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

Abstract

Alpha thalassemia due to nondeletional mutations usually leads to more severe disease than that caused by deletional mutations. Devastating outcomes such as hydrops fetalis can occur with two nondeletional mutations, therefore warranting DNA-based workup for suspected carriers with subtle hematological abnormalities for family counseling purposes. We describe three cases with hemoglobin (Hb) Adana, a nondeletional alpha chain mutation, compounded with an alpha globin gene deletion resulting in thalassemia intermedia. We review the literature, draw genotype-phenotype correlations from published cases of Hb Adana, and propose that this correlation can be used by clinicians to help direct diagnostic studies and urge hematologists to thoroughly workup high-risk patients.

The first report of hemoglobin E in combination with the highly unstable alpha‐globin variant Hb Adana: The importance of molecular confirmation

“…The complete blood count (CBC) (Horiba medical, ABX Micros 4 Especially when on the dominantly expressed alpha 2-globin gene, this mutation may even cause HbH hydrops fetalis in homozygosity or in combination with alpha 0-thalassemia. 2,5 Due to its unstable nature, heterozygosity for Hb Adana is not visible by routine biochemical assay such as HPLC and CE, 6 but the carrier does present with microcytic hypochromic parameters. As carriers of HbE may also present with mild microcytic hypochromic parameters, the co-inheritance of alpha-thalassemia defects could be easily overlooked unless the HbE percentage is taken into account, which is usually slightly decreased in those cases.…”

“…A recent literature study revealed that cases of Hb Adana associated with hydrops fetalis did not follow the classical alpha-thalassemia paradigm where four alpha-globin gene deletions are typically causal of Hb Bart's hydrops fetalis syndrome. If the partner is a carrier of Hb Adana on the alpha 2-globin gene as well or is carrier of SEA, in which alleles are particularly frequent in the Indonesian population(16% and 4%-14%, respectively), there is a 25% risk of having a HbH hydrops fetalis in the offspring 2,5,8. In addition, the alpha 2-globin variant (c.179G>A) found in our patient has been more associated, in the literature, with severe phenotypes in homozygous or in compound heterozygous states than alpha 1-globin gene Hb Adana mutation 2,9-11 which underlines the importance to determine the exact genotype of these variants in carriers.…”

Clinical and Haematological Parameters of Commonly Reported Non-deletional α-thalassaemia Mutations in Southeast Asia: A Review

“…Hb Adana originates from Turkey, and is named after a city in the country's south where the variant was first discovered in 1993 (31). However, the number of cases reported there (0.5 % to 0.6 %) was relatively low compared to Indonesia (16 %) and Malaysia (the incidence ranges from 1.0 % to 21.4 % in several studies) (32)(33)(34). In addition, the incidence was higher in Sarawakian natives at 3.7 %, compared with Malay, Chinese and the Orang Asli at 1.7 %, 0.14 % and 1.9 %, respectively (29).…”

Non-deletional alpha thalassaemia: a review

“…The investigation for Hb Adana is very difficult, because the carriers may have normal haematological parameters [37]. Hb Adana can be detected in the laboratory by alpha-globin gene sequencing or PCR-based amplification refractory mutation system testing [38]. When Hb Adana combines with other α-globin deletions, this may yield various forms of phenotypes, ranging from mild anaemia (Table 3) (as in -α 3.7 and -α 4.…”