Morbidity and mortality in Klinefelter syndrome (47,XXY)

REVIEW ARTICLE

Morbidity and mortality in Klinefelter syndrome (47,XXY)Anders Bojesen ([email protected])1, Claus H Gravholt2

1.Department of Clinical Genetics, Vejle Hospital, Sygehus Lillebaelt, Denmark2.Department of Endocrinology & Internal Medicine and Medical Research Laboratories, Aarhus University Hospital, Aarhus Sygehus NBG, Aarhus C, Denmark

Keywords47,XXY, Klinefelter syndrome, Morbidity, Mortality,Prevalence

CorrespondenceAnders Bojesen, Department of Clinical Genetics,Vejle Hospital, Sygehus Lillebaelt, DK-7100,Denmark.Tel: + 45 79406555 |Fax: + 45 79406871 |Email: [email protected]

Received31 August 2010; revised 16 January 2011;accepted 14 March 2011.

DOI:10.1111/j.1651-2227.2011.02274.x

ABSTRACTKlinefelter syndrome (KS) (47,XXY) is the most common sex chromosome disorder in

man and is a relatively common cause of male infertility and hypogonadism. The syndrome

has been known since 1942, and many reports of different diseases associated with KS

have been reported since that, but a more systematic knowledge about the long-term out-

come was not described until the last decade, where nation-wide epidemiological studies

were reported from Britain and Denmark. We here review the epidemiological data from

two cohorts of patients with KS in Denmark and Britain, showing a significant increase in

both mortality and morbidity from a variety of different causes. Mortality was increased by

50% (SMR 1.5 or HR 1.4) corresponding to a median loss of approximately 2 years. The

risk of being admitted to hospital with any diagnosis was increased by 70%. The

underlying reason for the poorer health in KS may be caused by interaction of genetic,

hormonal and socio-economic factors.Conclusion: Both morbidity and mortality are significantly increased in Klinefelter

syndrome with a 50% increase in mortality risk and a 70% increase in risk of being admit-

ted to hospital.

INTRODUCTIONKlinefelter syndrome (KS) is the most common sex-chro-mosome disorder in man with a prevalence of approxi-mately 1:600 males (1) and is defined as a male having akaryotype containing an extra X-chromosome (47,XXY)and variants hereof including mosaicims (2). The key find-ings in KS, small testes, azoospermia and increased LH andFSH, are found in practically all patients with KS, but otherfeatures like hypogonadism, gynecomastia, increasedheight, sparse beard and body hair, learning disabilities, psy-chiatric disturbances, increased risk of diabetes and meta-bolic syndrome, abdominal obesity, autoimmune diseasesand many other signs and symptoms have been found withvarying incidence in different cohorts of patients with KS(3–5). Yet relatively frequent, data about the long-term con-sequences of KS were sparse until the last decade, when lar-ger epidemiological studies were published (6–10).

Here, we will review the epidemiological studies performedin Denmark and in Britain in two relatively large cohorts ofpatients with KS, describing the increased morbidity andmortality in KS, but also the prevalence of the syndromeand the diagnostic delay or lack of diagnosis in Denmark.

Since 1942, after the first description of the syndrome(11), there has been an abundance of case reports describingfindings of rare complications ⁄ comorbidity, and it seems likeKS could be associated with virtually any other disease fromthe medical textbook. Thus, epidemiology may help us to dis-criminate between what may be true associations (and whereclinicians should focus their attention) and what may bemerely chance associations coming to our attention becauseof publication bias (typically when doctors are reporting tworare diseases in the same patient). The use of epidemiologycan also help us focus attention to new research areas in KSand consequently improve future clinical care.

Acta Pædiatrica ISSN 0803–5253

ª2011 The Author(s)/Acta Pædiatrica ª2011 Foundation Acta Pædiatrica 2011 100, pp. 807–813 807

PREVALENCE AND DIAGNOSTIC ACTIVITYIn Denmark, where all cytogenetic examinations since 1960have been kept in a central registry, we found the prenatalprevalence of KS to be 150 per 100 000 (1), exactly thesame number was found using pooled data from the cytoge-netic surveys performed in newborns during the period1964–1990 adding up to a total of approximately 55 000boys from around the world (12–19), emphasizing that150 KS per 100 000 live born boys is mostly likely the trueprevalence of the syndrome. However, in the postnatalgroup, the prevalence was much lower, with the highestnumbers diagnosed among the adults after the age of25 years (40 per 100 000), indicating that only about 25%of the expected cases of men with KS are diagnosed. Theage-distribution also showed that only a minority of boyswith KS were diagnosed before puberty. Whether the sameis the truth in other countries is unknown, but the data fromthe British studies indicate even lower diagnostic activity(7). In the British cohort that covers almost the entire coun-try, approximately 4800 patients with KS were found in apopulation of approximately 60 million people comparedwith the Danish cohort with around 900 patients with KSfound in a population of 5.5 million people during the sameperiod. Thus, a crude estimate indicates that only about 16per 100 000 KS men are diagnosed in Great Britain, consid-erably less than diagnosed in Denmark.

These results are important and should always be kept inmind when interpreting data from any study in relation toKS, because selection bias will unavoidably be present,which of course also applies to clinical studies. The onlyexception from this rule may be the aforementioned studiesin newborns, where follow-up on the diagnosed patientswith KS has been published (20,21), but the small sample ofKS subjects hampers these studies and curbs the universal-ity. It is also important to keep in mind that we are unawareof the clinical fate of the remaining 75% or more with nodiagnosis.

MORTALITY STUDIESStudies regarding mortality have been performed in boththe British and Danish cohorts. In Britain, two former stud-ies in smaller cohorts (6,22) have been embedded in themost recent study and therefore not mentioned further.

The British study on mortality showed a significantlyincreased all-cause standard mortality rate (SMR) of 1.5(95% CI, 1.4–1.7), which is absolutely comparable to theresult from our study, showing a hazard ratio of 1.40 (95%CI, 1.13–1.74) and corresponds to a median loss of approxi-mately 2.1 years in lifetime compared with non-KS subjects.The finding from the two studies is a significantly increasedrisk of dying form infectious, nervous, respiratory, and geni-tourinary diseases, and more specifically from diabetes, vas-cular insufficiency of the intestines, pulmonary embolism,epilepsy, femoral fractures and congenital malformations.Interestingly, the British study showed a decreased risk ofdying from ischaemic heart disease (7,9). The cause-specificmortality rates from the two studies are listed in Table 1.

STUDIES REGARDING CANCER IN KSHasle et al. (23) studied cancer incidence using the DanishCancer registry and found 39 cancers in 696 patients withKS corresponding to a general non-increased risk of cancer;however, four of the cancers were mediastinal germ celltumours, equivalent to a 66-fold increased risk of this spe-cific cancer type. Apart from mediastinal germ cell tumours,only gallbladder cancer was significantly more common inpatients with KS. No cases with breast cancer were found inthis study.

From the British cohort, a study concerning cancer-spe-cific mortality and cancer incidence (8) showed a nonsignif-icant increase in overall cancer mortality, SMR 1.2 (95% CI1.0–1.4, p = 0.13), but significantly increased risk of dyingfrom breast cancer, SMR 57.8 (18.8–135.0), lung cancer,SMR 1.5 (1.0–2.0) and non-Hodgkin lymphoma, SMR 3.5(1.6–6.6), but a significantly reduced risk of dying fromprostate cancer, SMR 0.0 (0.0–0.7). Several case reportshave also emphasized the increased risk of breast cancer(24,25), mediastinal germ cell cancer (26) and perhaps alsoother cancer types.

MORBIDITY STUDIESOur study regarding morbidity (10) based on hospital dis-charge diagnoses in 832 patients with KS and 4033 controlsubjects showed a generally increased risk of beinghospitalized with practically any diagnosis. Apart fromdiseases in the newborn period, patients with KS wereadmitted and discharged significantly more often with adiagnosis from all other ICD10 chapter diagnoses (seeFig. 1). The overall risk of being admitted to hospital wasincreased by 70% compared to the control group (HR 1.69,CI: 1.54–1.86).

The complete list of diagnoses where KS was admittedsignificantly more often is very long (more than 40 ICD10chapter and sub-chapter diagnoses) and therefore notshown here. Hazard ratios in diagnoses with special interestbecause of previous findings are listed in Table 2.

The increased morbidity was present even before thediagnosis of KS as judged by the presence of elevated risk ofhospitalization before the diagnosis of KS for most ICD10chapters (data not shown here), indicating that the elevatedrisk of hospitalization is true and not a phenomenon ofmedical surveillance bias (i.e. a diagnosis of one disordermay increase the chance of being diagnosed with anotherdisorder).

DISCUSSIONThe epidemiological studies in the British and Danishcohorts of Klinefelter patients clearly and significantly dem-onstrate an increased mortality and morbidity from a varietyof causes. The results represent a poorer health profile inpatients with KS in general compared to normal men, butthe reasons for this have so far proved elusive.

The results from the epidemiologic studies may also helpus to confirm results from clinical studies or vice versa.

Morbidity and mortality in KS Bojesen and Gravholt

808 ª2011 The Author(s)/Acta Pædiatrica ª2011 Foundation Acta Pædiatrica 2011 100, pp. 807–813

Previous and recent studies about bone mineral density inKS showed reduction in bone mineral density (27,28), andthe clinical relevance of these findings was confirmed bythe findings of both increased mortality from fracture of thefemur, but also increased risk of being admitted to hospitalwith fracture in the spine, hip or forearm. Likewise con-cerning diabetes; long-term clinical suspicion and someclinical studies (29–31) showed an increased risk of dia-betes, which has now been further validated by bothincreased morbidity and mortality from diabetes. The riskof diabetes may relate to abdominal obesity, recentlydescribed as a very frequent finding in a group of 70patients with KS (31) but also found in the morbidity study[HR = 3.41 (1.34–8.66)].

The risk of dying from breast cancer in the British studywas increased 60-fold, corroborating previous findings froma case–control study on male breast cancer, showing a 50-fold increase in breast cancer in KS (32). Previous studiesshowing an increased risk of leg ulcers (33) and risk of lungembolism (34) can also be confirmed by the British mortal-ity study and the Danish study on morbidity.

Not all diseases may lead to increased mortality; systemiclupus erythomatosus (SLE) and other autoimmune diseaseshave for long time been suggested more prevalent in KS

Table 1 Relative mortality, by main diagnostic groups

Mortality cause

Swerdlow et al.(7) Bojesen et al.(9)

No. of deaths Standard mortality rate (95% CI) No. of deaths Hazard ratio (95% CI)

All causes 461 1.5 (1.4–1.7) 124 1.4 (1.13–1.74)

Infectious and parasitic diseases NI 6 3.95 (1.25–12.5)

Malignant neoplasm’s 99 1.2 (1.0–1.4) 28 1.10 (0.72–1.68)

Endocrine, metabolic and nutritional disorders 20 4.8 (2.9–7.4) 10 1.8 (0.83–3.92)

Diabetes mellitus 17 5.8 (3.4–9.3) 7 1.64 (0.66–4.07)

Mental disorders 14 3.7 (2.0–6.2) 17 1.45 (0.81–2.55)

Diseases of the nervous system 15 2.8 (1.6–4.6) 7 3.62 (1.24–10.5)

Epilepsy 8 7.2 (3.1–14.1) NI

Diseases of the circulatory system 163 1.3 (1.1–1.5) 39 1.41 (1.03–1.93)

Ischaemic heart disease 60 0.7 (0.5–0.9) NI

Pulmonary embolism 8 5.7 (2.5–11.3) NI

Other heart disease 16 2.2 (1.3–3.6) NI

Aortic valve disease 2 2.0 (0.2–7.2) NI

Cerebrovascular disease 46 2.2 (1.6–3.0) NI

Subarachnoid haemorrhage 6 3.1 (1.2–6.8) NI

Peripheral vascular disease 6 7.9 (2.9–17.2) NI

Diseases of the respiratory system 65 2.3 (1.8–2.9) 36 2.97 (1.88–4.71)

Pneumonia 25 2.3 (1.5–3.4) 18 2.25 (1.20–4.21)

Chronic lower respiratory disease

⁄ Chronic obstructive airway disease

31 2.1 (1.4–3.0) 15 3.16 (1.51–6.59)

Diseases of the digestive system 19 1.6 (1.0–2.6) 9 1.31 (0.58–2.93)

Vascular insufficiency of the intestine 5 12.3 (4.0–28.8) 1 **

Disease of the genitourinary system 9 3.6 (1.6–6.8) 7 4.30 (1.41–13.1)

Renal and ureteric disease 7 5.0 (2.0–10.3) NI

Congenital anomalies 9 7.3 (2.4–17.1) 21* 79.4 (10.6–596)

Cardiovascular congenital anomalies 5 7.3 (2.4–17.1) NI

Accidents and violence 32 1.3 (0.9–1.8) 16 1.34 (0.76–2.36)

Fracture of bones 3 0.4 (0.1–1.3) NI

Fracture of femur 2 39.4 (4.8–142.3) NI

*Including Klinefelter syndrome as diagnosis.

**No estimate because of few informative strata.

NI = no information.

Figure 1 Hazard ratios and 95% CIs for discharge from hospital with differentICD 10 chapter diagnosis groups and for all diagnoses (10).

Bojesen and Gravholt Morbidity and mortality in KS


(35–37), but no significant increase in mortality was foundin either of the two studies, and only a nonsignificantincrease in autoimmune diseases and SLE was found in themorbidity study. However, because both KS and SLE arerare conditions, it may be that an association has beenmissed in epidemiological studies, despite inclusion of arather large group of KS persons, and recently differentgenetic mechanisms have been suggested as the cause forsuch an association (36,38).

Epidemiology will only tell us about associations, but notthe causes, and one can only speculate about what is actu-ally causing the increased morbidity.

Of course, it all begins at the genetic level. The genomicimbalance, caused by the over-expression of noninactivatedgenes on the extra X-chromosome, is the fundamental rea-son for the Klinefelter phenotype and associated morbidity.Some features of the syndrome, e.g. learning disability,gonadal dysfunction and increased height, may be directeffects of gene over-dose, e.g. the overdose of SHOX genemay be the cause of increased height (39), whereas otherfeatures, e.g. type 2 diabetes, breast cancer and deep veinthrombosis, may be caused by hormonal imbalances causedby the gonadal dysfunction. Furthermore, many of the diag-noses leading to increased morbidity and mortality may becaused by unfavourable life-style factors associated with lesseducation and socio-economic factors that may be causedby the learning disabilities and psychosocial problems,many patients with KS suffer from. It is evident from follow-up studies on patients with KS diagnosed as newborn (21)as well as other cohorts of both prenatally diagnosed andpostnatally diagnosed patients with KS (40,41), that learn-ing disability and psychiatric disturbances are common andcould have a massive effect on educational and vocationaloutcome.

We are currently investigating the socio-economic, edu-cational and marital status along with other measurements

of financial and social conditions in the Danish KS cohort.Future studies may show an impact of these factors on theobserved mortality and morbidity.

CONCLUSIONResults from the studies performed in the two relativelylarge cohorts of KS subjects, albeit with differences in sizeand design, are uniform, and it is obvious that KS is associ-ated with increased comorbidity, leading to more frequenthospitalizations and early demise. The specific causes ⁄ diag-noses deserve attention from a clinical point of viewbecause some of the diagnoses may be preventable, (e.g.osteoporosis, chronic obstructive airway disease or type 2diabetes), by testosterone treatment, avoidance of smokingand dietary guidance ⁄ weight loss. Other diagnoses are rare,but potentially curable, if diagnosed appropriately (e.g.mediastinal germ cell cancer, breast cancer, deep veinthrombosis and pulmonary embolism). The increased mor-bidity and mortality may be caused by both genetic and hor-monal imbalances, but it seems likely that an unfavourablesocioeconomic and educational profile is part of the expla-nation as well.

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Table 2 Diagnoses with specific interest because of previous findings

Disease Hazard ratio (95% CI)

No. Klinefeltersyndrome subjects⁄ control subjects

Breast cancer ¥* 3 ⁄ 0Mediastinal tumours 14.2* 3 ⁄ 1Diabetes 2.30 (1.61–3.29) 49 ⁄ 105

Type 1 diabetes 2.21 (1.18–4.14) 15 ⁄ 33

Type 2 diabetes 3.71 (2.14–6.40) 25 ⁄ 38

Thrombosis of the deep veins 5.29 (3.29–8.50) 39 ⁄ 41

Pulmonary embolism 3.60 (1.92–6.74) 19 ⁄ 26

Cerebrovascular disease 1.19 (0.78–1.81) 38 ⁄ 153

Intestinal thrombosis 7.89* 2 ⁄ 1Mitral valve prolapse 2.37 (0.66–8.50) 4 ⁄ 8Osteoporosis 8.01 (1.98–32.5) 6 ⁄ 6Generalised rheumatologic diseases 1.67 (0.44–6.34) 3 ⁄ 10

Systemic lupus erythematosus 4.47* 1 ⁄ 1Osteoporotic fractures 2.24 (1.44–3.48) 31 ⁄ 73

*Because of too few informative strata, confidence intervals are omitted.

Adapted from (10).



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APPENDIX: DISCUSSION FOLLOWING ANDERS BOJESEN’SPRESENTATIONMorbidity and mortality in KSAnders Juul (Copenhagen, Denmark):Your prevalence data indicate that Klinefelter syndrome(KS) is very rare in infancy and childhood. What is the con-tribution of the prenatal diagnosis to the postnatal preva-lence, and how many of these in the Danish Registry wereterminated by abortion or allowed to progress to term?

Anders Bojesen:The numbers have changed over the years. In the 1980–1990s, 75% of foetuses diagnosed prenatally with KS wereaborted, but now a large number of pregnancies continuealthough there are still many terminations.

Robert McLachlan (Melbourne, Australia):You routinely perform echo cardiology in patients newlydiagnosed with KS to look for mitral valve prolapse, butyour data suggest that the incidence in KS is no higher thanin the general population. What is the truth about mitralvalve disease and should we be introducing echocardiogra-phy for patients with KS in Australia?

Anders Bojesen:There was no increase in mitral valve disease in our morbid-ity study, but a study from the UK identified 20 patients with



KS with mitral valve prolapse suggesting an increased risk ofmitral valve disease (Fricke GR, Mattern HJ, SchweikertHU, Schwanitz G. Biomed Pharmacother 1984; 38: 88–97).At present, there is no indication for routine echocardiology,but more research is needed.

Claus Gravholdt (Aarhus, Denmark):Although echocardiography did not detect an increase inmitral valve prolapse, we did see discrete systolic perturba-tion with decreased systolic long axis function, but no majorproblems. This was linked to the presence of the metabolicsyndrome and truncal obesity [Andersen NH, Bojesen A,Kristensen K et al. Clin Endocrinol (Oxf) 2008; 69(5):785–91].

Hilgo Bruining (Ultrecht, The Netherlands):Your patients with KS were largely undetected because theyhad not been through a fertility screen, especially in thelower age cohort, and you implied that the undiagnosedcohort were unaffected in many ways. However, patientswith KS are at higher risk of developing certain morbiditiesboth before and after their diagnosis of KS. Can you extrap-olate from this the level of psychological or psychiatricaffectiveness? Do most men with KS live in isolationbecause of social difficulties?

Anders Bojesen:The hazard ratio for developing psychiatric disease is 5.10for patients before their diagnosis of KS and 3.03 forpatients with known KS, but I am not sure of the rele-vance of this. We have not performed any formal analysisbetween the two groups. There is an overlap in confidencelimits indicating that there might not be any significantdifference. It is possible that children with psychiatricconditions are at greater risk of being diagnosed as KSlater in life.

Hilgo Bruining:What is the marital status of your patients with KS? If allKS men were to marry, there would be a higher detectionrate because of infertility screening.

Anders Bojesen:I do not know what proportion of patients with KS remainsingle. A major proportion of all cases are diagnosedthrough infertility clinics, but there is a huge variation inphenotype. Those at the more severe end of the spectrumare more likely to be diagnosed.

Ronald Swerdloff:KS societies have support groups including a subgroup forthe gay population. Is there an indication in your registriesof male–male gender preference in the KS community incomparison to the general population? It is difficult totackle this problem because of biases in ascertainment.

Anders Bojesen:Such information is not recorded in our database.

Ronald Swerdloff:In relation to neurological and psychiatric disorders, thepatients with KS are known to have an increased rate ofexecutive dysfunction resulting in judgmental problemswith poor decision-making. They are more likely to get intodifficulties including substance abuse, which can causeadditional comorbidities.

Anders Bojesen:This may have a major role in the development of comor-bidities, but we have no information on this in our database.

Anders Juul:Studies in the UK and Denmark indicate that patients withKS are at increased risk of morbidity and mortality becauseof infections, but your table indicates that this significanceis lost in patients prior to their diagnosis of KS. If this is true,what is the mechanism for increased susceptibility toinfection?

Anders Bojesen:I can only speculate that the rate of infection might berelated to diabetes and raised plasma glucose levels. Wehave not performed immunological investigations.

Fred Wu (Manchester, UK):Parents of KS children often ask about the prevalence ofcriminality. Can you answer this from the Danish Registrystatistics?

Anders Bojesen:We have data on criminality in our statistics for patientswith KS in addition to XYY and XXX patients. These will bepublished later this year, and the figures are not suitable forpublication at this time.

Carole Samango-Sprouse (Washington DC, USA):Does your database include availability of special servicesfor young patients with KS? When they are diagnosed at thepaediatric stage, do you record if they receive speech oroccupational therapy? Is the diagnosis of psychiatric dis-ease made by psychiatrists or GPs?

Anders Bojesen:Data on special education and psychological treatment arenot recorded in our database. Our data are linked to diagno-ses made at somatic hospitals, and there are separate datafrom the psychiatric hospitals. Our psychiatric data are veryraw, and we are planning to obtain more robust informationso that we can make further analyses.

Martin Ritzen (Stockholm, Sweden):The Danish database of 850 patients with KS represents25% of all patients with KS in Denmark, and the Edinburghcohort of 3500 patients with KS represents 7.5% of allpatients with KS in the UK. Most cases remain undiag-nosed. There is a risk that patients with greater symptomsare diagnosed, but less severe cases are undiagnosed



resulting in a selected group with more adverse medicalevents, and a higher relative risk for all signs and symptoms.Can you sum up the spectrum of symptoms seen in patientswith KS which are likely to lead to a diagnosis. The medianage for diagnosis is 30, presumably for infertility. What leadsto the diagnosis in the younger population?

Anders Bojesen:When blood is submitted for karyotype examination for KS,the patient usually has symptoms that are being investi-gated. I plan to visit all the cytogenetic laboratories in Den-mark to identify the underlying indications for karyotypicanalysis.



Documents

Morbidity and mortality in Klinefelter syndrome (47,XXY)