Klippel-Trenaunay-Weber Syndrome

Etiology

Recent studies have linked the etiology of Klippel Trenaunay syndrome to somatic mutations in the phosphatidylinositol-4-5-bisphosphate 3 kinase, catalytic subunit (PIK3CA) gene. This leads to the activation of phosphatidylinositol-3-kinase (PI3K)/protein kinase and cell overgrowth by dysregulation of the mTORC2 pathway.[3][4] Mutations occur in the embryological stage of development involving angiogenesis, reflecting findings seen in this condition. Now, KTS is grouped under the umbrella of similar overgrowth syndromes - PIK3CA-related overgrowth spectrum (PROS). Several overgrowth syndromes with overlapping clinical manifestations involving a number of mutations in the PIK3CA gene have been identified. In rare instances, translocations of chromosomes 5-11 and 8-14 have been reported.[2]

Epidemiology

The estimated incidence is between 2 and 5 in 100,000 and is found equally in both sexes.[5]

History and Physical

Klippel Trenaunay syndrome primarily involves the capillary, venous and lymphatic systems to varying degrees with tissue and bone hypertrophy. This condition predominantly affects the lower limbs and unilaterally affects the right and left sides equally. In rare cases, upper extremity, head and neck area, and bilateral involvement may be seen.[6] Capillary manifestations are flat, red, or purple capillary port-wine stains and are seen in 90 to 100% of cases. This is usually the first clinical finding present at birth and enlarges as the child grows.[5] 

Venous malformations are seen in 70 to 100% of patients and consist of varicosities in the superficial and deep venous systems, persistent embryonic veins, and aplasia/hypoplasia with valvular incompetence. The embryonic veins, which usually regress prior to birth, are persistent and are functionally incompetent leading to venous stasis and chronic thrombosis. Venous malformations can occur in the GI tract, especially in the colon, and can present with GI bleeds. On exam, dilated tortuous veins can be seen in the affected limb with swelling and discoloration. Patients can also present with recurrent deep vein thrombosis, leading to pulmonary embolism.[5][7][8] 

Lymphatic malformations are seen in 15 to 50% of cases and consist of lymphedema and cystic lymphatic collections.[9] Musculoskeletal findings include soft tissue and bone hypertrophy in an extremity leading to the limb-length discrepancy. Rare physical findings include syndactyly, polydactyly, and clinodactyly. Other uncommon symptoms include seizures, developmental delay, and genitourinary abnormalities presenting as hematuria.[9][10]

Evaluation

Klippel Trenaunay syndrome is a clinical diagnosis with the presence of 2 of the three classic features. Imaging is recommended to evaluate the underlying venous/lymphatic malformations and soft tissue/bone hypertrophy, mapping the extent of disease and complications. A color doppler ultrasound can be an initial step to assess varicosities, venous malformation, or the presence of thrombus formation. However, MRI and MRV can be more useful in assessing the extent of all the underlying malformations.[5][10] Elevated D-dimer is seen in most patients.[7]

Treatment / Management

A multi-disciplinary team approach with care coordination is optimal in patients with Klippel Trenaunay syndrome. The mainstay is symptomatic care with medical management, with only a few cases needing surgical intervention.

Skincare is important to prevent superficial infections and bleeding secondary to scratching. Children are monitored closely for limb length discrepancy and referred to orthopedics for orthotics or surgical corrections as needed. Compression stockings, limb elevation, and intermittent pneumatic compression devices are used to minimize lymphedema and venous insufficiency. Sclerotherapy-both conventional and micro-foam have been used for capillary, venous, and lymphatic malformation with promising results.

Laser treatment can be offered for port-wine stains.[6] Surgical management is reserved only for cases refractory to medical therapy and consists of endovascular ligation of embryonic veins and stripping of severe varicose veins.[7] Estrogen-containing contraceptives should be avoided due to the risk of thrombosis.

Pregnant patients need anti-thrombotic therapy as prophylaxis due to a high risk of deep venous thrombosis and pulmonary embolism.[4] Bleeding due to coagulopathy should be recognized promptly and treated with supportive care, fresh frozen plasma, and low molecular weight heparin. Patients undergoing surgical procedures should receive low molecular weight heparin prior to the procedure to reduce the risk of intravascular coagulation.(B3)

Rapamycin is a relatively newer therapy that can halt the progression of vascular malformation and improve the quality of life in patients with KTS. This drug works by inhibiting the PI3K/AKT/mTOR pathway. Rapamycin-protein complex inhibits the action of mTOR1, leading to the arrest of cell growth, thereby preventing tissue overgrowth. Patients on this medication need to be monitored closely for adverse effects and toxicity, such as hematological and lipid abnormalities.[9]

Differential Diagnosis

Klippel Trenaunay syndrome should be differentiated by the other overgrowth syndromes presenting as hemihypertrophy and other vascular syndromes with cutaneous lesions such as CLOVES (congenital lipomatous overgrowth vascular malformation with epidermal nevus and skeletal abnormalities); MCAP syndrome (megalencephaly-capillary malformation); DCMO (diffuse capillary malformation with overgrowth); FAO (fibro adipose overgrowth); proteus syndrome-post-natal skeletal and connective tissue overgrowth with epidermal nevi and vascular malformation; Beckwith-Wiedemann syndrome characterized by hemihypertrophy, neonatal hypoglycemia, omphalocele, ear abnormalities; Maffucci syndrome-multiple enchondromas; plexiform neurofibromatosis in NF-1 presenting as localized hypertrophy.[11]

A special distinction should be made with respect to Parkes-Weber syndrome (PWS), as KTS and PWS can be easily confused and often mistaken for the other. PWS is characterized by soft-tissue and bone hypertrophy with high-flow arteriovenous malformations and fistulas.[1]

Prognosis

Klippel Trenaunay syndrome has a wide spectrum of clinical findings, and the prognosis is related to the severity of vascular malformations. The malformations progress over time with ongoing overgrowth and worsening venous insufficiency. Acute bleeding from GI malformation can lead to exsanguinating blood loss with mortality risk if not promptly treated. Recurrent deep venous thrombosis leads to the risk of pulmonary embolism, which can be massive and fatal.[2]

Complications

Cellulitis of an affected extremity due to stasis and the lymphatic leak can lead to sepsis from neglected skincare. Severe stasis from venous and lymphatic abnormalities leads to an increased risk of localized coagulopathy with elevated D-dimer levels in patients with KTS. Bleeding from GI tract vascular malformations can be chronic and occult, requiring multiple transfusions and iron supplementation, or bleeding may be life-threatening with associated disseminated intravascular coagulopathy (DIC). Recurrent pulmonary embolism secondary to deep venous thrombosis can cause chronic changes in the small vessels resulting in pulmonary hypertension. Limb hypertrophy may require de-bulking surgeries for mobility and ambulation.[9][10]