Stroke risk in siblings with sickle cell anemia

Abstract

Cerebrovascular disease is a common cause of morbidity in sickle cell anemia (HbSS): approximately 10% of patients have a clinical stroke before 20 years of age, and another 22% have silent infarction on magnetic resonance imaging. The phenotypic variation among patients with HbSS suggests a role for modifier genes and/or environmental influences. To assess the familial component of clinical stroke in HbSS, we estimated the prevalence of clinical stroke among all patients and among HbSS sibling pairs at 9 pediatric centers. The sample included 3425 patients with sickle cell disease who were younger than 21 years, including 2353 patients with HbSS. The stroke prevalence was 4.9% for all genotypes; 7.1% for patients with HbSS; 1.1% for patients with HbS␤ o thalassemia; 0.6% for patients with S␤ ؉ thalassemia; and 0% for patients with HbSC. In 207 sibships, more than 1 child had HbSS. There were 42 sibships in which at least 1 sibling had a stroke, and in 10 of the 42, 2 siblings had a stroke. A permutation test indicated that the number of families in which 2 children had strokes was larger than the number expected if strokes were randomly distributed among children in sibships (P ‫؍‬ .0012). There was no difference in stroke prevalence based on sex, nor was the mean age at stroke presentation significantly different between singletons and sibships with stroke. We conclude that there is a familial predisposition to stroke in HbSS. Attempts to identify genetic modifiers should be initiated with familybased studies. IntroductionCerebrovascular disease is the second leading cause of mortality and a common cause of morbidity in sickle cell anemia (HbSS): approximately 10% of patients will have a clinical stroke by age 20 years, and another 22% have evidence of silent infarction on magnetic resonance imaging (MRI). 1,2 The pathophysiology of cerebrovascular disease in sickle cell anemia may involve stenosis of large arteries of the circle of Willis, intracranial hemorrhage, and/or microvascular disease. 3,4 The histology of these vascular lesions demonstrates intimal hyperplasia and smooth muscle proliferation compatible with endothelial damage. 5 A moyamoya pattern of lenticulostriate collateral vessels develops around the areas of stenosis in about 30% of patients. 6 Patients with moyamoya also have a higher risk for recurrent stroke. 7 Features of sickle cell disease that predispose patients to endothelial damage include adhesive properties of sickle reticulocytes (promoted by adhesion proteins, von Willebrand factor, and thrombospondin), leukocyte adhesion, and biomechanical disturbances of fluid shear stresses generated by increased blood flow secondary to anemia. [8][9][10] The propensity for stroke is associated with abnormal blood flow velocity in large arteries that can be detected presymptomatically by transcranial Doppler (TCD). 11 A familial predisposition to stroke in sickle cell anemia has been suggested by the observation that the prevalence of stroke among siblings with HbSS appears to be increased. 12...

Stroke and conversion to high risk in children screened with transcranial Doppler ultrasound during the STOP study

“…11 TCD results indicating risk, 12 such as stroke, 13 have been reported to cluster among siblings. The STOP study is the largest prospective application of TCD (or any testing modality) for stroke prediction yet reported, and the screening and follow-up studies of STOP provide a unique opportunity to further the knowledge of TCD as a predictor for stroke in this setting.…”

Stroke prevention in the young child with sickle cell anaemia

“…Two of the strokes described above occurred in twin siblings, a few months apart. It has been previously reported that abnormal TCD measurements and stroke are more common in children with SCA, who have a sibling with SCA and either abnormal TCD velocities or prior stroke [12,13]. Earlier TCD screening should be considered for siblings with SCA if there is a family history of sickle-related cerebrovasculopathy.…”

Genetics of Sickle Cell-Associated Cardiovascular Disease: An Expert Review with Lessons Learned in Africa

“…Advocating for studies on genomics of cardiovascular diseases in SCD Familial studies have provided evidence that predisposition to specific phenotypes of SCD such as stroke can be genetically inherited (Driscoll et al, 2003). However, there is limited evidence on the genetic polymorphisms influencing the vast clinical heterogeneity and disease severity across populations, with very few studies particularly in Africa.…”

“…Underlying genetic contributions to stroke risk in SCD patients have been identified through sibling pair, epidemiologic, and animal model studies (Driscoll et al, 1997(Driscoll et al, , 2003. The alpha-thalassemia polymorphism, a 3.7 or 4.2 kb deletion (Flanagan et al, …”