Iron Deficiency Caused by Intestinal Iron Loss-Novel Candidate Genes for Severe Anemia.

Carolina Huettmann,Andrea U Steinbicker,Manfred Fobker,Sugirthan Sivalingam,Matthias Penke,Andreas Buness,Carola Wempe,Kerstin U Ludwig,Anne Exler,Martina U Muckenthaler,Christian Wenning,Matthias Stelljes,Alexis Vrachimis

doi:10.3390/genes12121869

Abstract

The adult human body contains about 4 g of iron. About 1–2 mg of iron is absorbed every day, and in healthy individuals, the same amount is excreted. We describe a patient who presents with severe iron deficiency anemia with hemoglobin levels below 6 g/dL and ferritin levels below 30 ng/mL. Although red blood cell concentrates and intravenous iron have been substituted every month for years, body iron stores remain depleted. Diagnostics have included several esophago-gastro-duodenoscopies, colonoscopies, MRI of the liver, repetitive bone marrow biopsies, psychological analysis, application of radioactive iron to determine intact erythropoiesis, and measurement of iron excretion in urine and feces. Typically, gastrointestinal bleeding is a major cause of iron loss. Surprisingly, intestinal iron excretion in stool in the patient was repetitively increased, without gastrointestinal bleeding. Furthermore, whole exome sequencing was performed in the patient and additional family members to identify potential causative genetic variants that may cause intestinal iron loss. Under different inheritance models, several rare mutations were identified, two of which (in CISD1 and KRI1) are likely to be functionally relevant. Intestinal iron loss in the current form has not yet been described and is, with high probability, the cause of the severe iron deficiency anemia in this patient.

Highlights

Anemia is a common disorder and represents a major burden of disease worldwide
We describe a patient who presents with severe iron deficiency anemia with hemoglobin levels below 6 g/dL and ferritin levels below 30 ng/mL
Sequencing of the patient and additional family members revealed 18 genes with rare mutations that represent candidate genes for causing the intestinal iron excretion, two of which could be prioritized based on literature review

Summary

Introduction

Anemia is a common disorder and represents a major burden of disease worldwide. While anemia might occur in people of all ages, a higher incidence has been reported in children younger than 5 years of age, pregnant women, and elderly people (>70 years) [1]. The most frequent types of anemia are (i) iron-deficiency anemia (IDA), affecting about 50% of anemic people, and (ii) anemia of chronic disease (ACD, >40%). Anemias caused by genetic defects encompass a heterogeneous group of rare disorders. Gulbis et al estimated the prevalence of rare anemias defined as less than one case per 2000 [3]. More than 80% of those rare anemias follow an autosomal-dominant inheritance pattern, which includes a probability of 50% for children to inherit the disease-causing allele. There are more than 90 rare anemias listed in the “European Network of Rare Congenital Anemias” [4]

Methods

Results

Conclusion