Klippel-Trenaunay-Weber syndrome
Ayşegül KARALEZLİ1, Seher SEVGİLİ1, Dilek ERNAM TURGUT2, Adnan HASANOĞLU3, H. Canan HASANOĞLU1
1 Ankara Atatürk Eğitim ve Araştırma Hastanesi, Göğüs Hastalıkları Bölümü,
2 Atatürk Göğüs Hastalıkları ve Göğüs Cerrahisi Eğitim ve Araştırma Hastanesi, Göğüs Hastalıkları Kliniği, 3 Ankara Eğitim ve Araştırma Hastanesi, Genel Cerrahi Bölümü, Ankara.
ÖZET
Klippel-Trenaunay-Weber sendromlu bir hastada pulmoner emboli
Klippel-Trenaunay-Weber sendromu (KTWS) kapiller malformasyonlar, venöz lenfatik anomaliler, arteriyovenöz fistüller ve bunların yer aldığı kemik ve yumuşak dokuda hipertrofiyle karakterize konjenital bir hastalıktır. Bu çalışmada 25 yaşın- da, arteriyovenöz malformasyonlar nedeniyle birkaç defa cerrahi operasyon geçiren, ardından profilaktik heparin tedavi- si almasına rağmen pulmoner emboli tanısı alan bir olgu sunuldu. KTWS olan hastalarda derin ven trombozu ve pulmo- ner emboli riskleri değerlendirildi ve hastalığın prognozunda erken tanının önemi vurgulandı.
Anahtar Kelimeler: Klippel-Trenaunay-Weber sendromu, derin ven trombozu, pulmoner emboli.
SUMMARY
Pulmonary embolism in a patient with Klippel-Trenaunay-Weber syndrome
Ayşegül KARALEZLİ1, Seher SEVGİLİ1, Dilek ERNAM TURGUT2, Adnan HASANOĞLU3, H. Canan HASANOĞLU1
1 Department of Pulmonary Diseases, Ankara Atatürk Educational and Research Hospital, Ankara, Turkey, 2 Department of Pulmonary Diseases, Atatürk Chest Diseases and Chest Surgery Center, Ankara, Turkey, 3 Department of General Surgery, Ankara State Hospital, Ankara, Turkey.
Yazışma Adresi (Address for Correspondence):
Dr. Seher SEVGİLİ, Bağlar Caddesi Murat Mahallesi Serhat Sokak Bayraktar Apartmanı No: 33/16 Büyükesat, ANKARA - TURKEY
e-mail: sevgiliseher@yahoo.com
Klippel-Trenaunay-Weber syndrome (KTWS) is a rare, congenital disorder that is described in 1900’s. This syndrome consists of venous and lymphatic anomalies, cutaneous capillary mal- formations; hypertrophy of soft tissue and bone mostly on extremities which have increased vas- cularity and arteriovenous fistula. Deep venous thrombosis can be seen as a complication in this syndrome. It is important to note that despite a higher incidence of deep venous thrombosis in patients with KTWS, pulmonary embolism is a rare event (1).
This case report outlines the clinical history of a patient with KTWS who had a pulmonary em- bolism attack after having many surgical opera- tions.
CASE REPORT
A 25 year old man with KTWS was referred to our state hospital with a history of sudden, bila- teral chest pain, shortness of breath, and he- moptysis for one time at the beginning of pain.
He had loss of power and pain on lower extremi- ties. He suffered from urinary and anal inconti- nence. On own history; he was taken to an uni- versity hospital when 27 days old because of fe- ver, cough and swelling on left lower extremity and had medical treatment with the diagnosis of bronchopneumonia. He was referred to orthope- dic and cardiovascular surgery departments be- cause of congenital hemihypertrophy of left leg.
After examined on these departments he was di- agnosed as KTWS when six months old. When five years old, he was hospitalized and treated for acute lymphangitis. Between 5 and 21 years old the patient was on the control of a university hospital. When 21 years old he had acute lymphangitis attack again and took medical tre-
atment. He was hospitalized in a university hos- pital with acute abdomen findings when he was 22 years old. On evaluation; lumbar puncture and cranial computerized tomogrophy (CT) fin- dings were normal. Abdomen ultrasonography (USG) revealed multiple acoustic shining areas on spleen. Abdomen CT revealed splenomegaly with multiple hypodense lesions on parenchy- ma, multiple mesenteric and paraaortic lympha- denopathies, lytic areas on vertebra corpuses (Figure 1). On bilateral leg magnetic resonance imaging (MRI) there were enlarged vascular structures in subcutaneous, intramuscular tissue and femur medulla compartment of left leg (Fi- gure 2). On thorax CT there were bilaterally multiple nodular infiltrative areas. With these fin- dings he dispatched to medical oncology de- partment with the suspicion of lymphoma. But the patient admitted to a special doctor outside the hospital and was taken six cures of cyclop- hosphamide, doxorubicin, vincristine and pred- Klippel-Trenaunay-Weber syndrome (KTWS) is a congenital disorder characterized by cutaneous capillary malformations, venous-lymphatic anomalies, hypertrophy of soft tissue and bone in the area of increased vascularity and arteriovenous fistulas with shunting. In this article we report the case of a 25 years old man with KTWS who had multiple surgical ope- rations because of arteriovenous malformations. He admitted with pulmonary embolism attack to the hospital although he was taking prophylactic heparin treatment. We evaluate the risk of pulmonary embolism in patients with KTWS, being aware of the risk of deep venous thrombosis in progress of the disease and the importance of early diagnosis in prognosis.
Key Words: Klippel-Trenaunay-Weber syndrome, deep venous thrombosis, pulmonary embolism.
Figure 1. Abdomen CT of the patient showing mul- tiple hypodence lesions on parenchyme of spleen.
nisone (CHOP) regimen chemotherapy with the prediagnosis of non-Hodgkin’s lymphoma wit- hout biopsy. After chemotherapy, radiotherapy had planned by the same doctor but the patient didn’t accept and admitted to a university hospi- tal. Then the patient was hospitalized for 45 days, the laparotomy operation was made in this hospital and on surgery there was no lymphade- nopathy. Splenectomy was made, and liver bi- opsy was taken. On histopathological examina- tion; multiple cystic lymphatic and vascular di- latation areas which have thrombosis were fo- und on spleen, there were no neoplastic chan- ges. With these results the clinical findings of patient was found to be related with KTWS. On spinal MRI there were cystic lesions on vertebra corpuses between T12-L2 segments (Figure 3) and these were suggested to be related to intra- medullar spinal arteriovenous malformations.
Then the patient had loss of power and sensati- on on both lower extremities, and he had his first operation at 23. When he was 25 he had two
more operations in neurosurgical department. In these operations; the branch of arteriovenous malformation feeding was closed by silver clip and coagulation; and then arteriovenous malfor- mation and T11-L3spinal vertebrates were exci- sed totally. After these operations prophylactic anticoagulation therapy with 8000 iu of enoxa- parin sodium was administered subcutaneously every 24 hours. Ten days after these operations the chest pain started.
On examination he had a blood pressure of 120/70 mmHg, a pulse of 86 beats/min and a respiratory rate of 21 breaths/minute On auscul- tation of lungs there were rare inspiratory rales on right basal area. There were operation incisi- on scars on abdomen at median line, on back at lumbar-lower thoracic vertebrate level. The left leg was larger in diameter and taller than the right one. There was reticular hyperpigmentous lesions and nonpitting edema on the left leg (Fi- gure 4). Patient had paraplegia, urinary and anal incontinence.
On laboratory examination, the patient had mic- roscopic hematuria. Serum d-dimer (933 ng/mL) and fibrin degradation proteins (> 500) levels were high. An arterial blood gas analysis revealed a PaO2of 68 mmHg, a PaCO2of 35.2 mmHg and a pH of 7.48. On chest X-ray there were bilateral discoid atelectasis at basal areas (Figure 5). Lower extremity venous doppler ult- rasound revealed intraluminal ecogenious thrombosis material in left posterotibial vein, spontaneous reflux blood flow on both left and right main femoral veins. A ventilation perfusion (V/Q) scan revealed a decrease in perfusion at right lung upper lobe apical segment as seg- mentary and right lung upper lobe posterior seg- ment as subsegmentary and at left lung lingula segment as subsegmentary defects, ventilation scan was normal. There was high probability of pulmonary embolism.
After the diagnosis of pulmonary embolism an- ticoagulation with 60 mg of enoxaparin sodium (6000 IU) administered subcutaneously every 12 hour, and then at fifth day the warfarin the- rapy was initiated in the dose of 10 mg/day.
Enoxaparin sodium was continued until the in- Figure 2. Bilateral leg MRI showing enlarged vascu-
lar structures in subcutaneous, intermuscular tissue and femur medulla compartment of left leg.
Figure 5. Chest X-ray of the patient showing bilate- ral discoid atelectasis at lower zones.
Figure 4. The left leg of the patient is larger and tal- ler than the right one.
renkli..
Figure 3. Spinal MRI showing cystic lesions on vertebra corpusus between T12-L2segments (related to intrame- dullar spinal arteriovenous malformations).
ternational normalized ratio (INR) had reached to the therapeutic range of 2.5-3 in seven days.
Then we decreased the dose of warfarin to 7.5 mg/day and then to 5 mg. We did not plan to place inferior vena cava filter, because there was only one thromboembolism source and the pati- ent had only one attack. With improved clinical and laboratory findings we discharged our pati- ent from the hospital. At least one year antico- agulation with warfarin at the dose of 5 mg/day, maintaining the INR in a 2.5 to 3 range was re- commended.
DISCUSSION
Klippel-Trenaunay syndrome (KTS) was first described by two French doctors, Klippel and Trenaunay in 1900. This congenital vascular di- sorder is described by three main symptoms, known as triad affecting one or more limbs. The triad consists of cutaneous hemangioma, vari- cose veins and bone and soft tissue hypertrophy.
In 1907, Parkes and Weber described a disorder with the same symptoms involved in KTS with the addition of arteriovenous fistula. This deriva- tive of KTS was called Klippel-Trenaunay-Weber syndrome (2-5).
Although the cause of KTWS is still unknown, there are some theories that have been argued by the medical community. These theories are;
a. KTWS is a mesodermal abnormality that ca- uses vascular and soft tissue malformations du- ring fetal development (Baskerville, 1985) (4), b. KTWS is caused by gene mutation (5q or 11p deletion, balanced translocations involving chromosomes 8q 22,3 and 14q 13) (6), c. KTWS is caused as a result of intrauterine injury to the sympathetic ganglia or intermediolateral tract resulting in dilatation of microscopic arteri- ovenous anastomosis (Bliznak and Staple) (2).
d. IGF2 overexpression is involved in the eti- ology of tissue hypertrophy (7).
As incidence there are nearly less than 1000 ca- ses worldwide. Males and females are affected equally. There is no racial predilection (1,3).
KTWS can be diagnosed by clinical observati- ons; laboratory findings, dermoscan, and radi-
ological examination of the bones of the limbs, doppler USG, photopletismography, venoscan and bone isotope scan (8). Recently in a study which made in King Edward Hospital a case of prenatal KTWS was presented with a description of the sonographically observed disease prog- ression in uterus (9). Especially CT and ultraso- und can demonstrate multiple low attenuation areas in the abdominal organs like liver, adrenal glands, kidneys and spleen (10). This finding can result in misdiagnosis, as in our case that was prediagnosed as lymphoma and administe- red chemotherapy of CHOP regimen.
KTWS presents at birth or during early infancy or childhood. Although there are reports of mul- tiple affected limbs, KTWS generally affects a single extremity. The leg is the most common si- te followed by the arms, trunk and rarely the he- ad and neck. Most patients demonstrate all four major signs of the clinical syndrome (1,5,8,11) (Table 1).
In a series of 252 patients with KTS at Mayo Cli- nic; 63% of patients had all features of port wine stain, varicosities and limb hypertrophy. Portwi- ne stain was seen in 98% of patients, varicositi- es in 72% and limb hypertrophy in 67% (2). Our patient had these characteristic features of this syndrome; one leg involvement with bone and soft tissue hypertrophy, dermatological findings with reticular pigmentous lesions and varicose veins, arteriovenous malformations in spleen and spinal column.
KTWS patients demonstrate some of minor fin- dings (2,10) (Table 1). The patient we reported had lymphedema, thrombophlebitis attacks, microscopic hematuria, splenomegaly, spinal arteriovenous fistulas.
There is no known cure for KTWS. Conservative treatment of symptoms seems to be most effec- tive without significant side effects. The nonope- rative management includes external compres- sion with graduated compression bandages or elastic stockings. Patients with recurrent attacks of cellulites may benefit from prophylactic anti- biotic therapy. Orthotic device using for leg length differences is also possible. In general operation should be done to improve cosmosis
at the expense of function. A reason for operati- ve treatment is a leg length discrepancy of mo- re than 2 cm (epiphysiodesis). Laser therapy is useful in some patients for decreasing the inten- sity of capillary malformations. Surgical inter- vention in the treatment of varicosities and ve- nous malformations is controversial. One might consider surgery for either significant cosmetic deformity or the symptoms of pain, heaviness of the leg, bleeding or infectious complications. Ve- nous legation, stripping, excision or sclerothe- rapy are contraindicated unless the surgery is directed to the superficial system. The deep sys- tem must be normal or demonstrate only mild to moderate reflux (2-4). As a result management in most patients with KTWS should be nonope- rative. May be in our patient it would be better if multiple surgical operations are not executed for curative purposes. Also it is important in the management of KTWS to develop an optimal doctor-patient relationship to provide adequate social support (5).
The pulmonary abnormalities associated with KTWS include:
a. Pulmonary lymphatic obstruction, lymphatic hyperplasia, aplasia and hypoplasia,
b. Pulmonary vein varicosities,
c. Cavernous hemangiomas of the pleura le- ading to hemathorax,
d. Thromboembolic phenomenon (1,11-13).
It is important to note that, although deep veno- us thrombosis seems in higher incidence, pul- monary embolism appears to be a rare compli- cation in patients with KTWS. In a small group of patients with KTWS (49 patients) Baskerville et al. estimated the incidence of pulmonary embo- lism to be %14 to %22 (14). Although nearly 1000 KTWS cases have been reported to date only 10 cases of pulmonary embolism in KTWS patients have been published (1,4,15). In some cases pulmonary embolism was recurrent le- ading to chronic thromboembolic pulmonary Table 1. Major and minor findings of KTWS.
Klippel-Trenaunay-Weber Syndrome Major findings
• Port wine stain
• Varicose veins
• Bone and soft tissue hypertrophies
• Arteriovenous fistula with shunting Minor findings
• Trombophlebitis
• Lymph edema
• Polydactyly, syndactyly or macrodactyly
• Length and diameter discrepancy between two extremities
• Congestive heart failure
• Asymmetric facial hypertrophy
• Cataracts, glaucoma
• Micro or macrocephaly
• Seizures or mental retardation
• Rectal bleeding
• Intestinal lymphangiectasia
• Hematuria
• Visceral vascular malformations involving liver, spleen, kidney and bladder
• Spinal arteriovenous fistulas
hypertension and subsequent death (15). Our patient had pulmonary embolism attack 10 days after surgical operations while he was taking prophylactic therapy with enoxaparine. This pul- monary embolism case can be accepted as a postoperative complication, but we think that al- so it can be accepted as a part of KTWS since he had venous thrombosis on the affected leg (left leg). Nevertheless we believe that none of the reasons can be excluded exactly.
In the literature there is no established treatment regimen for the thromboembolism in patients with KTWS. It is recommended that firstly some preventive procedures should be done like not using oral contraceptive drugs, to use deep ve- nous thrombosis prophylaxis regimens after sur- gical procedures etc. We recommend medical treatment if patients have one thrombosis sour- ce and have one attack. Medical treatment inc- ludes anticoagulation with warfarin to a goal INR between 2.5 and 3 for at least one year or life long therapy according to patient’s clinical fin- dings. If patient has recurrent multiple pulmo- nary embolism attacks despite anticoagulation, pulmonary thromboendarderectomy can be applied (11,15), and an inferior vena cava filter can be placed (1,16).
As a conclusion; KTWS is a rare and complex disease. To be aware of this syndrome and its clinical implications are necessary to improve the prognosis and to avoid misdiagnosis.
REFERENCES
1. Gianlupi A, Harper RW, Dwyre DM, Marelich GP. Recur- rent pulmonary embolism associated with Klippel-Trena- unay-Weber Syndrome. Chest 1999; 115: 1199-201.
2. Jacob AG, Driscoll DJ, Shaughnessy WJ, et al. Klippel- Trenaunay Syndrome: Its Spectrum and Management.
Mayo Clinic Proc 1998; 73: 28-36.
3. Lisko JH, Fish F. Klippel-Trenaunay-Weber syndrome.
Med J 2001; 2: 7.
4. Nole MS. Comparing the effects of surgical intervention, chemical intervention, and compression therapy in pati- ents with Klippel-Trenaunay syndrome. Baldwin-Walla- ce College Proc. November 23, 1998.
5. Van der Ploeg HM, Van der Ploeg MNS, Van der Ploeg JD.
Psychological aspects of the Klippel-Trenaunay syndro- me. Journal of Psychosomatic Research 1995; 39: 183-91.
6. Whelan AJ, Watson MS, Porter FD, Steiner RD. Klippel- Trenaunay-Weber syndrome associated with a 5:11 ba- lanced translocation. American Journal of Medical Gene- tics 1995; 59: 492-4.
7. Sperandeo MP, Ungaro P, Vernucci M, et al. Relaxation of insulin-like growth factor 2 imprinting and discordant methylation at KvDMR1 in two first cousins affected by Beckwith-Wiedeman and Klippel-Trenaunay-Weber syndromes. Am J Hum Genet 2000; 66: 841-7.
8. Dervendizi SD, Pavlova LT, V’lckova L, Nikolovska ST, Caca BN. Naevus varicosus osteohypertrophicus. An early diagnostic approach. Adv Exp Med Biol 1999; 455:
535-40.
9. Warhit JM, Goldman MA, Sachs L, Weiss LM, Pek H. Klip- pel-Trenaunay-Weber syndrome: Appearance in utero.
Journal of Ultrasound in Medicine 1983; 2: 515-8.
10. Jafri SZ, Bree RL, Glazer GM, et al. Computed tomog- raphy and ultrasound findings in Klippel-Trenaunay syndrome. Journal of Computer Assisted Tomography 1983; 7: 457-60.
11. Walder B, Kapelanski DP, Auger WR, Fedullo PF. Suc- cessful pulmonary thromboendarderectomy in a patient with Klippel-Trenaunay-Weber syndrome. Chest 2000;
117: 1520-2.
12. Joshi M, Cole S, Knibbs D, Diana D. Pulmonary abnor- malities in Klippel-Trenaunay syndrome. A histologic, ultrastructural and immunocytochemical study. Chest 1992; 102: 1274-7.
13. Owens DW, Garcia E, Pierce RR, Castrow FF. Klippel-Tre- naunay-Weber syndrome with pulmonary vein varico- sity. Archives of Dermatology 1973; 108: 111-3.
14. Baskerville PA. Thromboembolic disease and congenital venous abnormalities. Phlebologie 1987; 40: 531-6.
15. Mikula N, Gupta SM, Miller M, Felder S. Klippel- Trenaunay-Weber syndrome with recurrent pulmonary embolism. Clinical Nuclear Medicine 1991; 16: 253-5.
16. Dilege S. Klippel-Trenaunay sendromu. Fleboloji Dergisi 2001; 3: 11-3.
