Systematic evaluation of paediatric cohort with iron refractory iron deficiency anaemia (IRIDA) phenotype reveals multiple TMPRSS6 gene variations

Systematic screening identified patients with an iron refractory iron deficiency anaemia (IRIDA) phenotype and genotype in iron-deficient children in the Indian subcontinent. Cases of moderate to severe microcytosis and anaemia with no obvious cause and normal C-reactive protein, HbA(2) and tissue transglutaminase antibody levels (n=550) were put on a trial of oral iron for 4weeks. Sixty of these 550 cases (11%) were variably refractory to oral iron therapy (<10g/l Hb rise) at 4-6weeks and were subsequently evaluated for plasma iron, ferritin and hepcidin levels. The mean age of this cohort was 2.06years. Low-normal to normal ferritin and normal to high hepcidin levels were noted in 25/60 (41.6%) and 47/60 (78.3%), respectively. An IRIDA phenotype was noted in 38.3% (23/60) based on standard criteria. TMPRSS6 gene sequencing in 20 cases with IRIDA phenotype revealed 9 potentially deleterious intronic and two benign exonic variations in 12/20 cases (60%). Of these, 4 intronic and both exonic variations were noted in multiple cases and are likely to act synergistically leading to an IRIDA phenotype. However, given that only 38% (23/60 cases) of cases with iron refractoriness had IRIDA phenotype, a balanced approach is needed and other causes for refractoriness should be investigated before genetic studies for TMPRSS6 are undertaken.