Disparate phenotypic expression of ALAS2 R452H (nt 1407 G → A) in two brothers, one with severe sideroblastic anemia and iron overload, hepatic cirrhosis, and hepatocellular carcinoma

We report the case of a man with severe X-linked sideroblastic anemia, severe iron overload, and hepatic cirrhosis who died of hepatocellular carcinoma. Evaluation of family members using DNA sequencing revealed that he was hemizygous for the novel ALAS2 mutation R452H (exon 9; nt 1407 G → A). The proband's brother, an ALAS2 R452H hemizygote, had mild anemia and mild iron overload. Four female relatives were ALAS2 R452H heterozygotes, but they had mild or no anemia and no iron overload. Sequencing of TFR2, HFE, FPN1 (SLC40A1), HAMP, HJV, and the erythrocyte pyruvate kinase genes of family members was also performed. We thus detected the novel TFR2 missense mutation I449V (exon 10; nt 1345 A → G) in the proband's wife and daughter, neither of whom had anemia or iron overload. Possible explanations for the disparate red blood cell and iron phenotypes of the proband and his family members are discussed.