Sickle β‐thalassemia: Identical twins differing in severity implicate nongenetic factors influencing course

Abstract

25-yr old female identical twins of Italian-American origin concordant for sickle beta-thalassemia were studied to explain their clinical differences. One of them has been severely affected from childhood with one aplastic crisis, an earlier onset of vaso-occlusive crises, and recent cardiac decompensation; the other twin shows no cardiac decompensation. Similar are their degree of anemia, RBC indices, blood volumes, absence of splenic sequestration, depression of pO2, elevation of p50 and 2,3-DPG, hemoglobin composition, and peripheral blood globin-synthetic rates. Regarding differences, the more severely affected has a shorter 51Cr RBC life span, a greater menstrual blood loss, and is more overweight, whereas the less severely affected has functional asplenia by 99mTc scanning and a larger proportion of RBC with decreased cellular deformability. We conclude that in sickle beta-thalassemia: (1) genotype alone does not determine the clinical course; (2) significant differences in clinical course can occur with almost identical hemoglobin composition and globin synthetic rates; (3) cellular deformability changes do not correlate exactly with clinical course; and (4) functional asplenia and leanness may be advantageous.

Concordant fetal hemoglobin response to hydroxyurea in siblings with sickle cell disease

“…As siblings with sickle cell disease are likely to share the same ␤-globin genes and their linked regulatory seg-ments, we hypothesized that if some component of the regulation of HbF response to HU is linked to the ␤-globin gene cluster, then siblings might have concordant responses to treatment. Our data and very limited observations in untreated twins with sickle cell disease who have similar HbF levels whatever their disease phenotype support our hypothesis [25,26].…”

Genetic modifiers of the β‐haemoglobinopathies

“…Two case reports (Joishy et al , 1976; Amin et al , 1991) and a pilot twin study (Weatherall et al , 2005) showed that despite identical β‐ and α‐globin genotypes and similarities in growth, haematological and biochemical parameters, the identical twins had quite different prevalence and severity of painful crises and some of the sickle complications. Although sample size of the twin study was small, it does suggest that environmental factors may be of greater importance in determining clinical expression and complications of sickle disease.…”

Environmental determinants of severity in sickle cell disease

“…A better understanding of the relationship between patients and their environment may allow significant improvements in health, by giving simple advice and facilitating the development of appropriate public health policies; genetic factors are generally less amenable to modification. [18][19][20] Similarly, people with SCD have a much more severe course in most of Africa compared to genetically similar patients in the northern hemisphere, and this is likely to be related to environmental factors, including infections, climate and access to healthcare. Equally, there are marked differences in clinical severity between patients with the Arab-Indian β S haplotype in India and the Middle East, with there being both mildly and severely affected patients; 21,22 these differences are likely to be at least partly attributable to environmental factors.…”