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Pediatrics and Neonatology (2017) xx, 1e4

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Short Communication

Medical treatment of a female patient with

complicated KlippeleTrenaunay syndrome
Fang-Liang Huang a,b, Han-Yu Chen b, Te-Kau Chang a,c,*

a
Department of Pediatrics, Taichung Veterans General Hospital, Taichung, Taiwan
b
Hungkuang University, Taichung, Taiwan
c
Department of Pediatric, Cheng Hsin General Hospital, Taipei, Taiwan

Received Feb 15, 2017; received in revised form Apr 27, 2017; accepted Nov 15, 2017
Available online - - -

1. Introduction forearm was brought to our hospital through an arrange-

KlippeleTrenaunay syndrome (KTS) is a rare and sporadic
congenital vascular disorder characterized by capillary
and/or venous malformations or extensive distribution,
along with an early onset of varicose veins, in addition to
hypertrophy of the affected tissues.1 KTS has also been
postulated to be a result of an embryonic developmental
disorder of mesodermal tissues that affects angiogenesis at
different stages, possibly following an intrauterine insult.2,3
The conventional treatments for KTS are conservative
compression, sclerotherapy, lasers, and surgery4,5; howev-
er, there has been little discussion in the literature
regarding treatment involving internal medicine.
Herein, we report the case of a young girl with
congenital KTS who was treated with both internal medi-
cine and compression therapy, which had successfully
preserved the function of her right upper extremity during
her most recent follow-up visit, which was 6 years after
completion of treatment.
2. Case report
A 2-year-old girl from Cambodia with congenital gigantism
of the right upper extremity from the shoulder to the
* Corresponding author. Department of Pediatrics, Taichung
Veterans General Hospital, No. 1650, Taiwan Boulevard Sect. 4,
Taichung City 40705, Taiwan. Fax: þ886 4 2374 1359.
E-mail address: flhuang@vghtc.gov.tw (T.-K. Chang).
ment with the Formosa Budding Hope Association. Her birth
history indicated a full-term, normal, and spontaneous
delivery using a vacuum extractor and a birth body weight
of 3300 g. According to her mother, she had had an
extremely large right upper limb that did not obviously
change in size since birth. Since approximately 1 year old,
she had been suffering from frequent nose and mouth
bleeding, in addition to ecchymosis over her limbs and
trunk area. Occasionally, a cutaneous bleeding ulceration
spontaneously developed over her right hand; additionally,
oozing from ulcerations was noted.
A physical examination upon admission revealed normal
findings, with the exception of weakness and hypertrophy in
the right upper extremity, along with bleeding wounds on her
right hand. Her upper left extremity was normal in size with
good mobility. Anthropometric measurements confirmed
that the right upper limb was larger than the left [length
right:left (R:L), 25.5:22.5 cm; midupper arm circumference
R:L, 30.5:12.5 cm; and midforearm circumference R:L,
26.5:12.5 cm]. Extensive port-wine staining over the right
limb was noted (Fig. 1A). Developmental growth delay was
also noted, as she was unable to stand or walk until the age of
2 years. Her intelligence was normal for her age.
A complete blood count revealed a hemoglobin level of
10.8 g/dL, white blood cell count of 12.6
109 cell/L, and
platelet count of 9
109/L. Serum biochemistry and
coagulation investigations, including bleeding time, pro-
thrombin time, activated partial thromboplastin time, and
fibrinogen, were all within normal ranges. An X-ray of her

https://doi.org/10.1016/j.pedneo.2017.11.013
1875-9572/Copyright ª 2017, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-
NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Please cite this article in press as: Huang F-L, et al., Medical treatment of a female patient with complicated KlippeleTrenaunay
syndrome, Pediatrics and Neonatology (2017), https://doi.org/10.1016/j.pedneo.2017.11.013
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2 F.-L. Huang et al

Figure 1 (A) A 2-year-old girl presented with congenital gigantism of the right upper extremity from the shoulder to forearm with
extensive port-wine staining over the right limb (B) Multidetector-row Computed Tomography (MDCT) shows a diffuse circumfer-
ential soft-tissue hypertrophy with capillary malformation, muscle fatty infiltration, venous aneurysms and malformations (C) The
right arm without recurrent progressive enlargement was observed when the girl was 4 years old.

right arm revealed multiple foci of a well-defined osteol-
ysis, surrounded by a sclerotic margin at the right humerus,
and a proximal ulna where the most prominent area was
located at the distal third of the humerus (Supplementary
Fig. 2A).
Magnetic resonance angiography (MRA) and
multidetector-row computed tomography (MDCT) showed
diffuse circumferential soft-tissue hypertrophy with capil-
lary malformation, fatty muscle infiltration, venous aneu-
rysms, and malformations over both superficial and deep
veins; bone expansion and erosion over the right humerus,
along with the proximal ulna over the right upper limb, was
also discovered (Fig. 1C). No evidence of arteriovenous
malformation (AVM) or deep vein thrombosis was observed.
Lymphoscintigraphy showed a malfunction of the lymphatic
system in the right upper extremity. An arteriogram showed
a markedly increased number of abnormal capillary com-
ponents and small varicose veins over the medial side of
right upper limb. The patient’s venogram revealed
abnormal varicose veins running around the right cephalic
vein in the lateral part of the upper arm.
The capillary, venous, and lymphatic malformations with
varicose veins and hypertrophy of the affected tissues
affecting her right arm were identified. A clinical diagnosis
of KTS was then established based on these findings. A
chromosome study was performed on the G-banded chro-
mosomes from peripheral blood cultures, which revealed
46, XX without any abnormality. A genetic test showed no
E133K change in the VG5Q gene.
The patient received platelet transfusion to stabilize
both her bleeding tendency and thrombocytopenia. After
consultations with orthopedic, plastic, and vascular sur-
geons from our hospital, it was decided that surgical man-
agement, such as a right arm amputation or a debulking
procedure, was not a therapeutic option that would both
preserve arm function and avoid the high risk associated
with anesthesia6 and high bleeding tendencies in patients
with KTS. Therefore, the patient received internal medical
treatment and compression therapy and participated in a
rehabilitation program at our ward. After a full cardiovas-
cular and respiratory review and discussion with her family,
the initial regimen prescribed was oral propranolol (2 mg/
kg/d) for 6 months and prednisolone (an initial dosage of
3 mg/kg/d for the first month, followed by 2 mg/kg/d) for a
total of 3 months. Intravenous vincristine (0.05 mg/kg/wk
for 4 wk) was also given during the first month. A rehabil-
itation program of regularly scheduled sessions was estab-
lished to improve function in her right arm. In addition, the
patient wore a custom-made elastic sleeve to compress her
large right upper extremity.

Please cite this article in press as: Huang F-L, et al., Medical treatment of a female patient with complicated KlippeleTrenaunay
syndrome, Pediatrics and Neonatology (2017), https://doi.org/10.1016/j.pedneo.2017.11.013
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Medical treatment a child with KTS
As a result of this treatment, the circumference of the
right midupper arm reduced from 30.5 cm to 23 cm (a
reduction of 24.6%) and that of the midforearm reduced
from 26.5 cm to 21.5 cm (a reduction of 18.9%) during the 6-
month treatment period. The patient was able to stand,
walk, and raise her right hand over her head upon
completion of treatment. There were no obvious compli-
cations from the medical treatment, nor any further
thrombocytopenia or bleeding during the treatment period.
At the 2- and 6-year follow-up, the function of the right arm
was favorable and the patient showed no signs of recurrent
progressive enlargement of the limb. At the time of writing,
the patient is 8 years old and growing at a normal rate for a
girl of her age. The most recent MRA of her right arm
revealed regression in size, and X-ray revealed a dramatic
change in the right humerus, which had a normal appear-
ance (Supplementary Fig. 2B).
3. Discussion
KTS is a term used to describe the combination of a cuta-
neous capillary malformation, varicose veins or venous
malformation, and soft tissue and/or bony hypertrophy of an
extremity. The clinical presentation of the current case
included all the aforementioned conditions. KTS is typically
unilateral, affecting an isolated upper extremity in 5%e11%
of cases.5 It is thought to occur sporadically, with an inci-
dence rate of approximately 1 per 100,000 live births, and
carries no predilection for a particular sex or race.7 Because
no AVM was noted in our case, KTS was easily distinguished
from ParkereWeber Syndrome, in which an enlarged ex-
tremity occurs due to being related to an underlying AVM.
Although the mortality rate amongst KTS patients is low
(approximately 1%),5 our patient suffered from lift-
threatening complications, namely severe thrombocyto-
penia with mucosal bleeding and infectious ulcerations on
the right hand. The patient’s suffering from thrombocyto-
penia may have been due to long term active bleeding of
the lesion area with platelet consumption, or an association
with Kasabach-Merritt Syndrome-like symptoms in KTS.
After treatment, the patient’s platelet count recovered to
a normal level within one month. The syndrome in the
present case is rare, while it exactly matched the clinical
diagnostic definition and its associated complications,
obviating the need for a pathological biopsy examination.2
Although this syndrome was first chronicled more than
one-hundred years ago, the etiology of KTS remains un-
clear. With respect to the suspicious etiology of KTS, it is
generally considered to involve defects in both angiogen-
esis and regulation of vessel and tissue growth.2 The
increased angiogenesis of KTS may be due to mutations in
the VG5Q gene through transcription and increased activ-
ity.8 In the present case, genetic study revealed no muta-
tion of the VG5Q gene, and there was no associated mass or
tumor formation during 6 year follow-up.
The management of KTS is complex.4 Surgery has been
considered the standard therapy for vascular malforma-
tions,9 while amputation of the limb or surgical debulking has
been applied to treat progressive soft-tissue enlargement
when it causes interference with activities of daily living.10,11
We also initially considered surgical management but
Please cite this article in press as: Huang F-L, et al., Medical treatment of a female patient with complicated KlippeleTrenaunay
syndrome, Pediatrics and Neonatology (2017), https://doi.org/10.1016/j.pedneo.2017.11.013
3
rejected this approach to preserve her right arm and avoid
any potential surgical risks, particularly as she had bleeding
tendencies.
Although compression therapy helps to diminish the
symptoms of venous insufficiency and lymphedema, it has
no effect on the ultimate size of the limb.5 Considering our
patient’s young age, we decided that using radiofrequency
ablation and sclerotherapy to treat her vascular malfor-
mations was not appropriate. Therefore, we opted to use
internal medical treatment despite the lack of reference
data available in medical publications about treating KTS in
children using internal medicine.
Regarding the uncertain etiology of KTS, it is generally
considered to involve defects in angiogenesis and regula-
tion of both vessel and tissue growth; therefore, anti-
angiogenic agents were used to target the angiogenesis and
malformation of vessels and tissue. Vincristine is capable of
modulating angiogenesis as an antiangiogenic agent due to
its ability to directly attack the host vasculature, which
causes an endothelial retraction, swelling, and disrup-
tion.12 It has also been used to successfully treat capillary-
lymphatic malformation.12 The mechanisms through which
prednisolone controls vascular anomalies remain unclear,
although the medication appears to increase vasoconstric-
tion, inhibit fibrinolysis, and disrupt angiogenesis.13
Meta-analyses have indicated that propranolol has a
dramatic impact on the treatment of infantile hemangi-
omas without causing any severe side effects.14 The
possible mechanisms of action for propranolol are vaso-
constriction, inhibition of angiogenesis, and the triggering
of apoptosis in capillary endothelial cells.15 A case series
article reported that propranolol improved symptoms of
lymphatic anomalies, including cases of patients with
KTS.16 We used the three antiangiogenic agents and ach-
ieved an excellent response within a relatively short
treatment period. We did not use interferon or cyclophos-
phamide, as they are associated with more side effects.
4. Conclusion
To the best of our knowledge, we are the first to report on
the use of combination therapy comprising three anti-
angiogenic agents, vincristine, prednisolone and proprano-
lol, to successfully treat a child with congenital KTS. In
summary, congenital KTS may be managed through the use
of internal medicine and conservative therapy, as they are
capable of achieving a dramatic response, which allows for
the preservation of function in the affected extremity.
However, it should be noted that experience with KTS in
pediatrics remains limited.
Conflict of interest
None.
Acknowledgement
The authors acknowledge the assistance of the Formosa
Budding Hope Association, which made the arrangements to
bring the patient to our hospital.
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4 F.-L. Huang et al

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Please cite this article in press as: Huang F-L, et al., Medical treatment of a female patient with complicated KlippeleTrenaunay
syndrome, Pediatrics and Neonatology (2017), https://doi.org/10.1016/j.pedneo.2017.11.013