CASE PRESENTATION:
A nine-year-old, non-Indigenous, Caucasian Australian boy (twin #1) was referred by his general practitioner to the paediatric gastroenterology service at our State’s children hospital for investigation and workup of his severe microcytic anaemia that was not responding to a one-month trial of oral 5mg/kg of ferrous sulphate liquid (30mg/mL) therapy. His weight, height and growth were stable and normal for his age. His diet was varied and included regular red meat intake without excess cow’s milk consumption. Despite the anaemia (Hb 69g/L), he was asymptomatic and his mother reported no history of unexplained fevers or drenching night sweats He had no personal or family history of chronic inflammatory disorders.
On examination, his vital signs were within the normal range and his oxygen saturation was >95% on room air. He exhibited marked pallor of the palmar creases, conjunctiva and face. A comprehensive systems examination was otherwise unremarkable with no organomegaly or lymphadenopathy. Initial full blood count and serum iron studies (table 1 ) showed a profound hypochromic microcytic anaemia (Hb 69g/L, MCV 56fL), normal erythrocyte sedimentation rates (7.0 mm/hour), an increased red cell distribution width (22.0%), severe hypoferremia (<2.0μmol/L) with very low transferrin saturations (0.03%) and normal serum ferritin levels (32.0μg/L). Gastroenterological investigations were undertaken, including a gastroscopy, which elicited no evidence for Helicobacter pylorior Strongyloides stercoralis infections, coeliac disease, autoimmune gastritis or evidence of other chronic inflammatory diseases. The patient was subsequently referred to the paediatric haematology service for further investigation and continued with oral iron replacement therapy.
He was reviewed five months later in the outpatient haematology clinic alongside his fraternal twin brother (twin #2), who was noted to exhibit similar clinical features of central and peripheral pallor. Peripheral blood sampling of the second twin identified similar abnormalities to his brother (table 1 ) and he were also commenced on oral iron replacement therapy. The blood films from both twins showed persisting moderate erythrocyte anisopoikilocytosis, pencil cells and elliptocytes despite ongoing oral iron therapy (figure 1a,b ) with negligible improvements in red cell indices, serum iron and ferritin. Haemoglobin electrophoresis studies excluded a haemoglobinopathy in both siblings. Bone marrow biopsies were performed and showed normocellular trilineage haematopoiesis with no ringed sideroblasts or neoplasia. Occasional mild dyserythropoiesis characterised by nuclear budding, few binucleate forms and poor haemoglobinisation were seen (figure 1c,d ). Cytogenetic analyses were normal although iron stores within the marrow were absent (figure 1e,f ). Hepcidin levels were not measured as an approved assay for this hormone was not available in our laboratory.
Given the ongoing poor response in both twins to oral iron replacement therapy, a possible diagnosis of IRIDA was considered. Massively parallel gene sequencing was performed on a peripheral blood sample of twin #1 one month later to assess for a TMPRSS6 mutation. Two compound heterozygous c.(1324G>A; 1564G>A), p.(G442R; E522K) mutations were identified, confirming a diagnosis of IRIDA. No other novel mutations were identified in the TMPRSS6gene. Both twins were commenced on parenteral ferrous carboxymaltose 500mg administered over 15 minutes one month later with concurrent cessation of oral iron therapy. This resulted in marked improvements in red cell indices and serum ferritin parameters. At five years following their initial diagnosis, both twins remain clinically well and have not required further parenteral iron supplementation.