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| Compound heterozygous beta thalassaemia and hereditary persistence of foetal haemoglobin presenting as thalassemia intermedia |
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Rohinie Warushahennadi1, Champika Gamage2, Ruwanthi Ananda3, Kokulaamuthini Nirangan3
1 Department of Haematology, Consultant Haematologist, Medical Research Institute, Colombo, Sri Lanka
2 Consultant Haematologist, General Hospital, Matara, Sri Lanka
3 Medical Officer, Medical Research Institute, Colombo, Sri Lanka
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| Date of Submission | 17-Mar-2022 |
| Date of Decision | 12-May-2022 |
| Date of Acceptance | 16-May-2022 |
| Date of Web Publication | 18-Oct-2022 |
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How to cite this URL:
Warushahennadi R, Gamage C, Ananda R, Nirangan K. Compound heterozygous beta thalassaemia and hereditary persistence of foetal haemoglobin presenting as thalassemia intermedia. Indian J Pathol Microbiol [Epub ahead of print] [cited 2023 Dec 1]. Available from: https://www.ijpmonline.org/preprintarticle.asp?id=358851 |
An 8-month-old baby girl of Sinhalese ethnicity was admitted to the General hospital, Matara, Sri Lanka with fever, mild pallor, jaundice, and mild hepatosplenomegaly. She is a product of non-consanguineous parents, born preterm (31 weeks of period of gestation) by an emergency Caesarian section due to maternal pregnancy-induced hypertension. She also has a history of neonatal sepsis and jaundice with serum bilirubin below the phototherapy level. At the age of one month, her Hb dropped to 7.6g/dl; she was transfused with red cell concentrates, being managed as anemia of prematurity. She has been on haematinics since then.
On admission, her hemoglobin (Hb) was found to be 9.2 g/dl. The other parameters of blood count showed, red blood cell count (RBC) 4.18 × 103/L, mean cell volume (MCV) 70.7 fL, mean cell haemoglobin (MCH) 22.0 pg, mean cell hemoglobin concentration (MCHC) 31.1 g/dl, white blood cell count (WBC) 17.6 × 109/L, neutrophils 2.0 × 109/L, lymphocytes 14.4 × 109/L, platelet count 251 × 103/L. Peripheral blood film showed hypochromic microcytic red cells, tear drops, targets, polychromatic cells, and a few nucleated red blood cells [Figure 1]. Her serum bilirubin was high (4.1 mg/dL) with a high indirect fraction. Retic count was elevated (6.48%). Serum ferritin was normal (96.7 ng/ml). | Figure 1: Blood film of the proband showing features of chronic haemolysis with hypochromasia, irregularly contracted red cells, polychromatic cells, nucleated red blood cells and target cells
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Based on clinical and laboratory findings, hemolytic anemia was suspected. Automated high-performance liquid chromatography (HPLC) using the β-thalassemia short program on Bio-Rad Variant-II system showed; Hb A 2.9%, Hb A2 1.3%, Hb F 93.7% (normal range for age is 3-40%). Hb capillary electrophoresis (Sebia) showed HbA-5.4%, HbA2-1.2%, HbF-93.4% [Figure 2]. Parental screening showed; Father's HPLC with Hb A2 of 4.3%, compatible with beta thalassaemia trait. Mother's HPLC showed high Hb F (28.5%) with upper normal Hb and normal red cell indices, suggestive of heterozygous hereditary persistence of fetal Hb (HPFH). All hematological parameters of the index case and parents are shown in [Table 1]. | Table 1: Blood counts and HPLC findings of the proband, mother, father, maternal grandfather, paternal grandmother
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Based on the above findings, the baby was diagnosed as compound heterozygous beta thalassemia and HPFH, clinically presenting as thalassemia intermedia. Family screening done later confirmed the above diagnosis [Table 1]. Pedigree is shown in [Figure 3]. Molecular genetic studies were not done due to financial constraints. Extended red cell phenotyping, 2D ECHO, viral screening for Hepatitis B & C, and TSH were arranged. The parents were counseled. The importance of regular follow up and the possible need for occasional transfusions in the future (eg. during intercurrent infection) were explained.
HPFH is a genetic condition characterized by persistently elevated levels of fetal hemoglobin (Hb F) beyond infancy. HPFH can result from deletions within the beta globin gene cluster (deletional type) or from mutations or polymorphisms of regulatory genes either on beta gene or elsewhere (nondeletional type).[1],[2]
Deletional HPFH is quite common in some ethnic groups. Its prevalence in Afro-Americans is about 1:1000. There are known to be at least six different deletions classified as deletional HPFH, two occurring in Africans, one in Indians, two in Italians, and one in Vietnamese/South east Asians. In all of these, both the delta and beta genes are deleted but the two gamma genes are intact. Since there is no beta gene on the affected chromosome, homozygotes of deletional HPFH totally lack Hb A and have 100% Hb F. Heterozygotes have a variable Hb F percentage (15-30%) depending on the precise deletion. Hemoglobin concentration is normal in heterozygotes and has normal red cell indices as there is little or no imbalance of alpha: non-alpha globin chain synthesis. The blood film is normal or shows an occasional target cell.[1],[2]
Differentiation of deletional HPFH from delta beta thalassemia which belongs to the same spectrum of disorders can be done by Hb F% and MCH. Heterozygous deletional HPFH shows Hb F% of 15-30% with normal MCH while delta beta thalassemia heterozygotes show Hb F% of 5-15% with MCH of <27.[1],[2],[3]
Compound heterozygous for deletional HPFH and beta thalassemia is a rare hemoglobinopathy.[1],[4] Affected individuals have about 70-100% Hb F and reduced or absent hemoglobin A.[1],[2] Our index case had 96.7% of Hb F; much higher than age-related upper normal level of 40%. The phenotype of the compound heterozygous state is variable. In the case of two African types, the compound heterozygous state is phenotypically very mild, whereas, in the Indian type, the clinical picture is of thalassemia intermedia (Non transfusion dependent anemia).[1],[2] Our index case showed moderate anemia with mild hepatosplenomegaly and hematological evidence of chronic hemolysis, compatible with thalassemia intermedia. Similar cases published earlier showed that the compound heterozygous cases may present in childhood or later in life, depending on the severity of the clinical phenotype, causing diagnostic difficulties to the clinicians.[2],[3],[4],[5],[6]
In an infant with high Hb F% differential diagnosis includes homozygous beta thalassemia (beta thalassemia major/intermedia), beta thalassemia compound heterozygous states with variant Hb, homozygous delta beta thalassemia, homozygous HPFH.[1] To differentiate them, clinical characteristics, blood counts, and blood film morphology are necessary. Parental screening is always helpful in confirming the diagnosis. Molecular genetic studies are needed for the accurate characterization of these genetic diseases.[7],[8]
In regions with a high prevalence of beta thalassemia, identification of HPFH carriers is important to prevent compound heterozygous births.[9],[10] Partners of beta thalassemia carriers should always be screened before marriage, by HPLC/Hb electrophoresis regardless of Hb and red cell indices.
Contribution of authors to the work: All authors contributed to the work.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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| 3. | Ryan K, Bain BJ, Worthington D, James J, Plews D, Mason A, et al. Significant haemoglobinopathies: Guidelines for screening and diagnosis. Br J Haematol 2010;149:35-49. |
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| 7. | Pandey H, Ranjan R, Singh K, Sharma A, Kishor K, Seth T, et al. Contrasting co-inheritance of alpha and beta mutations in delta beta thalassemia and hereditary persistence of fetal hemoglobin: A study from India. Hematology 2018;23:692-6. |
| 8. | Kelkar AJ, Moses A. Thalassemia intermedia phenotype resulting from rare combination of c. 46delT [Codon15 (-T)] mutation of beta globin gene and HPFH3. Clin Case Rep 2017;5:1107-10. |
| 9. | Jiang F, Zuo L, Li D. Molecular epidemiology and hematologic characterization of δβ-thalassemia and hereditary persistence of fetal hemoglobin in 125,661 families of greater Guangzhou area, the metropolis of southern China. BMC Med Genet 2020;21:43. doi: 10.1186/s12881-020-0981-x. |
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Correspondence Address:
Rohinie Warushahennadi,
Medical Research Institute, Dr. Danister De Silva Mawatha, Colombo 08
Sri Lanka
 Source of Support: None, Conflict of Interest: None DOI: 10.4103/ijpm.ijpm_250_22
[Figure 1], [Figure 2], [Figure 3]
[Table 1] |
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