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Haemoglobin (Hb) Adana (HBA2qC.179>A) in interaction with deletional and nondeletional α-thalassaemia mutations leads to HbH or, less commonly to thalassaemia intermedia with clinical manifestations varying from asymptomatic forms to severe anemia. First line screening tests are unable to detect the highly unstable variant.

We report two cases of Hb Adana co-inheritance with the a-thalassaemia 3.7 kb deletion - the only α- thal and Hb Adana double heterozygosity cases diagnosed in subjects of Greek origin.

The first case concerns a 3 year old girl, born from parents referred for genetic counseling at the 11^th week of a second gestation. The mother showed an Hb of 10.7g/dl,RBC 4.04 X 10⁹ /L, MCV 80,7 fl, MCH 26.4 pg, Hb A2 2.8% and Hb F 1%,with positive inclusion bodies, and her ethnic (Greek) and regional background was of high risk for thalassaemia. The partner came from the same region, and he showed an Hb of 13.8g/dl, RBC 5.88 X 10⁹/L, MCV 73,1 fl, MCH 23.5 pg, Hb A2 2.4% and Hb F1% and inclusion bodies were found positive. DNA analysis was requested and, routine investigation was performed in their first offspring. The girl had an Hb of 8.2 g/dl, RBC 3.82 X 10⁹/L, MCV 70 fl, MCH 22 pg, Hb A2 1.9% and Hb F 2.3%, while her ferritin levels were 226ng/ml and inclusion bodies were found. On clinical examination she was found to be of normal weight and height for her age, but presented with paleness, icteric sclera and mild splenomegaly. Genetic analysis revealed that the mother carried the α-thalassaemia 3.7 kb deletion defect. The father carried the rare non deletional Hb Adana. As suspected from the haematological data, their offspring was a compound heterozygote for Hb Adana variant in trans to a 3.7 α+ thal deletion.The second case concerns a17-year-old boy, diagnosed with Hb Adana co-inheritance with the a-thalassemia 3.7 kb deletion at the age of 8 years. At diagnosis, findings were compatible with a very mild phenotype and growth was not impaired. The boy retained a mild hypochromic microcytic anemia (Hb~10g/dl, MCV 71 fl, MCH 23 pg, RDW 18.6%, reticulocyte count 5.1%), until adolescence but at the age of 11 transfusion inititation was decided due to marked splenomegaly and limited weight and height gain. For the following years he was transfused approximately once a month, necessitating chelation therapy. Weight, height and pubertal development were normal by the age of 15, but splenomegaly persisted. Splenectomy was decided and transfusions were stopped shortly afterwards. During the following months the boy retained an Hb of 9.5 g/dl, however, he complained of constant fatigue and impaired physical activity and asked to get back on a transfusion program.

In both cases diagnosis was incidental highlighting the mild phenotype. However, the co inheritance of Hb Adana with the 3.7 kb α+ thal deletion is rare, with only the presenting cases in Greece, and in a few other families in Turkey, Southeast Asia, Philippines and Albania. The clinical phenotype of the combination seems to be a mild disease with a non-transfusion-dependent thalassaemia intermedia phenotype. Nonetheless, clinical severity prediction is always a difficult issue and phenotypes may change overtime as demonstrated by the second case described above.