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High Risk of Venous Thromboembolism in Klinefelter Syndrome

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Background: Klinefelter syndrome (KS) is the most common sex chromosome disorder. The genetic background is the extra X chromosome. Venous thromboembolism (VTE) has been observed among KS patients. The aim of the present study was to examine whether KS is associated with VTE. Methods and results: We followed up all hospital in- and outpatients (N=1085) in Sweden with a diagnosis of KS between January 1, 1969, and December 31, 2010, for diagnosis of VTE. The reference population was the total male populace of Sweden. We calculated standardized incidence ratios for VTE, adjusted for age, sex, education, time period, and region of residence. The standardized incidence ratio for KS was 6.43 (95% CI 5.15-7.93), with the highest ratio observed at young age. The standardized incidence ratios for VTE were 12.10 (95% CI 6.22-21.21) before age 30 years, 11.00 (95% CI 7.86-14.99) between ages 30 and 49 years, 4.83 (95% CI 3.23-6.95) between ages 50 and 69 years, and 2.07 (95% CI 0.74-4.53) for ages ≥70 years. The cumulative incidence of VTE for KS patients was 8.6% at age 50 years and 20.8% at age 70 years. Conclusions: KS is associated with high risk of VTE. KS could be considered a genetic hypercoagulable state. This has clinical implications for the prevention and diagnosis of VTE among patients with KS.
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High Risk of Venous Thromboembolism in Klinefelter Syndrome
Bengt Z
oller, MD, PhD;* Jianguang Ji, MD, PhD;* Jan Sundquist, MD, PhD; Kristina Sundquist, MD, PhD
Background-Klinefelter syndrome (KS) is the most common sex chromosome disorder. The genetic background is the extra X
chromosome. Venous thromboembolism (VTE) has been observed among KS patients. The aim of the present study was to
examine whether KS is associated with VTE.
Methods and Results-We followed up all hospital in- and outpatients (N=1085) in Sweden with a diagnosis of KS between
January 1, 1969, and December 31, 2010, for diagnosis of VTE. The reference population was the total male populace of Sweden.
We calculated standardized incidence ratios for VTE, adjuste d for age, sex, education, time period, and region of residence. The
standardized incidence ratio for KS was 6.43 (95% CI 5.157.93), with the highest ratio observed at young age. The standardized
incidence ratios for VTE were 12.10 (95% CI 6.2221.21) before age 30 years, 11.00 (95% CI 7.8614.99) between ages 30 and
49 years, 4.83 (95% CI 3.236.95) between ages 50 and 69 years, and 2.07 (95% CI 0.744.53) for ages 70 years. The
cumulative incidence of VTE for KS patients was 8.6% at age 50 years and 20.8% at age 70 years.
Conclusions-KS is associated with high risk of VTE. KS could be considered a genetic hypercoagulable state. This has clinical
implications for the prevention and diagnosis of VTE among patients with KS. ( J Am Heart Assoc. 2016;5:e003567 doi:
10.1161/JAHA.116.003567)
Key Words: embolism epidemiology genetics risk factors thrombosis
K
linefelter syndrome (KS) is one of the most common
chromosomal disorders and occurs in 1:500 to 1:1000
newborn male infants.
13
KS, also known as 47,XXY, is the set
of symptoms that result from 2 X chromosomes in male
persons. Gene dosage effects of the supernumerary X
chromosome determine the clinical picture of KS.
3,4
The
primary features are hypogonadism and sterility.
13
Symp-
toms are often subtle; only 25% of male persons with KS are
diagnosed. Symptoms are someti mes more prominent and
may include greater than average height, learning disabilities,
less body hair, gynecomastia, and lack of libido. KS is often
accompanied by other disturbances such as epilepsy, varicose
veins, osteoporosis, abdominal obesity, metabolic syndrome,
glucose intolerance, and type 2 diabetes mellitus.
13
Venous
thromboembolism (VTE) has also been described in a number
of case reports.
57
In a cohort study of cau se-specic
mortality in 3518 KS patients, 8 cases of fatal pulmonary
embolism were observed.
8
The authors estimated a standard-
ized mortality rate of 5.7 (95% CI 2.511.3).
8
In another series
of 412 patients with KS, 11 were affected by deep venous
thrombosis.
9
The incidence of deep venous thrombosis was
22.8 cases per 10 000 patient-years at risk. In the same
study, 8 KS patients had pulmonary embolism. The frequency
of pulmonary embolism was 16 cases per 10 000 patient-
years at risk.
9
Although these previous studies suggested an
increased preponderance of VTE in KS patients, few VTE cases
have been reported. It remains to be conrmed in a larger
number of cases whether or not KS is a risk factor for VTE.
We hypothesized that KS may increase the risk of VTE. In
this nationwide follow-up stu dy, the risk of VTE in patients
with KS was analyzed with the aim of determining whether KS
is associated with VTE. The study used data from the total
Swedish male population linked to the Swedish Hospital
Register.
Methods
This study was approved by the ethics committee of Lund
University, Sweden. The ethics committee waived informed
consent as a requirement. Data used in this study repre-
sented information on all persons registere d as residents of
Sweden between 1969 and 2010. It included individual-level
From the Center for Primary Health Care Research, Lund University, Malm
o,
Sweden.
*Dr Z
oller and Dr Ji contributed equally to this work.
Correspondence to: Bengt Z
oller, MD, PhD, Center for Primary Health Care
Research, Clinical Research Center, Floor 11, Building 28, Entrance 72,
Malm
o University Hospital, S-205 02 Malm
o, Sweden. E-mail:
bengt.zoller@med.lu.se
Received March 15, 2016; accepted April 8, 2016.
ª 2016 The Authors. Published on behalf of the American Heart Association,
Inc., by Wiley Blackwell. This is an open access article under the terms of the
Creative Commons Attribution-NonCommercial License, which permits use,
distribution and reproduction in any medium, provided the original work is
properly cited and is not used for commercial purposes.
DOI: 10.1161/JAHA.116.003567 Journal of the American Heart Association 1
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information on age, sex, socioeconomic occupational status,
geographic region of residence, hospital and outpatient
diagnoses, dates of hospital admissions, date of emigration,
and date and cause of death. The data sources were multiple
national Swedish data registers including the Swedish
National Population and Housing Census, the Total Population
Register, and the Swedish Hospital Register (the Hospital
Discharge Register and the Hospital Outpatient Register).
1014
These registers were provided to us by Statistics Sweden and
the National Board of Health and Welfare. Using the Swedish
Hospital Register, we identied hospital inpatients and
outpatients with diagnoses of KS in Sweden between January
1, 1969, and December 31, 2010. Data were linked using the
individual personal identication numbers that are assigned to
all persons in Sweden for their lifetimes. These numbers were
replaced with serial numbers to maintain anonymity. The
serial numbers were used to check that each person was
entered only once for his or her rst diagnosis of VTE
diagnosis (in- or outpatient and death registers). The follow-up
period ran from January 1, 1969, until a VTE event, death,
emigration, or the end of follow-up on December 31, 2010,
whichever came rst. This register does not include data for
hospital outpatients or patients treated at primary health care
centers. Because KS is inborn, diagnosis of KS anytime during
follow-up was taken into account.
Outcome Variables and Ascertainment of Cases
Cases of VTE, classied according to the World Health
Organization International Classication of Diseases (ICD),
8th, 9th, and 10th revisions, were identied in the Hospital
Discharge Register and the Hospital Outpatient Register 2001
2010 (Table 1). Only main diagnoses of VTE were considered to
ensure high validity and to include mainly primary and not
secondary VTE cases. The Swedish Hospital Discharge Registe r
has nearly 90% overall validity or positive predictive values.
10,14
The positive predictive value for cardiovascular disorders such
as VTE, myoc ardial infarction, and stroke is 90% to
95%.
10,14,15
In a Swedish study of male per sons with VTE,
hospital records were available for 304 cases (19701998).
15
A total of 289 of 304 cases (95%) of diagnosed VTE were judged
to be diagnosed correctly.
15
Only 12 cases (3.9%) were not
diagnosed with an objectively veried method but were treated
with oral anticoagulation because of strong clinical probability.
In total, 277 cases (91%) were objectively diagnosed with
methods such as phlebography, ultrasound, computed tomog-
raphy scan, and pulmonary scintigraphy.
15
The Hospital
Outpatient Register has not been validated previously for
VTE. Sultan et al recently found that 43% of pregnant VTE
patients rst recorded as outpatient were not accompanied by
anticoagulant prescriptions, whereas this proportion was much
lower than those patients rst recorded in the inpatient register
(9%). Moreover, for cases of nonspecic thrombophlebitis
diagnoses, 25% had evidence of glucosaminoglycan polysulfate
(C05BA01) prescriptions. We also used ATC (Anatomical
Therapeutic Chemical) codes for anticoagulant drugs to
validate the entire outpatient and inpatient registers with
prescription of anticoagulant drugs after VTE diagnosis (B.
Z
oller, MD, PhD, H. Ohlsson, PhD, J. Sundquist, MD, PhD, and K.
Sundquist, MD, PhD, unpublished data, 2016); however, the
prescription register is available only from July 2005. The
positive predictive value for inpatient diagnosis of VTE was
similar to published data by Rosengren et al and Sultan et al
(unpublished data).
15,16
An outpatient diagnosis of VTE had less
validity, similar to Sultan et al,
16
but the presence of a VTE
diagnosis on 2 occasions in outpatients was associated with
high positive predictive value (ie, anticoagulant prescription),
similar to what was observed in the study by Rosengren et al
(unpublished data).
15
Consequently, we classied only outpa-
tient diagnosis of VTE if diagnosis had occurred 2 times for
outpatients, whereas 1 event of VTE for inpatients was enough
to be classied as VTE.
Main Predictor Variable
KS patients were identied from the Swedish Hospital
Register (in- and outpatients) by ICD-8 (759.51, 310.53,
311.53, 312.53, 313.53, 314.53, and 315.53), ICD-9 (758H),
Table 1. Venous Thromboembolism Manifestations in Klinefelter Syndrome Patients
International Classication of Diseases codes
Venous Thrombo embolism in
Klinefelter Syndrome Patients, n (%)8th Revision 9th Revision 10th Revision
Cerebral vein thrombosis 321 437G I63.6, I67.6 0 (0)
Venous thrombosis of the lower extremities 451 451 I80 37 (43)
Portal vein thrombosis 452 452 I81 0 (0)
Other venous embolism or thrombosis 453 453 I82 27 (31)*
Pulmonary embolism 450 415B, 416W I26 23 (26)
All venous thromboembolism 87 (100)
*One case was thrombophlebitis migrans, and 26 cases were in an unspecied vein.
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and ICD-10 (Q98.0, Q91.1, Q98.2, and Q98.4) codes (main or
secondary diagnosis). We did not have access to the mode of
diagnosis, but in Sweden, chromosomal testing is a clinical
routine when KS is suspected (Stefan Arver, personal
communication, 2013).
17,18
Adjustment Variables
Adjustments were made for sex, age, education, time period
(allowing adjustment for changes in incidence over time), and
geographic region of residence. Geographic region of residence
was included to adjust for possible regional differences in hospital
admissions and was categorized as (1) large cities, (2) southern
Sweden, and (3) northern Sweden. Large cities were dened as
municipalities with populations >200 000 and comprised the 3
largest cities in Sweden: Stockholm, Gothenburg, and Malm
o.
Education was used as a proxy for socioeconomic status.
Education was classied as completion of compulsory school or
less (9 years), of practical high school (1011 years), or of
theoretical high school and/or college (12 years).
Statistical Analysis
Person-years at risk (ie, number of persons at risk
multiplied by time at risk) were calculated from the time
at which participants were included in the study un til rst
hospitalization for VTE, death, emigration, or th e end of the
study period. Age-adjusted incidence rates based on the
European standard popu lation for the year 2000 were
calculated for the whole follow-up period. Person-years for
patients with KS were calcu lated from birth (if born after
1969) or from the start of the follow-up period (if born
before 1969). The expected number of cases was based on
the number of cases in the reference group (ie, all Swedish
male persons without KS). Standardized incidence ratios
(SIRs) were calculated as the ratio of observed and
expected numbers of VTE cases, using the indirect
standardization method:
19
SIR ¼
P
J
j¼1
o
j
P
J
j¼1
n
j
k
j
¼
O
E
O=
P
o
j
denotes the total observed number of cases in the
study group; E*, the expected number of cases, is calculated
by applying stratum-specic standard incidence rates (k
j
)
obtained from the reference group to the stratum-specic
person-years (n
j
) of risk for the study group; o
j
represents the
observed number of cases that the cohort participants
contributed to the jth stratum; and J represents the strata
dened by cross-classication of the different adjustm ent
Figure. Cumulative incidence of venous thromboembolism (VTE) among patients with Klinefelter
syndrome (KS) and the male population in Sweden. The cumulative incidence for the general population
at ages 50, 55, 60, 65, and 70 years was 0.63%, 0.85%, 1.23%, 1.72%, and 2.83%, respectively; for KS
patients, the cumulative incidence was 8.6%, 9.3%, 12.8%, 14.9%, and 20.8%, respectively.
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variables of age, sex, time period , education, and geographic
region of residence.
Sensitivity Analysis
The risk of VTE with determination of SIRs before and after
diagnosis of KS was estimated to determine whether the
diagnosis of KS affected the risk of VTE. A sensitivity analysis
was also done with inclusion of all VTE outpatients (even
those diagnosed only once).
Cumulative 5-year incidence rates were calculated by
lifetest in SAS (SAS Institute). The data were transferred to
Excel (Microsoft), and Figure was created in Excel.
The 95% CIs were calculated assuming a Poisson distribu-
tion. All analyses were performed using SAS version 9.2 (SAS
Institute).
Results
Table 1 shows the different manifestations of VTE in KS patients.
In total, 646 (60%) of all 1085 KS patients were diagnosed in the
outpatient register. The remaining 439 KS patients were diag-
nosed in the inpatient register. Table 2 shows characteristics for
all KS patients in Sweden. The median age for diagnosis was
33 years. Most KS patients were diagnosed during the period
20002010. Total person-years of follow-up was 35 171 person-
years for KS patients (not shown). The incidence rate was 340.0
per 100 000 person-years for KS patients and 60.5 per 100
000 person-years for the general population, according to the
European standard population in 2000.
Risk of VTE for KS Patients
Table 3 shows the adjusted SIR results for VTE risk of KS
patients. The SIR was highest in KS patients aged <30 years and
declined with age. Young patients with KS had higher SIRs than
older patients (aged <30 years, SIR 12.10; aged 70 years, SIR
2.07). The overall risk of both pulmonary embolism (SIR 6.56)
and deep venous thrombosis (SIR 5.57) were similarly
increased. Figure shows the cumulative incidence for KS
patients and the general male population. Cumulative incidence
for the general male population by ages 50, 55, 60, 65, and 70
years was 0.63%, 0.85%, 1.23%, 1.72%, and 2.83%, respectively;
for KS patients, the cumulative incidence was 8.6%, 9.3%,
12.8%, 14.9%, and 20.8%, respectively.
Sensitivity Analysis
The risk of VTE was assessed before and after diagnosis of KS
(Table 4). The VTE risk was increased both >1 year before
and >1 year after diagnosis of KS, although the risk was
highest within 1 year before and after diagnosis of KS.
A sensitivity analysis was done with inclusion of all VTE
outpatients (ie, even those who were diagnosed only once).
The risk of VTE was 6.25 (95% CI 5.087.61, n=99).
Discussion
This study showed a very high risk of VTE in KS patients. An
especially high risk at young age was observed. Our study is in
line with previous research
59
; however, the present study
showed that the thrombotic risk in KS patients is comparable
to inherited thrombophilias.
20
Consequently, KS is equivalent
to inherited thrombophilias such as factor V Leiden and the
prothrombin G20210A mutations with regard to VTE risk.
20
The estima ted prevalen ce in the po pulation of KS (1:500 to
1:1000 newborn male infants) is similar to the prevalence of
deciencies of antithrombin, protein C, and protein S.
20
This
Table 2. Patients With Klinefelter Syndrome in Sweden
Subtype No. %
Total 1085 100.0
Age at diagnosis, y
09 109 10.0
1019 168 15.5
2029 183 16.9
30 625 57.6
Median 33
Year of diagnosis
19691979 146 13.5
19801989 109 10.0
19901999 112 10.3
20002010 718 66.2
Median 2003
Year of birth
Before 1950 267 24.6
19501959 142 13.1
19601969 200 18.4
19701979 202 18.6
19801989 130 12.0
19901999 99 9.1
After 2000 45 4.1
Median 1966
Years of education
09 372 34.3
1011 296 27.3
12 280 25.8
Unknown 137 12.6
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has important clinical implications for the prevention and
diagnosis of VTE among patients with KS. Most important, the
risk was increased before diagnosis of KS, indicating that any
treatment for KS such as testosterone may not explain the
association between KS and VTE.
The mechanism of the association between VTE and KS is
unclear but may be multifactorial. The increased VTE risk may be
related to X-linked gene dosage as a contributing factor for
disease susceptibility.
14
The factor VIII gene, for example, is
localized to the X chromosome. Increased factor VIII levels were
observed in a KS patient with VTE and may contribute to increased
VTE risk and thus warrant further investigation.
21
Other possible
mechanisms are abdominal adiposity, metabolic syndrome,
diabetes, and systemic lupus erythematosus, all of which have
been associated with KS and could affect the risk of VTE.
14
The present study has a number of stre ngths. These
include nationwide coverage in a country with high medical
standards and surveillance by the Swedish National Board of
Health and Welfare, together with inpatient diagnoses of
patients by specialist physicians during examinations in
clinics. Data in the Swedish registers are almost complete.
In 2001, personal numbers were missing for only 0.4 % of
hospitalizations, and main diagnoses were missing for 0.9% of
hospitalizations.
11
A limitation is that we did not have access to individual-
level data for weight, smoking, blood pressure, karyotyping or
other blood tests, and estimated alcohol consumption;
however, we adjusted for education level, which is related
to several lifestyle factors. The observed increased throm-
boembolic risk reported in KS can be wor sened by the
coexistence of 1 well-known thrombophilic conditions (eg,
mutations in factor V [FV Leiden] and prothrombin). Because
KS often remains undiagnosed,
14
our sample contain s only
those who received chromosomal testing, which in Sweden is
a clinical routine if KS is suspected (Stefan Arver, personal
communication, 2013).
17,18
Undiagnosed persons with KS
may not experience VTE to the same extent as the identied
KS patients. In fact, our observed incidence rate for VTE
(340.2 per 100 000 person years) among KS patients is
similar to a UK case series of 412 KS patients in which the
incidence rate was 388 per 100 000 person-years (160 per
100 000 person-years for pulmonary embolism and 228 per
100 000 person-years for deep venous thrombosis).
9
Although associations could be weaker in a completely
representative sample, we believe that the large sample size
and the robust associations observed indicate a relationship
between KS and VTE. Furthermor e, it is possible that KS
patients are more likely to receive VTE diagnoses because
they already have 1 condition and thus have more contact
with health care (ascertainment bias). In our sample, however,
VTE risk was highly increased both before and after diagnosis
of KS. A bias is suggested within 1 year of diagnosis of KS
because VTE risk was highest during this period; however, this
did not affect the overall VTE risk over the whole follow-up
Table 3. Risk of Venous Thromboembolism in Patients With Klinefelter Syndrome
Age at
Diagnosis, y
Venous Thromboembolism Deep Venous Thrombosis Pulmonary Embolism
Observed
Standardized
Incidence Ratio 95% CI Observed
Standardized
Incidence Ratio 95% CI Observed
Standardized
Incidence Ratio 95% CI
<30 12 12.10* 6.2221.21 6 14.64* 5.2732.07 1 5.19 0.0029.77
3049 40 11.00* 7.8614.99 20 11.59* 7.0717.94 11 12.46* 6.1822.37
5069 29 4.83* 3.236.95 8 3.29* 1.406.51 9 4.78* 2.179.11
70 6 2.07 0.744.53 3 2.80 0.538.28 2 1.71 0.166.30
All 87 6.43* 5.157.93 37 6.56* 4.629.05 23 5.57* 3.538.38
Adjustments were made for sex, age, education, time period (allowing adjustment for changes in incidence over time), and geographic region of residence.
*P<0.05.
Table 4. Risk of Venous Thromboembolism in Patients With Klinefelter Syndrome by Time of Diagnosis
Date of Diagnosis Venous
Thromboembolism Related
to Klinefelter Syndrome
Venous Thromboembolism Deep Venous Thrombosis Pulmonary Embolism
Observed
Standardized
Incidence Ratio 95% CI Observed
Standardized
Incidence Ratio 95% CI Observed
Standardized
Incidence Ratio 95% CI
1 year before 26 6.6* 4.31 9.68 12 8.26* 4.2514.48 4 4.11* 1.07 10.63
Within 1 year 18 12.85* 7.620.35 4 6.83* 1.7817.65 6 13.67* 4.9229.95
After 1 year 43 5.68* 4.11 7.65 21 6.36* 3.939.74 13 5.13* 2.728.79
Adjustments were made for sex, age, education, time period (allowing adjustment for changes in incidence over time), and geographic region of residence.
*P<0.05.
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period. Consequently, we do not believe that ascertainment
bias explains the magnitude of the associations to any major
degree. Moreover, 646 KS patients (6 0%) were diagnosed in
the outpatient register; therefore, using the hospital inpatient
register would result in underestim ation of the VTE risk.
In conclusion, KS is associated with high risk for VTE. KS
could be considered to be a genetic hypercoagulable state.
This has clinical implications for the prevention and diagnosis
of VTE among patients with KS.
Acknowledgments
We thank Patrick Reilly for his useful comments on the text. The
registers used in the present study are maintained by Statistics
Sweden and the National Board of Health and Welfare.
Sources of Funding
This work was supported by grants awarded to Dr Z
oller by
the Swedish Heart-Lung Foundation, to Z
oller and Dr Kristina
Sundquist by the Swedish Research Council, and to Dr Jan
Sundquist by the Swedish Council for Working Life and Social
Research and the Swedish Freemasons Foundation, as well as
by ALF funding from Region Sk
ane awarded to Drs Z
oller,
Kristina Sundquist, and Jan Sundquist.
Disclosures
None.
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Klinefelter Syndrome and Venous Thromboembolism Z
oller et al
ORIGINAL RESEARCH
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Bengt Zöller, Jianguang Ji, Jan Sundquist and Kristina Sundquist
High Risk of Venous Thromboembolism in Klinefelter Syndrome
Online ISSN: 2047-9980
Dallas, TX 75231
is published by the American Heart Association, 7272 Greenville Avenue,Journal of the American Heart AssociationThe
doi: 10.1161/JAHA.116.003567
2016;5:e003567; originally published May 20, 2016;J Am Heart Assoc.
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... The pathogenesis of MMA in KS could be attributed to a thrombophilic milieu, caused by diverse mechanisms such as gene polymorphisms [11,12], arteriosclerosis due to low testosterone to estrogen ratio [13,14], increased plasminogen activator inhibitor-1 [11,13,14], persistent endothelial dysfunction [9], testosterone replacement therapy [15] or primary antiphospholipid antibody syndrome [16,17]. However, these explanations are unlikely in our case as no abnormalities were detected in the relevant thrombophilia panel and the patient was not on testosterone supplementation before a diagnosis of MMA. ...
... The pathogenesis of MMA in KS could be attributed to a thrombophilic milieu, caused by diverse mechanisms such as gene polymorphisms [11,12], arteriosclerosis due to low testosterone to estrogen ratio [13,14], increased plasminogen activator inhibitor-1 [11,13,14], persistent endothelial dysfunction [9], testosterone replacement therapy [15] or primary antiphospholipid antibody syndrome [16,17]. However, these explanations are unlikely in our case as no abnormalities were detected in the relevant thrombophilia panel and the patient was not on testosterone supplementation before a diagnosis of MMA. ...
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Moyamoya angiopathy, a rare cerebrovascular condition, can be primary (moyamoya disease) or secondary (moyamoya syndrome). Genetic factors such as the ring finger protein 213 (RNF213) have been associated with moyamoya disease. However, X-linked moyamoya angiopathy/moyamoya syndrome and hypergonadotropic hypogonadism associated with moyamoya syndrome are rare. We report a case of a 14-year-old boy who presented with transient alternating bilateral hemiparesis, recurrent seizures and cognitive decline. He previously had surgery for left-sided cryptorchidism and had been diagnosed with “epileptic attacks” or “functional movement disorders” in previous hospital admissions. Laboratory investigations and karyotyping revealed a diagnosis of Klinefelter syndrome. This case presents a unique association of moyamoya angiopathy and Klinefelter syndrome in a boy from a poor socio-economic background, where the diagnosis and adequate treatment were delayed due to a lack of awareness and expertise.
... The risk of venous thromboembolism (VTE) among men born with Klinefelter syndrome (KS, 47,XXY) overall is increased more than four-fold (1,2,3). In particular, the relative risk of VTE in KS compared with the background population in younger ages is elevated more than tenfold, and men with KS have a lifetime cumulative risk of VTE of around 20% (3,4). The background for this massive excessive risk of VTE in men with KS is not clear. ...
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Objective: Klinefelter syndrome (KS) is associated with increased risk of thrombosis. Hypogonadism and accumulating body fat in KS have a potential impact on fibrinolysis. We assessed the fibrinolytic system and the association with testosterone levels in KS. Design: Cross-sectional comparison of men with KS and age-matched male controls. Methods: Fibrin clot lysis was evaluated by turbidity measurements and by measuring levels of individual fibrinolytic proteins in plasma samples. Total testosterone was measured by liquid chromatography tandem mass spectrometry. Body fat was evaluated by dual-energy X-ray absorptiometry. Results: Forty-five men with KS and 45 age and education matched controls were included. Men with KS had a 24 % reduction in fibrin clot lysis compared with controls (46.2 ± 17.1 versus 60.6 ± 18.8 %/h, p=0.0003), and higher levels of fibrinogen, factor XIII (p≤0.01) and plasminogen activator inhibitor type 1 (p=0.04). Men with KS had lower total testosterone (p=0.008) and higher body fat (p=0.001). In KS, reduced fibrin clot lysability was associated with higher higher fibrinogen and body fat related to decreasing total testosterone and hypogonadism among men with KS. Conclusions: Fibrin clot lysis in KS was markedly reduced, potentially contributing to a prothrombotic state and increased thrombotic risk. Hypogonadism in KS was associated with increased fibrinogen and total body fat, predicting reduced fibrin clot lysis.
... In particolare, si ritiene necessaria la valutazione cardiologica e del profilo metabolico annualmente e un trattamento adeguato in tutti i pazienti con KS, se necessario. La mortalità cardiovascolare è più alta in questa popolazione e questo è solitamente correlato ad anomalie della valvola aortica, embolie polmonari, malattia vascolare periferica e trombosi venosa profonda (si raccomanda, pertanto, la profilassi della trombosi prima dei voli a lungo termine) [11,12]. ...
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Sommario Le conoscenze sulla sindrome di Klinefelter (KS) sono aumentate notevolmente dalla sua prima descrizione circa 80 anni fa. Tuttavia, il tasso diagnostico è ancora basso in relazione alla prevalenza. L’obiettivo di questa rassegna è quello di fornire gli strumenti diagnostici e terapeutici per la gestione dei pazienti con KS. Le caratteristiche cliniche sono molto variabili tra i soggetti con KS, sebbene le più comuni siano la grave compromissione della spermatogenesi e l’ipofunzione delle cellule di Leydig, con conseguente azoospermia e ipogonadismo ipergonadotropo. Inoltre, sono stati descritti diversi fenotipi neurocognitivi e psicosociali, così come una maggiore prevalenza di eventi avversi cardiovascolari, metabolici e correlati alla salute dell’osso che potrebbero spiegare l’incremento della mortalità osservato nella KS. Un’adeguata conoscenza e la corretta gestione clinico-diagnostica e terapeutica può incidere positivamente sulla qualità di vita dei pazienti KS.
... Indeed, testosterone is known to affect the immune system (34). Interestingly, a high prevalence of venous thromboembolic complications has been documented in Klinefelter Syndrome (35), characterized by genetically low testosterone and often accompanied by abdominal adiposity and metabolic syndrome. It could well be that the relation between low testosterone and secondary outcome is mediated by changes in vascular hemostasis and thrombosis. ...
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Aims: Low plasma testosterone levels have been shown to predict worse outcome in men with severe atherosclerotic disease. We hypothesized that a low plasma testosterone level affects disease risk through changes in gene expression in atherosclerotic plaques. Therefore, we studied plasma testosterone levels in relation to gene expression levels in atherosclerotic plaque tissue of men with advanced atherosclerotic disease. Methods: Plasma testosterone levels were measured in 203 men undergoing carotid endarterectomy. The corresponding atherosclerotic plaque tissue was used for RNA sequencing. First, we assessed how often the androgen receptor gene was expressed in the plaque. Second, correlations between plasma testosterone levels and pre-selected testosterone-sensitive genes were assessed. Finally, differences within the RNA expression profile of the plaque as a whole, characterized into gene regulatory networks and at individual gene level were assessed in relation to testosterone levels. Results: Testosterone plasma levels were low with a median of 11.6 nmol/L (IQR: 8.6–13.8). RNA-seq of the plaque resulted in reliable expression data for 18,850 genes to be analyzed. Within the RNA seq data, the androgen-receptor gene was expressed in 189 out of 203 (93%) atherosclerotic plaques of men undergoing carotid endarterectomy. The androgen receptor gene expression was not associated with testosterone plasma levels. There were no significant differences in gene expression of atherosclerotic plaques between different endogenous testosterone levels. This remained true for known testosterone-sensitive genes, the complete transcriptomic profile, male-specific gene co-expression modules as well as for individual genes. Conclusion: In men with severe atherosclerotic disease the androgen receptor is highly expressed in plaque tissue. However, plasma testosterone levels were neither associated with pre-selected testosterone sensitive genes, gene expression profiles nor gene regulatory networks in late-stage atherosclerotic plaques. The effect of testosterone on gene expression of the late-stage atherosclerotic plaque appears limited, suggesting that alternate mechanisms explain its effect on clinical outcomes.
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Purpose The study aimed to systematically ascertain male sex chromosome abnormalities, 47,XXY (Klinefelter syndrome [KS]) and 47,XYY, and characterize their risks of adverse health outcomes. Methods We analyzed genotyping array or exome sequence data in 207,067 men of European ancestry aged 40 to 70 years from the UK Biobank and related these to extensive routine health record data. Results Only 49 of 213 (23%) of men whom we identified with KS and only 1 of 143 (0.7%) with 47,XYY had a diagnosis of abnormal karyotype on their medical records or self-report. We observed expected associations for KS with reproductive dysfunction (late puberty: risk ratio [RR] = 2.7; childlessness: RR = 4.2; testosterone concentration: RR = –3.8 nmol/L, all P < 2 × 10–8), whereas XYY men appeared to have normal reproductive function. Despite this difference, we identified several higher disease risks shared across both KS and 47,XYY, including type 2 diabetes (RR = 3.0 and 2.6, respectively), venous thrombosis (RR = 6.4 and 7.4, respectively), pulmonary embolism (RR = 3.3 and 3.7, respectively), and chronic obstructive pulmonary disease (RR = 4.4 and 4.6, respectively) (all P < 7 × 10–6). Conclusion KS and 47,XYY were mostly unrecognized but conferred substantially higher risks for metabolic, vascular, and respiratory diseases, which were only partially explained by higher levels of body mass index, deprivation, and smoking.
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Objective Previous studies have suggested a higher prevalence of Klinefelter syndrome amongst transgender individuals. We undertook a systematic review to determine the prevalence of Klinefelter syndrome amongst transgender individuals presumed male at birth and summarise the clinical features and potential treatment implications for individuals with Klinefelter syndrome commencing gender-affirming hormone therapy. Design Using preferred reporting items for systematic review and meta-analysis guidelines, we searched EMBASE, MEDLINE and the Cochrane Central Register of Controlled Trials (CENTRAL) up to December 31, 2021. All studies reporting on the prevalence or clinical features of transgender individuals with Klinefelter syndrome were included. This study is registered with the International Prospective Register of Systematic Reviews, number CRD42021227916. Results Our search strategy retrieved 11 cohort studies comprising 1376 transgender individuals. In all, 14 of 1376 (1.02%) individuals were diagnosed with Klinefelter syndrome. Based on the 7 studies in which karyotype was undertaken in all individuals, the prevalence is 9/1013 (0.88%; 95% CI, 0.41%-1.68%). Case reports highlight unique treatment considerations in this population, including azoospermia, venous thromboembolism, and monitoring of breast cancer and bone health. Conclusions Compared to the general population, observational studies document a higher prevalence of Klinefelter syndrome amongst transgender individuals, though underdiagnosis in the general population limits conclusions. Routine karyotype in transgender people initiating gender-affirming hormone therapy is not supported unless clinical features of Klinefelter syndrome, such as small testicular volume, or hypergonadotropic hypogonadism are present. Transgender individuals with Klinefelter syndrome need to manage a unique risk profile if they desire feminising gender-affirming hormone therapy.
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Klinefelter syndrome is a form of male hypogonadism due to testicular sclerohyalinosis with atrophy and azoospermia, which is the most common cause of male infertility. The syndrome is usually accompanied by metabolic, morphological, and neurobehavioral manifestations; Venous thromboembolic diseases such as deep vein thrombosis and pulmonary embolism. The existence of chronic thromboembolic pulmonary hypertension in patients with Klinefelter syndrome is scarce in the literature. We present the imaging and genetic analysis of a 37 -year-old male with a history of deep vein thrombosis who was admitted for exertional dyspnea.
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Context Experimental studies on Klinefelter syndrome (KS) reported increased intratesticular testosterone (T) levels coexisting with reduced circulating levels. Abnormalities in testicular microcirculation have been claimed; however, no studies investigated in vivo testicular blood flow dynamics in humans with KS. Objective To analyze the testicular microcirculation in KS by contrast-enhanced ultrasonography (CEUS) and correlate vascular parameters with endocrine function. Design and Setting Prospective study. University Setting. Patients 68 testicular scans, 34 testes from 19 T-naïve subjects with KS and 34 testes from age-matched eugonadal men (CNT) who underwent CEUS for incidental nonpalpable testicular lesions. Main Outcomes. CEUS kinetic parameters. Results CEUS revealed slower testicular perfusion kinetics in subjects with KS than in age-matched CNT. Specifically, the wash-in time (Tin, p = 0.018), mean transit time (MTT, p = 0.035), time to peak (TTP, p < 0.001), and washout time (Tout 50%, p = 0.004) were all prolonged. Faster testicular blood flow was associated with higher total T levels. Principal component analysis and multiple linear regression analyses confirmed the findings, and supported a role for reduced venous blood flow as independent predictor of total T levels. Conclusions Testicular venous blood flow is altered in KS and independently predicts T peripheral release.
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Context: Recently, new clinically important information regarding Klinefelter syndrome (KS) has been published. We review aspects of epidemiology, endocrinology, metabolism, body composition, and neuropsychology with reference to recent genetic discoveries. Evidence acquisition: PubMed was searched for "Klinefelter," "Klinefelter's," and "XXY" in titles and abstracts. Relevant papers were obtained and reviewed, as well as other articles selected by the authors. Evidence synthesis: KS is the most common sex chromosome disorder in males, affecting one in 660 men. The genetic background is the extra X-chromosome, which may be inherited from either parent. Most genes from the extra X undergo inactivation, but some escape and serve as the putative genetic cause of the syndrome. KS is severely underdiagnosed or is diagnosed late in life, roughly 25% are diagnosed, and the mean age of diagnosis is in the mid-30s. KS is associated with an increased morbidity resulting in loss of approximately 2 yr in life span with an increased mortality from many different diseases. The key findings in KS are small testes, hypergonadotropic hypogonadism, and cognitive impairment. The hypogonadism may lead to changes in body composition and a risk of developing metabolic syndrome and type 2 diabetes. The cognitive impairment is mainly in the area of language processing. Boys with KS are often in need of speech therapy, and many suffer from learning disability and may benefit from special education. Medical treatment is mainly testosterone replacement therapy to alleviate acute and long-term consequences of hypogonadism as well as treating or preventing the frequent comorbidity. Conclusions: More emphasis should be placed on increasing the rate of diagnosis and generating evidence for timing and dose of testosterone replacement. Treatment of KS should be a multidisciplinary task including pediatricians, speech therapists, general practitioners, psychologists, infertility specialists, urologists, and endocrinologists.
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The Swedish National Inpatient Register (IPR), also called the Hospital Discharge Register, is a principal source of data for numerous research projects. The IPR is part of the National Patient Register. The Swedish IPR was launched in 1964 (psychiatric diagnoses from 1973) but complete coverage did not begin until 1987. Currently, more than 99% of all somatic (including surgery) and psychiatric hospital discharges are registered in the IPR. A previous validation of the IPR by the National Board of Health and Welfare showed that 85-95% of all diagnoses in the IPR are valid. The current paper describes the history, structure, coverage and quality of the Swedish IPR. In January 2010, we searched the medical databases, Medline and HighWire, using the search algorithm "validat* (inpatient or hospital discharge) Sweden". We also contacted 218 members of the Swedish Society of Epidemiology and an additional 201 medical researchers to identify papers that had validated the IPR. In total, 132 papers were reviewed. The positive predictive value (PPV) was found to differ between diagnoses in the IPR, but is generally 85-95%. In conclusion, the validity of the Swedish IPR is high for many but not all diagnoses. The long follow-up makes the register particularly suitable for large-scale population-based research, but for certain research areas the use of other health registers, such as the Swedish Cancer Register, may be more suitable.
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The Klinefelter syndrome (KS), with an incidence of 1 to 2 per 1000 male neonates, is one of the most frequent congenital chromosome disorders. The 47,XXY karyotype causes infertility, testosterone deficiency and a spectrum of further symptoms and comorbidities. In recent years, significant progress has been made in the elucidation of the pathophysiology and the treatment of the KS. It became clear that, to a large extent, the clinical picture is determined by gene dosage effects of the supernumerary X-chromosome. The origin of the extra X-chromosome from either the father or the mother influences behavioural features of patients with KS. The CAGn polymorphism of the androgen receptor, located on the X-chromosome, has a distinct impact on the KS phenotype. KS predisposes to the metabolic syndrome and its cardiovascular sequelae, contributing to the increased mortality of patients with KS. Neuroimaging studies have correlated anomalies in brain structures with psychosocial problems. The unexpected possibility to produce pregnancies and live birth with either ejaculated sperm - about 8% of KS men have a few sperm in semen - or with sperm extracted from individual tubules obtained by testicular biopsy can be considered a breakthrough. Testosterone substitution requires further optimisation in terms of when to initiate therapy and which preparations and dosages to use. Recently developed animal models help to further elucidation the genetic and pathopysiological basis and may lead to new therapeutic approaches to KS.
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Schizophrenia, bipolar disorder, autism spectrum disorders and ADHD might be overrepresented in Klinefelter syndrome, but previous investigations have yielded inconclusive results. We compared a national sample of 860 Klinefelter patients in Sweden with 86 000 matched population controls. To assess the risks of schizophrenia, bipolar disorder, autism spectrum disorder and ADHD in Klinefelter patients, we estimated odds ratios and 95% confidence intervals using conditional logistic regressions. Klinefelter patients had almost four times higher risks of schizophrenia, odds ratio (OR) = 3.6, 95% confidence interval (CI) 2.0-6.7 and bipolar disorder (OR = 3.8, CI 1.8-7.6) and about six times higher risk of autism spectrum disorder (OR = 6.2, CI 4.0-9.4) and ADHD (OR = 5.6, CI 4.0-7.8). The risk of psychosis, autism and ADHD is increased in Klinefelter patients. These findings indicate an X chromosome-related factor in the etiology of the studied psychiatric disorders, and may also have implications for treatment of patients with Klinefelter syndrome.
Article
Klinefelter syndrome (KS) with the karyotype 47,XXY is one of the commonest types of congenital chromosomal disorder in males, with an incidence of 0.1% to 0.2% of newborn male infants. It causes hypogonadism and infertility. Until now, however, only about one-quarter of all persons with KS received the diagnosis during their lifetimes. Selective review of the literature. KS is caused by aneuploidy of the sex chromosomes. Small, firm testes, the manifestations of androgen deficiency (sparse development of male-pattern body hair, greater than average height, lack of libido, erectile dysfunction) and, in more than 90% of affected men, azoospermia are its main features in adults. Affected boys may have verbalization difficulties and problems with learning and socialization. KS is often accompanied by other disturbances such as gynecomastia, varicose veins, thrombosis, osteoporosis, the metabolic syndrome, type 2 diabetes, and epilepsy. The most important therapeutic measure is testosterone supplementation, which should be initiated if the testosterone concentration drops below 12 nmol/L and should be given as directed in the guidelines for the treatment of hypogonadism. This recommendation is made even though there have not been any randomized controlled trials documenting the efficacy of testosterone therapy in adolescents or young adults. In some cases, viable sperm can be obtained from individual testicular tubules by biopsy, so that these patients are able to become fathers. The diagnosis of KS would be less frequently missed if doctors were more aware of, and attentive to, its key manifestations, particularly the small, firm testes, erectile dysfunction, and the comorbidities mentioned above. If the diagnosis were made more often, patients would more often be able to receive early treatment, which would improve their quality of life.
Chapter
Routine data are data collected continuously or at least repeatedly with some time intervals. They could be collected in various ways, e.g. registration by the health services or by interviews with patients or population groups. For epidemiological purposes, it is necessary that the disease cases collected can be related to a specified population base, thus providing the ability to calculate different epidemiological measures as incidence, prevalence etc. The data could then be stored and administered in registers. Health data or disease registers are restricted to persons with diseases or health-related events. The coverage can vary from a total registration to a sample of the population and from national to regional coverage. Data can be routinely collected for various reasons, from economic and administrative purposes to more strict epidemiological purposes.