eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Genetics

Klippel-Trenaunay-Weber Syndrome

Author: James H Tonsgard, MD, Associate Professor, Department of Pediatrics and Neurology, University of Chicago; Consulting Staff, Department of Neurology, Little Company of Mary Hospital; Consulting Staff, Department of Neurology, Lakeshore Hospital
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Updated: Apr 19, 2006

Introduction

Background

A number of rare congenital defects of skin, blood vessels, and underlying soft tissue exist. Klippel-Trenaunay syndrome (KTS) is defined by the presence of a combined vascular malformation of the capillaries, veins, and lymphatics, congenital venous abnormalities, and limb hypertrophy. Parkes Weber syndrome (PWS) is similar except that an arteriovenous malformation (AVM) occurs in association with a cutaneous capillary malformation and skeletal or soft tissue hypertrophy. Sturge-Weber syndrome is defined by the presence of a meningeal angioma, cutaneous capillary malformation of the face, and glaucoma; this often is accompanied by hemiparesis and hemiatrophy contralateral to the meningeal angioma. While each of these syndromes is distinct, overlap occurs in a single patient, rarely. This article focuses on KTS and PWS.

Isolated reports of cases of limb hypertrophy were published in the 19th century, but the combination of a congential vascular nevus of an extremity, venous varices on the affected side, and limb hypertrophy was not recognized as a consistent and unique syndrome until a 1900 article by Klippel and Trenaunay. A few years later, Frederick Parkes Weber published a report of similar patients in whom both arteries and veins were enlarged and not just venous abnormalities were present. Patients with limb hypertrophy, cutaneous capillary malformations, and venous and arterial malformations sometimes receive a diagnosis of Klippel-Trenaunay-Weber syndrome.

Pathophysiology

KTS is characterized by a combined type of vascular malformation of the skin, abnormalities of the venous system and lymphatic system, and limb enlargement due to hypertrophy of soft tissue and bone. The vascular malformation is frequently associated with lymphatic vesicles on the surface of the capillary malformation. The lymphatic vesicles may be present within the vascular malformation. The abnormal venous system may produce protrusions of veins on the surface of the skin called venous flares.

Limb hypertrophy is due to the presence of vascular, venous, and lymphatic abnormalities but also is due to the hypertrophy of soft tissue and bone. The hypertrophy is often asymmetric and often involves the digits. Ninety-five percent of cases involve the lower extremity. Because the vascular abnormalities in KTS are not associated with arterial malformations, flow through the malformations is slow. The combination of low flow vascular abnormalities and lymphatic involvement makes the skin lesions appear bluish or purplish.

In contrast, in Parkes Weber syndrome is characterized by the presence of arteriovenous fistulas. Flow through the cutaneous malformations is fast, and the color is pink. Cardiac hypertrophy or high-output congestive heart failure occurs.

Frequency

United States

KTS and PWS are rare sporadic conditions with no racial or geographic predisposition.

Mortality/Morbidity

KTS and PWS have a mortality rate of 1%. All patients have significant morbidity: Hypertrophy of the extremities or digits can be extreme requiring amputation. Lymphatic involvement with lymph vesicles may lead to poor wound healing. While superficial vein abnormalities are common, deep vein can also be involved with thrombosis. Pulmonary embolism may occur in 10% of patients, particularly after surgery. Pain may also be a feature of KTS. One half of patients can be treated solely using medical means.

Race

No racial predilection exists.

Sex

No sex predilection exists.

Age

The cutaneous vascular malformation is apparent at birth. The venous varicosities and limb hypertrophy may not be apparent initially. The average age of presentation of children to a medical center is 4 years.

Clinical

History

The cutaneous vascular malformation in both KTS and PWS is apparent at birth and may increase in size over the first few years. Natural involution of the cutaneous vascular malformation occurs in as many as 20% of patients.

Varicosities and limb hypertrophy occur over a few years and may not be apparent initially. Limb hypertrophy is due to a combination of factors (lymphatic obstruction, dilated veins, increase in soft tissue, and bone hypertrophy). The hypertrophy may preferentially involve the digits. This leads to leg length discrepancy and an unsteady gait.

Varicosities can produce venous stasis, which, in turn, can produce pain, bleeding, thrombophlebitis, and pulmonary emboli. Patients also commonly have lymphatic abnormalities that can produce lymphedema and susceptibility to infection and cellulitis. The vascular malformation in KTS is typically low flow and causes some trapping of platelets with mild-to-moderate depression of the platelet count. When an AVM is present as in PWS, congestive heartfailure may result from high output.

Physical

• Cutaneous vascular malformation and skin
  • The cutaneous vascular malformation in KTS is a flat blue or purplish capillary hemangioma (so-called port-wine stain). The combination of low flow and lymphatic involvement produces the blue or purple color. The cutaneous vascular malformations have been classified by Milliken. In KTS, the vascular malformations are a combined type with flat endothelium. While raised cavernous or mixed hemangiomas have been reported in patients with KTS or PWS, they are pathologically distinct from vascular malformations. Many authors feel that cavernous or mixed hemangiomas do not occur in KTS or PWS.
  • The cutaneous lesion usually is confined to part of an extremity, but, in 17-21% of patients, the entire limb or one side of the body is affected. In addition to the vascular abnormality, the skin may be hyperpigmented or thickened and have varicose veins, cherry red varicosities (venous flares), and lymphatic vesicles.
• Limb hypertrophy: In the vast majority of children, one leg is affected. In 5-11% of patients with KTS, an arm is affected, and in 13-19% of patients, an arm and leg are both affected. Lengthening of an extremity occurs in approximately 70% of patients, and an increase in thickness of the extremity occurs in at least 50%. Usually, hypertrophy and vascular lesions occur in the same extremity; only rarely do they occur in different limbs. Hypertrophy is due to a combination of muscular hypertrophy, thickened skin, and increase in vascular tissue. Bone overgrowth and lymphedema also contribute to increased size. The labia or scrotum may be hypertrophied when the venous abnormalities extend into the pelvis. The breasts may be affected by severe involvement of an upper extremity.
• Venous abnormalities: Typically, superficial lateral venous anomalies start along the foot and extend upwards. In at least one third of patients, the venous abnormalities extend the full length of the leg. Deep vein abnormalities (occlusion by fibrous bands, agenesis, atresia) have been reported in some patients. The frequency of these abnormalities is not clear because they are best demonstrated with surgical exploration (which usually is not recommended).
• Parkes Weber syndrome: PWS is defined by the presence of an AVM in addition to a cutaneous hemangioma and segmental hypertrophy. Similar to KTS, PWS more commonly affects the lower extremities. Patients with PWS have a higher incidence of severe complications than patients with KTS. The largest series reported was by Robertson. Of 28 patients, 3 required amputations, 6 had signs of cardiac enlargement, and 5 had significant leg length discrepancy requiring surgery. Ulcerations and severe lymphedema also are believed to occur frequently. Robertson believed that a positive bradycardiac reaction (compression of the artery feeding the AVM produces slowing of the pulse) indicated a poor prognosis.
  • Abnormalities of the lymphatic system, such as decreased number of lymph trunks and lymph nodes, are present in 70% of patients. As many as 23% of patients have lymphedema, cutaneous lymphatic vesicles, and weeping of lymph.
  • Pain and fatigability are common complaints.
  • At least one episode of thrombophlebitis occurs in 19-53% of patients. Venous thrombosis can lead to pulmonary emboli.
  • Deep vascular involvement (dilated veins) of the chest, abdomen, and pelvis may occur in one third of patients. Pelvic vein involvement may cause hematuria or rectal bleeding.
  • Hemangiomas of the GI tract or kidney also may occur and cause bleeding and compromise organ function.
  • The low flow vascular malformations in KTS may trap platelets resulting in a mild-to-moderate depression of the platelet count. Consumptive coagulopathy does not occur with the vascular malformations of KTS. In contrast, hemangiomas are associated with coagulopathy. Two types of hemangiomas are described: kaposiform hemangioendothelioma and tufted angiomas. Both of these lesions enlarge rapidly, usually in the first year of life, producing high-output congestive heart failure or a consumptive coagulopathy. Coagulopathy (Kasabach-Merritt syndrome) is marked by anemia, thrombocytopenia, prolonged prothrombin time (PT) and activated partial thromboplastin time (aPTT), reduced fibrinogen levels, and fibrin split products.
  • Rarely, ocular lesions and angiomas of the brainstem, cerebellum, and spinal cord are complications found in patients with KTS. Mental retardation is rare. Other congenital malformations, particularly bone dysplasias, occur in 9-29% of patients. A few patients with features of KTS and Sturge-Weber syndrome have been reported.

Causes

The etiologies of KTS and PWS are unknown. A defect in an angiogenic factor, VG5Q has recently been proposed. Males and females are affected equally, and no racial predominance exists. All cases are sporadic. One patient has been reported with a translocation of 5q and 11p, which raises the possibility that KTS is due to a single mutation at one of the sites. A paradominant mode of inheritance has been suggested by one author because of frequent hemangiomas in family members of patients with KTS. While KTS is uncommon, several large series of patients exist. PWS is much less common than KTS.

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