Clinico-Hematological Profile in Hemoglobin SE Disease: A Case Series from a Tertiary Care Centre

Abstract

Hemoglobin SE (HbSE) disease are rare globally and there is paucity of literature regarding this condition. Cases reported in the Indian scenario so far have been limited to the tribal populations. This case series aims to highlight the rarity of this double heterozygous state and to raise awareness of its community prevalence beyond the tribal population. This is a case series over a 5-year observation period with six cases of double heterozygosity for HbS and HbE in our tertiary care centre. Four cases were in the 8–15 years’ age group and 2 cases of 24–25 years’ age group reported for initial evaluation due to easy fatigability and weakness: Two cases were siblings with history of consanguineous marriages in the family. Mild Pallor, variable icterus, spleen was just palpable in three of the cases and low MCV recorded in all cases. Sickling tests were positive and high performance liquid chromatography (HPLC) revealed both HbS > 50% and HbE fractions ≥ 25%. It’s important to detect this rare condition, prevalent in consanguineous marriages as dreaded complications like sickling crisis may manifest during pregnancy and air travel. Detection and genetic counselling is important for prognosis, planning follow up and therapy for this uncommon double heterozygous state.

Introduction

Haemoglobinopathies are one of the most common monogenic diseases and particularly high incidences are noted in the developing countries of Sub-Saharan Africa and Asia [1]. The most commonly encountered haemoglobinopathies are thalassemia, sickle cell disease, HbC and HbE.[2]. In India, prevalence of HbS is 4.3% and mainly reported in the tribal communities of central India and some areas along the Eastern coast, and on the other hand, prevalence of HbE is 10.9% and mostly reported from the North-Eastern region [3, 4]. Cases of Hemoglobin SE (HbSE) disease have been reported only few and far in-between. Global literature available is also sparse and in the Indian context, cases prior to ours have mostly been reported in tribal populations [5, 6]. Here, we present a case series of six cases of Hemoglobin SE disease that were diagnosed in our tertiary care center over a period of five years.

Case Report

This study is a retrospective review of six cases of SE haemoglobinopathy. Clinical and haematological data were obtained from the six patients who attended our Hemoglobinopathies Control Unit Out-patient Department over a span of five years. They were referred to us owing to various complaints like easy fatigability, weakness, anemia, jaundice and recurrent respiratory tract infections. Detailed history which included present history, significant past history and family history along with details of complete physical examination were documented. Peripheral blood smear and complete blood count on potassium EDTA-anticoagulated blood was done using the Sysmex XT 2000i 32 parameters (including 6 differential counts) full automated cell counter, serum ferritin estimation by the ERBA Lisa scan and HbS solubility tests were done in all the cases. High-Performance Liquid Chromatography (HPLC) was performed using Variant II-thalassaemia Short Program (Bio-Rad Laboratories Diagnostics Group, Hercules, CA, USA).

The 6 cases belonged to non-tribal population. Two cases were siblings and one other had history of consanguineous marriages in the family. Four were in the 8–15 years’ age group and 2 cases were of 24–28 years’ age group. Pallor and splenomegaly were present in three of the cases. Icterus was noted in one case. A complete blood count revealed low mean corpuscular volumes (MCV) in all the cases. High performance liquid chromatography (HPLC) revealed both HbS > 50% and HbE fractions ≥ 25%. Sickling tests were positive which further confirmed the diagnosis. The clinico-haematological of all the cases have been summarized in Table 1. All the patients are kept in follow up under the haemoglobinopathies control unit. Apart from persisting anemia and recurrent infections one of the older patients also developed cholelithiasis (Table 1).

Fig. 1.

a High performance liquid chromatography (HPLC) graph of case 2 b HPLC graph of case 3

Table 1.

Clinico-haematological profiles of the six cases

Case no	Age/sex	Clinical findings	Family history	Haematological findings		HPLC values
				Haemoglobin (g/dl)	Mean corpuscular volume [MCV] (fl)	HbS	HbA2 + E
1	24 y/Male	Pallor Shortness of breath Weakness Easy Fatigability Splenomegaly	Parents could not be followed up for screening	10.40	73.10	61.30	29.70
2	8 y/Male [Fig. 1a]	Pallor Mild growth retardation	Father HbE trait Mother HbS trait H/o consanguineous marriage in the family	12.10	68.40	62.90	30.20
3	13 y/Male (Sibling of Case No. 2) [Fig. 1b]	Pallor Icterus Growth retardation Recurrent upper respiratory tract infections Recurrent urinary tract infections Fever	Father HbE trait Mother HbS trait H/o consanguineous marriage in the family	11.50	63.60	64.20	28.70
4	9y/Male	Pallor Fever Mild Growth retardation	Father HbS trait Mother HbE trait	9.20	66.50	63.90	27.30
5	15 y/Female	Pallor Fever Convulsion Growth retardation Blackish pigmentation of skin Splenomegaly	Father HbS trait Mother HbE trait H/o consanguineous marriage in the family	10.70	74.80	58.40	28.40
6	28y/Male	Pallor Bodyache Shortness of breath Easy fatigability Splenomegaly Cholelithiasis	Parents could not be followed up for screening	11.0	69.0	60.20	32.00

Informed consent was obtained from all the participating adults and parents of the children.

Discussion

Compound heterozygosity for haemoglobin SE is rare. A literature review tells us that up until now 31 cases have been reported worldwide, amongst these only 5 cases are from India. Though most cases have been seen in the Asian and African populations, the first ever case was reported in a 70-year-old Turkish female in the Nature magazine in 1957 by Aksoy et al. [7]. A possible explanation of the rarity of the condition could be the different geographical locations for the prevalence of Haemoglobin S (HbS) and Haemoglobin E (HbE). Globally, HbE is common in Southeast Asia while HbS is seen in populations from Africa to India [8]. In India HbE is prevalent in the north eastern part and HbS in the eastern and central parts amongst the tribal communities [8]. Our case series of six cases is the largest such of the double heterozygous SE in the non-tribal population.

There is heterogeneity in terms of presentation of this condition. Haemoglobin SE disease usually manifests in late childhood or beyond 20 years of age [9]. Literature reviewed by Masiello et al. suggests that severity of the disease is seen more often when patients present beyond 20 years of age while those that are 18-years or younger usually run a milder course [10]. In our series too, both patients aged 24 and 28 years respectively were having more significant symptoms unlike the younger patients [Table 1]. Overall the presentations might be with mild anaemia manifesting clinically as easy fatigability and weakness and do not require transfusions. Peripheral blood smears show a microcytic picture and sickle cells may or may not be seen. But there have been instances of sickling related complications like acute chest syndrome, severe pain possibly due to a vaso-occlusive crisis, avascular necrosis of the hip and shoulder, sickle cell retinopathy, bone marrow necrosis, frontal bossing, recurrent urinary tract infections and cholelithiasis [9–11]. So, the previously conceived notion of HbSE disease having a favourable course might not hold entirely true especially, for patients diagnosed beyond 20 years of age. It may be hypothesized that owing to years of accumulation of sickle cell vasculopathy, adults with HbSE disease like those with HbSC and Hb-S/β-thalassemia, more likely to become symptomatic [10].

Knox-Macaulay et al. found that the HbSE cases only infrequently showed disease severity even though their population in consideration have considerable prevalence of sickling haemoglobinopathies. They have hypothesized that the clue for heterogeneity in clinical features may lie in the molecular status of the α-globin gene along with the β-cluster haplotypes [9].

Even though the double heterozygous for HbSE may form a small clinical load but the prevalence of these cases in our population run the risk of propagating carriers of either HbE or HbS in the population. Additionally, as is evidenced in previous case reports there is always the risk of a sickling crisis especially in stressful situations like pregnancy or during air travel.

India has an endogamous population and consanguineous marriage customs are prevalent here. We are therefore more at risk of developing such genetic disorders though, epidemiological data is still scarce. Developing countries like ours are seeing an increase in population and as and when the public health facilities improve, increased numbers of individuals will be diagnosed with haemoglobinopathies, thus adding to a considerable global burden of disease [12]. Therefore, in resource constraint scenario like ours, always there should be focus on running public awareness and screening programmes nationwide. Furthermore, attention on documentation of all the diseased individuals is important in order to assess the burden and intercept further propagation of the disease.

All our patients are regularly followed up and counselled. We are keen and continuing our efforts to diagnose cases of HbSE in our Hemoglobinopathies control unit and hoping to make further progress in defining the clinico haematological profile with a sufficient sample size in future.

Conclusion

Our case series is the largest of its kind being reported from India. We hope to highlight the fact that the HbSE disease is prevalent even in the non-tribal populations. A database of these patients would help to follow them up on a regular basis and track the natural history of the HbSE disease which in turn might aid in formulating a prevention and treatment plan to reduce the morbidity associated with the disease. Regular screening of the pre-marital and antenatal population along with awareness of the downsides of consanguineous marriages is crucial.

Author Contributions

TB: manuscript preparation, literature search, editing; MD: concept, literature search, manuscript preparation, editing, critical review; MS: critical review; MGM: manuscript review.

Funding

None.

Declarations

Conflict of interest

None.