases in patients with Klinefelter syndrome. One is that there is increased expression of X-linked genes before inactivation, or increased dosage of genes on the X chromosome that escape X inactivation (26, 27), that might lead to raised risk. Another is that disease-causing genes in the parents might be associated with risk of nondysjunction as well as risk of disease. An additional possibility is that genes on the X chromosome might predispose to physiological abnormalities (e.g. low testosterone concentrations, a high estrogen/testosterone ratio, and sometimes raised estrogen concentrations) (14, 15, 16), which could themselves be risk factors for disease. Investigation of the reasons for the raised mortality in Klinefelter syndrome thus has potential to illuminate the broader role of the X chromosome in disease risk in people more generally.

	Acknowledgments

 
The United Kingdom Clinical Cytogenetics Group comprises the authors of this work plus Paul J. Batstone (Inverness Genetics Laboratory), Leslie J. Butler (NE Thames, Great Ormond Street Hospital Genetics Laboratory), Teresa Davies (Bristol Genetics Laboratory), Valerie Davison (Birmingham Genetics Laboratory), Zoe Docherty (SE Thames, Guy’s Hospital Genetics Laboratory), David P. Duckett (Leicestershire Genetics Centre), Margaret Fitchett (Oxford Genetics Laboratory), Alison Fordyce (MRC Human Genetics Unit, Edinburgh), Lorraine Gaunt (Manchester Genetics Laboratory), Elizabeth Grace (Edinburgh Genetics Laboratory), Peter Howard (Liverpool Genetics Laboratory), Gordon W. Lowther (Glasgow Genetics Laboratory), Christine Maliszewska (Dundee Genetics Laboratory), Edna L. Maltby (Sheffield Genetics Laboratory), Kevin P. Ocraft (Nottingham Genetics Laboratory), Selwyn Roberts (Wales Genetics Laboratory), Kim K. Smith (Cambridge Genetics Laboratory), Gordon S. Stephen (Aberdeen Genetics Laboratory), John W. Taylor (SW Thames, St. George’s Hospital Genetics Laboratory), Catherine S. Waters (NW Thames, Northwick Park Hospital Genetics Laboratory), Jeffery Williams (Leeds Genetics Laboratory), John Wolstenholme (Newcastle Genetics Laboratory), and Sheila Youings (Wessex Regional Genetics Laboratory).

We thank D. Allen, F. Barber, C. Maguire, P. Murnaghan, M. Pelerin, and M. Swanwick for assistance in data collection; E. Boyd, D. Couzin, J. Delhanty, P. Ellis, M. Faed, J. Fennell, A. Kessling, A. McDermott, A. Parkin, A. Potter, and D. Ravine for access to data; N. Mudie and A. Hart for help in coding; H. Nguyen for data entry; Z. Qiao for computer programming; N. Dennis and R. Stanhope for advice; the NHSCRs and cancer registries of England, Wales, and Scotland for follow-up data; and Mrs. M. Snigorska for secretarial help.

	Footnotes

 
This work was supported by a grant from the United Kingdom Medical Research Council.

First Published Online October 4, 2005

Abbreviations: CI, Confidence interval; ICD, International Classification of Diseases; SMR, standardized mortality ratio.

Received May 16, 2005.

Accepted September 22, 2005.

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