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 words: Fibrinolysis • Klinefelter’s syndrome • Leg ulcer • Prothrombotic
CASE
A 38-year-old male was evaluated at the
Georgetown University Center for Wound
Healing for bilateral lower extremity ulcers
that had been present for 4 years. Three years
prior to presentation he had been diagnosed
with type II diabetes, but his disease was well
controlled with a haemoglobin A1c of 5·9%
(normal less than 7%). He also had a history of
stage III chronic kidney disease, hypertension,
obstructive sleep apnea and obesity consistent
Authors: VK Shanmugam, MBBS, MRCP, Division of
Rheumatology, Immunology and Allergy, Georgetown University
Hospital, 3800 Reservoir Road, NW, Washington, DC, USA;
KC Tsagaris, DO, MPH, Department of Medicine, Georgetown
University Hospital, Washington, DC, USA; CE Attinger, MD,
Center for Wound Healing, Georgetown University Hospital,
Washington, DC, USA
Address for correspondence: Dr VK Shanmugam, MBBS,
MRCP, Division of Rheumatology, Immunology and Allergy,
Georgetown University Hospital, 3800 Reservoir Road, NW,
Washington, DC, USA
E-mail: [email protected]
© 2011 The Authors
© 2011 Blackwell Publishing Ltd and Medicalhelplines.com Inc
with a diagnosis of metabolic syndrome. The
patient attributed the wound development to
obesity, lower extremity oedema and immobility. At the time of presentation, he had circumferential ulcers on both legs below the knees.
He experienced constant pain from the ulcers
rated at 8 out of 10, which was present both at
rest and with ambulation. He did not have a
typical history of intermittent claudication, and
he denied prior thromboembolic disease. Treatment with local wound care, including silver
sulfadiazine cream and compression therapy,
had been ineffective.
The patient was single, lived with his mother
and had a 30-pack-year smoking history. He
had previously worked as a cashier and at the
time of evaluation was not working because
of disability. He experienced learning difficulties during childhood and young adulthood.
He also reported progressing through puberty
without erections and without increased testicular size. He had never fathered a child.
• International Wound Journal • doi: 10.1111/j.1742-481X.2011.00846.x
Key Points
• a 38-year-old male was eval-
•
•
•
•
•
•
uated at the Georgetown University Center for Wound Healing for bilateral lower extremity
ulcers that had been present for
4 years
three years prior to presentation
he had been diagnosed with
type II diabetes, but his disease
was well controlled
the patient attributed the
wound development to obesity,
lower extremity oedema and
immobility
at the time of presentation, he
had circumferential ulcers on
both legs below the knees
he experienced constant pain
from the ulcers rated at 8 out of
10, which was present both at
rest and with ambulation
treatment with local wound
care, including silver sulfadiazine cream and compression
therapy, had been ineffective
he also reported progressing
through puberty without erections and without increased testicular size
1
Leg Ulcers Associated with Klinefelter’s Syndrome
PHYSICAL EXAMINATION
Key Points
• on examination, the patient was
noted to have gynaecomastia and bilateral small testes,
approximately 10 ml each (normal 12–25 ml)
• the patient was heterozygous
for the 4G/5G plasminogen activator inhibitor (PAI)-1 mutation
• 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
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 complete 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 attributed 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 antinuclear antibody, negative double-stranded
DNA antibodies and negative extractable
nuclear antigen antibodies. Complement levels were within normal limits. C-reactive
Figure 1. Appearance of right leg at presentation.
2
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 reductase mutation and factor V Leiden mutation. 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, gynaecomastia, and history of infertility, a chromosomal 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 hormone (LH) at 32·8 mIU/ml (normal 1·5–9·3
mIU/ml). Thyroid-stimulating hormone, prolactin and insulin-like growth factor 1 were normal. These values suggest hypergonadotrophic
hypogonadism consistent with Klinefelter’s
syndrome. Testicular ultrasound showed bilateral 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 elsewhere, including venous stasis, peripheral
vascular disease, diabetes, autoimmune disease and prothrombotic states (1). Patients with
Figure 2. Appearance of right leg after commencing androgen
replacement therapy with testosterone gel.
© 2011 The Authors
© 2011 Blackwell Publishing Ltd and Medicalhelplines.com Inc
Leg Ulcers Associated with Klinefelter’s Syndrome
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 workup was remarkable only for the PAI-1 mutation.
Klinefelter’s syndrome, first described in
1942 by Harry F. Klinefelter, is the most common 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 approximately 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). Development of metabolic syndrome in these patients
is thought to be secondary to the hypogonadal 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 abnormalities 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
autoimmune diseases including systemic lupus
erythematosus have been reported (6).
Leg ulceration is a recognized complication
of Klinefelter’s syndrome (7). In a series of
Klinefelter’s patients observed for up to a
20-year period, the prevalence of leg ulcers was
6–13% (8). Furthermore, the genotypic variant
seen in our patient, 48 XXYY, has been found
in several studies to have an even stronger
association with cutaneous changes (9). Some
authors have suggested that because of these
findings and the increased risk of cognitive
abnormalities associated with the 48XXYY
karyotype, this particular karyotype should be
identified as a separate entity (10–12).
The aetiology of lower extremity ulcers in
Klinefelter’s patients is believed to be multifactorial with chronic venous insufficiency,
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 inhibiting fibrinolysis and promoting thrombosis. The
4G/5G polymorphism is a common polymorphism in the promoter region of the gene,
with the 4G variant exhibiting higher transcription and thereby increased plasma PAI-activity
relative to the 5G/5G variant. Low levels of
testosterone are associated with elevated levels of PAI-1, and increased activity of PAI-1
is implicated in the pathogenesis of ulceration (14). Zollner et al. (13) compared Klinefelter’s syndrome patients with and without
lower extremity ulcers and found a higher PAI1 activity in the group with ulcers. It has been
hypothesised that the increase in PAI-1 can lead
to impairment of fibrinolysis causing development 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 activity, because diabetes, arterial hypertension,
hypertriglyceridaemia, smoking and reduced
physical activity all influence PAI-1 activity.
Adipokines released by adipose tissue in obesity increase PAI-1 activity, and interventions
that treat the metabolic syndrome such as thiazolidinediones, metformin, and weight loss
and lifestyle changes can lower adipose expression of PAI-1.
Key Points
• 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
• the aetiology of lower extremity
ulcers in Klinefelter’s patients
is believed to be multifactorial with chronic venous insufficiency, obesity, arterial dysplasia in legs and decrease in
fibrinolysis because of elevated
levels of PAI-1 all reported
• it has been hypothesised that
the increase in PAI-1 can
lead to impairment of fibrinolysis causing development of
microthrombi that contribute to
skin ulceration
3
Leg Ulcers Associated with Klinefelter’s Syndrome
Key Points
• the positive outcome with
testosterone administration in
this case was consistent with
that seen in other cases of Klinefelter’s syndrome associated leg
ulcers
• in our case, we selected the
transdermal method of administration of testosterone because
it is known to produce normal
serum testosterone concentrations
• 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
healing and that inhibiting
testosterone activity improves
wound healing
• this case illustrates the importance of considering Klinefelter’s syndrome in a young infertile man presenting with lower
extremity ulcers
The positive outcome with testosterone
administration in this case was consistent with
that seen in other cases of Klinefelter’s syndrome associated leg ulcers (7). In our case,
we selected the transdermal method of administration of testosterone because it is known
to produce normal serum testosterone concentrations (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 healing and that inhibiting testosterone activity
improves wound healing (16–18). This case
illustrates the importance of considering Klinefelter’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.
REFERENCES
1 Sarkar S, Ballantyne S. Management of leg ulcers.
Postgrad Med J 2000;76:674–82.
2 O’Brien ML, Lawton JE, Conn CR, Ganley HE. Best
practice wound care. Int Wound J 2011;8:145–54.
3 Bojesen A, Juul S, Gravholt CH. Prenatal and
postnatal prevalence of Klinefelter syndrome: a
National Registry Study. J Clin Endocrinol Metab
2003;88:622–6.
4 Bojesen A, Gravholt CH. Klinefelter syndrome
in clinical practice. Nat Clin Pract Urol 2007;
4:192–204.
5 Bojesen A, Kristensen K, Birkebaek NH, Fedder
J, Mosekilde L, Bennett P, Laurberg P, Frystyk
J, Flyvbjerg A, Christiansen JS, Gravholt CH.
4
6
7
8
9
10
11
12
13
14
15
16
17
18
The metabolic syndrome is frequent in Klinefelter’s syndrome and is associated with abdominal obesity and hypogonadism. Diabetes Care
2006;29:1591–8.
Smyth CM, Bremner WJ. Klinefelter syndrome.
Arch Intern Med 1998;158:1309–14.
De Morentin H, Dodiuk-Gad R, Brenner S.
Klinefelter’s syndrome presenting with leg
ulcers. Skinmed 2004;3:274–8.
Campbell W, Newton M, Price W. Hypostatic leg
ulceration and Klinefelter’s syndrome. J Ment
Defic Res 24:115–7.
Peterson W, Gorlin R, Peagler F, Bruhl H. Cutaneous
aspects of the XXYY genotype: a variant of Klinefelter’s syndrome. Arch Dermatol 1966;94:695–8.
Parker C, Mavalwala J, Melnyk J, Fish C. The 48,
XXYY syndrome. Am J Med 1970;48:777–81.
Grammatico P, Bottoni U, De Sanctis S, Sulli N,
Tonanzi T, Onorio AC, Del Porto G. A male
patient with 48, XXYY syndrome: importance
of distinction from Klinefelter’s syndrome. Clin
Genet 1990;38:74–8.
Veraart J, Hamulyak K, Neumann H. Leg ulcers
and Klinefelter’s syndrome. Arch Dermatol
1995;131:958–9.
Zollner T, Veraart J, Wolter M, Hesse S, Villemur B,
Wenke A, Werner RJ, Boehncke WH, Jost SS,
Scharrer I, Kaufmann R. Leg ulcers in Klinefelter’s syndrome–further evidence for an involvement of plasminogen activator inhibitor-1. Br
J Dermatol 1997;136:341–4.
Spier C, Shear NH, Lester RS. Recurrent leg ulcerations as the initial clinical manifestation of Klinefelter’s syndrome. Arch Dermatol 1995;131:230.
Swerdloff RS, Wang C, Cunningham G, Dobs A,
Iranmanesh A, Matsumoto AM, Snyder PJ,
Weber T, Longstreth J, Berman N. Long-term
pharmacokinetics of transdermal testosterone
gel in hypogonadal men. J Clin Endocrinol Metab
2000;85:4500–10.
Gilliver SC, Ashworth JJ, Mills SJ, Hardman
MJ, Ashcroft GS. Androgens modulate the
inflammatory response during acute wound
healing. J Cell Sci 2006;119:722–32.
Gilliver SC. Sex steroids as inflammatory regulators.
J Steroid Biochem Mol Biol 2010;120:105–15.
Gilliver SC, Ruckshanthi JPD, Hardman MJ,
Zeef LAH, Ashcroft GS. 5α-Dihydrotestosterone
(DHT) retards wound closure by inhibiting reepithelialization. J Pathol 2009;217:73–82.
© 2011 The Authors
© 2011 Blackwell Publishing Ltd and Medicalhelplines.com Inc