Genetics of Klippel-Trenaunay-Weber Syndrome

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. See the image below.

Isolated reports of cases of limb hypertrophy were published in the 19th century, but the combination of a congenital 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 enlarged arteries and veins, rather than 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.

Parkes Weber syndrome (PWS) is closely associated with and similar to Klippel-Trenaunay syndrome, 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 is often accompanied by hemiparesis and hemiatrophy contralateral to the meningeal angioma.[1]

Although each of these syndromes is distinct, overlap does rarely occur. This article focuses on Klippel-Trenaunay syndrome and Parkes Weber syndrome.

Klippel-Trenaunay syndrome is characterized by a combined type of vascular malformation of the skin, abnormalities of the venous and lymphatic systems, and limb enlargement. Lymphatic vesicles appear on the surface of the capillary malformation; the lymph may also ooze at times. In addition, the abnormal venous system may produce protrusions of veins on the surface of the skin, called venous flares. Varicose veins appear in early childhood, and lateral venous anomalies are seen in 80% of cases.

Limb hypertrophy is due to the presence of vascular, venous, and lymphatic abnormalities but also to the hypertrophy of soft tissue and bone. The hypertrophy is often asymmetrical and often involves the digits. Ninety-five percent of cases involve the lower extremity.[2]

Because the vascular abnormalities in Klippel-Trenaunay syndrome 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, Parkes Weber syndrome is characterized by the presence of arteriovenous fistulas, and flow through the cutaneous malformations is fast, giving the lesions a pink color. Cardiac hypertrophy or high-output congestive heart failure occurs.

Frequency

United States

Klippel-Trenaunay syndrome and Parkes Weber syndrome are rare sporadic conditions with no racial or geographic predisposition. Parkes Weber syndrome is much less common than Klippel-Trenaunay syndrome.

Mortality/Morbidity

Klippel-Trenaunay syndrome and Parkes Weber syndrome 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. Although superficial vein abnormalities are common, the deep vein can also be involved with thrombosis. Pulmonary embolism may occur in 10% of patients, particularly after surgery.[3]

Pain may also be a feature of Klippel-Trenaunay syndrome. A retrospective study by Harvey et al found that out of 410 patients with Klippel-Trenaunay syndrome, 260 (63.4%) reported having pain in association with the condition.[4]

The Harvey study also determined that a psychiatric condition had been diagnosed in 95 (23.2%) of the report’s patients, with depression having the greatest incidence, followed by anxiety.[4]

A study from the Netherlands, by Horbach et al, found that 43% of pregnant women in the report with Klippel-Trenaunay syndrome experienced aggravation of the syndrome’s symptoms. Deep vein thrombosis and pulmonary embolism occurred in 5.8% and 2.3% of the pregnancies, respectively, with these rates being far greater than those seen in the reference population. Moreover, 11% of Klippel-Trenaunay syndrome pregnancies resulted in severe postpartum hemorrhage, versus 5.8% of reference population pregnancies.[5]

One half of patients with Klippel-Trenaunay syndrome can be treated solely with medical means.

Race

No racial predilection is noted.

Sex

No sex predilection is observed. A study by Sung et al of 19 patients with Klippel-Trenaunay syndrome found a nearly even sex distribution of nine males and 10 females.[6]

Age

The cutaneous vascular malformation is apparent at birth, but 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.

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.[7]

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.

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.[8] 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.[9]

• 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;[10] 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

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,[11] but family members can have isolated vascular nevi or varicose veins without having the disease itself.[12]

Translocations involving chromosomes 5 and 11 and 8 and 14 have been reported.[13, 14] As proposed by Chen et al, the mutation on chromosome 5q13.3 causes defective AGGF1 expression.[13] In addition, it has been proposed that bone morphogenetic protein is a trigger for AGGF1.[15] 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.[16]

Loss-of-function germline mutations of the RASA1 gene are now linked to Parkes Weber syndrome.[17]

See the list below:

• For the most part, patients with Klippel-Trenaunay-Weber syndrome are monitored for symptoms.

• Thrombocytopenia can occur and is diagnosed after an appropriate platelet cell count has been obtained.

See the list below:

• Ultrasonography

  • Color duplex ultrasonography appears to be a reliable means of detecting arteriovenous malformations (AVMs) in patients older than 1 year.

  • Obtain color duplex ultrasonography in any child with evidence of cardiac enlargement.

  • Color duplex ultrasonography may be indicated as a screening procedure.

• Radiography: When limb hypertrophy appears to be greater than 1.5 cm, scanography is performed to assess timing of epiphysiodesis.

• MRI

  • MRI and magnetic resonance arteriography (MRA) provide information regarding the extent of the vascular lesions, particularly deep-seated pelvic or thoracic vascular lesions.

  • MRI of the pelvis or chest is indicated if venous abnormalities extend the length of the extremity.

• Angiography

  • Arteriography is primarily indicated when spinal cord or brain involvement is suspected.

  • Venography is rarely indicated.

• Nuclear medicine: Lymphoscintigraphy may be indicated in children with significant limb asymmetry to assess the lymphatic system and the risk of infection.

Most patients with Klippel-Trenaunay syndrome (KTS) can be conservatively treated with compression stockings or pneumatic pumps. Compression stockings decrease edema, act as a barrier for minor trauma, and reduce venous insufficiency.[18]

In most series, patients with thrombophlebitis have been acutely treated without long-term prophylactic anticoagulants. However, aspirin is probably indicated in all patients.

Monitor cardiac status in all patients with arteriovenous malformations (AVMs). 

As a result of gain-of-function mutations in the gene encoding the catalytic alpha subunit of phosphatidylinositol-3 kinase (PIK3CA), activation of the PI3K-alpha and Akt-signaling cellular transformation occurs. PIK3CA gene mutations have been found in many, but not all, patients with Klippel-Trenaunay syndrome.[19]

In April 2022, alpelisib (Vijoice) became the first drug approved by the US Food and Drug Administration (FDA) for patients aged 2 years or older who have severe manifestations of PIK3CA-related overgrowth spectrum (PROS) and are in need of systemic therapy. FDA approval of alpelisib was supported by real world evidence from the open-label EPIK-P1 trial. The retrospective chart review found improvement in symptoms and manifestations associated with PROS as well as decreased target lesion volume, in patients treated with alpelisib.[20]

There are subtle differences between the surgical interventions for Klippel-Trenaunay syndrome and Parkes Weber syndrome. 

Servelle reported successful surgical intervention (resection or ligation of abnormal blood vessels) in more than 700 patients with Klippel-Trenaunay syndrome.[21] Most medical centers have tried to avoid surgical intervention. Surgical treatment can be complicated by infection, lymph seepage, and skin breakdown. In a series by the Mayo Clinic, surgical ligation and stripping of varicose veins produced improvement in only 40% of patients.[22] Venous varicosities recur after surgery in 90% of patients. Intravenous sclerotherapy has been proposed as an alternative to surgical intervention.

Clinicians at all centers agree that a leg-length discrepancy of more than 2 cm warrants epiphysiodesis in Klippel-Trenaunay syndrome. However, it is not preferred in Parkes Weber syndrome, since it can exacerbate the fast-flow lesions, especially if near the knee.[17]

Debulking surgeries to remove excess girth, while possible in Klippel-Trenaunay syndrome, are best avoided in Parkes Weber syndrome due to the arteriovenous malformations.

See the list below:

• Psychologist: Psychological support is important because of the cosmetic effects of Klippel-Trenaunay syndrome and Parkes Weber syndrome. A lay support group, the Klippel-Trenaunay Syndrome Support Group, is available.

 

See the list below:

• Patient activities are as tolerated.

Class Summary

These agents inhibit platelet function by blocking cyclooxygenase production and subsequent aggregation.

Aspirin (Anacin, Ascriptin, Bayer Aspirin)

Inhibits prostaglandin synthesis preventing formation of platelet-aggregating thromboxane A2. May be used in low dose to inhibit platelet aggregation and improve complications of venous stases and thrombosis.

Class Summary

These agents elicit anti-inflammatory and immunosuppressive properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.

Prednisolone (Pediapred)

Used to treat coagulopathy. Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reducing capillary permeability.

Class Summary

As a result of gain-of-function mutations in the gene encoding the catalytic alpha subunit of phosphatidylinositol-3 kinase (PIK3CA), activation of the PI3K-alpha and Akt-signaling cellular transformation occurs. PIK3CA gene mutations have been found in many, but not all, patients with Klippel-Trenaunay syndrome.[19]  

Alpelisib (Vijoice)

Indicated for patients aged 2 years or older who have severe manifestations of PIK3CA-related overgrowth spectrum (PROS) and are in need of systemic therapy.

See the list below:

• For complications of Klippel-Trenaunay-Weber syndrome, see Clinical.

See the list below:

• Recognition of the spectrum of severity is important, both in venous disease and in limb hypertrophy.

  • Jacob et al found that the rate of progression of limb length discrepancy was neither uniform nor predictable.[22] In Jacob et al's series, only 11% of patients had hypertrophy severe enough to warrant epiphysiodesis.

  • Amputation of an extremity is rarely necessary.

  • Patients with Klippel-Trenaunay syndrome (KTS) face a lifetime of potential problems, including cellulitis, lymph seepage, gangrene, skin breakdown, thrombophlebitis, and internal and superficial hemorrhage.

• Parkes Weber syndrome presents more severe problems, with hypertrophy, lymphedema, and cardiac hypertrophy. In one study by Robertson, 1 of 28 patients died from cardiac failure, and 5 of 28 required amputation of an extremity.[8]

See the list below:

• Information regarding the Klippel-Trenaunay Support Group is available online.