Heart, Lung and Circulation (2014) 23, 1149–1152

1443-9506/04/$36.00

http://dx.doi.org/10.1016/j.hlc.2014.07.056

ORIGINAL ARTICLE

Klinefelter Syndrome w

ith Fabry Disease – a Case of Nondisjunction of theX-chromosome with Sex-linked RecessiveMutation

Victoria J. Sadick, BAppSc(Hons) a, Michael J. Fietz, PhDb,Michel C. Tchan, MBBS, PhD c, Pramesh Kovoor, MBBS, PhDd,Liza Thomas, MBBS, PhD e, Norman Sadick, MBBS, PhDd,f*

aFaculty of Medicine, Dentistry and Health Science, University of Western Australia, Perth, AustraliabDepartment of Chemical Pathology, Women’s and Children’s Hospital, North Adelaide, SA, AustraliacDepartment of Genetic Medicine, Westmead Hospital, and Western Clinical School, University of Sydney, NSW, AustraliadDepartment of Cardiology, Westmead Hospital, Westmead NSW, AustraliaeDepartment of Cardiology Liverpool Hospital, Liverpool and UNSW, South Western Sydney Clinical School, NSW, AustraliafDepartment of Cardiology, Blacktown Hospital and University of Western Sydney, NSW, Australia

Received 1 April 2014; received in revised form 30 June 2014; accepted 6 July 2014;

online published-ahead-of-print 16 July 2014

A 52 year-old male with Klinefelter syndrome presented with chest tightness and rapid atrial fibrillation

with hypotension. His echocardiogram demonstrated symmetrical left ventricular hypertrophy with mini-

mal diastolic dysfunction. Subsequent investigations confirmed the diagnosis of Fabry cardiomyopathy.

This is the first reported case of Klinefelter syndrome with homozygous sex-linked recessive mutation

presenting primarily with cardiac manifestation.

Keywords Klinefelter syndrome � Nondisjunction of the X-chromosome � Fabry disease � Cardiomyopathy� Homozygous sex-linked recessive mutation.

IntroductionKlinefelter syndrome (KS) is caused by a supernumerary X

chromosome in males with an estimated prevalence of about

1 in 600 newborns and is one of the most frequent genetic

causes of male infertility [1]. Fabry disease is one of more

than 40 lysosomal storage diseases and is caused by muta-

tions of the GLA gene located on the X chromosome. Alpha-

galactosidase A is the gene product of the GLA gene. The

incidence of classical Fabry disease has been estimated at 1 in

40,000 to 117,000 [2]. The clinical and cardiac manifestations

of Fabry disease are well described by Desnick et al [3] and

O’Mahony & Elliott [4].

X-linked recessive disorders have rarely been described

in patients with coexisting Klinefelter syndrome; examples

© 2014 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) a

Inc. All rights reserved.

*Corresponding author at: 9 Hereward Highway, Blacktown NSW Australia 2148. T

include Alport syndrome, Duchenne muscular dystrophy

and X-linked lymphoproliferative disease [5–7]. There are

also cases where Klinefelter males have been diagnosed

with X-linked dominant and ordinarily male-lethal disor-

ders such as Rett syndrome and incontinentia pigmenti

[8,9].

Case HistoryA 52 year-old male presented with chest tightness and rapid

atrial fibrillation (AF) with hypotension. Sinus rhythm was

restored with cardioversion. The ECG showed left ventricu-

lar hypertrophy (LVH) with strain pattern (Figure 1). His

only medication on admission was testosterone 1000 mg

injection every three months. There was no past history of

any cardiac problem.

nd the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier

el.: +(02) 9831 2888; fax: +(02) 9831 6903, Email: normansadick@gmail.com

Figure 1 12 leads ECG.

1150 V.J. Sadick et al.

The patient was diagnosed with Klinefelter syndrome at

39 years of age following investigations for infertility. The

patient could not provide any documentation of his diagno-

sis and his past medical records were not available.

His father died of a myocardial infarction and his mother

died of a brain tumour. He was the youngest of three siblings.

The eldest brother was receiving fortnightly treatment for a

heart condition at a regional hospital in NSW and was

reportedly infertile. The second brother was well and had

refused any medical assessment. Details about his brother’s

cardiac condition were not available on admission.

Clinical examination revealed gynaecomastia with abdom-

inal obesity and small testicles. His blood pressure was nor-

mal. A late crescendo systolic murmur was noted in the mitral

area. The initial working diagnosis was Klinefelter syndrome

with unexplained LVH with mitral valve prolapse.

InvestigationsHis echocardiogram showed concentric LVH of 17 mm in both

the septal and posterior walls. The aortic valve was tricuspid

and normal. There was late mild mitral regurgitation. The left

ventricular systolic function was normal and the left atrium

(LA) was mildly enlarged. The E’ on tissue Doppler was

decreased (3cm/s). There was no left ventricular outflow

gradient or systolic anterior motion of the mitral leaflet.

A scrotal ultrasound revealed that his right testicle mea-

sured 8 x 8 x 7 mm and the left testicle measured 11 x 10 x

7 mm (normal 20-30 cm3). Cytogenetic study confirmed an

XXY karotype (Figure 2). His routine plasma sodium, potas-

sium and creatinine were all within normal limits. His

24-hour urinary collection revealed urinary protein of

0.13gm/day (normal 0.02-0.15). High sensitivity Troponin

T was 131 ng/L (normal <14) on admission and fell to

93 ng/L on the following morning.

Further history was obtained following the echocardio-

graphic findings. The patient gave a history of hypohydrosis

and a distal lancing neuropathic pain from the age of 10 to 18

years of age, which he had slowly outgrown. He complained

of some tinnitus in the left ear and had a long history of

abdominal pain with diarrhoea after meals. The patient’s

symptoms together with a family history of cardiac disease,

LVH and early diastolic dysfunction were suggestive of

Fabry disease.

In view of the raised Troponin level a coronary angiogram

with right ventricular biopsy was performed. The coronary

angiogram showed no significant epicardial lesions. The

haematoxylin and eosin stain of the right ventricular biopsy

showed extensive vacuolation of the myocytes. Electron

microscopy demonstrated several myelin bodies with a

dense lamellated appearance within these myocytes, sugges-

tive of Fabry disease. The leucocyte alpha-galactosidase A

level was 0.04 nmol/min/mg of protein (normal 0.7-3.3)

confirming the diagnosis.

Subsequent mutation analysis demonstrated the presence

of a single nucleotide change in exon 4 of the GLA gene

(c.640-859C>T) which is predicted to introduce a novel accep-

tor splice site. The patient was shown to be homozygous for

the mutation. Subsequently we were able to confirm that his

brother with the known heart condition was hemizygous for

the same mutation.

The patient was kept on his three-monthly injection of

testosterone. Sotalol 40 mg twice daily was commenced in

hospital after his cardioversion. The patient had two further

episodes of atrial fibrillation in the first two months after

Figure 2 Karyotype confirming Klinefelter syndrome.

Klinefelter with Fabry disease 1151

discharge which required further cardioversions. Fortnightly

enzyme replacement therapy was commenced and he has

remained free of atrial fibrillation.

DiscussionThis is the first documented case of Klinefelter syndrome

with mutation in the GLA gene causing symptomatic Fabry

disease with predominant cardiac manifestation.

About 3% of patients with hypertrophic cardiomyopathy

(HCM) have been reported to have Fabry disease [10]. It is

important to differentiate HCM for which there is no definitive

treatment from other infiltrative cardiomyopathies such as

Fabry disease where enzyme replacement therapy is available.

Patients with Fabry disease, especially those with LVH may

complain of angina. Diffuse arteriopathy affects the endothe-

lium, intima, and adventitia of blood vessels. Critical epicar-

dial coronary stenosis is however uncommon [4]. The rise in

high sensitivity troponin T in our patient with LVH was likely

the result of an imbalance between coronary supply and

demand during rapid atrial fibrillation. His persantin sesta-

mibi scan showed no evidence of reversible ischaemia.

Atrial fibrillation has been documented to occur in 17%

and ventricular arrthymias in 8% of patients with Fabry

cardiomyopathy [4]. Anticoagulation should always be con-

sidered in patients with atrial fibrillation, while the preferred

treatment for rate control in AF is Sotalol. Amiodarone has

the potential to interfere with the already abnormal lyso-

somal metabolism and should be avoided as a first-line

antiarrhythmic [11].

Ventricular tachycardia has also been reported to occur in

patients with Fabry cardiomyopathy and has been treated

with implantable defibrillator. It is not known if enzyme

replacement therapy will decrease or prevent the recurrence

of atrial or ventricular fibrillation in patients with Fabry

cardiomyopathy.

In male patients with normal XY karyotype, a low level of

alpha-galactosidase A is diagnostic of Fabry disease whereas

in heterozygous females the level of alpha-galactosidase A

can vary from low to within the normal range due to random

inactivation of the X chromosome. Mutation analysis is

required to confirm the diagnosis in females. If this patient

with two X chromosomes was heterozygous for a Fabry

disease mutation, one might have expected an intermediate

level of alpha-galactosidase A activity. The very low level of

alpha- galactosidase A in this case suggested a homozygote

state which was confirmed on subsequent mutation analysis.

Klinefelter syndrome is the most common sex-chromo-

some abnormality in males. Eighty percent of KS males have

karyotype 47,XXY and 20% have higher grade chromosome

aneuploides [1]. Infertility occurs in 91-99% of patients with

KS [12]. Patients with Fabry disease are generally fertile. Less

well known is that infertility has been recently well docu-

mented in patients with Fabry disease with a normal XY

karyotype. A case report has documented oligospermia in

two patients with Fabry disease where no other cause was

identified [13].

Nondisjunction of the X chromosome during meiosis I or II

is the cause of Klinefelter syndrome. Harvey et al. [14] dem-

onstrated that in 39 cases of Klinefelter syndrome of maternal

origin, nondisjunction occurred in 72% from an error in

1152 V.J. Sadick et al.

meiosis I and 28% from an error in meiosis II. As our patient

was homozygous for the GLA mutation, nondisjunction must

have occurred during meiosis II as paired chromosome dis-

joining in meiosis I results in heterozygous aneuploidy.

ConclusionIn conclusion, the diagnosis of Fabry disease in this patient

with Klinefelter syndrome (karyotype XXY) with mainly

cardiac manifestation was based on his symptoms, cardiac

biopsy and subsequent confirmation of a very low level of

alpha-galactosidase A activity in the range observed for

males hemizygous for a Fabry disease mutation. Subsequent

mutation studies confirmed this patient with Klinefelter syn-

drome was homozygous for a single X-linked recessive muta-

tion in the GLA gene.

AcknowledgmentsThere was no external financial support

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