Klippel-Trenaunay-Weber Syndrome 

Updated: Apr 11, 2022
Author: Camila K Janniger, MD; Chief Editor: Dirk M Elston, MD 

Overview

Background

Klippel-Trenaunay-Weber syndrome (KTWS) is characterized by a triad of port-wine stain, varicose veins, and bony and soft tissue hypertrophy involving an extremity. Note the image below.

Klippel-Trenaunay syndrome in a young person. Note Klippel-Trenaunay syndrome in a young person. Note the port-wine stain extending to the buttocks. These lesions can be associated with venous malformations involving the rectum and bladder.

In 1900, noted French physicians Klippel and Trenaunay first described a syndrome in 2 patients presenting with a port-wine stain and varicosities of an extremity associated with hypertrophy of the affected limb's bony and soft tissue. They termed the syndrome "naevus vasculosus osteohypertrophicus." In 1907, Parkes Weber, unaware of Klippel and Trenaunay's report, described a patient with the 3 aforementioned symptoms as well as an arteriovenous malformation of the affected extremity. He termed the process hemangiectatic hypertrophy.

Today, conflicting opinion exists in the literature as whether to separately designate the original triad as Klippel-Trenaunay syndrome and the triad with the addition of arteriovenous malformation as Parkes Weber syndrome. Making the distinction is probably wise given the increased morbidity associated with arteriovenous malformations. For this discussion, the 2 types are considered together.

Pathophysiology

The exact cause of Klippel-Trenaunay-Weber syndrome (KTWS) remains to be elucidated, although several theories exist. Bliznak and Staple suggested intrauterine damage to the sympathetic ganglia or intermediolateral tract leading to dilated microscopic arteriovenous anastomoses as the cause.[1] Servelle believes that deep vein abnormalities, with resultant obstruction of venous flow, lead to venous hypertension, the development of varices, and limb hypertrophy.[2] Baskerville et al contend that a mesodermal defect during fetal development causes maintenance of microscopic arteriovenous communications.[3] Finally, McGrory and Amadio believe that an underlying mixed mesodermal and ectodermal dysplasia is likely responsible for the development of KTWS.[4]

Most cases KTWS are sporadic, although a few cases in the literature report an autosomal dominant pattern of inheritance.[5] A case report of KTWS in a monozygotic twin with an unaffected twin advances the theory of a paradominant inheritance pattern.[6] This theory suggests that KTWS is produced by a single gene defect lethal in individuals who are homozygous for this gene. Heterozygotes carry the gene but are unaffected. The disease manifests in individuals who demonstrate loss of heterozygosity from a somatic mutation during embryogenesis. In these individuals, only the skin region harboring this cell population demonstrates the KTWS mutation.

The association between the angiogenic factor gene AGGF1 and KTS appears to be significant.[7] Common AGGF1 variants may confer risk of KTWS.

Kihiczak et al report that KTWS may result from a pathogenic gene for vascular and tissue overgrowth.[8]

Etiology

See Pathophysiology.

Epidemiology

Race

No racial predilection is documented for Klippel-Trenaunay-Weber syndrome (KTWS).

Sex

Klippel-Trenaunay-Weber syndrome (KTWS) affects females and males equally.[9]

Age

Klippel-Trenaunay-Weber syndrome (KTWS) presents at birth or during early infancy or childhood.

Prognosis

Hand or foot malformations in Klippel-Trenaunay-Weber syndrome (KTWS) may predict the presence of deep venous system anomalies.[10]

 

Presentation

History

Klippel-Trenaunay-Weber syndrome (KTWS) generally affects a single extremity, although cases of multiple affected limbs have been reported. The leg is the most common site followed by the arms, the trunk, and rarely the head and the neck. One report describes only upper limb involvement.[11]

Most patients demonstrate all 3 signs of the clinical syndrome: port-wine stain, varicose veins, and bony and soft tissue hypertrophies.

In a series of 252 patients at the Mayo Clinic, 63% of patients had all 3 features and 37% had 2 of the 3 features. Port-wine stain was seen in 98% of patients, varicosities or venous malformations in 72%, and limb hypertrophy in 67%. Atypical veins, including lateral veins and persistent sciatic vein, were present in 72% of patients. Finally, deep venous abnormalities included aneurysmal dilation, hypoplasia, aplasia, and absent or incompetent valves.

An anatomical analysis to determine the frequency of various vascular malformations and abnormal growth and assess any statistical relationship between vascular malformation type/location and abnormal growth in terms of length and girth was performed on 35 patients.[12] Leg bone circumferential hypoplasia was significantly related to the presence of intramuscular lesions. A single subcutaneous venous malformation was linked with subcutaneous hypertrophy.

Brain abnormalities include hemorrhage, infarction, hemimegalencephaly, venous malformation, arteriovenous malformations, cavernoma, aneurysm, hydrocephalus, choroid plexus abnormalities, atrophy, calcifications, leptomeningeal enhancement, cortical dysplasia, and seizures.[13] Pulmonary emboli secondary to venous limb thrombosis are a risk in patients with this syndrome.[14, 15] Cerebral infarctions are rare, as are brain tumors.[16]

Physical Examination

In Klippel-Trenaunay-Weber syndrome (KTWS), the capillary hemangioma or port-wine stain usually presents first.

This hemangioma has a distinct, linear border that respects the midline. Hemangioma is often noted on the lateral aspect of the limb.

It is typically of the nevus flammeus type, but cavernous hemangiomas or lymphangiomas may also occur. Nevus flammeus is a salmon pink patch, sometimes with a verrucous quality, which evolves to a deep purple color with time. Unlike strawberry hemangiomas, the port-wine stain hemangioma possesses neither a proliferative nor a regressing phase.

Hemangioma depth is variable. It may be limited to the skin or extend deeper to subcutaneous tissue, including muscle and bone. Visceral organs, such as the pleura, the spleen, the liver, the bladder, and the colon may also be affected. Visceral organ involvement portends greater morbidity secondary to internal hemorrhage that may manifest as hematuria or hematochezia.

If large enough, cutaneous hemangiomas may sequester platelets, leading to possible Kasabach-Merritt syndrome, a type of consumptive coagulopathy.[17] The hemangioma often overlies the vascular malformation.

Varicose veins in KTWS are congenital.

The Klippel-Trenaunay vein is a large, lateral, superficial vein sometimes seen at birth. This vein begins in the foot or the lower leg and travels proximally until it enters the thigh or the gluteal area. Otherwise, varicosities may not be clinically evident until the child begins to ambulate.

Varicosities may be extensive, though they often spare the saphenous distribution. They are seen below the knee, laterally above the knee, and occasionally in the pelvic region. Varicosities may affect the superficial, deep, and perforating venous systems.

Surgical exploration has demonstrated atresia and agenesis of deep veins, compression due to fibrous bands, aberrant arteries, abnormal muscles, or venous sheaths.

Rarely, varicosities have been found in the bladder, the colon, and the pulmonary vessels.

Varicosities may remain stable in size or gradually expand. Pain and lymphedema are commonly reported. These symptoms may worsen during pregnancy.

Arteriovenous fistulas, the feature that distinguishes Klippel-Trenaunay syndrome from Parkes-Weber syndrome, are rarely found in the affected extremity.

If present, they can occasionally be palpated as a pulsatile mass, thrill, or bruit on physical examination.

Hyperthermia and a positive Branham sign (bradycardia with the application of compression on an artery proximal to the malformation) are also indicators of an arteriovenous malformation.

Bony and soft tissue hypertrophies are the third sign of KTWS. However, a rapid-growing skull hemangioma may rarely be evident in these patients,[18] as may a vesical hemangioma.[19]

Limb hypertrophy can be secondary to increased length (bony involvement) and/or increased girth (soft tissue involvement). Hypertrophy may be appreciated at birth. It usually progresses during the first years of life. A greater degree of hypertrophy may be seen in patients with coexisting arteriovenous malformation. Although lymphedema is also seen in patients, true hypertrophy of the affected soft tissues is present.

Limb discrepancies of as much as 12 cm have been reported.

Occasionally, the involved limb may be atrophied rather than hypertrophied.

Other features include lymphatic obstruction, spina bifida, hypospadias, polydactyly, syndactyly, oligodactyly, hyperhidrosis, hypertrichosis, paresthesia, decalcification of involved bones, chronic venous insufficiency, stasis dermatitis, poor wound healing, ulceration, thrombosis, angiosarcoma, and emboli.[20, 21] Orofacial abnormalities may require specialized dental and anesthesia care.[22]

Magnetic resonance lymphangiography (MRL) with gadobenate dimeglumine as the contrast showed 31 of 32 patients exhibited lymphatic vessel and/or lymph node anomalies, including hyperplasia (11/31), hypoplasia or aplasia (20/31) of lymphatic vessels, and lymphedema (31/31) of the affected limbs. A high concomitance of malformations of the lymphatic system and veins in the affected limbs of were noted in patients with KTS.[23]

Complications

Complications of hemangiomas include skin breakdown and ulceration, bleeding, and secondary infection.

Complications due to varicosities include paresthesia, stasis ulcers, pulmonary emboli, thrombophlebitis, stasis dermatitis, hemorrhage, and cellulitis.

Hypertrophy of a limb may lead to subsequent vertebral scoliosis, gait abnormalities, and compromise of function.

Klippel-Trenaunay-Weber syndrome (KTWS) patients tend to develop degenerative joint disease at an early age.[24]

KTWS has been described as associated with radial artery coronary graft spasm, although its linkage should be regarded as speculative.[25]

A 72-year-old man with longstanding KTWS and chronic penile and scrotal edema had a low-grade angiosarcoma arising in the setting of the chronic lymphedema, but he died from massive hemorrhage due to traumatic rupture of malformed leg vessels.[26]

Infantile-onset secondary glaucoma is a substantial risk with periocular cutaneous vascular malformations.[27]

 

DDx

Diagnostic Considerations

Iliac vein thrombus in Klippel-Trenaunay-Weber syndrome (KTWS) should be distinguished from pelvic inflammatory disease.[28]

KTWS may be associated with arterial and venous malformations in the lower uterine segment.[29, 30, 31]

Sturge-Weber syndrome in combination with KTWS has been described in more than one patient.[32, 33]

Differential Diagnoses

 

Workup

Imaging Studies

In many instances, a thorough history and physical examination are all that is required to diagnose Klippel-Trenaunay-Weber syndrome (KTWS). However, when complications are present, imaging studies can be useful. Color Doppler sonography is an accurate, reliable, and noninvasive way to evaluate patients with possible KTWS.[34]

Multidetector row computed tomography arteriography may be of value in the preoperative assessment of patients with KTWS.[35]

Evaluation of the deep venous system can be completed with duplex scanning contrast venography, ultrasonography, contrast venography and arteriography, and nuclear MRI studies. Arteriography is especially helpful in the diagnosis of an arteriovenous fistula.

MRI is also helpful in imaging the soft tissue hypertrophy. In addition, magnetic resonance angiography can be very helpful in identifying and defining vascular malformations.

In the case of major limb length discrepancies, serial radiographic studies, including but not limited to scanograms, orthoroentgenograms, and CT scans, for measurement of limb length are necessary. Clinical measurements can only guarantee measurement within 0.5-1.0 cm, whereas radiographic examinations can be used to determine the exact differences to within 0.1 cm. These studies help to determine how fast a limb is growing and may help in determining proper timing for limb length equalization procedures.

Prenatal diagnosis by ultrasonography has been reported.

In lesions extending onto the perineum or abdomen, performing imaging studies can be helpful to rule out internal involvement. Vascular malformations have been reported throughout the gastrointestinal tract. Although this typically does not cause symptoms, gastrointestinal bleeding has been reported. Similarly, vascular malformations have also been reported within the genitourinary tract.

Lymphoscintigraphy may be used to evaluate potential KTWS candidates for thoracic duct decompression if needed.[36]

 

Treatment

Medical Care

Treatment for Klippel-Trenaunay-Weber syndrome (KTWS) is conservative and symptomatic. Compression garments are indicated for chronic venous insufficiency, lymphedema, recurrent cellulitis, and recurrent bleeding from capillary or venous malformations of the extremity. The compression garment may also protect the limb from trauma. Intermittent pneumatic compression pumps may also provide benefit. However, in some patients with absent or hypoplastic deep venous systems, elastic compression may increase venous stasis and cause discomfort. Pain management can be a very important aspect of caring for patients with KTWS. Referral to a pain clinic and/or a multidisciplinary team including a pain management specialist is recommended.[37]

Cellulitis and thrombophlebitis can be managed with analgesics, elevation, antibiotics, and corticosteroids. In patients with a history of recurrent cellulitis, intermittent or prophylactic antibiotics may be considered. Anticoagulant therapy is indicated in acute thrombosis and prophylactically prior to surgical procedures. Given the risk of thrombotic events, women with KTWS should avoid using oral contraceptive pills.

Regarding limb hypertrophy, heel inserts are generally sufficient for limb discrepancies of 1.5 cm or less. For greater discrepancies, orthopedic surgery may be considered. Possible orthopedic procedures include osteotomy, epiphysiodesis, or epiphyseal stapling. Rarely, amputation is required due to recurrent infections, nonhealing ulcers, or recurrent bleeding. 

Gain-of-function mutations in the gene encoding the catalytic alpha-subunit of phosphatidylinositol-3 kinase (PIK3CA) lead to activation of PI3K-alpha and Akt-signaling cellular transformation. Many, but not all patients with KTS have been found to have PIK3CA gene mutations.[38]   

Alpelisib (Vijoice) is the first drug approved for patients aged 2 years and older with severe manifestations of PIK3CA-related overgrowth spectrum (PROS) who require systemic therapy. US Food and Drug Administration (FDA) approval of alpelisib was supported by real world evidence from the open-label EPIK-P1 trial. A retrospective chart review showed patients treated with alpelisib had reduced target lesion volume and improvement in PROS-related symptoms and manifestations. After 24 weeks, 27% of patients (10/37) achieved a confirmed response to treatment, defined as 20% or greater reduction in the sum of PROS target lesion volume. Also, 23 or 31 patients (74%) showed some reduction in target lesion.[39]   

Women with KTWS have been reported to have normal pregnancies. These patients should be monitored carefully with serial ultrasounds because previously asymptomatic arteriovenous malformations within the uterine wall may become pronounced with the additional blood flow to the uterus during pregnancy.[40, 41]  Late puerperal hemorrhage has been described.[31]

Surgical Care

In Klippel-Trenaunay-Weber syndrome (KTWS), laser treatment of the hemangioma can be effective in lightening the color of the port-wine stain. Currently, the flashlamp-pumped pulsed dye laser is the treatment of choice in vascular lesions. Laser treatment is also indicated in the case of ulceration. Ulceration of hemangiomas can be painful and can impair functional abilities. When treated with laser, ulcers often heal more quickly. Laser treatment is most effective when performed early, as it can improve the long-term appearance of the port-wine stain and thereby also improve function. Typically, many treatments are required to achieve the desired effect. Laser treatment only helps with the superficial component of the hemangioma.[42]

Surgical intervention in the treatment of varicosities and venous malformations is controversial. One might consider surgery for either significant cosmetic deformity or the symptoms of pain, heaviness of the leg, bleeding, or infectious complications. Venous stripping, ligation, excision, or sclerotherapy are contraindicated unless the surgery involves the superficial system and the underlying deep system is normal or demonstrates only mild-to-moderate reflux. Lymphaticovenular anastomosis may represent a desirable approach.[43]

Inadequate evaluation prior to excision increases surgical complications. Symptomatic superficial varicosities can be removed without harm and with benefit to the patient when an adequate preoperative examination is performed. Although Baskerville et al demonstrated that some 90% of treated varicosities redevelop, treatment can provide lasting improvement for years.[3] Successful treatment of incompetent valves in the femoral vein of the affected limb with contralateral saphenous vein transplant has been reported.

Debulking procedures have limited use and may damage venous and lymphatic structures, leading to increased edema in the affected limb. The potential risks and benefits must be carefully weighed before attempting surgical intervention.

Radiotherapy has been reported to be of help in some cases of KTWS. The radiation may help to induce regression of hemangiomas; however, the results can be slow to develop.[44]

Endovenous laser therapy of the greater saphenous vein is gaining support for the management of varicosities in the general public and in patients with KTWS.[45] This therapy has been used alone and in combination with other surgical interventions. It is a novel and minimally invasive approach for the management of some varicosities. Vesical and uterine involvement may be treated by endoscopic and endovascular routes.[30]

Endovenous mechanochemical ablation for varicoses veins in pediatric KTWS patients appears safe and effective.[46]

Complications

Complications of hemangiomas include skin breakdown and ulceration, bleeding, and secondary infection.

Complications due to varicosities include paresthesia, stasis ulcers, pulmonary emboli, thrombophlebitis, stasis dermatitis, hemorrhage, and cellulitis.

Hypertrophy of a limb may lead to subsequent vertebral scoliosis, gait abnormalities, and compromise of function.

Klippel-Trenaunay-Weber syndrome (KTWS) patients tend to develop degenerative joint disease at an early age.[24]

KTWS has been described as associated with radial artery coronary graft spasm, although its linkage should be regarded as speculative.[25]

A 72-year-old man with longstanding KTWS and chronic penile and scrotal edema had a low-grade angiosarcoma arising in the setting of the chronic lymphedema, but he died from massive hemorrhage due to traumatic rupture of malformed leg vessels.[26]

Long-Term Monitoring

Patients with Klippel-Trenaunay-Weber syndrome (KTWS) should be monitored at least annually and more often if clinically indicated.

Stable disease can be followed clinically. KTWS is not always a static disease process. If progression of the disease arises, imaging studies should be performed. Medical or surgical intervention should be pursued if indicated.

 

Medication

Medication Summary

Alpelisib (Vijoice) is the first drug approved for patients aged 2 years and older with severe manifestations of PIK3CA-related overgrowth spectrum (PROS) who require systemic therapy.

PI3K Inhibitors

Class Summary

Gain-of-function mutations in the gene encoding the catalytic alpha-subunit of phosphatidylinositol-3 kinase (PIK3CA) lead to activation of PI3K-alpha and Akt-signaling cellular transformation. Many, but not all patients with KTS have been found to have PIK3CA gene mutations.[38]  

Alpelisib (Vijoice)

Indicated for patients aged 2 years and older with severe manifestations of PIK3CA-related overgrowth spectrum (PROS) who require systemic therapy.