Fetal haemoglobin levels and haematological characteristics of compound heterozygotes for haemoglobin S and deletional hereditary persistence of fetal haemoglobin

Abstract

Compound heterozygotes for sickle haemoglobin (HbS) and hereditary persistence of fetal haemoglobin (HPFH) have high fetal haemoglobin (HbF) levels but few, if any, sickle cell disease-related complications. We studied 30 cases of HbS-HPFH (types 1 and 2), confirmed by molecular analysis, and report the haematological features and change in HbF levels over time. These results were compared to those of patients with sickle cell anaemia or HbS-β(0) thalassaemia, including a subgroup of patients carrying the XmnI polymorphism, known to be associated with elevated HbF. Among the HbS-HPFH patients, HbF level was 50-90% during infancy and declined steeply within the first few years of life, stabilizing between ages 3 and 5years, at approximately 30%. Mean HbF of individuals age 5 or older was 31±3%, average haemoglobin concentration was 130±10g/l and average mean corpuscular volume (MCV) was 75±4 fl. Univariate and multivariate regression analyses significantly associated HbF with age, haemoglobin concentration, and MCV (P<0·001). There was a strong inverse association between HbF and age (r=-0·9, P<0·001). Despite having a much higher HbF level, patients with HbS-HPFH have a similar age-related pattern of HbF decline and associations as patients with sickle cell anaemia or HbS-β(0) thalassaemia.

Fig 1

Relative positions of HPFH 1 and 2 deletions. HPFH 1 deletion results in an 85 kb deletion on chromosome 11: 5 174 451 to 5 259 368. HPFH 2 deletion results in an 84 kb deletion on chromosome 11: 5 179 688 to 5 263 979. Coordinates are based on the human genome reference sequence 19. Arrows represent the hypersensitive sites of the HBB control region (β-LCR). HPFH, Hereditary persistence of fetal haemoglobin.

Fig 2

Association of HbF and age. (A) compound heterozygotes for HbS and HPFH, (B) sickle cell patients in Cooperative Study of Sickle Cell Disease (CSSCD) database, (C) sickle cell patients who carry at least one XmnI polymorphism, (D) Loess Curves of HbF plots from Figures A, B, C. HPFH, Hereditary persistence of fetal haemoglobin; HbS-HPFH: compound heterozygotes for HbS and HPFH.

Fig 3

HbF decline with age. There is a strong inverse correlation between HbF and log-transformed age in patients with HbS-HPFH as well as HbSS patients with or without XmnI polymorphism. CSSCD: Cooperative Study of Sickle Cell Disease. HbS-HPFH: compound heterozygotes for HbS and hereditary persistence of fetal haemoglobin.