Albertine Donker

Chapter 3 100 4, or ferroportin disease, is an autosomal dominant condition primarily characterized by iron overload with a heterogeneous phenotype. 30,31 In almost all case series and the available narrative reviews, mutations causing ferroportin disease are classified into two groups: loss-of-function (LOF, HH type 4A or classical HH) and gain-of- function (GOF, HH type 4B or atypical HH) mutations. 32,33 Functional studies and clinical data show that a LOF mutation typically leads to iron retention in the duodenal cell and macrophages due to reduced ferroportin activity and preserved inhibitory capacity of hepcidin. The phenotype is characterized by an elevated serum ferritin level in association with a low to normal TSAT and predominant iron deposition in macrophages with low tolerance to phlebotomy in some patients. 32 GOF mutations lead to increased iron absorption due to increased ferroportin activity, which is resistant to the inhibitory effect of hepcidin. As a consequence, the iron overload phenotype of these patients is indistinguishable from other forms of hereditary hemochromatosis, 30,31 and therefore this subtype of ferroportin disease does not fit into the category of “disorders due to low iron available for erythropoiesis”. For certain genotypes, however, the functional studies and the biochemical and histological phenotypes vary between studies and patients. 34 Therefore, the distinction between LOF and GOF mutations is not always straightforward. In order to define the type of mutation, we developed for the purpose of this guideline a classification system based on both phenotypic and functional characteristics ( Supplement 3 ). Based on this classification we identified 36 different LOF mutations and 15 GOF mutations. A total of 207 patients with a LOF mutation and 73 patients with a GOF were found worldwide. Clinical presentation and diagnosis Symptoms are related to iron overload and are non-specific. Since the current guideline is on anemias, in our evaluation of the literature on ferroportin disease we investigated the occurrence of anemia (defined by the WHO) 35 as presenting symptom. In 76 (27.7 %) and 24 (8.5 %) out of 280 patients, both Hb and MCV were numerically noted. Eight (10%) of the patients fulfilled the WHO criteria of anemia without additional causes of microcytic anemia ( Table 1 in Supplement 3 ). Five males had an Hb between 12.0 and 12.9 g/dL and three females had Hb between 11.1 and 11.5 g/dL without microcytosis. Seven of the 8 anemic patients were annotated a LOF mutation.