From the Guidelines
TMPRSS6 mutations lead to iron-refractory iron deficiency anemia (IRIDA), a rare inherited disorder characterized by iron deficiency that does not respond to oral iron supplementation, and require intravenous iron therapy to manage the condition. These mutations disrupt the normal regulation of hepcidin, a hormone that controls iron absorption and distribution in the body, leading to inappropriately high hepcidin levels, blocking iron absorption from the gut and iron release from storage sites 1. The effects of TMPRSS6 mutations include microcytic, hypochromic anemia, low serum iron, low transferrin saturation, and normal to elevated ferritin levels.
Pathogenesis and Epidemiology
TMPRSS6 encodes matriptase-2, a type II plasma membrane serine protease that senses iron deficiency and blocks hepcidin transcription by cleaving HJV 1. Pathogenic TMPRSS6 defects result in inhibited hepcidin production, causing IRIDA. The prevalence of pathogenic mutations leading to IRIDA is unknown, but underdiagnosis seems likely, with 61 patients in 39 families described in the literature 1.
Treatment
The recommended treatment for IRIDA involves parenteral iron formulations such as iron sucrose, ferric carboxymaltose, or iron dextran, administered until iron stores are replenished 1. Intravenous iron supplementation is the preferred treatment, as oral iron supplementation is often ineffective in patients with severe TMPRSS6 defects. The total intravenous iron cumulative doses should be calculated based on formulas of the deficit of body iron, allowing for the correction of the Hb deficit and rebuilding the iron stores 1. Serum ferritin levels should be monitored and preferably should not exceed 500 mg/L to avoid toxicity of iron overload, especially in children and adolescents 1.
Management
Genetic testing is necessary for definitive diagnosis, and long-term management often requires periodic intravenous iron administration to maintain adequate iron levels. Monitoring serum ferritin levels and adjusting intravenous iron doses accordingly is crucial to avoid iron overload and ensure effective management of IRIDA. The role of erythropoietin (EPO) treatment in IRIDA is controversial, and there is limited evidence to support its use in combination with intravenous iron supplementation 1.
From the Research
Effects of TMPRSS6 Mutations
- TMPRSS6 mutations can cause iron-refractory iron deficiency anemia (IRIDA), a rare autosomal recessive disorder characterized by hypochromic microcytic anemia, low transferrin saturation, and unresponsiveness to oral iron therapy 2, 3, 4.
- Patients with TMPRSS6 mutations have inappropriately high levels of hepcidin, a systemic iron regulatory hormone 2, 4.
- The disorder is typically refractory to oral iron therapy, but may respond partially to parenteral iron administration 2, 3, 4.
- TMPRSS6 mutations can lead to elevated serum hepcidin levels, which contribute to the development of iron deficiency anemia 3, 4.
- Polymorphisms in the TMPRSS6 gene have been associated with variation in iron and hematologic parameters, and may contribute to the development of iron deficiency anemia partially responsive to oral iron treatment 5.
- Novel missense mutations in the TMPRSS6 gene have been identified in patients with IRIDA, highlighting the genetic diversity of the disorder 6.
Clinical Characteristics
- Patients with TMPRSS6 mutations typically present with hypochromic microcytic anemia, low transferrin saturation, and elevated serum hepcidin levels 2, 3, 4.
- The disorder can be diagnosed by sequencing analysis of the TMPRSS6 gene, which can identify mutations and polymorphisms associated with IRIDA 2, 3, 5, 6.
- Patients with TMPRSS6 mutations may require parenteral iron therapy to manage their anemia, as oral iron therapy is often ineffective 2, 3, 4.