Genetics of Klippel-Trenaunay-Weber Syndrome Clinical Presentation

Updated: Aug 29, 2016
  • Author: Ravi Sunderkrishnan, MD; Chief Editor: Maria Descartes, MD  more...
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Presentation

History

The cutaneous vascular malformation in both Klippel-Trenaunay syndrome (KTS) and Parkes Weber syndrome (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. The vascular malformation in Klippel-Trenaunay syndrome is typically low flow and causes some trapping of platelets, with mild to moderate depression of the platelet count. When an arteriovenous malformation (AVM) is present as in Parkes Weber syndrome, congestive heart failure may result from high output. Spinal AVMs, while rare, have been reported in a case series. [4]

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.

Limb hypertrophy, which occurs over a few years and may not initially be apparent, results from a combination of factors, including 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.

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Physical

Cutaneous vascular malformation and skin

The cutaneous vascular malformation in Klippel-Trenaunay syndrome 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 Klippel-Trenaunay syndrome, the vascular malformations are a combined type with flat endothelium. Although raised cavernous or mixed hemangiomas have been reported in patients with Klippel-Trenaunay syndrome or Parkes Weber syndrome, they are pathologically distinct from vascular malformations.

The cutaneous lesion is usually confined to part of an extremity; however, 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 Klippel-Trenaunay syndrome, 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 is usually not recommended).

Parkes Weber syndrome

Parkes Weber syndrome is defined by the presence of an AVM in addition to a cutaneous hemangioma and segmental hypertrophy. Similar to Klippel-Trenaunay syndrome, Parkes Weber syndrome more commonly affects the lower extremities. Patients with Parkes Weber syndrome have a higher incidence of severe complications than patients with Klippel-Trenaunay syndrome. The largest series reported was by Robertson. [5] 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 are also 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.

Lymphatic system

Abnormalities of the lymphatic system, such as a decreased number of lymph trunks and nodes, are present in 70% of patients with Klippel-Trenaunay or Parkes Weber syndrome. As many as 23% of patients have lymphedema, cutaneous lymphatic vesicles, and weeping of lymph.

Miscellaneous

Other points to keep in mind include the following:

  • 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 may also occur and cause bleeding and compromise organ function
  • Klippel-Trenaunay syndrome is a pure low-flow condition. Parkes Weber syndrome, due to presence of significant arteriovenous fistulas, results in combined high-flow vascular malformation, causing high-output cardiac failure. In order to clinically differentiate Klippel-Trenaunay syndrome from Parkes Weber syndrome, it is important to remember that the cutaneous capillary malformation in Parkes Weber syndrome is more diffuse and pinker than in Klippel-Trenaunay syndrome. In addition, skin ulcerations are much more common in Parkes Weber syndrome ; they can be radiologically differentiated by magnetic resonance (MR) projection angiography. [6]
  • 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 Klippel-Trenaunay syndrome; one patient has been described with portosystemic encephalopathy due to intrahepatic portohepatic venous shunts; [7] cases of mental retardation are rare; other congenital malformations, particularly bone dysplasias, occur in 9-29% of patients; a few patients with features of Klippel-Trenaunay syndrome and Sturge-Weber syndrome have been reported
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Causes

The etiologies of the Klippel-Trenaunay and Parkes Weber syndromes are both still the subject of hypothesis. Most of the mutations of Klippel-Trenaunay syndrome are sporadic, and the idea that this disorder has a familial transmission is not yet proven. Autosomal dominant transmission of the gene with variable expressivity was considered long ago, [8] but family members can have isolated vascular nevi or varicose veins without having the disease itself. [9]

Translocations involving chromosomes 5 and 11 and 8 and 14 have been reported. [10, 11] As proposed by Chen et al, the mutation on chromosome 5q13.3 causes defective AGGF1 expression. [10] In addition, it has been proposed that bone morphogenetic protein is a trigger for AGGF1. [12] Ring chromosome 18 has also been reported in association with Klippel-Trenaunay syndrome.

One group proposed that a mutation in the angiogenic factor VG5Q is the cause of angiogenesis in Klippel-Trenaunay syndrome, but the reported mutation was subsequently identified as a nonspecific polymorphism. [13]

Loss-of-function germline mutations of the RASA1 gene are now linked to Parkes Weber syndrome. [14]

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