Albertine Donker

Rare Inherited Iron and Heme-related Anemias 131 3 Supplemental Table 1. Continued Anemia * Normal Hb p Gender (n) Male 5 (n=8) 38 (n=66) Female 3 28 ns Type of mutation+ Gain (n) 1 (n=8) 12 (n=68) Loss (n) 7 56 ns *, according to WHO criteria 42 . The mean values were compared using the Student t-test of independent samples, the median values were compared using the Mann-Whitney test of independent samples, while the distribution of gender and type of mutation between both groups were compared using a two-tailed Fisher’s exact test. A p value < 0.05 was considered as statistically significant. + , 2 types of mutations can be distinguished: 1. Gain-of-function (GOF) mutations: type 4B or atypical hereditary hemochromatosis (HH); 2. Loss-of-function (LOF) mutations: type 4A or classical HH. The type of mutation was classified implementing both phenotypic and functional features using the following definitions: a) Phenotype of a LOF mutation: a normal transferrin saturation, poor tolerance to phlebotomy and iron deposition primarily in the Kuffper cells and macrophages. b) Phenotype of a GOF mutation: an elevated transferrin saturation, good tolerance to phlebotomy and iron deposition in the hepatocytes in addition to the Kuppfer cells and macrophages. c) Function of a LOF mutation: an intracellular localisation of the defect in the protein, a reduced capacity of iron export and preserved sensitivity to the inhibitory effects of hepcidin (all according to functional studies). d) Function of a GOF mutation: a membrane localisation of the defect in the protein, preserved capacity of iron export and resistance to the inhibitory effects of hepcidin (all according to functional studies). Classification was done according to the following definition: 1. In case both the phenotypic and functional features were in accordance, the type of mutation was defined as “definite”. 2. In case of absence of data regarding functional features or when the data of the phenotypic and functional features were inconsistent the type of mutation was defined as “probable” in which the type of mutation was classified according to the phenotypic features. 3. For the classification of the type of mutation in this guideline the “definite” and “probable” definition were combined. Abbreviations: ns denotes not significant