PF500 A NEW FTL GENE MUTATION RESPONSIBLE FOR HYPOFERRITINEMIA WITHOUT IRON DEFICIENCY
Authors: Cunat S. , Giansily Blaizot M. , Azoury V. , Danton F. , Aguilar Martinez P. 
Published: December 2023

Background:

Serum ferritin (sFt), is widely considered the best test to assess iron deficiency, as it reflects tissue iron storage. A decrease in sFt is an early indicator of a lack of iron in the body and precedes the decrease of serum iron and the onset of iron deficiency anemia. We present an exceptional case of hypoferritinemia, without anemia or associated iron deficiency. Repeated injections of intravenous iron to the patient led to severe iron overload.

Aims:

Case report: A 34‐year‐old woman was referred to our Center for investigation of iron overload. She reported that three years ago a biological assessment to investigate asthenia revealed very low sFt (1 μg/L). The CBC showed no anemia nor microcytosis. The patient had previously received oral iron supplementation for 8 years because of this low sFt. She was given IV iron and received 18 injections in 15 months. Following these injections, ferritin normalized (69 μg/L), but transferrin saturation (TSat) was measured at 96%. The patient consulted a few months later for severe asthenia, anorexia, weight loss and dyspnoea and was hospitalized. Liver iron concentration (LIC) measured by MRI was 190 μmol/g (N <36 μmol/g). The diagnosis of secondary haemochromatosis was given and phlebotomies were started. When we saw the patient for second opinion, she already had 9 phlebotomies. Iron parameters showed a SFt at 2 μg/L, serum iron at 31.48 μmol/L and TSat at 92%. Hemoglobin (Hb) levels were normal at 128 g/L with a MCV at 98 fL. Due to a poor clinical tolerance of the phlebotomies, oral iron chelation was proposed. The patient reported that her father, mother, two sisters, and one brother also had unexplained hypoferritinemia and had received iron supplementation.

Methods:

After informed written consent, Sanger sequencing of the 5’UTR and exon 1 of the FTL (ferritin light chain) gene and NGS analysis of a panel of genes involved in hereditary iron overload (BMP6, HAMP, HFE, HJV, SLC40A1, TRF2) were performed.

Results:

An undescribed mutation of the FTL gene (c.92A> G or p.Y31C), was identified at the homozygous state. A mutation of the BMP6 gene (c: 337C> G or p.Gln133Glu) in the heterozygous state was also observed. This already described mutation is associated with a decrease expression of hepcidin and is thought to promote iron overload. However, hepcidin was measured 3 times at normal values in our patient.

Summary/Conclusion:

The mutation identified in the FTL gene is localized in the region involved in L ferritin secretion. Two hypotheses could account for the hypoferritinemia presented by the patient. It could be a lack of serum secretion of the L‐ferritin chain, despite normal tissue iron stores, or a modification of the recognition site by the antibodies used for ferritin assays (immunological). In order to explore these hypotheses, a study of family segregation and different assay techniques for ferritin were investigated. In addition, the BMP6 gene mutation could have played an aggravating cofactor role, favouring the occurrence of acquired iron overload in this patient. This case illustrates the importance of a pragmatic attitude in the presence of any discrepancies among iron parameters. This isolated hypoferritinemia without anemia or other evidence of iron deficiency, was not an indication of IV iron treatment, which led to iron overload and serious complications in the patient.