Klippel-Trenaunay-Weber syndrome

Disease Description (Causes and Pathophysiology, Main Symptoms)

Klippel-Trenaunay-Weber syndrome (KTWS) is a rare congenital vascular and overgrowth syndrome in which overgrowth of the soft tissues and bones and vascular malformations occur simultaneously, mainly in one limb (especially a lower limb). Typically, three features are observed together: capillary malformations (port-wine stains), venous and lymphatic malformations (prominent veins, varicose veins, lymphangiectasia), and limb hypertrophy (soft-tissue and bony hypertrophy). In the Parkes-Weber variant, a high-flow arteriovenous fistula (AVF) is present, increasing the risk of heart failure.

Cause: Most cases are sporadic (nonhereditary), but recent studies have reported that somatic PIK3CA gene abnormalities may be involved in many cases, and that RASA1 variants may be associated with cases accompanied by AVF. The exact pathogenic mechanism is understood to involve abnormal regulation of angiogenesis and cell proliferation due to localized activation of these genes (arising during embryonic development).

Main symptoms:

• Port-wine stains and telangiectasia of the skin
• Localized overgrowth of soft tissue and bone (limb hypertrophy, asymmetric growth)
• Superficial and deep venous malformations (varicose veins, prominent blue veins), and lymphatic abnormalities (edema, lymphangiomas)
• If an arteriovenous fistula (high-flow lesion) is present, increased warmth, rapid pulse, and increased risk of heart failure
• Complications may include ulcers, bleeding, thrombosis (DVT) and pulmonary embolism, and bacterial infection (in areas affected by lymphedema)

Treatment Methods

Principle: A multidisciplinary approach (including vascular surgery/interventional specialists, pediatric or adult vascular-anomaly specialists, dermatology, orthopedics, and rehabilitation medicine) is required, and treatment varies according to the individual symptoms, the type of lesion (low-flow vs. high-flow), and its extent.

Nonpharmacological/Conservative Treatment

• Compression therapy: For relieving edema and varicose veins and preventing thrombosis (medical compression stockings/bandages)
• Skin and wound care: Appropriate wound treatment and hygiene management in cases of ulcers or infection
• Physical therapy and orthoses: To preserve function and assist walking

Drug Treatment

• Anticoagulant and thrombosis-prevention medications (when necessary, depending on the risk of DVT/pulmonary embolism)
• Pain control (analgesics when necessary)
• Sirolimus (such as Emtorin, an mTOR inhibitor): There is evidence of symptom improvement (reduced edema, pain, and ulcers) for complex vascular malformations (lymphatic and venous lesions), and it is used at specialized centers
• PI3Kα inhibitors (e.g., alpelisib): Efficacy has been reported in PIK3CA-related overgrowth syndrome (PROS), and they may be considered in specific patients; however, treatment indications and adverse-effect monitoring must be determined under specialist supervision

Procedures and Surgery

• Percutaneous sclerotherapy: Effective for localized venous or lymphatic lesions
• Endovascular embolization/coil embolization: To control arteriovenous fistulas (high-flow lesions) or some hemangiomas
• Surgical excision/debulking: To treat severe soft-tissue or bony hypertrophy or control complicated ulcers or bleeding (there is a risk of recurrence)
• Laser treatment (e.g., pulsed-dye laser): To improve the color of capillary malformations (port-wine stains)
• Orthopedic surgery: To correct leg-length discrepancies and for other purposes

Precautions

• If a high-flow AVM is present, evaluation of the risks of heart failure and bleeding is essential before embolization or surgery
• Assess the need for anticoagulant and thrombosis management (in patients at risk of DVT)
• During pregnancy, varicose veins and edema may worsen and the risk of thrombosis may increase → consultation with a specialist before and after pregnancy is recommended
• Early treatment is necessary if infection or ulcers develop

Checklist Before an Outpatient Visit (Including Examples of Items and Records to Prepare)

Items/Documents to Bring

• A list of all medications currently being taken (prescription drugs, OTC medications, and supplements)
• Allergy records (medications, foods, etc.)
• Previous test results (ultrasound, MRI/MRA, CT, angiography, etc.) and original imaging files (DICOM if possible)
• Records of previous surgeries and procedures, including operative reports
• Recent photographs (the entire limb and the lesion area—several photos taken under different lighting conditions and from different angles)
• A symptom diary (when symptoms began; the frequency and course of pain, edema, bleeding, and ulcers; aggravating factors)
• Pregnancy plans or whether currently pregnant

Useful Items to Record for the Appointment

• When and how symptoms worsen (after exercise, at night or in the morning, etc.)
• Shortness of breath and palpitations (possible high-flow state due to an arteriovenous fistula)
• Whether there is a leg-length discrepancy or difficulty walking
• Recent history of DVT or PE, or hospitalization

Possible Need for Testing

• Vascular ultrasound (Doppler), MRI (including blood vessels, MRA), CT angiography, and angiography (if necessary)
• Blood tests: CBC, coagulation tests, and liver and kidney function tests (before administering medication)
• Genetic testing if necessary (PIK3CA, RASA1, etc.) — consultation with a genetics specialist is recommended

Examples of General Questions to Ask the Doctor

• How can the exact diagnosis of this condition (low-flow vs. high-flow lesion) be confirmed?
• What is my (or the patient’s) prognosis? How high is the risk of complications?
• What treatment options do you recommend, and what are their expected effects and side effects?
• Are there any additional imaging or blood tests that I should undergo?
• If I am planning a pregnancy or am pregnant, what precautions should I take?
• How often should follow-up examinations be conducted, and which tests should be performed?
• Is genetic testing necessary? How could the results affect treatment?

Examples of Disease-Specific Questions

1. “How can we determine with certainty whether my lesion is high-flow (with an arteriovenous fistula) or low-flow (venous or lymphatic)? What imaging tests are needed?”
2. “Do you recommend testing for the PIK3CA or RASA1 gene? Depending on the genetic test results, could I receive targeted treatment such as sirolimus or a PI3K inhibitor?”

(It may make the appointment more efficient to take notes of the questions above or show them directly to the doctor during the consultation.)

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Note: This information has been compiled for general clinical and educational purposes. Individual diagnosis and treatment should be recommended by the treating specialist after considering the patient’s lesion type and extent, comorbidities, and test results.