INTRODUCTION:
Iron deficiency anaemia in children is usually attributed to poor dietary intake of oral iron, malabsorption secondary to inhibitory substances (e.g. cow’s milk) and chronic inflammatory conditions affecting the gastrointestinal tract (e.g. coeliac disease,Strongyloides stercoralis ) [1-3]. Upon treatment of the underlying cause, most individuals respond to oral iron therapy with marked improvements in their clinical symptomatology and red cell indices [3]. However, patients who are refractory to oral supplementation should provoke further investigation into uncommon and rare disorders affecting iron absorption, metabolism and erythropoiesis (i.e. heme and globin manufacture). These disorders include thalassaemia, sideroblastic anaemia and iron-refractory iron-deficiency anaemia (IRIDA) [1,2].
IRIDA is a rare, autosomal recessive disorder and usually presents in early childhood [1,2]. Such patients present with severe microcytic anaemia, profound hypoferremia, low transferrin saturation, elevated hepcidin levels and negligible responses to oral iron replacement therapy [2]. The disorder arises from mutations affecting theTMPRSS6 gene located on the long arm of chromosome 22q12.3 [2,4]. The gene encodes matriptase-2 (MT-2), a transmembrane serine protease expressed by hepatocytes that once activated, downregulates hepcidin expression by interfering with hemojuvelin-hepcidin coupling. This abrogates the inhibitory functions of hepcidin, thereby augmenting iron absorption from the gut and facilitating the mobilisation of iron stores from macrophages [2,4].
Mutations affecting the TMPRSS6 gene were first discovered in five multiplex kindreds by Finberg and colleagues in 2008 [4]. Since then, several missense, nonsense, frameshift and splicing mutations presenting in compound heterozygote or single homozygote forms have been identified among an array of ethnicities and across all continents except Australasia [5-12]. Missense mutations affectingTMPRSS6 are generally associated with less severe microcytic anaemias and lower hepcidin levels in comparison to those IRIDA patients with other mutation types [4,6,7,12]. These patients also tend to show some clinical response to oral iron replacement therapy. IRIDA patients refractory to oral iron therapy require parental supplementation [2,6]. Newer agents targeting hepcidin signalling cascades have shown promising therapeutic benefits in murine models [13].
We report IRIDA in fraternal twins who failed to respond to oral replacement therapy. Massively parallel gene sequencing ofTMPRSS6 confirmed the presence of two missense mutations expressed in a compound heterozygous genotype. The case highlights the genetic and clinical heterogeneity of patients with IRIDA despite common mutations affecting TMPRSS6 and the occasional need for parenteral iron supplementation.