What are the causes of genetic inherited iron deficiency?

Genetic Causes of Inherited Iron Deficiency

The primary causes of genetic inherited iron deficiency include mutations in the transferrin (TF) gene, SLC11A2 (DMT1) gene, and TMPRSS6 gene, which disrupt normal iron metabolism and transport, leading to impaired erythropoiesis despite normal or elevated systemic iron levels. 1

Congenital Hypotransferrinemia

Pathophysiology

• Caused by autosomal recessive mutations in the TF gene
• Results in severely reduced or absent transferrin, the main iron transport protein in plasma
• Creates a paradoxical situation of:
  • Iron-deficient erythropoiesis (insufficient iron delivery to bone marrow)
  • Systemic iron overload (excess non-transferrin bound iron depositing in tissues) 1, 2

Clinical Presentation

• Early onset (infancy) of severe microcytic, hypochromic anemia
• Low serum iron despite high ferritin levels
• Transferrin levels extremely low (0-20% of normal) with full saturation
• Growth failure and developmental delays
• Progressive iron overload in liver, pancreas, and other organs 1

Diagnostic Features

• Severely reduced transferrin levels
• Paradoxical lab findings: low serum iron with high ferritin
• Bone marrow shows reduced iron content
• Genetic testing confirms mutations in TF gene 1, 3

SLC11A2 (DMT1) Deficiency

Pathophysiology

• Autosomal recessive mutations in SLC11A2 gene
• DMT1 is crucial for:
  • Intestinal iron absorption
  • Iron uptake by erythroid precursors 1

Clinical Presentation

• Microcytic anemia present from birth
• Increased transferrin saturation
• Variable ferritin levels (low to moderately increased)
• Progressive liver iron loading despite normal/mildly elevated ferritin 1

Diagnostic Features

• Microcytic anemia unresponsive to oral iron
• Liver iron overload on MRI or biopsy
• Genetic testing confirms mutations in SLC11A2 gene 1

Iron-Refractory Iron Deficiency Anemia (IRIDA)

Pathophysiology

• Caused by mutations in TMPRSS6 gene
• Results in inappropriately high hepcidin levels
• Hepcidin blocks intestinal iron absorption and iron release from macrophages 1

Clinical Presentation

• Microcytic, hypochromic anemia refractory to oral iron therapy
• Partial response to parenteral iron
• Low transferrin saturation with normal-to-low ferritin levels 1

Other Rare Genetic Causes

Aceruloplasminemia

• Mutations in CP gene (ceruloplasmin)
• Mild microcytic anemia with low serum iron
• Neurological symptoms typically appear in 4th-5th decade
• Iron accumulation in liver, pancreas, and brain 1, 4

STEAP3 Deficiency

• Rare cause of sideroblastic anemia
• Defective iron reduction in erythroid precursors
• Microcytic anemia with iron overload 1

Diagnostic Approach

Initial Workup

• Complete blood count (CBC) with indices
• Serum iron, ferritin, transferrin, and transferrin saturation
• Consider genetic testing when:
  • Anemia is refractory to iron therapy
  • Paradoxical lab findings (low iron with high ferritin)
  • Family history of similar condition 1

Differential Diagnosis

• Distinguish from acquired causes of iron deficiency
• Rule out thalassemias and other hemoglobinopathies
• Consider other causes of microcytic anemia with iron overload 1

Management Strategies

For Congenital Hypotransferrinemia

• Regular plasma transfusions (source of transferrin)
• May benefit from addition of oral iron supplementation
• Monitor for iron overload and consider chelation therapy 2, 5

For SLC11A2 Deficiency

• Erythrocyte transfusions for severe anemia
• Some patients respond to oral iron supplementation
• Monitor for liver iron loading 1

For IRIDA

• Parenteral iron administration (bypasses intestinal absorption block)
• Regular monitoring of iron parameters 1

Monitoring and Follow-up

• Regular assessment of hematological parameters
• Monitoring of iron status (ferritin, transferrin saturation)
• Surveillance for organ damage from iron overload:
  • Liver function tests
  • Cardiac evaluation
  • Endocrine function 1

Genetic Counseling

• Autosomal recessive inheritance pattern for most genetic iron disorders
• Family screening recommended for affected individuals
• Genetic counseling for reproductive planning 1

Pitfalls to Avoid

• Misdiagnosis as simple iron deficiency anemia
• Excessive iron supplementation in conditions with iron overload
• Failure to monitor for organ damage from iron deposition
• Overlooking genetic testing in refractory cases 1