Anemia, Hypochromic Microcytic, With Iron Overload 2

A number sign (#) is used with this entry because of evidence that hypochromic microcytic anemia with iron overload-2 (AHMIO2) is caused by heterozygous mutation in the STEAP3 gene (609671) on chromosome 2q14. One such family has been reported.

For a discussion of genetic heterogeneity of hypochromic microcytic anemia with iron overload, see AHMIO1 (206100).

Clinical Features

Grandchamp et al. (2011) reported 3 sibs, born of nonconsanguineous Pakistani parents, who had transfusion-dependent hypochromic microcytic anemia with iron overload. The proband was a 24-year-old man who had been pale since infancy and was documented to be anemic at 7.5 years of age. Follow-up revealed chronic hypochromic anemia, and biochemical data suggested the onset of iron overload. He presented with increasing fatigue at 19 years of age, at which time his spleen was palpable and he was severely anemic; regular transfusions were begun to maintain a hemoglobin level permitting normal physical activity. Blood smears revealed distinct aniso-poikilocytosis with hypochromasia and microcytosis, ovalocytes, a few target cells, and basophilic stippled cells, with single mature nucleated red cells present. There was moderate erythropoietic hyperplasia of the bone marrow, with dysplastic features in less than 3% of erythroblasts; late basophilic and polychromatophilic erythroblasts had a small rim of poorly hemoglobinized cytoplasm, with small inclusions in some cells. Perls staining showed iron-positive inclusions in most red cell precursors, with 40% ringed sideroblasts, and Pappenheimer bodies in a few red cells. Under transmission electron microscopy, deposits of iron could be seen inside as well as outside the mitochondria. The proband's 2 affected sibs had similar biochemical and morphologic data. The 23-year-old sister had only mild symptoms of anemia in childhood and began regular transfusions at 15 years of age, whereas the 18-year-old brother had a more severe form of anemia since infancy, requiring transfusions beginning at 7 years of age, with growth retardation, massive hepatosplenomegaly and high iron overload, and cafe-au-lait spots visible on his skin. All 3 sibs had high serum ferritin and low transferrin values, as well as distinctly increased transferrin saturation despite regular treatment with deferasirox. In addition, they all had hypogonadism, with azoospermia in the males and atrophy of the gonads in the female; complex dysfunction of the hypothalamo-pituitary-gonadal axis was present in all 3 patients, suggesting a primary defect of the gonads in addition to secondary hypogonadism. Latent adrenal and thyroid failure was also detected in the younger brother. Their father had normal blood counts and iron data, whereas their mother had mild microcytic anemia with a low serum ferritin, which responded to iron supplementation. She had had 2 miscarriages in addition to the 3 live births.

Molecular Genetics

In 3 sibs with hypochromic microcytic anemia and iron overload, born of nonconsanguineous Pakistani parents, Grandchamp et al. (2011) analyzed 7 candidate genes and identified heterozygosity for a nonsense mutation in the STEAP3 gene (C100X; 609671.0001) that was inherited from their unaffected father. Quantitative RT-PCR from blood mRNA of all 5 family members and 10 controls showed that the STEAP3 mRNA level was considerably lower in the 3 patients, whereas both parents had a level of STEAP3 mRNA corresponding to the low-normal range found in controls. In B-lymphocyte cell lines treated to prevent degradation due to nonsense-mediated mRNA decay, quantitative sequencing of a cDNA fragment encompassing the mutated nucleotide demonstrated that expression of the normal allele relative to that of the mutated allele was significantly higher in the father than in the 3 sibs. Grandchamp et al. (2011) suggested that the father was heterozygous with 1 null allele and 1 normal, highly expressed allele, whereas the mother had 2 weakly expressed alleles, and each affected offspring had inherited the mutated allele from their father and 1 of the weakly expressed alleles from their mother. This was supported by the fact that expression of both alleles from the mother produced an amount of mRNA that was roughly equivalent to the expression products from the single normal allele of the father.