Iron Overload in Histidine-to-Aspartic Acid Substitution at 63 (H63D) Gene Heterozygous Hereditary Hemochromatosis With Erythrocytosis: A Case Report

Hereditary hemochromatosis occurs due to genetic mutations, namely, cysteine-to-tyrosine substitution at amino acid 282 (C282Y) and histidine-to-aspartic acid substitution at 63 (H63D) mutations. The role of H63D mutation in hemochromatosis is less clear, and its penetrance is low even in homozygotes. Therefore, iron overload in H63D heterozygotes is extremely rare and scarcely reported. We report the case of an asymptomatic Sinhalese man, previously unscreened, who was found to have elevated liver enzymes and hemoglobin in a routine medical check-up. His ferritin was 1272 (ng/ml) (22-322) with a transferrin saturation of 61% (15-50%). MRI of the abdomen for iron content revealed primary early iron deposition in the liver and pancreas with sparing of the spleen. Genetic studies detected H63D heterozygous homeostatic iron regulator (HFE) gene mutation with a normal C282Y gene. In his erythrocytosis workup, his erythropoietin level was suppressed. However, bone marrow biopsy did not reveal morphology suggestive of a clonal disorder, and he was negative for JAK2 V617F mutation, MPL gene, JAK2 exon 12 mutations, and calreticulin gene. He was diagnosed with H63D heterozygous hereditary hemochromatosis with iron overload and erythrocytosis and commenced on venesections as treatment for both conditions, with a good response. This case report highlights the rare possibility of developing clinically significant iron overload in H63D heterozygous hereditary hemochromatosis. Furthermore, several studies have reported the detection of HFE mutations in patients previously diagnosed with 'idiopathic' erythrocytosis. Hence, this case report calls attention to the need to suspect the presence of HFE gene mutations in patients with erythrocytosis with a negative workup for clonal red cell disorders.