AUTHOR INFORMATION

Section 1 of 11

Authored by James H Tonsgard, MD, Associate Professor, Department of Pediatrics and Neurology, University of Chicago; Consulting Staff, Department of Neurology, Little Company of Mary Hospital; Consulting Staff, Department of Neurology, Lakeshore Hospital

Edited by Michael Fasullo, PhD, Associate Professor, Center for Immunology and Microbial Disease, Albany Medical College; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Margaret McGovern, MD, PhD, Vice Chair, Professor, Department of Human Genetics, Mount Sinai School of Medicine; Paul D Petry, DO, FACOP, FAAP, Clinical Assistant Professor of Pediatrics, University of North Dakota, School of Medicine and Health Sciences; Consulting Staff, Altru Health System; and Bruce A Buehler, MD, Professor, Department of Pathology and Microbiology, Chairman, Department of Pediatrics, Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center

Author's Email:	James H Tonsgard, MD
Editor's Email:	Michael Fasullo, PhD

eMedicine Journal, April 19 2006, VOLUME 7, Number 4

INTRODUCTION

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Background: A number of rare congenital defects of skin, blood vessels, and underlying soft tissue exist. 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. Parkes Weber syndrome (PWS) is similar 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 often is accompanied by hemiparesis and hemiatrophy contralateral to the meningeal angioma. While each of these syndromes is distinct, overlap occurs in a single patient, rarely. This article focuses on KTS and PWS.

Isolated reports of cases of limb hypertrophy were published in the 19th century, but the combination of a congential 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 both arteries and veins were enlarged and not 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.

Pathophysiology: KTS is characterized by a combined type of vascular malformation of the skin, abnormalities of the venous system and lymphatic system, and limb enlargement due to hypertrophy of soft tissue and bone. The vascular malformation is frequently associated with lymphatic vesicles on the surface of the capillary malformation. The lymphatic vesicles may be present within the vascular malformation. The abnormal venous system may produce protrusions of veins on the surface of the skin called venous flares.

Limb hypertrophy is due to the presence of vascular, venous, and lymphatic abnormalities but also is due to the hypertrophy of soft tissue and bone. The hypertrophy is often asymmetric and often involves the digits. Ninety-five percent of cases involve the lower extremity. Because the vascular abnormalities in KTS 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, in Parkes Weber syndrome is characterized by the presence of arteriovenous fistulas. Flow through the cutaneous malformations is fast, and the color is pink. Cardiac hypertrophy or high-output congestive heart failure occurs.

Frequency:

• In the US: KTS and PWS are rare sporadic conditions with no racial or geographic predisposition.

Mortality/Morbidity: KTS and PWS 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. While superficial vein abnormalities are common, deep vein can also be involved with thrombosis. Pulmonary embolism may occur in 10% of patients, particularly after surgery. Pain may also be a feature of KTS. One half of patients can be treated solely using medical means.

Race: No racial predilection exists.

Sex: No sex predilection exists.

Age: The cutaneous vascular malformation is apparent at birth. 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.

CLINICAL

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History: The cutaneous vascular malformation in both KTS and 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.

Varicosities and limb hypertrophy occur over a few years and may not be apparent initially. Limb hypertrophy is due to a combination of factors (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.

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. The vascular malformation in KTS is typically low flow and causes some trapping of platelets with mild-to-moderate depression of the platelet count. When an AVM is present as in PWS, congestive heart failure may result from high output.

Physical:

• Cutaneous vascular malformation and skin
  • The cutaneous vascular malformation in KTS 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 KTS, the vascular malformations are a combined type with flat endothelium. While raised cavernous or mixed hemangiomas have been reported in patients with KTS or PWS, they are pathologically distinct from vascular malformations. Many authors feel that cavernous or mixed hemangiomas do not occur in KTS or PWS.

  • The cutaneous lesion usually is confined to part of an extremity, but, 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 KTS, 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 usually is not recommended).



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


• • Abnormalities of the lymphatic system, such as decreased number of lymph trunks and lymph nodes, are present in 70% of patients. As many as 23% of patients have lymphedema, cutaneous lymphatic vesicles, and weeping of lymph.
  
  
  
• 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 also may occur and cause bleeding and compromise organ function.



• The low flow vascular malformations in KTS may trap platelets resulting in a mild-to-moderate depression of the platelet count. Consumptive coagulopathy does not occur with the vascular malformations of KTS. In contrast, hemangiomas are associated with coagulopathy. Two types of hemangiomas are described: kaposiform hemangioendothelioma and tufted angiomas. Both of these lesions enlarge rapidly, usually in the first year of life, producing high-output congestive heart failure or a consumptive coagulopathy. 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 KTS. Mental retardation is rare. Other congenital malformations, particularly bone dysplasias, occur in 9-29% of patients. A few patients with features of KTS and Sturge-Weber syndrome have been reported.

Causes: The etiologies of KTS and PWS are unknown. A defect in an angiogenic factor, VG5Q has recently been proposed. Males and females are affected equally, and no racial predominance exists. All cases are sporadic. One patient has been reported with a translocation of 5q and 11p, which raises the possibility that KTS is due to a single mutation at one of the sites. A paradominant mode of inheritance has been suggested by one author because of frequent hemangiomas in family members of patients with KTS. While KTS is uncommon, several large series of patients exist. PWS is much less common than KTS.

DIFFERENTIALS

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Other Problems to be Considered:

Hemihypertrophy
Congenital lymphatic obstruction
Sturge-Weber syndrome
Proteus syndrome
Kaposiform hemangioendothelioma

WORKUP

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Lab Studies:

• For the most part, patients are monitored for symptoms.



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

Imaging Studies:

• Ultrasound


• • Color duplex ultrasonography appears to be a reliable means of detecting 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, scanograms are performed to assess timing of epiphysiodesis.



• Magnetic resonance imaging


• • 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 indicated primarily when spinal cord or brain involvement is suspected.
  
  
  
  • Venography rarely is indicated.
  
  
  
• Nuclear medicine: Lymphoscintigraphy may be indicated in children with significant limb asymmetry to assess the lymphatic system and the risk of infection.

TREATMENT

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Medical Care:

• Most patients with KTS can be treated conservatively with compression stockings or pneumatic pumps. Compression stockings decrease edema, act as a barrier for minor trauma, and reduce venous insufficiency.



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



• Monitor cardiac status in all patients with AVMs.

Surgical Care: Servelle reported successful surgical intervention (resection or ligation of abnormal blood vessels) in more than 700 patients with KTS. 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 (Jacob, 1998). Venous varicosities recur after surgery in 90% of patients. Intravenous sclerotherapy has been proposed as an alternative to surgical intervention in KTS and to embolization in PWS. Reports exist of the use of a sclerosant in microfoam.

Clinicians at all centers agree that a leg length discrepancy of more than 2.0 cm warrants epiphysiodesis. Hypertrophied digits with severe deformity and infection may require amputation.

Consultations: Psychologist: Psychological support is important because of the cosmetic effects of KTS and PWS. A lay support group, the Klippel-Trenaunay Syndrome Support Group, is available.

Activity: Patient activities are as tolerated.

MEDICATION

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Drug Category: Antiplatelet agents -- Inhibit platelet function by blocking cyclooxygenase production and subsequent aggregation.

Drug Name	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.
Adult Dose	1-2 mg/kg/d PO for antiplatelet effect
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; liver damage; hypoprothrombinemia; vitamin K deficiency; bleeding disorders; asthma
Interactions	Effects may decrease with antacids and urinary alkalinizers; corticosteroids decrease salicylate serum levels; additive hypoprothrombinemic effects and increased bleeding time may occur with coadministration of anticoagulants or other antiplatelet agents; may antagonize uricosuric effects of probenecid and increase toxicity of phenytoin and valproic acid
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Pregnancy category D in third trimester; may cause transient decrease in renal function; may exacerbate chronic kidney disease

Drug Category: Corticosteroids -- Elicit anti-inflammatory and immunosuppressive properties and cause profound and varied metabolic effects. Corticosteroids modify the body’s immune response to diverse stimuli.

Drug Name	Prednisolone (Pediapred, Delta-Cortef, Econopred) -- Used to treat coagulopathy. Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reducing capillary permeability.
Adult Dose	5-60 mg/d PO
Pediatric Dose	2 mg/kg/d PO
Contraindications	Documented hypersensitivity; viral, fungal, or tubercular skin lesions
Interactions	Decreases effects of salicylates and toxoids (for immunizations); phenytoin, carbamazepine, barbiturates, and rifampin decrease effects
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in hyperthyroidism, osteoporosis, cirrhosis, nonspecific ulcerative colitis, peptic ulcer disease, diabetes, and myasthenia gravis

FOLLOW-UP

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Complications:

• See Clinical.

Prognosis:

• 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. In Jacob’s series, only 11% of patients had hypertrophy severe enough to warrant epiphysiodesis.
  
  
  
  • Amputation of an extremity rarely is necessary.
  
  
  
  • Patients with KTS face a lifetime of potential problems, including cellulitis, lymph seepage, gangrene, skin breakdown, thrombophlebitis, and internal and superficial hemorrhage.
  
  
  
• PWS 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.

Patient Education:

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

MISCELLANEOUS

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Medical/Legal Pitfalls:

• Failure to recognize the consumptive coagulopathy that is part of Kasabach-Merritt syndrome



• Failure to recognize and treat thrombophlebitis, which can be a complication in KTS

TEST QUESTIONS

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CME Question 1: Which of the following statements is correct regarding Klippel-Trenaunay syndrome (KTS)?

A: KTS is always inherited as an autosomal dominant trait.
B: Usually, KTS occurs sporadically.
C: KTS is an X-linked trait.
D: KTS is inherited maternally.
E: Inheritance of KTS is sex-linked.

The correct answer is B: While a few familial cases have been reported and a paradominant expression has been postulated, all cases essentially are sporadic, with a very low risk of recurrence within a family.

CME Question 2: Which of the following statements is correct regarding Klippel-Trenaunay syndrome (KTS)?

A: KTS is progressive.
B: KTS is always associated with a benign outcome.
C: Cardiac failure is a frequent complication.
D: Arteriovenous fistulae usually are present.
E: Surgical management is imperative.

The correct answer is A: In patients with KTS, 50% can be treated medically, and 50% require surgical intervention. A high rate of complications exists with KTS.

Pearl Question 1 (T/F): Kasabach-Merritt syndrome is a mild coagulopathy that is found as a complication in patients with Klippel-Trenaunay syndrome (KTS).

The correct answer is False: Kasabach-Merritt syndrome is a severe coagulopathy that is a complication in patients with KTS. Kasabach-Merritt syndrome is characterized by anemia, thrombocytopenia, prolonged prothrombin time (PT) and activated partial thromboplastin time (aPTT), and high-output congestive heart failure. Kasabach-Merritt syndrome is potentially fatal and requires emergent medical management.

Pearl Question 2 (T/F): Parkes Weber syndrome (PWS) differs from Klippel-Trenaunay syndrome (KTS) in that PWS has a lower frequency of complications.

The correct answer is False: Parkes Weber syndrome is defined by the presence of an arteriovenous malformation in addition to the 3 features of KTS (ie, a cutaneous capillary malformation of an extremity, congenital venous abnormalities, and skeletal or soft tissue hypertrophy). Parkes Weber syndrome has a higher frequency of complications.

Pearl Question 3 (T/F): Aggressive early surgical intervention is suggested in patients with Klippel-Trenaunay syndrome (KTS).

The correct answer is False: Surgical intervention should be avoided in patients with KTS, unless necessary. Vascular lesions recur following surgery with a very high incidence.

Pearl Question 4 (T/F): In most patients with Klippel-Trenaunay syndrome (KTS), medical treatment options include aspirin and compression stockings or pneumatic pumps.

The correct answer is True: Compression stockings or pneumatic pumps decrease edema and reduce venous insufficiency. Short-term management of thrombophlebitis is provided by therapy using anticoagulants. Infections should be treated with antibiotics. Treat patients with Kasabach-Merritt syndrome using high-dose prednisolone, platelets, packed red blood cells, and fresh frozen plasma.

BIBLIOGRAPHY

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• Cabrera J, Cabrera J, Garcia-Olmedo MA, Redondo P: Treatment of venous malformations with sclerosant in microfoam form. Arch Dermatol 2003 Nov; 139(11): 1409-16[Medline].
• Ceballos-Quintal JM, Pinto-Escalante D, Castillo-Zapata I: A new case of Klippel-Trenaunay-Weber (KTW) syndrome: evidence of autosomal dominant inheritance. Am J Med Genet 1996 Jun 14; 63(3): 426-7[Medline].
• Cohen MM: Klippel-Trenaunay syndrome. Am J Med Genet 2000 Jul 31; 93(3): 171-5[Medline].
• Huiras EE, Barnes CJ, Eichenfield LF, et al: Pulmonary thromboembolism associated with Klippel-Trenaunay syndrome. Pediatrics 2005 Oct; 116(4): e596-600[Medline].
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• Kasabach HH, Merritt KK: Capillary hemangioma with extensive purpura: a report of a case. Am J Dis Child 1940; 59: 1063-70.
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• Whelan AJ, Watson MS, Porter FD, Steiner RD: Klippel-Trenaunay-Weber syndrome associated with a 5:11 balanced translocation. Am J Med Genet 1995 Dec 4; 59(4): 492-4[Medline].
• Young AE, Ackroyd J, Baskerville P: Combined vascular malformations. In: Mulliken JB, Young AE, eds. Vascular Birthmarks: Hemangiomas and Malformations. WB Saunders Co; 1988:246-74.
• Ziyeh S, Spreer J, Rossler J, et al: Parkes Weber or Klippel-Trenaunay syndrome? Non-invasive diagnosis with MR projection angiography. Eur Radiol 2004 Nov; 14(11): 2025-9[Medline].

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