CASE REPORT

Leg ulcers associated

with Klinefelter’s syndrome:
a case report and review
of the literature
Victoria K Shanmugam, Katina C Tsagaris, Christopher E Attinger

Shanmugam VK, Tsagaris KC, Attinger CE. Leg ulcers associated with Klinefelter’s syndrome: a case report and
review of the literature. Int Wound J 2011; doi: 10.1111/j.1742-481X.2011.00846.x

ABSTRACT
We present the case of a young man with type II diabetes, stage III chronic kidney disease, hypertension, obstructive
sleep apnea and diabetes who presented to the Georgetown University Hospital Center for Wound Healing with
refractory lower extremity ulcers. Autoimmune work-up was negative. However, chromosome analysis showed
a genetic variant of Klinefelter’s syndrome (48 XXYY). Lower extremity ulceration is a recognised complication
of Klinefelter’s syndrome. The pathogenesis of ulcers in this endocrinopathy is unclear, but associations with
abnormalities of fibrinolysis and prothrombotic states are reported. This case emphasises the importance of
considering Klinefelter’s syndrome in the differential diagnosis of a sterile male patient with non healing lower
extremity ulcers. Key Points
Key words: Fibrinolysis • Klinefelter’s syndrome • Leg ulcer • Prothrombotic
• a 38-year-old male was eval-
uated at the Georgetown Uni-
versity Center for Wound Heal-
CASE with a diagnosis of metabolic syndrome. The ing for bilateral lower extremity
ulcers that had been present for
A 38-year-old male was evaluated at the patient attributed the wound development to
4 years
Georgetown University Center for Wound obesity, lower extremity oedema and immobil- • three years prior to presentation
Healing for bilateral lower extremity ulcers ity. At the time of presentation, he had circum- he had been diagnosed with
that had been present for 4 years. Three years ferential ulcers on both legs below the knees. type II diabetes, but his disease
prior to presentation he had been diagnosed was well controlled
He experienced constant pain from the ulcers
• the patient attributed the
with type II diabetes, but his disease was well rated at 8 out of 10, which was present both at wound development to obesity,
controlled with a haemoglobin A1c of 5·9% rest and with ambulation. He did not have a lower extremity oedema and
(normal less than 7%). He also had a history of typical history of intermittent claudication, and immobility
stage III chronic kidney disease, hypertension, he denied prior thromboembolic disease. Treat- • at the time of presentation, he
obstructive sleep apnea and obesity consistent had circumferential ulcers on
ment with local wound care, including silver both legs below the knees
sulfadiazine cream and compression therapy, • he experienced constant pain
Authors: VK Shanmugam, MBBS, MRCP, Division of had been ineffective. from the ulcers rated at 8 out of
Rheumatology, Immunology and Allergy, Georgetown University The patient was single, lived with his mother 10, which was present both at
Hospital, 3800 Reservoir Road, NW, Washington, DC, USA; rest and with ambulation
and had a 30-pack-year smoking history. He
KC Tsagaris, DO, MPH, Department of Medicine, Georgetown • treatment with local wound
University Hospital, Washington, DC, USA; CE Attinger, MD,
had previously worked as a cashier and at the care, including silver sulfadi-
Center for Wound Healing, Georgetown University Hospital, time of evaluation was not working because azine cream and compression
Washington, DC, USA of disability. He experienced learning difficul- therapy, had been ineffective
Address for correspondence: Dr VK Shanmugam, MBBS, • he also reported progressing
ties during childhood and young adulthood.
MRCP, Division of Rheumatology, Immunology and Allergy, through puberty without erec-
He also reported progressing through puberty tions and without increased tes-
Georgetown University Hospital, 3800 Reservoir Road, NW,
Washington, DC, USA without erections and without increased testic- ticular size
E-mail: vks4@gunet.georgetown.edu ular size. He had never fathered a child.

© 2011 The Authors

© 2011 Blackwell Publishing Ltd and Medicalhelplines.com Inc • International Wound Journal • doi: 10.1111/j.1742-481X.2011.00846.x 1

Key Points
• on examination, the patient was
noted to have gynaecomas-
tia and bilateral small testes,
approximately 10 ml each (nor-
mal 12–25 ml)
• the patient was heterozygous
for the 4G/5G plasminogen acti-
vator inhibitor (PAI)-1 mutation
• androgen replacement therapy
was initiated with topical testos-
terone gel 50 mg applied to non
lesional skin daily
• this therapy resulted in 75%
reduction in ulcer size
2 © 2011 Blackwell Publishing Ltd and Medicalhelplines.com Inc
Leg Ulcers Associated with Klinefelter’s Syndrome
PHYSICAL EXAMINATION
On examination, the patient was 192-cm tall,
194 kg and his body mass index was 49·4.
Cardiovascular, pulmonary and abdominal
exams were unremarkable. However, he was
noted to have gynaecomastia and bilateral
small testes, approximately 10 ml each (normal
12–25 ml). Joint examination did not show
any active synovitis; however, there was
soft tissue overgrowth. Evaluation of the
lower extremities showed bilateral multiple
draining ulcers with a fibrogranular base on
anterior and medial lower legs (Figure 1).
The periwound skin was erythematous and
infiltrated consistent clinically with chronic
obesity lymphedematous mucinosis although
biopsy was not performed. There were no
varicosities, but the patient had 2+ pitting
oedema bilaterally. Dorsalis pedis pulses were
palpable bilaterally.
LABORATORY DATA
Laboratory evaluation showed normal com-
plete blood count. Fasting serum glucose was
85 mg/dl, and haemoglobin A1c was 5·9%
(normal less than 7%). Serum creatinine was
elevated at 2·7 mg/dl (normal 0·76–1·27 mg/
dl). His chronic renal insufficiency was attrib-
uted to longstanding hypertension and use of
non steroidal anti-inflammatory drugs.
Consistent with our protocol for patients
with non healing leg ulcers, this patient was
evaluated by rheumatology and haematology.
Autoimmune screen showed negative antin-
uclear antibody, negative double-stranded
DNA antibodies and negative extractable
nuclear antigen antibodies. Complement lev-
els were within normal limits. C-reactive
Figure 1. Appearance of right leg at presentation.
protein was elevated at 15·8 mg/l (normal
0–4·9 mg/l) and erythrocyte sedimentation
rate was 56 mm/hour (normal 0–15 mg/l).
Prothrombotic evaluation showed negative
prothrombin gene, methytetrahydrofolate re-
ductase mutation and factor V Leiden muta-
tion. Proteins C, S and antithrombin III
activities were normal. However, the patient
was heterozygous for the 4G/5G plasminogen
activator inhibitor (PAI)-1 mutation.
In view of the testicular atrophy, gynaeco-
mastia, and history of infertility, a chromoso-
mal analysis was performed and showed 48,
XXYY karyotype consistent with a diagnosis
of variant Klinefelter’s syndrome. Endocrine
evaluation showed a low testosterone of
141 ng/dl (normal 241–827 ng/dl), elevated
follicle-stimulating hormone at 40·9 mIU/ml
(normal 1·4–18·1 mIU/ml) and luteinising hor-
mone (LH) at 32·8 mIU/ml (normal 1·5–9·3
mIU/ml). Thyroid-stimulating hormone, pro-
lactin and insulin-like growth factor 1 were nor-
mal. These values suggest hypergonadotrophic
hypogonadism consistent with Klinefelter’s
syndrome. Testicular ultrasound showed bilat-
eral atrophic testes. Androgen replacement
therapy was initiated with topical testosterone
gel 50 mg applied to non lesional skin daily.
This therapy resulted in 75% reduction in ulcer
size (Figure 2).
DISCUSSION
The differential diagnosis of non healing lower
extremity ulcers is well documented else-
where, including venous stasis, peripheral
vascular disease, diabetes, autoimmune dis-
ease and prothrombotic states (1). Patients with
Figure 2. Appearance of right leg after commencing androgen
replacement therapy with testosterone gel.
© 2011 The Authors

ulcers should be referred when they fail to
respond to local wound care therapy, are of
non venous origin, show rapid deterioration,
involve an ischemic foot or have an atypical
distribution (2).
This patient was young and had failed to
respond to conventional treatment. He had
no varicose veins and arterial supply was
intact based on normal capillary refill and
palpable arterial pulses. The appearance of
his lower extremities was consistent with
chronic obesity lymphedematous mucinosis,
which is often seen in the metabolic syndrome.
However, while this patient suffered from
diabetes, his disease was well controlled with
oral hypoglycaemic medications and he had
a normal serum glucose and haemoglobin
A1c. We postulate that his endocrinopathy
could have predisposed him to these changes.
Autoimmune work-up including evaluation by
a rheumatologist and autoimmune laboratory
evaluation was negative. Prothrombotic work-
up was remarkable only for the PAI-1 mutation.
Klinefelter’s syndrome, first described in
1942 by Harry F. Klinefelter, is the most com-
mon congenital abnormality causing primary
hypogonadism, occurring in 1 in 500 to 1 in
1000 live births (3). Patients with this syndrome
are phenotypically male, but have at least one
extra X chromosome, resulting from the non
disjunction of the sex chromosomes of either
parent during meiotic division. Hormonally,
patients have testosterone levels of approxi-
mately 50% of normal because of seminiferous
tubule dysgenesis. Gonadal consequences of
the syndrome include scant facial and body
hair, small, firm testes, reduced sperm count
and infertility (4).
Metabolic syndrome, which was present in
the reported case, is a known complication
of Klinefelter’s syndrome, occurring in up
to 40% of Klinefelter patients (5). Develop-
ment of metabolic syndrome in these patients
is thought to be secondary to the hypogo-
nadal state leading to truncal fat distribution,
decrease in muscle mass and inactivity, as
was reported by our patient. Other reported
extragonadal manifestations of Klinefelter’s
syndrome include long bone abnormalities
resulting in increased length of legs and there
are some reports of psychosocial abnormal-
ities leading to difficult social interactions.
In addition, associations with varicose veins,
thromboembolic disease, breast cancer and
© 2011 The Authors
© 2011 Blackwell Publishing Ltd and Medicalhelplines.com Inc
Leg Ulcers Associated with Klinefelter’s Syndrome
autoimmune diseases including systemic lupus
Key Points
erythematosus have been reported (6).
Leg ulceration is a recognized complication • metabolic syndrome, which was
of Klinefelter’s syndrome (7). In a series of present in the reported case, is a
Klinefelter’s patients observed for up to a known complication of Klinefel-
ter’s syndrome, occurring in up
20-year period, the prevalence of leg ulcers was
to 40% of Klinefelter patients
6–13% (8). Furthermore, the genotypic variant • the aetiology of lower extremity
seen in our patient, 48 XXYY, has been found ulcers in Klinefelter’s patients
in several studies to have an even stronger is believed to be multifacto-
association with cutaneous changes (9). Some rial with chronic venous insuf-
ficiency, obesity, arterial dys-
authors have suggested that because of these
plasia in legs and decrease in
findings and the increased risk of cognitive fibrinolysis because of elevated
abnormalities associated with the 48XXYY levels of PAI-1 all reported
karyotype, this particular karyotype should be • it has been hypothesised that
identified as a separate entity (10–12). the increase in PAI-1 can
lead to impairment of fibri-
The aetiology of lower extremity ulcers in
nolysis causing development of
Klinefelter’s patients is believed to be mul- microthrombi that contribute to
tifactorial with chronic venous insufficiency, skin ulceration
obesity, arterial dysplasia in legs and decrease
in fibrinolysis because of elevated levels of
PAI-1 all reported (13). The role PAI-1 plays in
Klinefelter’s syndrome, and its contribution to
leg ulceration in this case, is unclear. PAI-1 is
produced by endothelium and adipose tissue
and inhibits tissue plasminogen activator and
urokinase plasminogen activator, thus inhibit-
ing fibrinolysis and promoting thrombosis. The
4G/5G polymorphism is a common polymor-
phism in the promoter region of the gene,
with the 4G variant exhibiting higher transcrip-
tion and thereby increased plasma PAI-activity
relative to the 5G/5G variant. Low levels of
testosterone are associated with elevated lev-
els of PAI-1, and increased activity of PAI-1
is implicated in the pathogenesis of ulcera-
tion (14). Zollner et al. (13) compared Kline-
felter’s syndrome patients with and without
lower extremity ulcers and found a higher PAI-
1 activity in the group with ulcers. It has been
hypothesised that the increase in PAI-1 can lead
to impairment of fibrinolysis causing develop-
ment of microthrombi that contribute to skin
ulceration (12). There is also data to suggest
that the presence of the metabolic syndrome
may contribute to elevation of PAI-1 activ-
ity, because diabetes, arterial hypertension,
hypertriglyceridaemia, smoking and reduced
physical activity all influence PAI-1 activity.
Adipokines released by adipose tissue in obe-
sity increase PAI-1 activity, and interventions
that treat the metabolic syndrome such as thi-
azolidinediones, metformin, and weight loss
and lifestyle changes can lower adipose expres-
sion of PAI-1.
3

Key Points
• the positive outcome with
testosterone administration in
this case was consistent with
that seen in other cases of Kline-
felter’s syndrome associated leg
ulcers
• in our case, we selected the
transdermal method of adminis-
tration of testosterone because
it is known to produce normal
serum testosterone concentra-
tions
• however, both the association
of leg ulcers with Klinefel-
ter’s syndrome and the positive
response to testosterone ther-
apy are contradictory to animal
data suggesting that testos-
terone is detrimental to wound
healing and that inhibiting
testosterone activity improves
wound healing
• this case illustrates the impor-
tance of considering Klinefel-
ter’s syndrome in a young infer-
tile man presenting with lower
extremity ulcers
4 © 2011 Blackwell Publishing Ltd and Medicalhelplines.com Inc
Leg Ulcers Associated with Klinefelter’s Syndrome
The positive outcome with testosterone
administration in this case was consistent with
that seen in other cases of Klinefelter’s syn-
drome associated leg ulcers (7). In our case,
we selected the transdermal method of admin-
istration of testosterone because it is known
to produce normal serum testosterone con-
centrations (15). However, both the association
of leg ulcers with Klinefelter’s syndrome and
the positive response to testosterone therapy
are contradictory to animal data suggesting
that testosterone is detrimental to wound heal-
ing and that inhibiting testosterone activity
improves wound healing (16–18). This case
illustrates the importance of considering Kline-
felter’s syndrome in a young infertile man
presenting with lower extremity ulcers.
ACKNOWLEDGEMENT
Dr. Shanmugam is funded by award numbers
KL2RR031974 and UL1RR031975 from the
National Center for Research Resources. The
content is solely the responsibility of the
authors and does not represent the official
views of the National Center for Research
Resources or the National Institutes of Health.
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© 2011 The Authors