eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Genetics

Klippel-Trenaunay-Weber Syndrome

Bruce Buehler, MD, Professor, Department of Pediatrics, Pathology and Microbiology, Executive Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center

Updated: Jul 21, 2009

Introduction

Background

Numerous rare congenital defects of skin, blood vessels, and underlying soft tissue are noted. 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.

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.

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 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

Klippel-Trenaunay syndrome 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 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, 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

United States

• Klippel-Trenaunay syndrome and Parkes Weber syndrome are rare sporadic conditions with no racial or geographic predisposition.

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.
  • Pain may also be a feature of Klippel-Trenaunay syndrome.
  • One half of patients can be treated solely using medical means.

Race

• No racial predilection is noted.

Sex

• No sex predilection is observed.

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

History

• 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.
• 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 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.

Physical

• 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. Many authors feel that cavernous or mixed hemangiomas do not occur in Klippel-Trenaunay syndrome or Parkes Weber syndrome.
  • 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.¹ 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.
  • 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 may also occur and cause bleeding and compromise organ function.
  • The low flow vascular malformations in Klippel-Trenaunay syndrome may trap platelets resulting in a mild-to-moderate depression of the platelet count. Consumptive coagulopathy does not occur with the vascular malformations of Klippel-Trenaunay syndrome. 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 Klippel-Trenaunay syndrome. One patient has been described with portosystemic encephalopathy due to intrahepatic portohepatic venous shunts.²  Cases of mental retardation is 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.

Causes

• The etiologies of Klippel-Trenaunay syndrome and Parkes Weber syndrome are unknown. A defect in an angiogenic factor, VG5Q, has been proposed.
• Males and females are equally affected, and no racial predominance is noted. All cases are sporadic.
• One patient has been reported with a translocation of 5q and 11p, which raises the possibility that Klippel-Trenaunay syndrome 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 Klippel-Trenaunay syndrome.
• Although Klippel-Trenaunay syndrome is uncommon, several large series of patients have been reported. Parkes Weber syndrome is much less common than Klippel-Trenaunay syndrome.
• One group proposed that VG5Q is the cause of angiogenesis, but this has since been shown to be a nonspecific polymorphism.³ One patient had a translocation t(8;14)(q22.3;q13) that arose de novo. A specific gene for Klippel-Trenaunay-Weber syndrome in the 8 q region has been proposed but not identified. Presently, no specific gene for Klippel-Trenaunay-Weber syndrome or Parkes Weber syndrome has been identified.

Differential Diagnoses

Other Problems to Be Considered

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

Workup

Laboratory Studies

• 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.

Imaging Studies

• 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.

Treatment

Medical Care

• 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.
• 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).

Surgical Care

• Servelle reported successful surgical intervention (resection or ligation of abnormal blood vessels) in more than 700 patients with Klippel-Trenaunay syndrome.⁴ 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.⁵ Venous varicosities recur after surgery in 90% of patients. Intravenous sclerotherapy has been proposed as an alternative to surgical intervention in Klippel-Trenaunay syndrome and to embolization in Parkes Weber syndrome. Reports have detailed the use of a sclerosant in microfoam.
• Clinicians at all centers agree that a leg length discrepancy of more than 2 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 Klippel-Trenaunay syndrome and Parkes Weber syndrome. A lay support group, the Klippel-Trenaunay Syndrome Support Group, is available.

Activity

• Patient activities are as tolerated.

Medication

Antiplatelet agents

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.

Dosing

Adult

1-2 mg/kg/d PO for antiplatelet effect

Pediatric

Administer as in adults

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

Contraindications

Documented hypersensitivity; liver damage; hypoprothrombinemia; vitamin K deficiency; bleeding disorders; asthma

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Pregnancy category D in third trimester; may cause transient decrease in renal function; may exacerbate chronic kidney disease

Corticosteroids

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.

Dosing

Adult

5-60 mg/d PO

Pediatric

2 mg/kg/d PO

Interactions

Decreases effects of salicylates and toxoids (for immunizations); phenytoin, carbamazepine, barbiturates, and rifampin decrease effects

Contraindications

Documented hypersensitivity; viral, fungal, or tubercular skin lesions

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in hyperthyroidism, osteoporosis, cirrhosis, nonspecific ulcerative colitis, peptic ulcer disease, diabetes, and myasthenia gravis

Follow-up

Complications

• For complications of Klippel-Trenaunay-Weber syndrome, 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.⁵ 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.¹

Patient Education

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

Miscellaneous

Medicolegal 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 Klippel-Trenaunay syndrome (KTS)

Multimedia

Media file 1: 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.

References

1. Robertson DJ. Congenital arteriovenous fistulae of the extremities. Ann R Coll Surg Engl. 1956;18:73-98.

2. Yazaki M, Kaneko K, Tojo K, Miyazaki D, Shimojima Y, Ueda K. An unusual case of Klippel-Trénaunay-Weber syndrome presenting with portosystemic encephalopathy. Intern Med. 2008;47(18):1621-5. [Medline].

3. Brouillard P, Vikkula M. Genetic causes of vascular malformations. Hum Mol Genet. Oct 15 2007;16 Spec No. 2:R140-9. [Medline].

4. Servelle M. Klippel and Trenaunay's syndrome. 768 operated cases. Ann Surg. Mar 1985;201(3):365-73. [Medline].

5. Jacob AG, Driscoll DJ, Shaughnessy WJ, et al. Klippel-Trenaunay syndrome: spectrum and management. Mayo Clin Proc. Jan 1998;73(1):28-36. [Medline].

6. Berry SA, Peterson C, Mize W, et al. Klippel-Trenaunay syndrome. Am J Med Genet. Oct 2 1998;79(4):319-26. [Medline].

7. Cabrera J, Cabrera J, Garcia-Olmedo MA, Redondo P. Treatment of venous malformations with sclerosant in microfoam form. Arch Dermatol. Nov 2003;139(11):1409-16. [Medline].

8. 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. Jun 14 1996;63(3):426-7. [Medline].

9. Cohen MM. Klippel-Trenaunay syndrome. Am J Med Genet. Jul 31 2000;93(3):171-5. [Medline].

10. Huiras EE, Barnes CJ, Eichenfield LF, et al. Pulmonary thromboembolism associated with Klippel-Trenaunay syndrome. Pediatrics. Oct 2005;116(4):e596-600. [Medline].

11. Kasabach HH, Merritt KK. Capillary hemangioma with extensive purpura: a report of a case. Am J Dis Child. 1940;59:1063-70.

12. Kinmonth JB, Young AE, Edwards JM, et al. Mixed vascular deformities of the lower limbs, with particular reference to lymphography and surgical treatment. Br J Surg. Dec 1976;63(12):899-906. [Medline].

13. Klippel M, Trenaunay P. Du naevus variqueux osteohypertrophique. Arch Gen Med. 1900;185:641-72.

14. Lee A, Driscoll D, Gloviczki P, et al. Evaluation and management of pain in patients with Klippel-Trenaunay syndrome: a review. Pediatrics. Mar 2005;115(3):744-9. [Medline].

15. Maari C, Frieden IJ. Klippel-Trenaunay syndrome: the importance of "geographic stains" in identifying lymphatic disease and risk of complications. J Am Acad Dermatol. Sep 2004;51(3):391-8. [Medline].

16. Samuel M, Spitz L. Klippel-Trenaunay syndrome: clinical features, complications and management in children. Br J Surg. Jun 1995;82(6):757-61. [Medline].

17. Stephan MJ, Hall BD, Smith DW, Cohen MM Jr. Macrocephaly in association with unusual cutaneous angiomatosis. J Pediatr. Sep 1975;87(3):353-9. [Medline].

18. Stickler GB. Klippel-Trenaunay syndrome. In: Gomez MR, ed. Neurocutaneous Diseases: A Practical Approach. Butterworth-Heinemann; 1987:368-75.

19. Tian XL, Kadaba R, You SA, et al. Identification of an angiogenic factor that when mutated causes susceptibility to Klippel-Trenaunay syndrome. Nature. Feb 12 2004;427(6975):640-5. [Medline].

20. Weber PF. Angioma: formation in connection with hypertrophy of limbs and hemihypertrophy. Br J Dermatol. 1907;19:231-5.

21. Whelan AJ, Watson MS, Porter FD, Steiner RD. Klippel-Trenaunay-Weber syndrome associated with a 5:11 balanced translocation. Am J Med Genet. Dec 4 1995;59(4):492-4. [Medline].

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23. Ziyeh S, Spreer J, Rossler J, et al. Parkes Weber or Klippel-Trenaunay syndrome? Non-invasive diagnosis with MR projection angiography. Eur Radiol. Nov 2004;14(11):2025-9. [Medline].

Keywords

Parkes Weber syndrome, PWS, Klippel-Trenaunay syndrome, KTS, Kasabach-Merritt syndrome, angioosteohypertrophy syndrome, cutaneous capillary malformation, congenital vascular nevus, capillary hemangioma, port-wine stain, Klippel-Trenaunay-Weber syndrome, capillary hemangioma, port-wine stain, arteriovenous malformation, AVM, consumptive coagulopathy, mental retardation, treatment, diagnosis

Contributor Information and Disclosures

Author

Bruce Buehler, MD, Professor, Department of Pediatrics, Pathology and Microbiology, Executive Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center
Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association
Disclosure: Nothing to disclose.

Medical Editor

Michael Fasullo, PhD, Senior Scientist, Ordway Research Institute; Associate Professor, State University of New York at Albany; Adjunct Associate Professor, Center for Immunology and Microbial Disease, Albany Medical College
Michael Fasullo, PhD is a member of the following medical societies: Radiation Research Society
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

Margaret M McGovern, MD, PhD, Professor and Chair of Pediatrics, Stony Brook University, New York
Margaret M McGovern, MD, PhD is a member of the following medical societies: American Academy of Pediatrics and American Society of Human Genetics
Disclosure: Genzyme Grant/research funds PI

CME Editor

Paul D Petry, DO, FACOP, FAAP, Consulting Staff, Freeman Pediatric Care, Freeman Health System
Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association
Disclosure: Nothing to disclose.

Chief Editor

Bruce Buehler, MD, Professor, Department of Pediatrics, Pathology and Microbiology, Executive Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center
Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association
Disclosure: Nothing to disclose.

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author James H Tonsgard, MD, to the original writing and development of this article.

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