Clinical and Immunological Characterization of Combined Immunodeficiency Due to TFRC Mutation in Eight Patients

Abstract

Purpose Combined immunodeficiency (CID), due to mutations in TFRC gene that encodes the transferrin receptors (TfR1), is a rare monogenic disorder. In this study, we further characterize the clinical and immunological phenotypes in a cohort of eight patients. Methods A retrospective review of clinical and immunological features of patients diagnosed with a TFRC gene mutation between 2015 and 2019 in three tertiary centers. Results Eight patients from six unrelated families were enrolled. The patients had a median age of 7 years (4-32 years). All patients presented with recurrent sinopulmonary infections, chronic diarrhea, and failure to thrive in early life. Less common features were skin abscesses, conjunctivitis, global developmental delay, optic nerve atrophy, vitiligo, multinodular goiter, and hemophagocytic lymphohistiocytosis-like symptoms. All patients had intermittent neutropenia and 87% of the patients had recurrent thrombocytopenia. Anemia was found in 62%. All patients had hypogammaglobinemia and one had a persistent high IgM level. All patients had impaired function of T cells. The same homozygous missense mutation c.58T>C:p.Y20H, in the TFRC gene, was detected in all patients. Stem cell transplantation from matched donors was successful in two patients. Five patients did not receive stem cell transplantation, and they are on prophylactic treatment. One patient died due to severe sepsis and neurological complications. Conclusion This report provides a large cohort with a long follow up of patients with this disease. Our cohort showed variable disease severity.

Whole-genome sequencing association analysis of quantitative red blood cell phenotypes: The NHLBI TOPMed program

“…102 While common non-coding variants of TFRC have been associated with MCV and RDW, the only known TFRCrelated Mendelian disorder is a homozygous p.Tyr20His (rs863225436, chr3:196,075,339, GenBank: NM_00112 8148.3, c.58T>C, GenBank: NP_001121620.1, p.Tyr20His) substitution reported to cause combined immunodeficiency affecting leukocytes and platelets but not red cells. 103 Common variants of SLC12A7 encoding the potassium ion channel KCC4 have been associated with RDW and other RBC phenotypes. While KCC4 is expressed in erythroblasts, 104 its role in red blood cell function is not well described.…”

Dysregulated Transferrin Receptor Disrupts T Cell Iron Homeostasis to Drive Inflammation in Systemic Lupus Erythematosus

“…The Transferrin Receptor (CD71) is the primary iron receptor for immune cells and binds to Transferrin (Tf)-bound iron to facilitate internalization of the CD71-transferrin-iron complex. Iron flux and CD71 expression have been shown to be important for T cell activation because missense mutations in the gene for CD71, TFRC , result in combined immunodeficiency (CID) 15 with defective T cell proliferation 16 . Low serum iron conditions can also impede the primary CD8 T cell response to vaccinations 17 and Th1 responses 18 .…”

Transferrin Receptor (TFRC): A Potential Biomarker for The Diagnosis and Prognosis of Sepsis

“…In this case, there are TFRC mutations, and the proliferation, function and transformation of T cells and B lymphocytes are affected [30]. A study reported the clinical manifestations and immunological characteristics of 8 patients with TFRC mutations and found T cell function impairment in all patients [31].…”