Recommendations
| Part 1: Anemia due to low iron bioavailability for erythropoiesis |
| 1A. Iron-refractory iron deficiency anemia (IRIDA) due to defects TMPRSS6 |
| Clinical presentation and diagnostics |
| • In patients with unexplained microcytic anemia with low TSAT and normal or reduced serum ferritin concentration who do not respond to or partially respond to oral iron and (partially) respond to intravenous iron supplementation, IRIDA due to a TMPRSS6 defect should be considered. Determination of serum hepcidin is recommended if the diagnosis of IRIDA is suspected. |
| • Increased serum hepcidin in relation to TSAT (hepcidin:TSAT ratio > local upper reference limit is suggestive of IRIDA. TMPRSS6 mutation analysis is recommended. |
| • In case of a homozygous or compound heterozygous TMPRSS6 defect, IRIDA due to a dysfunctional matriptase-2 protein should be diagnosed. |
| • No recommendation can be made on the clinical significance of heterozygous TMPRSS6 defects with or without concomitant polymorphisms because of lack of evidence. |
| Treatment |
| • In a patient with iron deficiency anemia due to pathogenic TMPRSS6 defects, initial treatment with oral iron or oral iron combined with ascorbic acid should be considered. |
| • If this initial treatment does not result in acceptable hemoglobin (Hb) levels, the patient should be treated with intravenous iron supplementation. |
| • In IRIDA patients, the choice of the chemical form of intravenous iron should be based on its registration for the specific age group OR a proven good safety profile in adults during several years of postmarketing surveillance. |
| • The total intravenous iron cumulative doses should be calculated on the basis of formulas of the deficit of body iron, allowing for the correction of the Hb deficit and rebuilding the iron stores. Doses should be repeated every 3 to 7 days until the total dose is administered. Single doses should not exceed the maximum single dose. |
| • Serum ferritin levels should be monitored and preferably should not exceed 500 µg/L to avoid toxicity of iron overload, especially in children and adolescents. |
| • No recommendation can be made on the efficacy of the combination of intravenous supplementation and erythropoietin (EPO) treatment in IRIDA patients because of lack of evidence. This combination therapy might prevent toxic iron loading in some patients. |
| Family screening* |
| • The proband should be informed about the mostly autosomal recessive inheritance pattern of IRIDA. We recommend screening relatives of the proband for the IRIDA phenotype (siblings and spouse in case of consanguinity and reproductive age). If the proband is diagnosed at a young age, and his/her parents are of reproductive age, phenotyping of the parents is recommended. In case of a clinical IRIDA phenotype in the above-mentioned relatives, mutation analysis is recommended. |
| • Children of the proband should only be phenotyped and, in case of an IRIDA phenotype, genotyped in case of consanguinity of the proband and his/her spouse or in case of proven carriership of both proband and his/her spouse. |
| • Because of the complex genotype-phenotype correlation in IRIDA, we recommend referral to a clinical geneticist in case of an IRIDA phenotype and a pathogenic heterozygous TMPRSS6 defect. |
| 1B. Ferroportin disease due to defects in SLC40A1 |
| Clinical presentation and diagnostics |
| • Ferroportin disease due to LOF mutations should NOT be considered as a cause of microcytic anemia. |
| • When anemia occurs in a patient with primary iron overload during treatment with repeated phlebotomies, the presence of LOF ferroportin disease may be considered. |
| Treatment |
| • Patients with iron overload due to LOF and gain-of-function (GOF) ferroportin disease should be treated with repeated phlebotomies. |
| • For patients who develop anemia during phlebotomies despite elevated ferritin levels, extension of the phlebotomy interval is recommended |
| • In patients who develop anemia during phlebotomies, additional treatment with EPO may be considered. |
| Family screening* |
| • The proband should be informed about the autosomal dominant inheritance pattern of ferroportin disease. |
| • We recommend screening the first-degree relatives (parents, siblings, and children) and additional family members (via cascade screening) for the SLC40A1 mutation identified in the proband. Mutation carriers should be screened for the ferroportin disease phenotype. |
| 1C. Aceruloplasminemia (ACP) due to defects in CP |
| Clinical presentation and diagnostics |
| • In patients with the combination of insulin-dependent diabetes, neurodegenerative disease, retinal degeneration, and mild anemia with systemic iron loading, CP defects should be considered. |
| • In patients with absent or very low CP in combination with low serum copper and iron, high serum ferritin, and characteristic findings on magnetic resonance imaging (MRI) that are compatible with iron accumulation in liver, pancreas, and brain, ACP should be considered. |
| • In case of homozygous or compound heterozygous CP defects, ACP should be diagnosed. |
| Treatment |
| • In patients with ACP, anemia is mild and therefore treatment is not recommended. |
| • Iron chelation therapy should be considered for the treatment of ACP. |
| Family screening* |
| • The proband should be informed about the autosomal recessive inheritance pattern of ACP. Siblings of the proband may be also affected. Since CP defects are very rare, the chance that children of the proband are affected is negligible. |
| • We recommend screening for pathogenic CP mutations (siblings and spouse in case of consanguinity and reproductive age). In case a proband is diagnosed with ACP after the fourth decade, his or her parents are not likely to be of reproductive age, and genotyping is not recommended. |
| • Children of the proband should only be checked for CP mutations in case of consanguinity of the proband and his/her spouse or in case of proven carriership of both proband and his/her spouse. |
| • Individuals heterozygous or compound heterozygous for CP mutation should be screened for the ACP disease phenotype. |
| Part 2: Defects in iron acquisition by the erythroid precursors |
| 2A. Hypotransferrinemia due to defects in TF |
| Clinical presentation and diagnostics |
| • In patients with unexplained hypochromic microcytic anemia, low iron binding capacity (low serum transferrin concentrations) and increased ferritin concentrations, hypotransferrinemia should be considered. Mutation analysis of the TF gene is recommended. |
| • In case of a homozygous or compound heterozygous TF defect, hypotransferrinemia due to a TF defect should be diagnosed. |
| Treatment |
| • Transferrin supplementation by either plasma transfusion or apotransferrin infusion is recommended in patients with hypotransferrinemia due to a TF defect. |
| • Iron status should be monitored in patients with hypotransferrinemia due to a TF defect in order to detect toxic iron loading early. |
| • In case of systemic iron loading, phlebotomies are recommended. If phlebotomies are not tolerated because of decreasing Hb, chelation therapy is recommended. |
| Family screening* |
| • Recommendations are the same as those described in 1C. |
| 2B. Anemia with systemic iron loading due to defects in SLC11A2 (DMT1) |
| Clinical presentation and diagnosis |
| • In patients presenting in childhood with unexplained microcytic anemia with increased TSAT, SLC11A2 defects (among others) should be considered. Genotyping of SLC11A2 is recommended. |
| • In case of a homozygous or compound heterozygous SLC11A2 defect, diagnosis of microcytic anemia due to an SLC11A2 defect is confirmed. |
| Treatment |
| • Patients with microcytic anemia due to pathogenic SLC11A2 defects should be treated with oral iron supplementation and/or EPO and/or erythrocyte transfusions, according to the needs of the individual patient. |
| • In case of treatment with oral iron supplementation and/or erythrocyte transfusions, iron status should be monitored to detect toxic iron loading at an early stage. |
| • Since a normal serum ferritin concentration does not exclude liver iron loading in patients with SLC11A2 defects, MRI of the liver should be considered. |
| Family screening* |
| • Recommendations are the same as those described in 1C. |
| 2C. Sideroblastic anemia due to defects in STEAP3 |
| Clinical presentation and diagnosis |
| • In patients with unexplained hypochromic sideroblastic anemia with low or normal MCV, defects in the STEAP3 gene should be considered. |
| • In case of the combination of hypochromic anemia and gonadal dysfunction, STEAP3 defects should be considered. |
| Treatment |
| • Patients with hypochromic anemia due to STEAP3 defects can be treated with erythrocyte transfusions in combination with EPO. Systemic iron loading should be treated with iron chelation. |
| Family screening* |
| • Because sideroblastic anemia due to a STEAP3 defect has been described in only 1 family, the inheritance pattern is uncertain and the proband should be referred to a clinical geneticist. |
| Part 3: Defects in the heme and/or iron-sulfur (Fe-S) cluster synthesis |
| 3A. Sideroblastic anemia due to defects in SLC25A38 |
| Clinical presentation and diagnosis |
| • In children with severe unexplained microcytic sideroblastic anemia, defects in SLC25A38 should be considered. |
| Treatment |
| • Hematopoietic stem cell transplantation (HSCT) is recommended because it is the only curative option. |
| • Symptomatic treatment consists of erythrocyte transfusions and chelation therapy. |
| Family screening* |
| • Recommendations are the same as those described in 1C. |
| 3B. X-linked sideroblastic anemia (XLSA) with ataxia due to defects in ABCB7 |
| Clinical presentation and diagnosis |
| • In male patients presenting with the combination of a mild microcytic anemia and ataxia, a defect in ABCB7 should be considered. |
| • Increased protoporphyrin IX concentrations in red blood cells are suggestive of this disorder. |
| Treatment |
| • Treatment of (mild) anemia is not indicated. |
| Family screening* |
| • The proband should be informed about the X-linked inheritance pattern of anemia and ataxia due to ABCB7 defects. Brothers of the proband may be also affected. Sons of the proband are not affected. Daughters of the proband are obligate carriers of the relevant ABCB7 defect and have no or a mildly anemic clinical phenotype. |
| • We recommend offering screening for the ABCB7 mutation (the mother and sisters for carriership and the brothers). The spouse should be checked only in case of consanguinity and reproductive age. Daughters of the proband should be offered checking for carriership. |
| 3C. XLSA due to defects in ALAS2 |
| Clinical presentation and diagnosis |
| • XSLA due to an ALAS2 defect should be considered in patients of both gender and of all ages with pyridoxine responsive or unresponsive (mild) microcytic sideroblastic anemia with or without iron loading and in patients with unexplained iron loading. |
| • In patients suspected for XLSA, iron parameters (ferritin, TSAT) should be checked to detect iron loading, as well as liver enzymes, and signs of liver fibrosis or hepatocellular carcinoma. |
| • In case of elderly patients presenting with myelodysplastic syndrome (MDS) refractory anemia with ring sideroblasts or MDS-refractory cytopenia with multilineage dysplasia without specific cytogenetic abnormalities, the presence of ALAS2 defects should be considered, especially if the anemia is microcytic. |
| Treatment |
| • Management of patients with XLSA should involve treatment of anemia and prevention and treatment of iron overload. |
| • Initial treatment with pharmacologic doses of pyridoxine (50 to 200 mg per day) is recommended. Occasionally high doses (up to 300 mg per day) in overweight, active, or elderly patients may be considered. |
| • In case of pyridoxine responsiveness, lifelong supplementation with pyridoxine 10 to 100 mg daily is recommended. |
| • Once a response is obtained, evidence suggests the lifelong maintenance dose may be lowered to 10 to 100 mg per day, because doses that are too high may result in neurotoxicity. |
| • Iron loading should be treated, preferably by phlebotomies. |
| Family screening* |
| • The proband should be informed about the X-linked inheritance pattern of anemia and/or iron overload due to ALAS2 defects. Brothers of the proband may be also affected. Sons of the proband are not affected. Daughters of the proband are obligate carriers of the relevant ALAS2 defect. |
| • We recommend screening for the ALAS2 mutation (the brothers and also the mother, sisters, and daughters for carriership and because women may develop an XLSA phenotype later in life). The spouse should be checked only in case of consanguinity and reproductive age. |
| • Female carriers and male hemizygous individuals should be screened for the XLSA phenotype. |
| 3D. Sideroblastic anemia due to defects in GLRX5 |
| Clinical presentation and diagnosis |
| • In patients presenting with microcytic sideroblastic anemia and iron loading (among other symptoms), defects in GLRX5 should be considered. |
| • In case of microcytic sideroblastic anemia without ALAS2 or SLC25A38 defects, a lymphoblastic culture may be considered. Decreased activity of mitochondrial acitonase and succinate dehydrogenase (complex I-IV) as a manifestation of a defective Fe-S cluster synthesis is suggestive of a GLRX5 defect. |
| Treatment |
| • In patients with sideroblastic anemia and iron loading due to GLRX5 defects, monitoring of the iron status and possible complications of iron overload is recommended. Iron loading should be treated with chelation therapy. Severe anemia should be treated with blood transfusions. |
| Family screening* |
| • Recommendations are the same as those described in 1C. |
| 3E. EPP due to defects in FECH and GOF mutations in ALAS2 (XLDPP) |
| Clinical presentation and diagnosis |
| • In patients with an unexplained mild normocytic to microcytic anemia, low to normal serum ferritin, and cutaneous protoporphyria (a painful photosensitivity in childhood), EPP should be considered in both men and women. |
| • The diagnosis of EPP should be confirmed by fluorescent erythrocytes in an unstained smear and/or enhanced protoporphyrin in plasma and/or erythrocytes. |
| • To prove autosomal recessive EPP, FECH activity should be measured or FECH mutations should be determined. |
| • In case EPP is not explained by the FECH genotype, the ALAS2 gene should be investigated for the presence of GOF mutations. |
| Treatment |
| • If anemia is present in EPP, it is mild and treatment is not recommended. |
| Family screening* |
| • Because of complex genetics influenced by genetic background, we recommend referral to a clinical geneticist in case of EPP. Family screening for a proband with XLDPP due to an ALAS2 GOF mutation should initially include phenotyping and genotyping of all first-degree family members including women (mother in case of a male proband, both parents in case of a female proband, siblings, and children). |
| 3F. Congenital erythropoietic porphyria (CEP) due to defects in UROS or GATA1 |
| Clinical presentation and diagnosis |
| • In patients with an unexplained hemolytic anemia in combination with a painful cutaneous photosensitivity, autosomal recessive CEP has to be considered in both men and women. |
| • In patients with combined cutaneous photosensitivity and severe microcytic hypochromic hemolytic anemia, X-linked CEP should be considered. |
| • Since disease severity and onset of first symptoms is highly variable, CEP should be considered in both children and adults in case of the above-mentioned phenotype. |
| • Diagnosis should be based on increased urinary levels of uroporphyrin I and coproporphyrin I and confirmed by decreased UROS activity in the erythrocytes or the presence of pathogenetic homozygous or compound heterozygous mutations in UROS or in GATA1. |
| Treatment |
| • In patients with CEP, allogeneic HSCT should be considered as the only curative treatment. |
| • Chronic erythrocyte transfusion is recommended as a symptomatic treatment, and iron chelation is recommended according to guidelines for chronic transfusions. |
| Family screening* |
| • Recommendations for CEP due to UROS defects are the same as those described in 1C. |
| • Recommendations for CEP due to GATA1 are the same as those for XLDPP due to GOF ALAS2 mutations (see 3E). |
| Part 1: Anemia due to low iron bioavailability for erythropoiesis |
| 1A. Iron-refractory iron deficiency anemia (IRIDA) due to defects TMPRSS6 |
| Clinical presentation and diagnostics |
| • In patients with unexplained microcytic anemia with low TSAT and normal or reduced serum ferritin concentration who do not respond to or partially respond to oral iron and (partially) respond to intravenous iron supplementation, IRIDA due to a TMPRSS6 defect should be considered. Determination of serum hepcidin is recommended if the diagnosis of IRIDA is suspected. |
| • Increased serum hepcidin in relation to TSAT (hepcidin:TSAT ratio > local upper reference limit is suggestive of IRIDA. TMPRSS6 mutation analysis is recommended. |
| • In case of a homozygous or compound heterozygous TMPRSS6 defect, IRIDA due to a dysfunctional matriptase-2 protein should be diagnosed. |
| • No recommendation can be made on the clinical significance of heterozygous TMPRSS6 defects with or without concomitant polymorphisms because of lack of evidence. |
| Treatment |
| • In a patient with iron deficiency anemia due to pathogenic TMPRSS6 defects, initial treatment with oral iron or oral iron combined with ascorbic acid should be considered. |
| • If this initial treatment does not result in acceptable hemoglobin (Hb) levels, the patient should be treated with intravenous iron supplementation. |
| • In IRIDA patients, the choice of the chemical form of intravenous iron should be based on its registration for the specific age group OR a proven good safety profile in adults during several years of postmarketing surveillance. |
| • The total intravenous iron cumulative doses should be calculated on the basis of formulas of the deficit of body iron, allowing for the correction of the Hb deficit and rebuilding the iron stores. Doses should be repeated every 3 to 7 days until the total dose is administered. Single doses should not exceed the maximum single dose. |
| • Serum ferritin levels should be monitored and preferably should not exceed 500 µg/L to avoid toxicity of iron overload, especially in children and adolescents. |
| • No recommendation can be made on the efficacy of the combination of intravenous supplementation and erythropoietin (EPO) treatment in IRIDA patients because of lack of evidence. This combination therapy might prevent toxic iron loading in some patients. |
| Family screening* |
| • The proband should be informed about the mostly autosomal recessive inheritance pattern of IRIDA. We recommend screening relatives of the proband for the IRIDA phenotype (siblings and spouse in case of consanguinity and reproductive age). If the proband is diagnosed at a young age, and his/her parents are of reproductive age, phenotyping of the parents is recommended. In case of a clinical IRIDA phenotype in the above-mentioned relatives, mutation analysis is recommended. |
| • Children of the proband should only be phenotyped and, in case of an IRIDA phenotype, genotyped in case of consanguinity of the proband and his/her spouse or in case of proven carriership of both proband and his/her spouse. |
| • Because of the complex genotype-phenotype correlation in IRIDA, we recommend referral to a clinical geneticist in case of an IRIDA phenotype and a pathogenic heterozygous TMPRSS6 defect. |
| 1B. Ferroportin disease due to defects in SLC40A1 |
| Clinical presentation and diagnostics |
| • Ferroportin disease due to LOF mutations should NOT be considered as a cause of microcytic anemia. |
| • When anemia occurs in a patient with primary iron overload during treatment with repeated phlebotomies, the presence of LOF ferroportin disease may be considered. |
| Treatment |
| • Patients with iron overload due to LOF and gain-of-function (GOF) ferroportin disease should be treated with repeated phlebotomies. |
| • For patients who develop anemia during phlebotomies despite elevated ferritin levels, extension of the phlebotomy interval is recommended |
| • In patients who develop anemia during phlebotomies, additional treatment with EPO may be considered. |
| Family screening* |
| • The proband should be informed about the autosomal dominant inheritance pattern of ferroportin disease. |
| • We recommend screening the first-degree relatives (parents, siblings, and children) and additional family members (via cascade screening) for the SLC40A1 mutation identified in the proband. Mutation carriers should be screened for the ferroportin disease phenotype. |
| 1C. Aceruloplasminemia (ACP) due to defects in CP |
| Clinical presentation and diagnostics |
| • In patients with the combination of insulin-dependent diabetes, neurodegenerative disease, retinal degeneration, and mild anemia with systemic iron loading, CP defects should be considered. |
| • In patients with absent or very low CP in combination with low serum copper and iron, high serum ferritin, and characteristic findings on magnetic resonance imaging (MRI) that are compatible with iron accumulation in liver, pancreas, and brain, ACP should be considered. |
| • In case of homozygous or compound heterozygous CP defects, ACP should be diagnosed. |
| Treatment |
| • In patients with ACP, anemia is mild and therefore treatment is not recommended. |
| • Iron chelation therapy should be considered for the treatment of ACP. |
| Family screening* |
| • The proband should be informed about the autosomal recessive inheritance pattern of ACP. Siblings of the proband may be also affected. Since CP defects are very rare, the chance that children of the proband are affected is negligible. |
| • We recommend screening for pathogenic CP mutations (siblings and spouse in case of consanguinity and reproductive age). In case a proband is diagnosed with ACP after the fourth decade, his or her parents are not likely to be of reproductive age, and genotyping is not recommended. |
| • Children of the proband should only be checked for CP mutations in case of consanguinity of the proband and his/her spouse or in case of proven carriership of both proband and his/her spouse. |
| • Individuals heterozygous or compound heterozygous for CP mutation should be screened for the ACP disease phenotype. |
| Part 2: Defects in iron acquisition by the erythroid precursors |
| 2A. Hypotransferrinemia due to defects in TF |
| Clinical presentation and diagnostics |
| • In patients with unexplained hypochromic microcytic anemia, low iron binding capacity (low serum transferrin concentrations) and increased ferritin concentrations, hypotransferrinemia should be considered. Mutation analysis of the TF gene is recommended. |
| • In case of a homozygous or compound heterozygous TF defect, hypotransferrinemia due to a TF defect should be diagnosed. |
| Treatment |
| • Transferrin supplementation by either plasma transfusion or apotransferrin infusion is recommended in patients with hypotransferrinemia due to a TF defect. |
| • Iron status should be monitored in patients with hypotransferrinemia due to a TF defect in order to detect toxic iron loading early. |
| • In case of systemic iron loading, phlebotomies are recommended. If phlebotomies are not tolerated because of decreasing Hb, chelation therapy is recommended. |
| Family screening* |
| • Recommendations are the same as those described in 1C. |
| 2B. Anemia with systemic iron loading due to defects in SLC11A2 (DMT1) |
| Clinical presentation and diagnosis |
| • In patients presenting in childhood with unexplained microcytic anemia with increased TSAT, SLC11A2 defects (among others) should be considered. Genotyping of SLC11A2 is recommended. |
| • In case of a homozygous or compound heterozygous SLC11A2 defect, diagnosis of microcytic anemia due to an SLC11A2 defect is confirmed. |
| Treatment |
| • Patients with microcytic anemia due to pathogenic SLC11A2 defects should be treated with oral iron supplementation and/or EPO and/or erythrocyte transfusions, according to the needs of the individual patient. |
| • In case of treatment with oral iron supplementation and/or erythrocyte transfusions, iron status should be monitored to detect toxic iron loading at an early stage. |
| • Since a normal serum ferritin concentration does not exclude liver iron loading in patients with SLC11A2 defects, MRI of the liver should be considered. |
| Family screening* |
| • Recommendations are the same as those described in 1C. |
| 2C. Sideroblastic anemia due to defects in STEAP3 |
| Clinical presentation and diagnosis |
| • In patients with unexplained hypochromic sideroblastic anemia with low or normal MCV, defects in the STEAP3 gene should be considered. |
| • In case of the combination of hypochromic anemia and gonadal dysfunction, STEAP3 defects should be considered. |
| Treatment |
| • Patients with hypochromic anemia due to STEAP3 defects can be treated with erythrocyte transfusions in combination with EPO. Systemic iron loading should be treated with iron chelation. |
| Family screening* |
| • Because sideroblastic anemia due to a STEAP3 defect has been described in only 1 family, the inheritance pattern is uncertain and the proband should be referred to a clinical geneticist. |
| Part 3: Defects in the heme and/or iron-sulfur (Fe-S) cluster synthesis |
| 3A. Sideroblastic anemia due to defects in SLC25A38 |
| Clinical presentation and diagnosis |
| • In children with severe unexplained microcytic sideroblastic anemia, defects in SLC25A38 should be considered. |
| Treatment |
| • Hematopoietic stem cell transplantation (HSCT) is recommended because it is the only curative option. |
| • Symptomatic treatment consists of erythrocyte transfusions and chelation therapy. |
| Family screening* |
| • Recommendations are the same as those described in 1C. |
| 3B. X-linked sideroblastic anemia (XLSA) with ataxia due to defects in ABCB7 |
| Clinical presentation and diagnosis |
| • In male patients presenting with the combination of a mild microcytic anemia and ataxia, a defect in ABCB7 should be considered. |
| • Increased protoporphyrin IX concentrations in red blood cells are suggestive of this disorder. |
| Treatment |
| • Treatment of (mild) anemia is not indicated. |
| Family screening* |
| • The proband should be informed about the X-linked inheritance pattern of anemia and ataxia due to ABCB7 defects. Brothers of the proband may be also affected. Sons of the proband are not affected. Daughters of the proband are obligate carriers of the relevant ABCB7 defect and have no or a mildly anemic clinical phenotype. |
| • We recommend offering screening for the ABCB7 mutation (the mother and sisters for carriership and the brothers). The spouse should be checked only in case of consanguinity and reproductive age. Daughters of the proband should be offered checking for carriership. |
| 3C. XLSA due to defects in ALAS2 |
| Clinical presentation and diagnosis |
| • XSLA due to an ALAS2 defect should be considered in patients of both gender and of all ages with pyridoxine responsive or unresponsive (mild) microcytic sideroblastic anemia with or without iron loading and in patients with unexplained iron loading. |
| • In patients suspected for XLSA, iron parameters (ferritin, TSAT) should be checked to detect iron loading, as well as liver enzymes, and signs of liver fibrosis or hepatocellular carcinoma. |
| • In case of elderly patients presenting with myelodysplastic syndrome (MDS) refractory anemia with ring sideroblasts or MDS-refractory cytopenia with multilineage dysplasia without specific cytogenetic abnormalities, the presence of ALAS2 defects should be considered, especially if the anemia is microcytic. |
| Treatment |
| • Management of patients with XLSA should involve treatment of anemia and prevention and treatment of iron overload. |
| • Initial treatment with pharmacologic doses of pyridoxine (50 to 200 mg per day) is recommended. Occasionally high doses (up to 300 mg per day) in overweight, active, or elderly patients may be considered. |
| • In case of pyridoxine responsiveness, lifelong supplementation with pyridoxine 10 to 100 mg daily is recommended. |
| • Once a response is obtained, evidence suggests the lifelong maintenance dose may be lowered to 10 to 100 mg per day, because doses that are too high may result in neurotoxicity. |
| • Iron loading should be treated, preferably by phlebotomies. |
| Family screening* |
| • The proband should be informed about the X-linked inheritance pattern of anemia and/or iron overload due to ALAS2 defects. Brothers of the proband may be also affected. Sons of the proband are not affected. Daughters of the proband are obligate carriers of the relevant ALAS2 defect. |
| • We recommend screening for the ALAS2 mutation (the brothers and also the mother, sisters, and daughters for carriership and because women may develop an XLSA phenotype later in life). The spouse should be checked only in case of consanguinity and reproductive age. |
| • Female carriers and male hemizygous individuals should be screened for the XLSA phenotype. |
| 3D. Sideroblastic anemia due to defects in GLRX5 |
| Clinical presentation and diagnosis |
| • In patients presenting with microcytic sideroblastic anemia and iron loading (among other symptoms), defects in GLRX5 should be considered. |
| • In case of microcytic sideroblastic anemia without ALAS2 or SLC25A38 defects, a lymphoblastic culture may be considered. Decreased activity of mitochondrial acitonase and succinate dehydrogenase (complex I-IV) as a manifestation of a defective Fe-S cluster synthesis is suggestive of a GLRX5 defect. |
| Treatment |
| • In patients with sideroblastic anemia and iron loading due to GLRX5 defects, monitoring of the iron status and possible complications of iron overload is recommended. Iron loading should be treated with chelation therapy. Severe anemia should be treated with blood transfusions. |
| Family screening* |
| • Recommendations are the same as those described in 1C. |
| 3E. EPP due to defects in FECH and GOF mutations in ALAS2 (XLDPP) |
| Clinical presentation and diagnosis |
| • In patients with an unexplained mild normocytic to microcytic anemia, low to normal serum ferritin, and cutaneous protoporphyria (a painful photosensitivity in childhood), EPP should be considered in both men and women. |
| • The diagnosis of EPP should be confirmed by fluorescent erythrocytes in an unstained smear and/or enhanced protoporphyrin in plasma and/or erythrocytes. |
| • To prove autosomal recessive EPP, FECH activity should be measured or FECH mutations should be determined. |
| • In case EPP is not explained by the FECH genotype, the ALAS2 gene should be investigated for the presence of GOF mutations. |
| Treatment |
| • If anemia is present in EPP, it is mild and treatment is not recommended. |
| Family screening* |
| • Because of complex genetics influenced by genetic background, we recommend referral to a clinical geneticist in case of EPP. Family screening for a proband with XLDPP due to an ALAS2 GOF mutation should initially include phenotyping and genotyping of all first-degree family members including women (mother in case of a male proband, both parents in case of a female proband, siblings, and children). |
| 3F. Congenital erythropoietic porphyria (CEP) due to defects in UROS or GATA1 |
| Clinical presentation and diagnosis |
| • In patients with an unexplained hemolytic anemia in combination with a painful cutaneous photosensitivity, autosomal recessive CEP has to be considered in both men and women. |
| • In patients with combined cutaneous photosensitivity and severe microcytic hypochromic hemolytic anemia, X-linked CEP should be considered. |
| • Since disease severity and onset of first symptoms is highly variable, CEP should be considered in both children and adults in case of the above-mentioned phenotype. |
| • Diagnosis should be based on increased urinary levels of uroporphyrin I and coproporphyrin I and confirmed by decreased UROS activity in the erythrocytes or the presence of pathogenetic homozygous or compound heterozygous mutations in UROS or in GATA1. |
| Treatment |
| • In patients with CEP, allogeneic HSCT should be considered as the only curative treatment. |
| • Chronic erythrocyte transfusion is recommended as a symptomatic treatment, and iron chelation is recommended according to guidelines for chronic transfusions. |
| Family screening* |
| • Recommendations for CEP due to UROS defects are the same as those described in 1C. |
| • Recommendations for CEP due to GATA1 are the same as those for XLDPP due to GOF ALAS2 mutations (see 3E). |
Recommendations on family screening are based on Borry et al8 and Godard et al.9