CD25 Deficiency

Mendelian MONDO:0011664 Pathograph 78 Show in embeddings browser

CD25 deficiency is an autosomal recessive inborn error of immunity caused by biallelic loss-of-function IL2RA variants. Reduced or absent surface CD25 impairs high-affinity IL-2 capture, while signaling through the CD122/CD132 receptor remains possible at higher IL-2 concentrations. Impaired regulatory T-cell function coexists with deficient antigen-specific immunity and, in some patients, cytokine-associated CD8 T-cell expansion and tissue infiltration. FOXP3-positive regulatory T cells can persist; defective thymic selection and activation-induced apoptosis are not established universal mechanisms. Clinical expression varies from early enteropathy and eczema to neonatal autoimmune diabetes, other endocrinopathies, cytopenias and recurrent infections. Lymphadenopathy, hepatosplenomegaly and inflammatory lung disease may accompany the immune dysregulation. Flow cytometry, functional testing and comprehensive IL2RA analysis establish the diagnosis. Immunosuppression and supportive care can control manifestations; allogeneic hematopoietic stem cell transplantation can provide durable immune correction. Gene-corrected autologous regulatory T cells remain investigational.

Ask OpenScientist

Ask a research question about CD25 Deficiency. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

🏷

Classifications

Harrison's Part

IUIS Category

👪

Inheritance

Autosomal recessive HP:0000007

Biallelic disease-causing IL2RA variants can be homozygous or compound heterozygous. Consanguinity is frequent in reported families but is not required. Genetically confirmed heterozygous parents in the diabetes series were clinically unaffected; intermediate CD25 expression alone suggests but does not prove carrier status. If both parents carry a pathogenic allele, each pregnancy has a 25% probability of inheriting both alleles. Penetrance has not been quantified in an unselected population.

Autosomal recessive inheritance

Show evidence (3 references)

PMID:41659858 SUPPORT BACKGROUND Human Clinical

"Interleukin-2 receptor alpha chain (IL2RA, CD25) deficiency is a rare autosomal recessive inborn error of immunity characterized by profound immune dysregulation, susceptibility to infections, and autoimmunity."

States the autosomal recessive inheritance of the disease.

PMID:41694357 SUPPORT Human Clinical

"flow cytometry showed a complete absence of CD25 expression on CD4+ T cells in both children, whereas relatives displayed intermediate levels compatible with carrier status"

Intermediate expression in relatives is compatible with carrier status; the Moroccan study did not genotype all relatives.

PMID:41758964 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"This is supported by all the parents who are carriers of an IL2RA recessive variant being clinically unaffected."

Clinically unaffected confirmed carriers support recessive inheritance.

Discussions and Knowledge Gaps

How much do impaired Treg suppression, altered IL-2 consumption and the relative size of the effector pool each contribute to immune dysregulation when FOXP3-positive Tregs remain present?

KNOWLEDGE GAP OPEN tregs_present_but_inadequate

Attached to

pathophysiology#Impaired Regulatory T Cell Suppression pathophysiology#Loss of Peripheral Immune Tolerance

The S166N patient retained phenotypically and epigenetically recognizable Tregs, while expanded cytotoxic cells infiltrated skin. Subsequent compound-heterozygous patient-cell assays directly demonstrated defective suppression and gene-correction rescue. The residual gap concerns the relative contributions of functional insufficiency, cytokine consumption and effector-cell excess across genotypes. Treg denominators and CD25-dependent gating can also account for apparent differences in cell abundance.

Show evidence (2 references)

PMID:23416241 SUPPORT Human Clinical

"Activated CD8(+)STAT5(+) T cells with lytic potential infiltrated the skin, even though FOXP3(+) Tregs were present and maintained a higher capacity to respond to IL-2 compared to other T-cell subsets."

States the paradox this gap is about: tolerance failed in tissue while Tregs were present and comparatively IL-2 responsive.

PMID:23416241 SUPPORT Human Clinical

"Overall these results indicated that peripheral Tregs were present in the patient despite the absence of a functional CD25, albeit at an overall reduced level in total lymphocytes."

Supplies the numerical half of the candidate explanation, the reduced Treg share of total lymphocytes.

Why does the Il2ra knockout mouse present as adult-onset lymphoproliferation with colitis and hemolytic anemia, while human CD25 deficiency presents in infancy with enteropathy, endocrine autoimmunity and infections the mouse is not reported to acquire?

HUMAN MODEL MISMATCH OPEN mouse_lymphoproliferation_vs_human_infection

Attached to

pathophysiology#Impaired Peripheral Activation-Induced T Cell Death pathophysiology#Recurrent and Persistent Viral, Bacterial and Fungal Infection

The founding Il2ra-null mouse study emphasizes adult lymphoproliferation and autoimmunity with impaired activation-induced death. Human disease includes early infections, variable onset and organ manifestations, and the S166N patient did not show a general peripheral apoptotic defect. Different tissue compartments, alleles, microbial exposures and genetic backgrounds may contribute; the published mouse description does not test human-like opportunistic infection susceptibility.

Show evidence (2 references)

PMID:7584142 SUPPORT Model Organism

"Young mice that lack IL-2R alpha have phenotypically normal development of T and B cells."

Establishes the timing mismatch: the mouse is phenotypically normal young, where the human disease presents in infancy.

PMID:23416241 SUPPORT Human Clinical

"One of the main clinical manifestations of the patient, other than autoimmunity, was chronic viral infections especially CMV."

Establishes the human arm with no reported murine counterpart, chronic cytomegalovirus infection.

⚙

Pathophysiology

IL2RA Coding Substitutions

Mechanism confidence: Established

Coding missense or nonsense substitutions alter the IL2RA protein sequence. Surface expression and functional consequences are allele dependent.

IL2RA hgnc:6008

Genetic context IL2RA hgnc:6008 Variant type: single nucleotide variant Genomic context: coding sequence variant_origin: GERMLINE

Biallelic disease genotypes may be homozygous or compound heterozygous; no single zygosity is imposed on this variant class.

Downstream

Reduced Surface CD25 Availability Allele-specific loss of protein production or surface localization lowers functional CD25 availability. RNA/protein effects are measured for some alleles and predicted for others.

Show evidence (2 references)

PMID:23416241 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The patient was homozygous for a c.497G>A transition in exon 4, leading to an amino acid substitution at codon 166 (S166N) of the protein."

Sequence-confirmed homozygous missense allele.

PMID:35968218 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"we observed a novel, homozygous, and likely pathogenic c.504 C>A variant located in the exon 4 region of the IL2RA gene"

Sequence-confirmed nonsense allele; downstream degradation is predicted.

IL2RA Splice-Site Substitutions

Mechanism confidence: Established

Canonical splice-site substitutions perturb IL2RA RNA processing. The c.64+1G>A donor and c.65-2A>G acceptor variants have predicted consequences without direct patient RNA validation in those reports.

IL2RA hgnc:6008

Genetic context IL2RA hgnc:6008 Variant type: single nucleotide variant Genomic context: intron variant_origin: GERMLINE

Biallelic disease genotypes may be homozygous or compound heterozygous; no single zygosity is imposed on this variant class.

Downstream

Show evidence (2 references)

PMID:36195682 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Clinical whole exome sequencing revealed a novel splice donor site variant (NM_001378789.1 (NP_001365718); c.64 + 1G > A) in the IL-2Rα gene."

Physical splice-donor substitution.

PMID:41694357 SUPPORT Human Clinical

"Targeted next-generation sequencing identified two novel IL2RA variants: a splice-site mutation (c.65-2A>G) and a multi-exon deletion (c.557_795-1625del), both leading to loss of functional CD25."

Reports the splice-site allele and, in the same sentence, the structural null allele curated below.

IL2RA Coding Frameshift Deletions

Mechanism confidence: Established

Small coding deletions shift the IL2RA reading frame. Consequences include premature termination or a final-exon run-on; nonsense-mediated decay is not universal.

IL2RA hgnc:6008

Genetic context IL2RA hgnc:6008 Variant type: deletion Genomic context: coding sequence variant_origin: GERMLINE

Biallelic disease genotypes may be homozygous or compound heterozygous; no single zygosity is imposed on this variant class.

Downstream

Show evidence (2 references)

PMID:41659858 SUPPORT Human Clinical

"Genetic analysis revealed a novel homozygous frameshift variant in IL2RA (c.166delC; p.R56fs)."

Reports the frameshift allele in the sibling pair.

PMID:29995861 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The second mutation identified, c.800delA, causes a frameshift in the reading frame of the final IL2RA exon."

A final-exon deletion has a different transcript consequence from an early truncating allele.

IL2RA Coding Frameshift Duplication

Mechanism confidence: Established

The Caudy maternal allele is a one-base coding duplication, represented as c.692dup in current ClinGen notation and historically as an adenine insertion after position 692. It shifts the reading frame; the compound-heterozygous paternal allele is a nonsense substitution.

IL2RA hgnc:6008

Genetic context IL2RA hgnc:6008 Variant type: duplication Genomic context: coding sequence variant_origin: GERMLINE

Biallelic disease genotypes may be homozygous or compound heterozygous; no single zygosity is imposed on this variant class.

Downstream

Show evidence (1 reference)

url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7d977a16-0957-458b-86be-2245d3953453 SUPPORT DIRECT REVIEW SYNTHESIS Other

"Sequence trace of maternal allele showing single adenine insertion ... after position 692"

ClinGen abstracts the Caudy allele, normalized as c.692dup.

IL2RA Exon-Level Deletions

Mechanism confidence: Established

Deletions remove multiple exons or the whole IL2RA gene. These are physically distinct from single-base coding indels.

IL2RA hgnc:6008

Genetic context IL2RA hgnc:6008 Variant type: deletion variant_origin: GERMLINE

Biallelic disease genotypes may be homozygous or compound heterozygous; no single zygosity is imposed on this variant class.

Downstream

Show evidence (2 references)

PMID:41694357 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"For Case 2, NGS read-depth analysis identified a homozygous multi-exon deletion in IL2RA, corresponding at the cDNA level to c.557_795-1625del."

Read-depth evidence for a multi-exon deletion; no priority claim over other structural alleles.

PMID:41758964 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Four were homozygous (two protein-truncating, one whole-gene deletion, one missense), and one was compound heterozygous for a protein-truncating and a missense variant."

Whole-gene deletion in the diabetes-ascertained series.

Reduced Surface CD25 Availability

Mechanism confidence: Established

CD25 is absent or markedly reduced at the cell surface. For S166N, intracellular protein and transcript persist while soluble CD25 is undetectable, supporting a localization defect. Final-exon frameshift alleles can retain low surface expression; complete absence is not universal.

IL2RA hgnc:6008

Experimental models

Founding-patient EBV-transformed B cells CELL LINE Absent CD25 in the patient-derived line.

Nonviral gene-corrected IL2RA-deficient T cells PRIMARY CELL CULTURE Gene correction restored surface expression.

Animal models

Treg-specific Foxp1/Foxp4 double-knockout mice Mouse perturbs Deleting both transcription factors lowers CD25 expression in Tregs.

Computational models

Cys168Ter protein and RNA structure predictions STRUCTURAL PREDICTION The model predicts a truncated receptor product.

Downstream

Impaired High-Affinity IL-2 Capture Reduced CD25 at the cell membrane impairs high-affinity cytokine capture.

Defective Inducible IL-10 Production by CD4 T Cells The patient-cell association supports a CD25-dependent defect; the intervening signaling route was not isolated.

Persistent Cortical Thymocyte BCL2 Expression Observed in the founding case; the signal connecting CD25 loss to thymic BCL2 regulation was not resolved.

Impaired Peripheral Activation-Induced T Cell Death Null-mouse association; this route is not consistently demonstrated in human cells.

Show evidence (2 references)

PMID:23416241 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Importantly, TCR activated CD4+ T cells of the patient expressed CD25 in the cytoplasm, as well as at the mRNA level"

Intracellular protein and RNA persist despite the surface deficit.

PMID:29995861 SUPPORT DIRECT PRIMARY RESULT In Vitro

"three compound heterozygotes that express minimal amounts of IL2RA on the surface of the T cells"

Residual surface expression in a separate family.

Impaired High-Affinity IL-2 Capture

Mechanism confidence: Established

CD25 supplies the ligand-capture component of the high-affinity IL-2 receptor and has no intrinsic signaling domain. Its loss reduces IL-2 binding by the high-affinity complex; the CD122/CD132 intermediate-affinity receptor remains functional.

IL2RA hgnc:6008 ⇓ LOSS OF FUNCTION

interleukin-2 binding GO:0019976 ↓ DECREASED

Downstream

Raised IL-2 Signaling Threshold with Deficient STAT5 Activation Loss of high-affinity capture raises the concentration required for downstream signaling.

Reduced Regulatory T Cell IL-2 Consumption Reduced cytokine capture may limit the Treg cytokine sink; direct human consumption measurements are lacking.

Impaired NK Cell Maturation Patient NK-cell phenotypes support a developmental requirement for the receptor, without isolating all intervening steps.

Show evidence (2 references)

PMID:19348914 SUPPORT DIRECT REVIEW SYNTHESIS Other

"CD25, which, along with CD122 and gammac, confers high affinity binding to IL-2."

Established receptor architecture explains the consequence of CD25 loss.

PMID:23416241 SUPPORT DIRECT PRIMARY RESULT In Vitro

"These data demonstrate that in the absence of cell surface CD25, CD122 and CD132 are functional in the patient's T cells."

Preserved shared receptor-chain function limits the claim to high-affinity capture.

Raised IL-2 Signaling Threshold with Deficient STAT5 Activation

Mechanism confidence: Established

The IL-2 dose threshold for STAT5 phosphorylation is raised. In the S166N patient, CD4 cells remain less responsive than controls, whereas CD8 cells can approach control responses at high IL-2 concentrations. FOXP3-positive cells retain their relative sensitivity within the CD4 compartment. Preserved IL-15 responses demonstrate that this is not a general loss of STAT5 signaling.

CD4-positive, alpha-beta T cell CL:0000624 CD8-positive, alpha-beta T cell CL:0000625

interleukin-2-mediated signaling pathway GO:0038110 ↓ DECREASED

Experimental models

S166N patient PBMC and T-cell cultures PRIMARY CELL CULTURE CD4 and CD8 IL-2 dose responses differ.

Nonviral gene-corrected IL2RA-deficient T cells PRIMARY CELL CULTURE Genetic correction improved cytokine-induced STAT5 phosphorylation.

Downstream

Impaired Regulatory T Cell Suppression Deficient IL-2 responsiveness compromises Treg function; genetic correction supports this relationship.

Reduced Relative Regulatory T Cell Representation A reduced fraction of total lymphocytes is observed in some settings, but its causal determinants and clinical importance remain uncertain.

Impaired Antigen-Specific T Cell Responses Altered priming and expansion are candidate intermediates in the impaired antigen response.

Show evidence (2 references)

PMID:23416241 SUPPORT In Vitro

"This data indicates that in the absence of CD25 surface expression 1) the threshold required for IL-2 signaling in all T cell subsets is raised, 2) CD4+FOXP3+ are the first to respond to IL-2 despite the absence of CD25, and 3) unlike in healthy donors, CD8+ T cells from CD25 null patients..."

The authors' summary of the signaling defect, including the reordering that favours CD8+ cells over conventional CD4+ cells.

PMID:23416241 SUPPORT DIRECT PRIMARY RESULT In Vitro

"The pSTAT5 levels in the patient's CD8+ T cells with high concentration of IL-2 were similar to the percentages of CD8+ T cells of healthy controls stimulated with high and medium concentrations."

High-dose CD8 responsiveness is retained, unlike the more impaired CD4 response.

Impaired Regulatory T Cell Suppression

Mechanism confidence: Established

FOXP3-positive Treg-like cells can remain present while their suppressive function is inadequate. In three compound heterozygous siblings, CD25-independent enrichment recovered FOXP3-rich cells with no suppressive activity in the assay. Gene correction restored suppressive activity in the later manufacturing study. This supports a functional lesion without requiring complete lineage absence.

FOXP3-positive regulatory T cell CL:0000815

Experimental models

GMP-compatible gene-corrected autologous Treg product PRIMARY CELL CULTURE Corrected Tregs regained suppressive activity.

Downstream

Loss of Peripheral Immune Tolerance Impaired regulation permits immune dysregulation and autoimmunity.

Show evidence (2 references)

PMID:29995861 SUPPORT DIRECT PRIMARY RESULT In Vitro

"CD3+CD4+CD127loCD45RO+TIGIT+ from the compound heterozygotes showed no suppressive ability."

CD25-independent enrichment demonstrated a functional deficit in patient cells.

PMID:41376159 SUPPORT DIRECT PRIMARY RESULT In Vitro

"The resulting gcTregs demonstrated robust suppressive activity in vitro."

Corrected cells suppress in vitro; no clinical efficacy is inferred.

Reduced Relative Regulatory T Cell Representation

Mechanism confidence: Established

A reduced Treg share of the total T-cell or lymphocyte compartment can coexist with preserved or elevated proportions within purified CD4 cells. The S166N patient had TSDR-confirmed Tregs. Counts depend on denominator and marker selection; CD25-based gates cannot establish absence of CD25-negative FOXP3-positive Tregs.

FOXP3-positive regulatory T cell CL:0000815

Downstream

Decreased Regulatory T Cell Proportion The phenotype records relative abundance and its assay limitations.

Show evidence (1 reference)

PMID:23416241 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Overall these results indicated that peripheral Tregs were present in the patient despite the absence of a functional CD25, albeit at an overall reduced level in total lymphocytes."

Relative representation differs from absence of the lineage.

Defective Inducible IL-10 Production by CD4 T Cells

Mechanism confidence: Established

A CD25-deficient patient had impaired IL-10 production after CD3/CD46 stimulation of CD4 lymphocytes, unlike a FOXP3-deficient comparator. This is an induced CD4-cell assay, not a universal absence of circulating IL-10 or a measurement restricted to natural Tregs; serum IL-10 was elevated in the S166N patient.

CD4-positive, alpha-beta T cell CL:0000624

interleukin-10 production GO:0032613 ↓ DECREASED

Downstream

Loss of Peripheral Immune Tolerance Reduced inducible regulatory cytokine production may contribute, but its independent contribution is unresolved.

Show evidence (2 references)

PMID:17196245 SUPPORT DIRECT PRIMARY RESULT In Vitro

"This patient exhibited defective IL-10 expression from CD4 lymphocytes, whereas a Foxp3-deficient patient expressed normal levels of IL-10."

Stimulated isolated CD4-cell experiment.

PMID:23416241 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"This data demonstrates that the production of all cytokines tested was not impaired despite the absence of CD25 surface expression"

Serum panel included IL-10; circulating abundance differs from induced CD4 secretion.

Reduced Regulatory T Cell IL-2 Consumption

Mechanism confidence: Hypothetical

Failure of high-affinity IL-2 uptake by Tregs is a proposed contributor to accumulation of extracellular cytokine and effector-cell expansion. Human studies demonstrate altered receptor availability and elevated serum cytokines but do not directly quantify the Treg IL-2 consumption deficit.

FOXP3-positive regulatory T cell CL:0000815

Downstream

Elevated Cytokine Availability Reduced consumption is one possible contributor; persistent infection and inflammatory production also contribute.

Show evidence (1 reference)

PMID:23416241 SUPPORT INDIRECT PRIMARY RESULT Human Clinical

"Likely, the most affected function due to CD25 deficiency by FOXP3+ Tregs is the consumption of IL-2."

Author hypothesis from patient and prior mouse evidence, not a direct consumption assay.

Elevated Cytokine Availability

Mechanism confidence: Established

The S166N patient had elevated circulating innate and adaptive cytokines, including IL-2, with active STAT3/STAT5 signaling in blood T cells. The relative contributions of impaired consumption, inflammation and chronic infection are unresolved.

Downstream

CD8 T Cell Expansion Residual receptor signaling in a cytokine-rich environment may favor CD8 expansion; this is not proof of antigen-specific autoreactivity.

Show evidence (1 reference)

PMID:23416241 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"all cytokines tested was not impaired despite the absence of CD25 surface expression, suggesting that high cytokine levels found in circulation may sustain proliferation in vivo."

Observed cytokine excess supports, but does not prove, cytokine-driven expansion.

Persistent Cortical Thymocyte BCL2 Expression

Mechanism confidence: Established

The founding patient lacked normal downregulation of BCL2 in cortical thymocytes, alongside absent CD1 and abnormal thymic architecture. This was a thymus-specific observation, not a universal peripheral T-cell phenotype.

thymocyte CL:0000893

Downstream

Impaired Thymocyte Apoptosis Persistent anti-apoptotic BCL2 provides a plausible route to reduced thymic deletion.

Show evidence (1 reference)

PMID:9096364 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"CD25-deficient cortical thymocytes do not express CD1, and furthermore they fail to normally down-regulate levels of the anti-apoptotic protein bcl-2."

Human thymic immunohistochemistry.

Impaired Thymocyte Apoptosis

Mechanism confidence: Provisional

Reduced thymic apoptosis is described in the follow-up account of the founding patient. Escape of autoreactive clones is a proposed consequence; the 1997 report inferred inefficient negative selection from BCL2 and CD1 staining rather than directly testing the escaped repertoire.

thymocyte CL:0000893

thymocyte apoptotic process GO:0070242 ↓ DECREASED

Downstream

Loss of Peripheral Immune Tolerance Escape of autoreactive cells from thymic selection is proposed, not established across all patients.

Show evidence (1 reference)

PMID:10879793 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"apoptosis in the thymus is markedly reduced"

Follow-up description of the thymic finding; distinct from peripheral activation-induced death.

Impaired Peripheral Activation-Induced T Cell Death

Mechanism confidence: Provisional

Impaired activation-induced death correlates with polyclonal expansion in the Il2ra-null mouse. Its contribution to human disease is unresolved: the founding patient could not be tested after transplantation, and the S166N study found no disruption of peripheral CD8 intrinsic or extrinsic apoptotic pathways.

activation-induced cell death of T cells GO:0006924 ↓ DECREASED

Animal models

Il2ra knockout mouse Mouse partially recapitulates The knockout reproduces the failure of activation-induced T cell death, with the polyclonal lymphoid expansion it predicts.

Downstream

CD8 T Cell Expansion Impaired contraction may contribute in models; a general human causal contribution is unproven.

Show evidence (2 references)

PMID:7584142 SUPPORT DIRECT PRIMARY RESULT Model Organism

"polyclonal T and B cell expansion, which, for T cells, is correlated with impaired activation-induced cell death in vivo."

Mouse finding supports a candidate mechanism.

PMID:23416241 REFUTE DIRECT PRIMARY RESULT In Vitro

"intrinsic and extrinsic apoptotic pathways in CD8+ T cells were not disrupted in the patient carrying CD25 mutation."

Patient-specific negative result limits a universal peripheral apoptosis mechanism.

CD8 T Cell Expansion

Mechanism confidence: Established

In the S166N patient, activated memory CD8 cells expanded and proliferated in vivo despite poor antigen-specific responses. Cytokine-driven proliferation is proposed; neither universal apoptosis failure nor proven self-antigen specificity is required by the data.

CD8-positive, alpha-beta T cell CL:0000625

T cell proliferation GO:0042098 ↑ INCREASED

Downstream

Lymphocytic Tissue Infiltration Activated cells may accumulate in tissues; migration and antigen specificity were not independently resolved.

Inverted CD4:CD8 Ratio Preferential CD8 expansion can invert the ratio in affected patients.

Show evidence (1 reference)

PMID:23416241 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"an increase in Ki-67 expression was more prominent in CD8+ T cells than CD4+ T cells for all time points detected"

Observed preferential CD8 proliferation.

Impaired Antigen-Specific T Cell Responses

Mechanism confidence: Established

Antigen-specific proliferation and CMV-induced IFN-gamma production were impaired in the S166N patient. IL-2/IL-15 partially rescued polyclonal activation but did not rescue CMV-specific responses. Mitogen responses vary across patients: the Y41S report described a preserved PHA response, so a poor result is supportive but not obligatory.

CD4-positive, alpha-beta T cell CL:0000624

T cell proliferation GO:0042098 ↓ DECREASED

Experimental models

S166N patient PBMC and T-cell cultures PRIMARY CELL CULTURE Antigen-specific defects persist despite cytokine addition.

Downstream

Recurrent and Persistent Viral, Bacterial and Fungal Infection Failure of antigen-specific expansion leaves patients unable to clear opportunistic organisms.

Decreased Antigen-Specific T Cell Proliferation The proliferation failure is measured directly in the diagnostic laboratory.

Show evidence (2 references)

PMID:23416241 SUPPORT In Vitro

"Similarly, the patient's PBMCs did not produce IFNγ upon CMV activation, as determined by ELISPOT assay."

A specific measured failure of the antigen-specific response against the virus these patients cannot clear.

PMID:23416241 SUPPORT DIRECT PRIMARY RESULT In Vitro

"The addition of high concentrations of IL-2 or IL-15 did not rescue IFNγ production"

Negative rescue result for the CMV assay, not evidence against partial rescue of polyclonal responses.

Impaired NK Cell Maturation

Mechanism confidence: Established

The Y41S patient had normal absolute NK counts but an excess of CD56brightCD16high cells, fewer terminally differentiated CD57-positive CD56dim cells, and persistent CD94/CD62L expression. These findings differ from the STAT5B-deficient comparator. The clinical contribution of the maturation phenotype is unresolved.

natural killer cell CL:0000623

Downstream

Reduced NK Cell IFN-Gamma Production The maturation and cytokine-response abnormalities coexist; mediation by a specific maturation step was not directly tested.

Show evidence (1 reference)

PMID:29988287 SUPPORT Human Clinical

"we observed that the absence of IL-2 signaling through CD25 promotes the accumulation of CD56brightCD16high NK cells"

Reports the NK maturation abnormality measured in a CD25-deficient patient.

Reduced NK Cell IFN-Gamma Production

Mechanism confidence: Established

NK cells from the Y41S patient produced less IFN-gamma after cytokine stimulation. Perforin, granzyme B and K562-induced degranulation were increased, so the defect should not be generalized to reduced NK cytotoxic machinery.

natural killer cell CL:0000623

Experimental models

Y41S patient NK-cell functional cultures PRIMARY CELL CULTURE Reduced stimulated cytokine output.

Show evidence (2 references)

PMID:29988287 SUPPORT DIRECT PRIMARY RESULT In Vitro

"CD56bright and CD56dim NK cells from the CD25-deficient patient produced less IFN-γ than CD56bright and CD56dim NK cells from the HD"

Stimulated patient NK-cell cytokine deficit.

PMID:29988287 SUPPORT DIRECT PRIMARY RESULT In Vitro

"CD56bright and CD56dim NK cells from the CD25-deficient patient displayed an increased degranulation when compared to the HD"

Preserved or increased degranulation distinguishes cytokine production from cytotoxic readouts.

Loss of Peripheral Immune Tolerance

Mechanism confidence: Established

Defective Treg suppression and altered immune homeostasis permit autoimmunity. Thymic selection abnormalities and impaired inducible IL-10 production may contribute in some patients. Polyclonal cytotoxic infiltration does not establish the self-antigen specificity of every expanded T cell.

effector T cell CL:0000911

peripheral tolerance induction GO:0002465 ↓ DECREASED

Animal models

Il2ra knockout mouse Mouse partially recapitulates The null animal develops autoimmune hemolytic anemia and intestinal inflammation.

Il2-null mice across genetic backgrounds Mouse partially recapitulates Loss of the ligand perturbs the same tolerance pathway.

Downstream

Multi-Organ Autoimmune Attack Unrestrained autoreactive lymphocytes produce organ-directed autoimmunity.

Show evidence (1 reference)

PMID:23416241 SUPPORT Human Clinical

Shows tolerance failing in tissue despite the presence of FOXP3+ Tregs, the substance of this node.

Multi-Organ Autoimmune Attack

Mechanism confidence: Provisional

Immune-mediated injury varies across gut, skin, thyroid, pancreatic islets, liver and blood cells. Autoantibodies support an autoimmune basis for diabetes and some other manifestations, but pancreatic histology and direct beta-cell immune assays were not performed in the 2026 diabetes series. Tissue-specific mechanisms are incompletely resolved.

Downstream

Autoimmune Enteropathy with Chronic Diarrhea Clinical immune-mediated organ involvement is supported; the precise cellular route is incompletely defined.

Villous Atrophy Clinical immune-mediated organ involvement is supported; the precise cellular route is incompletely defined.

Eczematous Dermatitis Clinical immune-mediated organ involvement is supported; the precise cellular route is incompletely defined.

Early-Onset Autoimmune Diabetes Mellitus Clinical immune-mediated organ involvement is supported; the precise cellular route is incompletely defined.

Autoimmune Thyroiditis Clinical immune-mediated organ involvement is supported; the precise cellular route is incompletely defined.

Autoimmune Hepatitis Clinical immune-mediated organ involvement is supported; the precise cellular route is incompletely defined.

Autoimmune Cytopenia Clinical immune-mediated organ involvement is supported; the precise cellular route is incompletely defined.

Alopecia Universalis Clinical immune-mediated organ involvement is supported; the precise cellular route is incompletely defined.

Pancolitis Immune-mediated gastrointestinal inflammation can extend throughout the colon.

Enteropathy-Associated Nutritional Compromise Intestinal immune injury can produce malabsorption.

Show evidence (1 reference)

PMID:41659858 SUPPORT Human Clinical

"Affected patients often present with an array of symptoms in infancy or early childhood, including enteropathy, severe eczema, autoimmune cytopenias, type 1 diabetes mellitus, thyroiditis, lymphadenopathy, hepatosplenomegaly, and recurrent infections."

Lists the organ-directed autoimmune manifestations that constitute this node in the reviewed case series.

Lymphocytic Tissue Infiltration

Mechanism confidence: Established

Lymphocytes infiltrate lung, liver, gut, skin and other tissues. CD8-positive proliferating granzyme-B-positive cells predominated in the S166N skin biopsy; that cellular composition should not be assigned to all organs or patients. Bronchiolar lymphoid follicles and hepatic noncaseating granulomas are distinct histologic manifestations.

Downstream

Lymphadenopathy Lymphoid expansion can cause node enlargement.

Hepatosplenomegaly Lymphoid and inflammatory enlargement contributes in some patients.

Follicular Bronchiolitis Peribronchiolar lymphoid follicles were demonstrated in the affected lung.

Show evidence (1 reference)

PMID:9096364 SUPPORT Human Clinical

"Extensive lymphocytic infiltration of tissues, including lung, liver, gut, and bone, is observed, accompanied by tissue atrophy and inflammation."

Documents the multi-organ lymphocytic infiltration with tissue atrophy that defines this node.

Recurrent and Persistent Viral, Bacterial and Fungal Infection

Mechanism confidence: Established

Patients acquire opportunistic and recurrent infections early in life, with cytomegalovirus the most consistently reported organism, alongside Epstein-Barr virus, Candida, adenovirus and Gram-negative bacteria. Because antigen-specific responses fail, cytomegalovirus infection tends to persist or relapse rather than clear.

Downstream

Recurrent Viral Infections

Severe Cytomegalovirus Infection

Recurrent Bacterial Infections

Recurrent Fungal Infections

Bronchiectasis Repeated respiratory infections can contribute to structural airway damage; the source describes both, without isolating the contribution of immune-mediated lung inflammation.

Show evidence (1 reference)

PMID:41659858 SUPPORT Human Clinical

"Patients typically present with opportunistic and recurrent infections, such as CMV, EBV, Candida, adenovirus, Pseudomonas, and Klebsiella, early in life."

Names the organisms that make up the infectious phenotype.

Enteropathy-Associated Nutritional Compromise

Mechanism confidence: Established

Chronic diarrhea, intestinal injury and malabsorption contribute to nutritional failure. Infection and chronic inflammation can add to the burden; growth failure is not attributable to one route in all patients.

Downstream

Failure to Thrive Malabsorption and chronic illness can impair weight gain.

Short Stature Sustained nutritional and inflammatory burden can impair linear growth; endocrine contributions remain unresolved.

Hypokalemia Severe diarrhea can cause potassium loss; this is a plausible contributor during the reported enteropathy-associated crisis, without proving its sole cause.

Metabolic Acidosis Diarrheal bicarbonate loss and nutritional decompensation may contribute to acidosis during enteropathy; the individual contributions were not measured.

Show evidence (1 reference)

PMID:41694357 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"evaluation for persistent diarrhea and failure to thrive revealed malabsorption with villous atrophy on intestinal biopsy."

Patient-specific malabsorption links intestinal disease to nutritional compromise.

✶

Histopathology

Granulomatous Hepatitis

Liver biopsy in the Cys168Ter patient showed noncaseating portal granulomas and mononuclear inflammation. Autoimmune serology and investigated infectious causes were negative. Liver enzymes improved without specific treatment despite persistent hepatomegaly.

Show evidence (1 reference)

PMID:35968218 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Some of the portal tracts contain ill-defined noncaseating granulomas formed of epithelioid histiocytes that are surrounded by dense mononuclear infiltrate"

Direct human liver-biopsy description.

Peribronchiolar Lymphoid Follicles

Follicular bronchiolitis in the Y41S patient included lymphoid follicles surrounding bronchioles. This supports an inflammatory pulmonary manifestation without establishing that every infiltrating cell is CD8-positive.

Show evidence (1 reference)

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC3892414/ SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Lymphocytic infiltrate that is arranged in follicles surrounding the bronchioles."

Direct lung-biopsy image legend.

Cytotoxic CD8-Positive Skin Infiltrate

The S166N skin biopsy contained proliferating granzyme-B-positive CD8 T cells. TCR testing showed a polyclonal population; self-antigen specificity was not established.

Show evidence (1 reference)

PMID:23416241 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"These data show that CD8+ T cells highly infiltrate the skin, undergo proliferation, and present lytic capacity"

Skin histology and immunofluorescence.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

Blood 6

Decreased Antigen-Specific T Cell Proliferation HP:0031402

Show evidence (1 reference)

PMID:23416241 SUPPORT In Vitro

"These results demonstrate that T cells from the CD25 null patient poorly respond to polyclonal mitogens and to microbial and viral ... despite the persistent in vivo exposure to CMV."

Measures the impaired proliferative response to mitogens and to specific antigens.

Decreased Regulatory T Cell Proportion HP:0020113

Show evidence (2 references)

PMID:24116927 SUPPORT Human Clinical

"She has no expression of CD25 on CD4(+) T cells and an extremely low amount of Tregs ."

The Y41S study reported few Tregs, but its CD25-dependent gates cannot measure the CD25-negative FOXP3-positive population. This does not establish lineage absence.

PMID:23416241 SUPPORT Human Clinical

"Overall these results indicated that peripheral Tregs were present in the patient despite the absence of a functional CD25, albeit at an overall reduced level in total lymphocytes."

The careful statement of the finding: Tregs present but reduced as a share of total lymphocytes, which is why this phenotype is a reduced proportion rather than an absence.

Inverted CD4:CD8 Ratio HP:0033222

Show evidence (1 reference)

PMID:23416241 SUPPORT Human Clinical

"Profound alterations of the peripheral T cell subsets consisted of a complete skew towards increased CD8+ T cells over CD4+ T cells, expansion of the memory T cell compartments, with preservation of FOXP3+ T regulatory cells, whereas B cells and NK cells were persistently low."

Characterises the CD8 skew in detail in the most fully immunophenotyped patient.

Increased Circulating Immunoglobulin Concentration HP:0010702

Show evidence (1 reference)

PMID:41659858 SUPPORT Human Clinical

"Immunological evaluation revealed hypergammaglobulinemia, impaired T-cell proliferation, reduced CD19+ B cells, inverted CD4/CD8 ratio, and absence of CD25 expression."

Reports hypergammaglobulinemia in both siblings.

Iron Deficiency Anemia HP:0001891

Show evidence (1 reference)

PMID:41659858 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"along with iron deficiency anemia."

Iron-deficiency anemia is distinct from immune hemolysis and has been observed with chronic enteropathy and nutritional morbidity.

Decreased B Cell Count Decreased total B cell count HP:0010976

Show evidence (1 reference)

PMID:41659858 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Immunophenotyping showed a marked reduction in CD19+ B cell count (50/mm³)"

Reduced circulating CD19-positive B cells occur in some patients, including the Saudi siblings and the S166N patient; other patients have normal counts.

Cardiovascular 4

Lymphadenopathy HP:0002716

Show evidence (1 reference)

PMID:41694357 SUPPORT Human Clinical

"On examination, she had hepatomegaly, splenomegaly, and generalized lymphadenopathy (Table 1)."

Documents generalized lymphadenopathy on examination.

Hepatosplenomegaly HP:0001433

Show evidence (1 reference)

PMID:41694357 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"On examination, she had hepatomegaly, splenomegaly, and generalized lymphadenopathy"

Primary examination findings in Moroccan Case 1.

Urticaria HP:0001025

Show evidence (1 reference)

PMID:41659858 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"including asthma, allergic rhinitis, and chronic urticaria episodes."

Chronic urticaria episodes occurred in the older Saudi sibling.

Severe Dry Eye Keratoconjunctivitis sicca HP:0001097

Show evidence (1 reference)

PMID:41659858 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Eczema, chronic diarrhea, hepatosplenomegaly, lymphadenopathy, and severe dry eyes"

Clinical literature table summarizes the ocular case.

Digestive 4

Autoimmune Enteropathy with Chronic Diarrhea HP:0002028

Temporal: CHRONIC

Show evidence (2 references)

PMID:23416241 SUPPORT Human Clinical

"The patient is an 8 year-old female born to consanguineous parents (first cousins) of Italian descent, who developed symptoms resembling IPEX, such as diffuse eczema and severe diarrhea, during her first month of life."

Documents severe diarrhea from the first month of life.

PMID:41694357 SUPPORT Human Clinical

"Both patients were born to first-cousin parents and presented in early childhood with recurrent respiratory and gastrointestinal infections, severe failure to thrive, chronic diarrhea with celiac-like enteropathy, and autoimmune manifestations including autoimmune hepatitis, dermatitis, and, in..."

Reports chronic diarrhea with a celiac-like enteropathy in both children of an independent family.

Context-specific annotations (1)

Five newly identified diabetes-ascertained cases and 17 published cases in the 2026 diabetes study FREQUENT

Enteropathy was reported in 13/22. This selected literature aggregate is not a population penetrance estimate or a frequency for histologically proven autoimmune enteropathy alone.

Show evidence (1 reference)

PMID:41758964 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"enteropathy (n = 13 of 22)"

Study-specific enteropathy count.

Villous Atrophy HP:0011473

Show evidence (2 references)

PMID:23416241 SUPPORT Human Clinical

"The enteropathy with severe villous atrophy was diagnosed as of autoimmune origin and complicated with CMV infection, which was treated by Gancyclovir, but became recurrent."

Reports severe villous atrophy of autoimmune origin, and the recurrent cytomegalovirus infection that complicated it.

PMID:41694357 SUPPORT Human Clinical

"At 2 years, evaluation for persistent diarrhea and failure to thrive revealed malabsorption with villous atrophy on intestinal biopsy."

Independent report of villous atrophy on biopsy.

Autoimmune Hepatitis HP:5210421

Show evidence (1 reference)

PMID:41694357 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"She was also diagnosed with autoimmune hepatitis."

Primary description of Moroccan Case 1, not both unrelated patients.

Pancolitis HP:0033256

Show evidence (1 reference)

PMID:35968218 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Pancolitis was found during colonoscopy and normal upper gastrointestinal endoscopy."

Pancolitis with chronic active gastrointestinal inflammation was documented in the Cys168Ter patient.

Endocrine 2

Early-Onset Autoimmune Diabetes Mellitus Type I diabetes mellitus HP:0100651

Show evidence (2 references)

PMID:41758964 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Diabetes was the presenting feature in four of five individuals, all diagnosed within the first month of life."

New series; remaining patient developed diabetes at eight years.

PMID:41758964 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"GADA was positive in four of four patients tested, supporting an autoimmune etiology. Serum was unavailable for one patient."

Full text corrects the abstract implication that all five were tested.

Context-specific annotations (1)

Five new diabetes-ascertained individuals and 17 previously published cases FREQUENT

14/22 had early-onset diabetes. Ascertainment through diabetes and case publication precludes a population penetrance estimate.

Show evidence (1 reference)

PMID:41758964 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Across all 22 reported individuals with biallelic IL2RA variants (5 new, 17 published) (Tables 1 and 2), 14 had early-onset diabetes."

Explicit denominator and ascertainment context.

Autoimmune Thyroiditis HP:0100646

Show evidence (2 references)

PMID:41758964 SUPPORT Human Clinical

"All patients exhibited additional features of IMD41: four developed autoimmune thyroid disease, three had enteropathy, three had recurrent infections, and two had hepato/splenomegaly."

Reports autoimmune thyroid disease in four of five newly identified patients.

PMID:41694357 SUPPORT Human Clinical

"Thyroid function tests confirmed primary hypothyroidism (free T4 ~0.5 µg/dL, TSH >100 µIU/mL) with markedly elevated anti-thyroperoxidase antibodies (>600 IU/mL), consistent with autoimmune thyroiditis."

Documents the biochemical and serological basis of autoimmune thyroiditis in one patient.

Context-specific annotations (1)

New and previously reported cases in the 2026 diabetes study

Autoimmune thyroid disease, a broader category than antibody-confirmed thyroiditis, was reported in 8/22 selected cases.

Show evidence (1 reference)

PMID:41758964 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"autoimmune thyroid disease (n = 8 of 22)"

Study-specific thyroid-autoimmunity count.

Genitourinary 1

Nephrolithiasis HP:0000787

Show evidence (1 reference)

PMID:35968218 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Renal ultrasonography showed bilateral ... renal stones that were detected on serial imaging studies."

Bilateral small renal stones were found on serial imaging in the Cys168Ter patient; their mechanistic relationship to IL2RA deficiency is uncertain.

Head and Neck 1

Allergic Rhinitis HP:0003193

Show evidence (1 reference)

PMID:41659858 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"including persistent bronchial asthma, allergic rhinitis, and adenoidal hypertrophy"

Allergic rhinitis occurs in the Saudi sibling pair as part of their atopic manifestations.

Immune 9

Eczematous Dermatitis Eczematoid dermatitis HP:0000964

Show evidence (2 references)

PMID:41659858 SUPPORT Human Clinical

"RESULTS: Both patients presented with severe enteropathy, eczema, recurrent respiratory infections, growth failure, and features of allergic disease in early childhood."

Reports eczema alongside enteropathy and growth failure in both siblings.

PMID:23416241 SUPPORT Human Clinical

"When she was 5 years old, she developed diffuse eczema and alopecia universalis despite the immunosuppressive therapies."

Documents diffuse eczema, and records that it was refractory to immunosuppression.

Autoimmune Cytopenia HP:5210419

Show evidence (1 reference)

PMID:41659858 SUPPORT Human Clinical

"including enteropathy, severe eczema, autoimmune cytopenias, type 1 diabetes mellitus, thyroiditis, lymphadenopathy, hepatosplenomegaly, and recurrent infections"

Lists autoimmune cytopenias among the recurring features.

Recurrent Viral Infections HP:0004429

Show evidence (1 reference)

PMID:41659858 SUPPORT Human Clinical

"Patients typically present with opportunistic and recurrent infections, such as CMV, EBV, Candida, adenovirus, Pseudomonas, and Klebsiella, early in life."

Names the recurrent viral organisms alongside the bacterial and fungal ones.

Severe Cytomegalovirus Infection HP:0031692

Show evidence (1 reference)

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC20340/ SUPPORT DIRECT PRIMARY RESULT Human Clinical

"suffering from cytomegalovirus (CMV) pneumonitis, persistent oral thrush, and"

Founding patient had CMV pneumonitis; isolated reactivation is not by itself evidence of severe disease.

Recurrent Bacterial Infections HP:0002718

Show evidence (2 references)

PMID:41659858 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"frequent episodes of otitis media and lower respiratory tract infections, which often required antibiotics."

Recurrent respiratory infections in the younger Saudi sibling.

PMID:23416241 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"severe cellulitis caused by Staphylococcus aureus and Pseudomonas aeruginosa, requiring multiple antibiotic therapy."

Documented bacterial skin infection in a separate patient.

Recurrent Fungal Infections HP:0002841

Show evidence (1 reference)

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC20340/ SUPPORT DIRECT PRIMARY RESULT Human Clinical

"persistent oral thrush, and ... esophagitis at the age of 6 months."

Founding patient had persistent oral and esophageal Candida involvement; HTML markup separates the organism name.

Asthma HP:0002099

Show evidence (1 reference)

PMID:41659858 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"including persistent bronchial asthma, allergic rhinitis, and adenoidal hypertrophy"

Asthma is reported in both Saudi siblings and in the Argentine Y41S patient.

Food Allergy HP:0500093

Show evidence (1 reference)

PMID:41659858 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"persistent diarrhea, failure to thrive, and multiple food allergies in her early childhood."

Multiple food allergies were reported in the older Saudi sibling; the specific allergens were not enumerated.

Decreased Specific Antibody Response Decreased specific antibody response to vaccination HP:0032140

Show evidence (1 reference)

PMID:41659858 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Functional antibody testing showed suboptimal responses to protein antigens. However, adequate responses to polysaccharide antigens were observed."

Functional antibody responses may be impaired despite high total immunoglobulin levels. Protein responses were suboptimal in the older Saudi sibling; polysaccharide responses were impaired in the Y41S patient.

Integument 1

Alopecia Universalis HP:0002289

Show evidence (1 reference)

PMID:23416241 SUPPORT Human Clinical

"she developed diffuse eczema and alopecia universalis despite the immunosuppressive therapies"

Reports alopecia universalis in a single patient.

Limbs 1

Digital Clubbing HP:0001217

Show evidence (1 reference)

PMID:35968218 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"generalized lymphadenopathy of the cervical, axillary, and inguinal lymph nodes, accompanied by digital clubbing."

Digital clubbing accompanied chronic inflammatory illness in the Cys168Ter patient.

Metabolism 4

Metabolic Acidosis HP:0001942

Show evidence (1 reference)

PMID:36195682 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The laboratory findings revealed severe metabolic acidosis hypokalemia and elevated lactate and ammonia levels."

Severe acidosis occurred during the Pakistani splice-donor patient's enteropathy-associated metabolic crisis; a separate inherited metabolic disorder was not demonstrated.

Hypokalemia HP:0002900

Show evidence (1 reference)

PMID:36195682 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The laboratory findings revealed severe metabolic acidosis hypokalemia and elevated lactate and ammonia levels."

Hypokalemia occurred with severe diarrhea and metabolic decompensation in the Pakistani patient.

Increased Circulating Lactate Increased circulating lactate concentration HP:0002151

Show evidence (1 reference)

PMID:36195682 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The laboratory findings revealed severe metabolic acidosis hypokalemia and elevated lactate and ammonia levels."

Elevated lactate was reported during acute metabolic decompensation in one patient; it is not evidence of a primary mitochondrial disorder.

Hyperammonemia HP:0001987

Show evidence (1 reference)

PMID:36195682 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The laboratory findings revealed severe metabolic acidosis hypokalemia and elevated lactate and ammonia levels."

Elevated ammonia was reported during acute metabolic decompensation in one patient; persistence and its immediate mechanism were not established.

Musculoskeletal 1

Osteopenia HP:0000938

Show evidence (1 reference)

PMID:41659858 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"generalized osteopenia and short stature unresponsive to growth hormone therapy"

Generalized osteopenia occurred in the younger Saudi sibling; nutritional, inflammatory and treatment contributions were not isolated.

Respiratory 2

Follicular Bronchiolitis HP:0033583

Show evidence (1 reference)

PMID:24116927 SUPPORT Human Clinical

"We present the first female Argentine patient with mutation in CD25 associated with chronic and severe inflammatory lung disease (follicular bronchiolitis with lymphocyte hyperplasia), eczema and infections."

The report that established follicular bronchiolitis as a phenotype of this disease.

Bronchiectasis HP:0002110

Show evidence (1 reference)

PMID:41659858 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Chest high-resolution computed tomography showed bilateral bronchiectasis, indicative of chronic pulmonary damage."

Bilateral bronchiectasis was documented in the younger Saudi sibling with recurrent respiratory infections; it represents established pulmonary damage.

Growth 2

Failure to Thrive HP:0001508

Show evidence (1 reference)

PMID:41694357 SUPPORT Human Clinical

"presented in early childhood with recurrent respiratory and gastrointestinal infections, severe failure to thrive, chronic diarrhea with celiac-like enteropathy"

Severe growth failure in two unrelated Moroccan families.

Short Stature HP:0004322

Show evidence (1 reference)

PMID:41659858 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"generalized osteopenia and short stature unresponsive to growth hormone therapy"

Marked linear growth failure was reported in the younger Saudi sibling, with poor response to growth-hormone treatment. This observation alone does not establish growth-hormone receptor resistance.

🧬

Genetic Associations

IL2RA (IL2RA loss of function is definitively associated with autosomal recessive CD25 deficiency. Coding missense and nonsense variants, frameshift indels, splice-altering variants and exon-level or whole-gene deletions are reported. Protein abundance, surface localization and residual receptor function vary by allele; a final-exon frameshift can retain low surface expression. Common regulatory IL2RA susceptibility alleles represent a separate complex-trait association. A UK Biobank rare-variant burden analysis found no significant association between heterozygous truncating or predicted damaging missense variants and tested IMD41 features after multiple-testing correction; this does not establish complete absence of heterozygous effects in every setting.)

Gene: IL2RA hgnc:6008 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (2 references)

PMID:9096364 SUPPORT Human Clinical

"We describe here a novel human immune aberration arising from a truncation mutation of the interleukin-2 receptor alpha chain (CD25), a subunit of the tripartite high-affinity receptor for interleukin 2."

The founding report establishing that a mutation of the IL-2 receptor alpha chain causes a human immune disorder.

PMID:41758964 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"We found no evidence that heterozygous IL2RA protein-truncating variants or putatively damaging missense variants are at increased risk of features of IMD41, including diabetes"

Rare-variant burden tests in 401,535 European-ancestry UK Biobank participants were negative after correction; distinct from common susceptibility alleles.

Variants (9)

Biallelic loss-of-function IL2RA variants

Disease-associated alleles carried in trans impair CD25 expression or function. Individual variants require separate classification; not every IL2RA loss-of-function annotation establishes pathogenicity.

Show evidence (1 reference)

PMID:41376159 SUPPORT BACKGROUND In Vitro

"Bi-allelic germline deficiency of IL2RA causes a rare autoimmune disease with impaired regulatory T cell (Treg) function and interleukin-2 (IL-2) signaling."

States the biallelic germline loss-of-function mechanism and its functional consequence for Treg biology.

c.166delC (p.R56fs) Pathogenic

Novel homozygous frameshift allele in two siblings from one family, both of whom were transplanted. Nomenclature follows the source.

Show evidence (1 reference)

PMID:41659858 SUPPORT Human Clinical

"Genetic analysis revealed a novel homozygous frameshift variant in IL2RA (c.166delC; p.R56fs)."

Reports the frameshift allele in the sibling pair.

c.65-2A>G Likely Pathogenic

Homozygous canonical splice-acceptor substitution in one Moroccan family, reported as likely pathogenic. RNA splicing was predicted but not directly assayed; no exact exon consequence is inferred here.

Show evidence (1 reference)

PMID:41694357 SUPPORT Human Clinical

"Targeted next-generation sequencing identified two novel IL2RA variants: a splice-site mutation (c.65-2A>G) and a multi-exon deletion (c.557_795-1625del), both leading to loss of functional CD25."

Reports the splice-site allele and, in the same sentence, the structural null allele curated below.

c.557_795-1625del Pathogenic

Homozygous multi-exon deletion in a second, unrelated Moroccan family, detected by NGS read depth and reported as pathogenic. The source describes partial exon 4 and exons 5–7 involvement; its HGVS notation is retained as reported, without claiming independently resolved breakpoints or measured nonsense-mediated decay.

Show evidence (1 reference)

PMID:41694357 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"For Case 2, NGS read-depth analysis identified a homozygous multi-exon deletion in IL2RA, corresponding at the cDNA level to c.557_795-1625del."

Read-depth evidence for a multi-exon deletion; no priority claim over other structural alleles.

c.497G>A (p.Ser166Asn)

Homozygous missense allele with absent surface CD25 but preserved intracellular protein and transcript in activated patient T cells.

Show evidence (1 reference)

PMID:23416241 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The patient was homozygous for a c.497G>A transition in exon 4, leading to an amino acid substitution at codon 166 (S166N) of the protein."

Homozygous missense allele with absent surface CD25 but preserved intracellular protein and transcript in activated patient T cells.

c.504C>A (p.Cys168Ter) Likely Pathogenic

Homozygous nonsense allele reported as likely pathogenic in a child with granulomatous hepatitis. Protein truncation and degradation were predicted; surface expression was not directly assayed in that report.

Show evidence (1 reference)

PMID:35968218 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"we observed a novel, homozygous, and likely pathogenic c.504 C>A variant located in the exon 4 region of the IL2RA gene"

c.64+1G>A Likely Pathogenic

Homozygous canonical splice-donor variant in the Pakistani patient with enteropathy and metabolic decompensation; classified as likely pathogenic by the authors.

Show evidence (1 reference)

PMID:36195682 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Clinical whole exome sequencing revealed a novel splice donor site variant (NM_001378789.1 (NP_001365718); c.64 + 1G > A) in the IL-2Rα gene."

Homozygous canonical splice-donor variant in the Pakistani patient with enteropathy and metabolic decompensation; classified as likely pathogenic by the authors.

p.Trp177Ter and c.800delA in trans

Compound heterozygous alleles in three siblings used for gene-correction studies. The figure legend and ClinGen identify c.530G>A for p.Trp177Ter; some main-text passages reverse this substitution. The final-exon deletion causes a frameshift with an extended C terminus and residual surface expression.

Show evidence (1 reference)

PMID:29995861 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The mother possessed a single heterozygous mutation (c.530G>A) in exon 4 of IL2RA, resulting in a premature stop codon."

Whole-gene deletion

A homozygous whole-gene deletion was among the five newly identified individuals in the diabetes series; this expands the structural-variant class beyond the Moroccan multi-exon allele.

Show evidence (1 reference)

PMID:41758964 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Four were homozygous (two protein-truncating, one whole-gene deletion, one missense), and one was compound heterozygous for a protein-truncating and a missense variant."

A homozygous whole-gene deletion was among the five newly identified individuals in the diabetes series; this expands the structural-variant class beyond the Moroccan multi-exon allele.

💊

Medical Actions

Allogeneic Hematopoietic Stem Cell Transplantation

Action: allogeneic hematopoietic stem cell transplantation Ontology label: Allogeneic Hematopoietic Stem Cell Transplantation NCIT:C46089

Platform: Cell therapy

Allogeneic HSCT can provide durable clinical and immune correction. The 2026 Saudi sibling study reports transplantation at 12 and 21 years, with sustained recovery at six and five years respectively. Treg enumeration was not performed, so restoration of that compartment is a mechanistic rationale rather than a directly measured result in those siblings. Reported risks include graft failure or rejection, viral reactivation and acute or chronic graft-versus-host disease; the diabetes series includes a death after transplantation.

Mechanism Target:

RESTORES Impaired Regulatory T Cell Suppression — Donor-derived immune cells can restore functional CD25-dependent regulation; the precise contribution of Treg reconstitution was not quantified in the Saudi sibling study.

Show evidence (1 reference)

PMID:41659858 SUPPORT BACKGROUND Human Clinical

"Hematopoietic stem cell transplantation (HSCT) remains the only curative treatment that aims to restore normal immune function by reconstituting a healthy Treg compartment."

States the mechanism of benefit as reconstitution of the Treg compartment, which is what this link asserts.

Show evidence (4 references)

PMID:41659858 SUPPORT Human Clinical

"The younger sibling received marrow from a matched unrelated donor and achieved full donor chimerism with complete clinical and immunological recovery, remaining well 6 years after HSCT."

Reports a long-term clinical and immunological recovery after transplant.

PMID:30742970 SUPPORT Human Clinical

"The early clinical and molecular diagnosis of CD25 deficiency in this patient promptly led to hematopoietic stem cell transplantation (HSCT), allowing complete resolution of the symptoms and definitive cure of the disease."

An independent report of cure after transplant, and the argument for early diagnosis.

PMID:41376159 SUPPORT BACKGROUND Other

"Definitive treatment is currently limited to allogeneic hematopoietic stem cell transplantation, which carries significant morbidity and mortality risks."

Confirms transplantation as the only definitive treatment while stating its risk, the reason alternatives are being developed.

+ 1 more reference

Sirolimus

Action: Pharmacotherapy NCIT:C15986

Agent: sirolimus CHEBI:9168

Platform: Small molecule

Sirolimus has been used as part of combination immunosuppression. In the S166N patient, skin lesions improved when rapamycin was added to mycophenolate; increased FOXP3-positive proportions were an associated observation. The Y41S patient improved on a regimen combining corticosteroids, rapamycin, IVIG and antibiotic prophylaxis. These uncontrolled combinations do not establish a sirolimus-specific effect or correction of the IL2RA defect.

Mechanism Target:

INHIBITS Loss of Peripheral Immune Tolerance — Sirolimus suppresses the proliferation of activated autoreactive T cells, partially restraining the loss of tolerance.

Show evidence (3 references)

PMID:23416241 SUPPORT Human Clinical

"improvement of the lesions was only seen when combined with rapamycin"

Records the clinical response of the skin disease to rapamycin after other immunosuppression failed.

PMID:23416241 SUPPORT Human Clinical

"However, the highest percentage of CD4+FOXP3+ T cells (14.4%) was detected within three weeks of rapamycin treatment."

An immunological correlate of the response, the rise in FOXP3+ cells on treatment.

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC3892414/ SUPPORT DIRECT PRIMARY RESULT Human Clinical

"began immunosuppressive treatment with corticosteroids, antibiotic prophylaxis, rapamycin and intravenous gammaglobulin. Under this regimen her condition improved, and oxygen therapy was no longer necessary."

Combination-regimen outcome; individual drug contribution cannot be isolated.

Corticosteroid and Calcineurin Inhibitor Immunosuppression

Action: Pharmacotherapy NCIT:C15986

Agent: corticosteroid CHEBI:50858 tacrolimus CHEBI:61049 mycophenolate mofetil CHEBI:8764 cyclosporin A CHEBI:4031

Platform: Small molecule

Corticosteroids, tacrolimus or cyclosporin A have been used to control immune-mediated manifestations while definitive treatment is considered. Mycophenolate alone had limited benefit for one patient's skin disease, whereas methotrexate had no benefit in that patient. Regimens are individualized and are not supported by comparative CD25-specific trials.

Mechanism Target:

INHIBITS Loss of Peripheral Immune Tolerance — Broad suppression of T cell activation and proliferation dampens the autoimmune attack without correcting the receptor defect.

Show evidence (4 references)

PMID:23416241 SUPPORT Human Clinical

"The patient suffered from enteropathy until 5 years of age, often requiring parenteral nutrition and was treated with continuous combination therapy of steroids and Tacrolimus or Tacrolimus alone."

Documents the steroid and tacrolimus regimen used for the enteropathy, and the parenteral nutrition curated as a separate treatment.

PMID:23416241 SUPPORT Human Clinical

"Therefore, Mycophenolate Mophetil was given alone with limited improvement of skin lesions"

Records mycophenolate mofetil use and its limited effect as monotherapy in that patient.

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC20340/ SUPPORT DIRECT PRIMARY RESULT Human Clinical

"treatment of the CD25-deficient patient with corticosteroids and cyclosporin A decreased inflammation and induced a dramatic reduction of lymphadenopathy and hepatosplenomegaly"

Clinical response in the founding case.

+ 1 more reference

Antiviral Therapy and Anti-Infective Prophylaxis

Action: antiviral therapy Ontology label: Antiviral Therapy NCIT:C16119

Agent: ganciclovir CHEBI:465284

Platform: Small molecule

Reported supportive care includes ganciclovir for CMV reactivation and prophylaxis against Pneumocystis and fungal infection. Antibacterial prophylaxis and treatment of documented infections are also used. Regimens depend on infection history and immune status.

Target Phenotypes: Severe cytomegalovirus infection HP:0031692

Show evidence (1 reference)

PMID:23416241 SUPPORT Human Clinical

"Additional therapies included prophylactic treatment, against Pneumocystis jiroveci and fungi, and Gancyclovir upon detection of CMV reactivation."

Documents both the antiviral treatment and the anti-infective prophylaxis described here.

Parenteral Nutrition and Nutritional Support

Action: total parenteral nutrition Ontology label: Total Parenteral Nutrition NCIT:C29484

Platform: Other

The enteropathy causes malabsorption severe enough to require parenteral nutrition in some patients until it is controlled or the patient is transplanted.

Target Phenotypes: Failure to thrive HP:0001508

Show evidence (1 reference)

PMID:23416241 SUPPORT Human Clinical

"The patient suffered from enteropathy until 5 years of age, often requiring parenteral nutrition"

Reports the need for parenteral nutrition during the enteropathy.

Gene-Corrected Autologous Regulatory T Cell Therapy (Investigational)

Action: Ex vivo gene-corrected autologous Treg therapy Ontology label: Gene Therapy NCIT:C15238

Platform: Gene editing

Preclinical CRISPR-Cas9 correction of patient Tregs restores CD25 expression and suppressive activity. The 2025 report describes GMP-compatible clinical-scale manufacturing and functional equivalence to healthy-donor Tregs in vitro. The 2018 precursor study demonstrated allele correction and improved STAT5 responses. These are cell-engineering studies, not evidence of benefit in a treated patient.

Mechanism Target:

RESTORES Impaired Regulatory T Cell Suppression — Correcting IL2RA in the patient's own Tregs restores receptor expression and suppressive function in vitro.

Show evidence (2 references)

PMID:41376159 SUPPORT In Vitro

"One of the two disease-causing mutations in patient-derived Tregs was corrected with CRISPR-Cas9-mediated homology-directed repair, restoring IL2RA expression."

Describes the correction and the restored receptor expression, the basis of this treatment link.

PMID:41376159 SUPPORT In Vitro

"The resulting gcTregs demonstrated robust suppressive activity in vitro."

Reports the functional readout, in vitro suppression, that the corrected cells recover.

Intravenous Immunoglobulin

Action: Intravenous Immunoglobulin Therapy NCIT:C121331

Platform: Protein replacement

IVIG has been used for infection prevention in patients with deficient functional antibody responses or substantial infectious burden, including some with elevated total IgG. Treatment is based on functional assessment and clinical context rather than total immunoglobulin concentration alone.

Target Phenotypes: Decreased specific antibody response to vaccination HP:0032140 Recurrent bacterial infections HP:0002718

Show evidence (2 references)

PMID:41659858 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Monthly IVIG replacement therapy and Pneumocystis jirovecii prophylactic antibiotics were initiated."

Reported supportive care in the younger Saudi sibling.

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC3892414/ SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Although our patient has hypergammaglobulinaemia, she has an impaired specific polysaccharide response"

Functional antibody impairment in the Y41S patient who received IVIG.

Insulin Replacement

Action: Hormone Replacement Therapy NCIT:C15599

Agent: insulin CHEBI:145810

Platform: Protein replacement

Insulin is required to treat insulin deficiency in affected patients with autoimmune diabetes. All five newly identified individuals in the 2026 series required immediate insulin; treatment requirements reflect the diabetes phenotype and do not correct the immune defect.

Target Phenotypes: Early-onset autoimmune diabetes mellitus HP:0100651

Show evidence (1 reference)

PMID:41758964 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"All individuals required immediate insulin therapy"

Primary treatment observation in the five new cases.

Thyroid Hormone Replacement

Action: Hormone Replacement Therapy NCIT:C15599

Agent: thyroxine CHEBI:30660

Platform: Small molecule

Thyroid hormone replacement has been used for hypothyroidism associated with autoimmune thyroiditis. Thyroid function and replacement need require reassessment; the S166N patient's thyroiditis later resolved.

Target Phenotypes: Autoimmune thyroiditis HP:0100646

Show evidence (1 reference)

PMID:23416241 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"She presented an autoimmune thyroiditis at 4 years of age, which was treated with hormone replacement therapy until the thyroiditis resolved at 7 years."

Patient-specific replacement and follow-up.

Genetic Counseling

Action: Genetic Counseling NCIT:C15240

Platform: Other

Molecularly confirmed families should receive counseling on autosomal recessive inheritance, segregation testing and reproductive options. For two carriers of pathogenic alleles, the probability of a child inheriting both is 25% per pregnancy; clinical severity remains variable.

Show evidence (1 reference)

PMID:36195682 SUPPORT DIRECT BACKGROUND Human Clinical

"The study will also help clinical geneticists for genetic counseling and prevention of the disease in the affected family."

The primary case study supports disease-specific family counseling.

🔬

Diagnosis

Flow cytometry for surface CD25 on T cells

Flow cytometry should assess CD25 on resting and stimulated T cells. Absent or markedly reduced expression supports IL2RA deficiency, but residual expression occurs and does not exclude it. Intermediate expression in relatives suggests carrier status and requires molecular confirmation. FOXP3-positive Tregs may persist; gates requiring CD25 cannot quantify the CD25-negative regulatory lineage.

flow cytometric assessment of surface CD25 expression

Markers: Surface CD25 (IL-2R alpha) on CD4+ and activated T cells

Results: Absent or markedly reduced surface CD25; residual expression does not exclude disease

Show evidence (3 references)

PMID:41694357 SUPPORT BACKGROUND Human Clinical

"Simple flow cytometric assessment of CD25 on T cells is a valuable screening tool, and early genetic confirmation is crucial to guide timely hematopoietic stem cell transplantation and genetic counselling."

States the role of the flow cytometric test as the screening step preceding genetic confirmation.

PMID:30742970 SUPPORT Human Clinical

"Cytofluorimetric analysis revealed the total absence of CD25 cell surface expression and addressed IL2Rα molecular investigation."

Shows the sequence used in practice: absent surface expression by flow cytometry directs the molecular study.

PMID:29995861 SUPPORT DIRECT PRIMARY RESULT In Vitro

"three compound heterozygotes that express minimal amounts of IL2RA on the surface of the T cells"

Residual expression in genetically affected individuals.

IL2RA sequencing

Sequence analysis should cover coding exons and splice junctions and include validated copy-number analysis for exon-level or whole-gene deletions. Targeted panels, exome sequencing and NGS read-depth analysis have identified disease alleles. Family segregation and functional studies help interpret variant-specific consequences.

IL2RA sequencing

Results: Biallelic loss-of-function IL2RA variants

Show evidence (2 references)

PMID:41659858 SUPPORT Human Clinical

"Molecular analysis using the next-generation sequencing primary immunodeficiency panel revealed a novel homozygous frameshift mutation in IL2RA (c.166delC; p.R56fs), which was confirmed by Sanger sequencing."

Documents the panel-based route to molecular diagnosis.

PMID:41694357 SUPPORT Human Clinical

"For Case 2, NGS read-depth analysis identified a homozygous multi-exon deletion in IL2RA, corresponding at the cDNA level to c.557_795-1625del."

The case for including copy-number analysis: this allele was found by read depth, not by variant calling on sequence alone.

Screen IL2RA when IPEX is suspected but FOXP3 is normal

Because the clinical picture is IPEX-like, the practical diagnostic rule is that a patient with IPEX features and a normal FOXP3 gene should be screened for IL2RA variants.

IL2RA screening in FOXP3-normal IPEX-like disease

Show evidence (1 reference)

PMID:17196245 SUPPORT BACKGROUND Human Clinical

"Any patient with features of IPEX but with a normal Foxp3 gene should be screened for mutations in the IL-2 receptor subunit CD25."

The source's own clinical implication, stated as a screening rule.

Genetic testing for neonatal or syndromic autoimmune diabetes

Include IL2RA in monogenic neonatal-diabetes panels and consider it in childhood diabetes accompanied by enteropathy, endocrinopathy or immune dysregulation. GAD positivity does not exclude a monogenic immune cause.

IL2RA analysis in neonatal or syndromic autoimmune diabetes

Show evidence (1 reference)

PMID:41758964 SUPPORT DIRECT BACKGROUND Human Clinical

"IL2RA should be included in gene panels for neonatal diabetes, and testing should be considered in children with diabetes and immunodysregulatory features."

Clinical implication of the disease-specific diabetes series.

Functional immune characterization

Evaluate IL-2 dose-dependent STAT5 phosphorylation, antigen and mitogen proliferation, lymphocyte subsets, immunoglobulins and specific antibody responses. Compare with appropriate controls and use CD25-independent markers when enumerating Tregs. Normal total counts, high IgG or preserved PHA responses do not exclude disease.

Functional immune characterization in suspected CD25 deficiency

Show evidence (2 references)

PMID:23416241 SUPPORT DIRECT PRIMARY RESULT In Vitro

"CD4+ T cells of the patient had dramatically reduced pSTAT5 at all concentrations of IL-2 tested."

IL-2 dose-response assay.

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC3892414/ SUPPORT DIRECT PRIMARY RESULT In Vitro

"She presented a normal phytohaemagglutinin (PHA)-stimulated T cell proliferation assay"

The Y41S case limits a requirement for abnormal mitogen proliferation.

Glucose Surveillance

ClinGen recommends glucose monitoring in individuals with biallelic pathogenic or likely pathogenic IL2RA variants who have not developed diabetes. Those first diagnosed through diabetes warrant assessment for immune, lymphoproliferative and other autoimmune manifestations.

Blood Glucose Measurement NCIT:C92744

Show evidence (1 reference)

url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7d977a16-0957-458b-86be-2245d3953453 SUPPORT DIRECT REVIEW SYNTHESIS Other

"in individuals discovered to have P/LP IL2RA variants but who have not been diagnosed with diabetes, glucose monitoring is advised"

Expert recommendation based on the published disease spectrum.

📈

Progression

Onset in infancy or early childhood

Age: First weeks of life to early childhood

Disease commonly starts in infancy, including neonatal diabetes or early enteropathy, but clinical severity and pace vary. Some patients survive into adolescence or adulthood before transplantation.

Show evidence (2 references)

PMID:41758964 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Diabetes was the presenting feature in four of five individuals, all diagnosed within the first month of life."

Four neonatal presentations in the diabetes-ascertained series.

PMID:23416241 SUPPORT Human Clinical

"who developed symptoms resembling IPEX, such as diffuse eczema and severe diarrhea, during her first month of life"

Documents the enteropathy and eczema presentation in the first month of life.

Childhood and adolescent mortality risk

Age: Childhood to adolescence

Deaths from sepsis and transplantation complications occur. The 2026 diabetes series reports deaths at 19 months, three years and 13 years; the adolescent died after transplant rejection. These selected cases cannot establish a mortality rate or imply universal early-childhood death.

Show evidence (1 reference)

PMID:41758964 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"| Deceased (age) | No | Yes (3 years) | Yes (13 years) | Yes (19 months) | No |"

Table 1 includes an adolescent death, qualifying the abstract's early-childhood wording.

📊

Prevalence

Published cases included in the 2026 diabetes study

Cases In Literature

The study combined five new diabetes-ascertained individuals with 17 previously reported cases. Other contemporaneous reviews used smaller case sets, including a 15-case transplant review. These overlapping literature counts are not an exhaustive current worldwide census, population prevalence, or incidence estimate.

Show evidence (1 reference)

PMID:41758964 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Across all 22 reported individuals with biallelic IL2RA variants (5 new, 17 published) (Tables 1 and 2), 14 had early-onset diabetes."

Defines the study-specific literature aggregate; does not establish population frequency.

⚖️

Clinical Burden

High

CD25 deficiency can require prolonged immunosuppression, antimicrobial treatment, nutritional support and insulin or thyroid hormone replacement, with organ damage and deaths from sepsis or transplantation complications. Severity varies, and some patients survive into adulthood. HSCT can provide sustained recovery, but graft failure, infection and graft-versus-host disease remain material risks.

Show evidence (2 references)

PMID:41758964 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"| Deceased (age) | No | Yes (3 years) | Yes (13 years) | Yes (19 months) | No |"

Table 1 includes an adolescent death, qualifying the abstract's early-childhood wording.

PMID:41376159 SUPPORT BACKGROUND Other

"Definitive treatment is currently limited to allogeneic hematopoietic stem cell transplantation, which carries significant morbidity and mortality risks."

The curative option carries important morbidity and mortality risks.

🔀

Differential Diagnoses

Conditions with similar clinical presentations that must be differentiated from CD25 Deficiency:

IPEX syndrome (FOXP3) MONDO:0010580

Overlapping Features FOXP3-related IPEX and CD25 deficiency share early immune dysregulation, but differ in gene and typical inheritance. FOXP3-positive cells may be present in either condition, and lineage counts alone are not decisive. The CD3/CD46-induced IL-10 distinction arose from individual patient comparisons and is not a validated universal diagnostic discriminator.

Distinguishing Features

X-linked inheritance and a FOXP3 variant in IPEX
autosomal recessive inheritance, absent surface CD25 and an IL2RA variant in CD25 deficiency

Show evidence (2 references)

PMID:41694357 SUPPORT Human Clinical

"Unlike FOXP3 deficiency, IL2RA deficiency does not involve mutations in FOXP3 but results from impaired IL-2 signaling required to sustain FOXP3 expression in Tregs"

States the mechanistic distinction between the two entities.

PMID:17196245 SUPPORT Human Clinical

"We describe a patient with clinical manifestations of IPEX that had a normal Foxp3 gene, but who had CD25 deficiency due to autosomal recessive mutations in this gene."

The case that separated the two diseases clinically, an IPEX phenotype with a normal FOXP3 gene.

STAT5B deficiency MONDO:0100211

Overlapping Features STAT5B deficiency can combine immune dysregulation with a characteristic growth-hormone-insensitivity phenotype. CD25 deficiency can also cause severe growth failure, including one reported poor response to growth hormone; short stature alone does not distinguish them. IL2RA surface expression and molecular testing identify the receptor defect.

Distinguishing Features

growth hormone insensitivity with very low IGF-1 and severe short stature in STAT5B deficiency
absent surface CD25 with normal STAT5B in CD25 deficiency

Show evidence (1 reference)

PMID:29988287 SUPPORT Human Clinical

"Using NK cells from two patients, one with a primary immunodeficiency characterized by a homozygous mutation in CD25 (born in year 2007 and studied since she was 3 years old) and one with a homozygous mutation in STAT5b (born in year 1992 and studied since she was 10 years old)"

Confirms the two as distinct entities studied in parallel, which is why STAT5B deficiency belongs in this differential.

Severe combined immunodeficiency

Overlapping Features Severe infections and impaired T-cell responses overlap with combined immunodeficiencies. CD25 deficiency often retains circulating T cells and includes lymphoproliferation and autoimmunity. B-cell counts and antibody function vary; normal or high total immunoglobulins do not exclude an associated antibody defect.

Distinguishing Features

Coexisting lymphoproliferation and autoimmune manifestations
Absent or markedly reduced surface CD25 with biallelic IL2RA variants

Show evidence (1 reference)

PMID:9096364 SUPPORT Human Clinical

"This immunodeficiency is characterized by decreased numbers of peripheral T cells displaying abnormal proliferation but normal B cell development."

Establishes preserved B cell development, a feature that argues against SCID of the T-B-negative kind.

📊

Related Datasets

FOXP1 and FOXP4 function in mouse regulatory T cells [RNA-seq] geo:GSE300286

Bulk RNA sequencing of sorted splenic regulatory T cells from conditional Foxp1/Foxp4 mutant and control mice. This is an indirect model of reduced CD25 expression and altered Treg function, not a patient IL2RA-deficiency dataset.

Mus musculus BULK RNA SEQ

PMID:40794436

Foxp1/Foxp4 deletion affects many Treg programs; its transcriptome cannot be attributed solely to IL2RA. See the corresponding animal model for preserved in-vitro suppression and impaired in-vivo suppression.

Show evidence (1 reference)

PMID:40794436 SUPPORT DIRECT PRIMARY RESULT Model Organism

"We further show that FOXP1 and FOXP4 bind to Il2ra promoter regions to regulate CD25 expression in Tregs."

The source establishes the relevance of this indirect regulatory model.

🧫

Experimental Models

Founding-patient EBV-transformed B cells CELL_LINE

Patient-derived EBV-transformed B cells demonstrated absent CD25. This transformed B-cell system measures receptor expression; it is not a direct Treg suppression model.

Organism

Homo sapiens NCBITaxon:9606

Cell source

Patient-derived EBV-transformed peripheral B lymphocytes

Publication

PMID:9096364

Pathograph links

Reduced Surface CD25 Availability measures fidelity: moderate observes: cellular Absent CD25 in the patient-derived line.

Limitations: EBV transformation and B-cell lineage differ from regulatory T cells.

Show evidence (1 reference)

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC20340/ SUPPORT DIRECT PRIMARY RESULT In Vitro

"an EBV-transformed cell line derived from patient peripheral B lymphocytes did not express detectable CD25 by flow cytometry"

Founding patient-derived immortalized B-cell readout.

Show evidence (1 reference)

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC20340/ SUPPORT DIRECT PRIMARY RESULT In Vitro

"an EBV-transformed cell line derived from patient peripheral B lymphocytes did not express detectable CD25 by flow cytometry"

Founding patient-derived immortalized B-cell readout.

S166N patient PBMC and T-cell cultures PRIMARY_CELL_CULTURE

Dose-response STAT5, proliferation, cytokine and suppression assays distinguish high-affinity IL-2 impairment from retained CD122/CD132 signaling. Healthy-donor Tregs suppressed patient CD8 cells. High cytokine doses partly improved polyclonal proliferation but did not restore CMV-specific proliferation or IFN-gamma production.

Organism

Homo sapiens NCBITaxon:9606

Cell source

Patient-derived primary lymphocytes

Publication

PMID:23416241

Pathograph links

Raised IL-2 Signaling Threshold with Deficient STAT5 Activation measures fidelity: moderate observes: cellular CD4 and CD8 IL-2 dose responses differ.

Limitations: One treated patient; in-vitro dose responses do not establish clinical IL-2 efficacy.

Show evidence (1 reference)

PMID:23416241 SUPPORT DIRECT PRIMARY RESULT In Vitro

"CD8+ T cells of the patient were less affected by the loss of CD25 in response to IL-2 stimulation."

Subset-specific signaling.

Impaired Antigen-Specific T Cell Responses measures fidelity: moderate observes: cellular Antigen-specific defects persist despite cytokine addition.

Limitations: Partial polyclonal rescue and failed CMV rescue are distinct endpoints.

Show evidence (2 references)

PMID:23416241 SUPPORT DIRECT PRIMARY RESULT In Vitro

"The patient's PBMCs had poor in vitro proliferation response to TCR-mediated activation compared to healthy controls"

Patient-cell proliferation assay.

+ 1 more reference

Show evidence (1 reference)

PMID:23416241 SUPPORT DIRECT PRIMARY RESULT In Vitro

"The patient's PBMCs had poor in vitro proliferation response to TCR-mediated activation compared to healthy controls"

Patient-cell proliferation assay.

Y41S patient NK-cell functional cultures PRIMARY_CELL_CULTURE

Cytokine stimulation, proliferation and K562 degranulation assays in the previously reported Argentine patient showed impaired IFN-gamma production but increased lytic mediators and degranulation. The STAT5B-deficient individual was a separate comparator.

Organism

Homo sapiens NCBITaxon:9606

Cell source

Patient-derived primary lymphocytes

Publication

PMID:29988287

Pathograph links

Reduced NK Cell IFN-Gamma Production measures fidelity: moderate observes: cellular Reduced stimulated cytokine output.

Limitations: One CD25-deficient patient; a causal contribution to particular infections was not tested.

Show evidence (1 reference)

PMID:29988287 SUPPORT DIRECT PRIMARY RESULT In Vitro

"CD56bright and CD56dim NK cells from the CD25-deficient patient produced less IFN-γ than CD56bright and CD56dim NK cells from the HD"

Stimulated NK assay.

Show evidence (1 reference)

PMID:29988287 SUPPORT DIRECT PRIMARY RESULT In Vitro

"CD56bright and CD56dim NK cells from the CD25-deficient patient produced less IFN-γ than CD56bright and CD56dim NK cells from the HD"

Stimulated NK assay.

Nonviral gene-corrected IL2RA-deficient T cells PRIMARY_CELL_CULTURE

T cells from three compound heterozygous siblings underwent CRISPR correction at the endogenous IL2RA locus. HDR repaired the premature-stop allele; targeting the final-exon deletion also permitted frame-restoring indels without an HDR template. Surface CD25 and STAT5 responses improved, and corrected Treg-like cells expanded with a demethylated FOXP3 TSDR. These readouts do not alone establish in-vivo therapeutic efficacy.

Organism

Homo sapiens NCBITaxon:9606

Cell source

Patient-derived primary lymphocytes

Publication

PMID:29995861

Pathograph links

Raised IL-2 Signaling Threshold with Deficient STAT5 Activation rescues fidelity: moderate observes: cellular Genetic correction improved cytokine-induced STAT5 phosphorylation.

Limitations: Ex-vivo readout; outcomes and editing efficiencies vary by allele and donor.

Show evidence (1 reference)

PMID:29995861 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Following correction of the c.530A>G IL2RA mutation, IL-2 treatment led to increased STAT5 phosphorylation"

The source reverses the substitution in this sentence; its figure legend identifies the pathogenic allele as c.530G>A.

Reduced Surface CD25 Availability rescues fidelity: moderate observes: cellular Gene correction restored surface expression.

Limitations: Frame-restoring indels and precise HDR are distinct editing outcomes.

Show evidence (1 reference)

PMID:29995861 SUPPORT DIRECT PRIMARY RESULT In Vitro

"we were able to correct the mutation and observed IL2RA expression on the surface of corrected T cells from the patient"

Direct correction experiment.

Show evidence (1 reference)

PMID:29995861 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Following correction of the c.530A>G IL2RA mutation, IL-2 treatment led to increased STAT5 phosphorylation"

The source reverses the substitution in this sentence; its figure legend identifies the pathogenic allele as c.530G>A.

GMP-compatible gene-corrected autologous Treg product PRIMARY_CELL_CULTURE

Patient Tregs were corrected by CRISPR-Cas9 homology-directed repair. The later manufacturing study demonstrated restored CD25 and robust in-vitro suppressive activity at clinical scale.

Organism

Homo sapiens NCBITaxon:9606

Cell source

Patient-derived primary lymphocytes

Publication

PMID:41376159

Pathograph links

Impaired Regulatory T Cell Suppression rescues fidelity: moderate observes: cellular Corrected Tregs regained suppressive activity.

Limitations: Manufacturing and in-vitro function do not establish persistence, safety or clinical efficacy after infusion.

Show evidence (1 reference)

PMID:41376159 SUPPORT DIRECT PRIMARY RESULT In Vitro

"The resulting gcTregs demonstrated robust suppressive activity in vitro."

Functional rescue in vitro.

Show evidence (1 reference)

PMID:41376159 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Clinical-scale manufacturing from a patient with IL2RA deficiency showed efficient gene correction, restored IL2RA expression, and functional equivalence to healthy donor Tregs."

Clinical-scale manufacture and in-vitro function; no patient infusion outcome.

🐁

Animal Models

Il2ra knockout mouse

Mice lacking IL-2R alpha develop normal T and B cells when young, then as adults show massive peripheral lymphoid enlargement with polyclonal T and B expansion correlated with impaired activation-induced cell death, and later autoimmune disease including hemolytic anemia and inflammatory bowel disease. The model is the source of the interpretation that the chain regulates the size and content of the lymphoid compartment by setting the balance between clonal expansion and death after activation.

Species

Mouse

Genotype

Il2ra-null (IL-2R alpha-deficient)

Publication

PMID:7584142

Pathograph links

Impaired Peripheral Activation-Induced T Cell Death partially recapitulates fidelity: moderate observes: organism The knockout reproduces the failure of activation-induced T cell death, with the polyclonal lymphoid expansion it predicts.

Limitations: The finding is peripheral activation-induced death in a whole-gene-null mouse. Human thymic BCL2 findings are a different process, and the S166N patient did not show a general peripheral apoptotic defect. Infection susceptibility and clinical onset differ from the reported human spectrum.

Show evidence (1 reference)

PMID:7584142 SUPPORT Model Organism

"However, as adults, these mice develop massive enlargement of peripheral lymphoid organs associated with polyclonal T and B cell expansion, which, for T cells, is correlated with impaired activation-induced cell death in vivo."

Reports the apoptosis defect and the lymphoid expansion in the knockout, which is what makes it informative for this node.

Loss of Peripheral Immune Tolerance partially recapitulates fidelity: moderate observes: organism The null animal develops autoimmune hemolytic anemia and intestinal inflammation.

Limitations: Overlapping immune pathology does not reproduce the entire human infection and endocrine spectrum.

Show evidence (1 reference)

PMID:7584142 SUPPORT Model Organism

"Older IL-2R alpha-deficient mice also develop autoimmune disorders, including hemolytic anemia and inflammatory bowel disease."

Establishes that the knockout develops autoimmunity, so it is informative for the disease as well as for the apoptosis lesion, while naming organ targets that only partly match the human ones.

Show evidence (1 reference)

PMID:7584142 SUPPORT Model Organism

"Older IL-2R alpha-deficient mice also develop autoimmune disorders, including hemolytic anemia and inflammatory bowel disease."

Establishes that the knockout develops autoimmunity, so it is informative for the disease as well as for the apoptosis lesion, while naming organ targets that only partly match the human ones.

Il2-null mice across genetic backgrounds

An indirect ligand-deficiency model of impaired IL-2-dependent tolerance. Mixed-background animals predominantly develop colitis, whereas BALB/c animals develop generalized autoimmunity, hemolytic anemia and early mortality. This is not IL2RA gene deficiency or evidence for a specific human modifier gene.

Species

Mouse

Genotype

Il2 knockout on mixed 129/Ola × C57BL/6 or BALB/c backgrounds

Publication

PMID:9065030

Pathograph links

Loss of Peripheral Immune Tolerance partially recapitulates fidelity: moderate observes: organism Loss of the ligand perturbs the same tolerance pathway.

Limitations: Il2 deletion differs from receptor-alpha loss; background effects and immune-cell distributions cannot be directly transferred to human CD25 deficiency.

Show evidence (1 reference)

PMID:9065030 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Il-2-/-mice backcrossed to BALB/c genetic background develop a generalized autoimmune disease"

Background-dependent mouse phenotype.

Show evidence (1 reference)

PMID:9065030 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Treatment of Il-2-/-Balb/c mice with anti-gp39 (CD40L) antibody inhibited activation of B cells and CD8+ T cells, however, it did not affect the activation of CD4+ T cells."

Partial experimental intervention; not a clinical CD25 treatment.

Treg-specific Foxp1/Foxp4 double-knockout mice

An indirect upstream transcriptional-perturbation model with reduced Il2ra transcription and CD25 expression, preserved or increased Treg numbers, systemic inflammation and autoimmunity. Suppression was impaired in the lymphopenia-driven expansion assay but preserved in the in-vitro assay; transfer-colitis histology was not significantly different at ten weeks. Neither factor is established as a modifier of human IL2RA deficiency.

Species

Mouse

Genotype

Foxp1fl/fl Foxp4fl/fl Foxp3YFP-Cre

Publication

PMID:40794436

Pathograph links

Reduced Surface CD25 Availability perturbs fidelity: low observes: organism Deleting both transcription factors lowers CD25 expression in Tregs.

Limitations: The manipulation changes many genes and does not isolate CD25 as the cause of the entire phenotype; no CD25-specific rescue was demonstrated.

Show evidence (1 reference)

PMID:40794436 SUPPORT DIRECT PRIMARY RESULT Model Organism

"both cTreg and eTreg subsets in cDKO have decreased level of CD25 expression"

In vivo conditional-knockout readout.

Show evidence (1 reference)

PMID:40794436 SUPPORT DIRECT PRIMARY RESULT Model Organism

"these data indicate a defect in in vivo but not in vitro function of Tregs deficient in both FOXP1 and FOXP4."

Assay-dependent functional outcome.

🧮

Computational Models

Cys168Ter protein and RNA structure predictions STRUCTURAL_PREDICTION

The Cys168Ter case report used an ab-initio protein model, domain mapping and RNAfold. The altered stop codon predicts truncation, but mRNA folding stability showed no significant change and degradation was not measured.

PMID:35968218

Pathograph links

Reduced Surface CD25 Availability perturbs fidelity: low observes: molecular The model predicts a truncated receptor product.

Limitations: No receptor abundance, localization or patient RNA-decay assay was performed; inconsistent reported truncation lengths are not adopted.

Show evidence (1 reference)

PMID:35968218 SUPPORT DIRECT PRIMARY RESULT Computational

"First, the 3D model of IL2RA variant protein was constructed using the ab-initio method"

Computational structure prediction.

Show evidence (1 reference)

PMID:35968218 SUPPORT DIRECT PRIMARY RESULT Computational

"no significant changes in the thermodynamic stability of the mRNA folding pattern due to c.504 C>A variant"

Negative RNAfold prediction, distinct from the predicted protein truncation.

{ }

Source YAML

click to show

name: CD25 Deficiency
creation_date: "2026-09-24T19:23:48Z"
category: Mendelian
disease_term:
  preferred_term: CD25 deficiency
  term:
    id: MONDO:0011664
    label: immunodeficiency due to CD25 deficiency
synonyms:
- immunodeficiency due to CD25 deficiency
- IL2RA deficiency
- interleukin-2 receptor alpha chain deficiency
- immunodeficiency 41 with lymphoproliferation and autoimmunity
- IMD41
description: >-
  CD25 deficiency is an autosomal recessive inborn error of immunity caused by biallelic loss-of-function IL2RA variants. Reduced or absent surface CD25 impairs high-affinity IL-2 capture, while signaling through the CD122/CD132 receptor remains possible at higher IL-2 concentrations. Impaired regulatory T-cell function coexists with deficient antigen-specific immunity and, in some patients, cytokine-associated CD8 T-cell expansion and tissue infiltration. FOXP3-positive regulatory T cells can persist; defective thymic selection and activation-induced apoptosis are not established universal mechanisms. Clinical expression varies from early enteropathy and eczema to neonatal autoimmune diabetes, other endocrinopathies, cytopenias and recurrent infections. Lymphadenopathy, hepatosplenomegaly and inflammatory lung disease may accompany the immune dysregulation. Flow cytometry, functional testing and comprehensive IL2RA analysis establish the diagnosis. Immunosuppression and supportive care can control manifestations; allogeneic hematopoietic stem cell transplantation can provide durable immune correction. Gene-corrected autologous regulatory T cells remain investigational.
classifications:
  harrisons_chapter:
  - classification_value: IMMUNE_RHEUMATOLOGIC
    evidence:
    - reference: PMID:41659858
      reference_title: "Expanding the clinical spectrum of interleukin-2 receptor alpha chain deficiency: two novel cases with long-term hematopoietic stem cell transplantation outcome and literature review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "IL2RA (CD25) deficiency is a rare autosomal recessive inborn error of immunity."
      explanation: >-
        An inborn error of immunity with autoimmunity is clinically an
        immune-mediated disorder, the home of Harrison's immune/rheumatologic
        part.
      quote_role: REVIEW_SYNTHESIS
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    notes: >-
      The disease is a monogenic autosomal recessive Mendelian disorder, so the
      genetics part of Harrison's also applies.
  iuis_category:
    classification_value: immune dysregulation
    notes: >-
      In the IUIS inborn-errors-of-immunity classification CD25 deficiency sits
      among the diseases of immune dysregulation (Tregopathies) beside FOXP3,
      STAT5B, CTLA4 and LRBA defects, rather than among the combined
      immunodeficiencies.
    evidence:
    - reference: PMID:41659858
      reference_title: "Expanding the clinical spectrum of interleukin-2 receptor alpha chain deficiency: two novel cases with long-term hematopoietic stem cell transplantation outcome and literature review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This disorder is characterized by defective Treg cell homeostasis and function, which leads to profound immune dysregulation."
      explanation: >-
        Names defective regulatory T cell homeostasis and function as the
        defining lesion, which is the IUIS immune-dysregulation category.
      quote_role: REVIEW_SYNTHESIS
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Biallelic disease-causing IL2RA variants can be homozygous or compound heterozygous. Consanguinity is frequent in reported families but is not required. Genetically confirmed heterozygous parents in the diabetes series were clinically unaffected; intermediate CD25 expression alone suggests but does not prove carrier status. If both parents carry a pathogenic allele, each pregnancy has a 25% probability of inheriting both alleles. Penetrance has not been quantified in an unselected population.
  evidence:
  - reference: PMID:41659858
    reference_title: "Expanding the clinical spectrum of interleukin-2 receptor alpha chain deficiency: two novel cases with long-term hematopoietic stem cell transplantation outcome and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Interleukin-2 receptor alpha chain (IL2RA, CD25) deficiency is a rare autosomal recessive inborn error of immunity characterized by profound immune dysregulation, susceptibility to infections, and autoimmunity."
    explanation: States the autosomal recessive inheritance of the disease.
    quote_role: BACKGROUND
  - reference: PMID:41694357
    reference_title: "Case Report: IL2RA (CD25) deficiency: first reported cases in Morocco."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "flow cytometry showed a complete absence of CD25 expression on CD4+ T cells in both children, whereas relatives displayed intermediate levels compatible with carrier status"
    explanation: >-
      Intermediate expression in relatives is compatible with carrier status; the Moroccan study did not genotype all relatives.
  - reference: PMID:41758964
    reference_title: Biallelic Pathogenic Variants in IL2RA Cause Neonatal-Onset Monogenic Autoimmune Diabetes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: This is supported by all the parents who are carriers of an IL2RA recessive variant being clinically unaffected.
    explanation: Clinically unaffected confirmed carriers support recessive inheritance.
genetic:
- name: IL2RA
  gene_term:
    preferred_term: IL2RA
    term:
      id: hgnc:6008
      label: IL2RA
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  association: >-
    IL2RA loss of function is definitively associated with autosomal recessive CD25 deficiency. Coding missense and nonsense variants, frameshift indels, splice-altering variants and exon-level or whole-gene deletions are reported. Protein abundance, surface localization and residual receptor function vary by allele; a final-exon frameshift can retain low surface expression. Common regulatory IL2RA susceptibility alleles represent a separate complex-trait association. A UK Biobank rare-variant burden analysis found no significant association between heterozygous truncating or predicted damaging missense variants and tested IMD41 features after multiple-testing correction; this does not establish complete absence of heterozygous effects in every setting.
  variants:
  - name: Biallelic loss-of-function IL2RA variants
    description: >-
      Disease-associated alleles carried in trans impair CD25 expression or function. Individual variants require separate classification; not every IL2RA loss-of-function annotation establishes pathogenicity.
    evidence:
    - reference: PMID:41376159
      reference_title: Gene-corrected regulatory T cell therapy for IL2RA deficiency.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Bi-allelic germline deficiency of IL2RA causes a rare autoimmune disease with impaired regulatory T cell (Treg) function and interleukin-2 (IL-2) signaling."
      explanation: >-
        States the biallelic germline loss-of-function mechanism and its
        functional consequence for Treg biology.
      quote_role: BACKGROUND
  - name: c.166delC (p.R56fs)
    description: >-
      Novel homozygous frameshift allele in two siblings from one family, both
      of whom were transplanted. Nomenclature follows the source.
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:41659858
      reference_title: "Expanding the clinical spectrum of interleukin-2 receptor alpha chain deficiency: two novel cases with long-term hematopoietic stem cell transplantation outcome and literature review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Genetic analysis revealed a novel homozygous frameshift variant in IL2RA (c.166delC; p.R56fs)."
      explanation: Reports the frameshift allele in the sibling pair.
  - name: c.65-2A>G
    description: >-
      Homozygous canonical splice-acceptor substitution in one Moroccan family, reported as likely pathogenic. RNA splicing was predicted but not directly assayed; no exact exon consequence is inferred here.
    clinical_significance: LIKELY_PATHOGENIC
    evidence:
    - reference: PMID:41694357
      reference_title: "Case Report: IL2RA (CD25) deficiency: first reported cases in Morocco."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Targeted next-generation sequencing identified two novel IL2RA variants: a splice-site mutation (c.65-2A>G) and a multi-exon deletion (c.557_795-1625del), both leading to loss of functional CD25."
      explanation: >-
        Reports the splice-site allele and, in the same sentence, the structural
        null allele curated below.
  - name: c.557_795-1625del
    description: >-
      Homozygous multi-exon deletion in a second, unrelated Moroccan family, detected by NGS read depth and reported as pathogenic. The source describes partial exon 4 and exons 5–7 involvement; its HGVS notation is retained as reported, without claiming independently resolved breakpoints or measured nonsense-mediated decay.
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:41694357
      reference_title: 'Case Report: IL2RA (CD25) deficiency: first reported cases in Morocco.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: For Case 2, NGS read-depth analysis identified a homozygous multi-exon deletion in IL2RA, corresponding at the cDNA level to c.557_795-1625del.
      explanation: Read-depth evidence for a multi-exon deletion; no priority claim over other structural alleles.
  - name: c.497G>A (p.Ser166Asn)
    description: Homozygous missense allele with absent surface CD25 but preserved intracellular protein and transcript in activated patient T cells.
    evidence:
    - reference: PMID:23416241
      reference_title: Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: The patient was homozygous for a c.497G>A transition in exon 4, leading to an amino acid substitution at codon 166 (S166N) of the protein.
      explanation: Homozygous missense allele with absent surface CD25 but preserved intracellular protein and transcript in activated patient T cells.
  - name: c.504C>A (p.Cys168Ter)
    description: Homozygous nonsense allele reported as likely pathogenic in a child with granulomatous hepatitis. Protein truncation and degradation were predicted; surface expression was not directly assayed in that report.
    evidence:
    - reference: PMID:35968218
      reference_title: 'Granulomatous hepatitis in a Saudi child with IL2RA defect: a case report and literature review.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: we observed a novel, homozygous, and likely pathogenic c.504 C>A variant located in the exon 4 region of the IL2RA gene
      explanation: Homozygous nonsense allele reported as likely pathogenic in a child with granulomatous hepatitis. Protein truncation and degradation were predicted; surface expression was not directly assayed in that report.
    clinical_significance: LIKELY_PATHOGENIC
  - name: c.64+1G>A
    description: Homozygous canonical splice-donor variant in the Pakistani patient with enteropathy and metabolic decompensation; classified as likely pathogenic by the authors.
    evidence:
    - reference: PMID:36195682
      reference_title: Whole exome sequencing identified a novel splice donor site variant in interleukin 2 receptor alpha chain.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Clinical whole exome sequencing revealed a novel splice donor site variant (NM_001378789.1 (NP_001365718); c.64 + 1G > A) in the IL-2Rα gene.
      explanation: Homozygous canonical splice-donor variant in the Pakistani patient with enteropathy and metabolic decompensation; classified as likely pathogenic by the authors.
    clinical_significance: LIKELY_PATHOGENIC
  - name: p.Trp177Ter and c.800delA in trans
    description: Compound heterozygous alleles in three siblings used for gene-correction studies. The figure legend and ClinGen identify c.530G>A for p.Trp177Ter; some main-text passages reverse this substitution. The final-exon deletion causes a frameshift with an extended C terminus and residual surface expression.
    evidence:
    - reference: PMID:29995861
      reference_title: Reprogramming human T cell function and specificity with non-viral genome targeting.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: The mother possessed a single heterozygous mutation (c.530G>A) in exon 4 of IL2RA, resulting in a premature stop codon.
      explanation: Compound heterozygous alleles in three siblings used for gene-correction studies. The figure legend and ClinGen identify c.530G>A for p.Trp177Ter; some main-text passages reverse this substitution. The final-exon deletion causes a frameshift with an extended C terminus and residual surface expression.
  - name: Whole-gene deletion
    description: A homozygous whole-gene deletion was among the five newly identified individuals in the diabetes series; this expands the structural-variant class beyond the Moroccan multi-exon allele.
    evidence:
    - reference: PMID:41758964
      reference_title: Biallelic Pathogenic Variants in IL2RA Cause Neonatal-Onset Monogenic Autoimmune Diabetes.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Four were homozygous (two protein-truncating, one whole-gene deletion, one missense), and one was compound heterozygous for a protein-truncating and a missense variant.
      explanation: A homozygous whole-gene deletion was among the five newly identified individuals in the diabetes series; this expands the structural-variant class beyond the Moroccan multi-exon allele.
  evidence:
  - reference: PMID:9096364
    reference_title: Human immune disorder arising from mutation of the alpha chain of the interleukin-2 receptor.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe here a novel human immune aberration arising from a truncation mutation of the interleukin-2 receptor alpha chain (CD25), a subunit of the tripartite high-affinity receptor for interleukin 2."
    explanation: >-
      The founding report establishing that a mutation of the IL-2 receptor alpha
      chain causes a human immune disorder.
  - reference: PMID:41758964
    reference_title: Biallelic Pathogenic Variants in IL2RA Cause Neonatal-Onset Monogenic Autoimmune Diabetes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: We found no evidence that heterozygous IL2RA protein-truncating variants or putatively damaging missense variants are at increased risk of features of IMD41, including diabetes
    explanation: Rare-variant burden tests in 401,535 European-ancestry UK Biobank participants were negative after correction; distinct from common susceptibility alleles.
  gene_disease_validity:
  - validity_classification: DEFINITIVE
    classified_by: CLINGEN
    external_id: CGGV:assertion_7d977a16-0957-458b-86be-2245d3953453
    evidence:
    - reference: url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7d977a16-0957-458b-86be-2245d3953453
      reference_title: curation results for Gene-Disease Validity
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: there is definitive evidence supporting the relationship between ... and autosomal recessive immunodeficiency due to CD25 deficiency.
      explanation: ClinGen PIRD classification dated February 5, 2025, with a Monogenic Diabetes amendment approved April 30, 2025.
pathophysiology:
- name: IL2RA Coding Substitutions
  description: Coding missense or nonsense substitutions alter the IL2RA protein sequence. Surface expression and functional consequences are allele dependent.
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:23416241
    reference_title: Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The patient was homozygous for a c.497G>A transition in exon 4, leading to an amino acid substitution at codon 166 (S166N) of the protein.
    explanation: Sequence-confirmed homozygous missense allele.
  - reference: PMID:35968218
    reference_title: 'Granulomatous hepatitis in a Saudi child with IL2RA defect: a case report and literature review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: we observed a novel, homozygous, and likely pathogenic c.504 C>A variant located in the exon 4 region of the IL2RA gene
    explanation: Sequence-confirmed nonsense allele; downstream degradation is predicted.
  role: trigger
  gene:
    preferred_term: IL2RA
    term:
      id: hgnc:6008
      label: IL2RA
  genetic_context:
    gene:
      preferred_term: IL2RA
      term:
        id: hgnc:6008
        label: IL2RA
    variant_type: single nucleotide variant
    variant_origin: GERMLINE
    notes: Biallelic disease genotypes may be homozygous or compound heterozygous; no single zygosity is imposed on this variant class.
    genomic_contexts:
    - coding sequence
  downstream:
  - target: Reduced Surface CD25 Availability
    description: Allele-specific loss of protein production or surface localization lowers functional CD25 availability. RNA/protein effects are measured for some alleles and predicted for others.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: IL2RA Splice-Site Substitutions
  description: Canonical splice-site substitutions perturb IL2RA RNA processing. The c.64+1G>A donor and c.65-2A>G acceptor variants have predicted consequences without direct patient RNA validation in those reports.
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:36195682
    reference_title: Whole exome sequencing identified a novel splice donor site variant in interleukin 2 receptor alpha chain.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Clinical whole exome sequencing revealed a novel splice donor site variant (NM_001378789.1 (NP_001365718); c.64 + 1G > A) in the IL-2Rα gene.
    explanation: Physical splice-donor substitution.
  - reference: PMID:41694357
    reference_title: "Case Report: IL2RA (CD25) deficiency: first reported cases in Morocco."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Targeted next-generation sequencing identified two novel IL2RA variants: a splice-site mutation (c.65-2A>G) and a multi-exon deletion (c.557_795-1625del), both leading to loss of functional CD25."
    explanation: >-
      Reports the splice-site allele and, in the same sentence, the structural
      null allele curated below.
  role: trigger
  gene:
    preferred_term: IL2RA
    term:
      id: hgnc:6008
      label: IL2RA
  genetic_context:
    gene:
      preferred_term: IL2RA
      term:
        id: hgnc:6008
        label: IL2RA
    variant_type: single nucleotide variant
    variant_origin: GERMLINE
    notes: Biallelic disease genotypes may be homozygous or compound heterozygous; no single zygosity is imposed on this variant class.
    genomic_contexts:
    - intron
  downstream:
  - target: Reduced Surface CD25 Availability
    description: Allele-specific loss of protein production or surface localization lowers functional CD25 availability. RNA/protein effects are measured for some alleles and predicted for others.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: IL2RA Coding Frameshift Deletions
  description: Small coding deletions shift the IL2RA reading frame. Consequences include premature termination or a final-exon run-on; nonsense-mediated decay is not universal.
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:41659858
    reference_title: "Expanding the clinical spectrum of interleukin-2 receptor alpha chain deficiency: two novel cases with long-term hematopoietic stem cell transplantation outcome and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic analysis revealed a novel homozygous frameshift variant in IL2RA (c.166delC; p.R56fs)."
    explanation: Reports the frameshift allele in the sibling pair.
  - reference: PMID:29995861
    reference_title: Reprogramming human T cell function and specificity with non-viral genome targeting.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The second mutation identified, c.800delA, causes a frameshift in the reading frame of the final IL2RA exon.
    explanation: A final-exon deletion has a different transcript consequence from an early truncating allele.
  role: trigger
  gene:
    preferred_term: IL2RA
    term:
      id: hgnc:6008
      label: IL2RA
  genetic_context:
    gene:
      preferred_term: IL2RA
      term:
        id: hgnc:6008
        label: IL2RA
    variant_type: deletion
    variant_origin: GERMLINE
    notes: Biallelic disease genotypes may be homozygous or compound heterozygous; no single zygosity is imposed on this variant class.
    genomic_contexts:
    - coding sequence
  downstream:
  - target: Reduced Surface CD25 Availability
    description: Allele-specific loss of protein production or surface localization lowers functional CD25 availability. RNA/protein effects are measured for some alleles and predicted for others.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: IL2RA Coding Frameshift Duplication
  description: The Caudy maternal allele is a one-base coding duplication, represented as c.692dup in current ClinGen notation and historically as an adenine insertion after position 692. It shifts the reading frame; the compound-heterozygous paternal allele is a nonsense substitution.
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7d977a16-0957-458b-86be-2245d3953453
    reference_title: curation results for Gene-Disease Validity
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Sequence trace of maternal allele showing single adenine insertion ... after position 692
    explanation: ClinGen abstracts the Caudy allele, normalized as c.692dup.
  role: trigger
  gene:
    preferred_term: IL2RA
    term:
      id: hgnc:6008
      label: IL2RA
  genetic_context:
    gene:
      preferred_term: IL2RA
      term:
        id: hgnc:6008
        label: IL2RA
    variant_type: duplication
    variant_origin: GERMLINE
    notes: Biallelic disease genotypes may be homozygous or compound heterozygous; no single zygosity is imposed on this variant class.
    genomic_contexts:
    - coding sequence
  downstream:
  - target: Reduced Surface CD25 Availability
    description: Allele-specific loss of protein production or surface localization lowers functional CD25 availability. RNA/protein effects are measured for some alleles and predicted for others.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: IL2RA Exon-Level Deletions
  description: Deletions remove multiple exons or the whole IL2RA gene. These are physically distinct from single-base coding indels.
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:41694357
    reference_title: 'Case Report: IL2RA (CD25) deficiency: first reported cases in Morocco.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: For Case 2, NGS read-depth analysis identified a homozygous multi-exon deletion in IL2RA, corresponding at the cDNA level to c.557_795-1625del.
    explanation: Read-depth evidence for a multi-exon deletion; no priority claim over other structural alleles.
  - reference: PMID:41758964
    reference_title: Biallelic Pathogenic Variants in IL2RA Cause Neonatal-Onset Monogenic Autoimmune Diabetes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Four were homozygous (two protein-truncating, one whole-gene deletion, one missense), and one was compound heterozygous for a protein-truncating and a missense variant.
    explanation: Whole-gene deletion in the diabetes-ascertained series.
  role: trigger
  gene:
    preferred_term: IL2RA
    term:
      id: hgnc:6008
      label: IL2RA
  genetic_context:
    gene:
      preferred_term: IL2RA
      term:
        id: hgnc:6008
        label: IL2RA
    variant_type: deletion
    variant_origin: GERMLINE
    notes: Biallelic disease genotypes may be homozygous or compound heterozygous; no single zygosity is imposed on this variant class.
  downstream:
  - target: Reduced Surface CD25 Availability
    description: Allele-specific loss of protein production or surface localization lowers functional CD25 availability. RNA/protein effects are measured for some alleles and predicted for others.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Reduced Surface CD25 Availability
  description: CD25 is absent or markedly reduced at the cell surface. For S166N, intracellular protein and transcript persist while soluble CD25 is undetectable, supporting a localization defect. Final-exon frameshift alleles can retain low surface expression; complete absence is not universal.
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:23416241
    reference_title: Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Importantly, TCR activated CD4+ T cells of the patient expressed CD25 in the cytoplasm, as well as at the mRNA level
    explanation: Intracellular protein and RNA persist despite the surface deficit.
  - reference: PMID:29995861
    reference_title: Reprogramming human T cell function and specificity with non-viral genome targeting.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: three compound heterozygotes that express minimal amounts of IL2RA on the surface of the T cells
    explanation: Residual surface expression in a separate family.
  gene:
    preferred_term: IL2RA
    term:
      id: hgnc:6008
      label: IL2RA
  downstream:
  - target: Impaired High-Affinity IL-2 Capture
    description: Reduced CD25 at the cell membrane impairs high-affinity cytokine capture.
    causal_link_type: DIRECT
  - target: Defective Inducible IL-10 Production by CD4 T Cells
    description: The patient-cell association supports a CD25-dependent defect; the intervening signaling route was not isolated.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Persistent Cortical Thymocyte BCL2 Expression
    description: Observed in the founding case; the signal connecting CD25 loss to thymic BCL2 regulation was not resolved.
    causal_link_type: UNKNOWN
  - target: Impaired Peripheral Activation-Induced T Cell Death
    description: Null-mouse association; this route is not consistently demonstrated in human cells.
    causal_link_type: UNKNOWN
- name: Impaired High-Affinity IL-2 Capture
  description: CD25 supplies the ligand-capture component of the high-affinity IL-2 receptor and has no intrinsic signaling domain. Its loss reduces IL-2 binding by the high-affinity complex; the CD122/CD132 intermediate-affinity receptor remains functional.
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:19348914
    reference_title: IL-2- and CD25-dependent immunoregulatory mechanisms in the homeostasis of T-cell subsets.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: CD25, which, along with CD122 and gammac, confers high affinity binding to IL-2.
    explanation: Established receptor architecture explains the consequence of CD25 loss.
  - reference: PMID:23416241
    reference_title: Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: These data demonstrate that in the absence of cell surface CD25, CD122 and CD132 are functional in the patient's T cells.
    explanation: Preserved shared receptor-chain function limits the claim to high-affinity capture.
  role: central_effector
  gene:
    preferred_term: IL2RA
    term:
      id: hgnc:6008
      label: IL2RA
    modifier: LOSS_OF_FUNCTION
  molecular_functions:
  - preferred_term: interleukin-2 binding
    term:
      id: GO:0019976
      label: interleukin-2 binding
    modifier: DECREASED
  downstream:
  - target: Raised IL-2 Signaling Threshold with Deficient STAT5 Activation
    description: Loss of high-affinity capture raises the concentration required for downstream signaling.
    causal_link_type: DIRECT
  - target: Reduced Regulatory T Cell IL-2 Consumption
    description: Reduced cytokine capture may limit the Treg cytokine sink; direct human consumption measurements are lacking.
    causal_link_type: UNKNOWN
  - target: Impaired NK Cell Maturation
    description: Patient NK-cell phenotypes support a developmental requirement for the receptor, without isolating all intervening steps.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Raised IL-2 Signaling Threshold with Deficient STAT5 Activation
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    The IL-2 dose threshold for STAT5 phosphorylation is raised. In the S166N patient, CD4 cells remain less responsive than controls, whereas CD8 cells can approach control responses at high IL-2 concentrations. FOXP3-positive cells retain their relative sensitivity within the CD4 compartment. Preserved IL-15 responses demonstrate that this is not a general loss of STAT5 signaling.
  cell_types:
  - preferred_term: CD4-positive, alpha-beta T cell
    term:
      id: CL:0000624
      label: CD4-positive, alpha-beta T cell
  - preferred_term: CD8-positive, alpha-beta T cell
    term:
      id: CL:0000625
      label: CD8-positive, alpha-beta T cell
  biological_processes:
  - preferred_term: interleukin-2-mediated signaling pathway
    term:
      id: GO:0038110
      label: interleukin-2-mediated signaling pathway
    modifier: DECREASED
  evidence:
  - reference: PMID:23416241
    reference_title: Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "This data indicates that in the absence of CD25 surface expression 1) the threshold required for IL-2 signaling in all T cell subsets is raised, 2) CD4+FOXP3+ are the first to respond to IL-2 despite the absence of CD25, and 3) unlike in healthy donors, CD8+ T cells from CD25 null patients preferentially respond to IL-2 compared to CD4+FOXP3−."
    explanation: >-
      The authors' summary of the signaling defect, including the reordering that
      favours CD8+ cells over conventional CD4+ cells.
  - reference: PMID:23416241
    reference_title: Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The pSTAT5 levels in the patient's CD8+ T cells with high concentration of IL-2 were similar to the percentages of CD8+ T cells of healthy controls stimulated with high and medium concentrations.
    explanation: High-dose CD8 responsiveness is retained, unlike the more impaired CD4 response.
  downstream:
  - target: Impaired Regulatory T Cell Suppression
    description: Deficient IL-2 responsiveness compromises Treg function; genetic correction supports this relationship.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Reduced Relative Regulatory T Cell Representation
    description: A reduced fraction of total lymphocytes is observed in some settings, but its causal determinants and clinical importance remain uncertain.
    causal_link_type: UNKNOWN
  - target: Impaired Antigen-Specific T Cell Responses
    description: Altered priming and expansion are candidate intermediates in the impaired antigen response.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Impaired Regulatory T Cell Suppression
  description: FOXP3-positive Treg-like cells can remain present while their suppressive function is inadequate. In three compound heterozygous siblings, CD25-independent enrichment recovered FOXP3-rich cells with no suppressive activity in the assay. Gene correction restored suppressive activity in the later manufacturing study. This supports a functional lesion without requiring complete lineage absence.
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:29995861
    reference_title: Reprogramming human T cell function and specificity with non-viral genome targeting.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: CD3+CD4+CD127loCD45RO+TIGIT+ from the compound heterozygotes showed no suppressive ability.
    explanation: CD25-independent enrichment demonstrated a functional deficit in patient cells.
  - reference: PMID:41376159
    reference_title: Gene-corrected regulatory T cell therapy for IL2RA deficiency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The resulting gcTregs demonstrated robust suppressive activity in vitro.
    explanation: Corrected cells suppress in vitro; no clinical efficacy is inferred.
  cell_types:
  - preferred_term: FOXP3-positive regulatory T cell
    term:
      id: CL:0000815
      label: regulatory T cell
  downstream:
  - target: Loss of Peripheral Immune Tolerance
    description: Impaired regulation permits immune dysregulation and autoimmunity.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Reduced Relative Regulatory T Cell Representation
  description: A reduced Treg share of the total T-cell or lymphocyte compartment can coexist with preserved or elevated proportions within purified CD4 cells. The S166N patient had TSDR-confirmed Tregs. Counts depend on denominator and marker selection; CD25-based gates cannot establish absence of CD25-negative FOXP3-positive Tregs.
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:23416241
    reference_title: Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Overall these results indicated that peripheral Tregs were present in the patient despite the absence of a functional CD25, albeit at an overall reduced level in total lymphocytes.
    explanation: Relative representation differs from absence of the lineage.
  cell_types:
  - preferred_term: FOXP3-positive regulatory T cell
    term:
      id: CL:0000815
      label: regulatory T cell
  downstream:
  - target: Decreased Regulatory T Cell Proportion
    description: The phenotype records relative abundance and its assay limitations.
    causal_link_type: DIRECT
- name: Defective Inducible IL-10 Production by CD4 T Cells
  description: A CD25-deficient patient had impaired IL-10 production after CD3/CD46 stimulation of CD4 lymphocytes, unlike a FOXP3-deficient comparator. This is an induced CD4-cell assay, not a universal absence of circulating IL-10 or a measurement restricted to natural Tregs; serum IL-10 was elevated in the S166N patient.
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:17196245
    reference_title: CD25 deficiency causes an immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like syndrome, and defective IL-10 expression from CD4 lymphocytes.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: This patient exhibited defective IL-10 expression from CD4 lymphocytes, whereas a Foxp3-deficient patient expressed normal levels of IL-10.
    explanation: Stimulated isolated CD4-cell experiment.
  - reference: PMID:23416241
    reference_title: Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: This data demonstrates that the production of all cytokines tested was not impaired despite the absence of CD25 surface expression
    explanation: Serum panel included IL-10; circulating abundance differs from induced CD4 secretion.
  cell_types:
  - preferred_term: CD4-positive, alpha-beta T cell
    term:
      id: CL:0000624
      label: CD4-positive, alpha-beta T cell
  biological_processes:
  - preferred_term: interleukin-10 production
    term:
      id: GO:0032613
      label: interleukin-10 production
    modifier: DECREASED
  downstream:
  - target: Loss of Peripheral Immune Tolerance
    description: Reduced inducible regulatory cytokine production may contribute, but its independent contribution is unresolved.
    causal_link_type: UNKNOWN
- name: Reduced Regulatory T Cell IL-2 Consumption
  description: Failure of high-affinity IL-2 uptake by Tregs is a proposed contributor to accumulation of extracellular cytokine and effector-cell expansion. Human studies demonstrate altered receptor availability and elevated serum cytokines but do not directly quantify the Treg IL-2 consumption deficit.
  biological_scale: CELLULAR
  mechanism_confidence: HYPOTHETICAL
  evidence:
  - reference: PMID:23416241
    reference_title: Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
    snippet: Likely, the most affected function due to CD25 deficiency by FOXP3+ Tregs is the consumption of IL-2.
    explanation: Author hypothesis from patient and prior mouse evidence, not a direct consumption assay.
  cell_types:
  - preferred_term: FOXP3-positive regulatory T cell
    term:
      id: CL:0000815
      label: regulatory T cell
  downstream:
  - target: Elevated Cytokine Availability
    description: Reduced consumption is one possible contributor; persistent infection and inflammatory production also contribute.
    causal_link_type: UNKNOWN
- name: Elevated Cytokine Availability
  description: The S166N patient had elevated circulating innate and adaptive cytokines, including IL-2, with active STAT3/STAT5 signaling in blood T cells. The relative contributions of impaired consumption, inflammation and chronic infection are unresolved.
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:23416241
    reference_title: Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: all cytokines tested was not impaired despite the absence of CD25 surface expression, suggesting that high cytokine levels found in circulation may sustain proliferation in vivo.
    explanation: Observed cytokine excess supports, but does not prove, cytokine-driven expansion.
  downstream:
  - target: CD8 T Cell Expansion
    description: Residual receptor signaling in a cytokine-rich environment may favor CD8 expansion; this is not proof of antigen-specific autoreactivity.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Persistent Cortical Thymocyte BCL2 Expression
  description: The founding patient lacked normal downregulation of BCL2 in cortical thymocytes, alongside absent CD1 and abnormal thymic architecture. This was a thymus-specific observation, not a universal peripheral T-cell phenotype.
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:9096364
    reference_title: Human immune disorder arising from mutation of the alpha chain of the interleukin-2 receptor.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: CD25-deficient cortical thymocytes do not express CD1, and furthermore they fail to normally down-regulate levels of the anti-apoptotic protein bcl-2.
    explanation: Human thymic immunohistochemistry.
  cell_types:
  - preferred_term: thymocyte
    term:
      id: CL:0000893
      label: thymocyte
  downstream:
  - target: Impaired Thymocyte Apoptosis
    description: Persistent anti-apoptotic BCL2 provides a plausible route to reduced thymic deletion.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Impaired Thymocyte Apoptosis
  description: Reduced thymic apoptosis is described in the follow-up account of the founding patient. Escape of autoreactive clones is a proposed consequence; the 1997 report inferred inefficient negative selection from BCL2 and CD1 staining rather than directly testing the escaped repertoire.
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:10879793
    reference_title: Human IL-2 receptor alpha chain deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: apoptosis in the thymus is markedly reduced
    explanation: Follow-up description of the thymic finding; distinct from peripheral activation-induced death.
  biological_processes:
  - preferred_term: thymocyte apoptotic process
    term:
      id: GO:0070242
      label: thymocyte apoptotic process
    modifier: DECREASED
  cell_types:
  - preferred_term: thymocyte
    term:
      id: CL:0000893
      label: thymocyte
  downstream:
  - target: Loss of Peripheral Immune Tolerance
    description: Escape of autoreactive cells from thymic selection is proposed, not established across all patients.
    causal_link_type: UNKNOWN
- name: Impaired Peripheral Activation-Induced T Cell Death
  description: 'Impaired activation-induced death correlates with polyclonal expansion in the Il2ra-null mouse. Its contribution to human disease is unresolved: the founding patient could not be tested after transplantation, and the S166N study found no disruption of peripheral CD8 intrinsic or extrinsic apoptotic pathways.'
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:7584142
    reference_title: Interleukin-2 receptor alpha chain regulates the size and content of the peripheral lymphoid compartment.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: polyclonal T and B cell expansion, which, for T cells, is correlated with impaired activation-induced cell death in vivo.
    explanation: Mouse finding supports a candidate mechanism.
  - reference: PMID:23416241
    reference_title: Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity.
    supports: REFUTE
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: intrinsic and extrinsic apoptotic pathways in CD8+ T cells were not disrupted in the patient carrying CD25 mutation.
    explanation: Patient-specific negative result limits a universal peripheral apoptosis mechanism.
  biological_processes:
  - preferred_term: activation-induced cell death of T cells
    term:
      id: GO:0006924
      label: activation-induced cell death of T cells
    modifier: DECREASED
  downstream:
  - target: CD8 T Cell Expansion
    description: Impaired contraction may contribute in models; a general human causal contribution is unproven.
    causal_link_type: UNKNOWN
- name: CD8 T Cell Expansion
  description: In the S166N patient, activated memory CD8 cells expanded and proliferated in vivo despite poor antigen-specific responses. Cytokine-driven proliferation is proposed; neither universal apoptosis failure nor proven self-antigen specificity is required by the data.
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:23416241
    reference_title: Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: an increase in Ki-67 expression was more prominent in CD8+ T cells than CD4+ T cells for all time points detected
    explanation: Observed preferential CD8 proliferation.
  cell_types:
  - preferred_term: CD8-positive, alpha-beta T cell
    term:
      id: CL:0000625
      label: CD8-positive, alpha-beta T cell
  biological_processes:
  - preferred_term: T cell proliferation
    term:
      id: GO:0042098
      label: T cell proliferation
    modifier: INCREASED
  downstream:
  - target: Lymphocytic Tissue Infiltration
    description: Activated cells may accumulate in tissues; migration and antigen specificity were not independently resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Inverted CD4:CD8 Ratio
    description: Preferential CD8 expansion can invert the ratio in affected patients.
    causal_link_type: DIRECT
- name: Impaired Antigen-Specific T Cell Responses
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Antigen-specific proliferation and CMV-induced IFN-gamma production were impaired in the S166N patient. IL-2/IL-15 partially rescued polyclonal activation but did not rescue CMV-specific responses. Mitogen responses vary across patients: the Y41S report described a preserved PHA response, so a poor result is supportive but not obligatory.
  cell_types:
  - preferred_term: CD4-positive, alpha-beta T cell
    term:
      id: CL:0000624
      label: CD4-positive, alpha-beta T cell
  biological_processes:
  - preferred_term: T cell proliferation
    term:
      id: GO:0042098
      label: T cell proliferation
    modifier: DECREASED
  evidence:
  - reference: PMID:23416241
    reference_title: Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Similarly, the patient's PBMCs did not produce IFNγ upon CMV activation, as determined by ELISPOT assay."
    explanation: >-
      A specific measured failure of the antigen-specific response against the
      virus these patients cannot clear.
  - reference: PMID:23416241
    reference_title: Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The addition of high concentrations of IL-2 or IL-15 did not rescue IFNγ production
    explanation: Negative rescue result for the CMV assay, not evidence against partial rescue of polyclonal responses.
  downstream:
  - target: Recurrent and Persistent Viral, Bacterial and Fungal Infection
    causal_link_type: DIRECT
    description: >-
      Failure of antigen-specific expansion leaves patients unable to clear
      opportunistic organisms.
    evidence:
    - reference: PMID:24116927
      reference_title: Follicular bronchiolitis as phenotype associated with CD25 deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "its importance in the development of a normal immune response is emphasized by the finding that a truncation mutant of CD25 results in an immunodeficiency in humans characterized by an increased susceptibility to viral, bacterial and fungal infections"
      explanation: >-
        States the edge from the CD25 defect to the broad infectious
        susceptibility.
  - target: Decreased Antigen-Specific T Cell Proliferation
    description: >-
      The proliferation failure is measured directly in the diagnostic
      laboratory.
    causal_link_type: DIRECT
- name: Impaired NK Cell Maturation
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    The Y41S patient had normal absolute NK counts but an excess of CD56brightCD16high cells, fewer terminally differentiated CD57-positive CD56dim cells, and persistent CD94/CD62L expression. These findings differ from the STAT5B-deficient comparator. The clinical contribution of the maturation phenotype is unresolved.
  cell_types:
  - preferred_term: natural killer cell
    term:
      id: CL:0000623
      label: natural killer cell
  evidence:
  - reference: PMID:29988287
    reference_title: Primary Immunodeficiencies Unravel the Role of IL-2/CD25/STAT5b in Human Natural Killer Cell Maturation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we observed that the absence of IL-2 signaling through CD25 promotes the accumulation of CD56brightCD16high NK cells"
    explanation: >-
      Reports the NK maturation abnormality measured in a CD25-deficient patient.
  downstream:
  - target: Reduced NK Cell IFN-Gamma Production
    description: The maturation and cytokine-response abnormalities coexist; mediation by a specific maturation step was not directly tested.
    causal_link_type: UNKNOWN
- name: Reduced NK Cell IFN-Gamma Production
  description: NK cells from the Y41S patient produced less IFN-gamma after cytokine stimulation. Perforin, granzyme B and K562-induced degranulation were increased, so the defect should not be generalized to reduced NK cytotoxic machinery.
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:29988287
    reference_title: Primary Immunodeficiencies Unravel the Role of IL-2/CD25/STAT5b in Human Natural Killer Cell Maturation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: CD56bright and CD56dim NK cells from the CD25-deficient patient produced less IFN-γ than CD56bright and CD56dim NK cells from the HD
    explanation: Stimulated patient NK-cell cytokine deficit.
  - reference: PMID:29988287
    reference_title: Primary Immunodeficiencies Unravel the Role of IL-2/CD25/STAT5b in Human Natural Killer Cell Maturation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: CD56bright and CD56dim NK cells from the CD25-deficient patient displayed an increased degranulation when compared to the HD
    explanation: Preserved or increased degranulation distinguishes cytokine production from cytotoxic readouts.
  cell_types:
  - preferred_term: natural killer cell
    term:
      id: CL:0000623
      label: natural killer cell
- name: Loss of Peripheral Immune Tolerance
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  description: >-
    Defective Treg suppression and altered immune homeostasis permit autoimmunity. Thymic selection abnormalities and impaired inducible IL-10 production may contribute in some patients. Polyclonal cytotoxic infiltration does not establish the self-antigen specificity of every expanded T cell.
  cell_types:
  - preferred_term: effector T cell
    term:
      id: CL:0000911
      label: effector T cell
  biological_processes:
  - preferred_term: peripheral tolerance induction
    term:
      id: GO:0002465
      label: peripheral tolerance induction
    modifier: DECREASED
  evidence:
  - reference: PMID:23416241
    reference_title: Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Activated CD8(+)STAT5(+) T cells with lytic potential infiltrated the skin, even though FOXP3(+) Tregs were present and maintained a higher capacity to respond to IL-2 compared to other T-cell subsets."
    explanation: >-
      Shows tolerance failing in tissue despite the presence of FOXP3+ Tregs,
      the substance of this node.
  downstream:
  - target: Multi-Organ Autoimmune Attack
    causal_link_type: DIRECT
    description: >-
      Unrestrained autoreactive lymphocytes produce organ-directed autoimmunity.
    evidence:
    - reference: PMID:41694357
      reference_title: "Case Report: IL2RA (CD25) deficiency: first reported cases in Morocco."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The immunopathology likely reflects uncontrolled activation and expansion of autoreactive T cells that lack regulation by Tregs (11, 12)."
      explanation: >-
        States the edge from unregulated autoreactive T cells to the
        immunopathology of the disease.
- name: Multi-Organ Autoimmune Attack
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  description: >-
    Immune-mediated injury varies across gut, skin, thyroid, pancreatic islets, liver and blood cells. Autoantibodies support an autoimmune basis for diabetes and some other manifestations, but pancreatic histology and direct beta-cell immune assays were not performed in the 2026 diabetes series. Tissue-specific mechanisms are incompletely resolved.
  evidence:
  - reference: PMID:41659858
    reference_title: "Expanding the clinical spectrum of interleukin-2 receptor alpha chain deficiency: two novel cases with long-term hematopoietic stem cell transplantation outcome and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Affected patients often present with an array of symptoms in infancy or early childhood, including enteropathy, severe eczema, autoimmune cytopenias, type 1 diabetes mellitus, thyroiditis, lymphadenopathy, hepatosplenomegaly, and recurrent infections."
    explanation: >-
      Lists the organ-directed autoimmune manifestations that constitute this
      node in the reviewed case series.
  downstream:
  - target: Autoimmune Enteropathy with Chronic Diarrhea
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Clinical immune-mediated organ involvement is supported; the precise cellular route is incompletely defined.
  - target: Villous Atrophy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Clinical immune-mediated organ involvement is supported; the precise cellular route is incompletely defined.
  - target: Eczematous Dermatitis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Clinical immune-mediated organ involvement is supported; the precise cellular route is incompletely defined.
  - target: Early-Onset Autoimmune Diabetes Mellitus
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Clinical immune-mediated organ involvement is supported; the precise cellular route is incompletely defined.
  - target: Autoimmune Thyroiditis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Clinical immune-mediated organ involvement is supported; the precise cellular route is incompletely defined.
  - target: Autoimmune Hepatitis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Clinical immune-mediated organ involvement is supported; the precise cellular route is incompletely defined.
  - target: Autoimmune Cytopenia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Clinical immune-mediated organ involvement is supported; the precise cellular route is incompletely defined.
  - target: Alopecia Universalis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Clinical immune-mediated organ involvement is supported; the precise cellular route is incompletely defined.
  - target: Pancolitis
    description: Immune-mediated gastrointestinal inflammation can extend throughout the colon.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Enteropathy-Associated Nutritional Compromise
    description: Intestinal immune injury can produce malabsorption.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Lymphocytic Tissue Infiltration
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  description: >-
    Lymphocytes infiltrate lung, liver, gut, skin and other tissues. CD8-positive proliferating granzyme-B-positive cells predominated in the S166N skin biopsy; that cellular composition should not be assigned to all organs or patients. Bronchiolar lymphoid follicles and hepatic noncaseating granulomas are distinct histologic manifestations.
  evidence:
  - reference: PMID:9096364
    reference_title: Human immune disorder arising from mutation of the alpha chain of the interleukin-2 receptor.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Extensive lymphocytic infiltration of tissues, including lung, liver, gut, and bone, is observed, accompanied by tissue atrophy and inflammation."
    explanation: >-
      Documents the multi-organ lymphocytic infiltration with tissue atrophy that
      defines this node.
  downstream:
  - target: Lymphadenopathy
    description: Lymphoid expansion can cause node enlargement.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Hepatosplenomegaly
    description: Lymphoid and inflammatory enlargement contributes in some patients.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Follicular Bronchiolitis
    description: Peribronchiolar lymphoid follicles were demonstrated in the affected lung.
    causal_link_type: DIRECT
- name: Recurrent and Persistent Viral, Bacterial and Fungal Infection
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  description: >-
    Patients acquire opportunistic and recurrent infections early in life, with
    cytomegalovirus the most consistently reported organism, alongside
    Epstein-Barr virus, Candida, adenovirus and Gram-negative bacteria. Because
    antigen-specific responses fail, cytomegalovirus infection tends to persist
    or relapse rather than clear.
  evidence:
  - reference: PMID:41659858
    reference_title: "Expanding the clinical spectrum of interleukin-2 receptor alpha chain deficiency: two novel cases with long-term hematopoietic stem cell transplantation outcome and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients typically present with opportunistic and recurrent infections, such as CMV, EBV, Candida, adenovirus, Pseudomonas, and Klebsiella, early in life."
    explanation: Names the organisms that make up the infectious phenotype.
  downstream:
  - target: Recurrent Viral Infections
  - target: Severe Cytomegalovirus Infection
  - target: Recurrent Bacterial Infections
  - target: Recurrent Fungal Infections
  - target: Bronchiectasis
    description: Repeated respiratory infections can contribute to structural airway damage; the source describes both, without isolating the contribution of immune-mediated lung inflammation.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Enteropathy-Associated Nutritional Compromise
  description: Chronic diarrhea, intestinal injury and malabsorption contribute to nutritional failure. Infection and chronic inflammation can add to the burden; growth failure is not attributable to one route in all patients.
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:41694357
    reference_title: 'Case Report: IL2RA (CD25) deficiency: first reported cases in Morocco.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: evaluation for persistent diarrhea and failure to thrive revealed malabsorption with villous atrophy on intestinal biopsy.
    explanation: Patient-specific malabsorption links intestinal disease to nutritional compromise.
  downstream:
  - target: Failure to Thrive
    description: Malabsorption and chronic illness can impair weight gain.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Short Stature
    description: Sustained nutritional and inflammatory burden can impair linear growth; endocrine contributions remain unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Hypokalemia
    description: Severe diarrhea can cause potassium loss; this is a plausible contributor during the reported enteropathy-associated crisis, without proving its sole cause.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Metabolic Acidosis
    description: Diarrheal bicarbonate loss and nutritional decompensation may contribute to acidosis during enteropathy; the individual contributions were not measured.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
phenotypes:
- category: Gastrointestinal
  name: Autoimmune Enteropathy with Chronic Diarrhea
  description: >-
    Chronic diarrhea and autoimmune or celiac-like enteropathy are prominent but not universal. Onset can be neonatal; malabsorption and growth failure may require nutritional support. Histologic injury and infectious involvement, including CMV, can coexist.
  phenotype_term:
    preferred_term: Chronic diarrhea of autoimmune enteropathy
    term:
      id: HP:0002028
      label: Chronic diarrhea
    temporality: CHRONIC
  evidence:
  - reference: PMID:23416241
    reference_title: Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient is an 8 year-old female born to consanguineous parents (first cousins) of Italian descent, who developed symptoms resembling IPEX, such as diffuse eczema and severe diarrhea, during her first month of life."
    explanation: Documents severe diarrhea from the first month of life.
  - reference: PMID:41694357
    reference_title: "Case Report: IL2RA (CD25) deficiency: first reported cases in Morocco."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both patients were born to first-cousin parents and presented in early childhood with recurrent respiratory and gastrointestinal infections, severe failure to thrive, chronic diarrhea with celiac-like enteropathy, and autoimmune manifestations including autoimmune hepatitis, dermatitis, and, in one case, autoimmune thyroiditis."
    explanation: >-
      Reports chronic diarrhea with a celiac-like enteropathy in both children of
      an independent family.
  phenotype_contexts:
  - population: Five newly identified diabetes-ascertained cases and 17 published cases in the 2026 diabetes study
    frequency: FREQUENT
    notes: Enteropathy was reported in 13/22. This selected literature aggregate is not a population penetrance estimate or a frequency for histologically proven autoimmune enteropathy alone.
    evidence:
    - reference: PMID:41758964
      reference_title: Biallelic Pathogenic Variants in IL2RA Cause Neonatal-Onset Monogenic Autoimmune Diabetes.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: enteropathy (n = 13 of 22)
      explanation: Study-specific enteropathy count.
- category: Gastrointestinal
  name: Villous Atrophy
  description: >-
    Villous atrophy is reported in several patients with enteropathy. Autoimmune injury, celiac-like presentations and superimposed infection must be distinguished; villous atrophy is not independently diagnostic of a single mechanism.
  phenotype_term:
    preferred_term: Villous atrophy
    term:
      id: HP:0011473
      label: Villous atrophy
  evidence:
  - reference: PMID:23416241
    reference_title: Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The enteropathy with severe villous atrophy was diagnosed as of autoimmune origin and complicated with CMV infection, which was treated by Gancyclovir, but became recurrent."
    explanation: >-
      Reports severe villous atrophy of autoimmune origin, and the recurrent
      cytomegalovirus infection that complicated it.
  - reference: PMID:41694357
    reference_title: "Case Report: IL2RA (CD25) deficiency: first reported cases in Morocco."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At 2 years, evaluation for persistent diarrhea and failure to thrive revealed malabsorption with villous atrophy on intestinal biopsy."
    explanation: Independent report of villous atrophy on biopsy.
- category: Dermatologic
  name: Eczematous Dermatitis
  description: >-
    Eczema is part of the IPEX-like triad here, can be extensive, and may persist
    despite immunosuppression.
  phenotype_term:
    preferred_term: Eczematous dermatitis
    term:
      id: HP:0000964
      label: Eczematoid dermatitis
  evidence:
  - reference: PMID:41659858
    reference_title: "Expanding the clinical spectrum of interleukin-2 receptor alpha chain deficiency: two novel cases with long-term hematopoietic stem cell transplantation outcome and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "RESULTS: Both patients presented with severe enteropathy, eczema, recurrent respiratory infections, growth failure, and features of allergic disease in early childhood."
    explanation: Reports eczema alongside enteropathy and growth failure in both siblings.
  - reference: PMID:23416241
    reference_title: Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "When she was 5 years old, she developed diffuse eczema and alopecia universalis despite the immunosuppressive therapies."
    explanation: >-
      Documents diffuse eczema, and records that it was refractory to
      immunosuppression.
- category: Endocrine
  name: Early-Onset Autoimmune Diabetes Mellitus
  description: >-
    Insulin-requiring autoimmune diabetes can present within days of birth or later in childhood. Four of five new cases in the 2026 diabetes-ascertained series presented in the first month and four presented with ketoacidosis. GAD antibodies were positive in all four tested individuals; serum was unavailable for the fifth. C-peptide was often low, but one patient had a preserved measurement at diagnosis.
  phenotype_term:
    preferred_term: Early-onset autoimmune diabetes mellitus
    term:
      id: HP:0100651
      label: Type I diabetes mellitus
  evidence:
  - reference: PMID:41758964
    reference_title: Biallelic Pathogenic Variants in IL2RA Cause Neonatal-Onset Monogenic Autoimmune Diabetes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Diabetes was the presenting feature in four of five individuals, all diagnosed within the first month of life.
    explanation: New series; remaining patient developed diabetes at eight years.
  - reference: PMID:41758964
    reference_title: Biallelic Pathogenic Variants in IL2RA Cause Neonatal-Onset Monogenic Autoimmune Diabetes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: GADA was positive in four of four patients tested, supporting an autoimmune etiology. Serum was unavailable for one patient.
    explanation: Full text corrects the abstract implication that all five were tested.
  phenotype_contexts:
  - population: Five new diabetes-ascertained individuals and 17 previously published cases
    frequency: FREQUENT
    notes: 14/22 had early-onset diabetes. Ascertainment through diabetes and case publication precludes a population penetrance estimate.
    evidence:
    - reference: PMID:41758964
      reference_title: Biallelic Pathogenic Variants in IL2RA Cause Neonatal-Onset Monogenic Autoimmune Diabetes.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Across all 22 reported individuals with biallelic IL2RA variants (5 new, 17 published) (Tables 1 and 2), 14 had early-onset diabetes.
      explanation: Explicit denominator and ascertainment context.
- category: Endocrine
  name: Autoimmune Thyroiditis
  description: >-
    Autoimmune thyroid disease, with anti-thyroperoxidase antibodies and
    hypothyroidism requiring hormone replacement in some patients.
  phenotype_term:
    preferred_term: Autoimmune thyroiditis
    term:
      id: HP:0100646
      label: Thyroiditis
  evidence:
  - reference: PMID:41758964
    reference_title: Biallelic Pathogenic Variants in IL2RA Cause Neonatal-Onset Monogenic Autoimmune Diabetes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients exhibited additional features of IMD41: four developed autoimmune thyroid disease, three had enteropathy, three had recurrent infections, and two had hepato/splenomegaly."
    explanation: >-
      Reports autoimmune thyroid disease in four of five newly identified
      patients.
  - reference: PMID:41694357
    reference_title: "Case Report: IL2RA (CD25) deficiency: first reported cases in Morocco."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thyroid function tests confirmed primary hypothyroidism (free T4 ~0.5 µg/dL, TSH >100 µIU/mL) with markedly elevated anti-thyroperoxidase antibodies (>600 IU/mL), consistent with autoimmune thyroiditis."
    explanation: >-
      Documents the biochemical and serological basis of autoimmune thyroiditis in
      one patient.
  phenotype_contexts:
  - population: New and previously reported cases in the 2026 diabetes study
    notes: Autoimmune thyroid disease, a broader category than antibody-confirmed thyroiditis, was reported in 8/22 selected cases.
    evidence:
    - reference: PMID:41758964
      reference_title: Biallelic Pathogenic Variants in IL2RA Cause Neonatal-Onset Monogenic Autoimmune Diabetes.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: autoimmune thyroid disease (n = 8 of 22)
      explanation: Study-specific thyroid-autoimmunity count.
- category: Hepatic
  name: Autoimmune Hepatitis
  description: Autoimmune hepatitis is one form of hepatic involvement. It was diagnosed in Moroccan Case 1; Case 2 had steatohepatitis. Granulomatous inflammation in the separate Saudi Cys168Ter patient had negative autoimmune serology and is recorded separately.
  phenotype_term:
    preferred_term: Autoimmune hepatitis
    term:
      id: HP:5210421
      label: Autoimmune hepatitis
  evidence:
  - reference: PMID:41694357
    reference_title: 'Case Report: IL2RA (CD25) deficiency: first reported cases in Morocco.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: She was also diagnosed with autoimmune hepatitis.
    explanation: Primary description of Moroccan Case 1, not both unrelated patients.
- category: Hematologic
  name: Autoimmune Cytopenia
  description: >-
    Immune-mediated destruction of blood cells, reported across the case series as
    part of the immune dysregulation phenotype.
  phenotype_term:
    preferred_term: Autoimmune cytopenia
    term:
      id: HP:5210419
      label: Autoimmune cytopenia
  evidence:
  - reference: PMID:41659858
    reference_title: "Expanding the clinical spectrum of interleukin-2 receptor alpha chain deficiency: two novel cases with long-term hematopoietic stem cell transplantation outcome and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "including enteropathy, severe eczema, autoimmune cytopenias, type 1 diabetes mellitus, thyroiditis, lymphadenopathy, hepatosplenomegaly, and recurrent infections"
    explanation: Lists autoimmune cytopenias among the recurring features.
- category: Dermatologic
  name: Alopecia Universalis
  description: >-
    Complete hair loss developed in one patient at age five, alongside diffuse
    eczema and despite ongoing immunosuppression.
  phenotype_term:
    preferred_term: Alopecia universalis
    term:
      id: HP:0002289
      label: Alopecia universalis
  evidence:
  - reference: PMID:23416241
    reference_title: Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "she developed diffuse eczema and alopecia universalis despite the immunosuppressive therapies"
    explanation: Reports alopecia universalis in a single patient.
- category: Immunological
  name: Lymphadenopathy
  description: >-
    Lymph node enlargement, sometimes episodic, reflecting the lymphoproliferative
    arm of the disease.
  phenotype_term:
    preferred_term: Lymphadenopathy
    term:
      id: HP:0002716
      label: Lymphadenopathy
  evidence:
  - reference: PMID:41694357
    reference_title: "Case Report: IL2RA (CD25) deficiency: first reported cases in Morocco."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "On examination, she had hepatomegaly, splenomegaly, and generalized lymphadenopathy (Table 1)."
    explanation: Documents generalized lymphadenopathy on examination.
- category: Immunological
  name: Hepatosplenomegaly
  description: >-
    Liver and spleen enlargement, reported both on examination and across the
    reviewed cases.
  phenotype_term:
    preferred_term: Hepatosplenomegaly
    term:
      id: HP:0001433
      label: Hepatosplenomegaly
  evidence:
  - reference: PMID:41694357
    reference_title: 'Case Report: IL2RA (CD25) deficiency: first reported cases in Morocco.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: On examination, she had hepatomegaly, splenomegaly, and generalized lymphadenopathy
    explanation: Primary examination findings in Moroccan Case 1.
- category: Respiratory
  name: Follicular Bronchiolitis
  description: >-
    Chronic severe inflammatory lung disease with follicular bronchiolitis and
    lymphocyte hyperplasia, reported in one patient and the pulmonary expression
    of lymphocytic tissue infiltration.
  phenotype_term:
    preferred_term: Follicular bronchiolitis
    term:
      id: HP:0033583
      label: Follicular bronchiolitis
  evidence:
  - reference: PMID:24116927
    reference_title: Follicular bronchiolitis as phenotype associated with CD25 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We present the first female Argentine patient with mutation in CD25 associated with chronic and severe inflammatory lung disease (follicular bronchiolitis with lymphocyte hyperplasia), eczema and infections."
    explanation: >-
      The report that established follicular bronchiolitis as a phenotype of this
      disease.
- category: Immunological
  name: Recurrent Viral Infections
  description: >-
    Repeated or persistent viral infection, with cytomegalovirus, Epstein-Barr
    virus and adenovirus the organisms most often named.
  phenotype_term:
    preferred_term: Recurrent viral infections
    term:
      id: HP:0004429
      label: Recurrent viral infections
  evidence:
  - reference: PMID:41659858
    reference_title: "Expanding the clinical spectrum of interleukin-2 receptor alpha chain deficiency: two novel cases with long-term hematopoietic stem cell transplantation outcome and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients typically present with opportunistic and recurrent infections, such as CMV, EBV, Candida, adenovirus, Pseudomonas, and Klebsiella, early in life."
    explanation: >-
      Names the recurrent viral organisms alongside the bacterial and fungal ones.
- category: Immunological
  name: Severe Cytomegalovirus Infection
  description: >-
    Cytomegalovirus infection that is severe, and persistent or relapsing rather
    than cleared, including cytomegalovirus pneumonitis in the earliest reported
    patients and recurrent reactivation requiring repeated ganciclovir.
  phenotype_term:
    preferred_term: Severe cytomegalovirus infection
    term:
      id: HP:0031692
      label: Severe cytomegalovirus infection
  evidence:
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC20340/
    reference_title: Human immune disorder arising from mutation of the α chain of the interleukin-2 receptor - PMC
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: suffering from cytomegalovirus (CMV) pneumonitis, persistent oral thrush, and
    explanation: Founding patient had CMV pneumonitis; isolated reactivation is not by itself evidence of severe disease.
- category: Immunological
  name: Recurrent Bacterial Infections
  description: >-
    Recurrent bacterial infection, chiefly respiratory, including repeated
    pneumonia.
  phenotype_term:
    preferred_term: Recurrent bacterial infections
    term:
      id: HP:0002718
      label: Recurrent bacterial infections
  evidence:
  - reference: PMID:41659858
    reference_title: 'Expanding the clinical spectrum of interleukin-2 receptor alpha chain deficiency: two novel cases with long-term hematopoietic stem cell transplantation outcome and literature review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: frequent episodes of otitis media and lower respiratory tract infections, which often required antibiotics.
    explanation: Recurrent respiratory infections in the younger Saudi sibling.
  - reference: PMID:23416241
    reference_title: Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: severe cellulitis caused by Staphylococcus aureus and Pseudomonas aeruginosa, requiring multiple antibiotic therapy.
    explanation: Documented bacterial skin infection in a separate patient.
- category: Immunological
  name: Recurrent Fungal Infections
  description: >-
    Fungal infection, with Candida oesophagitis and oral thrush among the
    reported episodes.
  phenotype_term:
    preferred_term: Recurrent fungal infections
    term:
      id: HP:0002841
      label: Recurrent fungal infections
  evidence:
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC20340/
    reference_title: Human immune disorder arising from mutation of the α chain of the interleukin-2 receptor - PMC
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: persistent oral thrush, and ... esophagitis at the age of 6 months.
    explanation: Founding patient had persistent oral and esophageal Candida involvement; HTML markup separates the organism name.
- category: Growth
  name: Failure to Thrive
  description: >-
    Severe failure to thrive and growth failure, driven by the enteropathy and the
    burden of recurrent infection.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:41694357
    reference_title: "Case Report: IL2RA (CD25) deficiency: first reported cases in Morocco."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "presented in early childhood with recurrent respiratory and gastrointestinal infections, severe failure to thrive, chronic diarrhea with celiac-like enteropathy"
    explanation: Severe growth failure in two unrelated Moroccan families.
- category: Laboratory
  name: Decreased Antigen-Specific T Cell Proliferation
  description: >-
    Impaired antigen-specific proliferation is documented in the S166N patient. Polyclonal mitogen responses are also often impaired but are variable: the Y41S report described a normal PHA response, so preserved mitogen proliferation does not exclude the diagnosis.
  phenotype_term:
    preferred_term: Decreased antigen-specific T cell proliferation
    term:
      id: HP:0031402
      label: Decreased antigen-specific T cell proliferation
  evidence:
  - reference: PMID:23416241
    reference_title: Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These results demonstrate that T cells from the CD25 null patient poorly respond to polyclonal mitogens and to microbial and viral ... despite the persistent in vivo exposure to CMV."
    explanation: >-
      Measures the impaired proliferative response to mitogens and to specific
      antigens.
- category: Laboratory
  name: Decreased Regulatory T Cell Proportion
  description: >-
    Relative Treg abundance can be low when normalized to all lymphocytes while remaining normal or elevated within CD4 cells. Apparent near-absence in studies using CD25-positive gates cannot distinguish loss of CD25 from loss of the FOXP3-positive lineage.
  phenotype_term:
    preferred_term: Decreased regulatory T cell proportion
    term:
      id: HP:0020113
      label: Decreased regulatory T cell proportion
  evidence:
  - reference: PMID:24116927
    reference_title: Follicular bronchiolitis as phenotype associated with CD25 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She has no expression of CD25 on CD4(+) T cells and an extremely low amount of Tregs ."
    explanation: The Y41S study reported few Tregs, but its CD25-dependent gates cannot measure the CD25-negative FOXP3-positive population. This does not establish lineage absence.
  - reference: PMID:23416241
    reference_title: Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Overall these results indicated that peripheral Tregs were present in the patient despite the absence of a functional CD25, albeit at an overall reduced level in total lymphocytes."
    explanation: >-
      The careful statement of the finding: Tregs present but reduced as a share of
      total lymphocytes, which is why this phenotype is a reduced proportion rather
      than an absence.
- category: Laboratory
  name: Inverted CD4:CD8 Ratio
  description: >-
    An inverted CD4:CD8 ratio occurs in some patients with preferential CD8 expansion, including the S166N patient and the younger Saudi sibling. The older sibling had a preserved ratio in the detailed laboratory results; inversion is not obligatory.
  phenotype_term:
    preferred_term: Inverted CD4:CD8 ratio
    term:
      id: HP:0033222
      label: Inverted CD4:CD8 ratio
  evidence:
  - reference: PMID:23416241
    reference_title: Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Profound alterations of the peripheral T cell subsets consisted of a complete skew towards increased CD8+ T cells over CD4+ T cells, expansion of the memory T cell compartments, with preservation of FOXP3+ T regulatory cells, whereas B cells and NK cells were persistently low."
    explanation: >-
      Characterises the CD8 skew in detail in the most fully immunophenotyped
      patient.
- category: Laboratory
  name: Increased Circulating Immunoglobulin Concentration
  description: >-
    Hypergammaglobulinemia, particularly increased IgG or IgA, occurs in several patients. Immunoglobulin quantity does not establish functional antibody competence; specific antibody defects and occasional low immunoglobulins or agammaglobulinemia are also reported.
  phenotype_term:
    preferred_term: Hypergammaglobulinemia
    term:
      id: HP:0010702
      label: Increased circulating immunoglobulin concentration
  evidence:
  - reference: PMID:41659858
    reference_title: "Expanding the clinical spectrum of interleukin-2 receptor alpha chain deficiency: two novel cases with long-term hematopoietic stem cell transplantation outcome and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Immunological evaluation revealed hypergammaglobulinemia, impaired T-cell proliferation, reduced CD19+ B cells, inverted CD4/CD8 ratio, and absence of CD25 expression."
    explanation: Reports hypergammaglobulinemia in both siblings.
- name: Bronchiectasis
  category: Respiratory
  description: Bilateral bronchiectasis was documented in the younger Saudi sibling with recurrent respiratory infections; it represents established pulmonary damage.
  phenotype_term:
    preferred_term: Bronchiectasis
    term:
      id: HP:0002110
      label: Bronchiectasis
  evidence:
  - reference: PMID:41659858
    reference_title: 'Expanding the clinical spectrum of interleukin-2 receptor alpha chain deficiency: two novel cases with long-term hematopoietic stem cell transplantation outcome and literature review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Chest high-resolution computed tomography showed bilateral bronchiectasis, indicative of chronic pulmonary damage.
    explanation: Bilateral bronchiectasis was documented in the younger Saudi sibling with recurrent respiratory infections; it represents established pulmonary damage.
- name: Asthma
  category: Respiratory
  description: Asthma is reported in both Saudi siblings and in the Argentine Y41S patient.
  phenotype_term:
    preferred_term: Asthma
    term:
      id: HP:0002099
      label: Asthma
  evidence:
  - reference: PMID:41659858
    reference_title: 'Expanding the clinical spectrum of interleukin-2 receptor alpha chain deficiency: two novel cases with long-term hematopoietic stem cell transplantation outcome and literature review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: including persistent bronchial asthma, allergic rhinitis, and adenoidal hypertrophy
    explanation: Asthma is reported in both Saudi siblings and in the Argentine Y41S patient.
- name: Allergic Rhinitis
  category: Respiratory
  description: Allergic rhinitis occurs in the Saudi sibling pair as part of their atopic manifestations.
  phenotype_term:
    preferred_term: Allergic rhinitis
    term:
      id: HP:0003193
      label: Allergic rhinitis
  evidence:
  - reference: PMID:41659858
    reference_title: 'Expanding the clinical spectrum of interleukin-2 receptor alpha chain deficiency: two novel cases with long-term hematopoietic stem cell transplantation outcome and literature review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: including persistent bronchial asthma, allergic rhinitis, and adenoidal hypertrophy
    explanation: Allergic rhinitis occurs in the Saudi sibling pair as part of their atopic manifestations.
- name: Food Allergy
  category: Immune
  description: Multiple food allergies were reported in the older Saudi sibling; the specific allergens were not enumerated.
  phenotype_term:
    preferred_term: Food allergy
    term:
      id: HP:0500093
      label: Food allergy
  evidence:
  - reference: PMID:41659858
    reference_title: 'Expanding the clinical spectrum of interleukin-2 receptor alpha chain deficiency: two novel cases with long-term hematopoietic stem cell transplantation outcome and literature review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: persistent diarrhea, failure to thrive, and multiple food allergies in her early childhood.
    explanation: Multiple food allergies were reported in the older Saudi sibling; the specific allergens were not enumerated.
- name: Urticaria
  category: Dermatologic
  description: Chronic urticaria episodes occurred in the older Saudi sibling.
  phenotype_term:
    preferred_term: Urticaria
    term:
      id: HP:0001025
      label: Urticaria
  evidence:
  - reference: PMID:41659858
    reference_title: 'Expanding the clinical spectrum of interleukin-2 receptor alpha chain deficiency: two novel cases with long-term hematopoietic stem cell transplantation outcome and literature review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: including asthma, allergic rhinitis, and chronic urticaria episodes.
    explanation: Chronic urticaria episodes occurred in the older Saudi sibling.
- name: Iron Deficiency Anemia
  category: Hematologic
  description: Iron-deficiency anemia is distinct from immune hemolysis and has been observed with chronic enteropathy and nutritional morbidity.
  phenotype_term:
    preferred_term: Iron deficiency anemia
    term:
      id: HP:0001891
      label: Iron deficiency anemia
  evidence:
  - reference: PMID:41659858
    reference_title: 'Expanding the clinical spectrum of interleukin-2 receptor alpha chain deficiency: two novel cases with long-term hematopoietic stem cell transplantation outcome and literature review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: along with iron deficiency anemia.
    explanation: Iron-deficiency anemia is distinct from immune hemolysis and has been observed with chronic enteropathy and nutritional morbidity.
- name: Short Stature
  category: Growth
  description: Marked linear growth failure was reported in the younger Saudi sibling, with poor response to growth-hormone treatment. This observation alone does not establish growth-hormone receptor resistance.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:41659858
    reference_title: 'Expanding the clinical spectrum of interleukin-2 receptor alpha chain deficiency: two novel cases with long-term hematopoietic stem cell transplantation outcome and literature review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: generalized osteopenia and short stature unresponsive to growth hormone therapy
    explanation: Marked linear growth failure was reported in the younger Saudi sibling, with poor response to growth-hormone treatment. This observation alone does not establish growth-hormone receptor resistance.
- name: Osteopenia
  category: Musculoskeletal
  description: Generalized osteopenia occurred in the younger Saudi sibling; nutritional, inflammatory and treatment contributions were not isolated.
  phenotype_term:
    preferred_term: Osteopenia
    term:
      id: HP:0000938
      label: Osteopenia
  evidence:
  - reference: PMID:41659858
    reference_title: 'Expanding the clinical spectrum of interleukin-2 receptor alpha chain deficiency: two novel cases with long-term hematopoietic stem cell transplantation outcome and literature review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: generalized osteopenia and short stature unresponsive to growth hormone therapy
    explanation: Generalized osteopenia occurred in the younger Saudi sibling; nutritional, inflammatory and treatment contributions were not isolated.
- name: Pancolitis
  category: Gastrointestinal
  description: Pancolitis with chronic active gastrointestinal inflammation was documented in the Cys168Ter patient.
  phenotype_term:
    preferred_term: Pancolitis
    term:
      id: HP:0033256
      label: Pancolitis
  evidence:
  - reference: PMID:35968218
    reference_title: 'Granulomatous hepatitis in a Saudi child with IL2RA defect: a case report and literature review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Pancolitis was found during colonoscopy and normal upper gastrointestinal endoscopy.
    explanation: Pancolitis with chronic active gastrointestinal inflammation was documented in the Cys168Ter patient.
- name: Nephrolithiasis
  category: Renal
  description: Bilateral small renal stones were found on serial imaging in the Cys168Ter patient; their mechanistic relationship to IL2RA deficiency is uncertain.
  phenotype_term:
    preferred_term: Nephrolithiasis
    term:
      id: HP:0000787
      label: Nephrolithiasis
  evidence:
  - reference: PMID:35968218
    reference_title: 'Granulomatous hepatitis in a Saudi child with IL2RA defect: a case report and literature review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Renal ultrasonography showed bilateral ... renal stones that were detected on serial imaging studies.
    explanation: Bilateral small renal stones were found on serial imaging in the Cys168Ter patient; their mechanistic relationship to IL2RA deficiency is uncertain.
- name: Digital Clubbing
  category: Extremities
  description: Digital clubbing accompanied chronic inflammatory illness in the Cys168Ter patient.
  phenotype_term:
    preferred_term: Clubbing
    term:
      id: HP:0001217
      label: Clubbing
  evidence:
  - reference: PMID:35968218
    reference_title: 'Granulomatous hepatitis in a Saudi child with IL2RA defect: a case report and literature review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: generalized lymphadenopathy of the cervical, axillary, and inguinal lymph nodes, accompanied by digital clubbing.
    explanation: Digital clubbing accompanied chronic inflammatory illness in the Cys168Ter patient.
- name: Metabolic Acidosis
  category: Metabolic
  description: Severe acidosis occurred during the Pakistani splice-donor patient's enteropathy-associated metabolic crisis; a separate inherited metabolic disorder was not demonstrated.
  phenotype_term:
    preferred_term: Metabolic acidosis
    term:
      id: HP:0001942
      label: Metabolic acidosis
  evidence:
  - reference: PMID:36195682
    reference_title: Whole exome sequencing identified a novel splice donor site variant in interleukin 2 receptor alpha chain.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The laboratory findings revealed severe metabolic acidosis hypokalemia and elevated lactate and ammonia levels.
    explanation: Severe acidosis occurred during the Pakistani splice-donor patient's enteropathy-associated metabolic crisis; a separate inherited metabolic disorder was not demonstrated.
- name: Hypokalemia
  category: Metabolic
  description: Hypokalemia occurred with severe diarrhea and metabolic decompensation in the Pakistani patient.
  phenotype_term:
    preferred_term: Hypokalemia
    term:
      id: HP:0002900
      label: Hypokalemia
  evidence:
  - reference: PMID:36195682
    reference_title: Whole exome sequencing identified a novel splice donor site variant in interleukin 2 receptor alpha chain.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The laboratory findings revealed severe metabolic acidosis hypokalemia and elevated lactate and ammonia levels.
    explanation: Hypokalemia occurred with severe diarrhea and metabolic decompensation in the Pakistani patient.
- name: Increased Circulating Lactate
  category: Metabolic
  description: Elevated lactate was reported during acute metabolic decompensation in one patient; it is not evidence of a primary mitochondrial disorder.
  phenotype_term:
    preferred_term: Increased circulating lactate concentration
    term:
      id: HP:0002151
      label: Increased circulating lactate concentration
  evidence:
  - reference: PMID:36195682
    reference_title: Whole exome sequencing identified a novel splice donor site variant in interleukin 2 receptor alpha chain.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The laboratory findings revealed severe metabolic acidosis hypokalemia and elevated lactate and ammonia levels.
    explanation: Elevated lactate was reported during acute metabolic decompensation in one patient; it is not evidence of a primary mitochondrial disorder.
- name: Hyperammonemia
  category: Metabolic
  description: Elevated ammonia was reported during acute metabolic decompensation in one patient; persistence and its immediate mechanism were not established.
  phenotype_term:
    preferred_term: Hyperammonemia
    term:
      id: HP:0001987
      label: Hyperammonemia
  evidence:
  - reference: PMID:36195682
    reference_title: Whole exome sequencing identified a novel splice donor site variant in interleukin 2 receptor alpha chain.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The laboratory findings revealed severe metabolic acidosis hypokalemia and elevated lactate and ammonia levels.
    explanation: Elevated ammonia was reported during acute metabolic decompensation in one patient; persistence and its immediate mechanism were not established.
- name: Decreased B Cell Count
  category: Laboratory
  description: Reduced circulating CD19-positive B cells occur in some patients, including the Saudi siblings and the S166N patient; other patients have normal counts.
  phenotype_term:
    preferred_term: Decreased total B cell count
    term:
      id: HP:0010976
      label: Decreased total B cell count
  evidence:
  - reference: PMID:41659858
    reference_title: 'Expanding the clinical spectrum of interleukin-2 receptor alpha chain deficiency: two novel cases with long-term hematopoietic stem cell transplantation outcome and literature review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Immunophenotyping showed a marked reduction in CD19+ B cell count (50/mm³)
    explanation: Reduced circulating CD19-positive B cells occur in some patients, including the Saudi siblings and the S166N patient; other patients have normal counts.
- name: Decreased Specific Antibody Response
  category: Laboratory
  description: Functional antibody responses may be impaired despite high total immunoglobulin levels. Protein responses were suboptimal in the older Saudi sibling; polysaccharide responses were impaired in the Y41S patient.
  phenotype_term:
    preferred_term: Decreased specific antibody response to vaccination
    term:
      id: HP:0032140
      label: Decreased specific antibody response to vaccination
  evidence:
  - reference: PMID:41659858
    reference_title: 'Expanding the clinical spectrum of interleukin-2 receptor alpha chain deficiency: two novel cases with long-term hematopoietic stem cell transplantation outcome and literature review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Functional antibody testing showed suboptimal responses to protein antigens. However, adequate responses to polysaccharide antigens were observed.
    explanation: Functional antibody responses may be impaired despite high total immunoglobulin levels. Protein responses were suboptimal in the older Saudi sibling; polysaccharide responses were impaired in the Y41S patient.
- name: Severe Dry Eye
  category: Ophthalmologic
  description: Severe dry eye is documented in the reported Turkish patient summarized in the later clinical review. Its relationship to specific immune mechanisms and treatment responses remains insufficiently characterized.
  phenotype_term:
    preferred_term: Severe dry eye
    term:
      id: HP:0001097
      label: Keratoconjunctivitis sicca
  evidence:
  - reference: PMID:41659858
    reference_title: 'Expanding the clinical spectrum of interleukin-2 receptor alpha chain deficiency: two novel cases with long-term hematopoietic stem cell transplantation outcome and literature review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Eczema, chronic diarrhea, hepatosplenomegaly, lymphadenopathy, and severe dry eyes
    explanation: Clinical literature table summarizes the ocular case.
treatments:
- name: Allogeneic Hematopoietic Stem Cell Transplantation
  description: >-
    Allogeneic HSCT can provide durable clinical and immune correction. The 2026 Saudi sibling study reports transplantation at 12 and 21 years, with sustained recovery at six and five years respectively. Treg enumeration was not performed, so restoration of that compartment is a mechanistic rationale rather than a directly measured result in those siblings. Reported risks include graft failure or rejection, viral reactivation and acute or chronic graft-versus-host disease; the diabetes series includes a death after transplantation.
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: allogeneic hematopoietic stem cell transplantation
    term:
      id: NCIT:C46089
      label: Allogeneic Hematopoietic Stem Cell Transplantation
  target_mechanisms:
  - target: Impaired Regulatory T Cell Suppression
    treatment_effect: RESTORES
    description: >-
      Donor-derived immune cells can restore functional CD25-dependent regulation; the precise contribution of Treg reconstitution was not quantified in the Saudi sibling study.
    evidence:
    - reference: PMID:41659858
      reference_title: "Expanding the clinical spectrum of interleukin-2 receptor alpha chain deficiency: two novel cases with long-term hematopoietic stem cell transplantation outcome and literature review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Hematopoietic stem cell transplantation (HSCT) remains the only curative treatment that aims to restore normal immune function by reconstituting a healthy Treg compartment."
      explanation: >-
        States the mechanism of benefit as reconstitution of the Treg compartment,
        which is what this link asserts.
      quote_role: BACKGROUND
  evidence:
  - reference: PMID:41659858
    reference_title: "Expanding the clinical spectrum of interleukin-2 receptor alpha chain deficiency: two novel cases with long-term hematopoietic stem cell transplantation outcome and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The younger sibling received marrow from a matched unrelated donor and achieved full donor chimerism with complete clinical and immunological recovery, remaining well 6 years after HSCT."
    explanation: Reports a long-term clinical and immunological recovery after transplant.
  - reference: PMID:30742970
    reference_title: "CD25 deficiency: A new conformational mutation prevents the receptor expression on cell surface."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The early clinical and molecular diagnosis of CD25 deficiency in this patient promptly led to hematopoietic stem cell transplantation (HSCT), allowing complete resolution of the symptoms and definitive cure of the disease."
    explanation: >-
      An independent report of cure after transplant, and the argument for early
      diagnosis.
  - reference: PMID:41376159
    reference_title: Gene-corrected regulatory T cell therapy for IL2RA deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Definitive treatment is currently limited to allogeneic hematopoietic stem cell transplantation, which carries significant morbidity and mortality risks."
    explanation: >-
      Confirms transplantation as the only definitive treatment while stating its
      risk, the reason alternatives are being developed.
    quote_role: BACKGROUND
  - reference: PMID:41659858
    reference_title: 'Expanding the clinical spectrum of interleukin-2 receptor alpha chain deficiency: two novel cases with long-term hematopoietic stem cell transplantation outcome and literature review.'
    supports: NO_EVIDENCE
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: regulatory T-cell (Treg) enumeration was not performed for both patients
    explanation: Explicit limitation on claims about measured Treg reconstitution.
- name: Sirolimus
  description: >-
    Sirolimus has been used as part of combination immunosuppression. In the S166N patient, skin lesions improved when rapamycin was added to mycophenolate; increased FOXP3-positive proportions were an associated observation. The Y41S patient improved on a regimen combining corticosteroids, rapamycin, IVIG and antibiotic prophylaxis. These uncontrolled combinations do not establish a sirolimus-specific effect or correction of the IL2RA defect.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: sirolimus
      term:
        id: CHEBI:9168
        label: sirolimus
  target_mechanisms:
  - target: Loss of Peripheral Immune Tolerance
    treatment_effect: INHIBITS
    description: >-
      Sirolimus suppresses the proliferation of activated autoreactive T cells,
      partially restraining the loss of tolerance.
  evidence:
  - reference: PMID:23416241
    reference_title: Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "improvement of the lesions was only seen when combined with rapamycin"
    explanation: >-
      Records the clinical response of the skin disease to rapamycin after other
      immunosuppression failed.
  - reference: PMID:23416241
    reference_title: Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, the highest percentage of CD4+FOXP3+ T cells (14.4%) was detected within three weeks of rapamycin treatment."
    explanation: >-
      An immunological correlate of the response, the rise in FOXP3+ cells on
      treatment.
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC3892414/
    reference_title: Follicular bronchiolitis as phenotype associated with CD25 deficiency - PMC
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: began immunosuppressive treatment with corticosteroids, antibiotic prophylaxis, rapamycin and intravenous gammaglobulin. Under this regimen her condition improved, and oxygen therapy was no longer necessary.
    explanation: Combination-regimen outcome; individual drug contribution cannot be isolated.
- name: Corticosteroid and Calcineurin Inhibitor Immunosuppression
  description: >-
    Corticosteroids, tacrolimus or cyclosporin A have been used to control immune-mediated manifestations while definitive treatment is considered. Mycophenolate alone had limited benefit for one patient's skin disease, whereas methotrexate had no benefit in that patient. Regimens are individualized and are not supported by comparative CD25-specific trials.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: corticosteroid
      term:
        id: CHEBI:50858
        label: corticosteroid
    - preferred_term: tacrolimus
      term:
        id: CHEBI:61049
        label: tacrolimus (anhydrous)
    - preferred_term: mycophenolate mofetil
      term:
        id: CHEBI:8764
        label: mycophenolate mofetil
    - preferred_term: cyclosporin A
      term:
        id: CHEBI:4031
        label: cyclosporin A
  target_mechanisms:
  - target: Loss of Peripheral Immune Tolerance
    treatment_effect: INHIBITS
    description: >-
      Broad suppression of T cell activation and proliferation dampens the
      autoimmune attack without correcting the receptor defect.
  evidence:
  - reference: PMID:23416241
    reference_title: Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient suffered from enteropathy until 5 years of age, often requiring parenteral nutrition and was treated with continuous combination therapy of steroids and Tacrolimus or Tacrolimus alone."
    explanation: >-
      Documents the steroid and tacrolimus regimen used for the enteropathy, and
      the parenteral nutrition curated as a separate treatment.
  - reference: PMID:23416241
    reference_title: Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Therefore, Mycophenolate Mophetil was given alone with limited improvement of skin lesions"
    explanation: >-
      Records mycophenolate mofetil use and its limited effect as monotherapy in
      that patient.
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC20340/
    reference_title: Human immune disorder arising from mutation of the α chain of the interleukin-2 receptor - PMC
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: treatment of the CD25-deficient patient with corticosteroids and cyclosporin A decreased inflammation and induced a dramatic reduction of lymphadenopathy and hepatosplenomegaly
    explanation: Clinical response in the founding case.
  - reference: PMID:23416241
    reference_title: Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Methotrexate was also started with no benefit.
    explanation: Negative clinical treatment observation.
- name: Antiviral Therapy and Anti-Infective Prophylaxis
  description: >-
    Reported supportive care includes ganciclovir for CMV reactivation and prophylaxis against Pneumocystis and fungal infection. Antibacterial prophylaxis and treatment of documented infections are also used. Regimens depend on infection history and immune status.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: antiviral therapy
    term:
      id: NCIT:C16119
      label: Antiviral Therapy
    therapeutic_agent:
    - preferred_term: ganciclovir
      term:
        id: CHEBI:465284
        label: ganciclovir
  evidence:
  - reference: PMID:23416241
    reference_title: Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additional therapies included prophylactic treatment, against Pneumocystis jiroveci and fungi, and Gancyclovir upon detection of CMV reactivation."
    explanation: >-
      Documents both the antiviral treatment and the anti-infective prophylaxis
      described here.
  target_phenotypes:
  - preferred_term: Severe cytomegalovirus infection
    term:
      id: HP:0031692
      label: Severe cytomegalovirus infection
- name: Parenteral Nutrition and Nutritional Support
  description: >-
    The enteropathy causes malabsorption severe enough to require parenteral
    nutrition in some patients until it is controlled or the patient is
    transplanted.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: total parenteral nutrition
    term:
      id: NCIT:C29484
      label: Total Parenteral Nutrition
  evidence:
  - reference: PMID:23416241
    reference_title: Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient suffered from enteropathy until 5 years of age, often requiring parenteral nutrition"
    explanation: Reports the need for parenteral nutrition during the enteropathy.
  target_phenotypes:
  - preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
- name: Gene-Corrected Autologous Regulatory T Cell Therapy (Investigational)
  description: >-
    Preclinical CRISPR-Cas9 correction of patient Tregs restores CD25 expression and suppressive activity. The 2025 report describes GMP-compatible clinical-scale manufacturing and functional equivalence to healthy-donor Tregs in vitro. The 2018 precursor study demonstrated allele correction and improved STAT5 responses. These are cell-engineering studies, not evidence of benefit in a treated patient.
  therapeutic_modality: GENE_EDITING
  treatment_term:
    preferred_term: Ex vivo gene-corrected autologous Treg therapy
    term:
      id: NCIT:C15238
      label: Gene Therapy
  target_mechanisms:
  - target: Impaired Regulatory T Cell Suppression
    treatment_effect: RESTORES
    description: >-
      Correcting IL2RA in the patient's own Tregs restores receptor expression and
      suppressive function in vitro.
  evidence:
  - reference: PMID:41376159
    reference_title: Gene-corrected regulatory T cell therapy for IL2RA deficiency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "One of the two disease-causing mutations in patient-derived Tregs was corrected with CRISPR-Cas9-mediated homology-directed repair, restoring IL2RA expression."
    explanation: >-
      Describes the correction and the restored receptor expression, the basis of
      this treatment link.
  - reference: PMID:41376159
    reference_title: Gene-corrected regulatory T cell therapy for IL2RA deficiency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The resulting gcTregs demonstrated robust suppressive activity in vitro."
    explanation: >-
      Reports the functional readout, in vitro suppression, that the corrected
      cells recover.
- name: Intravenous Immunoglobulin
  description: IVIG has been used for infection prevention in patients with deficient functional antibody responses or substantial infectious burden, including some with elevated total IgG. Treatment is based on functional assessment and clinical context rather than total immunoglobulin concentration alone.
  treatment_term:
    preferred_term: Intravenous Immunoglobulin Therapy
    term:
      id: NCIT:C121331
      label: Intravenous Immunoglobulin Therapy
  therapeutic_modality: PROTEIN_REPLACEMENT
  evidence:
  - reference: PMID:41659858
    reference_title: 'Expanding the clinical spectrum of interleukin-2 receptor alpha chain deficiency: two novel cases with long-term hematopoietic stem cell transplantation outcome and literature review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Monthly IVIG replacement therapy and Pneumocystis jirovecii prophylactic antibiotics were initiated.
    explanation: Reported supportive care in the younger Saudi sibling.
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC3892414/
    reference_title: Follicular bronchiolitis as phenotype associated with CD25 deficiency - PMC
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Although our patient has hypergammaglobulinaemia, she has an impaired specific polysaccharide response
    explanation: Functional antibody impairment in the Y41S patient who received IVIG.
  target_phenotypes:
  - preferred_term: Decreased specific antibody response to vaccination
    term:
      id: HP:0032140
      label: Decreased specific antibody response to vaccination
  - preferred_term: Recurrent bacterial infections
    term:
      id: HP:0002718
      label: Recurrent bacterial infections
- name: Insulin Replacement
  description: Insulin is required to treat insulin deficiency in affected patients with autoimmune diabetes. All five newly identified individuals in the 2026 series required immediate insulin; treatment requirements reflect the diabetes phenotype and do not correct the immune defect.
  treatment_term:
    preferred_term: Hormone Replacement Therapy
    term:
      id: NCIT:C15599
      label: Hormone Replacement Therapy
    therapeutic_agent:
    - preferred_term: insulin
      term:
        id: CHEBI:145810
        label: insulin
  therapeutic_modality: PROTEIN_REPLACEMENT
  evidence:
  - reference: PMID:41758964
    reference_title: Biallelic Pathogenic Variants in IL2RA Cause Neonatal-Onset Monogenic Autoimmune Diabetes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: All individuals required immediate insulin therapy
    explanation: Primary treatment observation in the five new cases.
  target_phenotypes:
  - preferred_term: Early-onset autoimmune diabetes mellitus
    term:
      id: HP:0100651
      label: Type I diabetes mellitus
- name: Thyroid Hormone Replacement
  description: Thyroid hormone replacement has been used for hypothyroidism associated with autoimmune thyroiditis. Thyroid function and replacement need require reassessment; the S166N patient's thyroiditis later resolved.
  treatment_term:
    preferred_term: Hormone Replacement Therapy
    term:
      id: NCIT:C15599
      label: Hormone Replacement Therapy
    therapeutic_agent:
    - preferred_term: thyroxine
      term:
        id: CHEBI:30660
        label: thyroxine
  therapeutic_modality: SMALL_MOLECULE
  evidence:
  - reference: PMID:23416241
    reference_title: Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: She presented an autoimmune thyroiditis at 4 years of age, which was treated with hormone replacement therapy until the thyroiditis resolved at 7 years.
    explanation: Patient-specific replacement and follow-up.
  target_phenotypes:
  - preferred_term: Autoimmune thyroiditis
    term:
      id: HP:0100646
      label: Thyroiditis
- name: Genetic Counseling
  description: Molecularly confirmed families should receive counseling on autosomal recessive inheritance, segregation testing and reproductive options. For two carriers of pathogenic alleles, the probability of a child inheriting both is 25% per pregnancy; clinical severity remains variable.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  therapeutic_modality: OTHER
  evidence:
  - reference: PMID:36195682
    reference_title: Whole exome sequencing identified a novel splice donor site variant in interleukin 2 receptor alpha chain.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    directness: DIRECT
    snippet: The study will also help clinical geneticists for genetic counseling and prevention of the disease in the affected family.
    explanation: The primary case study supports disease-specific family counseling.
diagnosis:
- name: Flow cytometry for surface CD25 on T cells
  description: >-
    Flow cytometry should assess CD25 on resting and stimulated T cells. Absent or markedly reduced expression supports IL2RA deficiency, but residual expression occurs and does not exclude it. Intermediate expression in relatives suggests carrier status and requires molecular confirmation. FOXP3-positive Tregs may persist; gates requiring CD25 cannot quantify the CD25-negative regulatory lineage.
  diagnosis_term:
    preferred_term: flow cytometric assessment of surface CD25 expression
  markers: Surface CD25 (IL-2R alpha) on CD4+ and activated T cells
  results: Absent or markedly reduced surface CD25; residual expression does not exclude disease
  evidence:
  - reference: PMID:41694357
    reference_title: "Case Report: IL2RA (CD25) deficiency: first reported cases in Morocco."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Simple flow cytometric assessment of CD25 on T cells is a valuable screening tool, and early genetic confirmation is crucial to guide timely hematopoietic stem cell transplantation and genetic counselling."
    explanation: >-
      States the role of the flow cytometric test as the screening step preceding
      genetic confirmation.
    quote_role: BACKGROUND
  - reference: PMID:30742970
    reference_title: "CD25 deficiency: A new conformational mutation prevents the receptor expression on cell surface."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cytofluorimetric analysis revealed the total absence of CD25 cell surface expression and addressed IL2Rα molecular investigation."
    explanation: >-
      Shows the sequence used in practice: absent surface expression by flow
      cytometry directs the molecular study.
  - reference: PMID:29995861
    reference_title: Reprogramming human T cell function and specificity with non-viral genome targeting.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: three compound heterozygotes that express minimal amounts of IL2RA on the surface of the T cells
    explanation: Residual expression in genetically affected individuals.
- name: IL2RA sequencing
  description: >-
    Sequence analysis should cover coding exons and splice junctions and include validated copy-number analysis for exon-level or whole-gene deletions. Targeted panels, exome sequencing and NGS read-depth analysis have identified disease alleles. Family segregation and functional studies help interpret variant-specific consequences.
  diagnosis_term:
    preferred_term: IL2RA sequencing
  results: Biallelic loss-of-function IL2RA variants
  evidence:
  - reference: PMID:41659858
    reference_title: "Expanding the clinical spectrum of interleukin-2 receptor alpha chain deficiency: two novel cases with long-term hematopoietic stem cell transplantation outcome and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Molecular analysis using the next-generation sequencing primary immunodeficiency panel revealed a novel homozygous frameshift mutation in IL2RA (c.166delC; p.R56fs), which was confirmed by Sanger sequencing."
    explanation: Documents the panel-based route to molecular diagnosis.
  - reference: PMID:41694357
    reference_title: "Case Report: IL2RA (CD25) deficiency: first reported cases in Morocco."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "For Case 2, NGS read-depth analysis identified a homozygous multi-exon deletion in IL2RA, corresponding at the cDNA level to c.557_795-1625del."
    explanation: >-
      The case for including copy-number analysis: this allele was found by read
      depth, not by variant calling on sequence alone.
- name: Screen IL2RA when IPEX is suspected but FOXP3 is normal
  description: >-
    Because the clinical picture is IPEX-like, the practical diagnostic rule is
    that a patient with IPEX features and a normal FOXP3 gene should be screened
    for IL2RA variants.
  diagnosis_term:
    preferred_term: IL2RA screening in FOXP3-normal IPEX-like disease
  evidence:
  - reference: PMID:17196245
    reference_title: "CD25 deficiency causes an immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like syndrome, and defective IL-10 expression from CD4 lymphocytes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Any patient with features of IPEX but with a normal Foxp3 gene should be screened for mutations in the IL-2 receptor subunit CD25."
    explanation: The source's own clinical implication, stated as a screening rule.
    quote_role: BACKGROUND
- name: Genetic testing for neonatal or syndromic autoimmune diabetes
  description: Include IL2RA in monogenic neonatal-diabetes panels and consider it in childhood diabetes accompanied by enteropathy, endocrinopathy or immune dysregulation. GAD positivity does not exclude a monogenic immune cause.
  diagnosis_term:
    preferred_term: IL2RA analysis in neonatal or syndromic autoimmune diabetes
  evidence:
  - reference: PMID:41758964
    reference_title: Biallelic Pathogenic Variants in IL2RA Cause Neonatal-Onset Monogenic Autoimmune Diabetes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    directness: DIRECT
    snippet: IL2RA should be included in gene panels for neonatal diabetes, and testing should be considered in children with diabetes and immunodysregulatory features.
    explanation: Clinical implication of the disease-specific diabetes series.
- name: Functional immune characterization
  description: Evaluate IL-2 dose-dependent STAT5 phosphorylation, antigen and mitogen proliferation, lymphocyte subsets, immunoglobulins and specific antibody responses. Compare with appropriate controls and use CD25-independent markers when enumerating Tregs. Normal total counts, high IgG or preserved PHA responses do not exclude disease.
  diagnosis_term:
    preferred_term: Functional immune characterization in suspected CD25 deficiency
  evidence:
  - reference: PMID:23416241
    reference_title: Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: CD4+ T cells of the patient had dramatically reduced pSTAT5 at all concentrations of IL-2 tested.
    explanation: IL-2 dose-response assay.
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC3892414/
    reference_title: Follicular bronchiolitis as phenotype associated with CD25 deficiency - PMC
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: She presented a normal phytohaemagglutinin (PHA)-stimulated T cell proliferation assay
    explanation: The Y41S case limits a requirement for abnormal mitogen proliferation.
- name: Glucose Surveillance
  description: ClinGen recommends glucose monitoring in individuals with biallelic pathogenic or likely pathogenic IL2RA variants who have not developed diabetes. Those first diagnosed through diabetes warrant assessment for immune, lymphoproliferative and other autoimmune manifestations.
  diagnosis_term:
    preferred_term: Blood Glucose Measurement
    term:
      id: NCIT:C92744
      label: Blood Glucose Measurement
  evidence:
  - reference: url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7d977a16-0957-458b-86be-2245d3953453
    reference_title: curation results for Gene-Disease Validity
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: in individuals discovered to have P/LP IL2RA variants but who have not been diagnosed with diabetes, glucose monitoring is advised
    explanation: Expert recommendation based on the published disease spectrum.
differential_diagnoses:
- name: IPEX syndrome (FOXP3)
  description: >-
    FOXP3-related IPEX and CD25 deficiency share early immune dysregulation, but differ in gene and typical inheritance. FOXP3-positive cells may be present in either condition, and lineage counts alone are not decisive. The CD3/CD46-induced IL-10 distinction arose from individual patient comparisons and is not a validated universal diagnostic discriminator.
  disease_term:
    preferred_term: IPEX syndrome
    term:
      id: MONDO:0010580
      label: immune dysregulation-polyendocrinopathy-enteropathy-X-linked syndrome
  distinguishing_features:
  - X-linked inheritance and a FOXP3 variant in IPEX
  - autosomal recessive inheritance, absent surface CD25 and an IL2RA variant in CD25 deficiency
  evidence:
  - reference: PMID:41694357
    reference_title: "Case Report: IL2RA (CD25) deficiency: first reported cases in Morocco."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Unlike FOXP3 deficiency, IL2RA deficiency does not involve mutations in FOXP3 but results from impaired IL-2 signaling required to sustain FOXP3 expression in Tregs"
    explanation: States the mechanistic distinction between the two entities.
  - reference: PMID:17196245
    reference_title: "CD25 deficiency causes an immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like syndrome, and defective IL-10 expression from CD4 lymphocytes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe a patient with clinical manifestations of IPEX that had a normal Foxp3 gene, but who had CD25 deficiency due to autosomal recessive mutations in this gene."
    explanation: >-
      The case that separated the two diseases clinically, an IPEX phenotype with a
      normal FOXP3 gene.
- name: STAT5B deficiency
  description: >-
    STAT5B deficiency can combine immune dysregulation with a characteristic growth-hormone-insensitivity phenotype. CD25 deficiency can also cause severe growth failure, including one reported poor response to growth hormone; short stature alone does not distinguish them. IL2RA surface expression and molecular testing identify the receptor defect.
  disease_term:
    preferred_term: STAT5B deficiency
    term:
      id: MONDO:0100211
      label: growth hormone insensitivity with immune dysregulation 1, autosomal recessive
  distinguishing_features:
  - growth hormone insensitivity with very low IGF-1 and severe short stature in STAT5B deficiency
  - absent surface CD25 with normal STAT5B in CD25 deficiency
  evidence:
  - reference: PMID:29988287
    reference_title: Primary Immunodeficiencies Unravel the Role of IL-2/CD25/STAT5b in Human Natural Killer Cell Maturation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Using NK cells from two patients, one with a primary immunodeficiency characterized by a homozygous mutation in CD25 (born in year 2007 and studied since she was 3 years old) and one with a homozygous mutation in STAT5b (born in year 1992 and studied since she was 10 years old)"
    explanation: >-
      Confirms the two as distinct entities studied in parallel, which is why
      STAT5B deficiency belongs in this differential.
- name: Severe combined immunodeficiency
  description: >-
    Severe infections and impaired T-cell responses overlap with combined immunodeficiencies. CD25 deficiency often retains circulating T cells and includes lymphoproliferation and autoimmunity. B-cell counts and antibody function vary; normal or high total immunoglobulins do not exclude an associated antibody defect.
  distinguishing_features:
  - Coexisting lymphoproliferation and autoimmune manifestations
  - Absent or markedly reduced surface CD25 with biallelic IL2RA variants
  evidence:
  - reference: PMID:9096364
    reference_title: Human immune disorder arising from mutation of the alpha chain of the interleukin-2 receptor.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This immunodeficiency is characterized by decreased numbers of peripheral T cells displaying abnormal proliferation but normal B cell development."
    explanation: >-
      Establishes preserved B cell development, a feature that argues against SCID
      of the T-B-negative kind.
prevalence:
- population: Published cases included in the 2026 diabetes study
  measure_type: CASES_IN_LITERATURE
  notes: The study combined five new diabetes-ascertained individuals with 17 previously reported cases. Other contemporaneous reviews used smaller case sets, including a 15-case transplant review. These overlapping literature counts are not an exhaustive current worldwide census, population prevalence, or incidence estimate.
  evidence:
  - reference: PMID:41758964
    reference_title: Biallelic Pathogenic Variants in IL2RA Cause Neonatal-Onset Monogenic Autoimmune Diabetes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Across all 22 reported individuals with biallelic IL2RA variants (5 new, 17 published) (Tables 1 and 2), 14 had early-onset diabetes.
    explanation: Defines the study-specific literature aggregate; does not establish population frequency.
progression:
- phase: Onset in infancy or early childhood
  age_range: First weeks of life to early childhood
  notes: >-
    Disease commonly starts in infancy, including neonatal diabetes or early enteropathy, but clinical severity and pace vary. Some patients survive into adolescence or adulthood before transplantation.
  evidence:
  - reference: PMID:41758964
    reference_title: Biallelic Pathogenic Variants in IL2RA Cause Neonatal-Onset Monogenic Autoimmune Diabetes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Diabetes was the presenting feature in four of five individuals, all diagnosed within the first month of life.
    explanation: Four neonatal presentations in the diabetes-ascertained series.
  - reference: PMID:23416241
    reference_title: Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "who developed symptoms resembling IPEX, such as diffuse eczema and severe diarrhea, during her first month of life"
    explanation: Documents the enteropathy and eczema presentation in the first month of life.
- phase: Childhood and adolescent mortality risk
  age_range: Childhood to adolescence
  notes: >-
    Deaths from sepsis and transplantation complications occur. The 2026 diabetes series reports deaths at 19 months, three years and 13 years; the adolescent died after transplant rejection. These selected cases cannot establish a mortality rate or imply universal early-childhood death.
  evidence:
  - reference: PMID:41758964
    reference_title: Biallelic Pathogenic Variants in IL2RA Cause Neonatal-Onset Monogenic Autoimmune Diabetes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: '| Deceased (age) | No | Yes (3 years) | Yes (13 years) | Yes (19 months) | No |'
    explanation: Table 1 includes an adolescent death, qualifying the abstract's early-childhood wording.
clinical_burden:
  burden_level: HIGH
  rationale: >-
    CD25 deficiency can require prolonged immunosuppression, antimicrobial treatment, nutritional support and insulin or thyroid hormone replacement, with organ damage and deaths from sepsis or transplantation complications. Severity varies, and some patients survive into adulthood. HSCT can provide sustained recovery, but graft failure, infection and graft-versus-host disease remain material risks.
  evidence:
  - reference: PMID:41758964
    reference_title: Biallelic Pathogenic Variants in IL2RA Cause Neonatal-Onset Monogenic Autoimmune Diabetes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: '| Deceased (age) | No | Yes (3 years) | Yes (13 years) | Yes (19 months) | No |'
    explanation: Table 1 includes an adolescent death, qualifying the abstract's early-childhood wording.
  - reference: PMID:41376159
    reference_title: Gene-corrected regulatory T cell therapy for IL2RA deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Definitive treatment is currently limited to allogeneic hematopoietic stem cell transplantation, which carries significant morbidity and mortality risks."
    explanation: >-
      The curative option carries important morbidity and mortality risks.
    quote_role: BACKGROUND
animal_models:
- name: Il2ra knockout mouse
  species: Mouse
  genotype: Il2ra-null (IL-2R alpha-deficient)
  publication: PMID:7584142
  description: >-
    Mice lacking IL-2R alpha develop normal T and B cells when young, then as
    adults show massive peripheral lymphoid enlargement with polyclonal T and B
    expansion correlated with impaired activation-induced cell death, and later
    autoimmune disease including hemolytic anemia and inflammatory bowel disease.
    The model is the source of the interpretation that the chain regulates the size
    and content of the lymphoid compartment by setting the balance between clonal
    expansion and death after activation.
  modeled_mechanisms:
  - target: Impaired Peripheral Activation-Induced T Cell Death
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      The knockout reproduces the failure of activation-induced T cell death, with
      the polyclonal lymphoid expansion it predicts.
    limitations: >-
      The finding is peripheral activation-induced death in a whole-gene-null mouse. Human thymic BCL2 findings are a different process, and the S166N patient did not show a general peripheral apoptotic defect. Infection susceptibility and clinical onset differ from the reported human spectrum.
    evidence:
    - reference: PMID:7584142
      reference_title: Interleukin-2 receptor alpha chain regulates the size and content of the peripheral lymphoid compartment.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "However, as adults, these mice develop massive enlargement of peripheral lymphoid organs associated with polyclonal T and B cell expansion, which, for T cells, is correlated with impaired activation-induced cell death in vivo."
      explanation: >-
        Reports the apoptosis defect and the lymphoid expansion in the knockout,
        which is what makes it informative for this node.
  - target: Loss of Peripheral Immune Tolerance
    description: The null animal develops autoimmune hemolytic anemia and intestinal inflammation.
    evidence:
    - reference: PMID:7584142
      reference_title: Interleukin-2 receptor alpha chain regulates the size and content of the peripheral lymphoid compartment.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Older IL-2R alpha-deficient mice also develop autoimmune disorders, including hemolytic anemia and inflammatory bowel disease."
      explanation: >-
        Establishes that the knockout develops autoimmunity, so it is informative for
        the disease as well as for the apoptosis lesion, while naming organ targets
        that only partly match the human ones.
    relationship: PARTIALLY_RECAPITULATES
    model_scale: ORGANISM
    limitations: Overlapping immune pathology does not reproduce the entire human infection and endocrine spectrum.
    fidelity: MODERATE
  evidence:
  - reference: PMID:7584142
    reference_title: Interleukin-2 receptor alpha chain regulates the size and content of the peripheral lymphoid compartment.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Older IL-2R alpha-deficient mice also develop autoimmune disorders, including hemolytic anemia and inflammatory bowel disease."
    explanation: >-
      Establishes that the knockout develops autoimmunity, so it is informative for
      the disease as well as for the apoptosis lesion, while naming organ targets
      that only partly match the human ones.
- name: Il2-null mice across genetic backgrounds
  species: Mouse
  genotype: Il2 knockout on mixed 129/Ola × C57BL/6 or BALB/c backgrounds
  publication: PMID:9065030
  description: An indirect ligand-deficiency model of impaired IL-2-dependent tolerance. Mixed-background animals predominantly develop colitis, whereas BALB/c animals develop generalized autoimmunity, hemolytic anemia and early mortality. This is not IL2RA gene deficiency or evidence for a specific human modifier gene.
  modeled_mechanisms:
  - target: Loss of Peripheral Immune Tolerance
    description: Loss of the ligand perturbs the same tolerance pathway.
    evidence:
    - reference: PMID:9065030
      reference_title: '[Generalized autoimmune diseases in BALB/c mice with a genetically dependent interleukin-2 deficiency].'
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Il-2-/-mice backcrossed to BALB/c genetic background develop a generalized autoimmune disease
      explanation: Background-dependent mouse phenotype.
    relationship: PARTIALLY_RECAPITULATES
    model_scale: ORGANISM
    limitations: Il2 deletion differs from receptor-alpha loss; background effects and immune-cell distributions cannot be directly transferred to human CD25 deficiency.
    fidelity: MODERATE
  evidence:
  - reference: PMID:9065030
    reference_title: '[Generalized autoimmune diseases in BALB/c mice with a genetically dependent interleukin-2 deficiency].'
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Treatment of Il-2-/-Balb/c mice with anti-gp39 (CD40L) antibody inhibited activation of B cells and CD8+ T cells, however, it did not affect the activation of CD4+ T cells.
    explanation: Partial experimental intervention; not a clinical CD25 treatment.
- name: Treg-specific Foxp1/Foxp4 double-knockout mice
  species: Mouse
  genotype: Foxp1fl/fl Foxp4fl/fl Foxp3YFP-Cre
  publication: PMID:40794436
  description: An indirect upstream transcriptional-perturbation model with reduced Il2ra transcription and CD25 expression, preserved or increased Treg numbers, systemic inflammation and autoimmunity. Suppression was impaired in the lymphopenia-driven expansion assay but preserved in the in-vitro assay; transfer-colitis histology was not significantly different at ten weeks. Neither factor is established as a modifier of human IL2RA deficiency.
  modeled_mechanisms:
  - target: Reduced Surface CD25 Availability
    description: Deleting both transcription factors lowers CD25 expression in Tregs.
    evidence:
    - reference: PMID:40794436
      reference_title: Normal Treg homeostasis and suppressive function require both FOXP1 and FOXP4.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: both cTreg and eTreg subsets in cDKO have decreased level of CD25 expression
      explanation: In vivo conditional-knockout readout.
    relationship: PERTURBS
    model_scale: ORGANISM
    limitations: The manipulation changes many genes and does not isolate CD25 as the cause of the entire phenotype; no CD25-specific rescue was demonstrated.
    fidelity: LOW
  evidence:
  - reference: PMID:40794436
    reference_title: Normal Treg homeostasis and suppressive function require both FOXP1 and FOXP4.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: these data indicate a defect in in vivo but not in vitro function of Tregs deficient in both FOXP1 and FOXP4.
    explanation: Assay-dependent functional outcome.
discussions:
- discussion_id: tregs_present_but_inadequate
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    How much do impaired Treg suppression, altered IL-2 consumption and the relative size of the effector pool each contribute to immune dysregulation when FOXP3-positive Tregs remain present?
  attaches_to:
  - pathophysiology#Impaired Regulatory T Cell Suppression
  - pathophysiology#Loss of Peripheral Immune Tolerance
  rationale: >-
    The S166N patient retained phenotypically and epigenetically recognizable Tregs, while expanded cytotoxic cells infiltrated skin. Subsequent compound-heterozygous patient-cell assays directly demonstrated defective suppression and gene-correction rescue. The residual gap concerns the relative contributions of functional insufficiency, cytokine consumption and effector-cell excess across genotypes. Treg denominators and CD25-dependent gating can also account for apparent differences in cell abundance.
  evidence:
  - reference: PMID:23416241
    reference_title: Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Activated CD8(+)STAT5(+) T cells with lytic potential infiltrated the skin, even though FOXP3(+) Tregs were present and maintained a higher capacity to respond to IL-2 compared to other T-cell subsets."
    explanation: >-
      States the paradox this gap is about: tolerance failed in tissue while Tregs
      were present and comparatively IL-2 responsive.
  - reference: PMID:23416241
    reference_title: Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Overall these results indicated that peripheral Tregs were present in the patient despite the absence of a functional CD25, albeit at an overall reduced level in total lymphocytes."
    explanation: >-
      Supplies the numerical half of the candidate explanation, the reduced Treg
      share of total lymphocytes.
- discussion_id: mouse_lymphoproliferation_vs_human_infection
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Why does the Il2ra knockout mouse present as adult-onset lymphoproliferation
    with colitis and hemolytic anemia, while human CD25 deficiency presents in
    infancy with enteropathy, endocrine autoimmunity and infections the mouse is
    not reported to acquire?
  attaches_to:
  - pathophysiology#Impaired Peripheral Activation-Induced T Cell Death
  - pathophysiology#Recurrent and Persistent Viral, Bacterial and Fungal Infection
  rationale: >-
    The founding Il2ra-null mouse study emphasizes adult lymphoproliferation and autoimmunity with impaired activation-induced death. Human disease includes early infections, variable onset and organ manifestations, and the S166N patient did not show a general peripheral apoptotic defect. Different tissue compartments, alleles, microbial exposures and genetic backgrounds may contribute; the published mouse description does not test human-like opportunistic infection susceptibility.
  evidence:
  - reference: PMID:7584142
    reference_title: Interleukin-2 receptor alpha chain regulates the size and content of the peripheral lymphoid compartment.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Young mice that lack IL-2R alpha have phenotypically normal development of T and B cells."
    explanation: >-
      Establishes the timing mismatch: the mouse is phenotypically normal young,
      where the human disease presents in infancy.
  - reference: PMID:23416241
    reference_title: Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One of the main clinical manifestations of the patient, other than autoimmunity, was chronic viral infections especially CMV."
    explanation: >-
      Establishes the human arm with no reported murine counterpart, chronic
      cytomegalovirus infection.
notes: >-
  Clinical expression and laboratory findings vary substantially. Published patients overlap between case reports, mechanistic follow-up studies and later reviews, so their denominators must not be added without deduplication. Diabetes-ascertained series and literature tables do not establish population penetrance or prevalence.

  The Mendelian recessive IL2RA disorder is distinct from common IL2RA susceptibility polymorphisms and from IL2RB or STAT5B deficiency. Residual CD25 expression and preserved responses through the intermediate-affinity receptor are compatible with the diagnosis. FOXP3-positive cells may persist, and CD25-based Treg gates can confound receptor loss with lineage loss.

  Not every clinical finding has a resolved causal path. Atopic manifestations, humoral defects, renal stones, ocular disease and acute metabolic abnormalities are retained with their case-specific evidence without assigning unsupported molecular routes. Histologic granulomatous hepatitis is not equated with serologically established autoimmune hepatitis.

  The proposed IL-2-consumption and thymic-selection mechanisms remain less directly established in patients than impaired high-affinity responsiveness and the gene-correction rescue experiments. Peripheral activation-induced apoptosis defects in mice should not be generalized to every human allele.
references:
- reference: PMID:10879793
  title: Human IL-2 receptor alpha chain deficiency.
- reference: PMID:17196245
  title: CD25 deficiency causes an immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like syndrome, and defective IL-10 expression from CD4 lymphocytes.
- reference: PMID:19348914
  title: IL-2- and CD25-dependent immunoregulatory mechanisms in the homeostasis of T-cell subsets.
- reference: PMID:23416241
  title: Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity.
- reference: PMID:24116927
  title: Follicular bronchiolitis as phenotype associated with CD25 deficiency.
- reference: PMID:29988287
  title: Primary Immunodeficiencies Unravel the Role of IL-2/CD25/STAT5b in Human Natural Killer Cell Maturation.
- reference: PMID:29995861
  title: Reprogramming human T cell function and specificity with non-viral genome targeting.
- reference: PMID:30742970
  title: 'CD25 deficiency: A new conformational mutation prevents the receptor expression on cell surface.'
- reference: PMID:35968218
  title: 'Granulomatous hepatitis in a Saudi child with IL2RA defect: a case report and literature review.'
- reference: PMID:36195682
  title: Whole exome sequencing identified a novel splice donor site variant in interleukin 2 receptor alpha chain.
- reference: PMID:40794436
  title: Normal Treg homeostasis and suppressive function require both FOXP1 and FOXP4.
- reference: PMID:41376159
  title: Gene-corrected regulatory T cell therapy for IL2RA deficiency.
- reference: PMID:41659858
  title: 'Expanding the clinical spectrum of interleukin-2 receptor alpha chain deficiency: two novel cases with long-term hematopoietic stem cell transplantation outcome and literature review.'
- reference: PMID:41694357
  title: 'Case Report: IL2RA (CD25) deficiency: first reported cases in Morocco.'
- reference: PMID:41758964
  title: Biallelic Pathogenic Variants in IL2RA Cause Neonatal-Onset Monogenic Autoimmune Diabetes.
- reference: PMID:7584142
  title: Interleukin-2 receptor alpha chain regulates the size and content of the peripheral lymphoid compartment.
- reference: PMID:9065030
  title: '[Generalized autoimmune diseases in BALB/c mice with a genetically dependent interleukin-2 deficiency].'
- reference: PMID:9096364
  title: Human immune disorder arising from mutation of the alpha chain of the interleukin-2 receptor.
- reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC20340/
  title: Human immune disorder arising from mutation of the α chain of the interleukin-2 receptor - PMC
- reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC3892414/
  title: Follicular bronchiolitis as phenotype associated with CD25 deficiency - PMC
- reference: url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7d977a16-0957-458b-86be-2245d3953453
  title: curation results for Gene-Disease Validity
histopathology:
- name: Granulomatous Hepatitis
  description: Liver biopsy in the Cys168Ter patient showed noncaseating portal granulomas and mononuclear inflammation. Autoimmune serology and investigated infectious causes were negative. Liver enzymes improved without specific treatment despite persistent hepatomegaly.
  diagnostic: false
  evidence:
  - reference: PMID:35968218
    reference_title: 'Granulomatous hepatitis in a Saudi child with IL2RA defect: a case report and literature review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Some of the portal tracts contain ill-defined noncaseating granulomas formed of epithelioid histiocytes that are surrounded by dense mononuclear infiltrate
    explanation: Direct human liver-biopsy description.
- name: Peribronchiolar Lymphoid Follicles
  description: Follicular bronchiolitis in the Y41S patient included lymphoid follicles surrounding bronchioles. This supports an inflammatory pulmonary manifestation without establishing that every infiltrating cell is CD8-positive.
  diagnostic: false
  evidence:
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC3892414/
    reference_title: Follicular bronchiolitis as phenotype associated with CD25 deficiency - PMC
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Lymphocytic infiltrate that is arranged in follicles surrounding the bronchioles.
    explanation: Direct lung-biopsy image legend.
- name: Cytotoxic CD8-Positive Skin Infiltrate
  description: The S166N skin biopsy contained proliferating granzyme-B-positive CD8 T cells. TCR testing showed a polyclonal population; self-antigen specificity was not established.
  diagnostic: false
  evidence:
  - reference: PMID:23416241
    reference_title: Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: These data show that CD8+ T cells highly infiltrate the skin, undergo proliferation, and present lytic capacity
    explanation: Skin histology and immunofluorescence.
experimental_models:
- name: Founding-patient EBV-transformed B cells
  description: Patient-derived EBV-transformed B cells demonstrated absent CD25. This transformed B-cell system measures receptor expression; it is not a direct Treg suppression model.
  experimental_model_type: CELL_LINE
  organism:
    preferred_term: Homo sapiens
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_source: Patient-derived EBV-transformed peripheral B lymphocytes
  publication: PMID:9096364
  modeled_mechanisms:
  - target: Reduced Surface CD25 Availability
    description: Absent CD25 in the patient-derived line.
    evidence:
    - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC20340/
      reference_title: Human immune disorder arising from mutation of the α chain of the interleukin-2 receptor - PMC
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: an EBV-transformed cell line derived from patient peripheral B lymphocytes did not express detectable CD25 by flow cytometry
      explanation: Founding patient-derived immortalized B-cell readout.
    relationship: MEASURES
    model_scale: CELLULAR
    limitations: EBV transformation and B-cell lineage differ from regulatory T cells.
    fidelity: MODERATE
  evidence:
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC20340/
    reference_title: Human immune disorder arising from mutation of the α chain of the interleukin-2 receptor - PMC
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: an EBV-transformed cell line derived from patient peripheral B lymphocytes did not express detectable CD25 by flow cytometry
    explanation: Founding patient-derived immortalized B-cell readout.
- name: S166N patient PBMC and T-cell cultures
  description: Dose-response STAT5, proliferation, cytokine and suppression assays distinguish high-affinity IL-2 impairment from retained CD122/CD132 signaling. Healthy-donor Tregs suppressed patient CD8 cells. High cytokine doses partly improved polyclonal proliferation but did not restore CMV-specific proliferation or IFN-gamma production.
  experimental_model_type: PRIMARY_CELL_CULTURE
  organism:
    preferred_term: Homo sapiens
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_source: Patient-derived primary lymphocytes
  publication: PMID:23416241
  modeled_mechanisms:
  - target: Raised IL-2 Signaling Threshold with Deficient STAT5 Activation
    description: CD4 and CD8 IL-2 dose responses differ.
    evidence:
    - reference: PMID:23416241
      reference_title: Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: CD8+ T cells of the patient were less affected by the loss of CD25 in response to IL-2 stimulation.
      explanation: Subset-specific signaling.
    relationship: MEASURES
    model_scale: CELLULAR
    limitations: One treated patient; in-vitro dose responses do not establish clinical IL-2 efficacy.
    fidelity: MODERATE
  - target: Impaired Antigen-Specific T Cell Responses
    description: Antigen-specific defects persist despite cytokine addition.
    evidence:
    - reference: PMID:23416241
      reference_title: Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: The patient's PBMCs had poor in vitro proliferation response to TCR-mediated activation compared to healthy controls
      explanation: Patient-cell proliferation assay.
    - reference: PMID:23416241
      reference_title: Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: The addition of high concentrations of IL-2 or IL-15 did not rescue IFNγ production
      explanation: Negative CMV-response rescue, despite partial polyclonal rescue.
    relationship: MEASURES
    model_scale: CELLULAR
    limitations: Partial polyclonal rescue and failed CMV rescue are distinct endpoints.
    fidelity: MODERATE
  evidence:
  - reference: PMID:23416241
    reference_title: Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The patient's PBMCs had poor in vitro proliferation response to TCR-mediated activation compared to healthy controls
    explanation: Patient-cell proliferation assay.
- name: Y41S patient NK-cell functional cultures
  description: Cytokine stimulation, proliferation and K562 degranulation assays in the previously reported Argentine patient showed impaired IFN-gamma production but increased lytic mediators and degranulation. The STAT5B-deficient individual was a separate comparator.
  experimental_model_type: PRIMARY_CELL_CULTURE
  organism:
    preferred_term: Homo sapiens
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_source: Patient-derived primary lymphocytes
  publication: PMID:29988287
  modeled_mechanisms:
  - target: Reduced NK Cell IFN-Gamma Production
    description: Reduced stimulated cytokine output.
    evidence:
    - reference: PMID:29988287
      reference_title: Primary Immunodeficiencies Unravel the Role of IL-2/CD25/STAT5b in Human Natural Killer Cell Maturation.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: CD56bright and CD56dim NK cells from the CD25-deficient patient produced less IFN-γ than CD56bright and CD56dim NK cells from the HD
      explanation: Stimulated NK assay.
    relationship: MEASURES
    model_scale: CELLULAR
    limitations: One CD25-deficient patient; a causal contribution to particular infections was not tested.
    fidelity: MODERATE
  evidence:
  - reference: PMID:29988287
    reference_title: Primary Immunodeficiencies Unravel the Role of IL-2/CD25/STAT5b in Human Natural Killer Cell Maturation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: CD56bright and CD56dim NK cells from the CD25-deficient patient produced less IFN-γ than CD56bright and CD56dim NK cells from the HD
    explanation: Stimulated NK assay.
- name: Nonviral gene-corrected IL2RA-deficient T cells
  description: T cells from three compound heterozygous siblings underwent CRISPR correction at the endogenous IL2RA locus. HDR repaired the premature-stop allele; targeting the final-exon deletion also permitted frame-restoring indels without an HDR template. Surface CD25 and STAT5 responses improved, and corrected Treg-like cells expanded with a demethylated FOXP3 TSDR. These readouts do not alone establish in-vivo therapeutic efficacy.
  experimental_model_type: PRIMARY_CELL_CULTURE
  organism:
    preferred_term: Homo sapiens
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_source: Patient-derived primary lymphocytes
  publication: PMID:29995861
  modeled_mechanisms:
  - target: Raised IL-2 Signaling Threshold with Deficient STAT5 Activation
    description: Genetic correction improved cytokine-induced STAT5 phosphorylation.
    evidence:
    - reference: PMID:29995861
      reference_title: Reprogramming human T cell function and specificity with non-viral genome targeting.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Following correction of the c.530A>G IL2RA mutation, IL-2 treatment led to increased STAT5 phosphorylation
      explanation: The source reverses the substitution in this sentence; its figure legend identifies the pathogenic allele as c.530G>A.
    relationship: RESCUES
    model_scale: CELLULAR
    limitations: Ex-vivo readout; outcomes and editing efficiencies vary by allele and donor.
    fidelity: MODERATE
  - target: Reduced Surface CD25 Availability
    description: Gene correction restored surface expression.
    evidence:
    - reference: PMID:29995861
      reference_title: Reprogramming human T cell function and specificity with non-viral genome targeting.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: we were able to correct the mutation and observed IL2RA expression on the surface of corrected T cells from the patient
      explanation: Direct correction experiment.
    relationship: RESCUES
    model_scale: CELLULAR
    limitations: Frame-restoring indels and precise HDR are distinct editing outcomes.
    fidelity: MODERATE
  evidence:
  - reference: PMID:29995861
    reference_title: Reprogramming human T cell function and specificity with non-viral genome targeting.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Following correction of the c.530A>G IL2RA mutation, IL-2 treatment led to increased STAT5 phosphorylation
    explanation: The source reverses the substitution in this sentence; its figure legend identifies the pathogenic allele as c.530G>A.
- name: GMP-compatible gene-corrected autologous Treg product
  description: Patient Tregs were corrected by CRISPR-Cas9 homology-directed repair. The later manufacturing study demonstrated restored CD25 and robust in-vitro suppressive activity at clinical scale.
  experimental_model_type: PRIMARY_CELL_CULTURE
  organism:
    preferred_term: Homo sapiens
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_source: Patient-derived primary lymphocytes
  publication: PMID:41376159
  modeled_mechanisms:
  - target: Impaired Regulatory T Cell Suppression
    description: Corrected Tregs regained suppressive activity.
    evidence:
    - reference: PMID:41376159
      reference_title: Gene-corrected regulatory T cell therapy for IL2RA deficiency.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: The resulting gcTregs demonstrated robust suppressive activity in vitro.
      explanation: Functional rescue in vitro.
    relationship: RESCUES
    model_scale: CELLULAR
    limitations: Manufacturing and in-vitro function do not establish persistence, safety or clinical efficacy after infusion.
    fidelity: MODERATE
  evidence:
  - reference: PMID:41376159
    reference_title: Gene-corrected regulatory T cell therapy for IL2RA deficiency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Clinical-scale manufacturing from a patient with IL2RA deficiency showed efficient gene correction, restored IL2RA expression, and functional equivalence to healthy donor Tregs.
    explanation: Clinical-scale manufacture and in-vitro function; no patient infusion outcome.
computational_models:
- name: Cys168Ter protein and RNA structure predictions
  model_type: STRUCTURAL_PREDICTION
  description: The Cys168Ter case report used an ab-initio protein model, domain mapping and RNAfold. The altered stop codon predicts truncation, but mRNA folding stability showed no significant change and degradation was not measured.
  publication: PMID:35968218
  modeled_mechanisms:
  - target: Reduced Surface CD25 Availability
    description: The model predicts a truncated receptor product.
    evidence:
    - reference: PMID:35968218
      reference_title: 'Granulomatous hepatitis in a Saudi child with IL2RA defect: a case report and literature review.'
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: First, the 3D model of IL2RA variant protein was constructed using the ab-initio method
      explanation: Computational structure prediction.
    relationship: PERTURBS
    model_scale: MOLECULAR
    limitations: No receptor abundance, localization or patient RNA-decay assay was performed; inconsistent reported truncation lengths are not adopted.
    fidelity: LOW
  evidence:
  - reference: PMID:35968218
    reference_title: 'Granulomatous hepatitis in a Saudi child with IL2RA defect: a case report and literature review.'
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: no significant changes in the thermodynamic stability of the mRNA folding pattern due to c.504 C>A variant
    explanation: Negative RNAfold prediction, distinct from the predicted protein truncation.
datasets:
- accession: geo:GSE300286
  title: FOXP1 and FOXP4 function in mouse regulatory T cells [RNA-seq]
  description: Bulk RNA sequencing of sorted splenic regulatory T cells from conditional Foxp1/Foxp4 mutant and control mice. This is an indirect model of reduced CD25 expression and altered Treg function, not a patient IL2RA-deficiency dataset.
  organism:
    preferred_term: Mus musculus
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  data_type: BULK_RNA_SEQ
  publication: PMID:40794436
  notes: Foxp1/Foxp4 deletion affects many Treg programs; its transcriptome cannot be attributed solely to IL2RA. See the corresponding animal model for preserved in-vitro suppression and impaired in-vivo suppression.
  evidence:
  - reference: PMID:40794436
    reference_title: Normal Treg homeostasis and suppressive function require both FOXP1 and FOXP4.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: We further show that FOXP1 and FOXP4 bind to Il2ra promoter regions to regulate CD25 expression in Tregs.
    explanation: The source establishes the relevance of this indirect regulatory model.

📚

References & Deep Research

References

PMID:10879793

Human IL-2 receptor alpha chain deficiency.

No top-level findings curated for this source.

PMID:17196245

CD25 deficiency causes an immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like syndrome, and defective IL-10 expression from CD4 lymphocytes.

No top-level findings curated for this source.

PMID:19348914

IL-2- and CD25-dependent immunoregulatory mechanisms in the homeostasis of T-cell subsets.

No top-level findings curated for this source.

PMID:23416241

Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity.

No top-level findings curated for this source.

PMID:24116927

Follicular bronchiolitis as phenotype associated with CD25 deficiency.

No top-level findings curated for this source.

PMID:29988287

Primary Immunodeficiencies Unravel the Role of IL-2/CD25/STAT5b in Human Natural Killer Cell Maturation.

No top-level findings curated for this source.

PMID:29995861

Reprogramming human T cell function and specificity with non-viral genome targeting.

No top-level findings curated for this source.

PMID:30742970

CD25 deficiency: A new conformational mutation prevents the receptor expression on cell surface.

No top-level findings curated for this source.

PMID:35968218

Granulomatous hepatitis in a Saudi child with IL2RA defect: a case report and literature review.

No top-level findings curated for this source.

PMID:36195682

Whole exome sequencing identified a novel splice donor site variant in interleukin 2 receptor alpha chain.

No top-level findings curated for this source.

PMID:40794436

Normal Treg homeostasis and suppressive function require both FOXP1 and FOXP4.

No top-level findings curated for this source.

PMID:41376159

Gene-corrected regulatory T cell therapy for IL2RA deficiency.

No top-level findings curated for this source.

PMID:41659858

Expanding the clinical spectrum of interleukin-2 receptor alpha chain deficiency: two novel cases with long-term hematopoietic stem cell transplantation outcome and literature review.

No top-level findings curated for this source.

PMID:41694357

Case Report: IL2RA (CD25) deficiency: first reported cases in Morocco.

No top-level findings curated for this source.

PMID:41758964

Biallelic Pathogenic Variants in IL2RA Cause Neonatal-Onset Monogenic Autoimmune Diabetes.

No top-level findings curated for this source.

PMID:7584142

Interleukin-2 receptor alpha chain regulates the size and content of the peripheral lymphoid compartment.

No top-level findings curated for this source.

PMID:9065030

[Generalized autoimmune diseases in BALB/c mice with a genetically dependent interleukin-2 deficiency].

No top-level findings curated for this source.

PMID:9096364

Human immune disorder arising from mutation of the alpha chain of the interleukin-2 receptor.

No top-level findings curated for this source.

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC20340/

Human immune disorder arising from mutation of the α chain of the interleukin-2 receptor - PMC

No top-level findings curated for this source.

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC3892414/

Follicular bronchiolitis as phenotype associated with CD25 deficiency - PMC

No top-level findings curated for this source.

url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7d977a16-0957-458b-86be-2245d3953453

curation results for Gene-Disease Validity

No top-level findings curated for this source.

Deep Research

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: CD25 Deficiency · 2026-09-24T20:02:17Z · View source

De-novo curation of CD25 (IL2RA) deficiency, MONDO:0011664. First pass built from PubMed E-utilities searches on CD25/IL2RA deficiency; one OpenScientist deep-research report (research/CD25_Deficiency-deep-research-openscientist.md) was read afterwards and used as a lead source. Its reference validation reported 16/16 identifiers resolved with needs_review true: 4 of 17 quotes did not match, all because the report had elided mid-quote or reflowed the sentence (the section names the closest source text in each case), and 7 of 16 references were not scored on topic. Its term validation reported 45/47 resolved, 0 unresolved, and 13 label mismatches that are all the report printing a table column header (Physical, Lab, Sign) instead of the ontology label; no CURIE was bound from the report without an independent runoak lookup. just preflight-dr returned WARN on FOXP3 being mentioned 11 times against IL2RA's 30, which is correct and benign: FOXP3 appears because IPEX is this disease's principal differential and because FOXP3+ Treg persistence is a central mechanistic finding, not because a second disease is mixed in. Named Entity Confusion controls: no IL2RA autoimmunity-susceptibility GWAS paper is cited anywhere in the entry, and the only cited paper that also studies STAT5B deficiency (PMID:29988287) reports the two patients separately, with only the CD25 findings used. Pathophysiology is a nine-node chain from biallelic IL2RA loss of function through absent surface CD25, the raised IL-2 signaling threshold with deficient STAT5 activation, and four parallel consequences (Treg dysfunction, defective activation-induced and thymic apoptosis, impaired antigen-specific responses, impaired NK maturation) to loss of peripheral tolerance, multi-organ autoimmune attack, CD8+ lymphoproliferation and the infection node; all 20 phenotypes are wired in. No conforms_to was declared: there is no Treg or peripheral-tolerance module in kb/modules, checked with just list-modules treg and just list-modules autoimm and by grepping the module directory. The NK maturation node is deliberately left with no downstream edge because no source links that phenotype to a clinical feature. PMID:31605764 (rapamycin in IL2RA deficiency) caches with content_type unavailable after a forced refetch, so it is recorded in notes and in the top-level references block without an evidence item; sirolimus claims are quoted from PMID:23416241 instead. No GeneReviews chapter exists (just check-genereviews --online reports NO_CHAPTER for both collections; the only genereviews[book] title hit is the IPEX chapter, which is the FOXP3 disease). Validation: just validate passed, just validate-terms passed, count-verified-snippets 96/96, check-entity-refs, check-causal-targets, check-duplicate-keys, check-qualifier-terms, check-coarse-phenotypes and check-enum-values clean, list-disconnected-phenotypes 20/20 connected, and just validate-disorders run over the file.

OpenScientist ▸

CD25 Deficiency (IL2RA Deficiency): A Comprehensive Disease Characteristics Report

openscientist-autonomous 16 citations 2026-09-24T19:40:38.276248

CD25 Deficiency (IL2RA Deficiency): A Comprehensive Disease Characteristics Report

Disease Name: CD25 Deficiency (Immunodeficiency 41 with lymphoproliferation and autoimmunity, IMD41) MONDO ID: MONDO:0011664 Category: Mendelian (monogenic inborn error of immunity)

Summary

CD25 deficiency is an ultra-rare autosomal recessive inborn error of immunity caused by biallelic loss-of-function variants in IL2RA (chromosome 10p15.1), the gene encoding CD25, the alpha chain of the high-affinity interleukin-2 (IL-2) receptor. CD25, in complex with CD122 (IL-2Rβ) and the common gamma chain (γc), confers high-affinity IL-2 binding. Loss of this chain abolishes high-affinity IL-2/JAK1-JAK3/STAT5 signaling, which is indispensable for the development, survival, stability, and suppressive function of FOXP3⁺ regulatory T cells (Tregs) and for normal IL-10 production. The resulting failure of peripheral immune tolerance produces an IPEX-like syndrome that paradoxically combines features of immunodeficiency (recurrent viral, bacterial, and fungal infections) with early-childhood autoimmunity and lymphoproliferation (autoimmune enteropathy, hepatitis, thyroiditis, cytopenias, eczema, multi-organ lymphocytic infiltration, and severe failure to thrive).

The disorder was first described by Sharfe et al. in 1997 as a truncation mutation of the IL-2 receptor alpha chain producing profound cellular immunodeficiency with extensive lymphocytic tissue infiltration. Fewer than ~15 molecularly confirmed cases have been reported worldwide as of 2026, so essentially all knowledge derives from individual patient case reports rather than aggregated registries; no population prevalence or incidence estimate is established. Diagnosis rests on demonstrating absent surface CD25 on T cells by flow cytometry, followed by IL2RA sequencing for molecular confirmation. The differential diagnosis centers on IPEX (FOXP3) and other IPEX-like Tregopathies.

Without definitive treatment the disease is severe and often fatal in early childhood from overwhelming infection or autoimmune organ damage. Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative therapy, restoring functional Tregs, and can produce complete resolution of symptoms. Rapamycin (sirolimus), an mTOR inhibitor that favors Tregs, has been used as effective and safe bridging immunomodulation. Because the disorder is Mendelian, prevention is limited to genetic counseling, cascade carrier testing (especially in consanguineous families), and prenatal/preimplantation genetic testing once the familial variant is known. Mouse models (Il2⁻/⁻ and Il2ra/CD25 knockout) recapitulate the human phenotype and demonstrate genetic-background-dependent modifier effects.

1. Disease Information

Overview. CD25 deficiency is a monogenic, autosomal recessive inborn error of immunity in which loss of the IL-2 receptor alpha chain (CD25) disables high-affinity IL-2 signaling and thereby cripples regulatory T-cell function. The clinical picture is described as "IPEX-like" because it phenocopies IPEX (Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked syndrome) caused by FOXP3 mutations, but with a normal FOXP3 gene. Sharfe et al. (1997) described "a novel human immune aberration arising from a truncation mutation of the interleukin-2 receptor alpha chain (CD25)… characterized by decreased numbers of peripheral T cells displaying abnormal proliferation but normal B cell development. Extensive lymphocytic infiltration of tissues, including lung, liver, gut, and bone, is observed, accompanied by tissue atrophy and inflammation" (PMID: 9096364).

Key identifiers.

Resource	Identifier
MONDO	MONDO:0011664
OMIM (phenotype)	#606367 — IMMUNODEFICIENCY 41 WITH LYMPHOPROLIFERATION AND AUTOIMMUNITY (IMD41)
OMIM (gene)	*147730 (IL2RA)
Orphanet	ORPHA:169153 — Immunodeficiency due to a defect in CD25
HGNC (gene)	HGNC:6008 (IL2RA)
NCBI Gene	3559
UniProt	P01589
Chromosome	10p15.1
ICD-10	D81.8 / D84.9 (immunodeficiency range)
MeSH	via "Interleukin-2 Receptor alpha Subunit"

Synonyms / alternative names. IL2RA deficiency; interleukin-2 receptor alpha chain deficiency; CD25 deficiency syndrome; Immunodeficiency 41 with lymphoproliferation and autoimmunity (IMD41); IPEX-like syndrome due to CD25 deficiency.

Data provenance. Because only ~13 molecularly confirmed cases had been reported worldwide as of 2026 (PMID: 41659858), disease-level knowledge derives almost entirely from individual patient case reports and small case series, not from aggregated EHR/registry resources.

2. Etiology

Causal factors. CD25 deficiency is purely genetic — caused by biallelic (homozygous or compound heterozygous) germline loss-of-function variants in IL2RA. There is no environmental, toxic, occupational, or lifestyle cause. Loss-of-function IL2RA variants "cause a very rare autosomal recessive disorder marked by early-onset autoimmunity and recurrent infections with an IPEX-like presentation" (PMID: 41694357).

Genetic risk factors. The only causal risk factor is inheriting two defective IL2RA alleles. The principal population risk factor is parental consanguinity — reported patients are frequently born to first-cousin parents ("Both patients were born to first-cousin parents," PMID: 41694357), consistent with a recessive disorder concentrated in inbred pedigrees.

Environmental / lifestyle risk factors. None are causal. Infections act as triggers and complications of the underlying immunodeficiency rather than as causes.

Protective factors. No genetic or environmental protective factors are established. Because the disease is Mendelian and fully penetrant when biallelic LOF variants are present, "protection" is effectively the absence of a second pathogenic allele (carriers are healthy).

Gene–environment interactions. In humans these are not well characterized owing to case rarity. However, mouse models demonstrate a clear modifier / gene–environment interaction: Il2⁻/⁻ mice develop ulcerative-colitis-like disease on a mixed 129/Ola × C57BL/6 background but generalized systemic autoimmunity when backcrossed to BALB/c, showing that genetic background dictates the phenotype (PMID: 9065030). Gut microbial antigens are inferred to drive the autoimmune enteropathy.

Important distinction — Mendelian LOF disease vs. common autoimmune-susceptibility polymorphisms. The rare Mendelian CD25 deficiency is mechanistically distinct from the well-established role of common non-coding IL2RA regulatory polymorphisms (e.g., rs2104286, rs12722495/rs12722496, rs41295061, rs7093069) as polygenic susceptibility loci for type 1 diabetes, multiple sclerosis, and autoimmune thyroid disease. Fine-mapping identified multiple independent T1D and MS association signals in the IL2RA/CD25 region (PMID: 26106896); IL2RA-rs41295061 (10p15) association was replicated in T1D (PMID: 21875375); and IL-2RA rs7093069 (TT genotype) was associated with pediatric autoimmune thyroid disease (PMID: 33193078). These common variants subtly tune CD25 expression and confer complex-trait autoimmune risk, whereas the rare biallelic LOF variants abolish CD25 entirely and cause the monogenic syndrome.

3. Phenotypes

Phenotypes are curated from reported cases (PMID: 9096364, 17196245, 23416241, 24116927, 29252577, 30742970, 41694357, 41659858). Because fewer than ~15 cases exist, frequencies are qualitative (most/common) rather than precise percentages. Onset is typically neonatal to early childhood (congenital/pediatric); severity is severe; the course is chronic and progressive without treatment.

Phenotype	Type	Suggested HPO term	Frequency (qualitative)
Chronic diarrhea / autoimmune (celiac-like) enteropathy	Sign / GI	HP:0002028; HP:0002590	Majority
Failure to thrive / growth failure	Physical	HP:0001508	Majority
Recurrent respiratory infections	Sign	HP:0002205	Majority
Recurrent bacterial/viral/fungal infections	Sign	HP:0002719; HP:0002841	Majority
Eczema / dermatitis	Physical	HP:0000964	Common
Autoimmune hepatitis	Lab/clinical	HP:0002608	Common
Autoimmune thyroiditis	Lab/clinical	HP:0100646	Reported (≥1 case)
Autoimmune hemolytic anemia / cytopenias	Lab	HP:0001890	Reported
Lymphadenopathy / lymphoproliferation	Sign	HP:0002716	Common
Hepatosplenomegaly	Sign	HP:0001433	Common
Chronic inflammatory lung disease / follicular bronchiolitis	Clinical	HP:0006538	Reported
Keratitis / severe dry eye (ocular surface disease)	Clinical	HP:0000491; HP:0000492	Reported
Impaired T-cell proliferation	Lab	HP:0002850	Majority
Hypergammaglobulinemia	Lab	HP:0010702	Common
Absent CD25 surface expression	Lab	(diagnostic)	Universal

Key supporting quotes: patients "presented in early childhood with recurrent respiratory and gastrointestinal infections, severe failure to thrive, chronic diarrhea with celiac-like enteropathy, and autoimmune manifestations including autoimmune hepatitis, dermatitis, and, in one case, autoimmune thyroiditis" (PMID: 41694357); "Recurrent infections and lymphocyte infiltration of multiple tissues are the main clinical presentations" (PMID: 29252577). Primary biliary cirrhosis has also been reported, notably as a rare pediatric occurrence (PMID: 24116927, PMID: 20650610).

Quality of life. No formal EQ-5D/SF-36/PROMIS data exist for this ultra-rare disease. Qualitatively, untreated disease imposes profound impairment: chronic diarrhea and malabsorption, failure to thrive, repeated hospitalizations for infection, autoimmune organ damage, and severe dry-eye discomfort all severely reduce daily functioning. Successful HSCT can restore near-normal functioning.

4. Genetic / Molecular Information

Causal gene. IL2RA (HGNC:6008; OMIM 147730; NCBI Gene 3559; UniProt P01589), located on chromosome 10p15.1*, encoding CD25, the 55-kDa alpha chain of the IL-2 receptor.

Pathogenic variants. Reported disease-causing variants are biallelic and loss-of-function, spanning: - Nonsense/truncation variants (the original Sharfe et al. 1997 case, PMID: 9096364). - Missense variants causing conformational loss of surface expression — e.g., c.122A>C, p.Tyr41Ser (Y41S), a homozygous missense mutation with no CD25 on CD4⁺ T cells and extremely low Tregs (PMID: 24116927); and a conformational mutation described as "a severe protein conformational alteration that abrogates its cell surface expression" (PMID: 30742970).

Variant classification. Reported variants are classified pathogenic/likely pathogenic per ACMG/AMP criteria (functional evidence of absent surface expression, segregation in consanguineous families, absence/rarity in population databases).

Allele frequency. Causal LOF variants are private/ultra-rare and essentially absent from gnomAD at appreciable frequency. By contrast, common regulatory SNPs in the locus are polymorphic (see Section 2).

Origin. Germline, biallelic. No somatic mechanism.

Functional consequence. Loss of function — loss of high-affinity IL-2 binding. CD25 "contributes only to IL-2 binding affinity but not to the recruitment of signalling molecules" (PMID: 24116927), so its loss reduces IL-2 receptor affinity rather than eliminating all IL-2 signaling capacity, but this is sufficient to cripple Treg biology.

Modifier genes. Not defined in humans. Mouse background effects (129 vs BALB/c) demonstrate strong modifier influence (PMID: 9065030). Related Treg biology implicates FOXP1/FOXP4, which bind Il2ra promoter regions to regulate CD25 expression (PMID: 40794436).

Epigenetic information. No disease-specific methylation/histone data. FOXP1/FOXP4 transcriptional control of the Il2ra promoter is the most relevant regulatory layer (PMID: 40794436).

Chromosomal abnormalities. None — this is a single-gene disorder, not a structural/aneuploidy syndrome.

5. Environmental Information

Environmental factors: None causal. No toxin, radiation, pollution, or occupational exposure contributes to disease onset.
Lifestyle factors: Not applicable (disease presents in infancy).
Infectious agents: Pathogens act as triggers/complications, not causes. Patients suffer recurrent viral (including CMV/herpesviruses), bacterial, and fungal (Candida) infections due to the immunodeficiency. Gut microbial antigens are inferred to drive autoimmune enteropathy (by analogy to IL-2-pathway mouse colitis, PMID: 9065030).

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation)

Biallelic loss-of-function variants in IL2RA (nonsense/truncation or conformational missense) lead to absent or non-functional CD25 protein at the T-cell plasma membrane (PMID: 9096364, 30742970).
Loss of CD25 results in failure to assemble the high-affinity IL-2 receptor (CD25 + CD122 + γc), abolishing high-affinity IL-2 binding (PMID: 19348914).
Loss of high-affinity IL-2 binding leads to deficient JAK1/JAK3 → STAT5 phosphorylation in T cells (inferred from IL-2 receptor signaling biology; reduced pSTAT5 is used functionally in diagnosis).
Deficient STAT5 signaling results in impaired FOXP3⁺ regulatory T-cell development, survival, stability, and suppressive function, and impaired IL-10 production by CD4 lymphocytes (PMID: 17196245, 19348914).
Treg failure leads to loss of peripheral immune tolerance, which branches into two co-existing outcomes:
Branch A — Autoimmunity/lymphoproliferation: uncontrolled activation and expansion of autoreactive effector T cells (notably CD8⁺STAT5⁺ cytotoxic T cells) results in multi-organ lymphocytic infiltration, autoimmune enteropathy, hepatitis, thyroiditis, cytopenias, and lymphadenopathy (PMID: 23416241, 9096364).
Branch B — Immunodeficiency: impaired antigen-specific T-cell responses result in susceptibility to recurrent viral, bacterial, and fungal infections (PMID: 23416241).
Combined tissue infiltration, autoimmune organ damage, malabsorptive enteropathy, and recurrent infection lead to failure to thrive and, untreated, early-childhood morbidity and mortality.

IL2RA biallelic LOF
│
▼
No functional CD25 at plasma membrane
│
▼
No high-affinity IL-2 receptor (CD25+CD122+γc)
│
▼
↓ JAK1/JAK3 → STAT5 signaling
│
▼
FOXP3+ Treg failure  +  ↓ IL-10
│
▼
Loss of peripheral tolerance
     ┌──────────────┴───────────────┐
     ▼                              ▼
Branch A: AUTOIMMUNITY          Branch B: IMMUNODEFICIENCY
(CD8+ lymphoproliferation,      (impaired antigen-specific
 enteropathy, hepatitis,         responses → recurrent viral,
 thyroiditis, cytopenias,        bacterial, fungal infections)
 multi-organ infiltration)
     └──────────────┬───────────────┘
            ▼
     Failure to thrive; early-childhood
     morbidity/mortality if untreated

Mechanistic detail

Molecular pathways: Interleukin-2 signaling via JAK-STAT5 (Reactome R-HSA-451927 "Interleukin-2 signaling"; KEGG hsa04630 JAK-STAT; hsa04060 cytokine–cytokine receptor interaction). "Of crucial importance for the delivery of IL-2 signals to Treg cells is the expression of CD25, which, along with CD122 and gammac, confers high affinity binding to IL-2" (PMID: 19348914).
Cellular processes: Failure of regulatory T-cell differentiation and suppression; unrestrained effector T-cell proliferation and inflammation.
Protein dysfunction: Loss of function via truncation or conformational abrogation of surface expression (PMID: 30742970).
Immune involvement: Simultaneous immunodeficiency and autoimmunity — a "Tregopathy." Caudy et al. showed a CD25-deficient patient had "defective IL-10 expression from CD4 lymphocytes, whereas a Foxp3-deficient patient expressed normal levels of IL-10… although Foxp3 is not required for normal IL-10 expression by human CD4 lymphocytes, CD25 expression is important" (PMID: 17196245).
Tissue damage: Direct cytotoxic and inflammatory injury — "Activated CD8(+)STAT5(+) T cells with lytic potential infiltrated the skin, even though FOXP3(+) Tregs were present" (PMID: 23416241).

Suggested GO / CL terms. Biological processes: interleukin-2-mediated signaling pathway (GO:0038110); regulatory T cell differentiation (GO:0045066); positive regulation of T cell proliferation (GO:0042102); JAK-STAT cascade (GO:0007259); tolerance induction (GO:0002507); negative regulation of immune response (GO:0050777). Cell types: regulatory T cell (CL:0000792); CD8-positive, alpha-beta T cell (CL:0000625); CD4-positive, alpha-beta T cell (CL:0000624); thymocyte (CL:0000893); B cell (CL:0000236).

7. Anatomical Structures Affected

Organ / body-system level. Immune/hematologic (primary), digestive, respiratory, integumentary, hepatobiliary, and endocrine systems. Sharfe et al. documented "extensive lymphocytic infiltration of tissues, including lung, liver, gut, and bone… accompanied by tissue atrophy and inflammation" (PMID: 9096364).

Structure	UBERON term
Intestine / gut	UBERON:0000160
Liver	UBERON:0002107
Lung	UBERON:0002048
Skin	UBERON:0002097
Bone / bone marrow	UBERON:0002371
Thymus	UBERON:0002370
Lymph node	UBERON:0000029
Spleen	UBERON:0002106
Thyroid gland	UBERON:0002046
Lacrimal/ocular surface & cornea	UBERON:0000964

Tissue / cell level. Primarily lymphoid tissue and infiltrated epithelial organs. Key cell types: FOXP3⁺ regulatory T cells (CL:0000792), CD8⁺ and CD4⁺ αβ T cells (CL:0000625, CL:0000624), thymocytes (CL:0000893), B cells (CL:0000236).

Subcellular level. Plasma membrane (GO:0005886) — site of the CD25 receptor; LOF variants prevent surface localization (PMID: 30742970). Also external side of plasma membrane (GO:0009897) and receptor complex (GO:0043235).

Localization / lateralization. Multi-organ and bilateral/systemic (e.g., bilateral ocular surface disease, generalized lymphoproliferation), not focal or unilateral.

8. Temporal Development

Onset: Congenital/neonatal to early childhood, typically insidious-to-subacute with recurrent infections and chronic diarrhea in infancy.
Progression: Chronic and progressive without treatment, with accumulating autoimmune organ damage and lymphoproliferation. Episodic autoimmune flares are superimposed.
Duration: Chronic, lifelong; untreated cases carry high early-childhood mortality.
Remission: No spontaneous remission. Durable remission/cure is treatment-induced by HSCT; sirolimus induces medical control.
Critical period: Early molecular diagnosis and timely HSCT represent the key window of therapeutic opportunity — "early clinical and molecular diagnosis… promptly led to HSCT, allowing complete resolution of the symptoms and definitive cure" (PMID: 30742970).

9. Inheritance and Population

Epidemiology. Ultra-rare; ~13 molecularly confirmed cases reported worldwide as of 2026 (PMID: 41659858). No population prevalence or incidence estimate is established (data-level rarity).

Inheritance. Autosomal recessive, biallelic germline LOF variants — "a rare autosomal recessive inborn error of immunity" (PMID: 41659858). Both sexes affected (autosomal). Penetrance appears complete with biallelic LOF; expressivity is variable (spectrum from predominant enteropathy to lung, ocular, or hepatic involvement).

Consanguinity / founder effects. Consanguinity is the principal population risk factor — first-cousin unions are frequently reported (PMID: 41694357). No broad founder mutation established; variants are largely private.

Carrier frequency. Not established given rarity; heterozygous carriers are clinically unaffected.

Population demographics. Reported across multiple populations (Canada, Argentina, Italy, Morocco, others), with clustering in consanguineous families. No sex predilection. Age distribution is pediatric (presentation in infancy/early childhood). Data derive from individual case reports, not registries.

10. Diagnostics

Frontline immunophenotyping. Flow cytometry demonstrating absent/reduced surface CD25 on CD4⁺/activated T cells is the key rapid test: "Cytofluorimetric analysis revealed the total absence of CD25 cell surface expression and addressed IL2Rα molecular investigation" (PMID: 30742970); "flow cytometry showed a complete absence of CD25 expression" (PMID: 41694357).

Molecular confirmation. Sequencing of IL2RA — single-gene testing, IEI/immune-dysregulation gene panels, or whole-exome/whole-genome sequencing. Genetic distinction from IPEX is essential: "Any patient with features of IPEX but with a normal Foxp3 gene should be screened for mutations in the IL-2 receptor subunit CD25" (PMID: 17196245).

Supporting laboratory tests. Lymphocyte subsets (variable; often normal-to-low T cells with expanded activated CD8⁺); immunoglobulins (often normal-to-high, hypergammaglobulinemia); autoantibodies (broad spectrum, including anti-mitochondrial antibodies; PMID: 20650610); impaired in-vitro T-cell proliferation to mitogens (PMID: 9096364, 23416241).

Functional test. Reduced IL-2-induced STAT5 phosphorylation in responder cells.

Biopsy/pathology. Affected-organ biopsy shows lymphocytic infiltration and tissue inflammation (e.g., follicular bronchiolitis with lymphocyte hyperplasia in lung).

Differential diagnosis. IPEX (FOXP3); CD122/IL2RB deficiency; STAT5b deficiency; LRBA deficiency; CTLA4 haploinsufficiency; other IPEX-like Tregopathies; and severe combined immunodeficiency (SCID). CD25 deficiency is distinguished from SCID by lymphoproliferation, autoimmunity, and preserved B-cell development (PMID: 24116927).

Screening. Not part of standard newborn screening. Cascade carrier and prenatal/preimplantation testing available once the familial variant is known.

11. Outcome / Prognosis

Untreated course. Severe and progressive, with high risk of death in early childhood from overwhelming infection and/or autoimmune organ damage — analogous to the lethal Il2/Il2ra-null mouse phenotype (death within ~5 weeks on the BALB/c background, PMID: 9065030) and severe multi-organ infiltration in humans (PMID: 9096364).

Treated course. HSCT is potentially curative — "complete resolution of the symptoms and definitive cure of the disease" after early transplantation (PMID: 30742970); long-term HSCT outcomes are reviewed in two additional novel cases (PMID: 41659858).

Morbidity / QoL. Substantial untreated morbidity (malnutrition, autoimmune organ damage, recurrent infection, dry-eye disease). Formal disability/QoL metrics are not available.

Prognostic factors. Timely molecular diagnosis and access to HSCT are the dominant prognostic determinants; extent of established autoimmune organ damage at transplant influences outcome. No validated prognostic biomarkers beyond the diagnostic markers.

12. Treatment

Definitive / curative therapy. Allogeneic hematopoietic stem cell transplantation (HSCT) replaces the defective hematopoietic compartment and restores functional Tregs — the only curative option (NCIT:C15431 Hematopoietic Stem Cell Transplantation) (PMID: 30742970, 41659858).

Bridging / medical immunomodulation. - Rapamycin (sirolimus) — mTOR inhibitor that spares/favors Tregs; reported as an "effective and safe treatment of a novel IL2RA deficiency" (PMID: 31605764) (NCIT:C1212 Sirolimus; CHEBI:9168). - Corticosteroids and other immunosuppressants for autoimmune flares. - Immunoglobulin replacement and antimicrobial prophylaxis for infection control. - Nutritional support for enteropathy and failure to thrive.

Pharmacogenomics. Not specifically defined for this disease.

Personalized / genotype-guided approach. Diagnosis-driven: confirmation of IL2RA LOF directs the patient toward definitive HSCT with sirolimus bridging, and enables family cascade testing.

Treatment strategy (algorithm). (1) Recognize IPEX-like phenotype → (2) flow cytometry for surface CD25 → (3) IL2RA sequencing → (4) initiate sirolimus/immunosuppression + supportive care to control autoimmunity and infection → (5) proceed to allogeneic HSCT as definitive cure.

13. Prevention

Primary prevention: None possible for a Mendelian disorder (no modifiable exposure).
Secondary/tertiary prevention: Early molecular diagnosis, infection prophylaxis, immunosuppressive control of autoimmunity, and timely HSCT to prevent irreversible organ damage.
Reproductive prevention / counseling: Genetic counseling for autosomal recessive recurrence risk (25% per pregnancy for carrier couples); cascade carrier testing in consanguineous families; and prenatal or preimplantation genetic testing once the familial IL2RA variant is identified.
Immunization / public-health interventions: Not disease-specific, though routine infection prevention and prophylaxis are important for affected children.

14. Other Species / Natural Disease

Taxonomy: Mus musculus (NCBI Taxon 10090) is the principal model species. No described spontaneous natural companion-animal disease equivalent.
Orthologous gene: Il2ra (mouse ortholog of human IL2RA; MGI).
Comparative biology: Mouse Il2ra/Il2 knockouts recapitulate lymphoproliferation, autoimmune hemolytic anemia, and inflammatory bowel disease due to defective Treg-mediated peripheral tolerance, confirming evolutionary conservation of the IL-2/CD25 tolerance mechanism (PMID: 9065030).
Transmission / zoonotic potential: None (genetic disorder).

15. Model Organisms

Mammalian genetic models (mouse; NCBI Taxon 10090). - Il2⁻/⁻ knockout mice: On a mixed 129/Ola × C57BL/6 background, predominantly develop ulcerative-colitis-like disease; when backcrossed to BALB/c they develop generalized autoimmune disease — hemolytic anemia, follicular hyperplasia of lymphoid organs, and inflammation of pancreas, liver, heart, lungs, and thoracic vessels — dying within ~5 weeks, with uncontrolled polyclonal T- and B-cell activation and increased autoantibodies (PMID: 9065030). This demonstrates both phenotype recapitulation and genetic-background modifier effects. - Il2ra (CD25) knockout mice (Willerford et al., Immunity 1995): massive lymphoproliferation, autoimmune hemolytic anemia, and inflammatory bowel disease from defective Treg-mediated tolerance — a direct genetic model of the human disorder. - Foxp1/Foxp4 Treg-conditional knockouts: combined deletion causes lymphoproliferation, inflammation, autoimmunity, and early lethality with reduced CD25 expression, mechanistically linking FOXP1/FOXP4 → Il2ra promoter → CD25 → Treg function (PMID: 40794436).

Model characteristics. Recapitulation is strong for autoimmunity, lymphoproliferation, and colitis; the immunodeficiency/infection-susceptibility axis is less emphasized in murine models. Genetic-background dependence is a key limitation for translating a single model to the full human phenotype spectrum.

Resources. MGI, IMPC/KOMP, IMSR (for Il2ra/Il2 alleles).

Evidence Base

PMID	Title (abbrev.)	Role / how it supports findings
9096364	Human immune disorder from IL-2Rα mutation (Sharfe 1997)	Original description; truncation of CD25, tissue lymphocytic infiltration (lung, liver, gut, bone)
17196245	CD25 deficiency causes IPEX-like syndrome, defective IL-10	Establishes IPEX-like designation, CD25-dependent IL-10; IL2RA screening if FOXP3 normal
23416241	Human IL2RA null mutation	CD8⁺ lymphoproliferation, impaired antigen responses, tissue infiltration despite FOXP3⁺ Tregs
19348914	IL-2/CD25 immunoregulatory mechanisms	CD25 + CD122 + γc confer high-affinity IL-2 binding to Tregs
30742970	New conformational mutation; HSCT cure	Conformational missense abrogates surface CD25; flow-cytometry diagnosis; HSCT cure
41694357	First Moroccan cases	AR inheritance, consanguinity, core phenotype, absent CD25 on flow
41659858	Two novel cases + review (long-term HSCT)	Confirms rarity (~13 cases), AR IEI definition, HSCT outcomes
24116927	Follicular bronchiolitis phenotype	Y41S missense; absent CD25/very low Tregs; lung disease; distinction from SCID
29252577	Severe dry eye in CD25 deficiency	Ocular surface disease; multi-tissue lymphocytic infiltration
31605764	Rapamycin treatment	Sirolimus as effective/safe bridging therapy
9065030	Il2⁻/⁻ BALB/c autoimmune mice	Mouse model; genetic-background modifier effect
40794436	FOXP1/FOXP4 in Tregs	FOXP1/4 bind Il2ra promoter, regulate CD25; modifier biology
20650610	Autoantibody spectrum in IPEX	Broad autoantibodies; pediatric PBC linked to CD25 deficiency
26106896	Fine-mapping IL2RA region	Common IL2RA variants as MS/T1D susceptibility (distinct from LOF disease)
21875375	10p15 IL2RA in T1D	rs41295061 association replicated in T1D
33193078	IL2RA in autoimmune thyroid disease	rs7093069 TT genotype increases AITD risk

Limitations and Knowledge Gaps

Extreme rarity. With only ~13–15 molecularly confirmed cases, all epidemiologic parameters (prevalence, incidence, carrier frequency, sex ratio, precise phenotype frequencies) are unquantified; phenotype frequencies remain qualitative.
Case-report evidence base. Nearly all human data come from single cases/small series with inherent selection and publication bias. No natural-history cohort or registry exists.
Genotype–phenotype correlation is undefined given so few variants.
Mechanistic steps partly inferred. The STAT5-phosphorylation step and gut-microbial drive of enteropathy are inferred from IL-2 biology and mouse data rather than directly demonstrated in every patient.
Modifier genes in humans are unknown; mouse background effects suggest they exist.
No formal QoL/disability metrics or standardized outcome measures are available.
Long-term HSCT outcomes are based on very few transplanted patients.

Proposed Follow-up Experiments / Actions

Establish an international IL2RA-deficiency patient registry (via IEI consortia such as ESID/USIDNET) to aggregate genotype, phenotype, treatment, and outcome data.
Systematic functional characterization of each reported IL2RA variant (surface expression, IL-2 binding, pSTAT5 response) to build a variant-effect map.
Single-cell / immune profiling of patient PBMCs and affected tissues to resolve Treg vs. effector-cell dynamics and IL-10 deficits at cellular resolution.
Standardized HSCT outcome tracking (conditioning regimen, chimerism, autoimmunity resolution, long-term immune reconstitution).
Evaluate low-dose IL-2 and sirolimus as bridging therapies in a prospective, protocolized fashion (noting that high-affinity receptor loss may blunt low-dose IL-2 efficacy — a hypothesis worth testing).
Explore gene-correction / gene-editing (e.g., autologous HSC IL2RA correction) as a future curative alternative to allogeneic HSCT.
Carrier screening in consanguineous populations where cases have clustered, to enable earlier diagnosis and reproductive counseling.

Evidence source types are indicated throughout: human clinical (case reports/series), model organism (mouse knockouts), and in vitro/functional (flow cytometry, STAT5 assays). Ontology suggestions (HPO, GO, CL, UBERON, CHEBI, NCIT, MONDO) are provided inline for knowledge-base ingestion.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.3.0rc1.

Outcome	Count
References checked	16
Resolved	16
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	17
Quoted claims found in source	13
Quoted claims not found in source	4
References weighed for topical relevance	16
On topic	9
Off topic	0

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

Every one of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.

PMID:9096364 (abstract only): "a novel human immune aberration arising from a truncation mutation of the interleukin-2 receptor alpha chain (CD25)… characterized by decreased numbers of peripheral T cells displaying abnormal proliferation but normal B cell development. Extensive lymphocytic infiltration of tissues, including lung, liver, gut, and bone, is observed, accompanied by tissue atrophy and inflammation"
closest text in source: "Extensive lymphocytic infiltration of tissues, including lung, liver, gut, and bone, is observed, accompanied by tissue atrophy and inflammation"
PMID:17196245 (abstract only): "defective IL-10 expression from CD4 lymphocytes, whereas a Foxp3-deficient patient expressed normal levels of IL-10… although Foxp3 is not required for normal IL-10 expression by human CD4 lymphocytes, CD25 expression is important"
closest text in source: "This patient exhibited defective IL-10 expression from CD4 lymphocytes, whereas a Foxp3-deficient patient expressed normal levels of IL-10"
PMID:9096364 (abstract only): "extensive lymphocytic infiltration of tissues, including lung, liver, gut, and bone… accompanied by tissue atrophy and inflammation"
closest text in source: "Extensive lymphocytic infiltration of tissues, including lung, liver, gut, and bone, is observed, accompanied by tissue atrophy and inflammation"
PMID:30742970 (abstract only): "early clinical and molecular diagnosis… promptly led to HSCT, allowing complete resolution of the symptoms and definitive cure"
closest text in source: "The early clinical and molecular diagnosis of CD25 deficiency in this patient promptly led to hematopoietic stem cell transplantation (HSCT), allowing complete resolution of the symptoms and definitive cure of the disease."

Term Validation

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

Outcome	Count
Terms checked	47
Resolved	45
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	2
Terms whose name was checked	22
Terms named correctly	7
Terms named as a different term	13
Terms whose name is worth a second look	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:

MONDO:0011664 (2 mentions) - the report calls it "MONDO"; MONDO calls it immunodeficiency due to CD25 deficiency
HP:0001508 (1 mention) - the report calls it "Physical"; HP calls it Failure to thrive
HP:0002205 (1 mention) - the report calls it "Sign"; HP calls it Recurrent respiratory infections
HP:0000964 (1 mention) - the report calls it "Physical"; HP calls it Eczematoid dermatitis
HP:0002608 (1 mention) - the report calls it "Lab/clinical"; HP calls it Celiac disease
HP:0100646 (1 mention) - the report calls it "Lab/clinical"; HP calls it Thyroiditis
HP:0001890 (1 mention) - the report calls it "Lab"; HP calls it Autoimmune hemolytic anemia
HP:0002716 (1 mention) - the report calls it "Sign"; HP calls it Lymphadenopathy
HP:0001433 (1 mention) - the report calls it "Sign"; HP calls it Hepatosplenomegaly
HP:0006538 (1 mention) - the report calls it "Clinical"; HP calls it Recurrent bronchopulmonary infections
HP:0002850 (1 mention) - the report calls it "Lab"; HP calls it Decreased circulating IgM concentration
HP:0010702 (1 mention) - the report calls it "Lab"; HP calls it Increased circulating immunoglobulin concentration
UBERON:0000964 (1 mention) - the report calls it "Lacrimal/ocular surface & cornea"; UBERON calls it cornea

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

UBERON:0000160 (1 mention) - the report calls it "Intestine / gut"; UBERON calls it intestine
UBERON:0002097 (1 mention) - the report calls it "Skin"; UBERON calls it skin of body, and lists "skin" among its other names

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.

Ask OpenScientist

OpenScientist Report

Classifications

Inheritance

Discussions and Knowledge Gaps

Pathophysiology

Histopathology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Progression

Prevalence

Clinical Burden

Differential Diagnoses

Related Datasets

Experimental Models

Animal Models

Computational Models

Source YAML

References & Deep Research

References

Deep Research

CD25 Deficiency (IL2RA Deficiency): A Comprehensive Disease Characteristics Report

Summary

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic / Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation)

Mechanistic detail

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Evidence Base

Limitations and Knowledge Gaps

Proposed Follow-up Experiments / Actions

Artifacts

Reference Validation

Quotes not found in the cited source

Term Validation

Terms the report names something else

Terms whose name is worth a second look

Prefixes with no resolver