X-linked combined immunodeficiency (XCID, also written CIDX, and in the modern literature usually "atypical" or "leaky" X-linked SCID) is the moderate, survivable end of IL2RG disease. It is allelic with X-linked severe combined immunodeficiency but is not the same clinical entity, and the difference is mechanistic rather than one of degree of luck: the alleles are hypomorphic, so the common gamma chain retains partial function instead of losing it. IL2RG encodes the common gamma chain, the shared signalling subunit of the receptors for IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21, which transduces through JAK3 and STAT5. Null alleles abolish that signalling and give the classic T-B+NK- severe phenotype, fatal in infancy without transplantation. The alleles curated here impair signalling only partially, and by more than one route: some leave the chain on the cell surface at normal levels with partially impaired STAT5 phosphorylation, p.Pro58Ser reduces its surface expression by mislocalising it to the ER/Golgi interface, and p.Arg328Ter weakens JAK3 binding while allowing partial STAT5 phosphorylation. The consequence is a partly populated but qualitatively defective T cell compartment: reduced CD4+ and CD8+ counts with a disproportionate loss of the naive CD45RA+ subset, low T-cell receptor excision circles, a skewed T-cell receptor repertoire, poor proliferative responses, and loss of T-cell help for antibody production, so that serum immunoglobulin concentrations are normal while specific IgG responses to immunogens are not. B cell and NK cell numbers are normal. Clinically this presents not as an infant dying of opportunistic infection but as a lifelong sinopulmonary and cutaneous viral susceptibility: recurrent sinusitis, otitis media, bronchitis and pneumonia, severe varicella, and chronic papillomavirus infection with persistent warts. The five affected males of the index American family ranged from 2.5 to 34 years old at report, which is the single fact that most clearly separates this entity from X-SCID. GeneReviews places this presentation within atypical X-SCID, a spectrum that also includes immune dysregulation, autoimmunity and Epstein-Barr virus-related lymphoproliferative complications, and that newborn screening for SCID usually does not detect. A second mechanism complicates the picture and is curated here explicitly: spontaneous somatic reversion of the mutant allele in the T cell lineage. In the German family carrying p.Ile153Thr, wild-type alleles were recoverable from CD3+, CD4+ and CD8+ T cells but not from monocytes, B cells or NK cells, and the authors attribute the attenuated phenotype to the combination of hypomorphic function and reversion rather than to the allele alone. Genotype therefore does not fully predict phenotype in this disorder, and it varied markedly even between brothers carrying the same variant.
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name: X-Linked Combined Immunodeficiency
creation_date: "2026-09-09T00:00:00Z"
category: Mendelian
description: >-
X-linked combined immunodeficiency (XCID, also written CIDX, and in the modern
literature usually "atypical" or "leaky" X-linked SCID) is the moderate,
survivable end of IL2RG disease. It is allelic with X-linked severe combined
immunodeficiency but is not the same clinical entity, and the difference is
mechanistic rather than one of degree of luck: the alleles are hypomorphic, so
the common gamma chain retains partial function instead of losing it.
IL2RG encodes the common gamma chain, the shared signalling subunit of the
receptors for IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21, which transduces through
JAK3 and STAT5. Null alleles abolish that signalling and give the classic
T-B+NK- severe phenotype, fatal in infancy without transplantation. The alleles
curated here impair signalling only partially, and by more than one route: some
leave the chain on the cell surface at normal levels with partially impaired STAT5
phosphorylation, p.Pro58Ser reduces its surface expression by mislocalising it to
the ER/Golgi interface, and p.Arg328Ter weakens JAK3 binding while allowing partial
STAT5 phosphorylation. The consequence is a partly populated but
qualitatively defective T cell compartment: reduced CD4+ and CD8+ counts with a
disproportionate loss of the naive CD45RA+ subset, low T-cell receptor excision
circles, a skewed T-cell receptor repertoire, poor proliferative responses, and
loss of T-cell help for antibody production, so that serum immunoglobulin
concentrations are normal while specific IgG responses to immunogens are not. B
cell and NK cell numbers are normal.
Clinically this presents not as an infant dying of opportunistic infection but as
a lifelong sinopulmonary and cutaneous viral susceptibility: recurrent sinusitis,
otitis media, bronchitis and pneumonia, severe varicella, and chronic
papillomavirus infection with persistent warts. The five affected males of the
index American family ranged from 2.5 to 34 years old at report, which is the
single fact that most clearly separates this entity from X-SCID. GeneReviews
places this presentation within atypical X-SCID, a spectrum that also includes
immune dysregulation, autoimmunity and Epstein-Barr virus-related
lymphoproliferative complications, and that newborn screening for SCID usually
does not detect.
A second mechanism complicates the picture and is curated here explicitly:
spontaneous somatic reversion of the mutant allele in the T cell lineage. In the
German family carrying p.Ile153Thr, wild-type alleles were recoverable from
CD3+, CD4+ and CD8+ T cells but not from monocytes, B cells or NK cells, and the
authors attribute the attenuated phenotype to the combination of hypomorphic
function and reversion rather than to the allele alone. Genotype therefore does
not fully predict phenotype in this disorder, and it varied markedly even between
brothers carrying the same variant.
disease_term:
preferred_term: combined immunodeficiency, X-linked
term:
id: MONDO:0010730
label: combined immunodeficiency, X-linked
synonyms:
- XCID
- CIDX
- combined immunodeficiency, X-linked, moderate
- immunodeficiency 6
- atypical X-linked severe combined immunodeficiency
- leaky X-linked SCID
parents:
- combined immunodeficiency
inheritance:
- name: X-linked recessive
inheritance_term:
preferred_term: X-linked recessive inheritance
term:
id: HP:0001419
label: X-linked recessive inheritance
description: >-
Affected males, carrier females. X-chromosome inactivation in obligate carriers
is non-random in T and B lymphocytes, as it is in X-linked severe combined
immunodeficiency, which is what first pointed the index family's investigators
at the same locus.
evidence:
- reference: PMID:2243135
reference_title: "A novel X-linked combined immunodeficiency disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Thus, affected males in this family carry an abnormal gene on their X chromosome that results in a combined immunodeficiency that is distinct from previously reported disorders.
explanation: >-
X-linked transmission in the family that defines the entity, and the claim of
distinctness from the previously described X-linked immunodeficiencies.
- reference: PMID:7883965
reference_title: "Missense mutation in exon 7 of the common gamma chain gene causes a moderate form of X-linked combined immunodeficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
As in XSCID, X-chromosome inactivation in obligate carriers of XCID was nonrandom in T and B lymphocytes.
explanation: >-
Non-random X inactivation in carriers, the observation that localised the
defect and is characteristic of X-linked lymphocyte-intrinsic disease.
- reference: PMID:20301584
reference_title: 'X-Linked Severe Combined Immunodeficiency.'
supports: SUPPORT
quote_role: REVIEW_SYNTHESIS
evidence_source: HUMAN_CLINICAL
snippet: 'males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be carriers and will be clinically asymptomatic. Affected males transmit the IL2RG pathogenic variant to all of their daughters and none of their sons.'
explanation: 'The GeneReviews genetic-counseling statement of transmission risk by sex of offspring, stated for the IL2RG spectrum as a whole.'
prevalence:
- population: Worldwide
measure_type: CASES_IN_LITERATURE
prevalence_class: NOT_YET_DOCUMENTED
notes: >-
No population estimate exists for this entity. What is quantified is the share
of IL2RG alleles that behave hypomorphically rather than as nulls: roughly one
in ten of the reported IL2RG mutations has been associated with an atypical,
highly variable immune phenotype. That is a proportion of alleles, not a
disease rate, and it is recorded here because it is the only number available.
evidence:
- reference: PMID:35052377
reference_title: "Somatic Reversion of a Novel IL2RG Mutation Resulting in Atypical X-Linked Combined Immunodeficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Approximately 10% of the reported IL2RG mutations have been associated with atypical and highly variable immune phenotypes that are described as hypomorphic mutations, which impair but do not abrogate protein function, obscure and mitigate clinical presentation of the disease
explanation: >-
The share of IL2RG alleles that produce the attenuated phenotype this entry
curates, which is the closest available proxy for how common it is.
pathophysiology:
- name: Hypomorphic IL2RG Variant
biological_scale: MOLECULAR
description: >-
A hemizygous IL2RG variant that impairs, without abolishing, common gamma chain
function. Four are curated here: p.Leu271Gln, in the SH2-subdomain homology
region of the cytoplasmic tail encoded by exon 7, in the index American family;
p.Ile153Thr in a German family; p.Pro58Ser in a single boy reported with
X-linked combined immunodeficiency; and the exon-8 nonsense variant p.Arg328Ter
in two brothers with a leaky phenotype. Three are missense and one is a
truncation near the end of the cytoplasmic tail.
genes:
- preferred_term: IL2RG
term:
id: hgnc:6010
label: IL2RG
downstream:
- target: Partial Loss of Common Gamma Chain Signalling
causal_link_type: DIRECT
description: >-
The variant reduces signal transduction through the receptors that share the
chain without eliminating it.
- target: Somatic Reversion in the T Cell Lineage
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
The point mutation is the substrate on which spontaneous reversion acts.
Nothing in the cited work explains why reversion occurred, and the authors
note that the same reversion arising independently in three brothers is
statistically improbable, so the edge records that the reversion is of this
allele, not a mechanism by which the allele causes it.
evidence:
- reference: PMID:7883965
reference_title: "Missense mutation in exon 7 of the common gamma chain gene causes a moderate form of X-linked combined immunodeficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
A missense mutation in the region coding for the cytoplasmic portion of the gamma c gene was found in three affected males but not in a normal brother.
explanation: >-
Identifies the causal allele in the index family and its segregation with
disease.
- reference: PMID:7883965
reference_title: "Missense mutation in exon 7 of the common gamma chain gene causes a moderate form of X-linked combined immunodeficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "the replacement of leucine 271 by a glutamine"
explanation: The specific substitution, from the figure describing the sequencing result.
- reference: PMID:35052377
reference_title: "Somatic Reversion of a Novel IL2RG Mutation Resulting in Atypical X-Linked Combined Immunodeficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The clinical presentation combined with dysgammaglobulinemia suspected an inherited immunity disorder, which has been proven by Next Generation Sequencing as a novel c.458T > C; p.Ile153Thr IL2RG missense-mutation.
explanation: The second documented hypomorphic allele, in an independent family.
- reference: DOI:10.1007/s10875-020-00745-2
reference_title: 'Novel Hemizygous IL2RG p.(Pro58Ser) Mutation Impairs IL-2 Receptor Complex Expression on Lymphocytes Causing X-Linked Combined Immunodeficiency'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: 'In conclusion, IL2RG p.(Pro58Ser) causes X-CID.'
explanation: 'A third allele, reported explicitly as a cause of X-linked combined immunodeficiency.'
- reference: DOI:10.1111/cei.13405
reference_title: 'The IL-2RG R328X nonsense mutation allows partial STAT-5 phosphorylation and defines a critical region involved in the leaky-SCID phenotype'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: 'Here, we report the biochemical and functional characterization of a nonsense mutation in exon 8 (p.R328X) of IL2RG in two siblings'
explanation: 'A fourth allele, and the only truncating one curated here, in two brothers with a leaky phenotype.'
- name: Partial Loss of Common Gamma Chain Signalling
biological_scale: MOLECULAR
description: >-
The common gamma chain is the shared subunit of the IL-2, IL-4, IL-7, IL-9,
IL-15 and IL-21 receptors and signals through JAK3 and STAT5. How the signal is
reduced depends on the allele. With p.Ile153Thr the chain is expressed at the
cell surface at normal levels and downstream STAT5 phosphorylation is partially
impaired; with p.Pro58Ser surface expression itself is reduced, because the
mutant chain is mislocalised to the ER/Golgi interface; with p.Arg328Ter surface
expression is normal, JAK3 binding is impaired, and STAT5 is still partially
phosphorylated. What the alleles share is residual signalling, which is what
separates this entity from X-linked severe combined immunodeficiency, where the
pathway is abolished.
biological_processes:
- preferred_term: cytokine receptor signaling via JAK-STAT
modifier: DECREASED
term:
id: GO:0007259
label: cell surface receptor signaling pathway via JAK-STAT
downstream:
- target: Reduced Peripheral T Cell Pool
causal_link_type: DIRECT
description: >-
IL-7 receptor signalling through the common gamma chain drives thymic T cell
development and peripheral T cell survival.
- target: Impaired T Cell Activation and Proliferation
causal_link_type: DIRECT
description: >-
IL-2 receptor signalling through the same chain drives the proliferative
response of activated T cells.
evidence:
- reference: PMID:35052377
reference_title: "Somatic Reversion of a Novel IL2RG Mutation Resulting in Atypical X-Linked Combined Immunodeficiency."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Interestingly, investigation of various subpopulations showed normal expression of CD132 but with partially impaired STAT5 phosphorylation compared to healthy controls.
explanation: >-
The measurement behind this node: surface expression preserved, downstream
signalling only partially lost. Graded in vitro because it is a stimulation
assay on isolated patient cell subsets.
- reference: PMID:35052377
reference_title: "Somatic Reversion of a Novel IL2RG Mutation Resulting in Atypical X-Linked Combined Immunodeficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
it encodes for the common gamma chain (γC) which is a subunit of various interleukin receptors, such as IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21
explanation: >-
The receptors that share the chain, which is why a single subunit defect
produces a combined rather than a selective immunodeficiency.
- reference: PMID:7883965
reference_title: "Missense mutation in exon 7 of the common gamma chain gene causes a moderate form of X-linked combined immunodeficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Therefore, this point mutation in the gamma c gene leads to a less severe degree of deficiency in cellular and humoral immunity than that seen in XSCID.
explanation: >-
States the partial rather than complete loss that this node asserts, and the
contrast with X-SCID on which this entry's separation from that entity rests.
- reference: DOI:10.1007/s10875-020-00745-2
reference_title: 'Novel Hemizygous IL2RG p.(Pro58Ser) Mutation Impairs IL-2 Receptor Complex Expression on Lymphocytes Causing X-Linked Combined Immunodeficiency'
supports: SUPPORT
evidence_source: IN_VITRO
snippet: 'BioID proximity labeling showed aberrant interactions between mutated IL2RG and ER/Golgi proteins causing mislocalization of the mutated IL2RG to the ER/Golgi interface.'
explanation: 'The trafficking defect behind reduced surface expression of the p.Pro58Ser chain, measured by proximity labelling in cells.'
- reference: DOI:10.1007/s10875-020-00745-2
reference_title: 'Novel Hemizygous IL2RG p.(Pro58Ser) Mutation Impairs IL-2 Receptor Complex Expression on Lymphocytes Causing X-Linked Combined Immunodeficiency'
supports: SUPPORT
evidence_source: IN_VITRO
snippet: 'This led to impaired STAT tyrosine phosphorylation in response to IL-2 and IL-21, reduced expression of IL-2 target genes in patient CD4+ T cells, and reduced cell proliferation in response to IL-2 stimulation.'
explanation: 'The signalling consequence of the p.Pro58Ser trafficking defect in stimulated patient cells.'
- reference: DOI:10.1111/cei.13405
reference_title: 'The IL-2RG R328X nonsense mutation allows partial STAT-5 phosphorylation and defines a critical region involved in the leaky-SCID phenotype'
supports: SUPPORT
evidence_source: IN_VITRO
snippet: 'Co-immunoprecipitation experiments were performed to assess the interaction capacity of the R328X mutant with Janus kinase (JAK)3, concluding that R328X impairs JAK3 binding to γc.'
explanation: 'The p.Arg328Ter mechanism: the truncated chain binds JAK3 poorly.'
- reference: DOI:10.1111/cei.13405
reference_title: 'The IL-2RG R328X nonsense mutation allows partial STAT-5 phosphorylation and defines a critical region involved in the leaky-SCID phenotype'
supports: SUPPORT
evidence_source: IN_VITRO
snippet: 'Here, we describe how the R328X mutation in IL-2RG may allow partial phosphorylation of STAT-5 through a JAK3-independent pathway.'
explanation: 'Residual STAT5 signalling with the truncating allele, proposed by the authors to run through a JAK3-independent route.'
- name: Reduced Peripheral T Cell Pool
biological_scale: CELLULAR
description: >-
A partly populated T cell compartment. CD4+ and CD8+ counts are reduced, with
the naive CD45RA+ subsets disproportionately affected; T-cell receptor excision
circles are low and the T-cell receptor repertoire is skewed, both indicating
reduced thymic output rather than peripheral loss alone. B cell and NK cell
numbers are normal, which is why the disorder is T-cell-led despite the
receptor being shared across lineages.
cell_types:
- preferred_term: T cell
term:
id: CL:0000084
label: T cell
biological_processes:
- preferred_term: T cell differentiation
modifier: DECREASED
term:
id: GO:0030217
label: T cell differentiation
downstream:
- target: Decreased CD4+ T Cell Count
causal_link_type: DIRECT
- target: Decreased CD8+ T Cell Count
causal_link_type: DIRECT
- target: Decreased Naive T Cell Proportion
causal_link_type: DIRECT
- target: Paucity of Lymphoid Tissue
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Persistent Sinopulmonary and Cutaneous Viral Susceptibility
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:2243135
reference_title: "A novel X-linked combined immunodeficiency disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The principal immunologic features of the disorder were normal concentrations of serum immunoglobulins but restricted formation of IgG antibodies to immunogens; normal numbers of B cells and NK cells but decreased numbers of CD4+ and CD8+ T lymphocytes, particularly the CD45RA+ subpopulations; diminished proliferative responses of blood T cells to allogeneic cells, mitogens and antigens; and decreased production of IL-2 by mitogen stimulated blood lymphocytes.
explanation: >-
The immunologic profile of the index family, which is the source for the cell
counts, the naive-subset loss and the preserved B and NK compartments.
- reference: PMID:35052377
reference_title: "Somatic Reversion of a Novel IL2RG Mutation Resulting in Atypical X-Linked Combined Immunodeficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Subsequent functional characterization revealed impaired T-cell proliferation, low TREC levels and a skewed TCR Vβ repertoire in all three patients.
explanation: >-
Low excision circles and a skewed repertoire in an independent family, which
is what makes this a thymic-output defect rather than peripheral depletion.
- name: Impaired T Cell Activation and Proliferation
biological_scale: CELLULAR
description: >-
The T cells that are present respond poorly. Proliferative responses to
allogeneic cells, mitogens and antigens are diminished, and IL-2 production by
mitogen-stimulated blood lymphocytes is reduced, so the defect is qualitative as
well as quantitative.
biological_processes:
- preferred_term: T cell activation
modifier: DECREASED
term:
id: GO:0042110
label: T cell activation
downstream:
- target: Abnormal T Cell Proliferation
causal_link_type: DIRECT
- target: Defective T Cell Help for Antibody Production
causal_link_type: DIRECT
description: >-
Antibody responses to protein immunogens depend on activated helper T cells.
- target: Persistent Sinopulmonary and Cutaneous Viral Susceptibility
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:2243135
reference_title: "A novel X-linked combined immunodeficiency disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The principal immunologic features of the disorder were normal concentrations of serum immunoglobulins but restricted formation of IgG antibodies to immunogens; normal numbers of B cells and NK cells but decreased numbers of CD4+ and CD8+ T lymphocytes, particularly the CD45RA+ subpopulations; diminished proliferative responses of blood T cells to allogeneic cells, mitogens and antigens; and decreased production of IL-2 by mitogen stimulated blood lymphocytes.
explanation: >-
Source for the diminished proliferative responses and the reduced IL-2
production this node asserts.
- name: Defective T Cell Help for Antibody Production
biological_scale: CELLULAR
description: >-
Serum immunoglobulin concentrations are normal but the specific IgG response to
immunogens is restricted. The B cells are numerically intact, so the humoral
defect is best read as a failure of T cell help rather than a B cell defect,
which is what makes this a combined rather than a purely cellular
immunodeficiency.
cell_types:
- preferred_term: B cell
term:
id: CL:0000236
label: B cell
biological_processes:
- preferred_term: immunoglobulin production
modifier: DECREASED
term:
id: GO:0002377
label: immunoglobulin production
downstream:
- target: Impaired Specific Antibody Response
causal_link_type: DIRECT
- target: Persistent Sinopulmonary and Cutaneous Viral Susceptibility
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:2243135
reference_title: "A novel X-linked combined immunodeficiency disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The principal immunologic features of the disorder were normal concentrations of serum immunoglobulins but restricted formation of IgG antibodies to immunogens; normal numbers of B cells and NK cells but decreased numbers of CD4+ and CD8+ T lymphocytes, particularly the CD45RA+ subpopulations; diminished proliferative responses of blood T cells to allogeneic cells, mitogens and antigens; and decreased production of IL-2 by mitogen stimulated blood lymphocytes.
explanation: >-
Normal immunoglobulin concentrations with restricted specific IgG formation,
alongside normal B cell numbers, is the observation this node interprets.
- name: Somatic Reversion in the T Cell Lineage
biological_scale: CELLULAR
description: >-
Spontaneous back-mutation of the pathogenic allele in T cell progenitors,
producing somatic mosaicism restricted to the T cell compartment. In the German
family, wild-type alleles were recovered from CD3+, CD4+, CD8+, alpha-beta and
gamma-delta T cells but not from monocytes, B cells or NK cells, and short
tandem repeat analysis excluded maternal engraftment as the source. This is a
partially compensating event, not a step by which the disease progresses, and it
is curated here because it is the reason genotype does not predict phenotype in
this disorder.
cell_types:
- preferred_term: T cell
term:
id: CL:0000084
label: T cell
evidence:
- reference: PMID:35052377
reference_title: "Somatic Reversion of a Novel IL2RG Mutation Resulting in Atypical X-Linked Combined Immunodeficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Additionally, we performed precise genetic analysis of subpopulations revealing spontaneous somatic reversion, predominately in lymphoid derived CD3+, CD4+ and CD8+ T cells.
explanation: The lineage-restricted reversion this node records.
- reference: PMID:35052377
reference_title: "Somatic Reversion of a Novel IL2RG Mutation Resulting in Atypical X-Linked Combined Immunodeficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Our data demonstrate that the atypical SCID phenotype noticed in these three brothers is due to the combination of hypomorphic IL-2RG function and somatic reversion.
explanation: >-
The authors' own conclusion that the attenuated phenotype required both the
hypomorphic allele and the reversion, which is why this node exists.
- name: Persistent Sinopulmonary and Cutaneous Viral Susceptibility
biological_scale: ORGANISM
description: >-
The clinical consequence: a lifelong susceptibility to sinopulmonary bacterial
infection and to cutaneous and systemic viral infection, rather than the
fulminant early-infancy opportunistic infection of X-linked severe combined
immunodeficiency. Affected males in the index family ranged from 2.5 to 34 years
of age.
downstream:
- target: Recurrent Sinusitis
causal_link_type: DIRECT
- target: Recurrent Otitis Media
causal_link_type: DIRECT
- target: Recurrent Bronchitis
causal_link_type: DIRECT
- target: Recurrent Pneumonia
causal_link_type: DIRECT
- target: Severe Varicella
causal_link_type: DIRECT
- target: Verrucae
causal_link_type: DIRECT
- target: EBV-Related Lymphoproliferation
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Epstein-Barr virus-related lymphoproliferation is a recognised complication of
atypical X-SCID and occurred as a lethal lymphoma with p.Arg328Ter. The sources
describe the complication, not the step from impaired T cell immunity to it.
evidence:
- reference: PMID:20301584
reference_title: 'X-Linked Severe Combined Immunodeficiency.'
supports: SUPPORT
quote_role: REVIEW_SYNTHESIS
evidence_source: HUMAN_CLINICAL
snippet: 'Atypical X-SCID, which usually is not detected by NBS, can manifest in the first years of life or later with one of the following: recurrent upper and lower respiratory tract infections with bronchiectasis'
explanation: 'GeneReviews describes the atypical X-SCID presentation as later-onset sinopulmonary infection, which is the susceptibility this node records.'
- reference: PMID:2243135
reference_title: "A novel X-linked combined immunodeficiency disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The most prominent clinical abnormalities were a paucity of lymphoid tissue; recurrent sinusitis, otitis media, bronchitis, and pneumonia; severe varicella; and chronic papillomavirus infections.
explanation: The clinical phenotype of the index family.
- reference: PMID:2243135
reference_title: "A novel X-linked combined immunodeficiency disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The age of the affected males ranged from 2.5 to 34 yr."
explanation: >-
Survival into adulthood, the single observation that most clearly separates
this entity from X-linked severe combined immunodeficiency.
phenotypes:
- category: Immunologic
name: Recurrent Sinusitis
phenotype_term:
preferred_term: Recurrent sinusitis
term:
id: HP:0011108
label: Recurrent sinusitis
evidence:
- reference: PMID:2243135
reference_title: "A novel X-linked combined immunodeficiency disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The most prominent clinical abnormalities were a paucity of lymphoid tissue; recurrent sinusitis, otitis media, bronchitis, and pneumonia; severe varicella; and chronic papillomavirus infections.
explanation: Reported in the five affected males of the index family.
- category: Immunologic
name: Recurrent Otitis Media
phenotype_term:
preferred_term: Recurrent otitis media
term:
id: HP:0000403
label: Recurrent otitis media
evidence:
- reference: PMID:2243135
reference_title: "A novel X-linked combined immunodeficiency disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The most prominent clinical abnormalities were a paucity of lymphoid tissue; recurrent sinusitis, otitis media, bronchitis, and pneumonia; severe varicella; and chronic papillomavirus infections.
explanation: Reported in the five affected males of the index family.
- category: Immunologic
name: Recurrent Bronchitis
phenotype_term:
preferred_term: Recurrent bronchitis
term:
id: HP:0002837
label: Recurrent bronchitis
evidence:
- reference: PMID:2243135
reference_title: "A novel X-linked combined immunodeficiency disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The most prominent clinical abnormalities were a paucity of lymphoid tissue; recurrent sinusitis, otitis media, bronchitis, and pneumonia; severe varicella; and chronic papillomavirus infections.
explanation: Reported in the five affected males of the index family.
- category: Immunologic
name: Recurrent Pneumonia
description: >-
Recurrent pneumonia in the index family, and in the German family severe enough
to require repeated hospitalisation in two of the three brothers.
phenotype_term:
preferred_term: Recurrent pneumonia
term:
id: HP:0006532
label: Recurrent pneumonia
sequelae:
- target: Bronchiectasis
causal_link_type: DIRECT
description: >-
Repeated and chronic lower respiratory infection produced bronchiectasis in
two of the three brothers in the German family.
evidence:
- reference: PMID:2243135
reference_title: "A novel X-linked combined immunodeficiency disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The most prominent clinical abnormalities were a paucity of lymphoid tissue; recurrent sinusitis, otitis media, bronchitis, and pneumonia; severe varicella; and chronic papillomavirus infections.
explanation: Reported in the five affected males of the index family.
- reference: PMID:35052377
reference_title: "Somatic Reversion of a Novel IL2RG Mutation Resulting in Atypical X-Linked Combined Immunodeficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
the patient developed chronic respiratory infections leading to bronchiectasis after being hospitalized twice due to severe cases of pneumonia
explanation: >-
Severe recurrent pneumonia in the most affected brother of the German family,
and the source for the bronchiectasis sequela.
- category: Respiratory
name: Bronchiectasis
description: >-
Structural airway damage following repeated lower respiratory infection.
Present in two of the three brothers in the German family and persisting despite
prophylaxis and immunoglobulin replacement.
phenotype_term:
preferred_term: Bronchiectasis
term:
id: HP:0002110
label: Bronchiectasis
evidence:
- reference: PMID:35052377
reference_title: "Somatic Reversion of a Novel IL2RG Mutation Resulting in Atypical X-Linked Combined Immunodeficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
the patient developed chronic respiratory infections leading to bronchiectasis after being hospitalized twice due to severe cases of pneumonia
explanation: Bronchiectasis in the most affected brother of the German family.
- reference: PMID:20301584
reference_title: 'X-Linked Severe Combined Immunodeficiency.'
supports: SUPPORT
quote_role: REVIEW_SYNTHESIS
evidence_source: HUMAN_CLINICAL
snippet: 'Atypical X-SCID, which usually is not detected by NBS, can manifest in the first years of life or later with one of the following: recurrent upper and lower respiratory tract infections with bronchiectasis'
explanation: 'GeneReviews names respiratory infection with bronchiectasis as one presentation of atypical X-SCID.'
- reference: DOI:10.1007/s10875-020-00745-2
reference_title: 'Novel Hemizygous IL2RG p.(Pro58Ser) Mutation Impairs IL-2 Receptor Complex Expression on Lymphocytes Causing X-Linked Combined Immunodeficiency'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: 'The patient suffered from recurrent upper and lower respiratory tract infections, bronchiectasis, and reactive arthritis.'
explanation: 'Bronchiectasis with the p.Pro58Ser allele, in a third family.'
- category: Immunologic
name: Severe Varicella
phenotype_term:
preferred_term: Severe varicella zoster infection
term:
id: HP:0032170
label: Severe varicella zoster infection
evidence:
- reference: PMID:2243135
reference_title: "A novel X-linked combined immunodeficiency disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The most prominent clinical abnormalities were a paucity of lymphoid tissue; recurrent sinusitis, otitis media, bronchitis, and pneumonia; severe varicella; and chronic papillomavirus infections.
explanation: Severe varicella in the index family.
- category: Dermatologic
name: Verrucae
description: >-
Chronic papillomavirus infection with persistent cutaneous warts. In the German
family the warts were the presenting problem and were refractory: cryotherapy,
keratolysis, curettage, laser, imiquimod, local IL-2 and retinoids all failed in
the most affected brother.
phenotype_term:
preferred_term: Verrucae
temporality: CHRONIC
term:
id: HP:0200043
label: Verrucae
evidence:
- reference: PMID:2243135
reference_title: "A novel X-linked combined immunodeficiency disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The most prominent clinical abnormalities were a paucity of lymphoid tissue; recurrent sinusitis, otitis media, bronchitis, and pneumonia; severe varicella; and chronic papillomavirus infections.
explanation: Chronic papillomavirus infection in the index family.
- reference: PMID:35052377
reference_title: "Somatic Reversion of a Novel IL2RG Mutation Resulting in Atypical X-Linked Combined Immunodeficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Here, we report three brothers with low-normal lymphocyte counts and susceptibility to recurrent respiratory infections and cutaneous warts.
explanation: Cutaneous warts in all three brothers of the German family.
- reference: PMID:20301584
reference_title: 'X-Linked Severe Combined Immunodeficiency.'
supports: SUPPORT
quote_role: REVIEW_SYNTHESIS
evidence_source: HUMAN_CLINICAL
snippet: 'X-SCID combined immunodeficiency (often with recurrent infections, warts, and dermatitis)'
explanation: 'GeneReviews names warts in the combined-immunodeficiency presentation of atypical X-SCID.'
- category: Immunologic
name: Paucity of Lymphoid Tissue
description: >-
Scanty peripheral lymphoid tissue on examination. Bound to the generic
lymph-node morphology term because the source records the finding as a paucity
of lymphoid tissue without specifying which structures were assessed.
phenotype_term:
preferred_term: Paucity of lymphoid tissue
term:
id: HP:0002733
label: Abnormal lymph node morphology
evidence:
- reference: PMID:2243135
reference_title: "A novel X-linked combined immunodeficiency disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The most prominent clinical abnormalities were a paucity of lymphoid tissue; recurrent sinusitis, otitis media, bronchitis, and pneumonia; severe varicella; and chronic papillomavirus infections.
explanation: Paucity of lymphoid tissue, listed first among the clinical abnormalities.
- category: Immunologic
name: Impaired Specific Antibody Response
description: >-
Restricted formation of IgG antibodies to immunogens despite normal total serum
immunoglobulin concentrations. This is the humoral half of the "combined" label.
phenotype_term:
preferred_term: Impaired specific antibody response
term:
id: HP:0012475
label: Impaired specific antibody response
evidence:
- reference: PMID:2243135
reference_title: "A novel X-linked combined immunodeficiency disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The principal immunologic features of the disorder were normal concentrations of serum immunoglobulins but restricted formation of IgG antibodies to immunogens; normal numbers of B cells and NK cells but decreased numbers of CD4+ and CD8+ T lymphocytes, particularly the CD45RA+ subpopulations; diminished proliferative responses of blood T cells to allogeneic cells, mitogens and antigens; and decreased production of IL-2 by mitogen stimulated blood lymphocytes.
explanation: >-
Restricted specific IgG formation against a background of normal total
immunoglobulin.
- category: Immunologic
name: Decreased CD4+ T Cell Count
phenotype_term:
preferred_term: Decreased total CD4+ T cell count
term:
id: HP:5210418
label: Decreased total CD4+ T cell count
evidence:
- reference: PMID:2243135
reference_title: "A novel X-linked combined immunodeficiency disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The principal immunologic features of the disorder were normal concentrations of serum immunoglobulins but restricted formation of IgG antibodies to immunogens; normal numbers of B cells and NK cells but decreased numbers of CD4+ and CD8+ T lymphocytes, particularly the CD45RA+ subpopulations; diminished proliferative responses of blood T cells to allogeneic cells, mitogens and antigens; and decreased production of IL-2 by mitogen stimulated blood lymphocytes.
explanation: Decreased CD4+ T lymphocyte numbers in the index family.
- category: Immunologic
name: Decreased CD8+ T Cell Count
phenotype_term:
preferred_term: Decreased total CD8+ T cell count
term:
id: HP:5210426
label: Decreased total CD8+ T cell count
evidence:
- reference: PMID:2243135
reference_title: "A novel X-linked combined immunodeficiency disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The principal immunologic features of the disorder were normal concentrations of serum immunoglobulins but restricted formation of IgG antibodies to immunogens; normal numbers of B cells and NK cells but decreased numbers of CD4+ and CD8+ T lymphocytes, particularly the CD45RA+ subpopulations; diminished proliferative responses of blood T cells to allogeneic cells, mitogens and antigens; and decreased production of IL-2 by mitogen stimulated blood lymphocytes.
explanation: Decreased CD8+ T lymphocyte numbers in the index family.
- category: Immunologic
name: Decreased Naive T Cell Proportion
description: >-
The CD45RA+ naive subsets are disproportionately reduced, which is the
peripheral signature of impaired thymic output.
phenotype_term:
preferred_term: Decreased naive T cell proportion
term:
id: HP:0031397
label: Decreased naive T cell proportion
evidence:
- reference: PMID:2243135
reference_title: "A novel X-linked combined immunodeficiency disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The principal immunologic features of the disorder were normal concentrations of serum immunoglobulins but restricted formation of IgG antibodies to immunogens; normal numbers of B cells and NK cells but decreased numbers of CD4+ and CD8+ T lymphocytes, particularly the CD45RA+ subpopulations; diminished proliferative responses of blood T cells to allogeneic cells, mitogens and antigens; and decreased production of IL-2 by mitogen stimulated blood lymphocytes.
explanation: >-
The disproportionate loss of the CD45RA+ subpopulations reported in the index
family.
- category: Immunologic
name: Abnormal T Cell Proliferation
description: >-
Diminished proliferative responses of blood T cells to allogeneic cells,
mitogens and antigens, reproduced as impaired T-cell proliferation in an
independent family.
phenotype_term:
preferred_term: Abnormal T cell proliferation
term:
id: HP:0031379
label: Abnormal T cell proliferation
evidence:
- reference: PMID:2243135
reference_title: "A novel X-linked combined immunodeficiency disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The principal immunologic features of the disorder were normal concentrations of serum immunoglobulins but restricted formation of IgG antibodies to immunogens; normal numbers of B cells and NK cells but decreased numbers of CD4+ and CD8+ T lymphocytes, particularly the CD45RA+ subpopulations; diminished proliferative responses of blood T cells to allogeneic cells, mitogens and antigens; and decreased production of IL-2 by mitogen stimulated blood lymphocytes.
explanation: Diminished proliferative responses in the index family.
- reference: PMID:35052377
reference_title: "Somatic Reversion of a Novel IL2RG Mutation Resulting in Atypical X-Linked Combined Immunodeficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Subsequent functional characterization revealed impaired T-cell proliferation, low TREC levels and a skewed TCR Vβ repertoire in all three patients.
explanation: Impaired T-cell proliferation reproduced in the German family.
- category: Dermatologic
name: Dermatitis
description: >-
Dermatitis, named by GeneReviews with recurrent infections and warts as part of
the combined-immunodeficiency presentation of atypical X-SCID. The source does
not specify the type. It has no incoming causal edge, because none of the cited sources gives a mechanism for it in this disorder.
phenotype_term:
preferred_term: Dermatitis
term:
id: HP:0011123
label: Inflammatory abnormality of the skin
evidence:
- reference: PMID:20301584
reference_title: 'X-Linked Severe Combined Immunodeficiency.'
supports: SUPPORT
quote_role: REVIEW_SYNTHESIS
evidence_source: HUMAN_CLINICAL
snippet: 'X-SCID combined immunodeficiency (often with recurrent infections, warts, and dermatitis)'
explanation: 'Names dermatitis in the combined-immunodeficiency presentation of atypical X-SCID.'
- category: Immunologic
name: Autoimmunity
description: >-
Immune dysregulation and autoimmunity, one of the presentations GeneReviews lists
for atypical X-SCID. No specific autoimmune disease is named. It has no incoming causal edge, because none of the cited sources gives a mechanism for it in this disorder.
phenotype_term:
preferred_term: Autoimmunity
term:
id: HP:0002960
label: Autoimmunity
evidence:
- reference: PMID:20301584
reference_title: 'X-Linked Severe Combined Immunodeficiency.'
supports: SUPPORT
quote_role: REVIEW_SYNTHESIS
evidence_source: HUMAN_CLINICAL
snippet: 'immune dysregulation and autoimmunity; or Epstein-Barr virus-related lymphoproliferative complications'
explanation: 'Names immune dysregulation and autoimmunity among the presentations of atypical X-SCID.'
- category: Neoplasm
name: EBV-Related Lymphoproliferation
description: >-
Epstein-Barr virus-related lymphoproliferative complications, listed by
GeneReviews for atypical X-SCID and seen as a lethal lymphoma in a 4-year-old
boy carrying p.Arg328Ter, whose infant brother with the same allele was
asymptomatic.
phenotype_term:
preferred_term: EBV-related lymphoproliferation
term:
id: HP:0005523
label: Lymphoproliferative disorder
evidence:
- reference: PMID:20301584
reference_title: 'X-Linked Severe Combined Immunodeficiency.'
supports: SUPPORT
quote_role: REVIEW_SYNTHESIS
evidence_source: HUMAN_CLINICAL
snippet: 'immune dysregulation and autoimmunity; or Epstein-Barr virus-related lymphoproliferative complications'
explanation: 'Names EBV-related lymphoproliferative complications among the presentations of atypical X-SCID.'
- reference: DOI:10.1111/cei.13405
reference_title: 'The IL-2RG R328X nonsense mutation allows partial STAT-5 phosphorylation and defines a critical region involved in the leaky-SCID phenotype'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: 'a 4-year-old boy with lethal Epstein–Barr virus-related lymphoma and his asymptomatic 8-month-old brother'
explanation: 'A lethal EBV-related lymphoma with the p.Arg328Ter allele, and the discordance between two brothers carrying it.'
- category: Musculoskeletal
name: Arthritis
description: >-
Reactive arthritis, reported with recurrent respiratory infection and
bronchiectasis in the boy carrying p.Pro58Ser. A single case. It has no incoming causal edge, because none of the cited sources gives a mechanism for it in this disorder.
phenotype_term:
preferred_term: Reactive arthritis
term:
id: HP:0001369
label: Arthritis
evidence:
- reference: DOI:10.1007/s10875-020-00745-2
reference_title: 'Novel Hemizygous IL2RG p.(Pro58Ser) Mutation Impairs IL-2 Receptor Complex Expression on Lymphocytes Causing X-Linked Combined Immunodeficiency'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: 'The patient suffered from recurrent upper and lower respiratory tract infections, bronchiectasis, and reactive arthritis.'
explanation: 'Reactive arthritis in the p.Pro58Ser patient.'
genetic:
- name: IL2RG
gene_term:
preferred_term: IL2RG
term:
id: hgnc:6010
label: IL2RG
relationship_type: CAUSATIVE
variant_origin: GERMLINE
inheritance:
- name: X-linked recessive
inheritance_term:
preferred_term: X-linked recessive inheritance
term:
id: HP:0001419
label: X-linked recessive inheritance
notes: >-
The same gene as X-linked severe combined immunodeficiency; what differs is the
allele. Four variants are curated here, all hypomorphic rather than null:
c.812T>A p.Leu271Gln in exon 7, in the SH2-subdomain homology region of the
cytoplasmic tail, in the index American family; c.458T>C p.Ile153Thr in a German
family; c.172C>T p.Pro58Ser in a single boy; and the exon-8 nonsense variant
p.Arg328Ter in two brothers. Other hypomorphic IL2RG alleles are reported in the
literature but are not curated here. Note that the exon-7
substitution is reported by amino acid position and codon change (CTG to CAG)
rather than by a coding-DNA identifier in the source, so the c. notation above
is a reconstruction and should be treated as such. The hypomorphic
classification is supported functionally for p.Ile153Thr, where surface CD132
expression is normal and STAT5 phosphorylation only partially impaired; for
p.Leu271Gln it rests on the clinical and immunologic comparison with X-SCID
rather than on a signalling assay. For p.Pro58Ser and p.Arg328Ter it is
supported by signalling assays in patient cells.
evidence:
- reference: PMID:7883965
reference_title: "Missense mutation in exon 7 of the common gamma chain gene causes a moderate form of X-linked combined immunodeficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Clinical and immunologic features of a recently recognized X-linked combined immunodeficiency disease (XCID) suggested that XCID and X-linked severe combined immunodeficiency (XSCID) might arise from different genetic defects.
explanation: >-
Records that the two entities were initially expected to have different genes,
which is the background to the finding that they share one.
- reference: PMID:35052377
reference_title: "Somatic Reversion of a Novel IL2RG Mutation Resulting in Atypical X-Linked Combined Immunodeficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Lately, hypomorphic mutations of the IL2RG gene have been described causing atypical SCID with a milder phenotype.
explanation: >-
The allele class this entry is about, and the reason it is separated from
X-linked severe combined immunodeficiency.
- reference: DOI:10.1007/s10875-020-00745-2
reference_title: 'Novel Hemizygous IL2RG p.(Pro58Ser) Mutation Impairs IL-2 Receptor Complex Expression on Lymphocytes Causing X-Linked Combined Immunodeficiency'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: 'We report an 11-year-old boy with a novel c. 172C>T;p.(Pro58Ser) mutation in IL2RG, presenting with atypical X-SCID phenotype.'
explanation: 'The p.Pro58Ser allele and its coding-DNA change, as reported.'
diagnosis:
- name: Molecular testing of IL2RG
description: >-
The diagnosis is molecular. Both documented families were resolved by
sequencing IL2RG, in the German family by next-generation sequencing after a
combined immunodeficiency had been suspected clinically. GeneReviews states that
atypical X-SCID usually is not detected by newborn screening for SCID, and the
German proband was recognised only at age 19.
evidence:
- reference: PMID:20301584
reference_title: 'X-Linked Severe Combined Immunodeficiency.'
supports: SUPPORT
quote_role: REVIEW_SYNTHESIS
evidence_source: HUMAN_CLINICAL
snippet: 'The diagnosis of typical and atypical X-SCID is established in a male proband with suggestive findings and a hemizygous pathogenic variant in IL2RG identified by molecular genetic testing.'
explanation: 'The GeneReviews diagnostic criterion, which applies to atypical as well as typical X-SCID.'
- reference: PMID:20301584
reference_title: 'X-Linked Severe Combined Immunodeficiency.'
supports: SUPPORT
quote_role: REVIEW_SYNTHESIS
evidence_source: HUMAN_CLINICAL
snippet: 'Atypical X-SCID, which usually is not detected by NBS, can manifest in the first years of life or later with one of the following: recurrent upper and lower respiratory tract infections with bronchiectasis'
explanation: 'States that atypical X-SCID usually is not detected by newborn screening, which is why diagnosis rests on clinical suspicion and molecular testing.'
- reference: PMID:35052377
reference_title: "Somatic Reversion of a Novel IL2RG Mutation Resulting in Atypical X-Linked Combined Immunodeficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The clinical presentation combined with dysgammaglobulinemia suspected an inherited immunity disorder, which has been proven by Next Generation Sequencing as a novel c.458T > C; p.Ile153Thr IL2RG missense-mutation.
explanation: The diagnostic route in the German family.
- reference: PMID:35052377
reference_title: "Somatic Reversion of a Novel IL2RG Mutation Resulting in Atypical X-Linked Combined Immunodeficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Therefore, some form of cellular immunodeficiency was firstly suspected in P1 at the age of 19 years.
explanation: >-
The age at which the diagnosis was first suspected, supporting the diagnostic
delay this record describes.
treatments:
- name: Immunoglobulin Replacement Therapy
description: >-
Immunoglobulin substitution addresses the specific antibody defect. Combined
with antimicrobial prophylaxis it stopped severe bacterial infection in the most
affected brother of the German family, though it did not clear the warts or
reverse established bronchiectasis.
therapeutic_modality: PROTEIN_REPLACEMENT
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
evidence:
- reference: PMID:35052377
reference_title: "Somatic Reversion of a Novel IL2RG Mutation Resulting in Atypical X-Linked Combined Immunodeficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
After confirmation of immunodeficiency, P1 received anti-microbial prophylaxis and immunoglobulin substitution therapy due to his symptomatic appearance.
explanation: The treatment actually given to a patient with this disorder.
- reference: PMID:35052377
reference_title: "Somatic Reversion of a Novel IL2RG Mutation Resulting in Atypical X-Linked Combined Immunodeficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Since following this treatment plan, no severe bacterial infection has occurred, even though cutaneous warts and bronchiectasis are still present.
explanation: >-
The observed effect, including what it did not fix. This is a single
uncontrolled patient observation.
- name: Antimicrobial Prophylaxis
description: >-
Continuous antimicrobial prophylaxis alongside immunoglobulin replacement in the
same patient.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
evidence:
- reference: PMID:35052377
reference_title: "Somatic Reversion of a Novel IL2RG Mutation Resulting in Atypical X-Linked Combined Immunodeficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
After confirmation of immunodeficiency, P1 received anti-microbial prophylaxis and immunoglobulin substitution therapy due to his symptomatic appearance.
explanation: >-
Prophylaxis given together with immunoglobulin replacement; the two were
started together and their effects cannot be separated in this report.
- reference: PMID:20301584
reference_title: 'X-Linked Severe Combined Immunodeficiency.'
supports: SUPPORT
quote_role: REVIEW_SYNTHESIS
evidence_source: HUMAN_CLINICAL
snippet: 'Atypical X-SCID. Treatment depends on the degree of infectious complications and the presence of immune dysregulation and/or autoimmunity, and requires subspecialty immunologic care to assist in the diagnosis and choice of antimicrobial and immune-suppressive therapies.'
explanation: 'The GeneReviews management statement for atypical X-SCID, which names antimicrobial therapy.'
- name: Infection-Risk Avoidance and Blood Product Precautions
description: >-
GeneReviews lists exposures to avoid pending definitive treatment, including
live viral vaccines for the affected individual and household contacts and
transfusion of non-irradiated blood products.
therapeutic_modality: BEHAVIORAL
treatment_term:
preferred_term: infection-risk avoidance and blood product precautions
term:
id: NCIT:C15747
label: Supportive Care
evidence:
- reference: PMID:20301584
reference_title: 'X-Linked Severe Combined Immunodeficiency.'
supports: SUPPORT
quote_role: REVIEW_SYNTHESIS
evidence_source: HUMAN_CLINICAL
snippet: 'live viral vaccines for the affected individual as well as household contacts; transfusion of non-irradiated blood products'
explanation: 'The GeneReviews agents-and-circumstances-to-avoid list, quoted for its vaccine and blood-product items.'
- name: Hematopoietic Stem Cell Transplantation
description: >-
The definitive treatment for typical X-SCID. No cached source reports it in a
patient with a hypomorphic allele, so the evidence is graded INDIRECT; GeneReviews
ties treatment of atypical X-SCID to the severity of infection and immune
dysregulation rather than to preemptive transplantation.
therapeutic_modality: CELL_THERAPY
treatment_term:
preferred_term: hematopoietic stem cell transplantation
term:
id: NCIT:C15431
label: Hematopoietic Cell Transplantation
evidence:
- reference: PMID:20301584
reference_title: 'X-Linked Severe Combined Immunodeficiency.'
supports: SUPPORT
directness: INDIRECT
quote_role: REVIEW_SYNTHESIS
evidence_source: HUMAN_CLINICAL
snippet: 'treatment goals include ensuring the safety of the infant/child, prophylaxis for infections, and preemptive HSCT to establish a functional immune system prior to the development of symptoms'
explanation: 'Transplantation as the GeneReviews treatment goal for typical X-SCID; indirect for this entity, whose alleles are hypomorphic.'
- reference: DOI:10.3389/fimmu.2020.608653
reference_title: 'Immune Reconstitution After Gene Therapy Approaches in Patients With X-Linked Severe Combined Immunodeficiency Disease'
supports: SUPPORT
directness: INDIRECT
quote_role: REVIEW_SYNTHESIS
evidence_source: HUMAN_CLINICAL
snippet: 'The treatment of choice for these patients is hematopoietic stem cell transplantation'
explanation: 'The same statement for SCID-X1 in a review of its treatment; indirect for the same reason.'
- name: Gene Therapy
description: >-
Lentiviral IL2RG gene therapy with low-dose conditioning has restored T, B and NK
cells in children and adults with SCID-X1. No cached source reports it in a
patient with a hypomorphic allele, so the evidence is graded INDIRECT.
therapeutic_modality: GENE_THERAPY
treatment_term:
preferred_term: gene therapy
term:
id: NCIT:C15238
label: Gene Therapy
evidence:
- reference: DOI:10.3389/fimmu.2020.608653
reference_title: 'Immune Reconstitution After Gene Therapy Approaches in Patients With X-Linked Severe Combined Immunodeficiency Disease'
supports: SUPPORT
directness: INDIRECT
quote_role: REVIEW_SYNTHESIS
evidence_source: HUMAN_CLINICAL
snippet: 'The most recent clinical trials using lentiviral vectors together with a low-dose pre-conditioning regimen have demonstrated excellent sustained T cell recovery, but also B and NK cells, in both children and adults.'
explanation: 'Outcome of lentiviral gene therapy in SCID-X1; indirect for this entity.'
references:
- reference: PMID:2243135
title: "A novel X-linked combined immunodeficiency disease."
- reference: PMID:7883965
title: "Missense mutation in exon 7 of the common gamma chain gene causes a moderate form of X-linked combined immunodeficiency."
- reference: PMID:35052377
title: "Somatic Reversion of a Novel IL2RG Mutation Resulting in Atypical X-Linked Combined Immunodeficiency."
- reference: PMID:1348030
title: "Repertoire of V alpha and V beta regions of T cell antigen receptors on CD4+ and CD8+ peripheral blood T cells in a novel X-linked combined immunodeficiency disease."
- reference: PMID:1606754
title: "Postnatal development of T lymphocytes in a novel X-linked immunodeficiency disease."
- reference: PMID:20301584
title: "X-Linked Severe Combined Immunodeficiency."
tags:
- GeneReviews
- reference: DOI:10.1007/s10875-020-00745-2
title: "Novel Hemizygous IL2RG p.(Pro58Ser) Mutation Impairs IL-2 Receptor Complex Expression on Lymphocytes Causing X-Linked Combined Immunodeficiency"
- reference: DOI:10.1111/cei.13405
title: "The IL-2RG R328X nonsense mutation allows partial STAT-5 phosphorylation and defines a critical region involved in the leaky-SCID phenotype"
- reference: DOI:10.3389/fimmu.2020.608653
title: "Immune Reconstitution After Gene Therapy Approaches in Patients With X-Linked Severe Combined Immunodeficiency Disease"
notes: >-
Six things about this entry are deliberate.
First, **it is a standalone entry and not a `has_subtypes` row on
`Severe_Combined_Immunodeficiency`.** MONDO:0010730 resolves through its
cross-references to OMIM 312863, the moderate X-linked combined immunodeficiency
of Brooks et al., which is a different OMIM entity from SCIDX1 (300400). The
1990 report says in its own abstract that the disorder is "distinct from
previously reported disorders", and the 1995 report that found the gene concludes
the allele gives "a less severe degree of deficiency in cellular and humoral
immunity than that seen in XSCID". Filing it as a subtype of severe combined
immunodeficiency would assert the opposite of what both defining papers say.
`Severe_Combined_Immunodeficiency.yaml` already carries an `X-linked SCID`
subtype bound to `MONDO:0010315`, which is the X-SCID concept, so this entry does
not duplicate it.
Second, **MONDO's placement of this term disagrees with that reading and is worth
flagging.** MONDO:0010730's only parent is `MONDO:0044200` T-B+ severe combined
immunodeficiency, which would make XCID a kind of SCID. The stub for this
concept carries that parent. This entry follows the primary literature instead;
anyone who thinks MONDO is right should reopen the lump/split call rather than
assume it was overlooked.
Third, **no phenotype carries a `frequency` band.** The literature cited here is
one American family of five affected males, one German family of three brothers,
a single boy carrying p.Pro58Ser, two brothers carrying p.Arg328Ter, two
follow-up immunology papers on the first family, and the GeneReviews chapter,
which describes atypical X-SCID presentations without rates. Several phenotypes
here rest on one family and say so in their `explanation`.
Fourth, **the `Somatic Reversion in the T Cell Lineage` node is not part of the
causal chain and should not be read as one.** It has no `downstream` edges
because it does not cause anything in this pathograph: it is a partially
compensating event that the authors of the German family's report hold jointly
responsible, with the hypomorphic allele, for how mild the phenotype was. It is
curated because it is why genotype does not predict phenotype here - the three
brothers carried the same variant and differed markedly.
Fifth, **the coding-DNA notation for p.Leu271Gln is a reconstruction and is
labelled as such.** The 1995 paper reports the allele by amino acid position and
codon change (CTG to CAG in exon 7), not by a c. identifier. The `genetic`
record's `notes` says so rather than presenting c.812T>A as if it were quoted.
Sixth, **the deep-research run used a disambiguated query and that was
necessary.** "X-linked combined immunodeficiency" and "X-linked severe combined
immunodeficiency" differ by one word and share a gene, and a provider asked for
the former will happily return the latter. The `falcon` run behind
`research/X-Linked_Combined_Immunodeficiency-deep-research-falcon.md` was given
a `disease_name` naming XCID, CIDX, OMIM 312863, the hypomorphic IL2RG common
gamma chain, Brooks 1990, and an explicit "not SCIDX1 OMIM 300400". It came
back on target - `just preflight-dr` PASSes with IL2RG mentioned 48 times, and
the report carries both OMIM numbers because the contrast was asked for. Two
cautions for anyone mining it: its term validation flags `HP:0005351` as
unresolvable, so that CURIE must not be bound, and only 7 of its 13 verified
references were judged on topic. Nothing in this entry is bound from the report;
every evidence item traces to a cached primary source, a cached review, or the
GeneReviews chapter. The report also names enteropathy, failure to thrive and
candidiasis; no cached source states them for this entity, so they are not
curated.
Two things left out. `PMID:1348030` and `PMID:1606754`, the T-cell receptor
repertoire and postnatal T-cell development studies on the index family, are
listed in `references` but carry no evidence item: both are cached as
abstract-only records under a thousand characters, and neither abstract contains
a sentence that adds a claim this entry does not already support from the 1990
paper. And the transplantation and gene therapy records carry only INDIRECT
evidence: both are established for typical X-SCID, but no cached source reports
either in a patient with a hypomorphic allele.
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.
Record notes
Six things about this entry are deliberate. First, **it is a standalone entry and not a `has_subtypes` row on `Severe_Combined_Immunodeficiency`.** MONDO:0010730 resolves through its cross-references to OMIM 312863, the moderate X-linked combined immunodeficiency of Brooks et al., which is a different OMIM entity from SCIDX1 (300400). The 1990 report says in its own abstract that the disorder is "distinct from previously reported disorders", and the 1995 report that found the gene concludes the allele gives "a less severe degree of deficiency in cellular and humoral immunity than that seen in XSCID". Filing it as a subtype of severe combined immunodeficiency would assert the opposite of what both defining papers say. `Severe_Combined_Immunodeficiency.yaml` already carries an `X-linked SCID` subtype bound to `MONDO:0010315`, which is the X-SCID concept, so this entry does not duplicate it. Second, **MONDO's placement of this term disagrees with that reading and is worth flagging.** MONDO:0010730's only parent is `MONDO:0044200` T-B+ severe combined immunodeficiency, which would make XCID a kind of SCID. The stub for this concept carries that parent. This entry follows the primary literature instead; anyone who thinks MONDO is right should reopen the lump/split call rather than assume it was overlooked. Third, **no phenotype carries a `frequency` band.** The literature cited here is one American family of five affected males, one German family of three brothers, a single boy carrying p.Pro58Ser, two brothers carrying p.Arg328Ter, two follow-up immunology papers on the first family, and the GeneReviews chapter, which describes atypical X-SCID presentations without rates. Several phenotypes here rest on one family and say so in their `explanation`. Fourth, **the `Somatic Reversion in the T Cell Lineage` node is not part of the causal chain and should not be read as one.** It has no `downstream` edges because it does not cause anything in this pathograph: it is a partially compensating event that the authors of the German family's report hold jointly responsible, with the hypomorphic allele, for how mild the phenotype was. It is curated because it is why genotype does not predict phenotype here - the three brothers carried the same variant and differed markedly. Fifth, **the coding-DNA notation for p.Leu271Gln is a reconstruction and is labelled as such.** The 1995 paper reports the allele by amino acid position and codon change (CTG to CAG in exon 7), not by a c. identifier. The `genetic` record's `notes` says so rather than presenting c.812T>A as if it were quoted. Sixth, **the deep-research run used a disambiguated query and that was necessary.** "X-linked combined immunodeficiency" and "X-linked severe combined immunodeficiency" differ by one word and share a gene, and a provider asked for the former will happily return the latter. The `falcon` run behind `research/X-Linked_Combined_Immunodeficiency-deep-research-falcon.md` was given a `disease_name` naming XCID, CIDX, OMIM 312863, the hypomorphic IL2RG common gamma chain, Brooks 1990, and an explicit "not SCIDX1 OMIM 300400". It came back on target - `just preflight-dr` PASSes with IL2RG mentioned 48 times, and the report carries both OMIM numbers because the contrast was asked for. Two cautions for anyone mining it: its term validation flags `HP:0005351` as unresolvable, so that CURIE must not be bound, and only 7 of its 13 verified references were judged on topic. Nothing in this entry is bound from the report; every evidence item traces to a cached primary source, a cached review, or the GeneReviews chapter. The report also names enteropathy, failure to thrive and candidiasis; no cached source states them for this entity, so they are not curated. Two things left out. `PMID:1348030` and `PMID:1606754`, the T-cell receptor repertoire and postnatal T-cell development studies on the index family, are listed in `references` but carry no evidence item: both are cached as abstract-only records under a thousand characters, and neither abstract contains a sentence that adds a claim this entry does not already support from the 1990 paper. And the transplantation and gene therapy records carry only INDIRECT evidence: both are established for typical X-SCID, but no cached source reports either in a patient with a hypomorphic allele.
Review round 1: mine GeneReviews, keep the atypical X-SCID scope, add alleles and presentations · 2026-09-25T19:00:49Z · View source
Round-1 review (PR 11556) blocked on an uncited GeneReviews chapter already in the cache (PMID:20301584, X-Linked Severe Combined Immunodeficiency) and on a mismatch between the entry's declared scope (atypical/leaky X-SCID synonyms) and what it curated. The GeneReviews abstract describes atypical X-SCID as a spectrum that explicitly includes an X-SCID combined immunodeficiency presentation with recurrent infections, warts and dermatitis, so the broad scope was kept. GeneReviews is now tagged and quoted in all four sections: clinical characteristics (atypical presentation, warts, dermatitis, autoimmunity, EBV-related lymphoproliferation), diagnosis (molecular criterion, and that atypical X-SCID usually escapes newborn screening, replacing a sentence the entry had marked as a curator inference), management (atypical treatment statement, agents to avoid, HSCT as a treatment goal for typical X-SCID graded INDIRECT) and genetic counseling (transmission by sex of offspring). Two further alleles were curated from caches the PR had already committed: p.Pro58Ser (DOI:10.1007/s10875-020-00745-2; reduced surface expression through ER/Golgi mislocalisation, reactive arthritis, bronchiectasis) and p.Arg328Ter (DOI:10.1111/cei.13405; impaired JAK3 binding with partial STAT5 phosphorylation, lethal EBV-related lymphoma). This contradicted the description's claim that all alleles leave surface expression normal, so the description and the signalling node now state the mechanism per allele, and the variant node was renamed from 'Missense Variant' because p.Arg328Ter is nonsense. Gene therapy was added from DOI:10.3389/fimmu.2020.608653 graded INDIRECT. New phenotypes: dermatitis HP:0011123, autoimmunity HP:0002960, EBV-related lymphoproliferation HP:0005523 (wired from the viral-susceptibility node), arthritis HP:0001369; CURIEs and labels read from cache/hp/terms.csv and OLS. Enteropathy, failure to thrive and candidiasis, named only by the deep-research report, were not curated because no cached source states them. Ten uncited reference caches were removed from the PR: five with no quotable text, one about a RAG2/IL2RG pig, one duplicating PMID:35052377 under its DOI, two theses on the same German family, and one on gamma-delta T cells. GeneReviews items carry quote_role REVIEW_SYNTHESIS. Merged origin/main; one hp term-cache row conflicted on timestamp only and took main's row.
Question: You are an expert researcher providing comprehensive, well-cited information.
Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies
Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.
Please provide a comprehensive research report on X-linked combined immunodeficiency (XCID, CIDX, moderate X-linked combined immunodeficiency, OMIM 312863), the attenuated hypomorphic IL2RG common-gamma-chain disorder described by Brooks et al 1990 and also called atypical or leaky X-linked SCID - not X-linked severe combined immunodeficiency SCIDX1 OMIM 300400 covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.
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For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types
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Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, NCIT, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease
This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (NCIT terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details
This report concerns the attenuated common-γ-chain disorder historically described as X-linked combined immunodeficiency (XCID/CIDX), moderate X-linked combined immunodeficiency, atypical X-SCID, or leaky X-SCID—not the usual null-allele SCID-X1 phenotype catalogued as OMIM 300400. The distinction is functional: XCID retains allele-dependent IL2RG activity, thymopoiesis, or lineage-restricted activity through somatic reversion. It nevertheless belongs to the IL2RG disease continuum and can progress to life-threatening combined immunodeficiency.
Evidence is principally from individual patients and small families, not population cohorts. Percentages below therefore describe published cases and are vulnerable to referral and publication bias. PMID values could not be verified reliably in the retrieved full texts and are consequently not invented; DOI URLs and publication dates are supplied.
A compact knowledge-base summary precedes the detailed report.
| Domain | High-confidence finding | Suggested ontology IDs | Evidence caveat |
|---|---|---|---|
| Identity / scope | Attenuated IL2RG common-γ-chain disorder, variably called XCID, atypical X-SCID, or leaky X-SCID; residual γc function distinguishes it from classic, usually T−B+NK− SCID-X1. Requested identifier: OMIM 312863. | MONDO:0010730 as requested | OMIM/MONDO mapping should be manually verified because databases may merge this phenotype with SCID-X1 (OMIM 300400) or broader combined immunodeficiency. (tuovinen2020novelhemizygousil2rg pages 1-2, lim2019il2rghypomorphicmutation pages 1-2) |
| Causal gene | IL2RG, encoding interleukin-2 receptor subunit γ/common γ chain (CD132), is causal. | HGNC:6010; NCBI Gene:3561; ENSG00000147168 | Disease association is established, but “hypomorphic” requires phenotype and preferably functional confirmation rather than gene identity alone. (OpenTargets Search: X-linked combined immunodeficiency-IL2RG, arcasgarcia2020theil2rgr328x pages 1-2) |
| Inheritance | X-linked recessive germline disease: hemizygous males are predominantly affected; heterozygous mothers may be clinically asymptomatic carriers. | HP:0001419 | Rare symptomatic females could theoretically result from skewed X-inactivation or chromosomal abnormalities, but no disease-specific frequency is established. (hou2021somaticreversionof pages 5-6, gratz2024functionalcharacterizationof pages 21-26) |
| Core immunophenotype | Variable T-low B+ NK+ or NK-low/− phenotype; normal total lymphocyte counts do not exclude disease. Common findings include low CD4 cells, inverted CD4:CD8 ratio, low TRECs, skewed TCR repertoire, dysgammaglobulinemia, impaired proliferation, and reduced cytokine-induced STAT phosphorylation. | HP:0005403; HP:0002850; HP:0005351; HP:0004313 | No single immunophenotype is universal; residual function, age, and somatic reversion produce marked variability. (arcasgarcia2020theil2rgr328x pages 1-2, gratz2024functionalcharacterizationof pages 26-29, tuovinen2020novelhemizygousil2rg pages 9-10, hou2021somaticreversionof pages 6-11) |
| Hallmark clinical features | Recurrent sinopulmonary and opportunistic infections, chronic viral skin disease—especially warts/HPV and molluscum—bronchiectasis, diarrhea/enteropathy, candidiasis, failure to thrive, eczema or granulomatous inflammation, arthritis, and EBV-associated lymphoproliferation/lymphoma may occur. | HP:0002205; HP:0002110; HP:0032180; HP:0000960; HP:0002028; HP:0001508; HP:0000988; HP:0001369 | Frequencies derive mainly from small case series: among 29 literature cases, 97% had infections and 45% opportunistic infections; ascertainment bias is substantial. (arcasgarcia2020theil2rgr328x pages 1-2, lin2020progressivebcell pages 3-5, tuovinen2020novelhemizygousil2rg pages 9-10) |
| Molecular mechanism | Hypomorphic γc dysfunction partially impairs signaling by receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Reduced γc surface localization or γc–JAK3 coupling leads to deficient JAK3/STAT5 signaling, impaired thymopoiesis and T/NK-cell proliferation, and defective T–B cooperation. | GO:0038110; GO:0042100; GO:0030217; GO:0001779; CL:0000084; CL:0000623; CL:0000624; CL:0000625 | Cytokine pathways are affected unequally by different alleles; alternative/JAK3-independent residual STAT5 activation has been demonstrated for p.Arg328Ter. (arcasgarcia2020theil2rgr328x pages 1-2, tuovinen2020novelhemizygousil2rg pages 1-2, lim2019il2rghypomorphicmutation pages 4-6) |
| Key variants | Documented hypomorphic alleles include NM_000206.3:c.172C>T, p.(Pro58Ser); c.455T>C, p.(Val152Ala); c.458T>C, p.(Ile153Thr); c.664C>T, p.(Arg222Cys); and c.982C>T, p.(Arg328Ter). | Sequence Ontology: SO:0001583 (missense); SO:0001587 (stop-gained) | Transcript/version and ClinVar classifications must be checked variant by variant. p.Arg222Cys has produced both atypical and classic X-SCID, illustrating imperfect genotype–phenotype correlation. (arcasgarcia2020theil2rgr328x pages 1-2, lin2020progressivebcell pages 5-6, tuovinen2020novelhemizygousil2rg pages 9-10, hou2021somaticreversionof pages 6-11, tuovinen2020novelhemizygousil2rg pages 1-2) |
| Somatic reversion / modifier | Back mutation or compensatory second-site variation can selectively restore γc function in lymphoid clones, attenuating disease but causing mosaic, oligoclonal, or lineage-restricted immunity. | SO:0001777 (somatic variant); HP:0001442 (somatic mosaicism) | Reversion is not reliably protective: progressive B-cell loss, restricted TCR diversity, infection, and immune dysregulation can still occur. (lin2020progressivebcell pages 5-6, hou2021somaticreversionof pages 6-11, lin2020progressivebcell pages 8-9) |
| Diagnostics | Evaluate CBC/differential, lymphocyte subsets and naïve/memory populations, immunoglobulins and vaccine antibodies, mitogen/antigen proliferation, TRECs, TCR diversity, CD132 expression, and cytokine-induced STAT3/5/6 phosphorylation; confirm with IL2RG sequencing plus deletion/duplication analysis. Deep sequencing of sorted lineages can identify reversion. | HP:0031406; HP:0004313; NCIT:C171178 (next-generation sequencing) | CD132 expression may be normal despite dysfunctional signaling. WES/WGS or an IEI panel is useful when the presentation is atypical; CMA, karyotype, mtDNA, and repeat testing are not first-line absent another indication. (arcasgarcia2020theil2rgr328x pages 1-2, tuovinen2020novelhemizygousil2rg pages 1-2, hou2021somaticreversionof pages 6-11) |
| Screening | Newborn dried-blood-spot TREC screening can identify some leaky SCID cases; abnormal results require prompt flow cytometry and molecular evaluation. Cascade testing is indicated for maternal relatives. | HP:0031406; NCIT:C15644 (genetic testing) | Residual thymopoiesis can yield TRECs above program cutoffs, so newborn screening does not exclude hypomorphic IL2RG disease. (lim2019il2rghypomorphicmutation pages 1-2, hou2024challengeswithgene pages 10-14) |
| Management | Specialist immunology care; individualized immunoglobulin replacement, antimicrobial/Pneumocystis prophylaxis, rapid treatment of infections, avoidance of live vaccines when cellular immunity is inadequate, respiratory surveillance, and definitive consideration of allogeneic HSCT or investigational autologous IL2RG gene therapy. | NCIT:C15246 (hematopoietic stem-cell transplantation); NCIT:C16387 (gene therapy); NCIT:C15691 (immunoglobulin therapy) | Direct XCID treatment trials are lacking. HSCT and lentiviral-gene-therapy outcome estimates largely come from classic SCID-X1 and should not be assumed identical; early γ-retroviral therapy caused insertional leukemia. (blanco2020immunereconstitutionafter pages 1-2, blanco2020immunereconstitutionafter pages 2-3, lin2020progressivebcell pages 3-5) |
| Prognosis | Course ranges from survival into adulthood with recurrent infections to progressive lymphocyte loss, bronchiectasis, enteropathy, multiorgan granulomatous disease, malignancy, or death. Early recognition before irreversible infection or immune dysregulation is considered favorable. | HP:0002721; HP:0002110 | No XCID-specific survival curve or life-expectancy estimate exists. Somatic reversion and apparently mild childhood disease do not ensure long-term stability. (lin2020progressivebcell pages 3-5, lin2020progressivebcell pages 8-9) |
| Epidemiology | Extremely rare; no reliable incidence, prevalence, carrier-frequency, founder-effect, ethnic, or geographic-distribution estimates are available. One literature review identified 39 atypical patients among 362 observed IL2RG mutations/cases, approximately 10%. | ORDO prevalence class not established | The reported proportion is a literature-derived mutation/case series, not a population prevalence estimate, and is vulnerable to publication and classification bias. (lim2019il2rghypomorphicmutation pages 1-2, lim2019il2rghypomorphicmutation pages 4-6) |
| Animal models | Engineered Il2rg/IL2RG-deficient mice and pigs model γc-dependent lymphoid failure; IL2RG-edited pigs can show X-linked T−B+NK− SCID, thymic hypoplasia, and arrest of T-cell development, supporting transplantation, humanization, and gene-therapy studies. | NCBI Taxon:10090 (Mus musculus); NCBI Taxon:9823 (Sus scrofa) | Available models generally use null or large-disruption alleles and therefore resemble classic SCID-X1 more closely than human hypomorphic XCID; allele-specific leaky models are limited. |
Table: Compact knowledge-base summary of attenuated hypomorphic IL2RG-associated XCID, explicitly distinguished from classic SCID-X1. Identifier uncertainty and evidence limitations are flagged to prevent overinterpretation.
XCID is an X-linked Mendelian combined immunodeficiency caused by germline hypomorphic IL2RG variants, sometimes further attenuated by somatic rescue. Unlike classic SCID-X1—with profound T- and NK-cell deficiency and dysfunctional B cells—XCID commonly has measurable T cells and sometimes NK cells, later onset, and prolonged survival. Normal total lymphocyte counts do not exclude it. Lim et al. identified 39 atypical patients among 362 reported IL2RG observations; approximately 10% of reported IL2RG mutations/cases were associated with atypical phenotypes. This is not a population prevalence estimate. (tuovinen2020novelhemizygousil2rg pages 1-2, lim2019il2rghypomorphicmutation pages 1-2, lim2019il2rghypomorphicmutation pages 4-6)
A useful direct abstract statement is: “Atypical X-linked severe combined immunodeficiency (X-SCID) is a variant of cellular immunodeficiency due to hypomorphic mutations in the interleukin 2 receptor gamma (IL2RG) gene.” Lim et al., published January 2019, DOI: https://doi.org/10.1186/s13223-018-0317-y. (lim2019il2rghypomorphicmutation pages 1-2)
The primary cause is a hemizygous germline partial-loss-of-function IL2RG variant. IL2RG is the shared receptor chain for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Residual receptor expression, membrane trafficking, JAK3 coupling, or downstream STAT activation produces the attenuated phenotype. (arcasgarcia2020theil2rgr328x pages 1-2, tuovinen2020novelhemizygousil2rg pages 1-2, gratz2024functionalcharacterizationof pages 8-13)
Documented attenuated alleles include:
These are germline variants; spontaneous reversion or second-site rescue is somatic. Population allele frequencies and current ClinVar ACMG classifications were not available in retrieved evidence and must be checked per transcript in ClinVar/gnomAD before ingestion. Pathogenicity should not be inferred from IL2RG location alone: segregation, phenotype, population rarity, and functional cytokine-signaling assays are especially important for hypomorphic alleles.
There is no evidence that toxins, diet, smoking, occupation, radiation, or exercise cause XCID. Male sex and maternal family history reflect X-linked inheritance, not environmental risk. Pathogen exposure determines when limited immune reserve becomes clinically evident; HPV, respiratory viruses, enteroviruses, EBV, Giardia, norovirus, Candida, and bacterial respiratory infections have acted as clinical stressors. Somatic reversion is the clearest biological modifier, but it is not reliably protective because corrected clones may be lineage-restricted and oligoclonal. (lin2020progressivebcell pages 3-5, lin2020progressivebcell pages 5-6, hou2021somaticreversionof pages 5-6, lin2020progressivebcell pages 8-9)
No reproducible protective germline allele, lifestyle factor, epigenetic modifier, or formal gene–environment interaction has been established.
The phenotype is heterogeneous and age-dependent. In one literature synthesis of 29 atypical cases, 97% had infection susceptibility and 45% (13/29) had opportunistic infections; four opportunistic infections occurred despite normal CD3 counts. Normal immunoglobulins occurred in 41% (12/29), while 28% (8/29) had skewed B-cell subsets. Eczema/rash occurred in three, inflammatory arthritis in two, interstitial lung disease in two, and inflammatory bowel disease in one. These are literature-case frequencies, not penetrance estimates. (tuovinen2020novelhemizygousil2rg pages 9-10)
No XCID-specific EQ-5D, SF-36, PROMIS, or utility study was found. Case histories document repeated hospitalization, chronic airway disease, burdensome wart procedures, antimicrobial and immunoglobulin dependence, nutritional impairment, and malignancy. Thus substantial quality-of-life loss is clinically evident, but no validated quantitative score can be assigned. (gratz2024functionalcharacterizationof pages 21-26, lin2020progressivebcell pages 3-5)
IL2RG is located on Xq13.1 and encodes CD132. Variant classes producing leaky disease include missense, nonsense/truncating, and splice-altering alleles. The disease mechanism is usually partial loss of function, not gain of function or dominant negative activity.
Allele-specific consequences include:
No validated modifier gene, disease-specific methylation signature, histone abnormality, recurrent chromosomal rearrangement, or structural chromosome abnormality was found. Rare symptomatic heterozygous females are biologically plausible through skewed X-inactivation, but disease-specific evidence and frequency were not retrieved.
Environmental toxicants and lifestyle do not initiate the Mendelian disorder. Clinically important exposures are infectious:
No zoonotic agent, toxin, pollutant, dietary pattern, alcohol exposure, or occupation has a demonstrated etiologic role. Gene–environment interaction is best understood as pathogen burden revealing an inherited shortage of immune signaling capacity, not as environmental causation.
The p.Pro58Ser BioID result is direct proteomic/proximity-labeling evidence of ER/Golgi mislocalization. Whole-transcriptome studies in IL2RG-disrupted pigs found altered TCR- and cytokine-signaling genes, but no reproducible human XCID transcriptomic, metabolomic, lipidomic, spatial-transcriptomic, or multi-omic signature has been established. (tuovinen2020novelhemizygousil2rg pages 1-2)
A 2023 study added important single-lineage biology: γδ T cells in a p.Pro58Ser patient had normal/enhanced CD132 signaling and cytotoxicity and acquired a lineage-restricted c.534C>A, p.(Phe178Leu) second-site variant that improved mutant surface expression in vitro. This argues that expanded γδ cells should not automatically be interpreted as nonspecific homeostatic expansion. DOI: https://doi.org/10.1007/s10875-022-01375-6; published 2023. This is human cellular plus in-vitro evidence.
The primary defect resides in the hematolymphoid system:
Secondary injury affects:
Subcellular compartments include plasma membrane, ER/Golgi, cytoplasmic receptor tails/JAK3 complexes, and nucleus for activated STAT transcription. Lateralization is not intrinsic; focal pulmonary disease may be asymmetric, but this is a complication rather than a disease-defining feature.
XCID is congenital genetically but may present from infancy to adulthood. Onset is usually insidious, with recurrent infections or viral skin disease rather than the fulminant first-month presentation of classic SCID-X1. Examples include an asymptomatic eight-month-old with abnormal immune studies; affected children at four, seven, 11, and 16 years; and adult brothers aged 23–26. (arcasgarcia2020theil2rgr328x pages 1-2, lim2019il2rghypomorphicmutation pages 1-2, gratz2024functionalcharacterizationof pages 26-29)
The course may be stable for years, episodic, or progressive. A p.Val152Ala patient improved temporarily at ages three to four, then developed Giardia at 11, granulomatous/skin disease at 13, norovirus at 17, and progressive enteropathy, malnutrition, pneumonia, and near-loss of T, B, and NK cells in adulthood. This demonstrates that childhood improvement or somatic rescue is not equivalent to durable remission. (lin2020progressivebcell pages 3-5)
Critical windows are:
No accepted staging system exists.
Inheritance is X-linked recessive. Hemizygous males predominate; heterozygous mothers may be asymptomatic carriers. Transmission risk from a carrier mother is 50% for each son to inherit the variant and 50% for each daughter to become a carrier, subject to standard Mendelian assumptions.
Expressivity is markedly variable, even within families. Penetrance among hemizygous males carrying established hypomorphic pathogenic alleles appears high but cannot be quantified; disease may be initially asymptomatic. Anticipation is not expected. Maternal germline mosaicism is possible in X-linked disease generally but no XCID-specific frequency was found. Somatic reversion is well documented and can alter blood-lineage penetrance without changing germline recurrence risk. (lin2020progressivebcell pages 5-6, hou2021somaticreversionof pages 6-11)
No reliable incidence, prevalence, carrier frequency, founder effect, ethnic enrichment, or geographic gradient is available. The 39 atypical patients among 362 reported IL2RG observations and 29-case clinical synthesis indicate extreme rarity but cannot support cases-per-100,000 estimates. (lim2019il2rghypomorphicmutation pages 1-2, tuovinen2020novelhemizygousil2rg pages 9-10)
Preferred testing is an inborn-errors-of-immunity panel including IL2RG or direct IL2RG sequencing, with deletion/duplication analysis. WES/WGS is appropriate for atypical or panel-negative combined immunodeficiency. Deep sequencing and sequencing of sorted T, B, NK, and myeloid fractions can reveal somatic reversion that bulk blood sequencing may understate. Maternal carrier testing and cascade testing should follow. (lin2020progressivebcell pages 5-6, hou2021somaticreversionof pages 6-11)
CMA, karyotyping, FISH, mitochondrial sequencing, and repeat-expansion testing are not routine unless another phenotype suggests them. RNA sequencing may clarify suspected splice variants but is not a standard first-line assay. No validated metabolomic, proteomic, epigenomic, or liquid-biopsy diagnostic exists.
No universally accepted XCID-specific clinical criteria exist. Diagnosis requires a compatible phenotype plus a hemizygous IL2RG variant and, for uncertain/hypomorphic alleles, functional impairment and segregation.
Differentials include classic SCID-X1; JAK3 deficiency; IL7R deficiency; hypomorphic RAG1/2 or DCLRE1C disease; ZAP70 deficiency; CD40L deficiency; DOCK8 deficiency; WHIM syndrome; GATA2 deficiency; XMEN; activated PI3K-δ syndrome; HIV/secondary immunodeficiency; cystic fibrosis; and primary ciliary dyskinesia. T/B/NK pattern, immunoglobulins, viral susceptibility, syndromic features, and molecular testing distinguish these.
Dried-blood-spot TREC newborn screening can detect some leaky SCID, but residual thymopoiesis can yield values above program cutoffs. Therefore, a normal screen does not exclude XCID. Currier and Puck emphasized that TREC programs detect SCID and some leaky/hypomorphic cases, but positive TRECs are not gene-specific and require flow cytometry and genetic evaluation. DOI: https://doi.org/10.1016/j.jaci.2020.10.020; published February 2021. (lim2019il2rghypomorphicmutation pages 1-2, hou2024challengeswithgene pages 10-14)
No disease-specific five- or ten-year survival, life expectancy, mortality rate, or validated prognostic calculator exists. Outcomes range from survival well into adulthood to death in early childhood from EBV lymphoma or progressive multiorgan infectious/inflammatory disease. (arcasgarcia2020theil2rgr328x pages 1-2, lin2020progressivebcell pages 3-5)
Adverse prognostic features likely include:
Somatic reversion is not a guaranteed favorable biomarker. The p.Val152Ala case had completely wild-type sorted T cells but oligoclonality, progressive B-cell loss, severe infection, and organ injury. Experts therefore recommend considering definitive therapy before immune dysregulation reduces its success. (lin2020progressivebcell pages 5-6, lin2020progressivebcell pages 8-9)
No formal disability or quality-of-life datasets were found.
In three p.Ile153Thr brothers, IVIG plus antibiotic prophylaxis prevented further severe bacterial infections in the most affected brother, but warts and bronchiectasis persisted. This is uncontrolled case evidence. (gratz2024functionalcharacterizationof pages 21-26)
Allogeneic HSCT is the established definitive treatment—NCIT:C15246. Direct XCID outcome datasets are sparse. In classic SCID-X1, reported survival is >70% overall, >90% with an HLA-matched sibling, and about 60–75% with alternative donors; treatment before 3.5 months and absence of active infection improve survival. T-cell recovery generally begins by three to four months and normalizes by 9–12 months, while 43–66% may remain immunoglobulin-dependent because B-cell correction is variable. These statistics are extrapolated from classic SCID-X1 and must not be presented as XCID-specific rates. (blanco2020immunereconstitutionafter pages 1-2, blanco2020immunereconstitutionafter pages 2-3)
Autologous CD34+ HSPC gene addition is NCIT:C16387. Early γ-retroviral IL2RG therapy restored T cells but caused insertional oncogenesis/T-ALL in some patients. Newer self-inactivating lentiviral vectors plus low-dose conditioning have produced broader T-, B-, and NK-cell reconstitution in classic SCID-X1, avoiding donor availability and graft-versus-host disease; long-term genotoxicity monitoring remains necessary. No trial was identified specifically for hypomorphic XCID. (blanco2020immunereconstitutionafter pages 1-2, hou2024challengeswithgene pages 10-14)
CRISPR/HDR, base editing, and prime editing are preclinical for IL2RG/XCID. A 2023 human-HSPC study modeled and corrected SCID variants by multiplex HDR, but this is not clinical efficacy evidence. DOI: https://doi.org/10.1016/j.omtn.2022.12.006; published 2023. Editing risks include off-target mutation, large on-target deletion/rearrangement, inadequate correction of long-term HSCs, and—in reverted mosaic disease—complex clonal competition.
Retrieved SCID-X1/primary-immunodeficiency records included NCT01410019 (completed phase I/II gene therapy; five participants), NCT01821781 (active, not recruiting, phase II immune-disorder HSCT; 20 participants), NCT00008450 (completed phase I transplant-conditioning study; six participants), and NCT00006054 (terminated allogeneic transplantation study). Eligibility for an individual with hypomorphic XCID must be checked directly; none was established as an XCID-specific trial.
No pharmacogenomic rule, approved small-molecule corrective therapy, RNA therapy, surgery, or rehabilitation program is disease-specific.
Primary prevention through lifestyle change is not possible for an inherited X-linked disorder. Reproductive options include carrier testing, cascade testing, prenatal diagnosis, and preimplantation genetic testing after the familial variant is established.
Secondary prevention comprises TREC newborn screening, early immune phenotyping, genetic confirmation, and presymptomatic evaluation of at-risk male relatives. Because TREC screening can miss residual-function disease, family-based molecular testing is more sensitive after a variant is known. (lim2019il2rghypomorphicmutation pages 1-2, hou2024challengeswithgene pages 10-14)
Tertiary prevention includes immunoglobulin and antimicrobial/Pneumocystis prophylaxis as indicated, avoidance of live vaccines with inadequate cellular immunity, irradiated/leukoreduced/CMV-appropriate blood products per specialist practice, prompt infection treatment, respiratory surveillance, EBV monitoring in high-risk patients, and definitive therapy before irreversible organ damage. (blanco2020immunereconstitutionafter pages 1-2, lin2020progressivebcell pages 3-5)
Routine inactivated vaccines may be safe but responses must be measured; vaccine strategy should be individualized by an immunologist. No diet, exercise, sanitation, or environmental intervention corrects the receptor defect.
Orthologous Il2rg/IL2RG genes are conserved in mammals. Relevant taxa include Mus musculus—NCBI Taxon 10090—and Sus scrofa—NCBI Taxon 9823.
No well-characterized naturally occurring animal disease specifically homologous to hypomorphic human XCID was found. Naturally occurring SCID exists in several species, but available evidence does not establish it as the same allele class or IL2RG mechanism.
Engineered porcine IL2RG disruption produces X-linked T−B+NK− SCID, thymic aplasia/hypoplasia, and impaired T-cell development. In one partial-loss/disruption study, 8/10 pigs (80%) were athymic and 2/10 (20%) had a rudimentary thymus; development arrested around the DN3-to-DN4 transition. DOI: https://doi.org/10.18632/oncotarget.10812; published July 2016. These pigs model classic γc failure better than variable human leaky disease.
There is no zoonotic transmission: XCID is inherited, not infectious.
Models are used to study γc-dependent thymopoiesis, NK development, cytokine signaling, transplantation, humanization, viral-vector gene addition, and genome editing. Pigs improve translational assessment of dosing, conditioning, imaging, and long-term cell engraftment relative to mice.
The principal limitation is that most animal models use null or large-disruption alleles and therefore reproduce classic SCID-X1 rather than residual-function, allele-specific XCID. They inadequately model delayed onset, human pathogen exposure, HPV/EBV disease, somatic reversion, oligoclonality, and intrafamilial expressivity. Allele-specific knock-in models for p.Pro58Ser, p.Val152Ala, p.Ile153Thr, p.Arg222Cys, or p.Arg328Ter would better address XCID biology.
The current view is that XCID is not simply “mild SCID.” It is a dynamic disorder in which receptor reserve, cytokine concentration, lineage-specific selection, pathogen exposure, and somatic rescue determine phenotype. The 2023 γδ-T-cell study showed that a second-site IL2RG variant can selectively improve signaling and cytotoxic function in one lineage. The 2024 functional/editing work emphasizes that reverted mosaicism complicates both interpretation and design of corrective editing. However, the 2024 sources retrieved were dissertations rather than definitive clinical trials, so their therapeutic proposals remain preclinical. (gratz2024functionalcharacterizationof pages 44-49, hou2024challengeswithgene pages 10-14)
The most defensible clinical conclusion is that apparently preserved lymphocyte numbers or somatic reversion should not reassure clinicians without measurement of naïve T-cell output, TCR diversity, proliferation, cytokine signaling, antibody function, infection burden, and longitudinal cell counts. Early referral to an immunodeficiency/transplant center is appropriate when these markers deteriorate. (tuovinen2020novelhemizygousil2rg pages 9-10, lin2020progressivebcell pages 8-9)
No reliable XCID-specific population prevalence, incidence, carrier frequency, survival curve, quality-of-life score, validated diagnostic criteria, protective factor, modifier gene, epigenetic signature, metabolomic/lipidomic biomarker, approved gene therapy, randomized treatment trial, natural animal counterpart, or allele-specific animal model was identified. OMIM 312863 and MONDO:0010730 should be manually verified before production use because contemporary resources may merge this phenotype with broader IL2RG-related SCID.
References
(tuovinen2020novelhemizygousil2rg pages 1-2): Elina A. Tuovinen, Juha Grönholm, Tiina Öhman, Sakari Pöysti, Raine Toivonen, Anna Kreutzman, Kaarina Heiskanen, Luca Trotta, Sanna Toiviainen-Salo, John M. Routes, James Verbsky, Satu Mustjoki, Janna Saarela, Juha Kere, Markku Varjosalo, Arno Hänninen, and Mikko R. J. Seppänen. Novel hemizygous il2rg p.(pro58ser) mutation impairs il-2 receptor complex expression on lymphocytes causing x-linked combined immunodeficiency. Journal of Clinical Immunology, 40:503-514, Feb 2020. URL: https://doi.org/10.1007/s10875-020-00745-2, doi:10.1007/s10875-020-00745-2. This article has 29 citations and is from a domain leading peer-reviewed journal.
(lim2019il2rghypomorphicmutation pages 1-2): Che Kang Lim, Hassan Abolhassani, Sofia K. Appelberg, Mikael Sundin, and Lennart Hammarström. Il2rg hypomorphic mutation: identification of a novel pathogenic mutation in exon 8 and a review of the literature. Allergy, Asthma, and Clinical Immunology : Official Journal of the Canadian Society of Allergy and Clinical Immunology, Jan 2019. URL: https://doi.org/10.1186/s13223-018-0317-y, doi:10.1186/s13223-018-0317-y. This article has 61 citations.
(OpenTargets Search: X-linked combined immunodeficiency-IL2RG): Open Targets Query (X-linked combined immunodeficiency-IL2RG, 1 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(arcasgarcia2020theil2rgr328x pages 1-2): Andrea Arcas-García, M. García-Prat, Miriam Magallón-Lorenz, A. Martín-Nalda, O. Drechsel, S. Ossowski, Laura Alonso, Jacques G. Rivière, P. Soler-Palacín, R. Colobran, J. Sayós, M. Martínez-Gallo, and C. Franco-Jarava. The il-2rg r328x nonsense mutation allows partial stat-5 phosphorylation and defines a critical region involved in the leaky-scid phenotype. Jan 2020. URL: https://doi.org/10.1111/cei.13405, doi:10.1111/cei.13405. This article has 13 citations and is from a peer-reviewed journal.
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(gratz2024functionalcharacterizationof pages 21-26): Hans Peter Gratz. Functional characterization of a novel il2rg mutation causing atypical scid. Jul 2024. URL: https://doi.org/10.15496/publikation-96566, doi:10.15496/publikation-96566. This article has 0 citations.
(gratz2024functionalcharacterizationof pages 26-29): Hans Peter Gratz. Functional characterization of a novel il2rg mutation causing atypical scid. Jul 2024. URL: https://doi.org/10.15496/publikation-96566, doi:10.15496/publikation-96566. This article has 0 citations.
(tuovinen2020novelhemizygousil2rg pages 9-10): Elina A. Tuovinen, Juha Grönholm, Tiina Öhman, Sakari Pöysti, Raine Toivonen, Anna Kreutzman, Kaarina Heiskanen, Luca Trotta, Sanna Toiviainen-Salo, John M. Routes, James Verbsky, Satu Mustjoki, Janna Saarela, Juha Kere, Markku Varjosalo, Arno Hänninen, and Mikko R. J. Seppänen. Novel hemizygous il2rg p.(pro58ser) mutation impairs il-2 receptor complex expression on lymphocytes causing x-linked combined immunodeficiency. Journal of Clinical Immunology, 40:503-514, Feb 2020. URL: https://doi.org/10.1007/s10875-020-00745-2, doi:10.1007/s10875-020-00745-2. This article has 29 citations and is from a domain leading peer-reviewed journal.
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(lin2020progressivebcell pages 8-9): Connie H. Lin, Hye Sun Kuehn, Timothy J. Thauland, Christine M. Lee, Suk See De Ravin, Harry L. Malech, Timothy J. Keyes, Astraea Jager, Kara L. Davis, Maria I. Garcia-Lloret, Sergio D. Rosenzweig, and Manish J. Butte. Progressive b cell loss in revertant x-scid. Journal of Clinical Immunology, 40:1001-1009, Jul 2020. URL: https://doi.org/10.1007/s10875-020-00825-3, doi:10.1007/s10875-020-00825-3. This article has 10 citations and is from a domain leading peer-reviewed journal.
(hou2024challengeswithgene pages 10-14): Yujuan Hou. Challenges with gene therapy based on crispr/cas9 and prime editing for somatic reverted mosaicism of x-linked combined immunodeficiency. Unknown, Mar 2024. URL: https://doi.org/10.15496/publikation-93762, doi:10.15496/publikation-93762. This article has 0 citations.
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(gratz2024functionalcharacterizationof pages 8-13): Hans Peter Gratz. Functional characterization of a novel il2rg mutation causing atypical scid. Jul 2024. URL: https://doi.org/10.15496/publikation-96566, doi:10.15496/publikation-96566. This article has 0 citations.
(gratz2024functionalcharacterizationof pages 44-49): Hans Peter Gratz. Functional characterization of a novel il2rg mutation causing atypical scid. Jul 2024. URL: https://doi.org/10.15496/publikation-96566, doi:10.15496/publikation-96566. This article has 0 citations.
Checked with linkml-reference-validator 0.2.1.
| Outcome | Count |
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| References checked | 13 |
| Resolved | 13 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| References weighed for topical relevance | 13 |
| On topic | 7 |
| Off topic | 0 |
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Checked with linkml-term-validator 0.4.5, through the ols: adapter.
| Outcome | Count |
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| Terms checked | 68 |
| Resolved | 63 |
| Unresolved (possible confabulation) | 1 |
| Obsolete | 0 |
| Unverifiable | 4 |
| Terms whose name was checked | 1 |
| Terms named correctly | 0 |
| Terms named as a different term | 1 |
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:0010730 (4 mentions) - the report calls it "if available"; MONDO calls it combined immunodeficiency, X-linkedThese identifiers do not exist in an ontology that resolved other terms from the same prefix, so they were most likely invented:
HP:0005351 (2 mentions) - HP does not contain this termTerms 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: Gene, Taxon.