Epidemiological profile of 58 patients with Klippel-Trenaunay-Weber syndrome followed at Ambulatório da Santa Casa de São Paulo

Abstracts

CONTEXTO: A síndrome de Klippel-Trénaunay-Weber é uma doença rara sobre a qual encontramos poucos artigos na literatura (geralmente relatos de casos esporádicos relacionados a complicações). OBJETIVO: Avaliar o perfil epidemiológico dos portadores da referida síndrome. MÉTODOS: Foram copilados dados dos prontuários de 58 pacientes acompanhados no ambulatório de doenças linfáticas e angiodisplasias da disciplina de Cirurgia Vascular da Faculdade de Ciências Médicas da Santa Casa de São Paulo. RESULTADOS: A distribuição foi igual entre homens e mulheres (30 homens e 28 mulheres). A idade média dos pacientes em tratamento foi de 12,8 anos. Na maioria dos casos, a doença foi diagnosticada na infância, sendo a mancha em vinho do porto o primeiro sinal notado pela família, no nascimento ou primeiro ano de vida. O sintoma mais referido foi a dor, normalmente relacionada aos sintomas de estase venosa, sendo o sintoma considerado debilitante. Pela classificação CEAP, encontramos as crianças nas classes C0 e C1 e a maioria dos adultos nas classes avançadas. Foi diagnosticada a presença de fístulas arteriovenosas em 8,5% dos casos. Apenas 6,8% referiram história familiar. CONCLUSÃO: A síndrome de Klippel-Trénaunay e a síndrome de Parkes Weber são apresentações diferentes de uma única enfermidade e podem ser estudadas conjuntamente como síndrome de Klippel-Trénaunay-Weber. O melhor momento para reconhecer os portadores e poder amenizar a progressão de insuficiência venosa, hipertrofia óssea e tecidos moles é a infância. O tratamento compressivo deve ser indicado a todos os portadores com o intuito de diminuir a evolução da doença venosa periférica.

Angiodisplasias; Síndrome de Klippel-Trénaunay-Weber; vascular; síndrome

ORIGINAL ARTICLE

Epidemiological profile of 58 patients with Klippel-Trenaunay-Weber syndrome followed at Ambulatório da Santa Casa de São Paulo

André Luis Costa Villela; Luis Gustavo Schaefer Guedes; Victor Vinicius Augusto Paschoa; André Bernardes David, Thiago Marques Tenório; Henrique Pereira Lamego Junior; Henrique Jorge Guedes Neto; Roberto Augusto Caffaro^*

Correspondence

ABSTRACT

Background: Klippel-Trenaunay-Weber syndrome is a rare disorder about which there are few articles available (most of them are sporadic case reports related to complications).

Objective: To assess the epidemiological profile of patients with Klippel-Trenaunay-Weber syndrome.

Methods: Medical records of 58 patients followed at the lymphatic disease and angiodysplasia outpatient clinic for the discipline of Vascular Surgery at the School of Medical Sciences of Santa Casa de São Paulo were reviewed.

Results: The disorder affected males and females equally (30 males and 28 females). The mean age of patients under treatment was 12.8 years. In most cases, the syndrome had been diagnosed in childhood, with Port wine stain as the first sign noticed by the family at birth or during the first year of life. The most frequently reported symptom was debilitating pain usually associated with symptoms of venous stasis. The CEAP classification was C0 and C1 for younger patients and C4-C6 for most older patients. Arteriovenous fistulas were diagnosed in 8.5% of cases. Positive family history was reported by only 6.8% of patients.

Conclusion: Klippel-Trenaunay and Parkes Weber syndromes are different presentations of a same disorder and they can be studied as one, Klippel-Trenaunay-Weber syndrome. Childhood is the optimal moment to identify affected patients and to reduce progression of venous insufficiency and bony and soft tissue hypertrophy. Compression should be indicated for all affected patients to reduce progression of peripheral venous disease.

Keywords: Angiodysplasias, Klippel-Trenaunay-Weber syndrome, vascular, syndrome.

Introduction

Klippel-Trenaunay-Weber syndrome (KTWS) is the name for a condition which combines at least two of the following clinical signs: port-wine stains, venous anomalies and bone and soft tissue hypertrophy.

It was first described in 1900 by Maurice Klippel and Paul Trenaunay, who reported the cases of two patients presenting with port-wine stains, varicose veins and bone and soft tissue hypertrophy; they named it naevus vasculosus osteohypertrophicus.¹ Seven years later, Frederick Parkes Weber described cases with signs similar to those described by Klippel and Trenaunay.² In 1918, Parkes Weber described a case in which an arteriovenous fistula was associated with the triad of clinical signs referred to above.^3,4

Initially, these two syndromes were studied separately; the presence of arteriovenous fistula was considered an exclusive characteristic of Parkes-Weber syndrome. After observing cases in which they identified previously undiagnosed arteriovenous fistulas, capillary fistulas for both pathologies and similarities in their clinical statuses and evolution, some authors considered them as a unique syndrome and suggested a name for it: Klippel-Trenaunay-Weber syndrome.⁵

KTWS is a rare congenital mesodermal disorder of unknown etiology and varied expressions. It can be due to a mutation to autosomal dominant, arising during embryogenesis, or to autosomal dominant with incomplete penetrance. This explains familial occurrence. There is not a regular pattern of generational periods for this condition; it can be carried by many generations of phenotypically normal individuals.^6,7

KTWS is a syndrome that causes injuries in different levels, with diverse vascular malformations including capillary malformation, arterial or venous dysplasias, venous system malformations or arteriovenous fistulas. The triad of signs described above comprises flat hemangioma, which affects 98-100% of patients, venous abnormalities such as malformations and varicose veins, which affects 72% of patients, and bone and soft tissue hypertrophy, observed in 67% of cases. The presence of three clinical signs is observed in 63% of patients, while 37% of patients present with only two of them.^7,8

In the vast majority of cases, the syndrome affects only one lower limb (80-85%). Both lower limbs are affected in 12.5% of cases and contralateral limbs are affected in 2.5% of cases. In less than 1% of occurrences, it can affect both upper and lower limbs.⁸

Port-wine stains, observable at birth, are the first sign. They can appear in dermatomes or in random distribution. They frequently affect the hypertrophic limb, but can also affect other parts of the body and can vary in deepness (limited to the epidermis or affecting subcutaneous layers).⁹

Venous malformations include venous hypoplasia, absence of valves and aplasia of the deep venous system. They are more common on lower limbs and no predisposition was found for the saphenous vein. Due to changes in the venous systems, phlebitis, bleeding, deep venous thrombosis, pulmonary embolism and chronic venous insufficiency can occur.⁴

The presence of arterial or venous dysplasias is common and can affect any part of the body, from skin to visceral organs. Therefore, there is the possibility for bleeding in these areas, causing hemoperitoneum, hemothorax, hematuria or enteric hemorrhage.¹⁰

Bone and soft tissue hypertrophy is noticeble during the first years of life and progresses at different paces until 12 years of age. Length discrepancy between lower limbs varies from less than 1 cm to 12 cm. This difference can lead to changes in walking and scoliosis.⁴

Soft tissue hypertrophy seems to be a primary process, and not secondary to vascular malformation, as was once argued.⁴ The relationship of bone hypertrophy to vascular changes is not well established either, but it is believed that an increased arterial blood flow in the epiphysis due to arteriovenous fistulas or capillaries can cause the hypertrophy.⁴

Pain is the most frequent symptom and it can be triggered by venous disease, by scoliosis due to different length of limbs or by hemangiomas that affect diverse areas in the epidermis, subcutaneous layers or visceral organs.

Duplex scan should be the first examination to be performed because it is reliable in assessing the superficial and deep venous system and it is useful in identifying vascular dysplasias and arteriovenous fistulas. Computed tomography and magnetic resonance imaging are complementary to duplex scan and are used in order to assess vascular dysplasias and establish their characteristics so that the treatment can be defined.^11,12

A scanogram should be performed to assess the length discrepancy between lower limbs in order to evaluate the need for ortheses to compensate it.

Arteriography is useful to identify and plan the embolization of arteriovenous fistulas and vascular dysplasias. Venography can be useful to evaluate the need for interventions in the venous system, but this evaluation should be based on both the venography and the duplex scan. Magnetic resonance angiography has shown promising results as a substitute for angiography.^8,13,14

Treatment of KTWS is essentially conservative, with the use of compression therapy and venotonic and lymphokynetic drugs, as well as anti-inflammatory medication for pain control.^11,12

Surgical treatment for fistulas is contraindicated due to negative results and to recurrence of symptoms. Surgical intervention on the superficial venous system is controversial and should be reserved to very symptomatic patients who have a patent deep venous system. However, some authors presented satisfactory results of interventions on the deep venous system and new surgical techniques for the treatment of the superficial venous system such as radiofrequency ablation, endolaser and foam sclerotherapy.^13-19

The objetive of this study was to assess the epidemiological profile of patients with KTWS followed at the lymphatic disease and angiodysplasia outpatient clinic for the discipline of Vascular Surgery at the School of Medical Sciences of Santa Casa de São Paulo.

Methods

Medical records of 58 patients followed at the lymphatic disease and angiodysplasia outpatient clinic for the discipline of Vascular Surgery at the School of Medical Sciences of Santa Casa de São Paulo were reviewed. Patients included in this study attended at least one medical appointment between April 2007 and October 2008.

Since there were no changes in the treatment planned by the time of the survey, but only the observation of the treatment performed, the research ethics committee approved this study.

The venous disease was classified according to the CEAP classification, taking into consideration all the elements, as recommended.

Results

Our data revealed that the disorder affected males and females equally (30 males and 28 females). In the beginning of treatment, the age of patients ranged from 1 to 35 years, with a mean age of 12.8 years in the moment of diagnosis. The first sign observed by the family was the port-wine stain, either at birth or during the first year of life.

In most cases, one lower limb was affected (40% for left lower limb and 46% for right lower limb). In 9% of patients, KTWS affected both lower limbs, in 3% it affected both upper and lower limbs on the same side and in 2% it affected only the left upper limb.

Lower limb length discrepancy was observed in 77.5% of patients, but it exceeded 25 mm only in six patients, accounting for 10% of cases. Discrepancy ranged from 3 to 30 mm, with a mean of 11.5 mm. There were not any patients with indication for orthopedic surgery; the use of ortheses was indicated for all of them (Figure 1).

The most frequently reported symptom was pain, in 68% of cases; of which, 80% had pain associated with venous stasis. Edema was reported by 31 patients, accounting for 53%. Most patients tolerated symptoms, which were considered to be impairing by 10 patients, the cause for the pain by nine and to be associated with recurrent enteric hemorrhage by one.

Port-wine stains were found in 54 patients, accounting for 93.1% of cases. This was the first physical sign noticed by the family and also the one most frequently found. The second most common sign, which was found in 86.2% of cases, was bone or soft tissue hypertrophy.

Venous changes were present in 72.4% of patients, and they were observed as varicose veins in 56.8% and as vascular malformations including vascular dysplasias, deep venous system changes and arteriovenous fistulas in 25.8%. Varicose veins associated with malformations were observed in 7.4% of patients.

In relation to the classification of the venous disease according to CEAP, 56.8% of patients had visible varicose veins, 53% had edema and 13.7% had trophic changes secondary to venous stasis. Three patients presented with stasis ulcer, one patient had active ulcer and two had healed ulcer (Figure 2).

Arteriovenous fistulas were diagnosed in four out of 47 patients, since 11 patients (8.5%) did not undergo imaging studies because they were too young. Positive family history was reported by only 6.8% of patients. Other venous changes found were sporadic.

Discussion

Due to the observation that a patient presenting without arteriovenous fistulas in the first assessments can present them in future exams; to the fact that both Klippel-Trenaunay syndrome and Parkes Weber syndrome are characterized by capillary fistulas; and to the similarities between their symptoms and evolution, they are considered as a unique syndrome named Klippel-Trenaunay-Weber syndrome, in what we agree with Mullins in his 1962 article.⁵

It affected males and females equally. It is during childhood that the disorder is diagnosed, and the first sign to be noticed are port-wine stains, which are observable at birth and are also the most frequent sign, as was found by Curado, Mulliken and Viljoen.^9,10,12

Venous changes were observed in 72.4% of cases in our study; a similar distribution was reported by Curado in 2008 and by Dellis in 2007.^8,11 However, while venous changes are reported by these authors as the second most frequent sign of the syndrome, in our data, bone and soft tissue hypertrophy is the second most frequent change, found in 86.2% of cases.

Based on the CEAP classification, many cases under grades C0 and C1, which are more frequent in childhood, were found; trophic changes secondary to venous stasis are rare in this period of life. However, in general, grades C2 and C3 were the most frequent in our data.

This fact seems to be related to the large number of children in our sample, as more cases under C4, C5 and C6 were found among adults (patients over 16 years). This allows us to follow the evolution of venous disease in patients affected by the syndrome and claim that treating the venous disease is important, since the most commonly reported and debilitating symptom was pain associated with chronic venous insufficiency.

The incidence of arteriovenous fistulas was rare and it was not related to clinical status severity or to bone and soft tissue hypertrophy. The same findings were reported by Ziyeh in 2004.¹³ It reveals that there is not any pathophysiological relation between macroscopic arteriovenous fistulas and the other clinical signs of the syndrome, such as hypertrophy and venous changes.

Taking into consideration symptoms and bleeding, the factor that most contributed to severity of the syndrome were complex venous malformations, such as avalvular or hypoplasic deep venous system and vascular dysplasias in sites with difficult access.

Debilitating clinical consequences are usually related to bone and soft tissue hypertrophy in childhood, chronic venous insufficiency in adults and uncommon venous changes that cause recurrent bleeding.

Treatment should be focused on clinical control of chronic venous insufficiency and surgical intervention in patients with large varicose veins and patent deep venous system, as well as preventing complications caused by vascular dysplasias.

The great challenge in the treatment of this syndrome is to improve the quality of life of patients with enhanced bone and soft tissue hypertrophy. Great progress in the management of KTWS will be achieved when patients with a more severe clinical status are identified early and treatment options to reduce or control bone growth and soft tissue hypertrophy are developed, either through surgery or based on therapies to suppress the effect of the gene mutation that causes the syndrome. It will allow us to be more effective in treating severe patients without the side effects of current treatments offered to patients with the mild form of the syndrome.

Conclusion

Klippel-Trenaunay and Parkes Weber syndromes are different presentations of a same disorder and they can be studied as one, Klippel-Trenaunay-Weber syndrome.

In most patients, the syndrome is apparent during childhood. They do not present with clinical changes of high morbidity. This is the ideal moment to identify patients with KTWS in order to employ therapies that may reduce morbidity caused by the syndrome.

Treatment of choice is still conservative and it is focused on controlling the venous disease and relieving symptoms. Compression should be indicated for all patients with the syndrome in order to reduce peripheral venous disease, which was found in few children and adolescents and reported as a frequent cause of symptoms in adults. The use of insole or special shoes lessens the deformity in the spine caused by length discrepancy between lower limbs.

The patient with the syndrome should be followed by an experienced reference center with a diverse therapeutic arsenal in order to offer the best treatment in cases of advanced venous insufficiency, macroscopic arteriovenous fistulas and complex vascular dysplasias.

It is essential that information be conveyed to our fellow pediatricians on the importance of early diagnosis for the adequate treatment of this syndrome.

References

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• 2. Weber FP. Angioma formation in connection with hypertrophy of limbs and hemi-hypertrophy. Br J Dermatol Syph. 1907:19;231-5.
• 3. Weber FP. Haemangiectatic hypertrophy of limbs: congenital phlebarteriectasis and so-called congenital varicose veins. Br J Child Dis. 1918;15:13-7.
• 4. Kihiczak GG, Meine JG, Schwartz RA, Janniger CK. Klippel-Trenaunay syndrome: a multisystem disorder possibly resulting from a pathogenic gene for vascular and tissue overgrowth. Int J Dermatol. 2006;45:883-90.
• 5. Mullins JF, Naylor D, Redetzki J. The Klippel-Trenaunay-Weber syndrome. Arch Dermatol. 1962;86:202-6.
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• 7. Wang QK. Update on the molecular genetics of vascular anomalies. Lymphat Res Biol. 2005;3:226-33.
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• 12. Curado JH, Campos HGA. Angiodisplasias. In: Maffei FA. Doenças vasculares periféricas. 4Ş ed. Rio de Janeiro: Guanabara Koogan; 2008.
• 13. Ziyeh S, Spreer J, Rössler J, et al. Parkes Weber or Klippel-Trenaunay syndrome? Non-invasive diagnosis with MR projection angiography. Eur Radiol. 2004;14:2025-9.
• 14. Frasier K, Giangola G, Rosen R, Ginat DT. Endovascular radiofrequency ablation: a novel treatment of venous insufficiency in Klippel-Trenaunay patients. J Vasc Surg. 2008;47:1339-45.
• 15. Gloviczki P, Driscoll DJ. Klippel-Trenaunay syndrome: current management. Phlebology. 2007;22:291-8.
• 16. Lee A, Driscoll D, Gloviczki P, Clay R, Shaughnessy W, Stans A. Evaluation and management of pain in patients with Klippel-Trenaunay syndrome: a review. Pediatrics. 2005;115:744-9.
• 17. Nguyen S, Franklin M, Dudek AZ. Skin ulcers in Klippel-Trenaunay syndrome respond to sunitinib. Transl Res. 2008;151:194-6.
• 18. Nitecki S, Bass A. Ultrasound-guided foam sclerotherapy in patients with Klippel-Trenaunay syndrome. Isr Med Assoc J. 2007;9:72-5. Comment in: Isr Med Assoc J. 2007;9:112-4.
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*

Disciplina de Cirurgia Vascular, Faculdade de Ciências Médicas da Santa Casa de São Paulo, São Paulo, SP

Publication Dates

• Publication in this collection
  05 Jan 2010
• Date of issue
  Sept 2009

History

• Accepted
  01 July 2009
• Received
  23 Dec 2008