Morbidity and mortality in Klinefelter syndrome (47,XXY)Anders Bojesen (firstname.lastname@example.org)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@example.com
Received31 August 2010; revised 16 January 2011;accepted 14 March 2011.
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 Klinefeltersyndrome 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(35). 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 (610).
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 fromthemedical textbook. Thus, epidemiologymay help us to dis-criminate betweenwhatmay be true associations (andwhereclinicians 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 Pdiatrica ISSN 08035253
2011 The Author(s)/Acta Pdiatrica 2011 Foundation Acta Pdiatrica 2011 100, pp. 807813 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 period19641990 adding up to a total of approximately 55 000boys from around the world (1219), 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 in
mind 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 significantly
increased all-cause standard mortality rate (SMR) of 1.5(95% CI, 1.41.7), which is absolutely comparable to theresult from our study, showing a hazard ratio of 1.40 (95%CI, 1.131.74) 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% CI1.01.4, p = 0.13), but significantly increased risk of dyingfrom breast cancer, SMR 57.8 (18.8135.0), lung cancer,SMR 1.5 (1.02.0) and non-Hodgkin lymphoma, SMR 3.5(1.66.6), but a significantly reduced risk of dying fromprostate cancer, SMR 0.0 (0.00.7). 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: 1.541.86).The complete list of diagnoses where KS was admitted
significantly 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 the
diagnosis 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 help
us to confirm results from clinical studies or vice versa.
Morbidity and mortality in KS Bojesen and Gravholt
808 2011 The Author(s)/Acta Pdiatrica 2011 Foundation Acta Pdiatrica 2011 100, pp. 807813
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 (2931) 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 (1.348.66)].The risk of dying from breast cancer in the British study
was increased 60-fold, corroborating previous findings froma casecontrol 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
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 (1.41.7) 124 1.4 (1.131.74)
Infectious and parasitic diseases NI 6 3.95 (1.2512.5)
Malignant neoplasms 99 1.2 (1.01.4) 28 1.10 (0.721.68)
Endocrine, metabolic and nutritional disorders 20 4.8 (2.97.4) 10 1.8 (0.833.92)
Diabetes mellitus 17 5.8 (3.49.3) 7 1.64 (0.664.07)
Mental disorders 14 3.7 (2.06.2) 17 1.45 (0.812.55)
Diseases of the nervous system 15 2.8 (1.64.6) 7 3.62 (1.2410.5)
Epilepsy 8 7.2 (3.114.1) NI
Diseases of the circulatory system 163 1.3 (1.11.5) 39 1.41 (1.031.93)
Ischaemic heart disease 60 0.7 (0.50.9) NI
Pulmonary embolism 8 5.7 (2.511.3) NI
Other heart disease 16 2.2 (1.33.6) NI
Aortic valve disease 2 2.0 (0.27.2) NI
Cerebrovascular disease 46 2.2 (1.63.0) NI
Subarachnoid haemorrhage 6 3.1 (1.26.8) NI
Peripheral vascular disease 6 7.9 (2.917.2) NI
Diseases of the respiratory system 65 2.3 (1.82.9) 36 2.97 (1.884.71)
Pneumonia 25 2.3 (1.53.4) 18 2.25 (1.204.21)
Chronic lower respiratory disease
Chronic obstructive airway disease31 2.1 (1.43.0) 15 3.16 (1.516.59)
Diseases of the digestive system 19 1.6 (1.02.6) 9 1.31 (0.582.93)
Vascular insufficiency of the intestine 5 12.3 (4.028.8) 1 **
Disease of the genitourinary system 9 3.6 (1.66.8) 7 4.30 (1.4113.1)
Renal and ureteric disease 7 5.0 (2.010.3) NI
Congenital anomalies 9 7.3 (2.417.1) 21* 79.4 (10.6596)
Cardiovascular congenital anomalies 5 7.3 (2.417.1) NI
Accidents and violence 32 1.3 (0.91.8) 16 1.34 (0.762.36)
Fracture of bones 3 0.4 (0.11.3) NI
Fracture of femur 2 39.4 (4.8142.3) 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
2011 The Author(s)/Acta Pdiatrica 2011 Foundation Acta Pdiatrica 2011 100, pp. 807813 809
(3537), 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 not
the 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 genomic
imbalance, 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 (40,4...