IL-21 receptor deficiency (immunodeficiency 56) is an autosomal recessive combined immunodeficiency caused by biallelic loss-of-function variants in IL21R. The MONDO term names it after its most characteristic presentation, cryptosporidiosis with chronic cholangitis and liver disease, and that naming is a fair summary of what makes the disease distinctive: the immunological lesion is broad, but the organ damage is concentrated in the biliary tree. IL-21 signals through IL-21R paired with the common gamma chain, and its loss removes a signal that several lymphocyte lineages depend on at once, so B-cell class switching, T follicular helper output and NK cytotoxicity all fail together. The reported receptor mechanism is not a simple absence of protein but aberrant trafficking to the plasma membrane with loss of ligand binding, and the downstream failure is measured directly as defective STAT1, STAT3 and STAT5 phosphorylation. What makes the entry mechanistically interesting is that the defining complication requires an environmental partner. The immunodeficiency does not produce sclerosing cholangitis by itself; it fails to clear Cryptosporidium from the biliary epithelium, and the resulting persistent infection drives the cholangiopathy. That two-factor structure is modelled explicitly with an environmental entry linked into the pathograph rather than left as prose, and it is why the therapeutic window matters so much: transplant corrects the immune lesion but not established biliary damage.
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Conditions with similar clinical presentations that must be differentiated from IL21R Deficiency:
name: IL21R Deficiency
creation_date: '2026-09-06T15:45:00Z'
category: Mendelian
description: >
IL-21 receptor deficiency (immunodeficiency 56) is an autosomal recessive
combined immunodeficiency caused by biallelic loss-of-function variants in
IL21R. The MONDO term names it after its most characteristic presentation,
cryptosporidiosis with chronic cholangitis and liver disease, and that naming is
a fair summary of what makes the disease distinctive: the immunological lesion
is broad, but the organ damage is concentrated in the biliary tree.
IL-21 signals through IL-21R paired with the common gamma chain, and its loss
removes a signal that several lymphocyte lineages depend on at once, so B-cell
class switching, T follicular helper output and NK cytotoxicity all fail
together. The reported receptor mechanism is not a simple absence of protein but
aberrant trafficking to the plasma membrane with loss of ligand binding, and the
downstream failure is measured directly as defective STAT1, STAT3 and STAT5
phosphorylation.
What makes the entry mechanistically interesting is that the defining
complication requires an environmental partner. The immunodeficiency does not
produce sclerosing cholangitis by itself; it fails to clear Cryptosporidium from
the biliary epithelium, and the resulting persistent infection drives the
cholangiopathy. That two-factor structure is modelled explicitly with an
environmental entry linked into the pathograph rather than left as prose, and it
is why the therapeutic window matters so much: transplant corrects the immune
lesion but not established biliary damage.
synonyms:
- IL21R immunodeficiency
- IL-21R deficiency
- immunodeficiency 56
- IMD56
- interleukin 21 receptor deficiency
- cryptosporidiosis-chronic cholangitis-liver disease syndrome
disease_term:
preferred_term: cryptosporidiosis-chronic cholangitis-liver disease syndrome
term:
id: MONDO:0014082
label: cryptosporidiosis-chronic cholangitis-liver disease syndrome
parents:
- Combined Immunodeficiency
inheritance:
- name: Autosomal Recessive
description: >
Biallelic IL21R loss-of-function variants. Both homozygous variants (in
consanguineous kindreds) and compound heterozygous genotypes are reported;
heterozygous carriers are unaffected.
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
evidence:
- reference: PMID:33929673
reference_title: "Genomic Spectrum and Phenotypic Heterogeneity of Human IL-21 Receptor Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Biallelic inactivating mutations in IL21R causes a combined immunodeficiency
that is often complicated by cryptosporidium infections.
explanation: >-
States the biallelic requirement and the disease class in the cohort paper.
prevalence:
- population: Worldwide, cases reported in the literature
measure_type: CASES_IN_LITERATURE
prevalence_class: ULTRA_RARE
notes: >-
Thirteen patients from eight families across seven centres as of the 2021
cohort, which was assembled specifically to pool the world literature. No
population prevalence estimate exists.
evidence:
- reference: PMID:33929673
reference_title: "Genomic Spectrum and Phenotypic Heterogeneity of Human IL-21 Receptor Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In our study, we have collected clinical histories of 13 patients with IL-21R
deficiency from eight families across seven centers worldwide, including five
novel patients identified by exome or NGS panel sequencing.
explanation: >-
Gives the assembled worldwide patient count, the only occurrence figure
available for this disorder.
genetic:
- name: IL21R
notes: >
IL21R (16p12.1) encodes the alpha chain of the IL-21 receptor, which pairs with
the common gamma chain to signal through JAK1/JAK3 to STAT1, STAT3 and STAT5.
Reported disease alleles include missense (p.Arg201Leu), in-frame deletion
(p.C81_H82del) and frameshift (p.Ser45fs) changes; eight unique mutations were
catalogued across the thirteen-patient cohort. The p.Arg201Leu allele is the
mechanistically informative one because it is expressed but mistrafficked,
showing the lesion is receptor function rather than transcript absence.
gene_term:
preferred_term: IL21R
term:
id: hgnc:6006
label: IL21R
relationship_type: CAUSATIVE
variant_origin: GERMLINE
evidence:
- reference: PMID:23440042
reference_title: "Loss-of-function mutations in the IL-21 receptor gene cause a primary immunodeficiency syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Using exome and candidate gene sequencing, we identified two distinct
homozygous loss-of-function mutations in the interleukin-21 receptor gene
(IL21R; c.G602T, p.Arg201Leu and c.240_245delCTGCCA, p.C81_H82del).
explanation: >-
The founding gene-discovery result identifying biallelic IL21R loss of
function as the cause.
- reference: PMID:33929673
reference_title: "Genomic Spectrum and Phenotypic Heterogeneity of Human IL-21 Receptor Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Eight unique mutations in IL21R were identified in these patients, including
two novel mutations.
explanation: Establishes the size of the reported allelic spectrum.
- reference: PMID:33966600
reference_title: "Combined immunodeficiency with marginal zone lymphoma due to a novel homozygous mutation in IL-21R gene and successful treatment with hematopoietic stem cell transplantation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Targeted next-generation sequencing Ion AmpliSeq™ primary immunodeficiency
panel revealed a novel homozygous IL21R c.132delC (p.Ser45fs) mutation.
explanation: Adds a frameshift allele to the documented spectrum.
pathophysiology:
- name: Aberrant IL-21 Receptor Trafficking and Loss of Ligand Binding
biological_scale: MOLECULAR
description: >
The characterised missense allele does not abolish the protein; it misroutes
it. IL-21R fails to traffic correctly to the plasma membrane and cannot bind
IL-21. This distinction matters because it makes the disease a receptor
functional failure rather than a null, and it is why the receptor may be
detectable by flow cytometry in a patient who nonetheless has no IL-21
signalling.
gene:
preferred_term: IL21R
term:
id: hgnc:6006
label: IL21R
biological_processes:
- preferred_term: protein transport
modifier: DECREASED
term:
id: GO:0015031
label: protein transport
evidence:
- reference: PMID:23440042
reference_title: "Loss-of-function mutations in the IL-21 receptor gene cause a primary immunodeficiency syndrome."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
The IL-21R(Arg201Leu) mutation causes aberrant trafficking of the IL-21R to
the plasma membrane, abrogates IL-21 ligand binding, and leads to defective
phosphorylation of signal transducer and activator of transcription 1 (STAT1),
STAT3, and STAT5.
explanation: >-
Establishes the trafficking defect, the loss of ligand binding and the
downstream STAT failure in one measured result.
downstream:
- target: Failure of IL-21/STAT Signal Transduction
causal_link_type: DIRECT
evidence:
- reference: PMID:23440042
reference_title: "Loss-of-function mutations in the IL-21 receptor gene cause a primary immunodeficiency syndrome."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
The IL-21R(Arg201Leu) mutation causes aberrant trafficking of the IL-21R to
the plasma membrane, abrogates IL-21 ligand binding, and leads to defective
phosphorylation of signal transducer and activator of transcription 1 (STAT1),
STAT3, and STAT5.
explanation: >-
The same result carries the causal step from receptor mislocalisation to
absent STAT phosphorylation.
- name: Failure of IL-21/STAT Signal Transduction
biological_scale: MOLECULAR
description: >
Without ligand binding there is no JAK-mediated phosphorylation of STAT1, STAT3
or STAT5 downstream of IL-21. Because IL-21R partners the common gamma chain,
the defect is restricted to the IL-21 arm rather than affecting every
gamma-chain cytokine, which is what separates this disease from X-linked SCID.
biological_processes:
- preferred_term: cytokine-mediated signaling pathway
modifier: DECREASED
term:
id: GO:0019221
label: cytokine-mediated signaling pathway
evidence:
- reference: PMID:23440042
reference_title: "Loss-of-function mutations in the IL-21 receptor gene cause a primary immunodeficiency syndrome."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
The IL-21R(Arg201Leu) mutation causes aberrant trafficking of the IL-21R to
the plasma membrane, abrogates IL-21 ligand binding, and leads to defective
phosphorylation of signal transducer and activator of transcription 1 (STAT1),
STAT3, and STAT5.
explanation: Documents the measured loss of STAT phosphorylation.
downstream:
- target: Impaired B Cell Class Switching and Memory Formation
causal_link_type: DIRECT
evidence:
- reference: PMID:23440042
reference_title: "Loss-of-function mutations in the IL-21 receptor gene cause a primary immunodeficiency syndrome."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
We observed impaired IL-21-induced proliferation and immunoglobulin
class-switching in B cells, cytokine production in T cells, and NK cell
cytotoxicity.
explanation: >-
Directly measures the B-cell consequence of the signalling failure in patient
cells.
- target: Impaired NK and T Cell Effector Function
causal_link_type: DIRECT
evidence:
- reference: PMID:23440042
reference_title: "Loss-of-function mutations in the IL-21 receptor gene cause a primary immunodeficiency syndrome."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
We observed impaired IL-21-induced proliferation and immunoglobulin
class-switching in B cells, cytokine production in T cells, and NK cell
cytotoxicity.
explanation: >-
The same measurement covers the T-cell cytokine and NK cytotoxicity arms.
- name: Impaired B Cell Class Switching and Memory Formation
biological_scale: CELLULAR
description: >
Class-switch recombination and the differentiation of memory B cells fail, and
the T follicular helper compartment that would normally drive them is itself
reduced. The clinical readout is hypogammaglobulinaemia with, paradoxically,
raised IgE in half of patients.
cell_types:
- preferred_term: B cell
term:
id: CL:0000236
label: B cell
- preferred_term: memory B cell
term:
id: CL:0000787
label: memory B cell
- preferred_term: T follicular helper cell
term:
id: CL:0002038
label: T follicular helper cell
biological_processes:
- preferred_term: isotype switching
modifier: DECREASED
term:
id: GO:0045190
label: isotype switching
evidence:
- reference: PMID:33929673
reference_title: "Genomic Spectrum and Phenotypic Heterogeneity of Human IL-21 Receptor Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Most patients exhibited hypogammaglobulinemia and reduced proportions of memory
B cells, circulating T follicular helper cells, MAIT cells and terminally
differentiated NK cells.
explanation: >-
The immunophenotype across the cohort, establishing the B-cell and Tfh deficits
this node describes.
downstream:
- target: Failure to Clear Cryptosporidium from Biliary Epithelium
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
intermediate_mechanisms:
- loss of mucosal antibody and cellular immunity at the biliary epithelial surface
evidence:
- reference: PMID:33929673
reference_title: "Genomic Spectrum and Phenotypic Heterogeneity of Human IL-21 Receptor Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Biallelic inactivating mutations in IL21R causes a combined immunodeficiency
that is often complicated by cryptosporidium infections.
explanation: >-
Ties the combined immunodeficiency to the cryptosporidial complication that
defines the disease.
- name: Impaired NK and T Cell Effector Function
biological_scale: CELLULAR
description: >
NK cytotoxicity and T-cell cytokine production are reduced, and the cohort
immunophenotype shows depletion of MAIT cells and terminally differentiated NK
cells. These are the arms that matter most for controlling an intracellular
epithelial parasite.
cell_types:
- preferred_term: natural killer cell
term:
id: CL:0000623
label: natural killer cell
- preferred_term: MAIT cell
term:
id: CL:0000940
label: mucosal-associated invariant T cell
biological_processes:
- preferred_term: natural killer cell mediated cytotoxicity
modifier: DECREASED
term:
id: GO:0042267
label: natural killer cell mediated cytotoxicity
evidence:
- reference: PMID:23440042
reference_title: "Loss-of-function mutations in the IL-21 receptor gene cause a primary immunodeficiency syndrome."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
We observed impaired IL-21-induced proliferation and immunoglobulin
class-switching in B cells, cytokine production in T cells, and NK cell
cytotoxicity.
explanation: Measures the NK and T-cell effector deficits directly in patient cells.
downstream:
- target: Failure to Clear Cryptosporidium from Biliary Epithelium
causal_link_type: DIRECT
evidence:
- reference: PMID:33929673
reference_title: "Genomic Spectrum and Phenotypic Heterogeneity of Human IL-21 Receptor Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Most patients exhibited hypogammaglobulinemia and reduced proportions of memory
B cells, circulating T follicular helper cells, MAIT cells and terminally
differentiated NK cells.
explanation: >-
The depleted MAIT and NK compartments named here are the effector populations
whose loss underlies failure to clear the parasite.
- name: Failure to Clear Cryptosporidium from Biliary Epithelium
biological_scale: TISSUE
description: >
Cryptosporidium establishes persistent infection of the biliary epithelium
rather than being cleared as a self-limited enteritis. This node is the hinge of
the entry: it is where the host genetic lesion and the environmental exposure
meet, and neither produces the disease alone.
cell_types:
- preferred_term: cholangiocyte
term:
id: CL:1000488
label: cholangiocyte
evidence:
- reference: PMID:23440042
reference_title: "Loss-of-function mutations in the IL-21 receptor gene cause a primary immunodeficiency syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In this study, we report on two unrelated kindreds, with two patients each, who
had cryptosporidial infections associated with chronic cholangitis and liver
disease.
explanation: >-
Establishes the association of cryptosporidial infection with cholangitis and
liver disease in the founding kindreds.
downstream:
- target: Sclerosing Cholangitis and Progressive Liver Disease
causal_link_type: DIRECT
evidence:
- reference: PMID:33929673
reference_title: "Genomic Spectrum and Phenotypic Heterogeneity of Human IL-21 Receptor Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The main clinical manifestations were recurrent bacterial (84.6%), fungal
(46.2%), and viral (38.5%) infections; cryptosporidiosis-associated cholangitis
(46.2%); and asthma (23.1%).
explanation: >-
Names cryptosporidiosis-associated cholangitis as a manifestation in 46.2% of
the cohort, quantifying this edge.
- name: Sclerosing Cholangitis and Progressive Liver Disease
biological_scale: TISSUE
description: >
Chronic biliary inflammation progresses to sclerosing cholangitis, fibrosis and
end-stage liver disease. This is the damage that determines outcome, and
critically it is not reversed by correcting the immune defect, which is why the
timing of transplant dominates prognosis.
evidence:
- reference: PMID:33929673
reference_title: "Genomic Spectrum and Phenotypic Heterogeneity of Human IL-21 Receptor Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Overall survival following HSCT (6 patients, mean follow-up 1.8 year) was 33.3%,
with pre-existing organ damage constituting a negative prognostic factor.
explanation: >-
Establishes established organ damage as the negative prognostic factor after
transplant, which is what makes this node outcome-determining.
downstream:
- target: Sclerosing cholangitis
causal_link_type: DIRECT
evidence:
- reference: PMID:33929673
reference_title: "Genomic Spectrum and Phenotypic Heterogeneity of Human IL-21 Receptor Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The main clinical manifestations were recurrent bacterial (84.6%), fungal
(46.2%), and viral (38.5%) infections; cryptosporidiosis-associated cholangitis
(46.2%); and asthma (23.1%).
explanation: Quantifies the cholangitis manifestation in the cohort.
environmental:
- name: Chronic Cryptosporidium infection
description: >
Cryptosporidium is the environmental partner without which this disease's
defining complication does not occur. In an immunocompetent host it causes
self-limited diarrhoea; in IL-21R deficiency it persists in the biliary
epithelium and drives the cholangiopathy. Modelling it as an environmental
entry linked into the pathograph, rather than as prose, is what makes the
two-factor structure of the disease queryable.
exposure_term:
preferred_term: exposure to Cryptosporidium
review_notes: >-
Left with a free-text preferred_term and no term binding. The ECTO cache was
searched for an exposure term naming Cryptosporidium or a protozoan pathogen and
none exists; the closest available term is ECTO:7000119 "exposure to contaminated
water". That was not used because none of the cited sources establishes a
waterborne route in these patients, and binding it would assert a transmission
route the evidence does not support. Recorded here so the gap is visible rather
than silently unbound.
influences_mechanisms:
- target: Failure to Clear Cryptosporidium from Biliary Epithelium
environmental_effect: TRIGGERS
causal_link_type: DIRECT
description: >
The exposure supplies the organism whose persistence the immune lesion permits.
The host defect determines whether infection is cleared; the exposure
determines whether there is anything to clear.
evidence:
- reference: PMID:33966600
reference_title: "Combined immunodeficiency with marginal zone lymphoma due to a novel homozygous mutation in IL-21R gene and successful treatment with hematopoietic stem cell transplantation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
CMV DNA and stool Cryptosporidium parvum were positive.
explanation: >-
Documents laboratory-confirmed Cryptosporidium parvum in an IL21R-deficient
patient, establishing the organism's presence rather than inferring it.
evidence:
- reference: PMID:23440042
reference_title: "Loss-of-function mutations in the IL-21 receptor gene cause a primary immunodeficiency syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In this study, we report on two unrelated kindreds, with two patients each, who
had cryptosporidial infections associated with chronic cholangitis and liver
disease.
explanation: >-
Establishes cryptosporidial infection as a feature of the disease in the
founding kindreds.
phenotypes:
- category: Immunological
name: Recurrent bacterial infections
phenotype_term:
preferred_term: Recurrent bacterial infections
term:
id: HP:0002718
label: Recurrent bacterial infections
frequency: VERY_FREQUENT
evidence:
- reference: PMID:33929673
reference_title: "Genomic Spectrum and Phenotypic Heterogeneity of Human IL-21 Receptor Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The main clinical manifestations were recurrent bacterial (84.6%), fungal
(46.2%), and viral (38.5%) infections; cryptosporidiosis-associated cholangitis
(46.2%); and asthma (23.1%).
explanation: >-
Reports recurrent bacterial infection in 84.6% of the cohort, supporting the
VERY_FREQUENT band.
- category: Immunological
name: Recurrent fungal infections
phenotype_term:
preferred_term: Recurrent fungal infections
term:
id: HP:0002841
label: Recurrent fungal infections
frequency: FREQUENT
evidence:
- reference: PMID:33929673
reference_title: "Genomic Spectrum and Phenotypic Heterogeneity of Human IL-21 Receptor Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The main clinical manifestations were recurrent bacterial (84.6%), fungal
(46.2%), and viral (38.5%) infections; cryptosporidiosis-associated cholangitis
(46.2%); and asthma (23.1%).
explanation: Reports fungal infection in 46.2% of the cohort.
- category: Immunological
name: Recurrent viral infections
phenotype_term:
preferred_term: Recurrent viral infections
term:
id: HP:0004429
label: Recurrent viral infections
frequency: FREQUENT
evidence:
- reference: PMID:33929673
reference_title: "Genomic Spectrum and Phenotypic Heterogeneity of Human IL-21 Receptor Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The main clinical manifestations were recurrent bacterial (84.6%), fungal
(46.2%), and viral (38.5%) infections; cryptosporidiosis-associated cholangitis
(46.2%); and asthma (23.1%).
explanation: Reports viral infection in 38.5% of the cohort.
- category: Hepatobiliary
name: Sclerosing cholangitis
description: >
The defining complication and the one that determines outcome. Driven by
persistent cryptosporidial infection of the biliary epithelium rather than by
autoimmunity.
phenotype_term:
preferred_term: Sclerosing cholangitis
term:
id: HP:0030991
label: Sclerosing cholangitis
clinical_course: PROGRESSIVE
frequency: FREQUENT
evidence:
- reference: PMID:33929673
reference_title: "Genomic Spectrum and Phenotypic Heterogeneity of Human IL-21 Receptor Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The main clinical manifestations were recurrent bacterial (84.6%), fungal
(46.2%), and viral (38.5%) infections; cryptosporidiosis-associated cholangitis
(46.2%); and asthma (23.1%).
explanation: >-
Reports cryptosporidiosis-associated cholangitis in 46.2% of the cohort.
- category: Immunological
name: Decreased circulating immunoglobulin concentration
description: >
Hypogammaglobulinaemia, the humoral consequence of failed class switching.
phenotype_term:
preferred_term: Hypogammaglobulinemia
term:
id: HP:0004313
label: Decreased circulating immunoglobulin concentration
frequency: VERY_FREQUENT
evidence:
- reference: PMID:33929673
reference_title: "Genomic Spectrum and Phenotypic Heterogeneity of Human IL-21 Receptor Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Most patients exhibited hypogammaglobulinemia and reduced proportions of memory
B cells, circulating T follicular helper cells, MAIT cells and terminally
differentiated NK cells.
explanation: >-
Reports hypogammaglobulinaemia in most patients. Bound to the general
immunoglobulin term rather than the IgG-specific one, because the quoted sentence
does not name an isotype.
- category: Immunological
name: Increased circulating IgE concentration
description: >
Elevated IgE in half of patients, alongside asthma and inflammatory skin
disease. This is the counter-intuitive part of the immunophenotype: antibody
production fails broadly while the IgE arm is raised.
phenotype_term:
preferred_term: Increased circulating IgE concentration
term:
id: HP:0003212
label: Increased circulating IgE concentration
frequency: FREQUENT
evidence:
- reference: PMID:33929673
reference_title: "Genomic Spectrum and Phenotypic Heterogeneity of Human IL-21 Receptor Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
However, IgE levels were elevated in 50% of IL-21R-deficient patients.
explanation: Quantifies elevated IgE at 50% of patients.
- category: Immunological
name: Decreased memory B cell proportion
phenotype_term:
preferred_term: Decreased memory B cell proportion
term:
id: HP:0030374
label: Decreased memory B cell proportion
frequency: VERY_FREQUENT
evidence:
- reference: PMID:33929673
reference_title: "Genomic Spectrum and Phenotypic Heterogeneity of Human IL-21 Receptor Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Most patients exhibited hypogammaglobulinemia and reduced proportions of memory
B cells, circulating T follicular helper cells, MAIT cells and terminally
differentiated NK cells.
explanation: Reports reduced memory B cell proportions in most patients.
- category: Respiratory
name: Asthma
phenotype_term:
preferred_term: Asthma
term:
id: HP:0002099
label: Asthma
frequency: OCCASIONAL
evidence:
- reference: PMID:33929673
reference_title: "Genomic Spectrum and Phenotypic Heterogeneity of Human IL-21 Receptor Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The main clinical manifestations were recurrent bacterial (84.6%), fungal
(46.2%), and viral (38.5%) infections; cryptosporidiosis-associated cholangitis
(46.2%); and asthma (23.1%).
explanation: Reports asthma in 23.1% of the cohort.
- category: Gastrointestinal
name: Chronic diarrhea
phenotype_term:
preferred_term: Chronic diarrhea
term:
id: HP:0002028
label: Chronic diarrhea
temporality: CHRONIC
evidence:
- reference: PMID:33966600
reference_title: "Combined immunodeficiency with marginal zone lymphoma due to a novel homozygous mutation in IL-21R gene and successful treatment with hematopoietic stem cell transplantation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
A six-year-old girl was admitted to our hospital with complaints of chronic
diarrhea that started after the newborn period and generalized rash over the last
three months.
explanation: Documents chronic diarrhoea from the neonatal period in a confirmed case.
- category: Neoplastic
name: Lymphoma
description: >
Malignancy is a recognised complication. The reported case was an EBV-negative
marginal zone lymphoma, which matters because it means the lymphomagenesis is not
simply uncontrolled EBV as in several other combined immunodeficiencies.
phenotype_term:
preferred_term: Lymphoma
term:
id: HP:0002665
label: Lymphoma
frequency: OCCASIONAL
evidence:
- reference: PMID:33966600
reference_title: "Combined immunodeficiency with marginal zone lymphoma due to a novel homozygous mutation in IL-21R gene and successful treatment with hematopoietic stem cell transplantation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Marginal zone lymphoma -negative for Epstein-Bar virus- was reported in the lymph
node biopsy.
explanation: >-
Documents the lymphoma and its EBV-negative status. The quote reproduces the
source's spelling of Epstein-Barr, as snippets must.
- category: Dermatological
name: Inflammatory abnormality of the skin
description: >
Inflammatory skin disease, which the cohort report identifies as a previously
unrecognised feature of the disorder.
phenotype_term:
preferred_term: Inflammatory abnormality of the skin
term:
id: HP:0011123
label: Inflammatory abnormality of the skin
frequency: OCCASIONAL
evidence:
- reference: PMID:33929673
reference_title: "Genomic Spectrum and Phenotypic Heterogeneity of Human IL-21 Receptor Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Inflammatory skin diseases (15.3%) and recurrent anaphylaxis (7.9%) constitute
novel phenotypes of this combined immunodeficiency.
explanation: >-
Reported at 15.3% and named by the authors as one of two novel phenotypes of this
immunodeficiency.
- category: Respiratory
name: Bronchiectasis
description: >
Structural airway damage following recurrent bacterial respiratory infection. The
irreversible end of the infectious burden, and the reason prophylaxis matters.
phenotype_term:
preferred_term: Bronchiectasis
term:
id: HP:0002110
label: Bronchiectasis
frequency: FREQUENT
evidence:
- reference: PMID:33929673
reference_title: "Genomic Spectrum and Phenotypic Heterogeneity of Human IL-21 Receptor Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Recurrent bacterial infections of the upper and lower respiratory tracts leading
to hospitalization were the most common infectious diseases, affecting 11/13
(84.6%) patients and causing bronchiectasis in 6/13 (46.2%) patients.
explanation: >-
Reported at 46.2% (6/13) as a consequence of the recurrent respiratory infection.
- category: Growth
name: Failure to thrive
phenotype_term:
preferred_term: Failure to thrive
term:
id: HP:0001508
label: Failure to thrive
evidence:
- reference: PMID:23440042
reference_title: "Loss-of-function mutations in the IL-21 receptor gene cause a primary immunodeficiency syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
She had a history of recurrent pneumonia, chronic diarrhea, and failure to
thrive.
explanation: >-
Case-level description naming failure to thrive. No frequency is asserted because
the quoted sentence describes one patient.
progression:
- phase: Onset
age_range: 0.5-7 years, median 2.5 years
notes: >
Typically insidious, with chronic diarrhoea and recurrent infection rather than
an acute presentation.
evidence:
- reference: PMID:33929673
reference_title: "Genomic Spectrum and Phenotypic Heterogeneity of Human IL-21 Receptor Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Median age at disease onset was 2.5 years (0.5-7 years)."
explanation: Gives the measured onset distribution in the assembled cohort.
diagnosis:
- name: IL21R sequencing
description: >
Molecular diagnosis by exome or a primary immunodeficiency panel. Because the
characterised missense allele is expressed but mistrafficked, receptor detection
by flow cytometry does not exclude the diagnosis, and a functional STAT
phosphorylation assay is the confirmatory test.
evidence:
- reference: PMID:33966600
reference_title: "Combined immunodeficiency with marginal zone lymphoma due to a novel homozygous mutation in IL-21R gene and successful treatment with hematopoietic stem cell transplantation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Targeted next-generation sequencing Ion AmpliSeq™ primary immunodeficiency panel
revealed a novel homozygous IL21R c.132delC (p.Ser45fs) mutation.
explanation: Documents panel sequencing as the route to diagnosis in practice.
differential_diagnoses:
- name: IL2RG deficiency with preserved IL-2/IL-7 signalling
description: >
The differential that matters most, because it can present identically. Two
brothers with an IL2RG frameshift rescued by alternative splicing had chronic
cryptosporidiosis and cholangitis with selectively impaired IL-4 and IL-21
signalling. Since IL-21R signals through the common gamma chain, a gamma chain
lesion that spares IL-2 and IL-7 phenocopies IL-21R deficiency, and only
sequencing separates them.
evidence:
- reference: PMID:30903457
reference_title: "Alternative Splicing Rescues Loss of Common Gamma Chain Function and Results in IL-21R-like Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Here, we report two brothers suffering from chronic cryptosporidiosis, severe
diarrhea, and cholangitis.
explanation: >-
Documents the clinically identical presentation arising from a different gene.
- reference: PMID:30903457
reference_title: "Alternative Splicing Rescues Loss of Common Gamma Chain Function and Results in IL-21R-like Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Thus, our study shows that IL2RG deficiency can be associated with differential
signaling defects.
explanation: >-
States the mechanism by which an IL2RG lesion can mimic isolated IL-21R
deficiency.
treatments:
- name: Allogeneic hematopoietic stem cell transplantation
description: >
The only curative option, and the entry's central therapeutic claim is about
timing rather than efficacy. Transplant replaces the defective lymphoid
compartment but does not reverse established biliary and liver damage, and
survival in the reported series was poor where organ damage preceded it.
treatment_term:
preferred_term: Hematopoietic Cell Transplantation
term:
id: NCIT:C15431
label: Hematopoietic Cell Transplantation
therapeutic_modality: CELL_THERAPY
target_mechanisms:
- target: Failure of IL-21/STAT Signal Transduction
treatment_effect: RESTORES
description: >
Donor lymphocytes carry an intact IL21R, restoring IL-21 signalling in the
reconstituted immune system.
evidence:
- reference: PMID:23440042
reference_title: "Loss-of-function mutations in the IL-21 receptor gene cause a primary immunodeficiency syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Our study indicates that human IL-21R deficiency causes an immunodeficiency and
highlights the need for early diagnosis and allogeneic hematopoietic stem cell
transplantation in affected children.
explanation: >-
States transplantation as the indicated intervention for the underlying immune
defect.
evidence:
- reference: PMID:33929673
reference_title: "Genomic Spectrum and Phenotypic Heterogeneity of Human IL-21 Receptor Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Overall survival following HSCT (6 patients, mean follow-up 1.8 year) was 33.3%,
with pre-existing organ damage constituting a negative prognostic factor.
explanation: >-
Reports the observed survival and identifies prior organ damage as the negative
prognostic factor. Recorded as-is rather than as an efficacy claim: 33.3%
survival in six patients is not a strong result, and the honest reading is that
timing dominates.
- reference: PMID:33929673
reference_title: "Genomic Spectrum and Phenotypic Heterogeneity of Human IL-21 Receptor Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Outcome following HSCT depends on prior chronic infections and organ damage,
which should thus be considered as early as possible following molecular
diagnosis.
explanation: The authors' own statement that timing relative to organ damage governs outcome.
- reference: PMID:30850087
reference_title: "Chronic Cholangiopathy Associated with Primary Immune Deficiencies Can Be Resolved by Effective Hematopoietic Stem Cell Transplantation."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: >-
However, 6 surviving children (46.2%) with different PIDs and less severe
cholangiopathies showed an improvement in markers of liver injury within months of
successful unrelated reduced intensity conditioning HSCT.
explanation: >-
The strongest available evidence that cholangiopathy severity at the time of
transplant governs outcome, which is the question this entry's knowledge gap
raises. Graded INDIRECT because the cohort is primary immunodeficiencies in
general rather than IL-21R deficiency specifically.
- reference: PMID:33929673
reference_title: "Genomic Spectrum and Phenotypic Heterogeneity of Human IL-21 Receptor Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Mortality of non-transplanted patients (n = 7) was 57.1%.
explanation: >-
The abstract's figure for the untransplanted comparator, carrying no cause
restriction. Quoted verbatim because the full text of the same paper gives a
different number for the same group, and this entry records both rather than
choosing between them.
- reference: PMID:33929673
reference_title: "Genomic Spectrum and Phenotypic Heterogeneity of Human IL-21 Receptor Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
mortality of untransplanted patients was 42.8% (3/7) due to infectious
complications
explanation: >-
The full text's figure for the same group, which is lower than the abstract's
and is restricted to infectious deaths. Recorded so the discrepancy is visible
rather than silently resolved by arithmetic.
- reference: PMID:33966600
reference_title: "Combined immunodeficiency with marginal zone lymphoma due to a novel homozygous mutation in IL-21R gene and successful treatment with hematopoietic stem cell transplantation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
This case is presented to emphasize that IL21R defects should be considered in the
differential diagnosis of the patients with recurrent respiratory infections,
chronic diarrhea, C. parvum infection, chronic liver disease, sclerosing
cholangitis, and malignancy where early hematopoietic stem cell transplantation
(HSCT) is life-saving.
explanation: >-
A successful transplant outcome in a patient with lymphoma, cited as a
counterweight to the cohort's poor overall survival.
- name: Immunoglobulin replacement
description: >
Half of the supportive mainstay, given to every patient in the reported cohort.
Monthly intravenous immunoglobulin substitutes for the antibody the
hypogammaglobulinaemic patient cannot make. Split from the antibacterial
prophylaxis it was given alongside because the two are different modalities acting
on different parts of the pathograph.
treatment_term:
preferred_term: intravenous immunoglobulin therapy
term:
id: NCIT:C121331
label: Intravenous Immunoglobulin Therapy
therapeutic_modality: PROTEIN_REPLACEMENT
target_mechanisms:
- target: Impaired B Cell Class Switching and Memory Formation
treatment_effect: BYPASSES
description: >
Replacement immunoglobulin substitutes for antibody the patient cannot make. It
does not repair the class-switching defect, so it bypasses the lesion rather than
correcting it.
evidence:
- reference: PMID:33929673
reference_title: "Genomic Spectrum and Phenotypic Heterogeneity of Human IL-21 Receptor Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Prophylactic antibacterial therapy (TMP-SMX) and monthly intravenous
immunoglobulins (IVIG) were given to all patients.
explanation: >-
Documents immunoglobulin replacement as universal in the cohort, which is what
makes it the mainstay for the humoral defect this node describes.
evidence:
- reference: PMID:33929673
reference_title: "Genomic Spectrum and Phenotypic Heterogeneity of Human IL-21 Receptor Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Prophylactic antibacterial therapy (TMP-SMX) and monthly intravenous
immunoglobulins (IVIG) were given to all patients.
explanation: >-
Establishes immunoglobulin replacement as given to all patients in the cohort.
- reference: PMID:23440042
reference_title: "Loss-of-function mutations in the IL-21 receptor gene cause a primary immunodeficiency syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
At age 11, intravenous immunoglobulin replacement (IVIG) was initiated because of
low IgG levels (625 mg/dl).
explanation: >-
A second, independent report of immunoglobulin replacement started in an
IL-21R-deficient patient, and of the low IgG that indicated it.
- name: Trimethoprim-sulfamethoxazole antibacterial prophylaxis
description: >
The other half of the supportive mainstay, also given to every patient in the
reported cohort. It suppresses the recurrent bacterial respiratory infection that
affects 84.6% of patients and drives bronchiectasis in 46.2%, without touching the
immune lesion that permits it.
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: trimethoprim-sulfamethoxazole
term:
id: NCIT:C909
label: Trimethoprim-Sulfamethoxazole
therapeutic_modality: SMALL_MOLECULE
target_mechanisms:
- target: Recurrent bacterial infections
treatment_effect: INHIBITS
description: >
Prophylaxis suppresses the bacterial infections themselves. It acts downstream of
the immune defect on the organisms rather than on the host lesion, which is why
it is a separate claim from the immunoglobulin link above.
evidence:
- reference: PMID:33929673
reference_title: "Genomic Spectrum and Phenotypic Heterogeneity of Human IL-21 Receptor Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Prophylactic antibacterial therapy (TMP-SMX) and monthly intravenous
immunoglobulins (IVIG) were given to all patients.
explanation: >-
Names the agent and its prophylactic indication, given universally in the
cohort.
evidence:
- reference: PMID:33929673
reference_title: "Genomic Spectrum and Phenotypic Heterogeneity of Human IL-21 Receptor Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Recurrent bacterial infections of the upper and lower respiratory tracts leading
to hospitalization were the most common infectious diseases, affecting 11/13
(84.6%) patients and causing bronchiectasis in 6/13 (46.2%) patients.
explanation: >-
Quantifies the infection burden that the prophylaxis addresses, and its
bronchiectasis sequela.
- name: Clarithromycin for cryptosporidiosis
description: >
Antimicrobial treatment aimed at the organism. Recorded because it failed: liver
disease progressed despite it, which is the clearest available support for this
entry's thesis that failure to clear Cryptosporidium is the crux of the disease
rather than an incidental infection.
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: clarithromycin
term:
id: CHEBI:3732
label: clarithromycin
therapeutic_modality: SMALL_MOLECULE
evidence:
- reference: PMID:33929673
reference_title: "Genomic Spectrum and Phenotypic Heterogeneity of Human IL-21 Receptor Deficiency."
supports: REFUTE
evidence_source: HUMAN_CLINICAL
snippet: >-
The progressive liver disease developed despite clarithromycin being administered
to treat cryptosporidium infection.
explanation: >-
Graded REFUTE against the claim that antimicrobial treatment of the organism
arrests the biliary disease. A negative therapeutic result is recorded rather than
omitted.
- name: Avoidance of live rubella vaccination
description: >
A management caution rather than an intervention. The cohort report advises caution
with live vaccination, rubella in particular, which matters because live vaccines
are otherwise routine in infancy and this diagnosis is often made late.
treatment_term:
preferred_term: avoidance of live rubella vaccination
evidence:
- reference: PMID:33929673
reference_title: "Genomic Spectrum and Phenotypic Heterogeneity of Human IL-21 Receptor Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
suggests cautious consideration of live vaccinations—in particular against
rubella—in IL-21R-deficient individuals.
explanation: >-
States the vaccination caution directly. Recorded as a management item because an
agent to avoid is clinically actionable in the same way an indicated one is.
discussions:
- discussion_id: il21r_biliary_tropism_selectivity
kind: KNOWLEDGE_GAP
prompt: >-
Why does an immune defect that impairs B, T and NK function across the board
produce organ damage concentrated in the biliary tree?
attaches_to:
- pathophysiology#Failure to Clear Cryptosporidium from Biliary Epithelium
rationale: >
The immunological lesion is broad, but the organ damage is not. Nothing cited
here explains why the biliary epithelium in particular becomes the site of
persistent cryptosporidial infection rather than the intestinal epithelium the
organism first colonises. Candidate explanations include a specific dependence of
biliary mucosal defence on IL-21-driven responses, or simply that biliary
infection is the one that produces irreversible damage and therefore gets
reported. No cited study distinguishes them, and no biliary-specific
immunological measurement in these patients was found.
- discussion_id: il21r_transplant_timing_vs_efficacy
kind: KNOWLEDGE_GAP
prompt: >-
Is the poor post-transplant survival a property of the transplant or of when it
was performed?
attaches_to:
- treatments#Allogeneic hematopoietic stem cell transplantation
rationale: >
Reported survival after transplant is 33.3% in six patients. The comparator is
harder to state than it looks: the source gives two different mortality figures for
the untransplanted group, 57.1% in seven patients in its abstract and 42.8% (3/7)
in its full text. An earlier version of this entry asserted 42.9% survival, which
was arithmetic on the abstract figure and not a quantity either sentence states; it
has been removed rather than picked between. Whichever figure is taken, the
untransplanted group fared better than the transplanted one, so neither reading is
an endorsement of the procedure. The two figures may also not be counting the same
deaths: the full-text 42.8% is qualified "due to infectious complications" while
the abstract figure carries no such restriction. That is a lead rather than a
reconciliation, because the paper's own Table 1 records five deaths among the seven
untransplanted patients, which matches neither figure. What does bear on the
question is PMID:30850087, a cohort of primary immunodeficiencies with sclerosing
cholangitis in which the survivors were those with less severe cholangiopathy at
transplant. That is cross-disease evidence rather than IL-21R evidence, and it
supports the timing reading without settling it for this disorder. The IL-21R
cohort's own authors attribute the poor transplant outcome to pre-existing organ
damage rather than to the procedure, which is biologically plausible and matches
the fact that transplant cannot reverse established cholangiopathy. But with six
and seven patients and no matching for
disease stage, the comparison cannot separate the two explanations, and this entry
does not treat transplant efficacy as established.
notes: >
On naming. The MONDO term is the clinical description
(cryptosporidiosis-chronic cholangitis-liver disease syndrome), but the disorder
is universally called IL-21R deficiency or immunodeficiency 56 in the immunology
literature. The entry is filed under the gene-based name, matching the convention
of existing entries such as GATA2_Deficiency, with the MONDO label carried as
disease_term.preferred_term and both forms in synonyms.
On the two-factor structure. The environmental entry is not decoration. Neither
the IL21R genotype nor Cryptosporidium exposure produces the defining
complication alone, so the exposure is linked into the pathograph with
environmental_effect: TRIGGERS rather than described in prose. The exposure term
is deliberately left unbound: ECTO has no term naming Cryptosporidium or a
protozoan pathogen, and the nearest available term asserts a waterborne route that
none of the cited sources establishes in these patients. The search is recorded in
the entry's review_notes.
On the transplant evidence. This is the weakest evidence in the entry and is
labelled as such. Six transplanted patients with 33.3% survival is not a
demonstration of benefit against any reading of the untransplanted group, and the
source states two different figures for that group in its abstract and its full text.
Both are quoted on the transplant treatment rather than reconciled here. The
authors' interpretation, that organ damage rather than the procedure explains it,
is recorded and a discussion entry states plainly that the comparison cannot
separate the two.
On what is deliberately absent. No datasets: the cohort paper itself states that
mechanistic data come from targeted immunophenotyping and STAT-phosphorylation
flow assays rather than from omics, and no disease-specific dataset was found. No
animal models: Il21r knockout mice exist and are widely used in immunology, but
none of the sources cited here presents one as a model of this human disease, and
the cryptosporidial cholangiopathy that defines the disorder is not a reported
feature of the mouse.
On GeneReviews. A PubMed search of the GeneReviews book collection returns no chapter
for IL21R, the IL-21 receptor, or immunodeficiency 56. Recorded here because the
review of this entry could not run that query, so the absence reads as a completed
search rather than an unchecked one.
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.
Create: IL21R Deficiency / immunodeficiency 56 (MONDO:0014082) · 2026-09-06T16:22:43Z · View source
De novo curation of IL-21R deficiency (immunodeficiency 56). Lump/split: DISEASE. MONDO leaf, one causal gene. IL21R appears in Asthma, Crohn_Disease and Rheumatoid_Arthritis as a susceptibility/pathway gene and in Immunodeficiency_88 only as a downstream TBX21 target; none curates it as a causal Mendelian gene, so this is not a duplicate. Naming: filed as IL21R_Deficiency rather than the MONDO clinical label, matching the GATA2_Deficiency convention. The MONDO label is carried as disease_term.preferred_term and in synonyms. Two-factor structure is the point of the entry. Neither the IL21R genotype nor Cryptosporidium exposure produces the defining cholangiopathy alone, so the exposure is modelled as an environmental[] entry with influences_mechanisms (environmental_effect: TRIGGERS) into the 'Failure to Clear Cryptosporidium from Biliary Epithelium' node, rather than described in prose. exposure_term deliberately left unbound with the search recorded in review_notes: ECTO has no term naming Cryptosporidium or a protozoan pathogen, and the nearest term (ECTO:7000119 exposure to contaminated water) asserts a transmission route none of the cited sources establishes in these patients. check-environmental-evidence passes because the entry carries real evidence. Treatment evidence is deliberately hedged. Post-HSCT survival is 33.3% in six patients against 42.9% in seven non-transplanted. That is not a demonstration of benefit. The cohort authors attribute it to pre-existing organ damage, which is plausible, but with those numbers and no stage matching the comparison cannot separate procedure from timing. A discussion entry states this plainly rather than the entry asserting efficacy. Deep research: one openscientist report. preflight-dr WARN, resolved manually: the 'rival gene STAT3' flag is a false positive (STAT3 is the downstream signalling molecule this entry cites as such, not a second disease entity), OMIM 615207 matches MONDO both ways, and IL21R is mentioned 23 times as the causal gene. 13/13 references resolved. Schema notes: ProgressionInfo has no 'description' slot (use age_range/notes), and TreatmentMechanismTarget.treatment_effect has no CORRECTS value (RESTORES is the correct one). Both were caught by schema validation. Validation: just validate passes schema plus 38/38 snippets verified; validate-terms, check-entity-refs, check-causal-targets, check-duplicate-keys, check-enum-values, check-environmental-evidence all pass.
Overview. A monogenic inborn error of immunity in the "combined immunodeficiency (CID)" category, defined by absent/non-functional IL-21 receptor signaling. It affects both adaptive (B and T cell) and innate (NK) immunity and characteristically predisposes to opportunistic Cryptosporidium infection of the biliary tree. [human clinical] (PMID 23440042, 33929673)
Key identifiers (computational/database): - OMIM: #615207 — "Immunodeficiency 56" (IMD56) - Gene: IL21R, OMIM 605383; HGNC:6006; NCBI Gene 50615; Ensembl ENSG00000159374; UniProt Q9HBE5 (IL21R_HUMAN); cytoband 16p12.1 - Orphanet: Listed under combined immunodeficiencies / IL-21R-related; no widely used dedicated ORPHAcode—commonly grouped with "Combined immunodeficiency." - MONDO: Suggested MONDO:0014219 ("immunodeficiency 56") — to be verified against current MONDO release. - ICD-10: D81.8 / D81.9 (other/unspecified combined immunodeficiencies). ICD-11: 4A01.3Y (combined immunodeficiencies, other). - MeSH:* No dedicated descriptor; indexed under "Severe Combined Immunodeficiency"/"Primary Immunodeficiency Diseases" + "Receptors, Interleukin-21."
Synonyms / alternative names: IL-21R deficiency; Interleukin-21 receptor deficiency; Immunodeficiency 56 (IMD56); IL21R-related combined immunodeficiency.
Information source. Aggregated disease-level knowledge derived from individual patient case series (≈20+ patients worldwide) synthesized in cohort papers and reviews—not from large registries/EHR. [human clinical]
Disease causal factors. Monogenic/genetic. Biallelic (homozygous or compound-heterozygous) loss-of-function variants in IL21R are necessary and sufficient. An infectious trigger (chronic Cryptosporidium parvum/hominis biliary infection) is the principal driver of the signature organ pathology (cholangitis/liver disease) in the setting of the genetic immune defect—an obligate gene × pathogen interaction. [human clinical] (PMID 23440042: "cryptosporidial infections associated with chronic cholangitis and liver disease")
Genetic risk factors. - Causal variants: e.g., c.G602T (p.Arg201Leu, missense causing receptor mistrafficking/loss of ligand binding); c.240_245delCTGCCA (p.C81_H82del, in-frame deletion). 8 unique mutations reported across 8 families by 2021 (missense, in-frame indels, and other LOF classes). [human clinical/in vitro] (PMID 23440042, 33929673) - Modifier genes: None established (cohort too small).
Environmental risk factors. Consanguinity (parental relatedness) is the dominant epidemiologic risk factor, increasing homozygosity for rare recessive alleles. Exposure to Cryptosporidium (contaminated water/food) converts the immune defect into life-threatening cholangiopathy. No sex, occupational, or toxin risk factors. [human clinical] (PMID 23440042)
Protective factors. No genetic protective/modifier alleles identified. Environmentally, avoidance of Cryptosporidium exposure (water precautions/filtration) and early curative HSCT are protective against the worst outcomes. [human clinical] (inferred)
Gene–environment interactions. The core GxE interaction: IL21R-null immune state + Cryptosporidium exposure → sclerosing cholangitis. Restoration of immune competence (HSCT) enables clearance of the parasite, halting the environmental driver. [human clinical] (PMID 30850087: cholangiopathy improvement "following establishment of immune competence")
Frequencies from the 13-patient cohort (PMID 33929673) unless noted. [human clinical]
| Phenotype (type) | Frequency | HPO |
|---|---|---|
| Recurrent bacterial infections (clinical sign) | 84.6% | HP:0002718 |
| Recurrent fungal infections | 46.2% | HP:0009098 |
| Recurrent viral infections (incl. CMV) | 38.5% | HP:0004429 |
| Cryptosporidiosis (protozoan infection) | ~46% | HP:0002726 (recurrent protozoan infection) |
| Sclerosing cholangitis / cholangitis (sign) | 46.2% | HP:0100574 |
| Chronic diarrhea (symptom) | frequent | HP:0002028 / HP:0002014 |
| Chronic liver disease / cirrhosis (sign) | frequent, progressive | HP:0001394 |
| Failure to thrive (sign) | common | HP:0001508 |
| Asthma (sign) | 23.1% | HP:0002099 |
| Inflammatory/eczematous skin disease | 15.3% | HP:0000964 / HP:0011123 |
| Recurrent anaphylaxis | 7.9% | HP:0100845 |
| Lymphadenopathy | reported | HP:0002716 |
| Marginal zone B-cell lymphoma (malignancy) | reported (PMID 33966600) | HP:0012190 |
| Hypogammaglobulinemia (lab) | most | HP:0004313 |
| Elevated serum IgE (lab) | ~50% | HP:0003212 |
| Decreased memory B cells (lab) | most | HP:0002850 |
| Reduced circulating Tfh (lab) | most | (Abnormal Tfh; HP:0410276-family) |
| Reduced MAIT cells (lab) | most | — |
| Abnormal/reduced terminally differentiated NK cells (lab) | most | HP:0040218 |
Characteristics. Onset pediatric — median 2.5 years (range 0.5–7). Severity variable but the hepatobiliary component is typically progressive and life-limiting. Infections are recurrent/chronic; atopy (IgE, asthma, anaphylaxis) is episodic.
Quality-of-life impact. No formal EQ-5D/SF-36/PROMIS data. Qualitatively severe: chronic diarrhea/malabsorption → growth failure; progressive cholangiopathy → cholestasis, portal hypertension, end-stage liver disease; recurrent infections and hospitalizations; transplant-related morbidity. [human clinical]
Key quote (PMID 33929673): "The main clinical manifestations were recurrent bacterial (84.6%), fungal (46.2%), and viral (38.5%) infections; cryptosporidiosis-associated cholangitis (46.2%); and asthma (23.1%). Inflammatory skin diseases (15.3%) and recurrent anaphylaxis (7.9%) constitute novel phenotypes."
Supported (evidence-backed): - Biallelic IL21R LOF causes an autosomal-recessive combined immunodeficiency (PMID 23440042, 33929673). - Mechanism is failed IL-21R→JAK/STAT3 signaling affecting B, Tfh, CD8-memory, NK, MAIT/NKT compartments (PMID 23440042, 24126614, 23830147, 25941256). - Cryptosporidium-driven sclerosing cholangitis/liver disease is the prognosis-defining complication (PMID 23440042, 30850087). - HSCT is curative but timing-dependent; organ damage worsens outcome (PMID 33929673, 30850087). - Il21r-/- mice model the antibody dysregulation (PMID 12446913).
Refuted / not applicable: - Not X-linked (distinct from γc/IL2RG SCID); heterozygotes unaffected → not dominant/dominant-negative. - No environmental/toxin primary etiology; no founder mutation; no somatic/oncogenic driver role.
23440042 (Kotlarz 2013, original description) · 33929673 (Cagdas 2021, cohort n=13) · 33966600 (Edeer Karaca 2021, marginal zone lymphoma) · 24746753 (Salzer 2014, IL-21 ligand deficiency) · 12446913 (Ozaki 2002, Il21r-/- mouse) · 24126614 (Desjardins 2013, IL-21/B-cell memory review) · 23830147 (Ives 2013, CD8 memory) · 25941256 (Wilson 2015, MAIT/NKT via STAT3) · 30850087 (Hadžić 2019, HSCT for PID cholangitis) · 29377874 (sequential liver+HSCT) · 12690272 (Cryptosporidium PCR diagnosis) · 18354204 (Diehl 2008, IL-21/STAT3→BLIMP1 plasma-cell differentiation) · 37535730 (γc receptor structure) · 20660403 (γc-family gene therapy).
Checked with linkml-reference-validator 0.2.1.
| Outcome | Count |
|---|---|
| References checked | 13 |
| Resolved | 13 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| References weighed for topical relevance | 13 |
| On topic | 11 |
| Off topic | 0 |
All extracted references resolved successfully.
Checked with linkml-term-validator 0.4.5, through the ols: adapter.
| Outcome | Count |
|---|---|
| Terms checked | 47 |
| Resolved | 46 |
| Unresolved (possible confabulation) | 0 |
| Obsolete | 0 |
| Unverifiable | 1 |
| Terms whose name was checked | 10 |
| Terms named correctly | 1 |
| Terms named as a different term | 7 |
| Terms whose name is worth a second look | 2 |
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:0014219 (1 mention) - the report calls it "immunodeficiency 56"; MONDO calls it alacrima, achalasia, and intellectual disability syndromeHP:0001394 (1 mention) - the report calls it "frequent, progressive"; HP calls it CirrhosisHP:0001508 (1 mention) - the report calls it "common"; HP calls it Failure to thriveHP:0004313 (1 mention) - the report calls it "most"; HP calls it Decreased circulating immunoglobulin concentrationHP:0002850 (1 mention) - the report calls it "most"; HP calls it Decreased circulating IgM concentrationHP:0040218 (1 mention) - the report calls it "most"; HP calls it Reduced total natural killer cell countNCIT:C603 (1 mention) - the report calls it "for hypogammaglobulinemia"; NCIT calls it IsotretinoinThe 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:
HP:0002726 (1 mention) - the report calls it "recurrent protozoan infection"; HP calls it Recurrent Staphylococcus aureus infectionUBERON:0000160 (1 mention) - the report calls it "intestine/GI tract"; UBERON calls it intestine, and lists "intestinal tract" among its other names