Serious venous thromboembolism, heterozygous factor V Leiden and prothrombin G20210A mutations in a patient with Klinefelter syndrome and type 2 diabetes.
ABSTRACT Klinefelter's syndrome (KS) is a common cause of man infertility characterized by small testes, gynecomastia and hypogonadism. Deep vein thrombosis and thomboembolic events are frequent in these patients. Hormone imbalance and co-existent mutations in the coagulation system may be the primary factors in this hypercoagulable state. The increased thromboembolic risk in hypogonadic men has been explained by hypofibrinolysis due to androgen deficiency. Regarding the association between KS and congenital and acquired thrombophilias, to date, only three cases have been. Here, we present the youngest KS case with pulmonary thromboembolism with the heterozygous mutations in factor V Leiden and prothrombin genes, as detected by further tests. He had the previous diagnosis of diabetes mellitus and body mass index was 30 kg/m(2). Our report discusses the prothrombotic state in KS patients, with other possible causes for the young presentation and the importance of necessary tests in emergency service admissions with embolism.
[show abstract] [hide abstract]
ABSTRACT: The clinical features of patients with Klinefelter's syndrome attending a male infertility clinic have been investigated in order to consider their assisted reproduction treatment options. Over 12 years, a total of 148 patients with sterility due to azoospermia had Klinefelter's syndrome. Eight patients were shown by fluorescence in-situ hybridization (FISH) on metaphase spreads to be mosaic (46,XY/47,XXY), and 140 patients showed only 47,XXY. Small testes were observed in 95% of patients and gynaecomastia was seen in 12.4%. Half of the patients showed hypergonadotrophic hypogonadism, while others showed normogonadism (usually hypergonadotrophic). Spermatozoa were observed in semen from one patient with mosaicism and one without. Three-colour FISH revealed hyperploidy in 2.7% and 2.3% of these spermatozoa respectively. Multiple-site testicular biopsies in five recent patients were performed and yielded a specimen with round and elongated spermatids in one patient with 47,XXY karyotype. This sample was cryopreserved for future intracytoplasmic sperm injection. At follow-up, 46% of couples had chosen artificial insemination with donor sperm, and none had chosen adoption. Two patients developed testicular tumours, one a mature teratoma and the other a Leydig cell tumour. Two patients required androgen replacement therapy.Human Reproduction 05/1999; 14(4):946-52. · 4.47 Impact Factor
[show abstract] [hide abstract]
ABSTRACT: The objective of this study was to describe the prevalence of Klinefelter syndrome (KS) prenatally and postnatally in Denmark and determine the influence of maternal age. All chromosomal examinations in Denmark are registered in the Danish Cytogenetic Central Registry. Individuals with KS diagnosed prenatally or postnatally were extracted from the registry with information about age at the time of diagnosis and mother's age. In the period 1970-2000, 76,526 prenatal examinations on male fetuses resulted in the diagnosis of 163 fetuses with KS karyotype, corresponding to a prevalence of 213 per 100,000 male fetuses. Standardization according to maternal age resulted in a prevalence of 153 per 100,000 males. Postnatally, 696 males of 2,480,858 live born were diagnosed with KS, corresponding to a prevalence among adult men of approximately 40 per 100,000. Less than 10% of the expected number was diagnosed before puberty. Advanced maternal age had a significant impact on the prevalence. KS is severely underJ.Clin.Endocrinol.Metab. 88(2):622-626.
Article: 47,XXY (Klinefelter syndrome) and 47,XYY: estimated rates of and indication for postnatal diagnosis with implications for prenatal counselling.[show abstract] [hide abstract]
ABSTRACT: Cytogenetic surveys of neonates have found that approximately one boy in 500 is born with an extra sex chromosome. Some of these boys are now being diagnosed when prenatal karyotyping is done for the detection of Down syndrome and other major aneuploidies. This study estimates what proportion of those not detected prenatally will be diagnosed postnatally and what the indications for karyotyping are likely to be. We ascertained all 47,XXY and 47,XYY males detected prenatally and postnatally (during the 4 years 1990-1993) in the three cytogenetic laboratories in the North Thames (West) region. The age at diagnosis and indication for karyotyping were noted for cases diagnosed postnatally. Less than 10 per cent of the estimated number of affected fetuses were detected prenatally. This study suggests that most males born with these chromosome patterns will go through life without being karyotyped, that the commonest indication for a 47,XYY male to be karyotyped will be developmental delay and/or behaviour problems, and that the commonest indication for a Klinefelter male to be karyotyped will be hypogonadism and/or infertility. It would appear that most undiagnosed 47,XXY and 47,XYY males do not look or behave in a manner which prompts testing for a chromosome abnormality.Prenatal Diagnosis 05/1997; 17(4):363-8. · 2.11 Impact Factor
□ CASE REPORT □
Serious Venous Thromboembolism, Heterozygous Factor V
Leiden and Prothrombin G20210A Mutations in a Patient
with Klinefelter Syndrome and Type 2 Diabetes
Meltem Ayli1and Sibel Ertek
Klinefelter’s syndrome (KS) is a common cause of man infertility characterized by small testes, gyneco-
mastia and hypogonadism. Deep vein thrombosis and thomboembolic events are frequent in these patients.
Hormone imbalance and co-existent mutations in the coagulation system may be the primary factors in this
hypercoagulable state. The increased thromboembolic risk in hypogonadic men has been explained by hypofi-
brinolysis due to androgen deficiency. Regarding the association between KS and congenital and acquired
thrombophilias, to date, only three cases have been. Here, we present the youngest KS case with pulmonary
thromboembolism with the heterozygous mutations in factor V Leiden and prothrombin genes, as detected by
further tests. He had the previous diagnosis of diabetes mellitus and body mass index was 30 kg/m2. Our re-
port discusses the prothrombotic state in KS patients, with other possible causes for the young presentation
and the importance of necessary tests in emergency service admissions with embolism.
Key words: Klinefelter, XXY, factor V Leiden, prothrombin G20210A, diabetes, venous thromboembolism
(Inter Med 48: 1681-1685, 2009)
Klinefelter syndrome (KS) which is first described by
Klinefelter et al in 1942, is a common cause of man infertil-
ity characterized by small testes, gynecomastia, and hypogo-
nadism with high levels of follicle stimulating hormone. It is
genetically defined as the presence of extra X chromosome
(47, XXY) with prevalence of one in 500 to 1,000
man (1, 2). Non-disjunction of the paternal sex chromo-
somes or maternal meiotic error is the defined reason for
this chromosomalanomaly (2). Although
karyotype is 47, XXY there are some variant forms (like 48,
XXYY or 48, XXXY) and mosaic forms (for example 46
XY/ 47 XXY mosaicism) (3, 4). Leydig cell dysfunction is
manifested as small testes (<4 cm3), azospermia, and infertil-
ity in puberty and only approximately 25% of cases are di-
agnosed, most of them are diagnosed in adulthood (5, 6).
Venous thromboembolism risk is reported to be moderately
increased in KS due to decreased androgen and increased
estrogen levels. This can be partly explained by the reverse
relationship between PAI-1 and testosterone levels (7, 8) and
the prothrombotic effect of estrogens even at low levels (9).
An analysis of 412 KS patients over a period of 1 to 20
years, revealed that the deep-vein thrombosis risk is 22.8
cases per 10,000 patient-years at risk, and the pulmonary
embolism risk 16 cases/10,000 patient-years (10). Despite
some rare thrombophilic disorders in this syndrome (11, 12)
to date in the medical literature there are three cases of ve-
nous thromboembolism in KS. The case of Depaire-Duclos
et al presented a 62 year-old case with heterozygous Factor
V Leiden mutation (13). Ranganath and colleagues de-
scribed a 60-year-old man with antiphospholipid syn-
drome (14) and Lapecorella et al discussed a 39-year-old
man with heterozygosis mutations in both factor V Leiden
and prothrombin G20210A (15).
１Department of Hematology, Ufuk University Faculty of Medicine, Ankara, Turkey and
Ufuk University Faculty of Medicine, Ankara, Turkey
Received for publication December 25, 2008; Accepted for publication June 2, 2009
Correspondence to Dr. Sibel Ertek, firstname.lastname@example.org
２Department of Endocrinology and Metabolic Diseases,
Inter Med 48: 1681-1685, 2009 DOI: 10.2169/internalmedicine.48.1985
Tests: Results: Normal range:
Factor VIII……………...150.0 %..............................................50-150%
Protein C………………. 120.0%...............................................70-140 %
Total Protein S………… 98.7 %.................................................55.0-160 %
Free Protein S…………..77.1 %.................................................70-120 %
Antithrombin III….. ….. 100%.................................................70-121 %
Lupus anticoagulant……negative……………………………. negative.
Anticardiolipin IgG…. <2.0 GPL U/mL…………………….<11.0 GPL U/mL
Anticardiolipin IgM… <2.0 GPL U/mL…………………….<10.0 GPL U/mL
PAI-1 plasma concentration……………………………………6.3 IU/mL
Factor V G1691A……..Genotype: mutation in one allele/ Normal
Prothrombin G20210A..Genotype. mutation in one allele/ Normal
MTHFR C677T……….Genotype: Normal/ Normal
T a b l e 1 . C o a g u l a t i o n P a r a me t e r s a n d G e n e t i c A n a l y s e s
A 26-year-old man patient came to our emergency depart-
ment with sudden swelling and pain in his right leg. In his
medical history, he had a diagnosis of Klinefelter’s syn-
drome with 47 XXY karyotype and diabetes mellitus. He
was not a smoker. There was no family history of venous
thromboembolism. He had been using metformin 850 mg
three times a day and rosiglitazone 4 mg/day with the diag-
nosis of type 2 diabetes mellitus for 5 years; his body mass
index was 30 kg/m2. Since he had a 38℃ fever he was hos-
pitalized. Within three hours of his hospitalization he devel-
oped a non-productive cough, severe pain localized to the
right hemithorax, and hemoptysis. On Doppler ultra-
sonographic evaluation in his lower extremity there was
acute and early subacute thrombosis in popliteal and distal
crural veins, and chronic thrombosis in the superficial femo-
ral vein, and insufficiency in the great saphenous vein below
the knee level. In pulmonary tomography and angiography,
the left main pulmonary artery, superior lobe and apico-
posterior segment branches, lingual, lower lobe and lower
lobe posterior-lateral basal segment branches, on right the
lower lobe superior, posterior and lateral basal segmental ar-
teries revealed filling defects relevant to pulmonary venous
thromboembolism. D-dimer level on admission was 1,538
ng/mL (Normal range: 0-500 ng/mL), arterial blood pH was
7.46, pCO2: 32.6 mmHg and pO2 : 81.0 mmHg with oxygen
saturation of 97.4%. The patient had the diagnosis of deep
vein thrombosis and pulmonary thromboembolism, and anti-
coagulant therapy was started with intravenous continuous
infusion of non-fractioned heparin for the first 10 days
alone, later oral anticoagulation was added targeting INR
(International Normalized Ratio) values of between 2.0-3.0
and long-term anticoagulation with oral anticoagulants was
His blood glucose level on admission was 135 mg/dL
(two hours after lunch) (postprandial), and the glycemic
control during his hospitalisation was good and his glycohe-
moglobin level was 6.2%.
Hormone and coagulation related laboratory analyses
were performed before anticoagulation. His testosterone and
free testosterone levels were lower and gonadotropins were
increased as expected (Table 1). Coagulation test, plasma
Factor VIII, protein C, protein S and antithrombin III levels,
lupus anticoagulant, fibrinolytic parameters, and G1691A
mutation for Factor V gene, G20210A mutation for
prothrombin gene and C677T mutation for MTHFR (m-
tetrahydrofolate reducetase) gene were analyzed (Table 2).
The patient was a heterozygote for both factor V G1691A
with polymerase chain reaction and prothrombin G20210A
mutations with restriction fragment length polymorphism
analysis, without any mutation for MTHFR. Coagulation
tests, Factor VIII, antithrombin , protein C, protein S activ-
ity and levels and fibrinolytic parameters were normal. Lu-
pus anticoagulant was negative. PAI-1 level, analyzed with a
chromogenic assay kit for plasminogen activator inhibitor
type (SpectrolyseⓇ/pL PAI), was within normal limits.
His lipid levels were also checked and his low density
Inter Med 48: 1681-1685, 2009DOI: 10.2169/internalmedicine.48.1985
Tests: Results Normal range for men:
Testosterone……………………… …1.20 ……………… 2.80-8.00 ng/dL
Free testosterone………………… …2.80…………… 5.60-19 pg/dL
FSH……………………………… …4.41…………… 0.50-2.41U/L
LH………………………………… ……17.……….. 1.00-11.40mIU/mL
FSH: Follicle stimulating hormone, LH: Luteinizing hormone.
T a b l e 2 . H o r mo n a l T e s t s
lipoprotein (LDL) cholesterol level was 98 mg/dL, high den-
sity lipoprotein cholesterol (HDL) was 52 mg/dL and tri-
glyceride was 111 mg/dL, indicating the absence of any
type of dyslipidemia. Transthoracic echocardiography re-
vealed neither thrombus formation, nor dilatation of any
heart chambers, without valvulopathy.
Patients with Klinefelter syndrome are observed to be
more likely to have problems related to the coagulation sys-
tem, leading to thromboembolism or leg ulcers (10). The
most common hereditary disorders of coagulation are defi-
ciencies of antithrombin III, protein C, protein S, and muta-
tions in factor V Leiden, but also dysfibrinogenemia, in-
creased plasminogen activator inhibitor levels, and deficien-
cies of tissue plasminogen activator or heparin cofactor II,
homocystinuria may be found (16). However, the underlying
mechanisms are not clearly explained, it is possible to theo-
rize that increased platelet aggregability and defective fibri-
nolysis due to hormone imbalance or accompanying genetic
mutations are responsible (17); this relationship was already
reported twenty years ago (18). Elevated levels of PAI-1 are
thought to be responsible in most KS patients with leg ul-
cers, but later studies have shown that it may only be partly
responsible and there are likely some additional unknown
causes (19, 20). In the present case PAI-1 levels were nor-
mal, hyperestrogenism, hyperhomocysteinemia and hypofi-
brinolysis were not present. Together with detected muta-
tions, these findings also support the role of genetic muta-
tions in severe thromboembolism in our case.
The present case is similar to that presented by Lape-
corella et al, with the same heterozygous mutations in factor
V Leiden and prothrombin and these mutations explain the
hypercoagulant state in these two cases (15). The present
case is 15 years younger than the other case with the same
presentation. The co-existence of diabetes may be the reason
of earlier massive embolism, although the glycemic control
of the patient was favourable.
Diabetes mellitus is suggested to be associated with co-
agulation system changes, such as impaired fibrinolysis, hy-
perlipidemia, increased platelet reactivity and different per-
oxisome proliferator-activated receptor (PPAR) polymor-
phisms (21) may lead to thrombogenic tendency. Although
diabetes with hyperosmolar state and ketoacidosis were re-
ported with an increased risk of venous embolism (22, 23),
in the study of Petrauskiene et al, 302 patients were evalu-
ated and the diabetic patients revealed a two-fold higher risk
for venous thromboembolism even though they did not have
any acute hyperosmolar or ketoacidosis states (24). But the
data in the literature is conflicting, for example in the pro-
spective evaluation of 5,522 patients of HOPE-2 patients in-
cluding 2,209 diabetics, none of the metabolic syndrome
components were found to be related with venous throm-
boembolism risk (25). Obesity is another important risk fac-
tor for venous thromboembolism (26). Circulating procoagu-
lant microparticles which are the fragments from the plasma
membrane have been claimed to be responsible for the in-
creased venous embolism risk (27).
Thus, according to recent studies, atherosclerosis and ve-
nous thromboembolism share some common risk factors
such as age, diabetes, obesity and hyperlipidemia, metabolic
syndrome, the association and its clinical importance is not
clear (28). Also in the study of Linnemann et al, diabetes,
obesity, smoking and hypercholesterolemia were not found
to be related to venous thromboemolism recurrence (29).
But in the last meta-analysis, venous embolism was in-
creased 1.42 times in diabetes and 2.33 in obesity (30).
Considering the present case with a shorter duration of dia-
betes and acceptable glycemic control, the presence of dia-
betes may be a weaker factor but obesity may contribute
more to his procoagulant state.
The incidence of metabolic syndrome and diabetes is high
in KS patients (31) and it is a frequent cause of mortality
and morbidity (32). Hypogonadism may be the cause of un-
favourable change in body composition and the imbalance
between testosterone and its metabolite dihydrotestosterone
may cause insulin resistance (33).
In the medical literature there is another young case of
admission of to the emergency department with pulmonary
embolism, having the diagnosis of pulmonary embolism to-
gether with patent foramen ovale thrombosis (34); they sug-
Inter Med 48: 1681-1685, 2009DOI: 10.2169/internalmedicine.48.1985
gested the use of transesophageal echocardiography (TEE)
for cardiovascularly unstable patients and complex cases. In
transthoracic way, and on physical examination cardiac
evaluation was normal without any murmur, and cardiovas-
cular parameters were stable. Thus TEE was not needed.
But in KS patients with unstable vital signs, the high possi-
bility of valvulopathies and intracardiac thrombi should be
considered (34, 35).
It is known that the co-existence of mutations in factor V
Leiden and prothrombin cause a higher risk of recurrent
thromboembolic events when compared with the carriers of
each mutation alone (36). The prevalence of MTHFR
C677T mutation is also frequent with differing degrees in
different populations and the presence of mutations in all
three (factor V Leiden, prothrombin and MTHFR) is not
low (37, 38); the prevalence of prothrombin G20210A and
Factor V Leiden mutations in white Europeans are 1-3% and
3-7%, respectively (39). Thus, it should be investigated to-
gether with other mutations in hypercoagulable patients.
In conclusion, with the presentation of this patient we
would like to emphasize the hypercoagulable state in the KS
patient group, and that lifelong oral anticoagulant therapy
should be planned in thromboembolic patients who are car-
riers of factor V Leiden and prothrombin gene mutations, as
in the present patient.
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