Hyper-IgM syndrome type 2 (HIGM2) is a primary antibody deficiency caused by biallelic loss-of-function variants in AICDA, encoding activation-induced cytidine deaminase (AID). AID is a B-cell-restricted cytidine deaminase expressed in germinal center B cells that initiates both immunoglobulin class-switch recombination (CSR) and somatic hypermutation (SHM) by deaminating cytosine residues in immunoglobulin switch and variable regions. Its loss therefore abolishes two distinct arms of antigen-driven antibody maturation at once: patients cannot switch from IgM to IgG, IgA, or IgE, and cannot introduce the mutations that underpin affinity maturation. The serum profile is the diagnostic signature — normal or elevated IgM with absent or very low IgG, IgA, and IgE, and normal numbers of circulating B cells. Clinically this produces recurrent bacterial sinopulmonary and mucosal infection from infancy, together with a hallmark massive lymphoid hyperplasia (lymphadenopathy and tonsillar enlargement driven by giant germinal centers) that is far more prominent than in most other antibody deficiencies. A substantial minority develop autoimmune or inflammatory disease, which is now understood mechanistically: AID is independently required for the removal of developing autoreactive B cells, so its loss breaches both central and peripheral B-cell tolerance. SCOPE AND CONTRAST. The defect is strictly B-cell intrinsic. This is the key distinction from the CD40L (HIGM1) and CD40 (HIGM3) hyper-IgM syndromes, where the same CSR block arises from failed T-cell-to-B-cell licensing and the same CD40 pathway is additionally required for macrophage and dendritic cell activation. Because T-cell and macrophage effector function is intact in AID deficiency, HIGM2 patients are not susceptible to the opportunistic infections (Pneumocystis, Cryptosporidium, and other fungal or protozoal organisms) that define the CD40L/CD40 forms, and hematopoietic cell transplantation is correspondingly not a routine indication. The IUIS 2022 classification records the same split: AID deficiency sits in Table 3 (predominantly antibody deficiencies) whereas CD40LG and CD40 deficiency sit in Table 1 (combined immunodeficiencies). This entry covers the autosomal recessive disease as its primary subject; a rarer autosomal dominant form caused by heterozygous C-terminal AICDA variants, in which the CSR defect occurs with preserved SHM, is curated here as a distinct genetic and inheritance context rather than as a separate entry.
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Conditions with similar clinical presentations that must be differentiated from Hyper-IgM Syndrome Type 2:
name: Hyper-IgM Syndrome Type 2
creation_date: "2026-08-29T00:00:00Z"
category: Mendelian
synonyms:
- HIGM2
- AID deficiency
- AICDA deficiency
- Activation-induced cytidine deaminase deficiency
- Immunoglobulin class switch recombination deficiency 1
description: >-
Hyper-IgM syndrome type 2 (HIGM2) is a primary antibody deficiency caused by
biallelic loss-of-function variants in AICDA, encoding activation-induced
cytidine deaminase (AID). AID is a B-cell-restricted cytidine deaminase
expressed in germinal center B cells that initiates both immunoglobulin
class-switch recombination (CSR) and somatic hypermutation (SHM) by
deaminating cytosine residues in immunoglobulin switch and variable regions.
Its loss therefore abolishes two distinct arms of antigen-driven antibody
maturation at once: patients cannot switch from IgM to IgG, IgA, or IgE, and
cannot introduce the mutations that underpin affinity maturation. The serum
profile is the diagnostic signature — normal or elevated IgM with absent or
very low IgG, IgA, and IgE, and normal numbers of circulating B cells.
Clinically this produces recurrent bacterial sinopulmonary and mucosal
infection from infancy, together with a hallmark massive lymphoid hyperplasia
(lymphadenopathy and tonsillar enlargement driven by giant germinal centers)
that is far more prominent than in most other antibody deficiencies. A
substantial minority develop autoimmune or inflammatory disease, which is now
understood mechanistically: AID is independently required for the removal of
developing autoreactive B cells, so its loss breaches both central and
peripheral B-cell tolerance.
SCOPE AND CONTRAST. The defect is strictly B-cell intrinsic. This is the key
distinction from the CD40L (HIGM1) and CD40 (HIGM3) hyper-IgM syndromes,
where the same CSR block arises from failed T-cell-to-B-cell licensing and
the same CD40 pathway is additionally required for macrophage and dendritic
cell activation. Because T-cell and macrophage effector function is intact in
AID deficiency, HIGM2 patients are not susceptible to the opportunistic
infections (Pneumocystis, Cryptosporidium, and other fungal or protozoal
organisms) that define the CD40L/CD40 forms, and hematopoietic cell
transplantation is correspondingly not a routine indication. The IUIS 2022
classification records the same split: AID deficiency sits in Table 3
(predominantly antibody deficiencies) whereas CD40LG and CD40 deficiency sit
in Table 1 (combined immunodeficiencies). This entry covers the autosomal
recessive disease as its primary subject; a rarer autosomal dominant form
caused by heterozygous C-terminal AICDA variants, in which the CSR defect
occurs with preserved SHM, is curated here as a distinct genetic and
inheritance context rather than as a separate entry.
disease_term:
preferred_term: Hyper-IgM Syndrome Type 2
term:
id: MONDO:0011528
label: hyper-IgM syndrome type 2
parents:
- Primary Immunodeficiency
- Antibody Deficiency Disorder
- Hyper-IgM Syndrome
classifications:
harrisons_chapter:
- classification_value: IMMUNE_RHEUMATOLOGIC
notes: >-
A primary immunodeficiency; Harrison's covers the primary
immunodeficiency diseases in the immunology/rheumatology Part.
evidence:
- reference: PMID:17560278
reference_title: "Pathophysiology of B-cell intrinsic immunoglobulin class switch recombination deficiencies."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
B-cell intrinsic immunoglobulin class switch recombination (Ig-CSR)
deficiencies, previously termed hyper-IgM syndromes, are genetically
determined conditions characterized by normal or elevated serum IgM
levels and an absence or very low levels of IgG, IgA, and IgE.
explanation: >-
Characterizes the hyper-IgM syndromes as genetically determined
immunodeficiency disorders, placing HIGM2 in the immunologic Part.
- classification_value: GENETICS_ENVIRONMENT_DISEASE
notes: >-
Monogenic autosomal recessive disorder of AICDA.
iuis_category:
classification_value: predominantly antibody deficiency
notes: >-
IUIS 2022 phenotypic classification Table 3 (predominantly antibody
deficiencies), section 3 "Severe Reduction in Serum IgG and IgA with
Normal/Elevated IgM and Normal Numbers of B cells, Hyper IgM". Both the
autosomal recessive and the autosomal dominant AICDA rows sit in this
section. NOTE THE CONTRAST: the CD40LG and CD40 hyper-IgM syndromes are
NOT in Table 3 — IUIS 2022 places them in Table 1 (combined
immunodeficiencies), because the CD40 pathway defect impairs T-cell and
macrophage activation as well as B-cell class switching. Curating
"hyper-IgM syndrome" as a single disease would therefore straddle two
IUIS tables. The AICDA recessive row in the source PDF is corrupted by
text extraction — its disease label was lifted onto a later line and its
OMIM is misprinted as a 7-digit "6055258" (the correct identifier is
OMIM:605258, confirmed against MONDO:0011528) — so the section heading
and the label line are quoted here instead of the recessive row itself.
evidence:
- reference: PMID:35748970
reference_title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
supports: SUPPORT
evidence_source: OTHER
snippet: "3. Severe Reduction in Serum IgG and IgA with Normal/Elevated IgM and Normal Numbers of B cells, Hyper IgM"
explanation: >-
The section-3 heading of IUIS 2022 Table 3, the table of predominantly
antibody deficiencies, defines the hyper-IgM section that contains the
two AICDA rows ("AID deficiency AICDA", recessive and dominant). The
heading is quoted rather than the recessive row itself because that row
is corrupted in the source PDF (see notes).
inheritance:
- name: Autosomal recessive inheritance
description: >-
The classic form of HIGM2 is inherited as an autosomal recessive trait,
caused by mutations affecting both AICDA alleles.
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
evidence:
- reference: PMID:11007475
reference_title: "Activation-induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the Hyper-IgM syndrome (HIGM2)."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We herein report mutations in the human counterpart of AID in patients
with the autosomal recessive form of hyper-IgM syndrome (HIGM2).
explanation: >-
The gene-discovery study establishes AICDA mutations as the cause of the
autosomal recessive form of hyper-IgM syndrome.
- reference: PMID:15893695
reference_title: "Analysis of class switch recombination and somatic hypermutation in patients affected with autosomal dominant hyper-IgM syndrome type 2."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Autosomal recessive form of hyper-IgM syndrome type 2 (AR-HIGM2) is
secondary to mutations affecting both alleles of AICDA gene encoding
activation-induced cytidine deaminase
explanation: >-
Confirms that the recessive disease requires mutation of both AICDA
alleles.
- name: Autosomal dominant inheritance
description: >-
A rarer autosomal dominant form (AD-HIGM2) is caused by heterozygous
variants affecting the C-terminal region of AID, classically the R190X
nonsense variant. The C-terminus is required for the DNA-repair steps
specific to class-switch recombination but not for somatic hypermutation,
so these patients have a variable CSR defect with preserved SHM. IUIS 2022
Table 3 lists this dominant AICDA form as its own row (OMIM 605257)
alongside the recessive row, and records that the causal variants localise
uniquely to the nuclear export signal; those row fragments are too short
and too corrupted by PDF text extraction to quote as standalone evidence,
so the published patient series are cited instead.
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
evidence:
- reference: PMID:15893695
reference_title: "Analysis of class switch recombination and somatic hypermutation in patients affected with autosomal dominant hyper-IgM syndrome type 2."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Variable defect in in vivo CSR inherited as an autosomal dominant (AD)
trait strongly suggests that this heterozygous AICDA mutation causes
HIGM (AD-HIGM2).
explanation: >-
Establishes a dominantly inherited form of HIGM2 caused by a single
heterozygous AICDA variant.
- reference: PMID:32423680
reference_title: "From Dysgammaglobulinemia to Autosomal-Dominant Activation-Induced Cytidine Deaminase Deficiency: Unraveling an Inherited Immunodeficiency after 50 Years."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The genetic investigation of a family presenting with a dominant form of
hyper IgM syndrome published in 1963 and 1975 revealed a R190X nonsense
mutation in activation-induced cytidine deaminase.
explanation: >-
An independent kindred with dominantly inherited hyper-IgM syndrome
resolved to a heterozygous R190X AICDA variant.
prevalence:
- population: Worldwide
measure_type: CASES_IN_LITERATURE
prevalence_class: ULTRA_RARE
notes: >-
No population-based prevalence estimate for HIGM2 has been published. The
disease is known from small international case series: the largest
dedicated cohort assembled 29 patients from 22 families across multiple
European and Middle Eastern referral centres. Registry data give a sense of
its rarity relative to the CD40L form — in the Latin American HIGM registry
only 2 of 37 molecularly defined hyper-IgM patients had AID deficiency,
against 35 with CD40L deficiency. Both figures are referral-based counts,
not denominators, so no rate per 100,000 is asserted here.
evidence:
- reference: PMID:14962793
reference_title: "Clinical, immunologic and genetic analysis of 29 patients with autosomal recessive hyper-IgM syndrome due to Activation-Induced Cytidine Deaminase deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We retrospectively analyzed clinical, immunologic and genetic
characteristics of 29 patients from 22 families with AID deficiency.
explanation: >-
The largest dedicated AID-deficiency cohort comprises 29 patients from 22
families worldwide, consistent with an ultra-rare disease reported as
case series rather than population rates.
- reference: PMID:24402618
reference_title: "First report of the Hyper-IgM syndrome Registry of the Latin American Society for Immunodeficiencies: novel mutations, unique infections, and outcomes."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
CD40 ligand (CD40L) deficiency was found in 35 patients from 25 families
and activation-induced cytidine deaminase (AID) deficiency in 2 unrelated
patients.
explanation: >-
In a multinational hyper-IgM registry AID deficiency accounted for only 2
of 37 genetically defined patients, indicating it is a small minority of
an already rare syndrome.
pathophysiology:
- name: AID Enzymatic Loss of Function
conforms_to: "germinal_center_reaction#Germinal Center Reaction"
biological_scale: MOLECULAR
description: >-
Activation-induced cytidine deaminase is a member of the cytidine deaminase
family whose expression is restricted to germinal center B cells. It
initiates antibody diversification by deaminating cytosine to uracil in
single-stranded DNA at the immunoglobulin switch and variable regions,
creating the U:G mismatches that downstream repair pathways convert into
either switch-region double-strand breaks or point mutations. Biallelic
loss-of-function AICDA variants abolish this enzymatic activity, removing
the single upstream trigger for both antibody-diversification programs.
Anchors the module's conformance here rather than on either downstream
node (Failed Immunoglobulin Class-Switch Recombination, Failed Somatic
Hypermutation) because this is the molecular lesion that causes both of
them: neither downstream node alone covers the module's bundled
"Germinal Center Reaction" claim, but this one node, read alongside its
two direct downstream edges, does.
cell_types:
- preferred_term: Germinal center B cell
term:
id: CL:0000844
label: germinal center B cell
molecular_functions:
- preferred_term: cytidine deaminase activity
term:
id: GO:0004126
label: cytidine deaminase activity
modifier: LOSS_OF_FUNCTION
biological_processes:
- preferred_term: Somatic Hypermutation of Immunoglobulin Genes
term:
id: GO:0016446
label: somatic hypermutation of immunoglobulin genes
modifier: ABSENT
- preferred_term: Class Switch Recombination
term:
id: GO:0045190
label: isotype switching
modifier: ABSENT
evidence:
- reference: PMID:11007475
reference_title: "Activation-induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the Hyper-IgM syndrome (HIGM2)."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The activation-induced cytidine deaminase (AID) gene, specifically
expressed in germinal center B cells in mice, is a member of the cytidine
deaminase family.
explanation: >-
Identifies AID as a germinal-center-B-cell-restricted cytidine deaminase,
grounding the enzymatic activity and cell type of this node.
downstream:
- target: Failed Immunoglobulin Class-Switch Recombination
causal_link_type: DIRECT
description: >-
Without AID-mediated deamination of switch regions, the DNA lesions that
initiate class-switch recombination are never generated.
evidence:
- reference: PMID:11007475
reference_title: "Activation-induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the Hyper-IgM syndrome (HIGM2)."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Three major abnormalities characterize AID deficiency: (1) the absence
of immunoglobulin class switch recombination
explanation: >-
Absence of class-switch recombination is listed as the first cardinal
abnormality caused by AID deficiency.
- target: Failed Somatic Hypermutation
causal_link_type: DIRECT
description: >-
The same deamination step seeds the point mutations of somatic
hypermutation in immunoglobulin variable regions, so SHM fails in
parallel with CSR rather than as a consequence of it.
evidence:
- reference: PMID:11007475
reference_title: "Activation-induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the Hyper-IgM syndrome (HIGM2)."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "(2) the lack of immunoglobulin somatic hypermutations"
explanation: >-
Lack of somatic hypermutation is the second cardinal abnormality of AID
deficiency, establishing it as a parallel consequence of enzyme loss.
- name: Failed Immunoglobulin Class-Switch Recombination
biological_scale: MOLECULAR
description: >-
Class-switch recombination replaces the IgM/IgD constant region with a
downstream constant region, converting a naive B cell's output to IgG, IgA,
or IgE without altering antigen specificity. In AID deficiency this
recombination does not occur. The block is B-cell intrinsic: germline
switch transcripts are still produced and the upstream T-cell help signal
is intact, so the lesion lies at the DNA-modification step itself.
cell_types:
- preferred_term: Germinal center B cell
term:
id: CL:0000844
label: germinal center B cell
biological_processes:
- preferred_term: Immunoglobulin isotype switching
term:
id: GO:0045190
label: isotype switching
modifier: LOSS_OF_FUNCTION
evidence:
- reference: PMID:11007474
reference_title: "Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
AID-/- spleen cells stimulated in vitro with LPS and cytokines failed to
undergo class switch recombination although they expressed germline
transcripts.
explanation: >-
The AID-knockout mouse shows the switch block is at the recombination
step itself, downstream of germline transcription — evidence from a model
organism that defines where in the pathway the lesion sits.
- reference: PMID:17560278
reference_title: "Pathophysiology of B-cell intrinsic immunoglobulin class switch recombination deficiencies."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
the description of the activation-induced cytidine deaminase (AID)
deficiency (Ig-CSR deficiency 1), caused by recessive mutations of AICDA
gene, characterized by a defect in CSR and SHM
explanation: >-
A review of the CSR deficiencies characterizes recessive AICDA mutation
as producing a combined CSR and SHM defect.
downstream:
- target: IgM-Restricted Antibody Repertoire
causal_link_type: DIRECT
description: >-
With switching blocked, plasma cells can only secrete the IgM isotype
encoded by the unrearranged constant region.
evidence:
- reference: PMID:17560278
reference_title: "Pathophysiology of B-cell intrinsic immunoglobulin class switch recombination deficiencies."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
characterized by normal or elevated serum IgM levels and an absence or
very low levels of IgG, IgA, and IgE
explanation: >-
The failure to switch produces exactly this serum profile — retained
IgM with loss of the switched isotypes.
- target: Giant Germinal Center Formation
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: >-
B cells that cannot complete the switching program continue to be
stimulated and re-enter the germinal center reaction instead of exiting
it as switched memory or plasma cells, so germinal centers enlarge rather
than resolve.
evidence:
- reference: PMID:11007474
reference_title: "Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
AID deficiency caused a complete defect in class switching and showed a
hyper-IgM phenotype with enlarged germinal centers containing strongly
activated B cells before or after immunization.
explanation: >-
In AID-deficient mice the switching defect is accompanied by enlarged
germinal centers holding strongly activated B cells, linking the failed
switch to germinal-center overgrowth.
- name: Failed Somatic Hypermutation
biological_scale: MOLECULAR
description: >-
Somatic hypermutation introduces point mutations into immunoglobulin
variable-region genes, generating the sequence variation on which
affinity-based selection acts in the germinal center. AID deficiency
abolishes it. Memory B cells are still generated in normal numbers but
carry unmutated variable regions. This arm is independent of the CSR arm:
C-terminal AICDA variants can spare it while still blocking CSR.
cell_types:
- preferred_term: Germinal center B cell
term:
id: CL:0000844
label: germinal center B cell
- preferred_term: Memory B cell
term:
id: CL:0000787
label: memory B cell
biological_processes:
- preferred_term: Somatic hypermutation of immunoglobulin genes
term:
id: GO:0016446
label: somatic hypermutation of immunoglobulin genes
modifier: LOSS_OF_FUNCTION
evidence:
- reference: PMID:35748970
reference_title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
supports: SUPPORT
evidence_source: OTHER
snippet: "memory B cells but lacking"
explanation: >-
The IUIS Table 3 immunologic column for the recessive AICDA row records
normal memory B cells that nonetheless lack somatic hypermutation.
- reference: PMID:11007474
reference_title: "Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Immunization of AID-/- chimera with 4-hydroxy-3-nitrophenylacetyl (NP)
chicken gamma-globulin induced neither accumulation of mutations in the
NP-specific variable region gene nor class switching.
explanation: >-
Antigen challenge of AID-deficient mice produced no variable-region
mutation, demonstrating that AID is required for somatic hypermutation
in vivo.
downstream:
- target: Absent Affinity Maturation
causal_link_type: DIRECT
description: >-
Without variable-region mutation there is no sequence variation for
germinal-center selection to act on, so antibody affinity cannot improve
with successive antigen exposure.
evidence:
- reference: PMID:11007475
reference_title: "Activation-induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the Hyper-IgM syndrome (HIGM2)."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
demonstrates the absolute requirement for AID in several crucial steps
of B cell terminal differentiation necessary for efficient antibody
responses
explanation: >-
AID is required for the terminal B-cell differentiation steps that
produce efficient antibody responses, of which affinity maturation is
one.
- target: Breakdown of B-Cell Self-Tolerance
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: >-
Beyond diversification, AID is separately required to purge developing
autoreactive B cells. Its loss leaves an abnormal repertoire enriched for
self-reactive specificities at both the central and peripheral tolerance
checkpoints.
evidence:
- reference: PMID:21700883
reference_title: "Activation-induced cytidine deaminase (AID) is required for B-cell tolerance in humans."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
New emigrant/transitional and mature naive B cells from AID-deficient
patients express an abnormal Ig repertoire and high frequencies of
autoreactive antibodies, demonstrating that AID is required for the
establishment of both central and peripheral B-cell tolerance.
explanation: >-
Single-cell antibody cloning from AID-deficient patients shows loss of
both tolerance checkpoints, linking the enzyme defect to autoreactivity.
- name: IgM-Restricted Antibody Repertoire
biological_scale: ORGANISM
description: >-
The systemic consequence of the switching block is a humoral compartment
that produces only IgM. Serum IgM is normal or elevated — partly because
unswitched B cells continue to be driven by antigen — while IgG, IgA, and
IgE are absent or very low. Circulating B-cell numbers are normal, which
distinguishes HIGM2 from the agammaglobulinemias, where the lesion is a
developmental block upstream of B-cell egress.
cell_types:
- preferred_term: Plasma cell
term:
id: CL:0000786
label: plasma cell
- preferred_term: B cell
term:
id: CL:0000236
label: B cell
biological_processes:
- preferred_term: Immunoglobulin production
term:
id: GO:0002377
label: immunoglobulin production
modifier: DECREASED
evidence:
- reference: PMID:35748970
reference_title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
supports: SUPPORT
evidence_source: OTHER
snippet: "3. Severe Reduction in Serum IgG and IgA with Normal/Elevated IgM and Normal Numbers of B cells, Hyper IgM"
explanation: >-
The IUIS section heading defining this disease group states the exact
composition of this node: severely reduced IgG and IgA, normal or
elevated IgM, and normal numbers of circulating B cells.
- reference: PMID:36931691
reference_title: "Type 2 hyper-IgM syndrome with a rare variant of AICDA gene mutation in a young woman."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Blood investigations revealed increased IgM levels with reduced IgG, IgA
and IgE levels.
explanation: >-
A genetically confirmed HIGM2 patient shows the characteristic isotype
profile of raised IgM with all three switched isotypes reduced.
downstream:
- target: Loss of Opsonizing and Mucosal Antibody Function
causal_link_type: DIRECT
description: >-
IgM is a poor opsonin relative to IgG and cannot be transported across
mucosal epithelium in place of secretory IgA, so an IgM-only repertoire
cannot perform the effector functions those isotypes provide.
evidence:
- reference: PMID:17560278
reference_title: "Pathophysiology of B-cell intrinsic immunoglobulin class switch recombination deficiencies."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
CSR and SHM, the major events of antigen-triggered antibody maturation
explanation: >-
CSR and SHM are identified as the major events of antibody maturation,
so losing both leaves antibody function immature and ineffective.
- name: Absent Affinity Maturation
biological_scale: CELLULAR
description: >-
Memory B cells are produced but their variable regions remain in germline
configuration, so the antibody repertoire never improves in affinity across
repeated antigen encounters. Secondary responses are therefore no better
than primary ones, compounding the isotype deficit.
cell_types:
- preferred_term: Memory B cell
term:
id: CL:0000787
label: memory B cell
biological_processes:
- preferred_term: Somatic hypermutation of immunoglobulin genes
term:
id: GO:0016446
label: somatic hypermutation of immunoglobulin genes
modifier: LOSS_OF_FUNCTION
evidence:
- reference: PMID:11007475
reference_title: "Activation-induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the Hyper-IgM syndrome (HIGM2)."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The phenotype observed in HIGM2 patients (and in AID-/- mice)
demonstrates the absolute requirement for AID in several crucial steps of
B cell terminal differentiation necessary for efficient antibody
responses.
explanation: >-
AID is required for the terminal B-cell differentiation steps underlying
efficient antibody responses; affinity maturation is the step this node
represents.
downstream:
- target: Loss of Opsonizing and Mucosal Antibody Function
causal_link_type: DIRECT
description: >-
Low-affinity germline-encoded antibody binds pathogens poorly, further
degrading the protective quality of the residual IgM response.
- name: Loss of Opsonizing and Mucosal Antibody Function
biological_scale: ORGANISM
description: >-
The two arms converge here. The patient retains antibody, but it is of the
wrong isotype and of germline affinity: no IgG to opsonize encapsulated
bacteria and fix complement efficiently in tissue, no secretory IgA to
exclude organisms at respiratory and gastrointestinal mucosal surfaces, and
no affinity-matured binding to compensate. Humoral protection against
extracellular bacteria is therefore lost, while cellular immunity is
untouched.
biological_processes:
- preferred_term: Complement activation and opsonization by antibody
term:
id: GO:0006956
label: complement activation
modifier: DECREASED
evidence:
- reference: PMID:14962793
reference_title: "Clinical, immunologic and genetic analysis of 29 patients with autosomal recessive hyper-IgM syndrome due to Activation-Induced Cytidine Deaminase deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Most patients had suffered from recurrent and severe infections, however,
intravenous immunoglobulin (IVIG) replacement therapy resulted in a
dramatic decrease in the number of infections.
explanation: >-
That replacing IgG largely abolishes the infections demonstrates the
infections are caused by the missing antibody function rather than by any
cellular defect.
downstream:
- target: Recurrent Bacterial Sinopulmonary and Mucosal Infection
causal_link_type: DIRECT
description: >-
Absent opsonizing and mucosal antibody permits recurrent infection by
extracellular and encapsulated bacteria at respiratory and
gastrointestinal surfaces.
evidence:
- reference: PMID:35748970
reference_title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
supports: SUPPORT
evidence_source: OTHER
snippet: "Bacterial infections, enlarged lymph nodes and"
explanation: >-
The IUIS Table 3 associated-features column for AID deficiency lists
bacterial infections as the cardinal clinical consequence.
- name: Recurrent Bacterial Sinopulmonary and Mucosal Infection
biological_scale: ORGANISM
description: >-
Clinically the infections are bacterial and mucosal — recurrent sinusitis,
otitis media, and pneumonia progressing to bronchiectasis, with
gastrointestinal involvement. The spectrum is narrower than in the
CD40L/CD40 hyper-IgM syndromes: because AID acts only in B cells and leaves
T-cell and macrophage effector function intact, HIGM2 patients do not show
the Pneumocystis, Cryptosporidium, and other opportunistic infections that
characterize the CD40 pathway defects. Immunoglobulin replacement markedly
reduces infection frequency.
evidence:
- reference: PMID:24402618
reference_title: "First report of the Hyper-IgM syndrome Registry of the Latin American Society for Immunodeficiencies: novel mutations, unique infections, and outcomes."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Previously undescribed fungal and opportunistic infections were observed
in CD40L-deficient patients but not in the two patients with AID
deficiency.
explanation: >-
Direct within-registry comparison showing opportunistic and fungal
infections occurred in the CD40L form but not in AID deficiency — the
clinical signature of a B-cell-intrinsic rather than combined defect.
- reference: PMID:36931691
reference_title: "Type 2 hyper-IgM syndrome with a rare variant of AICDA gene mutation in a young woman."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Radiological imaging of the chest revealed bilateral bronchiectasis.
explanation: >-
Illustrates the end-organ consequence of untreated recurrent
sinopulmonary bacterial infection in a genetically confirmed HIGM2
patient.
- name: Giant Germinal Center Formation
biological_scale: TISSUE
description: >-
The histological hallmark of AID deficiency. B cells that cannot complete
the diversification program are repeatedly restimulated and re-enter the
germinal center rather than exiting as switched or affinity-matured
progeny. Germinal centers consequently become greatly enlarged and are
packed with strongly activated B cells — the "giant germinal centers"
described in the original report and reproduced in AID-null mice.
cell_types:
- preferred_term: Germinal center B cell
term:
id: CL:0000844
label: germinal center B cell
biological_processes:
- preferred_term: Germinal center formation
term:
id: GO:0002467
label: germinal center formation
modifier: INCREASED
evidence:
- reference: PMID:11007475
reference_title: "Activation-induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the Hyper-IgM syndrome (HIGM2)."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
lymph node hyperplasia caused by the presence of giant germinal centers
explanation: >-
Names giant germinal centers as the third cardinal abnormality of AID
deficiency and as the cause of the lymph node hyperplasia.
downstream:
- target: Massive Lymphoid Hyperplasia
causal_link_type: DIRECT
description: >-
Enlargement of germinal centers throughout secondary lymphoid tissue
produces clinically apparent lymph node and tonsillar enlargement.
evidence:
- reference: PMID:11007475
reference_title: "Activation-induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the Hyper-IgM syndrome (HIGM2)."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
lymph node hyperplasia caused by the presence of giant germinal centers
explanation: >-
States the causal relation directly: the giant germinal centers are
what produce the lymph node hyperplasia.
- name: Massive Lymphoid Hyperplasia
biological_scale: ORGANISM
description: >-
Generalized enlargement of secondary lymphoid tissue — lymphadenopathy and
tonsillar enlargement — is present in the majority of patients and is
disproportionate to that seen in other primary antibody deficiencies. It
can regress on immunoglobulin replacement but persists in a minority.
evidence:
- reference: PMID:14962793
reference_title: "Clinical, immunologic and genetic analysis of 29 patients with autosomal recessive hyper-IgM syndrome due to Activation-Induced Cytidine Deaminase deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Lymphoid hyperplasia developed in 22 patients and persisted in 7 at last
follow-up.
explanation: >-
Quantifies lymphoid hyperplasia in 22 of the 29-patient cohort, and shows
that it resolves in most but persists in some.
- name: Breakdown of B-Cell Self-Tolerance
biological_scale: CELLULAR
description: >-
AID has a role in B-cell tolerance that is separable from its
diversification role. In AID-deficient patients both the central checkpoint
(new emigrant/transitional B cells) and the peripheral checkpoint (mature
naive B cells) fail to remove autoreactive clones, and anti-nuclear IgM is
detectable in serum. This provides the mechanistic explanation for the
autoimmunity seen in a disease that is otherwise one of immune deficiency.
cell_types:
- preferred_term: B cell
term:
id: CL:0000236
label: B cell
biological_processes:
- preferred_term: B cell tolerance induction
term:
id: GO:0002514
label: B cell tolerance induction
modifier: LOSS_OF_FUNCTION
evidence:
- reference: PMID:21700883
reference_title: "Activation-induced cytidine deaminase (AID) is required for B-cell tolerance in humans."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
B-cell tolerance was further breached in AID-deficient patients as
illustrated by the detection of anti-nuclear IgM antibodies in the serum
of all patients.
explanation: >-
Anti-nuclear IgM in all patients tested demonstrates a breached tolerance
checkpoint in human AID deficiency.
downstream:
- target: Autoimmune and Inflammatory Disease
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: >-
Retained autoreactive B-cell clones provide the substrate from which
clinical autoimmune and inflammatory disease develops in a substantial
minority of patients.
evidence:
- reference: PMID:21700883
reference_title: "Activation-induced cytidine deaminase (AID) is required for B-cell tolerance in humans."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
patients with hyper-IgM syndromes who are deficient in
activation-induced cytidine deaminase (AID), which is required for
class-switch recombination and somatic hypermutation, are prone to
develop autoimmune diseases
explanation: >-
Links AID deficiency to a predisposition to clinical autoimmune disease.
- name: Autoimmune and Inflammatory Disease
biological_scale: ORGANISM
description: >-
A substantial minority of AID-deficient patients develop autoimmune or
inflammatory disease. The reported spectrum is broad and not confined to
one organ — autoimmune cytopenias (hemolytic anemia, immune
thrombocytopenia), polyarthritis, autoimmune hepatitis, type 1 diabetes,
Crohn's disease, and chronic uveitis have all been described in a single
cohort.
evidence:
- reference: PMID:14962793
reference_title: "Clinical, immunologic and genetic analysis of 29 patients with autosomal recessive hyper-IgM syndrome due to Activation-Induced Cytidine Deaminase deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
It is striking to note that six patients developed autoimmune or
inflammatory disorders including diabetes mellitus, polyarthritis,
autoimmune hepatitis, hemolytic anemia, immune thrombocytopenia, Crohn's
disease and chronic uveitis.
explanation: >-
Six of 29 cohort patients developed autoimmune or inflammatory disease,
establishing both the frequency band and the organ spectrum.
phenotypes:
- name: Recurrent Bacterial Infections
category: Immunologic
frequency: VERY_FREQUENT
description: >-
Recurrent and often severe bacterial infection from early childhood is the
presenting feature in most patients.
phenotype_term:
preferred_term: Recurrent bacterial infections
term:
id: HP:0002718
label: Recurrent bacterial infections
evidence:
- reference: PMID:14962793
reference_title: "Clinical, immunologic and genetic analysis of 29 patients with autosomal recessive hyper-IgM syndrome due to Activation-Induced Cytidine Deaminase deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Most patients had suffered from recurrent and severe infections
explanation: >-
"Most patients" in the 29-patient cohort supports the VERY_FREQUENT band
for recurrent infection.
- reference: PMID:35748970
reference_title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
supports: SUPPORT
evidence_source: OTHER
snippet: "Bacterial infections, enlarged lymph nodes and"
explanation: >-
IUIS lists bacterial infection as the leading associated feature of AID
deficiency.
- name: Lymphoid Hyperplasia
category: Immunologic
frequency: FREQUENT
description: >-
Generalized enlargement of secondary lymphoid tissue caused by giant
germinal centers; developed in 22 of 29 patients (76%) in the largest
cohort.
phenotype_term:
preferred_term: Lymphoid hyperplasia
term:
id: HP:0034839
label: Lymphoid hyperplasia
evidence:
- reference: PMID:14962793
reference_title: "Clinical, immunologic and genetic analysis of 29 patients with autosomal recessive hyper-IgM syndrome due to Activation-Induced Cytidine Deaminase deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Lymphoid hyperplasia developed in 22 patients and persisted in 7 at last
follow-up.
explanation: >-
22 of 29 patients (76%) developed lymphoid hyperplasia, placing it in the
FREQUENT band (30-79%).
- name: Lymphadenopathy
category: Immunologic
description: >-
Enlarged lymph nodes containing giant germinal centers, a hallmark finding
that distinguishes HIGM2 from most other primary antibody deficiencies.
phenotype_term:
preferred_term: Lymphadenopathy
term:
id: HP:0002716
label: Lymphadenopathy
evidence:
- reference: PMID:11007475
reference_title: "Activation-induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the Hyper-IgM syndrome (HIGM2)."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
lymph node hyperplasia caused by the presence of giant germinal centers
explanation: >-
Lymph node hyperplasia from giant germinal centers is one of the three
cardinal abnormalities of AID deficiency.
- reference: PMID:35748970
reference_title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
supports: SUPPORT
evidence_source: OTHER
snippet: "Bacterial infections, enlarged lymph nodes and"
explanation: >-
The IUIS Table 3 associated-features column for AID deficiency lists
enlarged lymph nodes alongside bacterial infections.
- name: Enlarged Tonsils
category: Immunologic
description: >-
Tonsillar enlargement is part of the same lymphoid hyperplasia and is often
apparent on physical examination.
phenotype_term:
preferred_term: Enlarged tonsils
term:
id: HP:0030812
label: Enlarged tonsils
evidence:
- reference: PMID:36931691
reference_title: "Type 2 hyper-IgM syndrome with a rare variant of AICDA gene mutation in a young woman."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
bilateral purulent ear discharge since childhood with tonsillar
enlargement on examination
explanation: >-
Tonsillar enlargement was an examination finding in a genetically
confirmed HIGM2 patient. A single case report, so no frequency band is
asserted.
- name: Increased Circulating IgM
category: Immunologic
frequency: VERY_FREQUENT
description: >-
Normal or elevated serum IgM alongside absent switched isotypes is the
defining laboratory signature of the hyper-IgM syndromes.
phenotype_term:
preferred_term: Increased circulating IgM level
term:
id: HP:0003496
label: Increased circulating IgM level
evidence:
- reference: PMID:17560278
reference_title: "Pathophysiology of B-cell intrinsic immunoglobulin class switch recombination deficiencies."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
characterized by normal or elevated serum IgM levels and an absence or
very low levels of IgG, IgA, and IgE
explanation: >-
Normal-to-elevated IgM is definitional for this disease group, supporting
the VERY_FREQUENT band.
- name: Decreased Circulating IgG
category: Immunologic
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Decreased circulating IgG concentration
term:
id: HP:0004315
label: Decreased circulating IgG concentration
evidence:
- reference: PMID:17560278
reference_title: "Pathophysiology of B-cell intrinsic immunoglobulin class switch recombination deficiencies."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
an absence or very low levels of IgG, IgA, and IgE
explanation: >-
Absent or very low IgG is definitional for the Ig-CSR deficiencies,
supporting the VERY_FREQUENT band.
- name: Decreased Circulating IgA
category: Immunologic
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Decreased circulating IgA concentration
term:
id: HP:0002720
label: Decreased circulating IgA concentration
evidence:
- reference: PMID:17560278
reference_title: "Pathophysiology of B-cell intrinsic immunoglobulin class switch recombination deficiencies."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
an absence or very low levels of IgG, IgA, and IgE
explanation: >-
Absent or very low IgA is definitional for the Ig-CSR deficiencies,
supporting the VERY_FREQUENT band.
- name: Autoimmune and Inflammatory Manifestations
category: Immunologic
frequency: OCCASIONAL
description: >-
Autoimmune or inflammatory disease developed in 6 of 29 patients (21%) in
the largest cohort, spanning autoimmune cytopenias, polyarthritis,
autoimmune hepatitis, diabetes mellitus, Crohn's disease, and uveitis.
phenotype_term:
preferred_term: Autoimmune and inflammatory disease
term:
id: HP:0002960
label: Autoimmunity
evidence:
- reference: PMID:14962793
reference_title: "Clinical, immunologic and genetic analysis of 29 patients with autosomal recessive hyper-IgM syndrome due to Activation-Induced Cytidine Deaminase deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
It is striking to note that six patients developed autoimmune or
inflammatory disorders including diabetes mellitus, polyarthritis,
autoimmune hepatitis, hemolytic anemia, immune thrombocytopenia, Crohn's
disease and chronic uveitis.
explanation: >-
6 of 29 patients (21%) is within the OCCASIONAL band (5-29%), and the
sentence enumerates the organ spectrum.
- name: Autoimmune Hemolytic Anemia
category: Hematologic
description: >-
One of the autoimmune cytopenias reported in AID deficiency.
phenotype_term:
preferred_term: Autoimmune hemolytic anemia
term:
id: HP:0001890
label: Autoimmune hemolytic anemia
evidence:
- reference: PMID:14962793
reference_title: "Clinical, immunologic and genetic analysis of 29 patients with autosomal recessive hyper-IgM syndrome due to Activation-Induced Cytidine Deaminase deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
It is striking to note that six patients developed autoimmune or
inflammatory disorders including diabetes mellitus, polyarthritis,
autoimmune hepatitis, hemolytic anemia, immune thrombocytopenia, Crohn's
disease and chronic uveitis.
explanation: >-
Hemolytic anemia is named among the autoimmune disorders occurring in the
cohort. The six affected patients span seven listed conditions, so
individual manifestations were reported in only one or two patients each
and no per-manifestation frequency band is asserted.
- name: Autoimmune Thrombocytopenia
category: Hematologic
description: >-
Immune thrombocytopenia reported among the autoimmune complications.
phenotype_term:
preferred_term: Autoimmune thrombocytopenia
term:
id: HP:0001973
label: Autoimmune thrombocytopenia
evidence:
- reference: PMID:14962793
reference_title: "Clinical, immunologic and genetic analysis of 29 patients with autosomal recessive hyper-IgM syndrome due to Activation-Induced Cytidine Deaminase deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
It is striking to note that six patients developed autoimmune or
inflammatory disorders including diabetes mellitus, polyarthritis,
autoimmune hepatitis, hemolytic anemia, immune thrombocytopenia, Crohn's
disease and chronic uveitis.
explanation: >-
Immune thrombocytopenia is named among the autoimmune disorders in the
cohort. Reported in one or two patients, so no frequency band is
asserted.
- name: Arthritis
category: Musculoskeletal
description: >-
Polyarthritis reported among the inflammatory complications.
phenotype_term:
preferred_term: Polyarthritis
term:
id: HP:0001369
label: Arthritis
evidence:
- reference: PMID:14962793
reference_title: "Clinical, immunologic and genetic analysis of 29 patients with autosomal recessive hyper-IgM syndrome due to Activation-Induced Cytidine Deaminase deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
It is striking to note that six patients developed autoimmune or
inflammatory disorders including diabetes mellitus, polyarthritis,
autoimmune hepatitis, hemolytic anemia, immune thrombocytopenia, Crohn's
disease and chronic uveitis.
explanation: >-
Polyarthritis is named among the autoimmune and inflammatory disorders in
the cohort. Reported in one or two patients, so no frequency band is
asserted.
- name: Autoimmune Hepatitis
category: Gastrointestinal
description: >-
Autoimmune hepatitis reported among the autoimmune complications.
phenotype_term:
preferred_term: Autoimmune hepatitis
term:
id: HP:5210421
label: Autoimmune hepatitis
evidence:
- reference: PMID:14962793
reference_title: "Clinical, immunologic and genetic analysis of 29 patients with autosomal recessive hyper-IgM syndrome due to Activation-Induced Cytidine Deaminase deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
It is striking to note that six patients developed autoimmune or
inflammatory disorders including diabetes mellitus, polyarthritis,
autoimmune hepatitis, hemolytic anemia, immune thrombocytopenia, Crohn's
disease and chronic uveitis.
explanation: >-
Autoimmune hepatitis is named among the autoimmune disorders in the
cohort. Reported in one or two patients, so no frequency band is
asserted.
- name: Crohn's Disease
category: Gastrointestinal
description: >-
Inflammatory bowel disease of Crohn type reported among the inflammatory
complications, representing the gastrointestinal arm of the immune
dysregulation.
phenotype_term:
preferred_term: Crohn's disease
term:
id: HP:0100280
label: Crohn's disease
evidence:
- reference: PMID:14962793
reference_title: "Clinical, immunologic and genetic analysis of 29 patients with autosomal recessive hyper-IgM syndrome due to Activation-Induced Cytidine Deaminase deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
immune thrombocytopenia, Crohn's disease and chronic uveitis
explanation: >-
Crohn's disease is named among the inflammatory disorders in the cohort.
- name: Bronchiectasis
category: Respiratory
description: >-
Structural airway damage resulting from repeated untreated bacterial
sinopulmonary infection.
phenotype_term:
preferred_term: Bronchiectasis
term:
id: HP:0002110
label: Bronchiectasis
evidence:
- reference: PMID:36931691
reference_title: "Type 2 hyper-IgM syndrome with a rare variant of AICDA gene mutation in a young woman."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Radiological imaging of the chest revealed bilateral bronchiectasis.
explanation: >-
Bilateral bronchiectasis in a genetically confirmed HIGM2 patient. Single
case report, so no frequency band is asserted.
- name: Otitis Media
category: Otolaryngologic
description: >-
Chronic suppurative otitis media as part of the recurrent bacterial
mucosal infection burden.
phenotype_term:
preferred_term: Chronic suppurative otitis media
term:
id: HP:0000388
label: Otitis media
evidence:
- reference: PMID:36931691
reference_title: "Type 2 hyper-IgM syndrome with a rare variant of AICDA gene mutation in a young woman."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Otoscopic examination showed features suggestive of chronic suppurative
otitis media.
explanation: >-
Chronic suppurative otitis media in a genetically confirmed HIGM2
patient.
genetic:
- name: AICDA
notes: >-
AICDA encodes activation-induced cytidine deaminase. Biallelic
loss-of-function variants cause the classic autosomal recessive HIGM2, with
combined loss of class-switch recombination and somatic hypermutation.
Fifteen distinct mutations were identified in the largest cohort with no
significant genotype-phenotype correlation.
relationship_type: CAUSATIVE
variant_origin: GERMLINE
gene_term:
preferred_term: AICDA
term:
id: hgnc:13203
label: AICDA
association: Causative
evidence:
- reference: PMID:11007475
reference_title: "Activation-induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the Hyper-IgM syndrome (HIGM2)."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We herein report mutations in the human counterpart of AID in patients
with the autosomal recessive form of hyper-IgM syndrome (HIGM2).
explanation: >-
The gene-discovery study identifying AICDA mutations as causative for
HIGM2.
- reference: PMID:14962793
reference_title: "Clinical, immunologic and genetic analysis of 29 patients with autosomal recessive hyper-IgM syndrome due to Activation-Induced Cytidine Deaminase deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Fifteen distinct AID mutations were found but there was no significant
genotype-phenotype correlation.
explanation: >-
Documents allelic heterogeneity at AICDA without a genotype-phenotype
correlation.
- name: AICDA C-terminal heterozygous variants (autosomal dominant HIGM2)
notes: >-
Heterozygous nonsense variants affecting the C-terminal region of AID —
classically R190X, which disrupts the nuclear export signal — cause a
dominantly inherited form of HIGM2. The C-terminus is dispensable for the
deaminase activity that drives somatic hypermutation but required for the
DNA-repair steps specific to class-switch recombination, so these patients
have a CSR-only defect with preserved SHM. Switch-region double-strand
breaks are still generated, placing the block downstream of the breaks
rather than at their creation. This is curated as a distinct genetic
context of the same disease rather than a separate entry.
gene_term:
preferred_term: AICDA
term:
id: hgnc:13203
label: AICDA
association: Causative
relationship_type: CAUSATIVE
variant_origin: GERMLINE
variants:
- name: AICDA R190X
type: nonsense
description: >-
Heterozygous C-terminal nonsense variant removing the AID nuclear export
signal. Causes a class-switch-recombination defect with preserved somatic
hypermutation, inherited as an autosomal dominant trait.
gene:
preferred_term: AICDA
term:
id: hgnc:13203
label: AICDA
evidence:
- reference: PMID:15893695
reference_title: "Analysis of class switch recombination and somatic hypermutation in patients affected with autosomal dominant hyper-IgM syndrome type 2."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We herein report the immunological phenotype of seven patients carrying
a single heterozygous R190X mutation in AICDA.
explanation: >-
Identifies R190X as the recurrent heterozygous AICDA variant underlying
the dominant form, in a series of seven patients.
evidence:
- reference: PMID:15893695
reference_title: "Analysis of class switch recombination and somatic hypermutation in patients affected with autosomal dominant hyper-IgM syndrome type 2."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We herein report the immunological phenotype of seven patients carrying a
single heterozygous R190X mutation in AICDA.
explanation: >-
Seven patients with a single heterozygous R190X AICDA variant define the
dominant form.
- reference: PMID:15893695
reference_title: "Analysis of class switch recombination and somatic hypermutation in patients affected with autosomal dominant hyper-IgM syndrome type 2."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The characteristics of the AD-HIGM2 phenotype indicate that the AID
C-terminal region may be involved in DNA repair machinery required for
CSR.
explanation: >-
Attributes the CSR-selective defect to loss of a C-terminal DNA-repair
function, the mechanistic basis of this genetic context.
- reference: PMID:32423680
reference_title: "From Dysgammaglobulinemia to Autosomal-Dominant Activation-Induced Cytidine Deaminase Deficiency: Unraveling an Inherited Immunodeficiency after 50 Years."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The genetic investigation of a family presenting with a dominant form of
hyper IgM syndrome published in 1963 and 1975 revealed a R190X nonsense
mutation in activation-induced cytidine deaminase.
explanation: >-
Independent confirmation that R190X underlies a dominantly inherited
hyper-IgM syndrome, in a family followed for six decades.
diagnosis:
- name: Immunoglobulin panel showing the hyper-IgM pattern
description: >-
The entry point is the serum immunoglobulin profile shared by every
hyper-IgM syndrome: normal or elevated IgM with absent or decreased IgG,
IgA and IgE. This identifies the syndrome but not the gene, which is why
molecular testing follows.
diagnosis_term:
preferred_term: serum immunoglobulin measurement
term:
id: NCIT:C18020
label: Diagnostic Procedure
evidence:
- reference: PMID:24402618
reference_title: "First report of the Hyper-IgM syndrome Registry of the Latin American Society for Immunodeficiencies: novel mutations, unique infections, and outcomes."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Hyper-IgM (HIGM) syndrome is a heterogeneous group of disorders characterized by normal or elevated serum IgM levels associated with absent or decreased IgG, IgA and IgE."
explanation: >-
States the laboratory pattern that defines the clinical phenotype before
the causal gene is known.
- name: Molecular genetic testing of AICDA
description: >-
Because the hyper-IgM laboratory pattern is shared across genes, the
diagnosis of AID deficiency rests on identifying biallelic AICDA variants
(or the dominant C-terminal allele). In the Latin American registry only
37 of 58 clinically diagnosed patients had a molecular defect identified,
so a negative panel does not exclude the syndrome.
diagnosis_term:
preferred_term: molecular genetic testing
term:
id: NCIT:C19770
label: Molecular Analysis
evidence:
- reference: PMID:24402618
reference_title: "First report of the Hyper-IgM syndrome Registry of the Latin American Society for Immunodeficiencies: novel mutations, unique infections, and outcomes."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Of the 58 patients from 51 families reported to the registry with the clinical phenotype of HIGM syndrome, molecular defects were identified in 37 patients thus far."
explanation: >-
Quantifies the molecular yield against the clinical phenotype in a
registry cohort.
- reference: PMID:14962793
reference_title: "Clinical, immunologic and genetic analysis of 29 patients with autosomal recessive hyper-IgM syndrome due to Activation-Induced Cytidine Deaminase deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Fifteen distinct AID mutations were found but there was no significant genotype-phenotype correlation."
explanation: >-
Establishes the allelic heterogeneity found on sequencing, and that the
variant identified does not predict severity.
differential_diagnoses:
- name: Hyper-IgM syndrome type 1 (CD40 ligand deficiency)
description: >-
The X-linked CD40LG defect produces the same serum immunoglobulin pattern,
and separating the two is the defining diagnostic act in a boy with
hyper-IgM. The discriminator is opportunistic infection: CD40L deficiency
additionally loses T-cell licensing of macrophages and dendritic cells, so
Pneumocystis, Cryptosporidium, and the fungal and opportunistic infections
of the registry cohort belong to it, not to AID deficiency, whose defect is
B-cell intrinsic. Massive lymphoid hyperplasia points the other way.
disease_term:
preferred_term: hyper-IgM syndrome type 1
term:
id: MONDO:0010626
label: hyper-IgM syndrome type 1
distinguishing_features:
- Opportunistic and fungal infections, neutropenia, and sclerosing cholangitis occur in CD40L deficiency but not in AID deficiency.
- Germinal-center hyperplasia with marked lymphadenopathy and preserved cell-mediated immunity characterize AID deficiency.
- Inheritance differs — X-linked for CD40L deficiency, autosomal recessive for AID deficiency.
evidence:
- reference: PMID:24402618
reference_title: "First report of the Hyper-IgM syndrome Registry of the Latin American Society for Immunodeficiencies: novel mutations, unique infections, and outcomes."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Previously undescribed fungal and opportunistic infections were observed in CD40L-deficient patients but not in the two patients with AID deficiency."
explanation: >-
The registry states the discriminating observation directly: the
opportunistic-infection burden separates CD40L deficiency from AID
deficiency.
- name: Hyper-IgM syndrome type 3 (CD40 deficiency)
description: >-
Biallelic CD40 loss is the autosomal recessive phenocopy of CD40L
deficiency — the same receptor-ligand axis failing from the B-cell and
myeloid side. It shares the opportunistic-infection susceptibility that
distinguishes the CD40 axis from AID deficiency, and so sits on the same
side of the discriminator.
disease_term:
preferred_term: hyper-IgM syndrome type 3
term:
id: MONDO:0011735
label: hyper-IgM syndrome type 3
distinguishing_features:
- Autosomal recessive like AID deficiency, but with the opportunistic infections of a CD40-axis defect.
- IUIS places CD40 deficiency in Table 1 (combined immunodeficiency) rather than among the predominantly antibody deficiencies.
progression:
- phase: Diagnosis and long-term follow-up
age_range: Median 4.9 years at diagnosis (range 0-53); median 14.2 years at last evaluation (range 2.7-63)
notes: >-
AID deficiency is not a neonatal presentation: in the 29-patient European
cohort the median age at diagnosis was nearly five years, and patients were
followed into adulthood, with the oldest evaluated at 63. Lymphoid
hyperplasia developed in 22 of 29 patients but persisted in only 7 at last
follow-up, so the germinal-center hyperplasia is not uniformly progressive.
evidence:
- reference: PMID:14962793
reference_title: "Clinical, immunologic and genetic analysis of 29 patients with autosomal recessive hyper-IgM syndrome due to Activation-Induced Cytidine Deaminase deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Patients' median age at diagnosis and at last evaluation was 4.9 years (range: 0 to 53) and 14.2 years (range: 2.7 to 63), respectively."
explanation: >-
Gives the diagnostic delay and the follow-up span in the defining cohort.
- reference: PMID:14962793
reference_title: "Clinical, immunologic and genetic analysis of 29 patients with autosomal recessive hyper-IgM syndrome due to Activation-Induced Cytidine Deaminase deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Lymphoid hyperplasia developed in 22 patients and persisted in 7 at last follow-up."
explanation: >-
Documents that the lymphoid hyperplasia regresses in most patients rather
than progressing.
clinical_burden:
burden_level: MODERATE
rationale: >-
The infectious burden is largely correctable: immunoglobulin replacement
produced a dramatic fall in infections in the defining cohort, and unlike
CD40L deficiency there is no mortality driver from opportunistic infection
or from sclerosing cholangitis — no deaths were attributed to AID
deficiency in the Latin American registry. The residual burden is autoimmune and
inflammatory disease, which affected roughly a fifth of the European cohort
and is not addressed by replacement therapy.
evidence:
- reference: PMID:14962793
reference_title: "Clinical, immunologic and genetic analysis of 29 patients with autosomal recessive hyper-IgM syndrome due to Activation-Induced Cytidine Deaminase deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Most patients had suffered from recurrent and severe infections, however, intravenous immunoglobulin (IVIG) replacement therapy resulted in a dramatic decrease in the number of infections."
explanation: >-
Establishes that the infectious component of the burden is largely
correctable with replacement therapy.
- reference: PMID:14962793
reference_title: "Clinical, immunologic and genetic analysis of 29 patients with autosomal recessive hyper-IgM syndrome due to Activation-Induced Cytidine Deaminase deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "It is striking to note that six patients developed autoimmune or inflammatory disorders including diabetes mellitus, polyarthritis, autoimmune hepatitis, hemolytic anemia, immune thrombocytopenia, Crohn's disease and chronic uveitis."
explanation: >-
Quantifies the autoimmune/inflammatory burden that replacement therapy
does not address (6 of 29 patients).
treatments:
- name: Immunoglobulin Replacement Therapy
description: >-
Regular intravenous or subcutaneous immunoglobulin replacement is the
cornerstone of management. It supplies the IgG that patients cannot make
and produces a marked reduction in infection frequency; early initiation
may also prevent the lymphoid hyperplasia. It does not correct the
underlying enzymatic defect.
therapeutic_modality: OTHER
treatment_term:
preferred_term: immunoglobulin replacement therapy
term:
id: NCIT:C62710
label: Immunoglobulin Therapy
target_mechanisms:
- target: Loss of Opsonizing and Mucosal Antibody Function
treatment_effect: BYPASSES
description: >-
Passive IgG supplies the opsonizing antibody the patient cannot generate,
bypassing rather than repairing the class-switch block.
evidence:
- reference: PMID:14962793
reference_title: "Clinical, immunologic and genetic analysis of 29 patients with autosomal recessive hyper-IgM syndrome due to Activation-Induced Cytidine Deaminase deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
intravenous immunoglobulin (IVIG) replacement therapy resulted in a
dramatic decrease in the number of infections
explanation: >-
IVIG replacement dramatically reduced infections in the cohort,
confirming it substitutes for the missing antibody function.
- target: Massive Lymphoid Hyperplasia
treatment_effect: INHIBITS
description: >-
Early-onset immunoglobulin replacement may prevent the lymphoid
hyperplasia as well as the infections.
evidence:
- reference: PMID:14962793
reference_title: "Clinical, immunologic and genetic analysis of 29 patients with autosomal recessive hyper-IgM syndrome due to Activation-Induced Cytidine Deaminase deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
AID-deficient patients are prone to infections and lymphoid
hyperplasia, which may be prevented by early-onset IVIG replacement
explanation: >-
The authors conclude that early IVIG may prevent lymphoid hyperplasia
as well as infection; "may" is preserved here as a hedged claim.
evidence:
- reference: PMID:36931691
reference_title: "Type 2 hyper-IgM syndrome with a rare variant of AICDA gene mutation in a young woman."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The patient was started on monthly intravenous immunoglobulin replacement
therapy and is currently symptomatically better
explanation: >-
Monthly IVIG is the treatment given to a genetically confirmed HIGM2
patient, with symptomatic improvement.
- name: Antibiotic Therapy and Prophylaxis
description: >-
Antibiotics treat the recurrent bacterial sinopulmonary and mucosal
infections, and prophylactic regimens are used alongside immunoglobulin
replacement in patients with continuing infection or established
bronchiectasis.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: antibiotic therapy
term:
id: NCIT:C15620
label: Antibiotic Therapy
target_mechanisms:
- target: Recurrent Bacterial Sinopulmonary and Mucosal Infection
treatment_effect: INHIBITS
description: >-
Antibiotics eradicate or suppress the bacterial infections that the
missing switched antibody cannot prevent or clear.
notes: >-
No AID-deficiency-specific antibiotic trial exists; use follows general
primary-antibody-deficiency practice, so no evidence item is attached to
this treatment rather than citing a source that does not address HIGM2.
- name: Hematopoietic Cell Transplantation (rarely indicated)
description: >-
Unlike the CD40L and CD40 hyper-IgM syndromes — where the combined
immunodeficiency and its opportunistic infections make transplantation a
standard consideration — HIGM2 is a B-cell-intrinsic antibody deficiency
that is generally well controlled by immunoglobulin replacement, and
transplantation is not a routine indication. This entry records the
contrast rather than asserting a HIGM2 transplantation indication: in the
Latin American registry the transplanted patients were CD40L-deficient, and
all AID-deficient patients were alive on conventional management.
therapeutic_modality: CELL_THERAPY
treatment_term:
preferred_term: hematopoietic cell transplantation
term:
id: NCIT:C15431
label: Hematopoietic Cell Transplantation
evidence:
- reference: PMID:24402618
reference_title: "First report of the Hyper-IgM syndrome Registry of the Latin American Society for Immunodeficiencies: novel mutations, unique infections, and outcomes."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Four CD40L-deficient patients underwent successful bone marrow
transplantation.
explanation: >-
In the registry transplantation was performed in CD40L-deficient
patients; none of the AID-deficient patients was transplanted, supporting
the statement that HSCT is not a routine HIGM2 indication.
discussions:
- discussion_id: higm2_population_prevalence_unknown
kind: KNOWLEDGE_GAP
status: OPEN
attaches_to:
- prevalence#Worldwide
prompt: >-
What is the population prevalence of AID deficiency, and does it differ
between populations with high and low rates of consanguinity?
rationale: >-
Every published estimate of HIGM2 frequency is a referral-based case count
rather than a denominator-based rate, so the disease's true prevalence is
unknown. Because it is autosomal recessive, prevalence should be markedly
higher in populations with high consanguinity — the original cohorts drew
heavily on Turkish and Middle Eastern families — but no population-based
screening study has tested this. Without a denominator it is impossible to
say what fraction of AID-deficient people are diagnosed, and the
consistently mild infectious phenotype relative to CD40L deficiency makes
under-ascertainment plausible.
- discussion_id: higm2_aid_tolerance_direct_or_indirect
kind: KNOWLEDGE_GAP
status: OPEN
attaches_to:
- pathophysiology#Breakdown of B-Cell Self-Tolerance
prompt: >-
Is the tolerance defect in AID deficiency a direct consequence of losing
deaminase activity in developing B cells, or an indirect consequence of the
abnormal germinal-center environment?
rationale: >-
AID is required for removal of autoreactive B cells at both the central and
peripheral checkpoints, but the central checkpoint operates in the bone
marrow, before B cells enter a germinal center and before AID is
conventionally described as being expressed. Whether the tolerance defect
reflects a distinct, low-level developmental role for AID or is secondary
to systemic effects of the failed germinal-center reaction is unresolved,
and it determines whether autoimmunity in HIGM2 could be predicted from
genotype or only observed.
references:
- reference: PMID:11007475
title: "Activation-induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the Hyper-IgM syndrome (HIGM2)."
- reference: PMID:11007474
title: "Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme."
- reference: PMID:14962793
title: "Clinical, immunologic and genetic analysis of 29 patients with autosomal recessive hyper-IgM syndrome due to Activation-Induced Cytidine Deaminase deficiency."
- reference: PMID:15893695
title: "Analysis of class switch recombination and somatic hypermutation in patients affected with autosomal dominant hyper-IgM syndrome type 2."
- reference: PMID:21700883
title: "Activation-induced cytidine deaminase (AID) is required for B-cell tolerance in humans."
- reference: PMID:17560278
title: "Pathophysiology of B-cell intrinsic immunoglobulin class switch recombination deficiencies."
- reference: PMID:24402618
title: "First report of the Hyper-IgM syndrome Registry of the Latin American Society for Immunodeficiencies: novel mutations, unique infections, and outcomes."
- reference: PMID:32423680
title: "From Dysgammaglobulinemia to Autosomal-Dominant Activation-Induced Cytidine Deaminase Deficiency: Unraveling an Inherited Immunodeficiency after 50 Years."
- reference: PMID:36931691
title: "Type 2 hyper-IgM syndrome with a rare variant of AICDA gene mutation in a young woman."
- reference: PMID:35748970
title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."