Fatores bioquímicos, genéticos e clínicos implicados no déficit estatural de crianças e adolescentes com anemia falciforme

Abstract

Sickle cell anemia (SCA) is characterized by the homozygous inheritance of a point mutation in the β chain of hemoglobin (Hb) forming an abnormal Hb called HbS. The disease is characterized by episodes of hemolysis and vasoocclusion triggered by the deoxygenation of HbS and presents variable degrees of organic dysfunction, which can compromise multiple organs and affect height growth and the GH/IGF-1 axis (growth hormone/factor insulin-like growth 1). The severity of organ dysfunction in SCA is influenced by modifying factors, which may be genetic, including allelic variants associated with fetal hemoglobin (HbF) levels and coinheritance of alpha-thalassemia, or non-genetic, such as treatment with hydroxyurea (HU). On the other hand, genetic factors could also influence the height of individuals with SCA, given that studies with twins estimate the heritability of height at 90%. Objectives: To evaluate height, bone maturation and GH/IGF-1 axis, test association with laboratory and clinical parameters, modifying factors and genotypes of the polymorphism in the ZBTB38 gene (rs724016) in children and adolescents with SCA. Methods: Cross-sectional study with individuals with SCA, of both sexes and ages ranging from 3 to 20 years, followed at the Hemocentro de Governador Valadares of Fundação Hemominas between August 2018 and July 2019. We evaluated clinical data collected from in-person assessment, laboratory markers collected from medical records, bone age (BA), serum levels of IGF-1 and IGFBP-3, target height (TH) calculated by the mean Z score (ZS) of the parents' height, ZS of adult height prediction (AHP) calculated using IO. We define adjusted growth potential as TH subtracted from AHP. In addition, genotyping of deletional alpha-thalassemia and the rs724016 polymorphism was performed. Results and conclusions: We evaluated 80 individuals with SCA, 53% (43/80) male, 50% (40/80) under treatment with HU, 50.6% (40/79) pre-pubertal, 14.1% (11/78) with co-inheritance of alpha-thalassemia and 15% (12/80) with short stature. In multivariate evaluation, treatment with HU was associated with higher serum levels of IGF-1 and IGFBP-3. The presence of alpha-thalassemia was associated with lower IGF-1 levels. High HbF levels were associated with a smaller deficit in adjusted growth potential (TH-AHP). The G variant of rs724016 was associated with lower ZS of height (p<0.001, recessive model), in a different sense of effect from other studies with children without SCA or another identified disease. Additionally, the G variant of rs724016, in a dominant genetic model, was negatively 8 associated with HbF levels (p=0.016), which should be relevant for growth. A model of the relationship between the rs724016 variant and the GH/IGF-1 axis and HbF levels was created. We conclude that HU therapy significantly contributes to the balance of the GH/IGF-1 axis. Furthermore, we showed that the presence of the ZBTB38 variant rs724016 in the genotype implies shorter stature and lower HbF levels. On the other hand, co-inheritance of alpha-thalassemia negatively affects this axis. This study contributes with new findings regarding the height development of children/adolescents with SCA and opens perspectives to clarify the intricate relationship between the main known modulating factors of SCA: HbF levels and alpha-thalassemia.