Homozygous Factor V Leiden Mutation in a Child With Budd-Chiari Syndrome

Budd-Chiari syndrome is characterized by hepatic venous outflow obstruction. Conditions associated with hepatic vein obstruction include tumors, trauma, surgery, congenital anomalies, parenteral nutrition, ventricular atrial shunt, and thrombosis secondary to hereditary or acquired thrombophilic states (1,2). Despite extensive investigation, no underlying cause can be identified in up to 30% of cases. Factor V Leiden (FVL) mutation, which has been defined recently, is the most common inherited risk factor for venous thrombosis. It has been shown in a few adults with portal or hepatic venous thrombosis (3). We report a child with Budd-Chiari syndrome who was homozygous for the FVL mutation. CASE REPORT A 3-year-old girl, first child of remotely consanguineous parents, was brought to our center with a 1-week history of abdominal distension and edema in the feet, after a few days of vomiting and diarrhea. Examination showed massive ascites and dyspnea and no dehydration. Pulsed Doppler ultrasonography revealed obstruction of the middle and right hepatic veins, retrograde flow in the left hepatic vein, and caudate lobe enlargement of the liver. Inferior vena cavography revealed decreased flow in the inferior vena cava and thrombosis in the hepatic veins. Liver function test results were normal. Hemoglobin was 12.9 g/dl, leukocytes 17.7 × 106/l, and platelets 363 × 109/l. Results of hepatitis serology, an autoantibody screen including anticardiolipin antibodies, an acid Ham's test, and a sickling test were all negative. Prothrombin time was 17 seconds (normal, 12 seconds). Partial thromboplastin time and fibrinogen were normal. Ascites fluid was transudate, without bacterial contamination. Protein C activity was low and S activity normal (26%, normal range, 60-175%; 123%, normal range, 70-123%, respectively). Antithrombin III activity was normal (90%, normal range, 85-115%). The factor V Leiden mutation was determined to be homozygous by amplification of the factor V gene by polymerase chain reaction (PCR) and by digestion of the fragment with MnLI as described by Bertina et al. (4). The patient's mother and father were heterozygous for this mutation. Prothrombin 20210 A mutation was negative. Serum homocysteine level was not determined, but the methyltetrahydrofolate reductase (MTHFR 6TT C-T) mutation, which results in hyperhomocysteinemia when found together with folic acid deficiency, was not present in a homozygous form. DISCUSSION Budd-Chiari syndrome is rare in children. The largest series consists of 22 young patients (5). Among 157 patients from Japan, only 4 were in the pediatric age group (6). It can appear in an acute or chronic form. The acute syndrome is characterized by sudden onset of abdominal distension caused by ascites, abdominal pain, tender hepatomegaly, jaundice, and edema, and it usually progresses to hepatic failure. In chronic form these symptoms and signs develop slowly, over months or years. Although hepatic venography and analysis of a specimen obtained in percutaneous liver biopsy are essential for diagnosis, pulsed Doppler ultrasonography has been used recently with high accuracy and may obviate the need for invasive procedures (7). The association between hepatic vein thrombosis and hereditary or acquired thrombophilic states has been reported (8,9). Inactivation of activated factor V and VIII by the protein C/protein S system is the most important normal anticoagulant mechanism preventing thrombosis formation. The FVL defect is caused by a point mutation in the factor V gene, that leads to activated protein C resistance (4). An impaired anticoagulant response to activated protein C is found in 20% to 30% of patients with idiopathic thromboembolism and in 2% to 5% of healthy people (10). Heterozygotes for this mutation have a 5- to 10-fold increased risk of thrombosis compared with normal people, whereas homozygotes are 50- to 100-fold more susceptible (11). Factor V Leiden mutation has a high prevalence in whites, with a heterozygous rate ranging from 2.9% to 6% (3). The carrier rate is 7.1% in Turkey (12). Despite the high prevalence of the mutation, thrombotic events caused by this defect are relatively rare in children (13-15). It is now recognized that combination of the FVL mutation with other acquired or hereditary risk factors such as protein C or S deficiencies increases the risk of venous thrombosis (16). Budd-Chiari syndrome and activated protein C resistance are described in adults, usually together with a myeloproliferative disorder, protein C and S deficiencies, or antiphospholipid antibodies (16,17). Deninger et al. (18) have evaluated the incidence of FVL mutation in 33 adult patients with hepatic vein thrombosis. The prevalence was 27.3% and FVL was the single recognized risk factor in five of them. The symptoms and signs and clinical course did not differ among patients, with or without the mutation. Mahmoud et al. (3) have also found a carrier rate of 23% among 30 adults with Budd-Chiari syndrome (6 heterozygous, 1 homozygous). This was a rare case in the pediatric age group of acute Budd-Chiari syndrome and homozygous FVL mutation, with no additional risk factor, other than diarrhea. The low-to-normal activity of protein C is attributed to consumption and liver insufficiency, although congenital deficiency is also possible but not easy to confirm because the parents were not studied. FVL mutation is an important diagnosis for planning the therapeutic strategy, for genetic counseling, and for a prophylactic approach to the family members. When relatives are investigated for FVL, anticoagulant therapy can be initiated for those carrying the mutation in conditions with increased risk for thromboembolism, such as surgery or pregnancy (19). Because FVL mutation is highly prevalent and diagnosed easily, it should be sought in patients with Budd-Chiari syndrome.