Abstract
Abstract 2558
Poster Board II-535
Hemoglobinopathies can usually be classified under two major categories. Qualitative abnormalities resulting from missense mutations in the globin genes, leading to the production of mostly asymptomatic Hb variants, and quantitative defects, which result in the synthesis of structurally normal globin chains in reduced quantities (thalassemias). However there are known globin chain variants that cause alterations of the globin structure as well as a decrease in synthesis, leading to a thalassemic phenotype. The occurrence of multiple abnormalities of α, β and δ globin chains can lead to an unusual and complex phenotype. We report here the inheritance of triple globin gene abnormalities in an African American child with a genotype that is heterozygous for three abnormalities: α-thal-2 (-α3.7 deletion), thalassemic Hb Showa-Yakushiji (β110[G12] Leu→Pro), and a δ-chain variant Hb B2 (δ16[A13]Gly→ Arg) . Although Hb Showa Yakushiji presents with a severe hemolytic anemia and a thalassemia-like phenotype in the heterozygous state; when co-inherited with Hb B2 and α-thal-2, a milder phenotype was observed. We report the diagnostic approach, molecular characteristics and genotype/phenotype correlations of this complex hemoglobinopathy syndrome. A 2 year old African American boy presented with anemia which was not responsive to iron therapy. CBC revealed: Hb 9.9 g/dL, Hct 31.3 %, MCV 62.5 fl, MCH 19.8 pg, MCHC 31.7 g/dl. The reticulocyte count was 1.1%. The iron profile showed a TIBC of 368; Iron 119; Transferrin 257, Ferritin 30; and % Iron saturation 32. The peripheral blood smear revealed a microcytic anemia suggestive of a thalassemic phenotype. The patient's hemolysate was analyzed by isoelectric focusing (IEF) showed Hb's A, F, A2, and a minor peak Hb X which was significantly slower than Hb A2 . Quantitative values by high performance liquid chromatography (HPLC) were: Hb F : 5.0%, Hb A: 91.0%, Hb A2: 2. 0% and Hb X (B2): 2.0%. Reverse Phase HPLC was also performed and no additional abnormality was detected. Sequencing of the β-globin genes revealed a heterozygous T→C mutation at the codon 110 consistent with Hb Showa-Yakushiji (β110[G12] Leu →Pro) which was not detectable with IEF and HPLC. Sequencing of the δ-globin genes showed a heterozygous G→C mutation at codon 16, Hb B2 (δ16[A13] Gly →Arg) which was also not detectible by IEF or HPLC unless over applied. A 590 bp long fragment of the β-globin gene (Accession # EU605697/APR-2008) and a 780 bp long fragment of the δ-globin gene (Accession # EU605698/APR-2008) sequences have been submitted to NCBI/GenBank. Detection of alpha thalasemia (α−3.7) deletion by PCR analysis, revealed one alpha gene deletion (−3.7α/αα). The leucine to proline substitution at residue 110 of β-globin chain, disrupts the G helix and the α1β1 contact of the hemoglobin molecule. As a result, an extremely unstable Hb variant will be produced, which leads to a thalassemic phenotype because of the reduced stability/viability of the mutant beta chain. Previously reported cases of Hb Showa-Yakushiji showed a more severe clinical picture in the heterozygous state than that observed in our patient. This is the first time Hb Showa-Yakushiji is identified in an African American child who presented with a moderate anemia and a thalassemia-like phenotype. The milder phenotype observed in our case may be due to the co-inheritance of α-thal-2 (α−3.7) deletion. The decreased production of α- globin chains may ameliorate the effect of the chain imbalances thus leading to milder clinical and hematologic manifestations.
Disclosures:
No relevant conflicts of interest to declare.
Two Novel Mutations Identified in an African-American Child with Chediak-Higashi Syndrome
