1
Diagnosis and Management of the Venous Malformations of Klippel-Trenaunay
Syndrome
S. Keisin Wang MD
1,2
, Natalie A. Drucker MD
1
, Alok K. Gupta
1,2
, Francis E.
Marshalleck MD
3
, and Michael C. Dalsing MD
1,2
Indiana University School of Medicine,
1
Departments of Surgery,
2
Division of Vascular
Surgery, and
3
Department of Radiology
Corresponding Authors:
Michael C. Dalsing, MD
mdalsing@iupui.edu
1801 N. Senate St
Suite 3500
Indianapolis, IN 46202
S. Keisin Wang, MD
wangkei@iupui.edu
1801 N. Senate St
Suite 3500
Indianapolis, IN 46202
___________________________________________________________________
This is the author's manuscript of the article published in final edited form as:
Wang, S. K., Drucker, N. A., Gupta, A. K., Marshalleck, F. E., & Dalsing, M. C. (2017). Diagnosis and management of
the venous malformations of Klippel-Trénaunay syndrome. Journal of Vascular Surgery: Venous and Lymphatic
Disorders, 5(4), 587-595. https://doi.org/10.1016/j.jvsv.2016.10.084
2
Abstract:
Objective
A dearth of information exists in the literature regarding current practice in the
management of Klippel-Trenaunay Syndrome (KTS), a rare condition. We seek to
review and describe the etiology, diagnosis, and treatment of the KTS patient.
Methods
Relevant data was synthesized from a Medline review using a combination of key
terms “Klippel” and “Trenaunay”. Majority of hits described singular case reports and
were subsequently excluded. Remaining papers were then reviewed and included based
on quality of evidence and author discretion.
Conclusion
KTS is characterized by a clinical triad of extremity varicosities, cutaneous
vascular malformations, and hypertrophy of soft tissues and/or long bones. The diagnosis
is clinically supplemented with MRI and CT scanning. Although this syndrome is
associated with significant comorbidities such as pain, edema, ulcerations, and pruritus –
it is rarely the cause of mortality. The backbone of treatment is nonoperative in nature but
should be supplemented with minimally invasive, endovascular, and rarely open surgical
procedures for refractory cases.
3
Introduction:
Vascular malformations of Klippel-Trenaunay syndrome (KTS) usually affect the
capillary, venous, and lymphatic systems of the lower extremities. Rarely, these defects
are seen in the upper extremities, are bilateral, or involve the trunk. Although first
described by Hilaire in 1832, KTS was truly recognized as an entity in itself by its
namesakes at the turn of the 20
th
century.
(1)
The duo of Frenchmen defined a cohort of
patients presenting with a triad of asymmetric limb hypertrophy, localized capillary
malformation (nevus flammeus, “port-wine stain”), and congenital lower extremity
varicosities. Although KTS is generally benign in course, the diseased limb can exhibit
pain, swelling, hyperpigmentation, thrombophlebitis, variceal bleeding, and ulceration.
Shortly after description by Klippel and Trenaunay, Weber designated a similar
vascular syndrome with the addition of arteriovenous fistulas (AVFs) termed the Parkes-
Weber Syndrome (PWS).
(2)
This separate pathology has been the source of much
confusion since the mid-20
th
century as clinicians have often ascribed one as the other.
However, there are crucial differences which affect the clinical course. With addition of
high flow AVFs, those suffering from PWS have a decreased lifespan and more
significant arterial complications compared to the more benign KTS.
Much effort has been made to unify the criteria of KTS in order to clarify the
clinical condition, the first step in diagnosis and management. Currently, the best
classification of venous malformations, of which KTS is one, is the Hamburg
4
Classification of Congenital Vascular Malformations. Utilizing this tool, KTS would be
classified as a predominantly venous defect of the truncular anatomic form presenting
with aplasia, obstruction, and/or dilatation. Truncular forms arises after developmental
arrest and during vascular trunk formation; in other words, these lesions do not have the
ability to proliferate after removal.
(3, 4)
The true pathogenesis of KTS has been elusive. While most patients demonstrate
a normal karyotype, sporadic translocations have been reported of chromosomes 5-11 and
8-14; a supernumerary ringed chromosome 18 have also been described. Familial cases
are rarely (and often unreliably) reported.
(5)
The affected limbs tend to exhibit increased
blood flow; this has been thought related to VEGF-mediated angiogenesis, but no
definitive evidence has been brought forth. There also may be involvement of gain-of-
function PIK3CA gene mutations causing upregulation of AKT and mTOR signaling.
(6)
PI3K and mTOR inhibitors are currently being investigated as treatment options with
promising results in mice and humans.
(7-9)
At least 6 hypothetical causes of KTS have
been suggested in the literature; of which, none completely explains the entire clinical
spectrum.
(5)
5
Presentation:
KTS is clinically diagnosed by the observation of a triad of cutaneous capillary
malformations, varicosities, and hypertrophy soft tissues and/or long bones. However, a
spectrum and combination of the aforementioned is usually appreciated in the real world.
In addition, while this classical presentation is usually observed in a singular limb,
multiple and even whole body cases have been described.
(10)
Limb length discrepancy is most often secondary to underlying soft tissue growth
but can be associated with long bone hypertrophy. The difference in growth occurs
during childhood before stabilizing in young adulthood with minimal changes after the
teenage years.
(11)
Capillary malformations present on the hypertrophied limb and clinically appear
as flat hemangiomas. In contrast, true flow-limiting arterial pathology is exceedingly rare
in KTS and more characteristic of the more pathologic PWS. A cutaneous capillary
malformation is often the first and most obvious sign on examination of the patient
suspected of KTS. This is often referred to in the literature as a “port-wine stain”.
Frequently dermatomal in distribution, these lesions tend to bleed and persist as the
patient ages. The frequency of which these skin findings coexist in KTS cannot be
understated; in fact, the prevalence of capillary malformations approaches 100% in the
reported literature.
(12)