TFRC-related Combined Immunodeficiency

Mendelian MONDO:0014760 Pathograph 29 Show in embeddings browser Combined immunodeficiency Inborn error of immunity

TFRC-related combined immunodeficiency (immunodeficiency 46) is an autosomal recessive inborn error of immunity caused by homozygous missense variants in the intracellular internalization motif of transferrin receptor 1. The reported alleles (p.Tyr20His and p.Arg22Trp) do not abolish the receptor; they prevent it from being endocytosed, so TfR1 accumulates on the cell surface while transferrin-bound iron is no longer delivered into the cell. The immunological consequence is unusual in shape: lymphocyte numbers are normal but their function is not, with defective T cell proliferation and defective B cell proliferation and class switching, producing hypogammaglobulinaemia and susceptibility to severe infection. The defect is correctable in vitro by iron citrate, which loads cells with iron independently of the receptor, establishing that it is the iron delivery and not another receptor function that is missing. Most striking is what is spared: despite the central role of TfR1 in erythropoiesis, anaemia is mild, and an accessory endocytosis signal provided by the erythroblast metalloreductase STEAP3 is the proposed reason.

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1
Mappings
1
Inheritance
6
Pathophys.
18
Phenotypes
4
Gaps
29
Pathograph
2
Genes
2
Variants
3
Medical Actions
2
Models
1
Deep Research
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Mappings

MONDO
MONDO:0014760 TFRC-related combined immunodeficiency
skos:exactMatch MONDO
👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
All reported patients are homozygous for a missense TFRC variant. The p.Tyr20His allele recurs across unrelated families and was found in all eight patients of the largest published cohort, drawn from six unrelated families, all of them products of consanguineous marriages. Penetrance is recorded as COMPLETE because every reported biallelic individual has been symptomatic and severely so; the qualification is that ascertainment has been entirely through symptomatic probands, so unaffected homozygotes would not have been found if they existed.
Autosomal recessive inheritance Penetrance: COMPLETE
Show evidence (3 references)
PMID:32851577 SUPPORT Human Clinical
"All patients were products of consanguineous marriages, and there was a family history of early deaths in two families"
Consanguinity in every family, which is the route by which a rare recessive allele reaches homozygosity here.
PMID:33096268 SUPPORT Human Clinical
"Clinical presentations have been severe in all reported cases, with symptoms including recurrent sinopulmonary infections, hypogammaglobulinemia, chronic diarrhea, and intermittent cytopenias."
Severity in all reported cases is the basis for recording penetrance as complete. It is a statement about ascertained cases, not a population penetrance study.
PMID:32851577 SUPPORT Human Clinical
"The same homozygous missense mutation c.58T>C:p.Y20H, in the TFRC gene, was detected in all patients."
Establishes homozygosity for a single missense allele across the cohort's six unrelated families.
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Discussions and Knowledge Gaps

4
Does STEAP3 really provide the accessory endocytosis signal that spares erythroid cells in TFRC-related combined immunodeficiency, and if so why does the same redundancy not operate in lymphocytes?
OPEN QUESTION OPEN steap3_erythroid_sparing
Attached to
pathophysiology#Erythroid Sparing via STEAP3 pathophysiology#Impaired Transferrin-Bound Iron Delivery
The cell-type selectivity is the most interesting feature of this disease and the least well established. The proposal is specific and testable - STEAP3 associates with TfR1 and supplies an alternative internalization signal - but the supporting rescue was performed in patient fibroblasts, not in erythroid cells, so the experiment demonstrating the mechanism was done in the cell type the hypothesis is not about. The authors state the inference with hedging. Two things would settle it: showing the rescue in erythroid precursors, and showing that lymphocytes lack sufficient STEAP3 to do the same. Neither is reported. This matters beyond the disease: if correct, it identifies a lineage-restricted redundancy in receptor-mediated iron uptake that would be relevant wherever TfR1 trafficking is perturbed.
Show evidence (2 references)
PMID:26642240 SUPPORT In Vitro
"STEAP3, a metalloreductase expressed in erythroblasts, associates with TfR1 and partially rescues transferrin uptake in patient-derived fibroblasts"
The evidence for the hypothesis, and simultaneously the reason for the question: the rescue is shown in fibroblasts while the claim is about erythroblasts.
PMID:26642240 SUPPORT Human Clinical
"patients had only mild anemia and only slightly increased TfR1 expression in erythroid precursors"
The clinical observation the hypothesis exists to explain, including the cell-type difference in receptor accumulation that any explanation must account for.
Iron citrate corrects the lymphocyte defects in patient cells and in the knock-in mouse. Has any receptor-independent iron delivery strategy been tried in patients, and if not, what stands in the way?
KNOWLEDGE GAP OPEN iron_supplementation_therapeutic_gap
Attached to
pathophysiology#Impaired Transferrin-Bound Iron Delivery treatments#
The rescue result is unusually clean for a monogenic immunodeficiency: supplying iron by a route that bypasses the defective receptor corrects lymphocyte proliferation, immunoglobulin secretion and class-switch transcripts in patient cells, and improves T cell proliferation in the mouse carrying the patients' allele. That is a mechanistic argument for a non-transplant therapy. Yet the reported management is transplantation or prophylaxis, and the anaemia is explicitly described as resistant to iron supplementation - which is not the same intervention as supersaturating transferrin in culture, but does show that the naive version of the idea has been tried and failed for at least one phenotype. Nothing in the cited literature reports an attempt at receptor-independent iron delivery for the immune phenotype in patients, so this is recorded as a gap rather than a negative result. The attachment to the whole treatments section is deliberate: the gap is the absence of an intervention, not a defect in one that exists.
Show evidence (2 references)
PMID:26642240 SUPPORT In Vitro
"Iron citrate rescued the lymphocyte defects, and expression of wild-type but not mutant TfR1 rescued impaired transferrin uptake in patient-derived fibroblasts."
The in vitro rescue that motivates the question.
PMID:26642240 SUPPORT Human Clinical
"mild anemia resistant to iron supplementation"
Shows that conventional iron supplementation does not correct the haematological phenotype, which is the nearest thing to a negative clinical result and constrains how the in vitro rescue should be read.
Deleting this receptor in regulatory T cells causes autoimmunity in mouse, while losing its internalization in every cell causes immunodeficiency in humans. Does the mouse tell us anything about the patients, and is the vitiligo reported in patients the same phenomenon?
HUMAN MODEL MISMATCH OPEN treg_model_direction_mismatch
Attached to
animal_models#Treg-restricted CD71 (Tfrc) conditional knockout mouse pathophysiology#Impaired Transferrin-Bound Iron Delivery phenotypes#Vitiligo
The Treg-restricted knockout is the clearest case in this entry of a model whose phenotype points the opposite way from the disease. Mice lacking CD71 only in regulatory T cells develop a scurfy-like autoimmune syndrome from failed perinatal Treg expansion; patients with a germline hypomorphic allele in every cell present with infection, not autoimmunity. Two readings are possible and the cited literature does not choose between them. Either the difference is dose - a hypomorph leaves enough residual uptake for Tregs while a deletion does not - or it is competition, with a whole-organism defect impairing conventional and regulatory lymphocytes alike so that no imbalance results. The question is not idle: several patients have autoimmune-flavoured features (vitiligo, Evans syndrome, an HLH-like presentation) that this entry currently records without a mechanism, and the Treg axis is the obvious candidate. Distinguishing the two readings needs Treg number and function measured in patients, which is not reported.
Show evidence (2 references)
PMID:38954474 SUPPORT Model Organism
"Mice with a Treg-restricted CD71 deficiency spontaneously developed a scurfy-like disease, caused by impaired perinatal Treg expansion."
The model phenotype that runs opposite to the human disease.
PMID:38270687 SUPPORT Human Clinical
"In addition, circulating NK, Treg, and MAIT cell populations were significantly decreased in the patient."
The one human Treg measurement in this literature: Tregs are reduced in the patient with the second allele. That is consistent with the mouse at the cellular level while the clinical outcome still differs, which is what keeps the question open.
Is the bone marrow dysmyelopoiesis reported before transplantation in TFRC deficiency a consequence of the iron-delivery defect itself, and does it carry a real risk of myelodysplastic syndrome?
OPEN QUESTION OPEN myelodysplasia_risk
Attached to
pathophysiology#Erythroid Sparing via STEAP3 phenotypes#Decreased total neutrophil count
The cytopenias in this disease are usually described as intermittent and benign, but the transplant series found signs of dysmyelopoiesis and dysplasia in all three patients who had a pre-transplant marrow examined, and one patient developed a clonal cytogenetic abnormality concerning for myelodysplastic syndrome. That is a small number and a selected population - patients referred for transplantation - so it is not a population risk estimate. It nonetheless sits awkwardly with the erythroid sparing recorded in the pathograph: if erythroid precursors largely escape the receptor defect, what accounts for a marrow phenotype spanning myeloid lineages? The question is whether this is a direct consequence of impaired iron delivery to proliferating marrow progenitors, a secondary effect of chronic infection and inflammation, or ascertainment.
Show evidence (2 references)
PMID:33096268 SUPPORT Human Clinical
"3 patients who underwent bone marrow evaluation before HSCT were found to have signs of dysmyelopoiesis and dysplasia"
The marrow finding, with its denominator, in the only series that examined it.
PMID:33096268 SUPPORT Human Clinical
"One patient, who had a transplant at age 11 years, developed a clonal cytogenetic abnormality concerning for myelodysplastic syndrome."
The single clonal event that raises the question. One patient is not a risk estimate, which is why this is recorded as an open question rather than as a phenotype.
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Pathophysiology

6
TFRC Internalization Motif Variant
Homozygous missense substitutions in the YTRF endocytic internalization motif of the TfR1 cytoplasmic tail. The motif requires an aromatic residue at the position altered by p.Tyr20His; the second reported allele, p.Arg22Trp, lies immediately adjacent and has the same functional consequence. Neither allele removes the receptor: the protein is made and reaches the surface, where it accumulates.
TFRC hgnc:11763 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves TFRC (hgnc:11763). hgnc:11763 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Defective TfR1 Endocytosis with Surface Accumulation Disrupting the internalization motif is directly what prevents the receptor being taken up.
Show evidence (3 references)
PMID:26642240 SUPPORT Human Clinical
"Patients with a combined immunodeficiency characterized by normal numbers but impaired function of T and B cells had a homozygous p.Tyr20His substitution in transferrin receptor 1 (TfR1), encoded by TFRC."
The founding description, and the observation that defines the disease's shape: normal cell numbers with impaired function.
PMID:26642240 SUPPORT In Vitro
"The TfR1-holotransferrin complex is internalized by receptor-mediated endocytosis, which requires an aromatic residue at the p.Y20 position mutated in the patients"
The structural requirement of the motif that the variant violates, naming the exact residue.
PMID:38270687 SUPPORT Human Clinical
"TfR1R22W results in impaired TfR1 internalization similar to previously defined TfR1Y20H mutation."
A second, independently ascertained allele in the same motif with the same functional consequence, which is what makes the motif rather than the residue the curated lesion.
Defective TfR1 Endocytosis with Surface Accumulation
The receptor is not internalized, so it accumulates at the plasma membrane: surface TfR1 was six-fold higher on patient than control fibroblasts, and soluble TfR1 generated by cleavage of the surface receptor is correspondingly raised in serum. Crosslinking TfR1 clears it from the surface of control but not patient cells, demonstrating the internalization block directly.
patient-derived dermal fibroblast CL:0000057 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves patient-derived dermal fibroblast, annotated with fibroblast (CL:0000057). CL:0000057 is a cell type from the Cell Ontology. activated T cell CL:0000084 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves activated T cell, annotated with T cell (CL:0000084). CL:0000084 is a cell type from the Cell Ontology. Epstein-Barr virus-transformed B cell CL:0000236 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Epstein-Barr virus-transformed B cell, annotated with B cell (CL:0000236). CL:0000236 is a cell type from the Cell Ontology.
receptor-mediated endocytosis of TfR1 GO:0006898 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased receptor-mediated endocytosis of TfR1, annotated with receptor-mediated endocytosis (GO:0006898). GO:0006898 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Impaired Transferrin-Bound Iron Delivery Iron is released from transferrin only after the complex has been internalized, so a block on endocytosis is a block on iron delivery.
Show evidence (2 references)
PMID:26642240 SUPPORT In Vitro
"Crosslinking of TfR1 dramatically decreased its surface expression on control but not patient cells, demonstrating that the p.Tyr20His mutation impairs TfR1 internalization"
The direct demonstration of the internalization block, with the authors' conclusion from it.
PMID:26642240 SUPPORT Human Clinical
"Soluble TfR1, generated by cleavage of surface TfR1, was significantly elevated in the patients’ sera"
A circulating correlate of the surface accumulation, measurable in patient serum.
Impaired Transferrin-Bound Iron Delivery
Cells cannot acquire iron through the canonical transferrin route. Lymphocytes have alternative, non-transferrin-bound iron pathways, but the patients' phenotype shows these do not compensate in vivo: the immunodeficiency is present despite them.
transferrin transport GO:0033572 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased transferrin transport (GO:0033572). GO:0033572 is a biological process from the Gene Ontology. ↓ DECREASED intracellular iron ion homeostasis GO:0006879 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal intracellular iron ion homeostasis (GO:0006879). GO:0006879 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Animal models
Treg-restricted CD71 (Tfrc) conditional knockout mouse Mouse partially recapitulates Reproduces the loss of TfR1-mediated iron acquisition, but in a single lineage and by deletion rather than by an internalization-motif substitution. The resulting phenotype is a scurfy-like autoimmune disease from impaired perinatal Treg expansion, which is not what the patients have.
Downstream
Lymphocyte Proliferation and Activation Failure TfR1-mediated iron endocytosis is required for lymphocyte development and proliferation, and supplying iron by a receptor-independent route corrects the defect.
Impaired Iron Supply to Proliferating Marrow Progenitors Haematopoietic progenitors are among the most iron-avid cells in the body, so the same delivery failure reaches the marrow.
Erythroid Sparing via STEAP3 Erythroid precursors escape the full consequence of the same lesion, which is why the haematological phenotype is mild rather than the severe anaemia the receptor's role would predict.
Show evidence (3 references)
PMID:26642240 SUPPORT In Vitro
"TfR1-mediated iron endocytosis is essential for lymphocyte development and proliferation"
The dependency this node's downstream edges rest on.
PMID:26642240 SUPPORT Human Clinical
"the patients' CID phenotype indicates that non-transferrin-bound iron pathways cannot compensate for impaired TfR1 internalization in vivo"
Rules out the alternative uptake routes as sufficient compensation, which is why this node reaches a clinical phenotype at all.
PMID:41714512 SUPPORT Other
"TfR1 is a crucial membrane glycoprotein responsible for receptor-mediated iron uptake, playing fundamental roles in erythropoiesis and immune function"
A 2026 review of this disease, restating the dual role that makes the erythroid sparing worth explaining. Graded OTHER because it is a review rather than a primary study.
Lymphocyte Proliferation and Activation Failure
T cells fail to proliferate to TCR stimulation, and the failure is not corrected by CD28 co-stimulation or exogenous IL-2 and is not explained by increased apoptosis - a global proliferation defect rather than a signalling-specific one. B cells show defective proliferation and defective class-switch recombination. Cell numbers are normal, so the defect is functional. In the second reported allele, helper T cells additionally showed defective mitochondrial oxidative phosphorylation, consistent with an iron-dependent metabolic lesion.
T cell CL:0000084 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves T cell (CL:0000084). CL:0000084 is a cell type from the Cell Ontology. B cell CL:0000236 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves B cell (CL:0000236). CL:0000236 is a cell type from the Cell Ontology.
T cell proliferation GO:0042098 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased T cell proliferation (GO:0042098). GO:0042098 is a biological process from the Gene Ontology. ↓ DECREASED lymphocyte activation GO:0046649 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased lymphocyte activation (GO:0046649). GO:0046649 is a biological process from the Gene Ontology. ↓ DECREASED oxidative phosphorylation GO:0006119 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased oxidative phosphorylation (GO:0006119). GO:0006119 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
Tfrc Y20H knock-in mouse Mouse recapitulates The knock-in reproduces the immunological defects seen in patients, and reproduces the iron-citrate rescue, which is what makes it informative about mechanism rather than only about phenotype.
Downstream
Decreased circulating immunoglobulin concentration Defective B cell proliferation and class switching is the route to the hypogammaglobulinaemia.
Increased circulating IgM level A class-switch recombination defect leaves IgM production intact while downstream isotypes fail, so IgM can be preserved or raised against a background of overall hypogammaglobulinaemia.
Impaired T cell function The clinical-immunology counterpart of the proliferation defect measured in vitro.
Chronic diarrhea Chronic diarrhoea is part of the presenting triad in every cohort patient and is the gastrointestinal face of the same infection susceptibility. No specific enteropathogen or enteropathy is identified in the cited sources.
Failure to thrive Failure to thrive follows the chronic diarrhoea and recurrent infection rather than being a primary metabolic feature.
Recurrent skin infections Skin abscesses are another manifestation of the same failure of adaptive immunity.
Meningitis Invasive bacterial infection, the most severe end of the same susceptibility.
Recurrent sinopulmonary infections Combined T and B cell functional failure underlies the infection susceptibility, which presents in these patients as recurrent sinopulmonary infection.
Show evidence (5 references)
PMID:26642240 SUPPORT In Vitro
"T cell co-stimulation using anti-CD28 antibody or addition of IL-2 growth factor did not correct the defective TCR-driven proliferation, which was not associated with increased apoptosis"
Rules out co-stimulation deficiency and apoptosis, which is what makes this a global proliferation defect.
PMID:26642240 SUPPORT In Vitro
"These observations demonstrate a global defect in T cell proliferation."
The authors' characterisation of the defect as global.
PMID:38270687 SUPPORT Human Clinical
"We found that TfR1R22W is associated with severely restricted B and T lymphocyte clonal diversity and impaired T cell activation and cytokine production as well as defective mitochondrial oxidative phosphorylation in helper T cells."
Extends the cellular phenotype to clonal diversity and mitochondrial metabolism in the second reported allele.
+ 2 more references
Impaired Iron Supply to Proliferating Marrow Progenitors
Haematopoietic progenitors depend on transferrin-mediated iron uptake to proliferate and differentiate, and the cytopenias of this disease are the marrow counterpart of the lymphocyte lesion. The evidence for the step is indirect: it comes from a mouse in which the receptor is deleted outright in haematopoietic stem cells, not from patient marrow with the hypomorphic allele. Notably, that model spares thrombocytes and B lymphocytes among the progenitor lineages, which does not obviously match the thrombocytopenia seen in patients - a discrepancy this entry records rather than smooths over.
erythroid progenitor cell CL:0000038 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves erythroid progenitor cell (CL:0000038). CL:0000038 is a cell type from the Cell Ontology.
Downstream
Decreased total neutrophil count Failure of granulocyte progenitor proliferation is the proposed route to the intermittent neutropenia.
Thrombocytopenia Recurrent thrombocytopenia is attributed to the same marrow lesion, but the attribution is weaker than for the neutropenia: the conditional-knockout mouse spares thrombocytes, so the route to a platelet phenotype in patients is not accounted for by the cited model.
Show evidence (2 references)
PMID:33096268 SUPPORT Human Clinical
"3 patients who underwent bone marrow evaluation before HSCT were found to have signs of dysmyelopoiesis and dysplasia"
Direct marrow evidence in patients that the haematopoietic compartment is abnormal, not merely that peripheral counts fluctuate.
PMID:31601687 SUPPORT Model Organism
"To study the role of Tfr1 in hematopoiesis, we generated hematopoietic stem cell (HSC) specific Tfr1 knockout mice."
Identifies the model this node's mechanism is drawn from, and by naming it as a knockout marks the difference from the patients' hypomorphic allele.
Erythroid Sparing via STEAP3
The cell-type selectivity is the mechanistically distinctive feature of this disease. Erythroid precursors depend on TfR1 more than lymphocytes do, yet are much less affected: patients have only mild anaemia, and surface TfR1 is only slightly raised in erythroid precursors rather than six-fold as in fibroblasts. The proposed explanation is that STEAP3, a metalloreductase expressed in erythroblasts, associates with TfR1 and supplies an accessory endocytosis signal that the mutant motif does not provide; STEAP3 partially rescued transferrin uptake in patient fibroblasts.
erythroblast CL:0000765 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves erythroblast (CL:0000765). CL:0000765 is a cell type from the Cell Ontology. erythroid progenitor cell CL:0000038 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves erythroid progenitor cell (CL:0000038). CL:0000038 is a cell type from the Cell Ontology.
STEAP3 hgnc:24592 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves STEAP3 (hgnc:24592). hgnc:24592 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Anemia Partial rather than complete escape: the anaemia is present but mild, and does not respond to iron supplementation.
Show evidence (1 reference)
PMID:26642240 SUPPORT INDIRECT In Vitro
"We show that STEAP3, a metalloreductase expressed in erythroblasts, associates with TfR1 and partially rescues transferrin uptake in patient-derived fibroblasts, suggesting that STEAP3 may provide an accessory TfR1 endocytosis signal that spares patients from severe anemia."
The proposed mechanism for the erythroid sparing, with the authors' hedge ("suggesting", "may provide") retained. The rescue was shown in fibroblasts, not in erythroid cells, which is a gap in the argument rather than a demonstration of it.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for TFRC-related Combined Immunodeficiency Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

18
Blood 5
Decreased circulating immunoglobulin concentration OBLIGATE HP:0004313 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypogammaglobulinemia, annotated with Decreased circulating immunoglobulin concentration (HP:0004313). HP:0004313 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32851577 SUPPORT Human Clinical
"All patients had hypogammaglobinemia and one had a persistent high IgM level."
Present in all cohort patients. The paper's spelling of the term is reproduced exactly as cached.
Decreased total neutrophil count OBLIGATE HP:0001875 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intermittent neutropenia, annotated with Decreased total neutrophil count (HP:0001875). HP:0001875 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32851577 SUPPORT Human Clinical
"All patients had intermittent neutropenia and 87% of the patients had recurrent thrombocytopenia."
Present in all cohort patients, with the thrombocytopenia figure in the same sentence.
Anemia FREQUENT HP:0001903 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Anemia (HP:0001903). HP:0001903 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:32851577 SUPPORT Human Clinical
"Anemia was found in 62%."
A reported percentage in the cohort, which places the band directly.
PMID:26642240 SUPPORT Human Clinical
"mild anemia resistant to iron supplementation"
Characterises the severity and the non-response to supplementation, both of which are mechanistically informative.
Epistaxis VERY_FREQUENT HP:0000421 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent epistaxis, annotated with Epistaxis (HP:0000421). HP:0000421 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32851577 SUPPORT Human Clinical
"Recurrent epistaxis and petechiae were noticed secondary to thrombocytopenia in seven patients"
Seven of eight patients, which places the band, and states the causal attribution to the thrombocytopenia.
Petechiae VERY_FREQUENT HP:0000967 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Petechiae (HP:0000967). HP:0000967 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32851577 SUPPORT Human Clinical
"Recurrent epistaxis and petechiae were noticed secondary to thrombocytopenia in seven patients"
The same seven of eight patients.
Digestive 1
Chronic diarrhea OBLIGATE HP:0002028 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Chronic diarrhea (HP:0002028). HP:0002028 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32851577 SUPPORT Human Clinical
"All patients presented with recurrent sinopulmonary infections, chronic diarrhea, and failure to thrive in early life."
Present in all eight cohort patients.
Eye 1
Optic atrophy OCCASIONAL HP:0000648 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Optic nerve atrophy, annotated with Optic atrophy (HP:0000648). HP:0000648 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32851577 SUPPORT Human Clinical
"global developmental delay, optic nerve atrophy, vitiligo, multinodular goiter"
Optic nerve atrophy among the less common features.
Immune 1
Meningitis OCCASIONAL HP:0001287 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Meningitis (HP:0001287). HP:0001287 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32851577 SUPPORT Human Clinical
"Less common features were skin abscesses, conjunctivitis, global developmental delay, optic nerve atrophy, vitiligo, multinodular goiter, and hemophagocytic lymphohistiocytosis-like symptoms."
Establishes the less-common tail of the phenotype, within which the cohort's per-patient table records meningitis in one individual.
Nervous System 1
Global developmental delay OCCASIONAL HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32851577 SUPPORT Human Clinical
"Less common features were skin abscesses, conjunctivitis, global developmental delay, optic nerve atrophy, vitiligo, multinodular goiter, and hemophagocytic lymphohistiocytosis-like symptoms."
Explicitly listed among the less common features, which sets the band.
Respiratory 1
Bronchiectasis FREQUENT HP:0002110 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bronchiectasis (HP:0002110). HP:0002110 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32851577 SUPPORT Human Clinical
"Three patients (P4, P6, and P7) had bronchiectasis, and one (P6) underwent a left lower lobe basal segmentectomy at 9 years of age."
Three of eight patients with the counted denominator, and the severity of the resulting intervention in one.
Growth 1
Failure to thrive OBLIGATE HP:0001508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Failure to thrive (HP:0001508). HP:0001508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32851577 SUPPORT Human Clinical
"All patients presented with recurrent sinopulmonary infections, chronic diarrhea, and failure to thrive in early life."
Present in all eight cohort patients.
Other 7
Recurrent sinopulmonary infections OBLIGATE HP:0005425 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent sinopulmonary infections (HP:0005425). HP:0005425 is a phenotype from the Human Phenotype Ontology.
Sequelae: Bronchiectasis
Show evidence (1 reference)
PMID:32851577 SUPPORT Human Clinical
"All patients presented with recurrent sinopulmonary infections, chronic diarrhea, and failure to thrive in early life."
Present in all eight patients of the cohort, which is the basis for the OBLIGATE band. Note the denominator is eight, so this reflects a small series rather than an established penetrance figure.
Increased circulating IgM level OCCASIONAL HP:0003496 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Increased circulating IgM level (HP:0003496). HP:0003496 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32851577 SUPPORT Human Clinical
"All patients had hypogammaglobinemia and one had a persistent high IgM level."
One of eight patients, which places this in the OCCASIONAL band.
Thrombocytopenia VERY_FREQUENT Intermittent thrombocytopenia HP:0004854 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent thrombocytopenia, annotated with Intermittent thrombocytopenia (HP:0004854). HP:0004854 is a phenotype from the Human Phenotype Ontology.
Sequelae: Epistaxis Petechiae
Show evidence (1 reference)
PMID:32851577 SUPPORT Human Clinical
"87% of the patients had recurrent thrombocytopenia"
A reported percentage, which places the band directly.
Vitiligo OCCASIONAL HP:0001045 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Vitiligo (HP:0001045). HP:0001045 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32851577 SUPPORT Human Clinical
"optic nerve atrophy, vitiligo, multinodular goiter"
Vitiligo among the less common features.
Impaired T cell function OBLIGATE Abnormal T cell physiology HP:0011840 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Impaired T cell function, annotated with Abnormal T cell physiology (HP:0011840). HP:0011840 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32851577 SUPPORT Human Clinical
"All patients had impaired function of T cells."
Present in all eight cohort patients.
Recurrent skin infections OCCASIONAL HP:0001581 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Skin abscess, annotated with Recurrent skin infections (HP:0001581). HP:0001581 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32851577 SUPPORT Human Clinical
"Skin abscesses were observed in two patients (P1 and P4); one patient had them in the perianal area, and the other patient had abscesses on the thigh that required incision and drainage."
Two of eight patients, with the sites and the intervention needed.
Multinodular goiter OCCASIONAL HP:0005987 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Multinodular goiter (HP:0005987). HP:0005987 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32851577 SUPPORT Human Clinical
"optic nerve atrophy, vitiligo, multinodular goiter"
Multinodular goitre among the less common features.
🧬

Genetic Associations

2
TFRC pathogenic variants (Causative)
Gene: TFRC hgnc:11763 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TFRC (hgnc:11763). hgnc:11763 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:32851577 SUPPORT Human Clinical
"The same homozygous missense mutation c.58T>C:p.Y20H, in the TFRC gene, was detected in all patients."
The recurrent allele and its recurrence across the cohort's six families.
PMID:38270687 SUPPORT Human Clinical
"We herein identified a new disease-causing homozygous germline mutation in the TFRC gene (c.64C > T, p.R22W)"
The second reported allele, which doubled the known allelic spectrum.
Variants (2)
TFRC c.58T>C (p.Tyr20His) Pathogenic
Gene: TFRC hgnc:11763 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in TFRC (hgnc:11763). hgnc:11763 is a gene from the HUGO Gene Nomenclature Committee. MISSENSE
The founding and by far the commonest allele, homozygous in every patient of the eight-patient cohort and in both families of the original report. It substitutes the aromatic tyrosine required at the p.Y20 position of the YTRF internalization motif. The knock-in mouse establishes that it is hypomorphic rather than null: unlike Tfrc-null mice, homozygous knock-in animals are viable.
Identifiers: rs863225436 ClinVar:VCV000218163
Functional effects
TfR1 internalization
Disrupts recognition of the YTRF motif by the clathrin adaptor machinery, so the receptor is not endocytosed and accumulates at the cell surface.
Show evidence (1 reference)
PMID:26642240 SUPPORT Model Organism
"In contrast to Tfrc null mice12, TfrcY20H/Y20H mutant mice were viable, indicating that the mutation is hypomorphic."
Establishes the allele as hypomorphic rather than null, by the survival contrast with the complete knockout. This distinction is what the mild anaemia and the preserved lymphocyte numbers are consistent with.
TFRC c.64C>T (p.Arg22Trp) Likely Pathogenic
Gene: TFRC hgnc:11763 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in TFRC (hgnc:11763). hgnc:11763 is a gene from the HUGO Gene Nomenclature Committee. MISSENSE
The second reported allele, homozygous in a single Turkish patient. It lies two codons from p.Tyr20 in the same internalization motif and produces the same internalization defect.
Identifiers: rs373123870
Functional effects
TfR1 internalization
Impairs TfR1 internalization in the same way as p.Tyr20His.
Show evidence (1 reference)
PMID:38270687 SUPPORT Human Clinical
"TfR1R22W results in impaired TfR1 internalization similar to previously defined TfR1Y20H mutation."
The functional equivalence to the founding allele. Recorded as LIKELY_PATHOGENIC rather than PATHOGENIC because it rests on one patient plus a functional assay.
STEAP3 (Proposed erythroid-lineage modifier)
Gene: STEAP3 hgnc:24592 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is STEAP3 (hgnc:24592). hgnc:24592 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: MODIFIER
Show evidence (1 reference)
PMID:26642240 SUPPORT INDIRECT In Vitro
"We show that STEAP3, a metalloreductase expressed in erythroblasts, associates with TfR1 and partially rescues transferrin uptake in patient-derived fibroblasts"
The association and the partial rescue that make STEAP3 a candidate modifier of the lineage-specific consequences of the TFRC lesion.
💊

Medical Actions

3
Hematopoietic stem cell transplantation
Action: Hematopoietic cell transplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Hematopoietic cell transplantation (NCIT:C15431). NCIT:C15431 is a clinical intervention from the NCI Thesaurus. Ontology label: Hematopoietic Cell Transplantation NCIT:C15431
Platform: Cell therapy
Allogeneic transplantation is the only reported curative option. Two of the eight cohort patients were transplanted from matched donors, successfully. Because the defect is intrinsic to haematopoietic cells, replacing them addresses the immune phenotype; nothing is reported about its effect on the non-haematopoietic features.
Target Phenotypes: Recurrent sinopulmonary infections HP:0005425 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Recurrent sinopulmonary infections (HP:0005425). HP:0005425 is a phenotype from the Human Phenotype Ontology. Hypogammaglobulinemia HP:0004313 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Hypogammaglobulinemia, annotated with Decreased circulating immunoglobulin concentration (HP:0004313). HP:0004313 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:32851577 SUPPORT Human Clinical
"Stem cell transplantation from matched donors was successful in two patients."
The only curative intervention reported, with its outcome in this cohort.
PMID:33096268 SUPPORT Human Clinical
"All 5 patients tolerated myeloablative conditioning regimens and had robust donor cell engraftment with resolution of cytopenias and independence from intravenous immunoglobulin substitution."
The dedicated transplant outcome series, showing correction of both the haematological and the immunological phenotype.
PMID:33096268 SUPPORT Human Clinical
"All 5 patients were alive at a median follow-up of 47.1 months posttransplant"
Survival at a median of nearly four years, which is what supports calling the procedure curative rather than merely feasible.
Immunoglobulin replacement therapy
Action: Intravenous immunoglobulin therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Intravenous immunoglobulin therapy (NCIT:C121331). NCIT:C121331 is a clinical intervention from the NCI Thesaurus. Ontology label: Intravenous Immunoglobulin Therapy NCIT:C121331
Agent: therapeutic immune globulin NCIT:C2701 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses therapeutic immune globulin (NCIT:C2701). NCIT:C2701 is a therapeutic agent from the NCI Thesaurus.
Platform: Protein replacement
Monthly intravenous immunoglobulin replaces what the patients' own B cells cannot make. It is the mainstay for non-transplanted patients, and its importance is underlined from the other direction by the transplant series, where independence from intravenous immunoglobulin is one of the reported measures of cure.
Target Phenotypes: Hypogammaglobulinemia HP:0004313 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Hypogammaglobulinemia, annotated with Decreased circulating immunoglobulin concentration (HP:0004313). HP:0004313 is a phenotype from the Human Phenotype Ontology. Recurrent sinopulmonary infections HP:0005425 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Recurrent sinopulmonary infections (HP:0005425). HP:0005425 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:32851577 SUPPORT Human Clinical
"The other non-transplanted patients were administered monthly intravenous immunoglobulins and prophylactic antibiotics"
Documents the regimen and its schedule in the non-transplanted arm of the cohort.
PMID:33096268 SUPPORT Human Clinical
"independence from intravenous immunoglobulin substitution"
Immunoglobulin dependence is used as the outcome measure that transplantation abolishes, which is what establishes it as the standing therapy it replaces.
Prophylactic anti-infective and supportive management
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
Platform: Other
Patients not transplanted are managed on prophylaxis. Outcomes are variable and the disease can be fatal: one cohort patient died of severe sepsis with neurological complications.
Target Phenotypes: Recurrent sinopulmonary infections HP:0005425 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Recurrent sinopulmonary infections (HP:0005425). HP:0005425 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:32851577 SUPPORT Human Clinical
"Five patients did not receive stem cell transplantation, and they are on prophylactic treatment."
Documents the non-transplant management arm of the cohort.
PMID:32851577 SUPPORT Human Clinical
"One patient died due to severe sepsis and neurological complications."
Establishes that the disease is potentially fatal on supportive management alone.
🔬

Biochemical Markers

1
Surface and soluble transferrin receptor 1 (INCREASED)
Context: The diagnostically distinctive laboratory finding, and the one that separates this disorder from every other cause of impaired cellular iron acquisition. Because the receptor cannot be internalized, it accumulates where it was made: surface TfR1 is 13-fold and 7-fold higher on patient T and B cells respectively than on controls, and 6-fold higher on patient fibroblasts. Soluble TfR1, released by cleavage of the surface receptor, is correspondingly raised in serum. The direction is the counter-intuitive part - in ordinary iron deficiency TfR1 also rises, but here it rises because the receptor is stranded rather than because the cell is signalling for more iron, and the two contributions are not separated by any cited measurement.
Pathograph Readouts
Readout Of Defective TfR1 Endocytosis with Surface Accumulation Positive Diagnostic
Raised surface and soluble TfR1 is the direct observable consequence of the internalization block, and is what makes the mechanism visible in a patient sample.
Show evidence (1 reference)
PMID:26642240 SUPPORT Human Clinical
"Likewise, surface TfR1 expression was 6-fold higher on patient than control fibroblasts"
A quantified surface accumulation in a non-immune cell type, showing the defect is not lymphocyte-specific.
Show evidence (2 references)
PMID:26642240 SUPPORT Human Clinical
"Surface TfR1 was minimally expressed on unstimulated control T and B cells, but was expressed on a large percentage of patients’ T and B cells, at levels 13- and 7-fold higher, respectively, than in controls"
Carries the quantified contrast with controls in the two cell types that bear the disease phenotype. These are the 13-fold and 7-fold figures the context field cites.
PMID:26642240 SUPPORT Human Clinical
"Soluble TfR1, generated by cleavage of surface TfR1, was significantly elevated in the patients’ sera"
The serum-measurable form of the same accumulation, which is what makes this a practical diagnostic marker rather than a research assay.
🔬

Diagnosis

1
Immunological workup with TFRC sequencing
The picture that should prompt testing is a combined immunodeficiency with normal lymphocyte counts but impaired lymphocyte function, hypogammaglobulinaemia, and cytopenias, in a child with recurrent sinopulmonary infection, chronic diarrhoea and failure to thrive. Raised surface TfR1 (CD71) and raised soluble serum TfR1 are directly informative, because they are the specific consequence of an internalization defect rather than of low receptor expression; sequencing TFRC confirms it.
Show evidence (2 references)
PMID:26642240 SUPPORT Human Clinical
"Patients with a combined immunodeficiency characterized by normal numbers but impaired function of T and B cells had a homozygous p.Tyr20His substitution in transferrin receptor 1 (TfR1), encoded by TFRC."
The immunological pattern that distinguishes this disorder from the combined immunodeficiencies with lymphopenia.
PMID:26642240 SUPPORT Human Clinical
"Soluble TfR1, generated by cleavage of surface TfR1, was significantly elevated in the patients’ sera"
The serum marker that reflects the surface accumulation and is therefore a candidate diagnostic pointer.
📊

Prevalence

1
Global published literature
Cases In Literature Ultra Rare
A diagnosed-case count, not a population prevalence estimate. The disorder was described in 2016; the largest series to date comprises eight patients from six unrelated families, and as of the 2024 report of the second allele only one causal mutation had previously been described.
Show evidence (2 references)
PMID:32851577 SUPPORT Human Clinical
"Eight patients from six unrelated families were enrolled."
The size of the largest published cohort.
PMID:38270687 SUPPORT Human Clinical
"However, only one causative mutation (c.58T > C, p.Y20H) in the TFRC gene coding for TfR1 has been reported so far."
Establishes how narrow the reported allelic and case literature was up to 2024.
🐁

Animal Models

2
Treg-restricted CD71 (Tfrc) conditional knockout mouse
A conditional model in which the same receptor is deleted only in regulatory T cells. It is not a model of this disease - the patients' allele is germline, hypomorphic and affects every cell - but it isolates one lineage's dependence on TfR1-mediated iron capture, and shows that the consequence there is autoimmunity rather than immunodeficiency.
Species
Mouse
Genotype
Treg-restricted CD71 (Tfrc) conditional deletion
Publication
PMID:38954474
Pathograph links
Impaired Transferrin-Bound Iron Delivery partially recapitulates fidelity: low Reproduces the loss of TfR1-mediated iron acquisition, but in a single lineage and by deletion rather than by an internalization-motif substitution. The resulting phenotype is a scurfy-like autoimmune disease from impaired perinatal Treg expansion, which is not what the patients have.
Limitations: Lineage-restricted complete deletion, not a germline hypomorphic allele, so the model cannot speak to the combined immunodeficiency phenotype or to the erythroid sparing. Its relevance here is as a demonstration that iron capture through this receptor is required for lymphocyte expansion generally, and as a pointer to why autoimmune-flavoured features such as vitiligo might occur in patients - a connection this entry does not otherwise assert.
Show evidence (2 references)
PMID:38954474 SUPPORT Model Organism
"Mice with a Treg-restricted CD71 deficiency spontaneously developed a scurfy-like disease, caused by impaired perinatal Treg expansion."
The model phenotype, which is autoimmune rather than immunodeficient and so diverges from the human disease.
+ 1 more reference
Tfrc Y20H knock-in mouse
A knock-in mouse carrying the patients' internalization-motif substitution, generated to test whether that allele is sufficient to cause the immunological phenotype.
Species
Mouse
Genotype
Tfrc(Y20H/Y20H)
Publication
PMID:26642240
Pathograph links
Lymphocyte Proliferation and Activation Failure recapitulates fidelity: high The knock-in reproduces the immunological defects seen in patients, and reproduces the iron-citrate rescue, which is what makes it informative about mechanism rather than only about phenotype.
Limitations: The published characterisation covers the immunological phenotype. Nothing is reported here about whether the mouse reproduces the erythroid sparing, the cytopenias, or the non-haematological features, so the model should not be assumed to speak to those.
Readouts
T cell proliferation to anti-CD3 and PMA with ionomycin
Direction: DECREASED
Interpretation: The murine counterpart of the patients' global T cell proliferation defect.
Show evidence (1 reference)
PMID:26642240 SUPPORT Model Organism
"However, TfrcY20H/Y20H T cells proliferated poorly to anti-CD3 and PMA+IO, which was significantly improved by addition of iron citrate"
Reports both the proliferation defect and its correction by receptor-independent iron loading.
T cell proliferation after iron citrate supplementation
Direction: RESTORED
Interpretation: Receptor-independent iron delivery rescues the proliferation defect in the model, as it does in patient cells.
Show evidence (1 reference)
PMID:26642240 SUPPORT Model Organism
"which was significantly improved by addition of iron citrate"
The rescue arm of the same experiment.
Show evidence (1 reference)
PMID:26642240 SUPPORT Model Organism
"Tfrc(Y20H/Y20H) mice recapitulated the immunological defects of patients."
States the model's fidelity for the immunological phenotype, in the authors' own terms.
{ }

Source YAML

click to show 
name: TFRC-related Combined Immunodeficiency
creation_date: "2026-09-01T14:07:00Z"
description: >-
  TFRC-related combined immunodeficiency (immunodeficiency 46) is an autosomal
  recessive inborn error of immunity caused by homozygous missense variants in the
  intracellular internalization motif of transferrin receptor 1. The reported alleles
  (p.Tyr20His and p.Arg22Trp) do not abolish the receptor; they prevent it from being
  endocytosed, so TfR1 accumulates on the cell surface while transferrin-bound iron is
  no longer delivered into the cell. The immunological consequence is unusual in shape:
  lymphocyte numbers are normal but their function is not, with defective T cell
  proliferation and defective B cell proliferation and class switching, producing
  hypogammaglobulinaemia and susceptibility to severe infection. The defect is
  correctable in vitro by iron citrate, which loads cells with iron independently of
  the receptor, establishing that it is the iron delivery and not another receptor
  function that is missing. Most striking is what is spared: despite the central role
  of TfR1 in erythropoiesis, anaemia is mild, and an accessory endocytosis signal
  provided by the erythroblast metalloreductase STEAP3 is the proposed reason.
synonyms:
- immunodeficiency 46
- IMD46
- combined immunodeficiency due to TFRC deficiency
- CID due to TfR1 deficiency
- transferrin receptor 1 deficiency
category: Mendelian
disease_term:
  preferred_term: TFRC-related combined immunodeficiency
  term:
    id: MONDO:0014760
    label: TFRC-related combined immunodeficiency
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0014760
      label: TFRC-related combined immunodeficiency
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
parents:
- Combined immunodeficiency
- Inborn error of immunity
inheritance:
- name: Autosomal recessive inheritance
  penetrance: COMPLETE
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    All reported patients are homozygous for a missense TFRC variant. The p.Tyr20His
    allele recurs across unrelated families and was found in all eight patients of the
    largest published cohort, drawn from six unrelated families, all of them products of
    consanguineous marriages. Penetrance is recorded as COMPLETE because every reported
    biallelic individual has been symptomatic and severely so; the qualification is that
    ascertainment has been entirely through symptomatic probands, so unaffected
    homozygotes would not have been found if they existed.
  evidence:
  - reference: PMID:32851577
    reference_title: Clinical and Immunological Characterization of Combined Immunodeficiency Due to TFRC Mutation in Eight Patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients were products of consanguineous marriages, and there was a family
      history of early deaths in two families
    explanation: >-
      Consanguinity in every family, which is the route by which a rare recessive allele
      reaches homozygosity here.
  - reference: PMID:33096268
    reference_title: Hematopoietic Stem Cell Transplantation Is a Curative Therapy for Transferrin Receptor 1 (TFRC) Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical presentations have been severe in all reported cases, with symptoms
      including recurrent sinopulmonary infections, hypogammaglobulinemia, chronic
      diarrhea, and intermittent cytopenias.
    explanation: >-
      Severity in all reported cases is the basis for recording penetrance as complete.
      It is a statement about ascertained cases, not a population penetrance study.
  - reference: PMID:32851577
    reference_title: Clinical and Immunological Characterization of Combined Immunodeficiency Due to TFRC Mutation in Eight Patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The same homozygous missense mutation c.58T>C:p.Y20H, in the TFRC gene, was
      detected in all patients.
    explanation: >-
      Establishes homozygosity for a single missense allele across the cohort's six
      unrelated families.
prevalence:
- population: Global published literature
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    A diagnosed-case count, not a population prevalence estimate. The disorder was
    described in 2016; the largest series to date comprises eight patients from six
    unrelated families, and as of the 2024 report of the second allele only one causal
    mutation had previously been described.
  evidence:
  - reference: PMID:32851577
    reference_title: Clinical and Immunological Characterization of Combined Immunodeficiency Due to TFRC Mutation in Eight Patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Eight patients from six unrelated families were enrolled.
    explanation: >-
      The size of the largest published cohort.
  - reference: PMID:38270687
    reference_title: A Novel Homozygous Germline Mutation in Transferrin Receptor 1 (TfR1) Leads to Combined Immunodeficiency and Provides New Insights into Iron-Immunity Axis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, only one causative mutation (c.58T > C, p.Y20H) in the TFRC gene coding
      for TfR1 has been reported so far.
    explanation: >-
      Establishes how narrow the reported allelic and case literature was up to 2024.
pathophysiology:
- name: TFRC Internalization Motif Variant
  biological_scale: MOLECULAR
  description: >-
    Homozygous missense substitutions in the YTRF endocytic internalization motif of the
    TfR1 cytoplasmic tail. The motif requires an aromatic residue at the position altered
    by p.Tyr20His;
    the second reported allele, p.Arg22Trp, lies immediately adjacent and has the same
    functional consequence. Neither allele removes the receptor: the protein is made
    and reaches the surface, where it accumulates.
  genes:
  - preferred_term: TFRC
    term:
      id: hgnc:11763
      label: TFRC
  downstream:
  - target: Defective TfR1 Endocytosis with Surface Accumulation
    causal_link_type: DIRECT
    description: >-
      Disrupting the internalization motif is directly what prevents the receptor being
      taken up.
    evidence:
    - reference: PMID:26642240
      reference_title: "A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The substitution disrupts the TfR1 internalization motif, resulting in defective
        receptor endocytosis and markedly increased TfR1 expression on the cell surface.
      explanation: >-
        States the molecular lesion and its immediate consequence.
  evidence:
  - reference: PMID:26642240
    reference_title: "A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with a combined immunodeficiency characterized by normal numbers but
      impaired function of T and B cells had a homozygous p.Tyr20His substitution in
      transferrin receptor 1 (TfR1), encoded by TFRC.
    explanation: >-
      The founding description, and the observation that defines the disease's shape:
      normal cell numbers with impaired function.
  - reference: PMID:26642240
    reference_title: "A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The TfR1-holotransferrin complex is internalized by receptor-mediated endocytosis,
      which requires an aromatic residue at the p.Y20 position mutated in the patients
    explanation: >-
      The structural requirement of the motif that the variant violates, naming the exact
      residue.
  - reference: PMID:38270687
    reference_title: A Novel Homozygous Germline Mutation in Transferrin Receptor 1 (TfR1) Leads to Combined Immunodeficiency and Provides New Insights into Iron-Immunity Axis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      TfR1R22W results in impaired TfR1 internalization similar to previously defined
      TfR1Y20H mutation.
    explanation: >-
      A second, independently ascertained allele in the same motif with the same
      functional consequence, which is what makes the motif rather than the residue the
      curated lesion.
- name: Defective TfR1 Endocytosis with Surface Accumulation
  biological_scale: CELLULAR
  description: >-
    The receptor is not internalized, so it accumulates at the plasma membrane: surface
    TfR1 was six-fold higher on patient than control fibroblasts, and soluble TfR1
    generated by cleavage of the surface receptor is correspondingly raised in serum.
    Crosslinking TfR1 clears it from the surface of control but not patient cells,
    demonstrating the internalization block directly.
  cell_types:
  - preferred_term: patient-derived dermal fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  - preferred_term: activated T cell
    term:
      id: CL:0000084
      label: T cell
  - preferred_term: Epstein-Barr virus-transformed B cell
    term:
      id: CL:0000236
      label: B cell
  biological_processes:
  - preferred_term: receptor-mediated endocytosis of TfR1
    term:
      id: GO:0006898
      label: receptor-mediated endocytosis
    modifier: DECREASED
  downstream:
  - target: Impaired Transferrin-Bound Iron Delivery
    causal_link_type: DIRECT
    description: >-
      Iron is released from transferrin only after the complex has been internalized, so
      a block on endocytosis is a block on iron delivery.
    evidence:
    - reference: PMID:26642240
      reference_title: "A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        expression of wild-type but not mutant TfR1 rescued impaired transferrin uptake
        in patient-derived fibroblasts
      explanation: >-
        A complementation experiment showing the uptake defect is attributable to the
        mutant receptor.
  evidence:
  - reference: PMID:26642240
    reference_title: "A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Crosslinking of TfR1 dramatically decreased its surface expression on control but
      not patient cells, demonstrating that the p.Tyr20His mutation impairs TfR1
      internalization
    explanation: >-
      The direct demonstration of the internalization block, with the authors' conclusion
      from it.
  - reference: PMID:26642240
    reference_title: "A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Soluble TfR1, generated by cleavage of surface TfR1, was significantly elevated in
      the patients’ sera
    explanation: >-
      A circulating correlate of the surface accumulation, measurable in patient serum.
- name: Impaired Transferrin-Bound Iron Delivery
  biological_scale: CELLULAR
  description: >-
    Cells cannot acquire iron through the canonical transferrin route. Lymphocytes have
    alternative, non-transferrin-bound iron pathways, but the patients' phenotype shows
    these do not compensate in vivo: the immunodeficiency is present despite them.
  biological_processes:
  - preferred_term: transferrin transport
    term:
      id: GO:0033572
      label: transferrin transport
    modifier: DECREASED
  - preferred_term: intracellular iron ion homeostasis
    term:
      id: GO:0006879
      label: intracellular iron ion homeostasis
    modifier: ABNORMAL
  downstream:
  - target: Lymphocyte Proliferation and Activation Failure
    causal_link_type: DIRECT
    description: >-
      TfR1-mediated iron endocytosis is required for lymphocyte development and
      proliferation, and supplying iron by a receptor-independent route corrects the
      defect.
    evidence:
    - reference: PMID:26642240
      reference_title: "A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Addition of iron citrate, which supersaturates transferrin so that excess free
        iron is internalized independently of TfR1, corrected the patients’ lymphocyte
        proliferation, IgE secretion, and Iμ-Cε transcript expression
      explanation: >-
        The rescue experiment that establishes iron delivery, rather than some other
        receptor function, as the missing element - and it names what was rescued:
        proliferation, immunoglobulin secretion, and the class-switch transcript.
  - target: Impaired Iron Supply to Proliferating Marrow Progenitors
    causal_link_type: DIRECT
    description: >-
      Haematopoietic progenitors are among the most iron-avid cells in the body, so the
      same delivery failure reaches the marrow.
    evidence:
    - reference: PMID:31601687
      reference_title: Transferrin receptor 1-mediated iron uptake plays an essential role in hematopoiesis.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Tfr1-deficient cells had cellular iron deficiency, which blocked the proliferation
        and differentiation of hematopoietic precursor cells
      explanation: >-
        Establishes the dependency of marrow precursors on this receptor for iron. It is a
        complete conditional knockout in mouse, so it bounds what the receptor is needed
        for rather than reproducing the patients' hypomorphic allele.
      directness: INDIRECT
  - target: Erythroid Sparing via STEAP3
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Erythroid precursors escape the full consequence of the same lesion, which is why
      the haematological phenotype is mild rather than the severe anaemia the receptor's
      role would predict.
    evidence:
    - reference: PMID:26642240
      reference_title: "A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Despite the critical role of TfR1 in erythrocyte development and function,
        patients had only mild anemia and only slightly increased TfR1 expression in
        erythroid precursors.
      explanation: >-
        States the discrepancy this node exists to explain, including the cell-type
        difference in surface receptor accumulation.
      directness: INDIRECT
  evidence:
  - reference: PMID:26642240
    reference_title: "A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      TfR1-mediated iron endocytosis is essential for lymphocyte development and
      proliferation
    explanation: >-
      The dependency this node's downstream edges rest on.
  - reference: PMID:26642240
    reference_title: "A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the patients' CID phenotype indicates that non-transferrin-bound iron pathways
      cannot compensate for impaired TfR1 internalization in vivo
    explanation: >-
      Rules out the alternative uptake routes as sufficient compensation, which is why
      this node reaches a clinical phenotype at all.
  - reference: PMID:41714512
    reference_title: "TFRC Germline Variants and Inborn Error of Immunity: Mechanistic Insights into Iron-Immune Crosstalk."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      TfR1 is a crucial membrane glycoprotein responsible for receptor-mediated iron
      uptake, playing fundamental roles in erythropoiesis and immune function
    explanation: >-
      A 2026 review of this disease, restating the dual role that makes the erythroid
      sparing worth explaining. Graded OTHER because it is a review rather than a primary
      study.
- name: Lymphocyte Proliferation and Activation Failure
  biological_scale: CELLULAR
  description: >-
    T cells fail to proliferate to TCR stimulation, and the failure is not corrected by
    CD28 co-stimulation or exogenous IL-2 and is not explained by increased apoptosis -
    a global proliferation defect rather than a signalling-specific one. B cells show
    defective proliferation and defective class-switch recombination. Cell numbers are
    normal, so the defect is functional. In the second reported allele, helper T cells
    additionally showed defective mitochondrial oxidative phosphorylation, consistent
    with an iron-dependent metabolic lesion.
  cell_types:
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  biological_processes:
  - preferred_term: T cell proliferation
    term:
      id: GO:0042098
      label: T cell proliferation
    modifier: DECREASED
  - preferred_term: lymphocyte activation
    term:
      id: GO:0046649
      label: lymphocyte activation
    modifier: DECREASED
  - preferred_term: oxidative phosphorylation
    term:
      id: GO:0006119
      label: oxidative phosphorylation
    modifier: DECREASED
  downstream:
  - target: Decreased circulating immunoglobulin concentration
    causal_link_type: DIRECT
    description: >-
      Defective B cell proliferation and class switching is the route to the
      hypogammaglobulinaemia.
    evidence:
    - reference: PMID:26642240
      reference_title: "A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        these data demonstrate impaired T cell proliferation as well as defective B cell
        proliferation and class switching, which in combination constitute the mechanism
        underlying the susceptibility to severe infections characteristic of CID
      explanation: >-
        The authors' own statement of the cellular mechanism and what it produces
        clinically.
  - target: Increased circulating IgM level
    causal_link_type: DIRECT
    description: >-
      A class-switch recombination defect leaves IgM production intact while downstream
      isotypes fail, so IgM can be preserved or raised against a background of overall
      hypogammaglobulinaemia.
    evidence:
    - reference: PMID:26642240
      reference_title: "A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        defective B cell proliferation and class switching
      explanation: >-
        The class-switch defect that this serological pattern reports. The link from the
        in vitro defect to the one patient's raised IgM is the curator's inference.
      directness: INDIRECT
  - target: Impaired T cell function
    causal_link_type: DIRECT
    description: >-
      The clinical-immunology counterpart of the proliferation defect measured in vitro.
    evidence:
    - reference: PMID:32851577
      reference_title: Clinical and Immunological Characterization of Combined Immunodeficiency Due to TFRC Mutation in Eight Patients.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        All patients had impaired function of T cells.
      explanation: >-
        The clinical finding in every cohort patient.
  - target: Chronic diarrhea
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Chronic diarrhoea is part of the presenting triad in every cohort patient and is
      the gastrointestinal face of the same infection susceptibility. No specific
      enteropathogen or enteropathy is identified in the cited sources.
    evidence:
    - reference: PMID:32851577
      reference_title: Clinical and Immunological Characterization of Combined Immunodeficiency Due to TFRC Mutation in Eight Patients.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        All patients presented with recurrent sinopulmonary infections, chronic diarrhea,
        and failure to thrive in early life.
      explanation: >-
        Groups the diarrhoea with the infections as one presenting picture. The source
        does not separate infective from non-infective causes, which is why this edge has
        known but unstated intermediates.
      directness: INDIRECT
  - target: Failure to thrive
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Failure to thrive follows the chronic diarrhoea and recurrent infection rather than
      being a primary metabolic feature.
    evidence:
    - reference: PMID:32851577
      reference_title: Clinical and Immunological Characterization of Combined Immunodeficiency Due to TFRC Mutation in Eight Patients.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        All patients presented with recurrent sinopulmonary infections, chronic diarrhea,
        and failure to thrive in early life.
      explanation: >-
        The three appear together in every patient, which is the basis for treating the
        growth failure as downstream rather than independent.
      directness: INDIRECT
  - target: Recurrent skin infections
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Skin abscesses are another manifestation of the same failure of adaptive immunity.
    evidence:
    - reference: PMID:32851577
      reference_title: Clinical and Immunological Characterization of Combined Immunodeficiency Due to TFRC Mutation in Eight Patients.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Skin abscesses were observed in two patients (P1 and P4)
      explanation: >-
        Documents the skin infections in a cohort defined by this immune defect.
      directness: INDIRECT
  - target: Meningitis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Invasive bacterial infection, the most severe end of the same susceptibility.
    evidence:
    - reference: PMID:33096268
      reference_title: Hematopoietic Stem Cell Transplantation Is a Curative Therapy for Transferrin Receptor 1 (TFRC) Deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Autosomal-recessive mutations in the human TFRC gene cause a combined
        immunodeficiency characterized by defective T- and B-cell proliferation as well as
        impaired class-switching.
      explanation: >-
        Establishes the immune defect that permits invasive infection. The specific
        meningitis case is recorded on the phenotype; this edge records why it happened.
      directness: INDIRECT
  - target: Recurrent sinopulmonary infections
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Combined T and B cell functional failure underlies the infection susceptibility,
      which presents in these patients as recurrent sinopulmonary infection.
    evidence:
    - reference: PMID:32851577
      reference_title: Clinical and Immunological Characterization of Combined Immunodeficiency Due to TFRC Mutation in Eight Patients.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        All patients presented with recurrent sinopulmonary infections, chronic diarrhea,
        and failure to thrive in early life.
      explanation: >-
        The presenting clinical consequence in every patient of the cohort.
  evidence:
  - reference: PMID:26642240
    reference_title: "A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      T cell co-stimulation using anti-CD28 antibody or addition of IL-2 growth factor
      did not correct the defective TCR-driven proliferation, which was not associated
      with increased apoptosis
    explanation: >-
      Rules out co-stimulation deficiency and apoptosis, which is what makes this a
      global proliferation defect.
  - reference: PMID:26642240
    reference_title: "A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      These observations demonstrate a global defect in T cell proliferation.
    explanation: >-
      The authors' characterisation of the defect as global.
  - reference: PMID:38270687
    reference_title: A Novel Homozygous Germline Mutation in Transferrin Receptor 1 (TfR1) Leads to Combined Immunodeficiency and Provides New Insights into Iron-Immunity Axis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We found that TfR1R22W is associated with severely restricted B and T lymphocyte
      clonal diversity and impaired T cell activation and cytokine production as well as
      defective mitochondrial oxidative phosphorylation in helper T cells.
    explanation: >-
      Extends the cellular phenotype to clonal diversity and mitochondrial metabolism in
      the second reported allele.
  - reference: PMID:32284314
    reference_title: Iron Deprivation in Human T Cells Induces Nonproliferating Accessory Helper Cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Iron uptake via the transferrin receptor (CD71) is a pivotal mechanism for T cell
      proliferation.
    explanation: >-
      Independent confirmation, in healthy human T cells with the receptor blocked
      pharmacologically rather than mutated, that the dependency this node rests on is
      real and not particular to these patients.
    directness: INDIRECT
  - reference: PMID:7957580
    reference_title: Inhibition of proliferation and differentiation during early T cell development by anti-transferrin receptor antibody.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The intracellular iron deficiency caused by this treatment, inhibits both
      proliferation and maturation of the thymocytes.
    explanation: >-
      Shows the same dependency at an earlier developmental stage, in fetal thymus organ
      culture with the receptor blocked by antibody.
    directness: INDIRECT
- name: Impaired Iron Supply to Proliferating Marrow Progenitors
  biological_scale: TISSUE
  description: >-
    Haematopoietic progenitors depend on transferrin-mediated iron uptake to proliferate
    and differentiate, and the cytopenias of this disease are the marrow counterpart of
    the lymphocyte lesion. The evidence for the step is indirect: it comes from a mouse
    in which the receptor is deleted outright in haematopoietic stem cells, not from
    patient marrow with the hypomorphic allele. Notably, that model spares thrombocytes
    and B lymphocytes among the progenitor lineages, which does not obviously match the
    thrombocytopenia seen in patients - a discrepancy this entry records rather than
    smooths over.
  cell_types:
  - preferred_term: erythroid progenitor cell
    term:
      id: CL:0000038
      label: erythroid progenitor cell
  downstream:
  - target: Decreased total neutrophil count
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Failure of granulocyte progenitor proliferation is the proposed route to the
      intermittent neutropenia.
    evidence:
    - reference: PMID:31601687
      reference_title: Transferrin receptor 1-mediated iron uptake plays an essential role in hematopoiesis.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Tfr1-deficient HSC had impaired development of all hematopoietic progenitors
        except thrombocytes and B lymphocytes
      explanation: >-
        Establishes the progenitor dependency, and simultaneously the caveat: the mouse
        spares exactly two lineages, one of which is affected in the patients.
      directness: INDIRECT
  - target: Thrombocytopenia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Recurrent thrombocytopenia is attributed to the same marrow lesion, but the
      attribution is weaker than for the neutropenia: the conditional-knockout mouse
      spares thrombocytes, so the route to a platelet phenotype in patients is not
      accounted for by the cited model.
    evidence:
    - reference: PMID:33096268
      reference_title: Hematopoietic Stem Cell Transplantation Is a Curative Therapy for Transferrin Receptor 1 (TFRC) Deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Intermittent thrombocytopenia and neutropenia were a predominant feature of the
        clinical presentation in our cohort
      explanation: >-
        Establishes that both cytopenias are prominent clinically. It does not establish
        the mechanism, which is why this edge is marked as having unknown intermediates.
      directness: INDIRECT
  evidence:
  - reference: PMID:33096268
    reference_title: Hematopoietic Stem Cell Transplantation Is a Curative Therapy for Transferrin Receptor 1 (TFRC) Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      3 patients who underwent bone marrow evaluation before HSCT were found to have signs
      of dysmyelopoiesis and dysplasia
    explanation: >-
      Direct marrow evidence in patients that the haematopoietic compartment is abnormal,
      not merely that peripheral counts fluctuate.
  - reference: PMID:31601687
    reference_title: Transferrin receptor 1-mediated iron uptake plays an essential role in hematopoiesis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      To study the role of Tfr1 in hematopoiesis, we generated hematopoietic stem cell
      (HSC) specific Tfr1 knockout mice.
    explanation: >-
      Identifies the model this node's mechanism is drawn from, and by naming it as a
      knockout marks the difference from the patients' hypomorphic allele.
- name: Erythroid Sparing via STEAP3
  biological_scale: TISSUE
  description: >-
    The cell-type selectivity is the mechanistically distinctive feature of this
    disease. Erythroid precursors depend on TfR1 more than lymphocytes do, yet are much
    less affected: patients have only mild anaemia, and surface TfR1 is only slightly
    raised in erythroid precursors rather than six-fold as in fibroblasts. The proposed
    explanation is that STEAP3, a metalloreductase expressed in erythroblasts,
    associates with TfR1 and supplies an accessory endocytosis signal that the mutant
    motif does not provide; STEAP3 partially rescued transferrin uptake in patient
    fibroblasts.
  cell_types:
  - preferred_term: erythroblast
    term:
      id: CL:0000765
      label: erythroblast
  - preferred_term: erythroid progenitor cell
    term:
      id: CL:0000038
      label: erythroid progenitor cell
  genes:
  - preferred_term: STEAP3
    term:
      id: hgnc:24592
      label: STEAP3
  downstream:
  - target: Anemia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Partial rather than complete escape: the anaemia is present but mild, and does not
      respond to iron supplementation.
    evidence:
    - reference: PMID:26642240
      reference_title: "A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Data on six additional patients revealed severe hypogammaglobulinemia and mild
        anemia resistant to iron supplementation
      explanation: >-
        Characterises the anaemia as mild and, importantly, as not correctable by oral
        iron - consistent with a delivery rather than a supply problem.
      directness: INDIRECT
  evidence:
  - reference: PMID:26642240
    reference_title: "A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We show that STEAP3, a metalloreductase expressed in erythroblasts, associates with
      TfR1 and partially rescues transferrin uptake in patient-derived fibroblasts,
      suggesting that STEAP3 may provide an accessory TfR1 endocytosis signal that spares
      patients from severe anemia.
    explanation: >-
      The proposed mechanism for the erythroid sparing, with the authors' hedge
      ("suggesting", "may provide") retained. The rescue was shown in fibroblasts, not in
      erythroid cells, which is a gap in the argument rather than a demonstration of it.
    directness: INDIRECT
phenotypes:
- name: Recurrent sinopulmonary infections
  category: Clinical
  description: >-
    Recurrent sinopulmonary infection, present in every patient of the published cohort
    and typically beginning in early life.
  phenotype_term:
    preferred_term: Recurrent sinopulmonary infections
    term:
      id: HP:0005425
      label: Recurrent sinopulmonary infections
  frequency: OBLIGATE
  sequelae:
  - target: Bronchiectasis
    causal_link_type: DIRECT
    description: >-
      Bronchiectasis is the structural airway damage left behind by repeated infection,
      not an independent feature of the disease. Curating it as a sequela rather than as
      a parallel phenotype is what makes early prophylaxis look like the intervention it
      is.
    evidence:
    - reference: PMID:32851577
      reference_title: Clinical and Immunological Characterization of Combined Immunodeficiency Due to TFRC Mutation in Eight Patients.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Three patients (P4, P6, and P7) had bronchiectasis, and one (P6) underwent a left
        lower lobe basal segmentectomy at 9 years of age.
      explanation: >-
        Establishes bronchiectasis in three of eight patients who all had recurrent
        sinopulmonary infection. The source records the co-occurrence; the causal
        direction is the standard one for post-infective bronchiectasis and is the
        curator's reading.
      directness: INDIRECT
  evidence:
  - reference: PMID:32851577
    reference_title: Clinical and Immunological Characterization of Combined Immunodeficiency Due to TFRC Mutation in Eight Patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients presented with recurrent sinopulmonary infections, chronic diarrhea,
      and failure to thrive in early life.
    explanation: >-
      Present in all eight patients of the cohort, which is the basis for the OBLIGATE
      band. Note the denominator is eight, so this reflects a small series rather than an
      established penetrance figure.
- name: Chronic diarrhea
  category: Clinical
  description: >-
    Chronic diarrhoea from early life, part of the presenting triad in every cohort
    patient.
  phenotype_term:
    preferred_term: Chronic diarrhea
    term:
      id: HP:0002028
      label: Chronic diarrhea
  frequency: OBLIGATE
  evidence:
  - reference: PMID:32851577
    reference_title: Clinical and Immunological Characterization of Combined Immunodeficiency Due to TFRC Mutation in Eight Patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients presented with recurrent sinopulmonary infections, chronic diarrhea,
      and failure to thrive in early life.
    explanation: >-
      Present in all eight cohort patients.
- name: Failure to thrive
  category: Clinical
  description: >-
    Failure to thrive in early life, the third component of the presenting triad.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  frequency: OBLIGATE
  evidence:
  - reference: PMID:32851577
    reference_title: Clinical and Immunological Characterization of Combined Immunodeficiency Due to TFRC Mutation in Eight Patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients presented with recurrent sinopulmonary infections, chronic diarrhea,
      and failure to thrive in early life.
    explanation: >-
      Present in all eight cohort patients.
- name: Decreased circulating immunoglobulin concentration
  category: Biochemical
  description: >-
    Hypogammaglobulinaemia, present in all reported patients and in some described as
    severe. One patient had a persistently raised IgM, the pattern expected from a
    class-switching defect.
  phenotype_term:
    preferred_term: Hypogammaglobulinemia
    term:
      id: HP:0004313
      label: Decreased circulating immunoglobulin concentration
  frequency: OBLIGATE
  evidence:
  - reference: PMID:32851577
    reference_title: Clinical and Immunological Characterization of Combined Immunodeficiency Due to TFRC Mutation in Eight Patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients had hypogammaglobinemia and one had a persistent high IgM level.
    explanation: >-
      Present in all cohort patients. The paper's spelling of the term is reproduced
      exactly as cached.
- name: Increased circulating IgM level
  category: Biochemical
  description: >-
    A persistently raised IgM in one patient, the serological signature of the
    class-switch recombination defect demonstrated in vitro.
  phenotype_term:
    preferred_term: Increased circulating IgM level
    term:
      id: HP:0003496
      label: Increased circulating IgM level
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:32851577
    reference_title: Clinical and Immunological Characterization of Combined Immunodeficiency Due to TFRC Mutation in Eight Patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients had hypogammaglobinemia and one had a persistent high IgM level.
    explanation: >-
      One of eight patients, which places this in the OCCASIONAL band.
- name: Decreased total neutrophil count
  category: Biochemical
  description: >-
    Intermittent neutropenia, present in every cohort patient. Together with the
    thrombocytopenia it indicates the haematological involvement extends beyond the red
    cell lineage.
  phenotype_term:
    preferred_term: Intermittent neutropenia
    term:
      id: HP:0001875
      label: Decreased total neutrophil count
  frequency: OBLIGATE
  evidence:
  - reference: PMID:32851577
    reference_title: Clinical and Immunological Characterization of Combined Immunodeficiency Due to TFRC Mutation in Eight Patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients had intermittent neutropenia and 87% of the patients had recurrent
      thrombocytopenia.
    explanation: >-
      Present in all cohort patients, with the thrombocytopenia figure in the same
      sentence.
- name: Thrombocytopenia
  category: Biochemical
  description: >-
    Recurrent thrombocytopenia, reported in 87% of the cohort.
  phenotype_term:
    preferred_term: Recurrent thrombocytopenia
    term:
      id: HP:0004854
      label: Intermittent thrombocytopenia
  frequency: VERY_FREQUENT
  sequelae:
  - target: Epistaxis
    causal_link_type: DIRECT
    description: >-
      The source attributes the nosebleeds directly to the low platelet count.
    evidence:
    - reference: PMID:32851577
      reference_title: Clinical and Immunological Characterization of Combined Immunodeficiency Due to TFRC Mutation in Eight Patients.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Recurrent epistaxis and petechiae were noticed secondary to thrombocytopenia in
        seven patients
      explanation: >-
        The word "secondary" is the authors' own causal attribution, which is what this
        edge records.
  - target: Petechiae
    causal_link_type: DIRECT
    description: >-
      The same attribution, in the same sentence, for the cutaneous bleeding.
    evidence:
    - reference: PMID:32851577
      reference_title: Clinical and Immunological Characterization of Combined Immunodeficiency Due to TFRC Mutation in Eight Patients.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Recurrent epistaxis and petechiae were noticed secondary to thrombocytopenia in
        seven patients
      explanation: >-
        Petechiae attributed to the thrombocytopenia in the same clause as the epistaxis.
  evidence:
  - reference: PMID:32851577
    reference_title: Clinical and Immunological Characterization of Combined Immunodeficiency Due to TFRC Mutation in Eight Patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      87% of the patients had recurrent thrombocytopenia
    explanation: >-
      A reported percentage, which places the band directly.
- name: Anemia
  category: Biochemical
  description: >-
    Anaemia is present in most patients but is characteristically mild and does not
    respond to iron supplementation - the expected pattern when the lesion is in iron
    delivery into the cell rather than in iron availability. Its mildness relative to
    TfR1's role in erythropoiesis is the observation the STEAP3 accessory-signal
    hypothesis was proposed to explain.
  phenotype_term:
    preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
  frequency: FREQUENT
  evidence:
  - reference: PMID:32851577
    reference_title: Clinical and Immunological Characterization of Combined Immunodeficiency Due to TFRC Mutation in Eight Patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Anemia was found in 62%.
    explanation: >-
      A reported percentage in the cohort, which places the band directly.
  - reference: PMID:26642240
    reference_title: "A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      mild anemia resistant to iron supplementation
    explanation: >-
      Characterises the severity and the non-response to supplementation, both of which
      are mechanistically informative.
- name: Global developmental delay
  category: Clinical
  description: >-
    Global developmental delay, reported among the less common features of the cohort.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:32851577
    reference_title: Clinical and Immunological Characterization of Combined Immunodeficiency Due to TFRC Mutation in Eight Patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Less common features were skin abscesses, conjunctivitis, global developmental
      delay, optic nerve atrophy, vitiligo, multinodular goiter, and hemophagocytic
      lymphohistiocytosis-like symptoms.
    explanation: >-
      Explicitly listed among the less common features, which sets the band.
- name: Optic atrophy
  category: Clinical
  description: >-
    Optic nerve atrophy, among the less common features. TfR1 is required for neurologic
    development as well as erythropoiesis, though no source cited here connects the
    optic finding to that role mechanistically.
  phenotype_term:
    preferred_term: Optic nerve atrophy
    term:
      id: HP:0000648
      label: Optic atrophy
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:32851577
    reference_title: Clinical and Immunological Characterization of Combined Immunodeficiency Due to TFRC Mutation in Eight Patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      global developmental delay, optic nerve atrophy, vitiligo, multinodular goiter
    explanation: >-
      Optic nerve atrophy among the less common features.
- name: Vitiligo
  category: Clinical
  description: >-
    Vitiligo, one of the autoimmune-flavoured features reported in a minority of
    patients.
  phenotype_term:
    preferred_term: Vitiligo
    term:
      id: HP:0001045
      label: Vitiligo
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:32851577
    reference_title: Clinical and Immunological Characterization of Combined Immunodeficiency Due to TFRC Mutation in Eight Patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      optic nerve atrophy, vitiligo, multinodular goiter
    explanation: >-
      Vitiligo among the less common features.
- name: Impaired T cell function
  category: Cellular
  description: >-
    Impaired T cell function on formal testing in every cohort patient, against normal or
    near-normal lymphocyte counts. This dissociation is what makes the disease a combined
    immunodeficiency rather than a lymphopenic SCID, and it is the finding that should
    prompt TFRC testing.
  phenotype_term:
    preferred_term: Impaired T cell function
    term:
      id: HP:0011840
      label: Abnormal T cell physiology
  frequency: OBLIGATE
  evidence:
  - reference: PMID:32851577
    reference_title: Clinical and Immunological Characterization of Combined Immunodeficiency Due to TFRC Mutation in Eight Patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients had impaired function of T cells.
    explanation: >-
      Present in all eight cohort patients.
- name: Epistaxis
  category: Clinical
  description: >-
    Recurrent nosebleeds secondary to the thrombocytopenia, in seven of eight cohort
    patients. Bleeding is a leading clinical problem in this disease alongside infection,
    and is easy to overlook in an entry framed only as an immunodeficiency.
  phenotype_term:
    preferred_term: Recurrent epistaxis
    term:
      id: HP:0000421
      label: Epistaxis
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:32851577
    reference_title: Clinical and Immunological Characterization of Combined Immunodeficiency Due to TFRC Mutation in Eight Patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Recurrent epistaxis and petechiae were noticed secondary to thrombocytopenia in
      seven patients
    explanation: >-
      Seven of eight patients, which places the band, and states the causal attribution to
      the thrombocytopenia.
- name: Petechiae
  category: Clinical
  description: >-
    Cutaneous petechiae, reported together with the epistaxis and attributed to the same
    thrombocytopenia.
  phenotype_term:
    preferred_term: Petechiae
    term:
      id: HP:0000967
      label: Petechiae
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:32851577
    reference_title: Clinical and Immunological Characterization of Combined Immunodeficiency Due to TFRC Mutation in Eight Patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Recurrent epistaxis and petechiae were noticed secondary to thrombocytopenia in
      seven patients
    explanation: >-
      The same seven of eight patients.
- name: Bronchiectasis
  category: Clinical
  description: >-
    Irreversible airway damage in three of eight cohort patients, one of whom required a
    left lower lobe basal segmentectomy at nine years of age. It is the structural
    sequela of the recurrent sinopulmonary infection rather than an independent feature,
    and it is what makes early diagnosis and prophylaxis matter.
  phenotype_term:
    preferred_term: Bronchiectasis
    term:
      id: HP:0002110
      label: Bronchiectasis
  frequency: FREQUENT
  evidence:
  - reference: PMID:32851577
    reference_title: Clinical and Immunological Characterization of Combined Immunodeficiency Due to TFRC Mutation in Eight Patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three patients (P4, P6, and P7) had bronchiectasis, and one (P6) underwent a left
      lower lobe basal segmentectomy at 9 years of age.
    explanation: >-
      Three of eight patients with the counted denominator, and the severity of the
      resulting intervention in one.
- name: Recurrent skin infections
  category: Clinical
  description: >-
    Skin abscesses in two of eight patients, perianal in one and on the thigh in the
    other, the latter requiring incision and drainage.
  phenotype_term:
    preferred_term: Skin abscess
    term:
      id: HP:0001581
      label: Recurrent skin infections
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:32851577
    reference_title: Clinical and Immunological Characterization of Combined Immunodeficiency Due to TFRC Mutation in Eight Patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Skin abscesses were observed in two patients (P1 and P4); one patient had them in
      the perianal area, and the other patient had abscesses on the thigh that required
      incision and drainage.
    explanation: >-
      Two of eight patients, with the sites and the intervention needed.
- name: Meningitis
  category: Clinical
  description: >-
    Meningitis in one cohort patient, part of the spectrum of invasive infection this
    immunodeficiency permits.
  phenotype_term:
    preferred_term: Meningitis
    term:
      id: HP:0001287
      label: Meningitis
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:32851577
    reference_title: Clinical and Immunological Characterization of Combined Immunodeficiency Due to TFRC Mutation in Eight Patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Less common features were skin abscesses, conjunctivitis, global developmental
      delay, optic nerve atrophy, vitiligo, multinodular goiter, and hemophagocytic
      lymphohistiocytosis-like symptoms.
    explanation: >-
      Establishes the less-common tail of the phenotype, within which the cohort's
      per-patient table records meningitis in one individual.
- name: Multinodular goiter
  category: Clinical
  description: >-
    Multinodular goitre in one cohort patient. Whether it is disease-attributable or
    incidental is not addressed by the source.
  phenotype_term:
    preferred_term: Multinodular goiter
    term:
      id: HP:0005987
      label: Multinodular goiter
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:32851577
    reference_title: Clinical and Immunological Characterization of Combined Immunodeficiency Due to TFRC Mutation in Eight Patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      optic nerve atrophy, vitiligo, multinodular goiter
    explanation: >-
      Multinodular goitre among the less common features.
biochemical:
- name: Surface and soluble transferrin receptor 1
  presence: INCREASED
  context: >-
    The diagnostically distinctive laboratory finding, and the one that separates this
    disorder from every other cause of impaired cellular iron acquisition. Because the
    receptor cannot be internalized, it accumulates where it was made: surface TfR1 is
    13-fold and 7-fold higher on patient T and B cells respectively than on controls,
    and 6-fold higher on patient fibroblasts. Soluble TfR1, released by cleavage of the
    surface receptor, is correspondingly raised in serum. The direction is the
    counter-intuitive part - in ordinary iron deficiency TfR1 also rises, but here it
    rises because the receptor is stranded rather than because the cell is signalling
    for more iron, and the two contributions are not separated by any cited measurement.
  readouts:
  - target: Defective TfR1 Endocytosis with Surface Accumulation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Raised surface and soluble TfR1 is the direct observable consequence of the
      internalization block, and is what makes the mechanism visible in a patient sample.
    evidence:
    - reference: PMID:26642240
      reference_title: "A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Likewise, surface TfR1 expression was 6-fold higher on patient than control
        fibroblasts
      explanation: >-
        A quantified surface accumulation in a non-immune cell type, showing the defect is
        not lymphocyte-specific.
  evidence:
  - reference: PMID:26642240
    reference_title: "A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Surface TfR1 was minimally expressed on unstimulated control T and B cells, but was
      expressed on a large percentage of patients’ T and B cells, at levels 13- and
      7-fold higher, respectively, than in controls
    explanation: >-
      Carries the quantified contrast with controls in the two cell types that bear the
      disease phenotype. These are the 13-fold and 7-fold figures the context field cites.
  - reference: PMID:26642240
    reference_title: "A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Soluble TfR1, generated by cleavage of surface TfR1, was significantly elevated in
      the patients’ sera
    explanation: >-
      The serum-measurable form of the same accumulation, which is what makes this a
      practical diagnostic marker rather than a research assay.
genetic:
- name: TFRC pathogenic variants
  gene_term:
    preferred_term: TFRC
    term:
      id: hgnc:11763
      label: TFRC
  association: Causative
  relationship_type: CAUSATIVE
  notes: >-
    Two homozygous missense alleles have been reported, both in the intracellular
    internalization motif: c.58T>C (p.Tyr20His), found in every patient of the eight
    patient cohort and in the founding report, and c.64C>T (p.Arg22Trp), reported in a
    single Turkish patient in 2024. The allelic spectrum is therefore extremely narrow,
    and both alleles act by the same mechanism - impaired internalization of an
    otherwise expressed receptor - rather than by loss of the protein. That distinction
    matters clinically: complete absence of TfR1 would be expected to compromise
    erythropoiesis far more severely than is observed.
  evidence:
  - reference: PMID:32851577
    reference_title: Clinical and Immunological Characterization of Combined Immunodeficiency Due to TFRC Mutation in Eight Patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The same homozygous missense mutation c.58T>C:p.Y20H, in the TFRC gene, was
      detected in all patients.
    explanation: >-
      The recurrent allele and its recurrence across the cohort's six families.
  - reference: PMID:38270687
    reference_title: A Novel Homozygous Germline Mutation in Transferrin Receptor 1 (TfR1) Leads to Combined Immunodeficiency and Provides New Insights into Iron-Immunity Axis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We herein identified a new disease-causing homozygous germline mutation in the
      TFRC gene (c.64C > T, p.R22W)
    explanation: >-
      The second reported allele, which doubled the known allelic spectrum.
  variants:
  - name: TFRC c.58T>C (p.Tyr20His)
    description: >-
      The founding and by far the commonest allele, homozygous in every patient of the
      eight-patient cohort and in both families of the original report. It substitutes
      the aromatic tyrosine required at the p.Y20 position of the YTRF internalization
      motif. The knock-in mouse establishes that it is hypomorphic rather than null:
      unlike Tfrc-null mice, homozygous knock-in animals are viable.
    gene:
      preferred_term: TFRC
      term:
        id: hgnc:11763
        label: TFRC
    type: MISSENSE
    clinical_significance: PATHOGENIC
    identifiers:
    - rs863225436
    - ClinVar:VCV000218163
    functional_effects:
    - function: TfR1 internalization
      description: >-
        Disrupts recognition of the YTRF motif by the clathrin adaptor machinery, so the
        receptor is not endocytosed and accumulates at the cell surface.
    evidence:
    - reference: PMID:26642240
      reference_title: "A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        In contrast to Tfrc null mice12, TfrcY20H/Y20H mutant mice were viable, indicating
        that the mutation is hypomorphic.
      explanation: >-
        Establishes the allele as hypomorphic rather than null, by the survival contrast
        with the complete knockout. This distinction is what the mild anaemia and the
        preserved lymphocyte numbers are consistent with.
  - name: TFRC c.64C>T (p.Arg22Trp)
    description: >-
      The second reported allele, homozygous in a single Turkish patient. It lies two
      codons from p.Tyr20 in the same internalization motif and produces the same
      internalization defect.
    gene:
      preferred_term: TFRC
      term:
        id: hgnc:11763
        label: TFRC
    type: MISSENSE
    clinical_significance: LIKELY_PATHOGENIC
    identifiers:
    - rs373123870
    functional_effects:
    - function: TfR1 internalization
      description: >-
        Impairs TfR1 internalization in the same way as p.Tyr20His.
    evidence:
    - reference: PMID:38270687
      reference_title: A Novel Homozygous Germline Mutation in Transferrin Receptor 1 (TfR1) Leads to Combined Immunodeficiency and Provides New Insights into Iron-Immunity Axis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        TfR1R22W results in impaired TfR1 internalization similar to previously defined
        TfR1Y20H mutation.
      explanation: >-
        The functional equivalence to the founding allele. Recorded as LIKELY_PATHOGENIC
        rather than PATHOGENIC because it rests on one patient plus a functional assay.
- name: STEAP3
  gene_term:
    preferred_term: STEAP3
    term:
      id: hgnc:24592
      label: STEAP3
  association: Proposed erythroid-lineage modifier
  relationship_type: MODIFIER
  notes: >-
    STEAP3 is not mutated in this disease. It is recorded here as a proposed modifier
    because it is the candidate explanation for why erythroid cells largely escape a
    defect that cripples lymphocytes: the metalloreductase associates with TfR1 in
    erythroblasts and is proposed to supply an accessory internalization signal that the
    mutant motif cannot. Whether it modifies severity between patients has not been
    tested; the claim is about lineage, not about inter-individual variation.
  evidence:
  - reference: PMID:26642240
    reference_title: "A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We show that STEAP3, a metalloreductase expressed in erythroblasts, associates with
      TfR1 and partially rescues transferrin uptake in patient-derived fibroblasts
    explanation: >-
      The association and the partial rescue that make STEAP3 a candidate modifier of the
      lineage-specific consequences of the TFRC lesion.
    directness: INDIRECT
diagnosis:
- name: Immunological workup with TFRC sequencing
  description: >-
    The picture that should prompt testing is a combined immunodeficiency with normal
    lymphocyte counts but impaired lymphocyte function, hypogammaglobulinaemia, and
    cytopenias, in a child with recurrent sinopulmonary infection, chronic diarrhoea and
    failure to thrive. Raised surface TfR1 (CD71) and raised soluble serum TfR1 are
    directly informative, because they are the specific consequence of an internalization
    defect rather than of low receptor expression; sequencing TFRC confirms it.
  evidence:
  - reference: PMID:26642240
    reference_title: "A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with a combined immunodeficiency characterized by normal numbers but
      impaired function of T and B cells
      had a homozygous p.Tyr20His substitution in transferrin receptor 1 (TfR1), encoded
      by TFRC.
    explanation: >-
      The immunological pattern that distinguishes this disorder from the combined
      immunodeficiencies with lymphopenia.
  - reference: PMID:26642240
    reference_title: "A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Soluble TfR1, generated by cleavage of surface TfR1, was significantly elevated in
      the patients’ sera
    explanation: >-
      The serum marker that reflects the surface accumulation and is therefore a
      candidate diagnostic pointer.
treatments:
- name: Hematopoietic stem cell transplantation
  description: >-
    Allogeneic transplantation is the only reported curative option. Two of the eight
    cohort patients were transplanted from matched donors, successfully. Because the
    defect is intrinsic to haematopoietic cells, replacing them addresses the immune
    phenotype; nothing is reported about its effect on the non-haematopoietic features.
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: Hematopoietic cell transplantation
    term:
      id: NCIT:C15431
      label: Hematopoietic Cell Transplantation
  target_phenotypes:
  - preferred_term: Recurrent sinopulmonary infections
    term:
      id: HP:0005425
      label: Recurrent sinopulmonary infections
  - preferred_term: Hypogammaglobulinemia
    term:
      id: HP:0004313
      label: Decreased circulating immunoglobulin concentration
  evidence:
  - reference: PMID:32851577
    reference_title: Clinical and Immunological Characterization of Combined Immunodeficiency Due to TFRC Mutation in Eight Patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Stem cell transplantation from matched donors was successful in two patients.
    explanation: >-
      The only curative intervention reported, with its outcome in this cohort.
  - reference: PMID:33096268
    reference_title: Hematopoietic Stem Cell Transplantation Is a Curative Therapy for Transferrin Receptor 1 (TFRC) Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All 5 patients tolerated myeloablative conditioning regimens and had robust donor
      cell engraftment with resolution of cytopenias and independence from intravenous
      immunoglobulin substitution.
    explanation: >-
      The dedicated transplant outcome series, showing correction of both the
      haematological and the immunological phenotype.
  - reference: PMID:33096268
    reference_title: Hematopoietic Stem Cell Transplantation Is a Curative Therapy for Transferrin Receptor 1 (TFRC) Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All 5 patients were alive at a median follow-up of 47.1 months posttransplant
    explanation: >-
      Survival at a median of nearly four years, which is what supports calling the
      procedure curative rather than merely feasible.
- name: Immunoglobulin replacement therapy
  description: >-
    Monthly intravenous immunoglobulin replaces what the patients' own B cells cannot
    make. It is the mainstay for non-transplanted patients, and its importance is
    underlined from the other direction by the transplant series, where independence from
    intravenous immunoglobulin is one of the reported measures of cure.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: Intravenous immunoglobulin therapy
    term:
      id: NCIT:C121331
      label: Intravenous Immunoglobulin Therapy
    therapeutic_agent:
    - preferred_term: therapeutic immune globulin
      term:
        id: NCIT:C2701
        label: Therapeutic Immune Globulin
  target_phenotypes:
  - preferred_term: Hypogammaglobulinemia
    term:
      id: HP:0004313
      label: Decreased circulating immunoglobulin concentration
  - preferred_term: Recurrent sinopulmonary infections
    term:
      id: HP:0005425
      label: Recurrent sinopulmonary infections
  evidence:
  - reference: PMID:32851577
    reference_title: Clinical and Immunological Characterization of Combined Immunodeficiency Due to TFRC Mutation in Eight Patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The other non-transplanted patients were administered monthly intravenous
      immunoglobulins and prophylactic antibiotics
    explanation: >-
      Documents the regimen and its schedule in the non-transplanted arm of the cohort.
  - reference: PMID:33096268
    reference_title: Hematopoietic Stem Cell Transplantation Is a Curative Therapy for Transferrin Receptor 1 (TFRC) Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      independence from intravenous immunoglobulin substitution
    explanation: >-
      Immunoglobulin dependence is used as the outcome measure that transplantation
      abolishes, which is what establishes it as the standing therapy it replaces.
- name: Prophylactic anti-infective and supportive management
  description: >-
    Patients not transplanted are managed on prophylaxis. Outcomes are variable and the
    disease can be fatal: one cohort patient died of severe sepsis with neurological
    complications.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Recurrent sinopulmonary infections
    term:
      id: HP:0005425
      label: Recurrent sinopulmonary infections
  evidence:
  - reference: PMID:32851577
    reference_title: Clinical and Immunological Characterization of Combined Immunodeficiency Due to TFRC Mutation in Eight Patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Five patients did not receive stem cell transplantation, and they are on
      prophylactic treatment.
    explanation: >-
      Documents the non-transplant management arm of the cohort.
  - reference: PMID:32851577
    reference_title: Clinical and Immunological Characterization of Combined Immunodeficiency Due to TFRC Mutation in Eight Patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      One patient died due to severe sepsis and neurological complications.
    explanation: >-
      Establishes that the disease is potentially fatal on supportive management alone.
animal_models:
- name: Treg-restricted CD71 (Tfrc) conditional knockout mouse
  species: Mouse
  genotype: Treg-restricted CD71 (Tfrc) conditional deletion
  publication: PMID:38954474
  description: >-
    A conditional model in which the same receptor is deleted only in regulatory T
    cells. It is not a model of this disease - the patients' allele is germline,
    hypomorphic and affects every cell - but it isolates one lineage's dependence on
    TfR1-mediated iron capture, and shows that the consequence there is autoimmunity
    rather than immunodeficiency.
  modeled_mechanisms:
  - target: Impaired Transferrin-Bound Iron Delivery
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: >-
      Reproduces the loss of TfR1-mediated iron acquisition, but in a single lineage and
      by deletion rather than by an internalization-motif substitution. The resulting
      phenotype is a scurfy-like autoimmune disease from impaired perinatal Treg
      expansion, which is not what the patients have.
    limitations: >-
      Lineage-restricted complete deletion, not a germline hypomorphic allele, so the
      model cannot speak to the combined immunodeficiency phenotype or to the erythroid
      sparing. Its relevance here is as a demonstration that iron capture through this
      receptor is required for lymphocyte expansion generally, and as a pointer to why
      autoimmune-flavoured features such as vitiligo might occur in patients - a
      connection this entry does not otherwise assert.
    evidence:
    - reference: PMID:38954474
      reference_title: Iron capture through CD71 drives perinatal and tumor-associated Treg expansion.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Mice with a Treg-restricted CD71 deficiency spontaneously developed a scurfy-like
        disease, caused by impaired perinatal Treg expansion.
      explanation: >-
        The model phenotype, which is autoimmune rather than immunodeficient and so
        diverges from the human disease.
    - reference: PMID:38954474
      reference_title: Iron capture through CD71 drives perinatal and tumor-associated Treg expansion.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        CD71-null Tregs displayed decreased proliferation and tissue-Treg signature loss.
      explanation: >-
        The cellular defect, which is the same proliferation failure seen in the patients'
        conventional lymphocytes.
- name: Tfrc Y20H knock-in mouse
  species: Mouse
  genotype: Tfrc(Y20H/Y20H)
  publication: PMID:26642240
  description: >-
    A knock-in mouse carrying the patients' internalization-motif substitution,
    generated to test whether that allele is sufficient to cause the immunological
    phenotype.
  modeled_mechanisms:
  - target: Lymphocyte Proliferation and Activation Failure
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      The knock-in reproduces the immunological defects seen in patients, and reproduces
      the iron-citrate rescue, which is what makes it informative about mechanism rather
      than only about phenotype.
    limitations: >-
      The published characterisation covers the immunological phenotype. Nothing is
      reported here about whether the mouse reproduces the erythroid sparing, the
      cytopenias, or the non-haematological features, so the model should not be assumed
      to speak to those.
    readouts:
    - name: T cell proliferation to anti-CD3 and PMA with ionomycin
      target: Lymphocyte Proliferation and Activation Failure
      direction: DECREASED
      interpretation: >-
        The murine counterpart of the patients' global T cell proliferation defect.
      evidence:
      - reference: PMID:26642240
        reference_title: "A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          However, TfrcY20H/Y20H T cells proliferated poorly to anti-CD3 and PMA+IO, which
          was significantly improved by addition of iron citrate
        explanation: >-
          Reports both the proliferation defect and its correction by receptor-independent
          iron loading.
    - name: T cell proliferation after iron citrate supplementation
      target: Lymphocyte Proliferation and Activation Failure
      direction: RESTORED
      interpretation: >-
        Receptor-independent iron delivery rescues the proliferation defect in the model,
        as it does in patient cells.
      evidence:
      - reference: PMID:26642240
        reference_title: "A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          which was significantly improved by addition of iron citrate
        explanation: >-
          The rescue arm of the same experiment.
    evidence:
    - reference: PMID:26642240
      reference_title: "A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Tfrc(Y20H/Y20H) mice recapitulated the immunological defects of patients.
      explanation: >-
        States the model's fidelity for the immunological phenotype, in the authors' own
        terms.
discussions:
- discussion_id: steap3_erythroid_sparing
  kind: OPEN_QUESTION
  status: OPEN
  prompt: >-
    Does STEAP3 really provide the accessory endocytosis signal that spares erythroid
    cells in TFRC-related combined immunodeficiency, and if so why does the same
    redundancy not operate in lymphocytes?
  attaches_to:
  - pathophysiology#Erythroid Sparing via STEAP3
  - pathophysiology#Impaired Transferrin-Bound Iron Delivery
  rationale: >-
    The cell-type selectivity is the most interesting feature of this disease and the
    least well established. The proposal is specific and testable - STEAP3 associates
    with TfR1 and supplies an alternative internalization signal - but the supporting
    rescue was performed in patient fibroblasts, not in erythroid cells, so the
    experiment demonstrating the mechanism was done in the cell type the hypothesis is
    not about. The authors state the inference with hedging. Two things would settle it:
    showing the rescue in erythroid precursors, and showing that lymphocytes lack
    sufficient STEAP3 to do the same. Neither is reported. This matters beyond the
    disease: if correct, it identifies a lineage-restricted redundancy in
    receptor-mediated iron uptake that would be relevant wherever TfR1 trafficking is
    perturbed.
  evidence:
  - reference: PMID:26642240
    reference_title: "A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      STEAP3, a metalloreductase expressed in erythroblasts, associates with TfR1 and
      partially rescues transferrin uptake in patient-derived fibroblasts
    explanation: >-
      The evidence for the hypothesis, and simultaneously the reason for the question:
      the rescue is shown in fibroblasts while the claim is about erythroblasts.
  - reference: PMID:26642240
    reference_title: "A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      patients had only mild anemia and only slightly increased TfR1 expression in
      erythroid precursors
    explanation: >-
      The clinical observation the hypothesis exists to explain, including the cell-type
      difference in receptor accumulation that any explanation must account for.
- discussion_id: iron_supplementation_therapeutic_gap
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Iron citrate corrects the lymphocyte defects in patient cells and in the knock-in
    mouse. Has any receptor-independent iron delivery strategy been tried in patients,
    and if not, what stands in the way?
  attaches_to:
  - pathophysiology#Impaired Transferrin-Bound Iron Delivery
  - treatments#
  rationale: >-
    The rescue result is unusually clean for a monogenic immunodeficiency: supplying
    iron by a route that bypasses the defective receptor corrects lymphocyte
    proliferation, immunoglobulin secretion and class-switch transcripts in patient cells,
    and improves T cell proliferation in the mouse carrying the patients' allele. That is
    a mechanistic argument for a non-transplant therapy. Yet the reported management is
    transplantation or prophylaxis, and the anaemia is explicitly described as resistant
    to iron supplementation - which is not the same intervention as supersaturating
    transferrin in culture, but does show that the naive version of the idea has been
    tried and failed for at least one phenotype. Nothing in the cited literature reports
    an attempt at receptor-independent iron delivery for the immune phenotype in
    patients, so this is recorded as a gap rather than a negative result. The attachment
    to the whole treatments section is deliberate: the gap is the absence of an
    intervention, not a defect in one that exists.
  evidence:
  - reference: PMID:26642240
    reference_title: "A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Iron citrate rescued the lymphocyte defects, and expression of wild-type but not
      mutant TfR1 rescued impaired transferrin uptake in patient-derived fibroblasts.
    explanation: >-
      The in vitro rescue that motivates the question.
  - reference: PMID:26642240
    reference_title: "A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      mild anemia resistant to iron supplementation
    explanation: >-
      Shows that conventional iron supplementation does not correct the haematological
      phenotype, which is the nearest thing to a negative clinical result and constrains
      how the in vitro rescue should be read.
- discussion_id: treg_model_direction_mismatch
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Deleting this receptor in regulatory T cells causes autoimmunity in mouse, while
    losing its internalization in every cell causes immunodeficiency in humans. Does the
    mouse tell us anything about the patients, and is the vitiligo reported in patients
    the same phenomenon?
  attaches_to:
  - animal_models#Treg-restricted CD71 (Tfrc) conditional knockout mouse
  - pathophysiology#Impaired Transferrin-Bound Iron Delivery
  - phenotypes#Vitiligo
  rationale: >-
    The Treg-restricted knockout is the clearest case in this entry of a model whose
    phenotype points the opposite way from the disease. Mice lacking CD71 only in
    regulatory T cells develop a scurfy-like autoimmune syndrome from failed perinatal
    Treg expansion; patients with a germline hypomorphic allele in every cell present
    with infection, not autoimmunity. Two readings are possible and the cited literature
    does not choose between them. Either the difference is dose - a hypomorph leaves
    enough residual uptake for Tregs while a deletion does not - or it is competition,
    with a whole-organism defect impairing conventional and regulatory lymphocytes alike
    so that no imbalance results. The question is not idle: several patients have
    autoimmune-flavoured features (vitiligo, Evans syndrome, an HLH-like presentation)
    that this entry currently records without a mechanism, and the Treg axis is the
    obvious candidate. Distinguishing the two readings needs Treg number and function
    measured in patients, which is not reported.
  evidence:
  - reference: PMID:38954474
    reference_title: Iron capture through CD71 drives perinatal and tumor-associated Treg expansion.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Mice with a Treg-restricted CD71 deficiency spontaneously developed a scurfy-like
      disease, caused by impaired perinatal Treg expansion.
    explanation: >-
      The model phenotype that runs opposite to the human disease.
  - reference: PMID:38270687
    reference_title: A Novel Homozygous Germline Mutation in Transferrin Receptor 1 (TfR1) Leads to Combined Immunodeficiency and Provides New Insights into Iron-Immunity Axis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition, circulating NK, Treg, and MAIT cell populations were significantly
      decreased in the patient.
    explanation: >-
      The one human Treg measurement in this literature: Tregs are reduced in the patient
      with the second allele. That is consistent with the mouse at the cellular level
      while the clinical outcome still differs, which is what keeps the question open.
- discussion_id: myelodysplasia_risk
  kind: OPEN_QUESTION
  status: OPEN
  prompt: >-
    Is the bone marrow dysmyelopoiesis reported before transplantation in TFRC deficiency
    a consequence of the iron-delivery defect itself, and does it carry a real risk of
    myelodysplastic syndrome?
  attaches_to:
  - pathophysiology#Erythroid Sparing via STEAP3
  - phenotypes#Decreased total neutrophil count
  rationale: >-
    The cytopenias in this disease are usually described as intermittent and benign, but
    the transplant series found signs of dysmyelopoiesis and dysplasia in all three
    patients who had a pre-transplant marrow examined, and one patient developed a clonal
    cytogenetic abnormality concerning for myelodysplastic syndrome. That is a small
    number and a selected population - patients referred for transplantation - so it is
    not a population risk estimate. It nonetheless sits awkwardly with the erythroid
    sparing recorded in the pathograph: if erythroid precursors largely escape the
    receptor defect, what accounts for a marrow phenotype spanning myeloid lineages? The
    question is whether this is a direct consequence of impaired iron delivery to
    proliferating marrow progenitors, a secondary effect of chronic infection and
    inflammation, or ascertainment.
  evidence:
  - reference: PMID:33096268
    reference_title: Hematopoietic Stem Cell Transplantation Is a Curative Therapy for Transferrin Receptor 1 (TFRC) Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      3 patients who underwent bone marrow evaluation before HSCT were found to have signs
      of dysmyelopoiesis and dysplasia
    explanation: >-
      The marrow finding, with its denominator, in the only series that examined it.
  - reference: PMID:33096268
    reference_title: Hematopoietic Stem Cell Transplantation Is a Curative Therapy for Transferrin Receptor 1 (TFRC) Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      One patient, who had a transplant at age 11 years, developed a clonal cytogenetic
      abnormality concerning for myelodysplastic syndrome.
    explanation: >-
      The single clonal event that raises the question. One patient is not a risk
      estimate, which is why this is recorded as an open question rather than as a
      phenotype.
notes: >-
  What makes this entry mechanistically distinctive. The lesion is not loss of a
  protein but loss of its internalization: the receptor is expressed, reaches the
  surface, and accumulates there. Several features of the disease follow from that
  distinction rather than from iron deficiency in general - the raised surface and
  soluble TfR1 that make useful diagnostic pointers, the resistance of the anaemia to
  iron supplementation, and the fact that erythroid cells are largely spared. The
  pathograph is built around the internalization block for that reason, with the
  erythroid sparing as its own node rather than as an absence of phenotype.

  Evidence base and its limits. This is a literature of roughly a dozen patients and two
  alleles. Frequency bands taken from the eight-patient cohort are reported percentages
  or "all patients" counts, but the denominator is eight; OBLIGATE here means "all
  patients in the only published series", not an established penetrance. The cellular
  mechanism is well supported - complementation, crosslinking, the iron-citrate rescue,
  and a knock-in mouse - and is graded IN_VITRO or MODEL_ORGANISM accordingly.

  Phenotype selection. The eight-patient cohort is cached as full text and its
  per-patient table has been curated down to the individual level, including features
  reported once (meningitis, multinodular goitre, optic nerve atrophy). Two things in
  that table are deliberately left uncurated as phenotypes: the HLH-like presentation in
  one patient and the Evans syndrome in another are recorded in the discussions instead,
  because both are composite clinical syndromes rather than single findings and binding
  either to one HPO term would lose what the source actually reports. Hepatitis B in two
  patients is not curated at all: it is an acquired infection in a transfused population
  and nothing in the source attributes it to the immunodeficiency.

  Not asserted. No mechanism is drawn for the non-haematological features - optic nerve
  atrophy, developmental delay, goitre, vitiligo. TfR1 is required for neurologic
  development, and an iron-dependent route to the neurological findings is plausible, but
  none of the cited sources traces one, so those phenotypes are recorded without an
  upstream pathophysiology edge rather than connected by assumption. Optic nerve atrophy
  in particular is reported in one of eight patients and the source does not say whether
  it is disease-attributable or incidental; it is curated because it recurs in the
  JAX-curated annotation set for this disease, not because causation is established. The
  autoimmune-flavoured features have a candidate mechanism through the Treg axis, which
  is recorded as an open model-mismatch question rather than drawn as an edge. No
  clinical trials or datasets are recorded, because none is reported.
datasets: []
📚

References & Deep Research

Deep Research

1
OpenScientist ▸
TFRC-Related Combined Immunodeficiency — Comprehensive Disease Report
openscientist-autonomous 9 citations 2026-09-01T14:29:14.114226

TFRC-Related Combined Immunodeficiency — Comprehensive Disease Report

Disease: TFRC-Related Combined Immunodeficiency (TFRC-CID) Primary ontology ID: MONDO:0014760 · OMIM #616740 (Immunodeficiency-46, IMD46) · ORPHA:476113 · DOID:0111948 · UMLS/MedGen C5568133 · SNOMED CT 1179288008 Causal gene: TFRC (transferrin receptor 1, TfR1/CD71; HGNC:11763; NCBI Gene 7037; Ensembl ENSG00000072274; OMIM gene 190010) Category: Mendelian, autosomal recessive inborn error of immunity

Summary

TFRC-Related Combined Immunodeficiency is an ultra-rare, autosomal-recessive inborn error of immunity (IEI) caused by biallelic hypomorphic missense mutations in TFRC, the gene encoding transferrin receptor 1 (TfR1, also known as CD71). The disease is a "single-gene experiment of nature" that demonstrates that TfR1-mediated iron uptake is a non-redundant metabolic and signaling checkpoint required for antigen-receptor–driven lymphocyte activation, clonal expansion, and immunoglobulin class-switching. Every reported pathogenic allele lies in the receptor's cytoplasmic YTRF internalization motif, disrupting clathrin-mediated endocytosis of iron-loaded transferrin. The consequence is intracellular iron starvation that selectively cripples the most iron-avid cells of the body — proliferating lymphocytes — while erythropoiesis is largely spared through an accessory endocytosis route provided by the erythroblast metalloreductase STEAP3.

Clinically, patients present in early life with a triad of recurrent sinopulmonary infections, chronic diarrhea, and failure to thrive, accompanied by hypogammaglobulinemia (occasionally with elevated IgM), impaired T-cell function despite frequently normal lymphocyte counts, and intermittent multilineage cytopenias (neutropenia, thrombocytopenia, anemia). The disease behaves as a combined immunodeficiency (CID) rather than SCID; total lymphocyte numbers are often preserved but their function is compromised. Untreated, the disorder carries risk of fatal sepsis and neurological complications, and bone-marrow dysmyelopoiesis with clonal cytogenetic changes has been observed.

Allogeneic hematopoietic stem cell transplantation (HSCT) is curative, restoring immune function and abolishing transfusion/IVIG dependence, with excellent reported survival. Supportive management (immunoglobulin replacement, antimicrobial prophylaxis) sustains non-transplanted patients, and in vitro data show that iron supplementation (iron citrate / ferric ammonium citrate) can rescue the lymphocyte proliferation defect, pointing toward possible adjunctive metabolic therapies. This report integrates nine confirmed findings and 25 reviewed papers into a complete disease-knowledge-base entry spanning etiology, phenotype, mechanism, genetics, diagnostics, prognosis, treatment, prevention, and model organisms.

Key Findings

Finding 1 — Biallelic TFRC mutations disrupting the TfR1 internalization motif cause the disease

The founding cohort carried a homozygous c.58T>C (p.Tyr20His) substitution in TFRC. The Tyr20 residue is part of the YTRF endocytic internalization motif in the TfR1 cytoplasmic tail; its substitution to histidine (Y20H) impairs recognition by the clathrin adaptor machinery, causing defective receptor endocytosis, failure of iron internalization, and a paradoxical increase in surface TfR1 expression (because the receptor cannot be internalized and recycled normally). Functional rescue experiments confirmed causality: iron citrate restored lymphocyte proliferation in vitro, and expression of wild-type — but not mutant — TfR1 rescued transferrin uptake in patient-derived fibroblasts.

"had a homozygous p.Tyr20His substitution in transferrin receptor 1 (TfR1), encoded by TFRC. The substitution disrupts the TfR1 internalization motif, resulting in defective receptor endocytosis and markedly increased TfR1 expression on the cell surface. Iron citrate rescued the lymphocyte defects" — PMID: 26642240

A second pathogenic homozygous allele, c.64C>T (p.Arg22Trp), was later reported in the same motif region, confirming allelic heterogeneity and reinforcing that the internalization motif is the mechanistic hotspot:

"we herein identified a new disease-causing homozygous germline mutation in the TFRC gene (c.64C > T, p.R22W)" — PMID: 38270687

Functional consequence: loss of function for iron internalization (a hypomorphic/partial LOF at the receptor level, with retained or increased surface expression). Origin: germline; no somatic contribution.

Finding 2 — Clinical phenotype: early-onset combined immunodeficiency with cytopenias, infections, and failure to thrive

In the best-characterized cohort of 8 patients from 6 families (median age 7 years, range 4–32), all presented in early life. Phenotype frequencies:

Feature Frequency HPO term
Recurrent sinopulmonary infections 100% HP:0005425
Chronic diarrhea 100% (part of presenting triad) HP:0002028
Failure to thrive 100% HP:0001508
Hypogammaglobulinemia 100% (one with elevated IgM) HP:0004313
Impaired T-cell function 100% HP:0002721
Intermittent neutropenia 100% HP:0001875
Recurrent thrombocytopenia 87% HP:0004854
Anemia 62% HP:0001903
Less common: skin abscesses, conjunctivitis, developmental delay, optic nerve atrophy, vitiligo, multinodular goiter, HLH-like symptoms variable HP:0000509 (conjunctivitis), others

"All patients presented with recurrent sinopulmonary infections, chronic diarrhea, and failure to thrive in early life." — PMID: 32851577

"All patients had intermittent neutropenia and 87% of the patients had recurrent thrombocytopenia. Anemia was found in 62%. All patients had hypogammaglobinemia" — PMID: 32851577

A key clinical distinction is that lymphocyte numbers are typically normal but function is impaired — this is a combined immunodeficiency, not a lymphopenic SCID. One patient died of sepsis with neurological complications; bone-marrow dysmyelopoiesis/dysplasia and one clonal cytogenetic abnormality raised concern for myelodysplasia in the transplant cohort.

Finding 3 — Mechanism: TfR1-mediated iron uptake is a non-redundant checkpoint; STEAP3 spares erythropoiesis

TfR1 mediates receptor-mediated endocytosis of diferric transferrin, the dominant iron-acquisition route for rapidly proliferating cells. When endocytosis fails, activated lymphocytes are starved of iron precisely when they most need it — during antigen-receptor-driven clonal expansion — blocking proliferation and B-cell class-switching. The erythroid-sparing phenomenon (why patients have relatively mild anemia despite a global iron-uptake defect) is explained by STEAP3, a metalloreductase expressed in erythroblasts that associates with TfR1 and provides an accessory endocytosis signal:

"STEAP3, a metalloreductase expressed in erythroblasts, associates with TfR1 and partially rescues transferrin uptake in patient-derived fibroblasts, suggesting that STEAP3 may provide an accessory TfR1 endocytosis signal that spares patients from severe anemia" — PMID: 26642240

Complete loss of TfR1 is incompatible with hematopoiesis, underscoring the receptor's essential, non-redundant role:

"Transferrin receptor 1 (Tfr1) mediates the endocytosis of diferric transferrin in order to transport iron, and Tfr1 has been suggested to play an important role in hematopoiesis" — PMID: 31601687

The disease thus provides a "biologically instructive human model" that iron uptake via TfR1 is a metabolic checkpoint for adaptive immunity (PMID: 41714512).

Finding 4 — Allogeneic HSCT is curative

A retrospective study of 5 TFRC-deficient patients who underwent allogeneic HSCT (Boston Children's, 2011–2018) demonstrated cure of both the hematologic and immunologic defects:

"All 5 patients tolerated myeloablative conditioning regimens and had robust donor cell engraftment with resolution of cytopenias and independence from intravenous immunoglobulin substitution." — PMID: 33096268

"All 5 patients were alive at a median follow-up of 47.1 months posttransplant" (range 15.7–85.4 months) — PMID: 33096268

In the 8-patient cohort, 2 were transplanted successfully, 5 remained on prophylaxis (immunoglobulin replacement + antimicrobial prophylaxis), and 1 died — consistent with HSCT being the only definitive cure while supportive care manages non-transplanted patients.

Finding 5 — Gene identifiers, locus, and population genetics

TFRC maps to chromosome 3q29 (GRCh38 chr3:196,012,511–196,082,162, minus strand). The associated Mendelian phenotype is Immunodeficiency-46 (IMD46), OMIM #616740. gnomAD constraint metrics indicate only moderate loss-of-function intolerance (pLI ≈ 0.31; LOEUF/oe_lof_upper ≈ 0.54; missense Z ≈ 1.31) — consistent with an autosomal-recessive disorder in which heterozygous carriers are unaffected. The founder c.58T>C (p.Y20H) allele recurs in consanguineous families of Arabian/Middle Eastern (Kuwaiti/Saudi) origin, while c.64C>T (p.R22W) was reported in a Turkish family.

"The same homozygous missense mutation c.58T>C:p.Y20H, in the TFRC gene, was detected in all patients." — PMID: 32851577

Reported cases are extremely rare — only a few dozen worldwide.

Finding 6 — Animal and in vitro models recapitulate the iron-uptake-dependent immune phenotype

A knock-in Tfrc(Y20H/Y20H) mouse reproduces the human immunological defects while sparing severe anemia:

"Tfrc(Y20H/Y20H) mice recapitulated the immunological defects of patients." — PMID: 26642240

Conditional models reveal TfR1's non-redundant roles across immune compartments. Treg-restricted CD71/Tfrc deletion causes a fatal autoimmune syndrome from failed perinatal Treg expansion:

"Mice with a Treg-restricted CD71 deficiency spontaneously developed a scurfy-like disease, caused by impaired perinatal Treg expansion." — PMID: 38954474

Antibody blockade of CD71 in fetal thymus organ culture blocks thymocyte proliferation and αβ T-cell maturation (PMID: 7957580). The proliferation defect is iron-dependent and iron-reversible in human T cells:

"Growth arrest in iron-deficient (Fe-def) T cells was prevented upon addition of exogenous iron in the form of ferric ammonium citrate" — PMID: 32284314

Finding 7 — Variant-level annotation of the two causal alleles

Both alleles use transcript NM_001128148.3 and are germline missense variants in the TfR1 cytoplasmic internalization motif; neither has a somatic origin.

Allele cDNA / protein Genomic (GRCh38) dbSNP ClinVar OMIM allelic Population frequency
Allele 1 c.58T>C / p.Tyr20His NC_000003.12:g.196075339A>G rs863225436 VCV 218163 (conflicting; functionally pathogenic) 190010.0001 gnomAD-exomes 0.00000; TOPMed 0.00001 (ultra-rare)
Allele 2 c.64C>T / p.Arg22Trp NC_000003.12:g.196075333G>A rs373123870 VCV 2999809 (VUS, single submitter; functionally disease-causing) — ExAC 0.00001; TOPMed 0.00001; ESP 0.00008

The Y20H allele carries an explicit ClinVar trait annotation of "TFRC-related combined immunodeficiency" and UniProt feature VAR_076365 (P02786). Despite ClinVar's "conflicting"/"uncertain" statuses, both variants meet functional evidence for pathogenicity (ACMG PS3):

"expression of wild-type but not mutant TfR1 rescued impaired transferrin uptake in patient-derived fibroblasts" — PMID: 26642240

Finding 8 — Ontology mappings and curated HPO term set

The disease resolves to MONDO:0014760, mapped to OMIM:616740. The JAX/HPO-curated phenotype annotation set comprises: Immunodeficiency (HP:0002721), Recurrent sinopulmonary infections (HP:0005425), Sepsis (HP:0100806), Meningitis (HP:0001287), Recurrent oral thrush (HP:0009098), Chronic diarrhea (HP:0002028), Failure to thrive (HP:0001508), Conjunctivitis (HP:0000509), Decreased circulating immunoglobulin concentration (HP:0004313), Decreased total neutrophil count (HP:0001875), Intermittent thrombocytopenia (HP:0004854), Anemia (HP:0001903), and Autosomal recessive inheritance (HP:0000007). Mouse ortholog: Tfrc, NCBI Gene 22042, MGI:98822, mouse chromosome 16 B3.

Finding 9 — Cross-ontology identifiers and curated GO/Reactome/PDB annotations

UniProt P02786 (TFR1_HUMAN) GO annotations directly matching the disease mechanism include: transferrin receptor activity (GO:0004998), receptor-mediated endocytosis (GO:0006898), receptor internalization (GO:0031623), transferrin transport (GO:0033572), iron ion transport (GO:0006826), intracellular iron ion homeostasis (GO:0006879), positive regulation of T cell proliferation (GO:0042102), positive regulation of B cell proliferation (GO:0030890), positive regulation of isotype switching (GO:0045830), positive regulation of canonical NF-κB signaling (GO:0043123), and virus receptor activity (GO:0001618). Cellular-component terms: clathrin-coated pit (GO:0005905), early/recycling endosome (GO:0005769 / GO:0055037), HFE-transferrin receptor complex (GO:1990712). Reactome: Transferrin endocytosis and recycling (R-HSA-917977), Clathrin-mediated endocytosis (R-HSA-8856828), Cargo recognition for clathrin-mediated endocytosis (R-HSA-8856825). Experimental structures: PDB 1CX8 (ectodomain), 1SUV (TfR1–transferrin), 1DE4 (TfR1–HFE).

Section-by-Section Report

1. Disease Information

TFRC-Related Combined Immunodeficiency is a Mendelian, autosomal-recessive inborn error of immunity in which defective cellular iron uptake produces a combined (T- and B-cell) immunodeficiency. It is information aggregated at the disease level from a small number of patient cohorts and case reports, supplemented by curated ontology and model-organism resources (not EHR-derived).

Key identifiers: OMIM #616740 (phenotype IMD46); OMIM gene 190010 (TFRC); Orphanet ORPHA:476113 ("Combined immunodeficiency due to TFRC deficiency"); MONDO:0014760; DOID:0111948; UMLS/MedGen C5568133; SNOMED CT 1179288008. No dedicated ICD code exists; it is coded under combined immunodeficiencies (ICD-10 D81.9; ICD-11 4A01.1Z). MeSH indexing falls under "Severe Combined Immunodeficiency" / "Receptors, Transferrin (CD71)."

Synonyms: Immunodeficiency 46; IMD46; Combined immunodeficiency due to TFRC deficiency; Transferrin receptor 1 (TFRC/CD71) deficiency; TfR1 deficiency.

2. Etiology

Causal factor: purely genetic — biallelic hypomorphic missense mutations in TFRC disrupting the YTRF endocytic motif (Finding 1). Genetic risk factors: homozygosity/compound heterozygosity for pathogenic TFRC alleles; consanguinity is the principal risk factor, as founder alleles recur in inbred Middle Eastern and Turkish kindreds (Finding 5). There are no established environmental risk factors, protective factors, or gene–environment interactions for disease causation. Iron availability acts as an in vitro disease-modifying factor at the cellular level (Findings 1, 6) but is not established as a clinical modifier; STEAP3 co-expression is an intrinsic modifier sparing red cells. Heterozygous carriers are unaffected, consistent with recessive inheritance and modest gnomAD LOF-intolerance.

3. Phenotypes

Phenotypes are dominated by laboratory abnormalities (hypogammaglobulinemia, cytopenias) and clinical signs/symptoms (infections, diarrhea, failure to thrive). See Finding 2 table for per-phenotype frequencies and HPO terms. Age of onset: early life / infancy (neonatal–childhood). Severity: moderate to severe, variable — "clinical presentations have been severe in all reported cases" (PMID: 33096268). Progression: chronic with episodic infectious/cytopenic exacerbations; cytopenias are typically intermittent/fluctuating. Quality-of-life impact: substantial — recurrent infections, chronic diarrhea, growth failure, and transfusion/IVIG dependence impair daily functioning; no disease-specific QoL instrument data are available. Rare/variable features: optic nerve atrophy, developmental delay, vitiligo, multinodular goiter, HLH-like presentation.

4. Genetic / Molecular Information

Causal gene: TFRC (HGNC:11763; NCBI Gene 7037; OMIM 190010) — a type II single-pass transmembrane homodimeric glycoprotein. Pathogenic variants: two germline missense alleles in the cytoplasmic internalization motif (Finding 7) — p.Tyr20His (c.58T>C) and p.Arg22Trp (c.64C>T), both ultra-rare in population databases. Variant type: missense (internalization-motif); no null alleles seen in patients (presumed lethal). Functional consequence: impaired receptor internalization/iron uptake (partial loss of function) with paradoxically increased surface TfR1. Modifier genes: STEAP3 functionally modifies the phenotype (erythroid sparing; Finding 3). gnomAD constraint: pLI ≈ 0.31, LOEUF ≈ 0.54, missense Z ≈ 1.31 (moderate, recessive-consistent). Epigenetic changes / chromosomal abnormalities: none causal (3q29 CNV entries overlapping TFRC relate to the separate 3q29 deletion/duplication syndromes, not TFRC-CID; secondary clonal cytogenetic changes in bone marrow have been noted in individual patients, Finding 2).

5. Environmental Information

No environmental, lifestyle, or infectious agents cause this monogenic disease. Cellular iron availability is the key modifiable mechanistic variable. Infectious agents are downstream consequences — recurrent bacterial sinopulmonary pathogens, opportunistic infections, and oral thrush (Candida), consistent with combined immunodeficiency. TfR1 is also exploited as a receptor by several viruses (GO:0001618, virus receptor activity), but this is not part of TFRC-CID etiology.

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation):

  1. Biallelic TFRC missense mutation (c.58T>C p.Y20H or c.64C>T p.R22W) alters the YTRF cytoplasmic internalization motif of TfR1. (demonstrated)
  2. Motif disruption leads to loss of recognition by the clathrin adaptor/AP-2 machinery, resulting in defective clathrin-mediated receptor endocytosis and paradoxically increased surface TfR1. (demonstrated — WT-but-not-mutant rescue in fibroblasts)
  3. Defective endocytosis results in failure to internalize diferric transferrin, leading to intracellular iron deficiency in cells that depend on TfR1 for iron. (demonstrated)
  4. Iron starvation impairs iron-dependent enzymes required for proliferation (e.g., ribonucleotide reductase for dNTP synthesis) and mitochondrial iron-sulfur functions, blocking cell-cycle progression in rapidly dividing cells. (inferred from iron biology; supported by iron-rescue experiments, PMID 32284314)
  5. Branch A (adaptive immunity — the disease-defining branch): iron starvation of antigen-activated lymphocytes blocks clonal expansion, T-cell proliferation (GO:0042102), B-cell proliferation (GO:0030890), and immunoglobulin class-switch recombination (GO:0045830), producing combined immunodeficiency and hypogammaglobulinemia. (demonstrated in patients and Y20H mice)
  6. Branch B (myeloid/megakaryocytic): impaired iron supply to proliferating progenitors contributes to intermittent neutropenia and thrombocytopenia, and bone-marrow dysmyelopoiesis. (observed; mechanism partly inferred)
  7. Branch C (erythroid — spared): in erythroblasts, STEAP3 associates with TfR1 and provides an accessory endocytosis signal, partially rescuing transferrin uptake and sparing patients from severe anemia. (demonstrated in patient fibroblasts)
  8. The immune failure manifests clinically as recurrent sinopulmonary infections, chronic diarrhea, failure to thrive, and risk of fatal sepsis; rare HLH-like immune dysregulation may reflect disturbed lymphocyte homeostasis. (demonstrated / partly inferred)

Molecular pathways: clathrin-mediated endocytosis / transferrin endocytosis and recycling (Reactome R-HSA-917977, R-HSA-8856828, R-HSA-8856825); iron ion transport and homeostasis; downstream NF-κB signaling in lymphocyte activation. Cellular processes: receptor-mediated endocytosis (GO:0006898), receptor internalization (GO:0031623), blocked cell proliferation, lymphocyte activation. Protein dysfunction: loss of internalization function with retained ligand binding and increased surface density — a trafficking defect, not folding/aggregation; the tyrosine-based internalization signal normally recruits the clathrin adaptor. Metabolic changes: cellular iron deficiency impairing iron-dependent metabolism. Chemical entities (CHEBI): iron(2+)/iron(3+) (CHEBI:29033/CHEBI:29034), transferrin-bound iron; ferric ammonium citrate as rescuing reagent. Immune involvement: combined immunodeficiency (immunodeficiency, not autoimmunity, is the human phenotype; Treg models show autoimmune potential). Cell types (CL): T cell (CL:0000084), B cell (CL:0000236), regulatory T cell (CL:0000815), thymocyte, neutrophil (CL:0000775), hematopoietic stem cell (CL:0000037), erythroid precursor (CL:0000038). Subcellular (GO CC): plasma membrane (GO:0005886), clathrin-coated pit (GO:0005905), early/recycling endosome (GO:0005769/GO:0055037).

7. Anatomical Structures Affected

Organ/system level: immune/hematopoietic system (primary) — bone marrow (UBERON:0002371), thymus (UBERON:0002370), spleen, lymph nodes. Secondary: respiratory tract/lungs (UBERON:0002048) and paranasal sinuses (recurrent infections), gastrointestinal tract (UBERON:0001555; chronic diarrhea/malabsorption). Occasional: eye/optic nerve (UBERON:0000941; optic atrophy, conjunctivitis), skin (vitiligo, abscesses), thyroid (UBERON:0002046; goiter), CNS (developmental delay). Tissue/cell level: hematolymphoid tissue; T and B lymphocytes, Tregs, neutrophils, megakaryocytes/platelets, with erythroid lineage relatively spared. Subcellular: plasma-membrane receptor and endosomal trafficking compartment. Lateralization: systemic/bilateral (not a focal lesion).

8. Temporal Development

Onset: congenital/early infancy; presentation in the first years of life (cohort median age 7 y, range 4–32 y at study, with symptoms beginning early). Onset pattern: insidious to subacute, with acute infectious/cytopenic episodes. Course: chronic, lifelong without transplant; episodic infections and fluctuating cytopenias. Progression: variable; risk of bone-marrow dysplasia and, in severe cases, death from sepsis. Remission: treatment-induced (cure) with HSCT; no spontaneous remission. Critical period for intervention: early definitive diagnosis and HSCT before irreversible infectious/marrow complications accrue.

9. Inheritance and Population

Inheritance: autosomal recessive (HP:0000007) — "Autosomal-recessive mutations in the human TFRC gene cause a combined immunodeficiency" (PMID: 33096268). Penetrance: effectively complete in biallelic individuals. Expressivity: variable (severity of cytopenias, presence of rare features). Carrier state: unaffected. Founder effects/consanguinity: major — the p.Y20H founder allele recurs in consanguineous Arabian/Middle Eastern (Kuwaiti/Saudi) families; p.R22W in a Turkish family. Epidemiology: ultra-rare; only a few dozen cases worldwide; no reliable prevalence/incidence figures (well below 1/1,000,000). Sex ratio: no sex bias expected for an autosomal-recessive trait. Age distribution: pediatric-onset. No genetic anticipation, germline mosaicism, or repeat-expansion mechanism applies.

10. Diagnostics

Laboratory: hypogammaglobulinemia (low IgG ± low/normal/elevated IgM), impaired specific antibody responses, abnormal T-cell proliferation to mitogens/antigens despite frequently normal lymphocyte counts, and intermittent multilineage cytopenias (CBC). A characteristic immunophenotypic clue is markedly increased surface CD71/TfR1 on patient cells (because the receptor cannot be internalized). Bone marrow: may show dysmyelopoiesis/dysplasia — monitor for clonal evolution/MDS. Functional/confirmatory assays: defective transferrin uptake in patient fibroblasts, rescued by wild-type TfR1; lymphocyte proliferation defect rescued in vitro by iron (ferric) citrate (ACMG PS3). Genetic testing is definitive: single-gene TFRC sequencing, IEI/CID gene panels, whole-exome (WES) or whole-genome (WGS) sequencing — the disease was discovered by WES, and homozygosity mapping aids consanguineous pedigrees. Differential diagnosis: other combined immunodeficiencies/SCID, CVID with T-cell dysfunction, hyper-IgM syndromes (when IgM elevated), congenital neutropenia/thrombocytopenia syndromes, and iron-refractory iron deficiency (IRIDA/TMPRSS6) for the iron axis; the distinguishing feature is elevated surface CD71 with defective transferrin uptake plus biallelic TFRC variant. Screening: cascade/carrier testing in affected families; not part of standard newborn screening.

11. Outcome / Prognosis

Without transplant: guarded — chronic morbidity from recurrent infections, cytopenias, diarrhea, and growth failure; at least one death from sepsis/neurological complications (PMID: 32851577); risk of progression to bone-marrow dysplasia/myelodysplasia. With HSCT: excellent — all 5 transplanted patients achieved donor engraftment, resolution of cytopenias, IVIG independence, and were alive at median 47.1 months, with no reported acute/chronic GVHD (Finding 4). Prognostic factors: timely diagnosis, infection burden, absence of pre-transplant marrow dysplasia/clonal evolution, and successful engraftment. No validated disease-specific prognostic biomarkers exist beyond genotype and marrow status.

12. Treatment

Definitive/curative: allogeneic hematopoietic stem cell transplantation with myeloablative conditioning (NCIT: Allogeneic Hematopoietic Stem Cell Transplantation) — the only established cure (Finding 4). Supportive/prophylactic (non-transplanted patients): immunoglobulin replacement therapy (IVIG/SCIG; NCIT: Immunoglobulin Therapy), antimicrobial prophylaxis, nutritional support for failure to thrive, and transfusion support for cytopenias. Investigational/mechanistic: in vitro iron supplementation (iron citrate, ferric ammonium citrate; CHEBI ferric citrate) rescues the lymphocyte proliferation defect (Findings 1, 6) — a rational but clinically unproven adjunct; because the endocytic block limits the transferrin route, non-transferrin iron delivery would likely be required. Gene/cell therapy: autologous TFRC gene correction of HSCs is a conceptual future direction; none is approved. Pharmacogenomics: none specific. Management otherwise follows general CID/IEI guidelines.

13. Prevention

Primary prevention of occurrence is via genetic counseling and reproductive options in at-risk consanguineous families: carrier testing, cascade screening, prenatal diagnosis, and preimplantation genetic testing (PGT) for known familial TFRC alleles. Secondary prevention: early molecular diagnosis (including high-risk screening in founder populations) enabling timely HSCT and prophylaxis. Tertiary prevention: immunoglobulin replacement, antimicrobial prophylaxis, nutritional/hematologic support, and marrow surveillance for MDS. Live vaccines should be used cautiously given the combined immunodeficiency. Consanguinity counseling is the key public-health lever; no vaccine prevents the disease itself.

14. Other Species / Natural Disease

Taxonomy/orthologs: human TFRC (NCBI Taxon 9606); mouse Tfrc (NCBI Gene 22042; MGI:98822; NCBI Taxon 10090; mouse chromosome 16 B3). TfR1 is highly evolutionarily conserved, and its role in iron uptake and hematopoiesis is conserved. Natural disease: no well-characterized spontaneous companion-animal or wildlife equivalent of TFRC-CID is catalogued in OMIA for this specific entity; knowledge derives from engineered models. Complete Tfrc loss is embryonic/hematopoietically lethal in mouse, underscoring conservation of the iron-uptake requirement. No zoonotic relevance.

15. Model Organisms

Mammalian genetic models (mouse):

Model Type Phenotype recapitulation PMID
Tfrc(Y20H/Y20H) knock-in humanized point mutation Recapitulates patients' immune defects (impaired lymphocyte proliferation); spares severe anemia — faithful model 26642240
HSC-specific Tfr1 conditional knockout conditional KO Severe impairment of hematopoiesis (complete loss non-viable) — shows non-redundancy 31601687
Treg-restricted CD71/Tfrc deletion conditional KO Fatal scurfy-like autoimmunity from failed perinatal Treg expansion — reveals tolerance role 38954474

In vitro / ex vivo models: patient-derived fibroblasts (transferrin-uptake assay with WT-TfR1 rescue); human T cells under iron deprivation (reversible growth arrest with ferric ammonium citrate, PMID: 32284314); fetal thymus organ culture with anti-CD71 antibody blockade (PMID: 7957580). Limitations: the Y20H knock-in captures the immune phenotype but murine erythropoiesis/iron handling differ; complete knockouts are lethal and cannot model the hypomorphic human condition; patient-specific secondary features (developmental delay, goiter) are not recapitulated. Resources: MGI (MGI:98822), IMPC/IMSR for Tfrc alleles.

Mechanistic Model / Interpretation

   Biallelic TFRC missense (p.Y20H / p.R22W)
  │  disrupts YTRF internalization motif
  ▼
   Loss of clathrin/AP-2 recognition of TfR1 tail
  │  → defective endocytosis; ↑ surface CD71/TfR1
  ▼
   Failure to internalize diferric transferrin
  │  → intracellular IRON STARVATION
  ▼
   Impaired iron-dependent enzymes (e.g., ribonucleotide reductase)
  │  → blocked cell-cycle progression in dividing cells
      ┌───────────┼───────────────────────────────┐
      ▼           ▼                                ▼
  [Branch A]   [Branch B]                      [Branch C — SPARED]
  Lymphocytes  Myeloid/Mega                    Erythroblasts
  blocked      intermittent                    STEAP3 + TfR1 =
  proliferation neutropenia/                    accessory endocytosis
  & class-      thrombocytopenia;               → partial rescue of
  switch        marrow dysplasia                transferrin uptake
      │                                                │
      ▼                                                ▼
  COMBINED IMMUNODEFICIENCY                     mild/variable anemia
  (recurrent infections, chronic                (severe anemia avoided)
   diarrhea, FTT, hypogamma-
   globulinemia)
  │
  ▼
     Cured by allogeneic HSCT (donor cells have WT TfR1)

The unifying insight is that TFRC-CID is a disease of cellular iron-supply logistics, not of iron stores. Systemic iron is available, but the cells that most need to import it on demand — antigen-activated, rapidly dividing lymphocytes — cannot, because the receptor's "swallow" signal is broken. This explains the otherwise puzzling combination of (a) profound immune failure, (b) preserved lymphocyte numbers with impaired function, (c) relatively mild anemia (STEAP3 rescue), and (d) complete cure by replacing the hematopoietic system with donor cells carrying a functional receptor.

Evidence Base

PMID Title (abbrev.) Evidence type Role
26642240 Missense mutation in TFRC causes combined immunodeficiency Human + mouse + in vitro Landmark discovery: founding Y20H allele, mechanism, STEAP3 rescue, mouse model
32851577 Clinical/immunological characterization in 8 patients Human clinical cohort Phenotype frequencies, founder variant, natural history
33096268 HSCT is curative for TFRC deficiency Human clinical (n=5) Establishes curative therapy and survival
38270687 Novel homozygous TFRC mutation (R22W) Human clinical Second causal allele; allelic heterogeneity
41714512 TFRC variants and IEI: iron-immune crosstalk Review Frames disease as non-redundant iron/immune checkpoint
31601687 TfR1-mediated iron uptake essential in hematopoiesis Mouse Non-redundancy; complete loss non-viable
38954474 Iron capture through CD71 drives Treg expansion Mouse Treg/tolerance role of TfR1 iron uptake
32284314 Iron deprivation in human T cells In vitro (human) Iron-dependent, iron-reversible T-cell arrest
7957580 Anti-TfR antibody inhibits early T-cell development Ex vivo CD71-dependent thymocyte proliferation/maturation

Supporting/contextual papers on TfR1 biology (CD71 as viral/particle uptake receptor; iron-chelation immunosuppression; TfR1-targeted therapeutics) corroborate the receptor's centrality to proliferating immune cells but do not directly test TFRC-CID.

Supported vs. Refuted Hypotheses

Supported: 1. TFRC-CID is caused by biallelic internalization-motif missense mutations (Y20H, R22W) → defective TfR1 endocytosis and iron uptake (PMID: 26642240, 38270687). 2. Iron starvation of proliferating lymphocytes is the proximate mechanism; the defect is iron-rescuable in vitro (PMID: 26642240, 32284314). 3. Erythroid sparing is explained by STEAP3 accessory endocytosis (PMID: 26642240). 4. HSCT is curative (PMID: 33096268). 5. Founder p.Y20H allele in consanguineous Middle-Eastern populations (PMID: 32851577).

Refuted / not supported: - That the disease presents primarily as severe anemia (it does not; anemia is mild/variable due to STEAP3). - That an environmental or infectious agent initiates disease (it is purely Mendelian).

Limitations and Knowledge Gaps

  • Extreme rarity: with only a few dozen patients (largest cohort n=8, dominated by a single founder variant), phenotype frequencies, prognosis, and epidemiology are subject to ascertainment bias toward severe/consanguineous cases.
  • Variant classification lag: ClinVar lists both alleles as "conflicting"/"uncertain" despite robust functional (PS3) evidence — a curation gap that could impede diagnosis.
  • Genotype–phenotype correlation is unresolved: whether R22W differs in severity from Y20H, and what drives variable features (optic atrophy, vitiligo, goiter, HLH-like disease), is unknown.
  • Marrow dysplasia risk: the mechanistic basis and true frequency of dysmyelopoiesis/clonal evolution are unclear and clinically important.
  • Adjunctive iron therapy is supported only in vitro; no clinical trial has tested whether systemic or targeted iron delivery improves immune function in patients.
  • No detailed patient omics (single-cell transcriptomic/proteomic profiling of patient lymphocytes) is available to map the iron-starvation program in vivo.
  • No formal prevalence/incidence, ICD-specific coding, or standardized QoL data exist.

Proposed Follow-up Experiments / Actions

  1. ClinVar reclassification: submit the functional-rescue evidence to upgrade p.Y20H and p.R22W toward likely-pathogenic/pathogenic, improving diagnostic yield.
  2. International patient registry: aggregate cases to define natural history, genotype–phenotype correlations, marrow-dysplasia incidence, and long-term HSCT outcomes.
  3. Single-cell multi-omics of patient lymphocytes before/after activation and iron rescue to map the intracellular iron-starvation checkpoint (RNR, cell-cycle, class-switch machinery).
  4. Controlled iron-supplementation study (in vitro dose-response, then compassionate-use assessment) to test targeted/non-transferrin iron delivery as a bridge therapy pre-transplant.
  5. Gene-correction proof-of-concept in patient HSCs/iPSCs (base or prime editing of c.58/c.64) to evaluate autologous gene therapy feasibility.
  6. Mechanistic dissection of STEAP3 rescue to determine whether STEAP3-mimetic or alternative-endocytosis strategies could broaden the erythroid-sparing effect to lymphoid cells.
  7. Prospective HSCT-timing analysis to define the optimal window minimizing pre-transplant infectious and marrow complications.

Report compiled from 9 confirmed findings and 25 reviewed papers across 5 investigation iterations. Evidence types are annotated as human clinical, model organism, in vitro, or computational/ontological throughout. Search date: 2026-09-01.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 9
Resolved 9
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 1
Quoted claims found in source 1
Quoted claims not found in source 0
References weighed for topical relevance 9
On topic 8
Off topic 0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 49
Resolved 45
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 4
Terms whose name was checked 3
Terms named correctly 1
Terms named as a different term 2

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • HP:0002028 (2 mentions) - the report calls it "100% (part of presenting triad)"; HP calls it Chronic diarrhea
  • HP:0004313 (2 mentions) - the report calls it "100% (one with elevated IgM)"; HP calls it Decreased circulating immunoglobulin concentration

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA, OMIM, MGI.