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Klippel-Trénaunay Syndrome

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NORD is very grateful to John B. Mulliken, MD, Co-Director, Vascular Anomalies Center; Director, Craniofacial Center, Boston Children's Hospital, for assistance in the preparation of this report.

Synonyms of Klippel-Trénaunay Syndrome

Disorder Subdivisions

General Discussion

Summary
Klippel-Trénaunay syndrome (KTS) is a rare disorder that is present at birth (congenital) and is characterized by a triad of cutaneous capillary malformation ("port-wine stain"), lymphatic anomalies, and abnormal veins in association with variable overgrowth of soft tissue and bone. KTS occurs most frequently in the lower limb and less commonly in the upper extremity and trunk. KTS equally affects males and females.

Introduction
The eponym KTS has generated controversy in the medical literature since the first report of the condition in the early 20th century. The French physicians, Klippel and Trénaunay, described patients with capillary stains (improperly called "hemangiomas" at that time), venous varicosities, and overgrowth. At about the same time, the English dermatologist Parkes Weber reported the combination of "hemangiomas" and overgrowth of a limb. For many years, the names of all three physicians were linked as a confusing (and incorrect) term "Klippel-Weber-Trénaunay syndrome," which still is (unfortunately) used to this day.

Since the latter 20th century, it is well-recognized that Parkes Weber and Klippel-Trénaunay syndromes are entirely different. Parkes Weber syndrome consists of fast-flow, multiple microscopic arteriovenous connections with variable capillary staining of an enlarged limb (usually the lower extremity). By genetic testing, many of these patients have a dominant, germline mutation in the gene RASA1.

In contrast, KTS is a slow-flow combined vascular disorder involving abnormal capillaries (C), lymphatics (L) and veins (V). Therefore, many investigators use the abbreviation CLVM, rather than KTS, and restrict the designation for patients who have all three vascular anomalies. Other authors apply the KTS term more broadly and include patients with only capillary stain (CM) or only capillary and venous anomalies (CVM) in the limb in the absence of lymphatic abnormalities.

Once the genetic cause for KTS is discovered, it will be possible to more precisely designate patients with these various combinations of vascular anomalies.

Symptoms

Capillary Malformation (CM)
At birth, KTS presents with scattered, geographic capillary stains. With age, the surface of the CM becomes studded with tiny lymphatic vesicles that often turn black due to intralesional bleeding.

Lymphatic Malformation (LM)
LM presents as localized or generalized overgrowth caused by micro- and macrocystic anomalies, sometimes in association with lymphedema. Often there is lymphatic swelling and fatty deposition on the contralateral foot. The lymphatic anomalies can also occur in the pelvis, bladder and lower gastrointestinal tract. Lymphatic cysts in the spleen are also common. LM is documented by ultrasonography and/or MRI. Lymphography shows that lymphedema is the result of diminished number or absence of lymphatic channels.

Episodic infections (cellulitis) are common and probably related to poor lymphatic drainage in the limb.

Venous Malformation (VM)
Venous abnormalities are always present but variable and involve the entire affected extremity. Typically there are anomalous embryonic veins called the "marginal system." Dilatation of superficial veins may not be apparent in infancy, but becomes more prominent with age. LM and VM can also involve the pelvic or abdominal organs resulting in bleeding from the rectum, vagina or urinary bladder. Abnormal fatty deposits accompany the venous and lymphatic anomalies.

Stagnant blood in the abnormal veins may clot and trigger a bleeding disorder called "disseminated intravascular coagulopathy."

Overgrowth
Enlargement of the limb can be minimal to grotesque. Overgrowth in length is typical; however, in some patients the affected limb is shorter than normal. Frequently there is enlargement of the opposite foot.

Causes

The cause of KTS is unknown. The presumption is that it begins as a new gene mutation in primitive cells that form a limb that were destined to form blood and lymphatic vessels, fat, and bones. Researchers are actively trying to discover this mutation.

Affected Populations

Klippel-Trénaunay Syndrome is a rare disorder affecting males and females in equal numbers. The disorder occurs worldwide.

Related Disorders

KTS can be confused with other combined vascular disorders.

Parkes Weber syndrome
Tiny arteriovenous shunts in the thigh region have been found in KTS; however these are not clinically important. In contrast, multiple arteriovenous shunts and increased blood flow are the hallmarks of Parkes Weber syndrome.

CLOVES syndrome
In the past, patients with CLVM of the trunk were usually diagnosed as having KTS. Recently, it has been recognized that many of these patients have another, specific disorder of combined vascular anomalies and enlarged tissues designated by the acronym CLOVES = congenital lipomatous overgrowth with vascular anomalies, epidermal nevus and skeletal anomalies. CLOVES is caused by a somatic mutation in the gene PIK3CA.

Standard Therapies

Diagnosis
KTS is diagnosed based on physical signs and symptoms. Computed axial tomography (CAT) and magnetic resonance imaging (MRI) scans, and color doppler studies may be useful in determining the scope of the syndrome and how best to manage it.

Treatment
Recommended management for the following malformations associated with KTS is as follows:

Capillary Malformation
The vesicles in the CM can be improved by laser therapy, sclerotherapy or sometimes
resection and closure or replacement with a split-thickness skin graft.

Lymphatic Malformation
Macrocystic LM can be deflated by sclerotherapy (injection of irritating solutions), whereas, microcystic LM requires resection.

Venous Malformation
Blood stagnates in large dilated veins, and thus there is a risk for initiating a clotting disorder or thrombosis and pulmonary embolism. Anticoagulation with heparin is often necessary prior to radiologic or surgical intervention. Large venous channels can be obliterated by sclerotherapy or endovascular laser. Chronic bleeding from the colon may require surgical resection. Bleeding lesions in the bladder can be controlled by laser done through a cystoscope. An elastic compressive stocking is often useful to minimize discomfort and swelling due to venous distension.

Overgrowth
Enlarged toes may require amputation to narrow the foot and permit footwear. Discrepancy in leg length can be corrected by inserting a lift in the shoe on the normal foot to prevent compensatory curvature of the spine (scoliosis). Surgical closure of the growth plate at the knee (epiphysiodesis) is often needed to equalize leg length.

Staged contour resection is possible to diminish girth of the limb. These procedures are less effective if the abnormal fat and vasculature extends beneath the deep fascia of the leg into the muscle layer.

Investigational Therapies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

Contact for additional information about Klippel-Trénaunay syndrome:

John B. Mulliken, MD,
Co-Director, Vascular Anomalies Center
Director, Craniofacial Centre
Boston Children’s Hospital
300 Longwood Avenue
Boston, MA 02115
617-355-7686

Klippel-Trénaunay Syndrome Resources

NORD Member Organizations:

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References

JOURNAL ARTICLES
Oduber CEU, van der Horst CMAM, Hennekam RCM. Klippel-Trénaunay syndrome: diagnostic criteria and hypothesis on etiology. Ann Plast Surg. 2008;60(2):217-23.

Delis KT, Gloviczki P, Wennberg T, et al. Hemodynamic impairment, venous segmental disease (VSDS) and clinical severity (VCSS) scoring in limbs with Klippel-Trénaunay syndrome. J. Vasc.Surg. 2007;45:56-567.

Husmann DA, Rathburn SR, Driscoll DJ. Klippel-Trénaunay syndrome: incidence and treatment of genitourinary sequelae. J Urol. 2007;177(4):1244-9.

Cohen MM Jr. Klippel-Trénaunay syndrome. Am J Med Genet. 2000 Jul;93(3):171-5.
Jacob A, Driscoll D, Shaugnessy W, et al. Klippel-Trénaunay syndrome: Its spectrum and management . Mayo Clinic Proc. 1998;73:28-36

Happle R. Klipple-Trénaunay syndrome: Is it a paradominant trait? Br J. Dermatol. 1993;128:465-66.

INTERNET
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Klippel-Trénaunay-Weber syndrome. Entry No: 149000. Last Edited July 3, 2012. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed July 12, 2012.

Report last updated: 2012/07/12 00:00:00 GMT+0