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.