A Case Series of α-Thalassemia Intermedia Due to Compound Heterozygosity for Hb Adana [HBA2: c179G>A (orHBA1); p.Gly60Asp] With Other α-Thalassemias in Malay Families

Abstract

Hb Adana [HBA2: c179G>A (or HBA1); p.Gly60Asp] is a rare hemoglobin (Hb) variant due to a mutation at codon 59 of the α2- or α1-globin gene resulting in a glycine to aspartic acid substitution. Two siblings with a unique coinheritance of Hb Adana and Hb Constant Spring (Hb CS, α142, Term→Gln, TAA>CAA; HBA2: c.427 T>C) (α(codon 59)α/α(CS)α), were compared phenotypically with another two siblings carrying the Hb Adana mutation and a 3.7 kb deletion (α(codon 59)α/-α(3.7)). Although they all had α-thalassemia intermedia (α-TI), the former were clinically more severe than the latter. The first pair of siblings presented at a much younger age than the second pair and showed lower Hb levels and significant extramedullay hemopoiesis. Another case of a hydropic fetus as a result of Hb H/Hb Adana is also described. Their clinical phenotypes and hematological parameters are all presented for comparison.

Hb Adana (HBA2 or HBA1: c.179G > A) and alpha thalassemia: Genotype–phenotype correlation

“…11 This amino acid substitution replaces small noncharged glycine with a large charged aspartic acid molecule, which compromises alpha chain stability and leads to abnormal precipitation on red cell membranes, hemolysis, and ineffective erythopoiesis. 12,13 Diagnosis of Hb Adana is challenging as carriers often have normal or subtle hematological abnormalities [14][15][16][17][18][19][20][21][22][23][24][25][26] (Table 1) and the unstable protein product is not detectable on routine studies such as Hb electrophoresis, high performance liquid chromatography, and isopropanol Hb stability testing. Carriers for Hb Adana are unlikely to be diagnosed on newborn screening as Hb Barts is unlikely to reach a clinically significant level.…”

“…The difference in the outputs of the alpha 1 and 2 genes was apparent when we compared the homozygous alpha 1 Adana state (α α Adana /αα Adana ) with homozygous alpha 2 Adana (α Adana α/α Adana α), with homozygous alpha 1 yielding a mild anemia presentation in a single patient while homozygous alpha 2 led to hydrops fetalis in three different patients (Table ). Compound heterozygosity led to a range of phenotypes, with hydrops fetalis clustering only to cases of Adana with co‐inheritance of an α 0 gene deletion (− − SEA and − − FIL ) . The remainder of Adana cases compounded with alpha globin deletions yielded varying phenotypes, ranging from mild anemia (−α 3.7 and −α 4.2 ) to severe HbH‐like disease (− − 20.5 and −α 4.2‐QT [Q‐Thailand]) .…”

“…11,19,37,38 The cases of Adana alpha 2 mutations that combined with a single alpha 2 nondeletional mutation in general gave more severe HbH-like presentations ( 2 CS [Constant Spring], 2 Paksé , 2 IVS-II-142 , 2 IVS-I-1 , 2 codon24 , 2 codon22 , and rSNP 149709T > C). 15,17,22,35,36,39,40 The incidence of hydrops fetalis was generally associated with genotype and not ethnicity. Mild differences in clinical severity between patients of identical genotype were likely due to various unknown genetic factors implicated in HbH disease that require further study.…”

DNA studies are necessary for accurate patient diagnosis in compound heterozygosity for Hb Adana (HBA2:c.179>A) with deletional or nondeletional α-thalassaemia

“…Compound heterozygosity for Hb Adana with deletional and non-deletional mutations have been reported in Malaysian patients with varying clinical phenotypes 12 13 15 . In a Malaysian patient with severe anaemia, but without family history of thalassaemia, HPLC detected Hb A, Hb A 2 , Hb F and a pre-run peak of Hb Bart’s with absence of abnormal haemoglobins 14 .…”

“…Results from this study are similar to other reports where compound heterozygosity for Hb Adana with nondeletional mutations produce HbH disease with more severe anaemia, earlier presentation and possible blood transfusion requirements when compared with the less severe disorders of deletional HbH disease 3 6 18 . In a case series where two siblings with compound heterozygosity for Hb Adana and HbCS were compared with another two siblings with Hb Adana and a 3.7 kb α-globin gene deletion, the siblings with compound heterozygosity for Hb Adana and the nondeletional mutation HbCS produced more severe clinical manifestations 15 .…”