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.