NORD gratefully acknowledges John B. Mulliken, MD, Co-Director, Vascular Anomalies Center; Director, Craniofacial Center, Boston Children's Hospital, for assistance in the preparation of this report.
Klippel-Trenaunay 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.
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 Trenaunay, 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-Trenaunay syndrome,” which still is (unfortunately) sometimes used to this day.
Since the latter 20th century, it is well-recognized that Parkes Weber and Klippel-Trenaunay 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. Now that germline and somatic mutations have been identified, it will be possible to more precisely designate patients with these various combinations of vascular anomalies.
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 ooze clear fluid and 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.
Many patients with extensive abnormal veins have a low-grade hematologic condition called “localized intravascular coagulopathy” (LIC) which can be determined by measuring increased D-dimers in the blood. Stagnant blood in the dilated veins may clot and trigger a generalized bleeding disorder called “disseminated intravascular coagulopathy” (DIC).
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.
The cause of KTS is a mutation in primitive cells that form a limb that are destined to become blood and lymphatic vessels, fat, and bones. This is a somatic mutation, meaning it happens after fertilization, in the gene PIK3CA. This genetic alteration does not occur in the germ cells (egg and sperm), therefore, KTS cannot be passed on in a family.
Klippel-Trenaunay Syndrome is a rare disorder affecting males and females in equal numbers. The disorder occurs worldwide.
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 extent of the condition and how best to manage it.
Recommended management for the following malformations associated with KTS:
The vesicles in the CM can be improved by laser therapy, sclerotherapy or sometimes
resection and closure of the skin or replacement with a split-thickness skin graft.
Macrocystic LM can be deflated by sclerotherapy (injection of irritating solutions), whereas, microcystic LM may require resection.
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 through a cystoscope. An elastic compressive stocking is often useful to minimize discomfort and swelling due to venous distension in the limb.
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.
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Contact for additional information about Klippel-Trenaunay syndrome:
Clinical Practice Guidelines for Klippel-Trenaunay Syndrome (KTS)
https://k-t.org/assets/images/content/BCH-Klippel-Trenaunay-Syndrome-Management-Guidelines-1-6-2016.pdf Updated 1/6/2016. Accessed July 16, 2018.
Mulliken JB, Burrows PE, Fishman SJ (eds). Mulliken and Young’s Vascular Anomalies: Hemangiomas and Malformations. 2nd edition. New York: Oxford University Press. 2013.
Luks VL, Kamitaki N, Vivero MP, et al. Lymphatic and other vascular malformative/overgrowth disorders are caused by somatic mutations in PIK3CA. J Pediatr. 2015 Apr;166(4):1048-54.e1-5. doi: 10.1016/j.jpeds.2014.12.069. Epub 2015 Feb 11. https://www.ncbi.nlm.nih.gov/pubmed/25681199
Klippel-Trenaunay syndrome. Genetics Home Reference. Reviewed July 2016. https://ghr.nlm.nih.gov/condition/klippel-trenaunay-syndrome. Accessed July 16, 2018.
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