Phenotypic variation in sickle cell disease: the role of beta globin haplotype, alpha thalassemia, and fetal hemoglobin in HbSS

ABSTRACT

Introduction

The hematological and clinical features vary markedly between the different genotypes of sickle cell disease. Even within the single genotype of homozygous sickle cell disease (HbSS), there is marked variability that is presumed to result from interacting genetic and environmental factors.

Areas Covered

The classification of the different genotypes of sickle cell disease with approximate prevalence at birth in different communities and some of the major clinical and hematological differences. This assessment includes three potential genetic factors influencing hematology and clinical outcome in HbSS, the beta globin haplotype, alpha thalassemia, and persistence of fetal hemoglobin (HbF).

Expert Opinion

The author is a clinician with experience of sickle cell disease primarily in Jamaica but also in Greece, Uganda, Saudi Arabia, and India. It is therefore necessarily an account of clinical data and does not address current debates on molecular mechanisms. Most data derive from Jamaica where efforts have been made to reduce any symptomatic bias by long-term follow-up of patients all over the Island and further reduced by a cohort study based on newborn screening, which has been in operation for over 48 years.

KEYWORDS:

• Sickle cell disease
• phenotypes
• beta globin haplotype
• alpha thalassemia
• fetal hemoglobin
• Jamaican cohort study

Article Highlights

• Proliferative sickle retinopathy is more common in the mild genotypes HbSC and HbS/beta;⁺thalassaemia than in severe forms HbSS and HbS/beta;^othalassaemia.

• DNA polymorphisms in HbSS have identified three principal African haplotypes, Benin, Bantu and Senegal and a fourth Asian haplotype in eastern Saudi Arabia and India.

• The bone pain crisis of HbSS has features of a ‘steal syndrome’.

• High levels of HbF in the Asian haplotype allow persistence of splenic function beyond the high risk period for pneumococcal septicaemia.

• The Asian haplotype is always associated with persistence of fetal haemoglobin (HbF).

Declaration of Interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.