Brief Communications Combined Genetic Defects in a Child With Ischemic Stroke: Case Report to pain and touch on the right side. The patient was diagnosed with right ABSTRACT bin time were normal. Electroencephalographic examination was normal. Cranial computed tomographic scan was normal. At the age of 10 years, magnetic resonance imaging demonstrated, on T.~ weighted sequences, the hemiparesis. During that time, laboratory examinations were normal, including complete blood cell counts, liver function tests, renal function tests, blood glucose level, and urinalysis. Prothrombin time, bleeding time, and throm- A 10-year-old Turkish boy was admitted with mild right spastic hemi- plegia. First, he experienced sudden numbness and weakness in the right extremities at the age of 2 years and was diagnosed with right hemiparesis. His parents were generally healthy and nonconsanguineous. His mother suffered from deep vein thrombosis of the left lower extremity during pregnancy and had recurrent fetal loss. At the age of 10 years, a thrombophilia marker examination revealed that plasma-free protein S was 49.3% (normal range 70-123%), and factor VIII level was found to be 470 IU/dL (normal = 150 IU/dL). The patient and his two siblings were found to be het= erozygous for factor V Leiden mutation. His mother was also heterozygous for factor V Leiden mutation and had protein S deficiency A combination of protein S deficiency, factor V Leiden mutation, presence of a gliotic area in the superior limb of the internal capsule of the left thalamus (Figure 1). At the age of 10 years, he exhibited mild right spastic hemiplegia. A thrombophilia marker examination revealed that protein C, antiphospholipid antibodies, factor IX, and antithrombin III levels were within normal limits, and the prothrombin 20210G-A mutation was negative. Plasma-free protein S was 49.3% (normal range 70-123%), and the factor VIII level was found to be 470 IU/dL (normal 150 IU/dL). The patient, his parents, and his two siblings were examined for factor V Leiden mutation. The patient and his two siblings were found to be heterozygous for factor V Leiden muta= = tion. His mother was heterozygous for the factor V Leiden mutation and had protein S deficiency. In the patient, a combination of protein S deficiency, factor V Leiden mutation, and a high level of factor VIII was detected. After his first attack at the age of 2 years, despite no prophylaxis, he did not experience any other ischemic insult. and a high level of factor VIII was detected in our patient. After his first attack at the age of 2 years, in spite of no prophylaxis, he did not experience any other ischemic insult. To our knowledge, this is the first patient with these combinations of genetic defects and ischemic stroke to be reported in the literature. (J Child Neurol 2002;17:533-534). Childhood stroke is increasingly recognized, but studies remain largely descriptive. The incidence of childhood ischemic stroke exceeds 3.3 in 100,000 children per year, more than double the estimates from past decades.’ The most common cause of ischemic Discussion Thrombophilias are known to promote ischemic stroke. Inherited gene defects related to coagulation system have been reported as risk factors for stroke.’ The three major thrombophilias that have been identified are deficiencies of antithrombin III, protein C, and protein S.’ Several reports revealed that familial protein S deficiency commonly results in recurrent deep venous thrombosis in patients and their family members.8 Both our patient and his mother had factor V Leiden mutation. Furthermore, protein S deficiency is a recognized risk factor for venous thrombosis, and factor V Leiden mutation can play a role in women having recurrent abortions.’,&dquo; stroke in children is thrombotic vessel occlusion. Risk factors for venous thrombosis are prothrombin 20210G-A (PT20210), the fac- tor V Leiden 1691 G-A mutation, and hereditary deficiencies of pro- tein S, protein C, and antithrombin III. 2,3 Recently, another thrombophilic factor has been described, that is, an increased plasma concentration of factor VIII.4 Studies have shown that an elevated level of factor VIII procoagulant activity is likely an independent, relatively prevalent risk factor for venous thrombosis.5 We report a 10-year-old boy who presented with ischemic stroke associated with combination of heterozygous factor V Leiden mutation, protein S deficiency, and a high plasma level of factor VIII. This is the first pediatric case with this combination of genetic defects. Case Report A Turkish boy was bom after a normal pregnancy and uneventful delivery weighing 3500 g. His parents are healthy and nonconsanguineous. His mother suffered from deep vein thrombosis of the left lower extremity during pregnancy and had recurrent fetal loss. At the age of 2 years, his right extremities experienced sudden numbness and weakness. On examination, mental function, cranial nerves, and strength and sensation of the left upper and lower extremities were normal. Reflexes were also normal on the left side of the body. However, both right upper and lower extremities were flaccid, paralyzed, and areflexic, and plantar response could not be obtained on the right lower extremity. There was also sensory diminution Axial T 2-weighted image shows a gliotic area in the superior limb of the internal capsule of the left thalamus. Figure 1. 533 Downloaded from jcn.sagepub.com at Uni of Southern Queensland on June 20, 2015 534 His mother had deep vein thrombosis and recurrent fetal loss Hüseyin Qaksen, MD Department of Pediatrics Faculty of Medicine owing to a combined hemostatic defect (protein S deficiency and factor V Leiden). The factor V Leiden mutation, causing resistance to activated Yüzüncü Yil University protein C, has been recognized as the most important genetic thrombophilia. Carriers of this mutation have a five- to seven-fold increased risk of ischemic stroke. Previously, we have found a high , concordance of pediatric cerebral infarcts and the presence of factor V Leiden mutation.ll Recent reports have suggested that elevated plasma levels of factor VIII:C are a significant, prevalent, independent, and dose- Van, Turkey Nejat Akar, MD Department of Pediatric Molecular Genetics Faculty of Medicine Ankara University Ankara, Turkey dependent risk factor for venous thromboembolism. Individuals with factor VIII: C exceeding 1500 IU/L had a six-fold increased risk compared with those with factor VIII:C levels less than 1000 IU/L. Also, prospective follow-up has shown that patients with high factor VIII:C levels are at increased risk for episodes of recurrent venous thrombosis. Received Nov 29, 2001. Accepted for publication April 17, 2002. This work was carried out in the Department of Pediatrics, Faculty of Medicine, Ankara University, Ankara, Turkey. Address correspondence to Dr Dilara lqagasioglu, Department of Pediatrics, Faculty of Medicine, Cumhuriyet University, Sivas, Turkey. Tel: + 0 90 432 217 61 28; fax: + 0 90 432 215 04 79; e-mail: sense70@hotmail.com. However, the mechanism underlying the elevation in factor VIII remains unknown. A family study indicated a high concordance for elevated factor VIII:C plasma concentrations among first-degree family members.4,5,12 Plasma factor VIII level was determined to be 470 IU/dL in our patient. Our patient had a severe protein S deficiency, heterozygous for factor V Leiden, and a high plasma factor VIII level, and his mother had a protein S deficiency, heterozygous for factor V Leiden. Additionally, his siblings were found to be heterozygous for References factor V Leiden mutation. The simultaneous occurrence of hered- itary thrombophilias and prothrombotic polymorphisms was shown to substantially increase the risk of thromboembolic events. 13 Moreover, recent reports have also described an enhanced risk for the development of thrombosis in individuals with a combined defect compared with a single defect. Our recent report indicated that two patients with ischemic stroke had a combination of a factor V Leiden and a prothrombin G20210A mutation. 11 Lewandowski et al 14 noted combined hemostatic defects with symptomatic car- 1. de Veber G, Roach ES, Riela AR, Wiznitzer M: Stroke in children: Recognition, treatment, and future directions. Semin Pediatr Neurol 2000;7:309-317. 2. Dusser A, Goutieres F, Aicardi J: Ischemic strokes in children. J Child Neurol 1986;1:131-136. 3. Comp PC, Nixon RR, Cooper MR, Esmon CT: Familial protein S deficiency is associated with recurrent thrombosis. J Clin Invest 1984;74: 2082-2088. 4. 5. Kraaijenhagen RA, in’t Anker PS, Koopman MM, et al: High plasma concentration of factor VIIIc is a major risk factor for venous thromboembolism. Thromb Haemost 2000;83:5-9. 6. Nowak-Gottl U, Strater R, Heinecke A, et al: Lipoprotein (a) and genetic polymorphisms of clotting factor V, prothrombin, and methylenetetrahydrofolate reductase are risk factors of spontaneous ischemic stroke in childhood. Blood 1999;94:3678-3682. 7. Lane DA, Mannucci PM, Bauer KA, et al: Inherited thrombophilia: Part 1. Thromb Haemost 1996;76:651-662. 8. Makris M, Leach M, Beauchamp NJ, et al: Genetic analysis, phenotypic diagnosis, and risk of venous thrombosis in families with inherited deficiencies of protein S. Blood 2000;95:1935-1941. 9. Meinardi JR, Middeldrop S, de Kam PJ, et al: Increased risk for fetal loss in carriers of the factor V Leiden mutation. Ann Intern Med 1999; 130:736-739. 10. Rosendaal FR: High levels of factor VIII and venous thrombosis. Thromb Haemost 2000;83:1-2. 11. Akar N, Akar E, Deda G, et al: Factor V1691 G-A, prothrombin 20210 G-A and methylenetrahydrofolate reductase 677 C-T variants in Turkish children with cerebral infarct. J Child Neurol 1999;14:749-751. 12. O’Donnell J, Laffan M: Elevated plasma factor VIII levels—A novel risk factor for venous thromboembolism. Clin Lab 2001;47:1-6. 13. Mustafa S, Mannhalter C, Rintelen C, et al: Clinical features of thrombophilia in families with gene defects in protein C or protein S combined with factor V Leiden. Blood Coagul Fibrinolysis 1998;9:85-89. Dilara Içağasioğlu, MD 14. Department of Pediatrics Faculty of Medicine Cumhuriyet University Sivas, Turkey Lewandowski K, Rozek M, Turowiecka Z, et al: Combined hemostatic defects in family members of symptomatic carriers of Leiden mutations of factor V. Pol Arch Med Wewn 1998;99:211-217. 15. Kenet G, Sadetzki S, Murad H, et al: Factor V Leiden and antiphospholipid antibodies are significant risk factors for ischemic stroke in riers of Leiden mutations of factor V (eg, factor V Leiden with protein S deficiency, prothrombin G20210A mutation, and antithrombin III deficiency). This report and the other data indicate a higher risk for development of thrombosis in individuals with combined defect. ~-i5 Our patient presented with ischemic stroke associated with a combination of O’Donnell J, Andrew DM, Richard AM, et al: Elevation of FVIII:C in independent of the acute phase response. Blood 1998;93(Suppl):501. venous thromboembolism is persistent and heterozygous factor V Leiden mutation, protein S deficiency, and a high plasma level of factor VIII. Despite these three risk factors and a lack of prophylaxis, the patient experienced only one ischemic attack. To our knowledge, this is the first patient with these combinations of ischemic stroke to be reported in the literature. Gillhis Deda, MD Department of Pediatric Neurology Faculty of Medicine Ankara University Ankara, Turkey children. Stroke 2000;31:1283-1288. Downloaded from jcn.sagepub.com at Uni of Southern Queensland on June 20, 2015