A20 Haploinsufficiency

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Classifications

IUIS Category

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Inheritance

1

Autosomal dominant HP:0000006

Autosomal dominant, with familial occurrence being one of the features that distinguishes this disease from sporadic Behcet disease.

Autosomal dominant inheritance

Show evidence (2 references)

PMID:29916847 SUPPORT Human Clinical

"Patients may present with dominantly inherited, early-onset systemic inflammation and a Behçet-like disease, or a variety of autoinflammatory and autoimmune features."

States dominant inheritance together with the early onset that accompanies it.

PMID:39715316 SUPPORT Human Clinical

"Many individuals diagnosed with HA20 have an affected parent; some individuals have the disorder as the result of a de novo TNFAIP3 pathogenic variant. Each child of an individual with HA20 has a 50% chance of inheriting the TNFAIP3 pathogenic variant."

Gives the transmission risk and records that de novo cases occur, which matters because familial occurrence is one of the discriminators against Behcet disease and a de novo case will not show it.

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Pathophysiology

5

TNFAIP3 Loss of Function

The initiating lesion. A heterozygous loss-of-function variant in TNFAIP3 halves functional A20. Nonsense, missense and whole-gene deletion alleles have all been reported, including a 236 kb deletion at 6q23.3, which is consistent with true haploinsufficiency rather than a dominant negative effect.

TNFAIP3 hgnc:11896

Downstream

Failure of A20-Mediated Deubiquitination Reduced A20 protein means reduced deubiquitinase activity at the NF-kappa-B signalling nodes A20 normally acts on.

Show evidence (3 references)

PMID:31164164 SUPPORT Human Clinical

"We identified c.1434C>A:p.(Cys478*) in one family and a 236 kb deletion at 6q23.3 containing TNFAIP3 in another family."

A nonsense allele and a whole-gene deletion causing the same disease, which is the evidence that the mechanism is dosage rather than an altered protein.

PMID:26642243 SUPPORT Human Clinical

"Herein we describe a new disease caused by high-penetrance heterozygous germline mutations in TNFAIP3, which encodes the NF-κB regulatory protein A20, in six unrelated families with early-onset systemic inflammation."

The original description of the disease, in six unrelated families, establishing heterozygous germline TNFAIP3 mutation as the cause.

PMID:26642243 SUPPORT In Vitro

"Mutant, truncated A20 proteins are likely to act through haploinsufficiency because they do not exert a dominant-negative effect in overexpression experiments."

The experiment that establishes haploinsufficiency rather than dominant negative action, by testing for a dominant-negative effect and not finding one.

Failure of A20-Mediated Deubiquitination

A20 terminates NF-kappa-B signalling by editing ubiquitin chains on upstream components. Its loss removes a brake rather than adding an accelerator, which is why the resulting phenotype is broad and variable rather than stereotyped.

protein deubiquitination GO:0016579 ↓ DECREASED negative regulation of canonical NF-kappaB signal transduction GO:0043124 ↓ DECREASED

Downstream

Constitutive NF-kappa-B Pathway Activation Without adequate termination, canonical NF-kappa-B signalling persists.

Show evidence (2 references)

PMID:24242761 SUPPORT Other

"Therefore, to keep the inflammatory response in check, elaborate negative regulatory mechanisms operate to terminate NF-κB activation at multiple levels by de novo synthesis of NF-κB inhibitory proteins, and orchestration of protein ubiquitination and deubiquitination."

Places deubiquitination among the mechanisms that terminate NF-kappa-B signalling, which is the arm lost in this disease.

PMID:26642243 SUPPORT In Vitro

"A20 restricts NF-κB signals via its deubiquitinase activity."

Names the specific enzymatic activity through which A20 restrains the pathway.

Constitutive NF-kappa-B Pathway Activation

Persistent canonical NF-kappa-B signalling in immune cells, demonstrated functionally in patient-derived mononuclear cells and in cell lines expressing the mutant protein.

monocyte CL:0000576

canonical NF-kappaB signal transduction GO:0007249 ↑ INCREASED

Downstream

Systemic Autoinflammation Unterminated NF-kappa-B drives the proinflammatory transcriptional programme that produces the clinical disease.

Inflammasome Derepression A20 also restrains the NLRP3 inflammasome, a second arm shown in mouse myeloid cells. Whether it contributes in human A20 haploinsufficiency is not established in these sources.

Show evidence (2 references)

PMID:34808442 SUPPORT In Vitro

"Functional studies were performed in A20(c.1804A > T, p.T602S) patient-derived peripheral blood mononuclear cells (PBMCs) and THP-1 cell lines by lentivirus mediating stable over-expression of A20 and A20(c.1804A > T, p.T602S) to analyze the activity of NF-κB signaling pathway."

Describes the functional demonstration in both patient cells and a cell line, which is how a missense allele is shown to be loss of function rather than benign.

PMID:26642243 SUPPORT In Vitro

"Patient-derived cells show increased degradation of IκBα and nuclear translocation of the NF-κB p65 subunit together with increased expression of NF-κB-mediated proinflammatory cytokines."

Measures the pathway at three points in patient cells - inhibitor degradation, p65 nuclear translocation and cytokine output - rather than inferring activation from phenotype.

Inflammasome Derepression

Mechanism confidence: Hypothetical

A second regulatory arm. A20 negatively regulates the NLRP3 inflammasome, and losing it in mouse myeloid cells produces an erosive arthritis that does not depend on TNF receptor 1. Graded HYPOTHETICAL for this disease because the evidence is a myeloid-specific complete knockout in mice rather than heterozygous loss in humans.

macrophage CL:0000235

negative regulation of NLRP3 inflammasome complex assembly GO:1900226 ↓ DECREASED

Animal models

A20 myeloid-specific knockout mouse Mouse partially recapitulates Demonstrates that losing A20 derepresses the NLRP3 inflammasome and produces spontaneous arthritis that does not require TNF receptor 1, which is the evidence for a second arm beyond NF-kappa-B.

Downstream

Systemic Autoinflammation If operative in humans, inflammasome derepression would add IL-1 driven inflammation to the NF-kappa-B arm.

Show evidence (1 reference)

PMID:25043000 SUPPORT Model Organism

"Rheumatoid arthritis in A20(myel-KO) mice is not rescued by deletion of tumour necrosis factor receptor 1 (ref. 2)."

The arthritis persists without TNF receptor 1, which is what argues for a second pathway rather than a purely TNF-driven one.

Systemic Autoinflammation

The clinical disease, and unusually broad for a monogenic condition. Mucosal ulceration dominates, but the phenotype spans fever, skin, gut, joints, eye and liver, and includes autoimmune as well as autoinflammatory features in the same patient. That breadth follows from losing a general brake on NF-kappa-B rather than from a lesion in one effector pathway.

Downstream

Oral Ulcer Recurrent painful oral ulceration during flares, the commonest manifestation.

Genital Ulcers Recurrent genital ulceration, occurring with the oral ulcers and together forming the Behcet-like picture.

Recurrent Fever Fever attacks lasting three to seven days, and one of the features that separates this from Behcet disease.

Pustular Rash Skin involvement, which is heterogeneous and includes pustular rash, folliculitis, vasculitic purpura and lupus-like macular rashes.

Abdominal Pain Gastrointestinal disease ranging from dull pain to severe inflammation with risk of perforation.

Arthritis Relapsing and remitting nonerosive inflammatory polyarthritis with synovitis.

Show evidence (1 reference)

PMID:39715316 SUPPORT Human Clinical

"Haploinsufficiency of A20 (HA20), a complex immune dysregulation disease, is characterized by recurrent systemic immune dysfunction (i.e., inflammation and/or immune deficiency)."

Characterises the disease as systemic immune dysregulation rather than a single inflammatory syndrome.

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Pathograph

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

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Phenotypes

6

Genitourinary 1

Genital Ulcers FREQUENT HP:0003249

Temporal: RECURRENT

Show evidence (1 reference)

PMID:39715316 SUPPORT Human Clinical

"recurrent painful oral/genital ulcers, typically during disease flares (>70% of persons)"

Same reported frequency, covering both ulcer sites.

Head and Neck 1

Oral Ulcer FREQUENT HP:0000155

Temporal: RECURRENT Onset: CHILDHOOD

Show evidence (1 reference)

PMID:39715316 SUPPORT Human Clinical

"recurrent painful oral/genital ulcers, typically during disease flares (>70% of persons)"

Gives the frequency band supporting FREQUENT.

Immune 1

Pustular Rash OCCASIONAL HP:0033605

Show evidence (1 reference)

PMID:39715316 SUPPORT Human Clinical

"skin involvement (~40%), including pustular rashes, folliculitis, vasculitic purpura, urticaria, lupus-like macular rashes, and eczematoid dermatitis"

The 40% is for skin involvement overall rather than for pustular rash specifically, which is why this phenotype is banded OCCASIONAL rather than FREQUENT.

Metabolism 1

Recurrent Fever FREQUENT HP:0001954

Temporal: RECURRENT Onset: CHILDHOOD

Show evidence (1 reference)

PMID:39715316 SUPPORT Human Clinical

"recurrent fevers (~50%), typically lasting for three to seven days that can rarely progress to a cytokine storm and/or hemophagocytic lymphohistiocytosis"

Gives the frequency band and the attack duration.

Musculoskeletal 1

Arthritis OCCASIONAL HP:0001369

Temporal: RECURRENT

Show evidence (1 reference)

PMID:39715316 SUPPORT Human Clinical

"arthralgia/arthritis (~34%), typically relapsing and/or remitting nonerosive inflammatory polyarthritis with synovitis, and rarely resembling rheumatoid arthritis or psoriatic-like erosions"

The 34% covers arthralgia and arthritis together rather than arthritis alone, which is why this phenotype is banded OCCASIONAL rather than FREQUENT - the same one-band-down rule applied to pustular rash above.

Constitutional 1

Abdominal Pain OCCASIONAL HP:0002027

Show evidence (1 reference)

PMID:39715316 SUPPORT Human Clinical

"gastrointestinal disease (~40%), ranging from dull abdominal pain (due to serositis, ulcers, or bowel inflammation) to severe inflammation with risk of bowel perforation"

Gives the frequency of gastrointestinal disease and its severity range.

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Genetic Associations

1

TNFAIP3 (Heterozygous Loss of Function)

Gene: TNFAIP3 hgnc:11896 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (3 references)

PMID:31164164 SUPPORT Human Clinical

"We identified c.1434C>A:p.(Cys478*) in one family and a 236 kb deletion at 6q23.3 containing TNFAIP3 in another family."

Two very different alleles producing the same disease, which is the argument for a dosage mechanism.

PMID:34808442 SUPPORT Human Clinical

"Herein, we reported a novel TNFAIP3 (c.1804A > T, p.T602S) variation, which has not been reported before."

A missense allele reported in a patient. Regraded from IN_VITRO on review - this sentence reports a clinical finding, and the paper is indexed as a case report.

PMID:34808442 SUPPORT In Vitro

"Functional studies were performed in A20(c.1804A > T, p.T602S) patient-derived peripheral blood mononuclear cells (PBMCs) and THP-1 cell lines by lentivirus mediating stable over-expression of A20 and A20(c.1804A > T, p.T602S) to analyze the activity of NF-κB signaling pathway."

The genuinely in-vitro half of the same paper, split into its own item so the grading matches the sentence rather than the publication.

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Medical Actions

4

Tumour Necrosis Factor Blockade

Action: biological therapy Ontology label: Biological Therapy NCIT:C15187

Agent: infliximab NCIT:C1789 adalimumab NCIT:C65216 etanercept NCIT:C2381

Platform: Other

The most effective single class in the largest treatment series. In a Japanese national survey, molecular targeted drugs were given to 44.4% of patients and anti-TNF agents were effective in 59.5% of those treated. Note what that means: roughly forty per cent did not respond, so this is the best available option rather than a reliable one, and eleven patients failed to achieve control on their initial agent.

Mechanism Target:

INHIBITS Systemic Autoinflammation — Neutralises TNF, one of the proinflammatory cytokines whose expression rises when NF-kappa-B is unrestrained.

Show evidence (1 reference)

PMID:40574834 SUPPORT Human Clinical

"Molecular target drugs (MTDs) were administered in 44.4% of patients, among which anti-tumor necrosis factor (TNF)-α agents showed efficacy in 59.5% of patients."

Gives both the proportion treated and the response rate, which together define how much of the disease this approach actually controls.

Show evidence (3 references)

PMID:40574834 SUPPORT Human Clinical

"Seventy-two HA20 patients were identified in Japan. And, 54 patients from 37 unrelated families were analyzed in detail."

Establishes the size of the series behind the treatment figures, which is the largest available for this disease.

PMID:40574834 REFUTE Human Clinical

"The severity of A20 haploinsufficiency (HA20) varies, with no established clinical guidelines for treatment."

Recorded against any reading of the efficacy figure as a standard of care. The same survey states there are no established treatment guidelines.

PMID:39715316 SUPPORT Human Clinical

"Supportive treatment: TNF inhibitors, the most used medications, directly target abnormal NF-κB signaling."

Names TNF inhibitors as the most used agents and states the mechanistic rationale - they act on the pathway this disease de-represses.

Interleukin-1 Blockade

Action: biological therapy Ontology label: Biological Therapy NCIT:C15187

Agent: anakinra NCIT:C38717 canakinumab NCIT:C80971

Platform: Protein replacement

A second-line option for patients not controlled by TNF blockade, which is a substantial group given the roughly forty per cent non-response rate. Anakinra is a recombinant IL-1 receptor antagonist; canakinumab and rilonacept are biologics against IL-1 beta. Described as effective in many individuals, which is not a rate.

Mechanism Target:

INHIBITS Systemic Autoinflammation — Neutralises IL-1 signalling, one cytokine output of the derepressed pathway.

Show evidence (1 reference)

PMID:39715316 SUPPORT Human Clinical

"In addition, IL-1 targeted therapy and JAK inhibitors are effective in many individuals."

States effectiveness for IL-1 targeted therapy. Note "many individuals" is not a rate, so this supports availability of the option rather than a quantified expectation.

Show evidence (1 reference)

PMID:39715316 SUPPORT Human Clinical

"The IL-1 receptor antagonist anakinra is considered relatively safe during pregnancy due to its extremely short half-life, although data are limited."

Names anakinra as an IL-1 receptor antagonist, which is the basis for the PROTEIN_REPLACEMENT modality on this entry rather than SMALL_MOLECULE, and records its pregnancy safety profile with the authors' own caveat.

JAK Inhibition

Action: pharmacotherapy Ontology label: Pharmacotherapy NCIT:C15986

Platform: Small molecule

The other second-line option, and a small-molecule class unlike IL-1 blockade. Contraindicated in pregnancy, which matters in a disease presenting in childhood and continuing through reproductive life.

Mechanism Target:

INHIBITS Systemic Autoinflammation — Acts downstream of the cytokine and interferon receptors engaged by the derepressed pathway.

Show evidence (1 reference)

PMID:39715316 SUPPORT Human Clinical

"In addition, IL-1 targeted therapy and JAK inhibitors are effective in many individuals."

States effectiveness for JAK inhibitors, with the same caveat that "many individuals" is not a quantified rate.

Show evidence (1 reference)

PMID:39715316 SUPPORT Human Clinical

"JAK inhibitors are contraindicated during pregnancy."

A hard contraindication, recorded because it constrains use in exactly the population this disease affects.

Haematopoietic Stem Cell Transplantation

Action: allogeneic stem cell transplantation Ontology label: Allogeneic Stem Cell Transplantation NCIT:C201466

Platform: Cell therapy

Reserved for severe or refractory disease. It is the only listed option that addresses the mutant haematopoietic compartment itself rather than a cytokine downstream of it, and it is stated as something that may be considered rather than as established therapy.

Show evidence (1 reference)

PMID:39715316 SUPPORT Human Clinical

"In some instances of severe or refractory disease, hematopoietic stem cell transplantation may be considered."

States the indication and, in its own hedged phrasing, the strength of the recommendation.

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Biochemical Markers

1

Acute phase reactant panel (PRESENT)

Show evidence (2 references)

PMID:39715316 SUPPORT Human Clinical

"Typical evaluations include medical history, physical examination, and laboratory testing of acute phase reactants including CRP, ESR, fibrinogen, CBC with differential, SAA, and urinalysis for evidence of proteinuria."

Names the panel used for surveillance. Note it is entirely non-specific, so it tracks inflammatory activity rather than confirming the diagnosis.

PMID:39715316 SUPPORT Human Clinical

"Monitor at least annually by a rheumatologist, and more frequently for individuals with evidence of systemic inflammation and/or organ involvement."

Gives the monitoring interval and what shortens it.

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Diagnosis

2

Distinguishing A20 haploinsufficiency from Behcet disease (PRESENT)

The central diagnostic problem. Patients present with recurrent oral and genital ulcers and are diagnosed and treated as Behcet disease; roughly half of reported cases had reached that diagnosis. A comparison of 54 patients with this disease against 520 Japanese Behcet patients identified the discriminating features: early onset, familial occurrence and recurrent fever. None of those is a laboratory test, so recognition depends on taking a family history and noticing the fever pattern.

Show evidence (2 references)

PMID:31164164 SUPPORT Human Clinical

"A comparison of clinical features between HA20 patients and cohorts of BD patients revealed several critical features specific to HA20. These were early-onset, familial occurrence, recurrent fever attacks, gastrointestinal involvement, and infrequent ocular involvement."

The full discriminator list from a direct cohort comparison. Note the last item is a negative - ocular involvement is infrequent here, whereas it is characteristic of Behcet disease, so its absence is part of what separates them.

PMID:31164164 SUPPORT Human Clinical

"Four HA20 patients in the two families presented with childhood-onset recurrent oral and genital ulcers and were initially diagnosed and treated as BD."

A concrete instance of the misdiagnosis this entry is warning about.

Molecular genetic testing of TNFAIP3 (PRESENT)

Diagnosis is molecular. Whole exome sequencing found the causal variants in the families described, and copy number analysis matters too, since whole-gene deletion is one of the mechanisms and would be missed by sequencing alone.

Show evidence (2 references)

PMID:31164164 SUPPORT Human Clinical

"Probands of these families were analyzed by whole exome sequencing (WES) and subsequent Sanger sequencing."

States the testing approach used to make the diagnosis in these families.

PMID:39715316 SUPPORT Human Clinical

"The diagnosis of HA20 is established in an individual by identification of either a heterozygous TNFAIP3 pathogenic variant (~95% of affected individuals) or a heterozygous deletion of 6q23 including TNFAIP3 (<5% of affected individuals) by molecular genetic testing."

Gives the two diagnostic routes with their relative yields. The under 5% deletion share is the practical reason sequence analysis alone is not sufficient - copy number must also be assessed.

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Epidemiology

3

Reported case count

Newly described in 2016 and still uncommon in the literature. Sixty-one cases had been reported worldwide at the time of one 2021 review, of which 29 had ultimately been diagnosed as Behcet disease.

Show evidence (1 reference)

PMID:34011076 SUPPORT Human Clinical

"Sixty-one cases of HA20 have been reported worldwide, among which 29 cases were diagnosed with Behcet disease ultimately."

Gives the reported total and, more usefully, the proportion that reached a Behcet diagnosis, which quantifies the misclassification problem.

Manifestation frequencies

In the largest synthesis, recurrent oral and genital ulcers occur in more than 70%, recurrent fevers in about 50%, skin involvement and gastrointestinal disease in about 40% each, and arthralgia or arthritis in about 34%.

Show evidence (1 reference)

PMID:39715316 SUPPORT Human Clinical

"The most common manifestations and their frequency include: (1) recurrent painful oral/genital ulcers, typically during disease flares (>70% of persons); (2) recurrent fevers (~50%), typically lasting for three to seven days that can rarely progress to a cytokine storm and/or hemophagocytic..."

The source for every frequency band used in the phenotypes below, quoted in full so a reader can verify each band directly from this one sentence.

Reclassification from Behcet subtype to inborn error of immunity

Originally described as an autosomal dominant form of Behcet disease, the condition is now regarded as a complex inborn error of immunity with a broad immunologic and clinical spectrum. That shift matters for curation: it is not a Behcet subtype and should not be modelled as one.

Show evidence (1 reference)

PMID:38451381 SUPPORT Human Clinical

"Originally described as an autosomal dominant form of Behcet's disease, HA20 is now considered a complex inborn error of immunity with a broad spectrum of immunologic and clinical phenotypes."

States the reclassification directly, which is the reason this entry is separate from the Behcet disease entry rather than a subtype of it.

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Animal Models

1

A20 myeloid-specific knockout mouse

A conditional knockout deleting A20 in the myeloid lineage. It is the source of the inflammasome arm modelled in this entry, and it is a poor genetic match for the human disease, which is why that arm is graded HYPOTHETICAL.

Species

Mouse

Genotype

Tnfaip3 fl/fl LysM-Cre (A20 myel-KO)

Publication

PMID:25043000

Pathograph links

Inflammasome Derepression partially recapitulates fidelity: low Demonstrates that losing A20 derepresses the NLRP3 inflammasome and produces spontaneous arthritis that does not require TNF receptor 1, which is the evidence for a second arm beyond NF-kappa-B.

Limitations: Three mismatches against the human disease, and they run in the same direction. The mouse is a complete knockout, not haploinsufficiency. It is restricted to the myeloid lineage rather than germline. And the arthritis it produces is erosive, whereas the arthritis in this disease is typically nonerosive. The model therefore supports the existence of the pathway rather than its operation in patients.

Show evidence (1 reference)

PMID:25043000 SUPPORT Model Organism

"Rheumatoid arthritis in A20(myel-KO) mice is not rescued by deletion of tumour necrosis factor receptor 1 (ref. 2)."

The TNF receptor 1 independence is what argues for a second pathway rather than a purely TNF-driven one.

Show evidence (1 reference)

PMID:25043000 SUPPORT Model Organism

"Myeloid-cell-specific deletion of the rheumatoid arthritis susceptibility gene A20/Tnfaip3 in mice (A20(myel-KO) mice) triggers a spontaneous erosive polyarthritis that resembles rheumatoid arthritis in patients."

Establishes the model and the phenotype it produces.

{ }

Source YAML

click to show

name: A20 Haploinsufficiency
creation_date: '2026-09-09T09:00:00Z'
description: >-
  An autosomal dominant autoinflammatory disease caused by loss-of-function
  variants in TNFAIP3, which encodes A20. A20 is a deubiquitinase that terminates
  canonical NF-kappa-B signalling, so losing one functional copy leaves the
  pathway insufficiently restrained and produces early-onset systemic
  inflammation. Most patients present with recurrent oral and genital ulceration
  and are diagnosed as Behcet disease, which is the central clinical problem: the
  two are separable, but only on features a clinician has to be looking for -
  early onset, familial occurrence and recurrent fever. The mechanism is a loss
  of negative regulation rather than a gain of signal, and the phenotype is
  correspondingly broad, spanning autoinflammatory and autoimmune features in the
  same patient.
categories:
- Autoinflammatory Disease
- Inborn Error of Immunity
- NF-kappa-B Regulatory Disorder
parents:
- autoinflammatory syndrome
synonyms:
- HA20
- haploinsufficiency of A20
- TNFAIP3 haploinsufficiency
epidemiology:
- name: Reported case count
  description: >-
    Newly described in 2016 and still uncommon in the literature. Sixty-one cases
    had been reported worldwide at the time of one 2021 review, of which 29 had
    ultimately been diagnosed as Behcet disease.
  evidence:
  - reference: PMID:34011076
    reference_title: 'Mutation analysis of the TNFAIP3 in A20 haploinsufficiency: A case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Sixty-one cases of HA20 have been reported worldwide, among which 29 cases were
      diagnosed with Behcet disease ultimately.'
    explanation: Gives the reported total and, more usefully, the proportion that reached a Behcet
      diagnosis, which quantifies the misclassification problem.
- name: Manifestation frequencies
  description: >-
    In the largest synthesis, recurrent oral and genital ulcers occur in more than
    70%, recurrent fevers in about 50%, skin involvement and gastrointestinal
    disease in about 40% each, and arthralgia or arthritis in about 34%.
  evidence:
  - reference: PMID:39715316
    reference_title: Haploinsufficiency of A20.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'The most common manifestations and their frequency include: (1) recurrent painful
      oral/genital ulcers, typically during disease flares (>70% of persons); (2) recurrent fevers
      (~50%), typically lasting for three to seven days that can rarely progress to a cytokine
      storm and/or hemophagocytic lymphohistiocytosis; (3) skin involvement (~40%), including
      pustular rashes, folliculitis, vasculitic purpura, urticaria, lupus-like macular rashes,
      and eczematoid dermatitis; (4) gastrointestinal disease (~40%), ranging from dull abdominal
      pain (due to serositis, ulcers, or bowel inflammation) to severe inflammation with risk
      of bowel perforation; and (5) arthralgia/arthritis (~34%), typically relapsing and/or
      remitting nonerosive inflammatory polyarthritis with synovitis, and rarely resembling
      rheumatoid arthritis or psoriatic-like erosions.'
    explanation: The source for every frequency band used in the phenotypes below, quoted in full
      so a reader can verify each band directly from this one sentence.
- name: Reclassification from Behcet subtype to inborn error of immunity
  description: >-
    Originally described as an autosomal dominant form of Behcet disease, the
    condition is now regarded as a complex inborn error of immunity with a broad
    immunologic and clinical spectrum. That shift matters for curation: it is not
    a Behcet subtype and should not be modelled as one.
  evidence:
  - reference: PMID:38451381
    reference_title: 'The Complexity of Being A20: From Biological Functions to Genetic Associations.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Originally described as an autosomal dominant form of Behcet''s disease, HA20 is
      now considered a complex inborn error of immunity with a broad spectrum of immunologic and
      clinical phenotypes.'
    explanation: States the reclassification directly, which is the reason this entry is separate
      from the Behcet disease entry rather than a subtype of it.
pathophysiology:
- name: TNFAIP3 Loss of Function
  biological_scale: MOLECULAR
  description: >-
    The initiating lesion. A heterozygous loss-of-function variant in TNFAIP3
    halves functional A20. Nonsense, missense and whole-gene deletion alleles have
    all been reported, including a 236 kb deletion at 6q23.3, which is consistent
    with true haploinsufficiency rather than a dominant negative effect.
  genes:
  - preferred_term: TNFAIP3
    term:
      id: hgnc:11896
      label: TNFAIP3
  evidence:
  - reference: PMID:31164164
    reference_title: "Haploinsufficiency of A20 caused by a novel nonsense variant or entire deletion of TNFAIP3\
      \ is clinically distinct from Behçet's disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'We identified c.1434C>A:p.(Cys478*) in one family and a 236 kb deletion at 6q23.3
      containing TNFAIP3 in another family.'
    explanation: A nonsense allele and a whole-gene deletion causing the same disease, which is
      the evidence that the mechanism is dosage rather than an altered protein.
  - reference: PMID:26642243
    reference_title: Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early-onset
      autoinflammatory disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Herein we describe a new disease caused by high-penetrance heterozygous germline
      mutations in TNFAIP3, which encodes the NF-κB regulatory protein A20, in six unrelated
      families with early-onset systemic inflammation.'
    explanation: The original description of the disease, in six unrelated families, establishing
      heterozygous germline TNFAIP3 mutation as the cause.
  - reference: PMID:26642243
    reference_title: Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early-onset
      autoinflammatory disease.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: 'Mutant, truncated A20 proteins are likely to act through haploinsufficiency because
      they do not exert a dominant-negative effect in overexpression experiments.'
    explanation: The experiment that establishes haploinsufficiency rather than dominant negative
      action, by testing for a dominant-negative effect and not finding one.
  downstream:
  - target: Failure of A20-Mediated Deubiquitination
    causal_link_type: DIRECT
    description: Reduced A20 protein means reduced deubiquitinase activity at the NF-kappa-B
      signalling nodes A20 normally acts on.
    evidence:
    - reference: PMID:24242761
      reference_title: A20-mediated negative regulation of canonical NF-κB signaling pathway.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: 'The NF-κB target genes, IκBα and A20, play critical roles in termination of the
        active canonical NF-κB pathway.'
      explanation: Establishes A20 as one of the two principal terminators of NF-kappa-B
        signalling, which is the function lost here.
- name: Failure of A20-Mediated Deubiquitination
  biological_scale: MOLECULAR
  description: >-
    A20 terminates NF-kappa-B signalling by editing ubiquitin chains on upstream
    components. Its loss removes a brake rather than adding an accelerator, which
    is why the resulting phenotype is broad and variable rather than stereotyped.
  biological_processes:
  - preferred_term: protein deubiquitination
    modifier: DECREASED
    term:
      id: GO:0016579
      label: protein deubiquitination
  - preferred_term: negative regulation of canonical NF-kappaB signal transduction
    modifier: DECREASED
    term:
      id: GO:0043124
      label: negative regulation of canonical NF-kappaB signal transduction
  evidence:
  - reference: PMID:24242761
    reference_title: A20-mediated negative regulation of canonical NF-κB signaling pathway.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'Therefore, to keep the inflammatory response in check, elaborate negative regulatory
      mechanisms operate to terminate NF-κB activation at multiple levels by de novo synthesis
      of NF-κB inhibitory proteins, and orchestration of protein ubiquitination and
      deubiquitination.'
    explanation: Places deubiquitination among the mechanisms that terminate NF-kappa-B
      signalling, which is the arm lost in this disease.
  - reference: PMID:26642243
    reference_title: Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early-onset
      autoinflammatory disease.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: 'A20 restricts NF-κB signals via its deubiquitinase activity.'
    explanation: Names the specific enzymatic activity through which A20 restrains the pathway.
  downstream:
  - target: Constitutive NF-kappa-B Pathway Activation
    causal_link_type: DIRECT
    description: Without adequate termination, canonical NF-kappa-B signalling persists.
    evidence:
    - reference: PMID:29916847
      reference_title: Haploinsufficiency of A20 and other paediatric inflammatory disorders with mucosal
        involvement.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'A20 haploinsufficiency is a newly described autoinflammatory disease caused by
        loss-of-function mutations in TNFAIP3 that result in the activation of the nuclear factor
        (NF)-kB pathway.'
      explanation: States the causal chain from the loss-of-function mutation to NF-kappa-B
        activation.
- name: Constitutive NF-kappa-B Pathway Activation
  biological_scale: CELLULAR
  description: >-
    Persistent canonical NF-kappa-B signalling in immune cells, demonstrated
    functionally in patient-derived mononuclear cells and in cell lines expressing
    the mutant protein.
  cell_types:
  - preferred_term: monocyte
    term:
      id: CL:0000576
      label: monocyte
  biological_processes:
  - preferred_term: canonical NF-kappaB signal transduction
    modifier: INCREASED
    term:
      id: GO:0007249
      label: canonical NF-kappaB signal transduction
  evidence:
  - reference: PMID:34808442
    reference_title: A novel missense mutation in TNFAIP3 causes haploinsufficiency of A20.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: 'Functional studies were performed in A20(c.1804A > T, p.T602S) patient-derived
      peripheral blood mononuclear cells (PBMCs) and THP-1 cell lines by lentivirus mediating
      stable over-expression of A20 and A20(c.1804A > T, p.T602S) to analyze the activity of NF-κB
      signaling pathway.'
    explanation: Describes the functional demonstration in both patient cells and a cell line,
      which is how a missense allele is shown to be loss of function rather than benign.
  - reference: PMID:26642243
    reference_title: Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early-onset
      autoinflammatory disease.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: 'Patient-derived cells show increased degradation of IκBα and nuclear translocation
      of the NF-κB p65 subunit together with increased expression of NF-κB-mediated proinflammatory
      cytokines.'
    explanation: Measures the pathway at three points in patient cells - inhibitor degradation,
      p65 nuclear translocation and cytokine output - rather than inferring activation from
      phenotype.
  downstream:
  - target: Systemic Autoinflammation
    causal_link_type: DIRECT
    description: Unterminated NF-kappa-B drives the proinflammatory transcriptional programme
      that produces the clinical disease.
    evidence:
    - reference: PMID:29916847
      reference_title: Haploinsufficiency of A20 and other paediatric inflammatory disorders with mucosal
        involvement.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'Patients may present with dominantly inherited, early-onset systemic inflammation
        and a Behçet-like disease, or a variety of autoinflammatory and autoimmune features.'
      explanation: Names the clinical consequence and, importantly, its breadth - autoinflammatory
        and autoimmune features together.
  - target: Inflammasome Derepression
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: A20 also restrains the NLRP3 inflammasome, a second arm shown in mouse myeloid
      cells. Whether it contributes in human A20 haploinsufficiency is not established in these
      sources.
    evidence:
    - reference: PMID:25043000
      reference_title: Negative regulation of the NLRP3 inflammasome by A20 protects against arthritis.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: 'Myeloid-cell-specific deletion of the rheumatoid arthritis susceptibility gene
        A20/Tnfaip3 in mice (A20(myel-KO) mice) triggers a spontaneous erosive polyarthritis that
        resembles rheumatoid arthritis in patients.'
      explanation: Establishes the mouse model on which the inflammasome arm rests. Note this is
        a myeloid-specific complete deletion, not haploinsufficiency, so it is a different genetic
        situation from the human disease.
- name: Inflammasome Derepression
  biological_scale: CELLULAR
  mechanism_confidence: HYPOTHETICAL
  description: >-
    A second regulatory arm. A20 negatively regulates the NLRP3 inflammasome, and
    losing it in mouse myeloid cells produces an erosive arthritis that does not
    depend on TNF receptor 1. Graded HYPOTHETICAL for this disease because the
    evidence is a myeloid-specific complete knockout in mice rather than
    heterozygous loss in humans.
  cell_types:
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: negative regulation of NLRP3 inflammasome complex assembly
    modifier: DECREASED
    term:
      id: GO:1900226
      label: negative regulation of NLRP3 inflammasome complex assembly
  evidence:
  - reference: PMID:25043000
    reference_title: Negative regulation of the NLRP3 inflammasome by A20 protects against arthritis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: 'Rheumatoid arthritis in A20(myel-KO) mice is not rescued by deletion of tumour necrosis
      factor receptor 1 (ref. 2).'
    explanation: The arthritis persists without TNF receptor 1, which is what argues for a second
      pathway rather than a purely TNF-driven one.
  downstream:
  - target: Systemic Autoinflammation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: If operative in humans, inflammasome derepression would add IL-1 driven
      inflammation to the NF-kappa-B arm.
    evidence:
    - reference: PMID:25043000
      reference_title: Negative regulation of the NLRP3 inflammasome by A20 protects against arthritis.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: 'Interleukin-1 is an important mediator of cartilage destruction in rheumatic diseases,
        but our understanding of the upstream mechanisms leading to production of interleukin-1β
        in rheumatoid arthritis is limited by the absence of suitable mouse models of the disease
        in which inflammasomes contribute to pathology.'
      explanation: States the IL-1 output of this arm and, in the same sentence, the modelling
        limitation that makes its human relevance uncertain.
- name: Systemic Autoinflammation
  biological_scale: ORGANISM
  description: >-
    The clinical disease, and unusually broad for a monogenic condition. Mucosal
    ulceration dominates, but the phenotype spans fever, skin, gut, joints, eye
    and liver, and includes autoimmune as well as autoinflammatory features in the
    same patient. That breadth follows from losing a general brake on NF-kappa-B
    rather than from a lesion in one effector pathway.
  evidence:
  - reference: PMID:39715316
    reference_title: Haploinsufficiency of A20.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Haploinsufficiency of A20 (HA20), a complex immune dysregulation disease, is
      characterized by recurrent systemic immune dysfunction (i.e., inflammation and/or immune
      deficiency).'
    explanation: Characterises the disease as systemic immune dysregulation rather than a single
      inflammatory syndrome.
  downstream:
  - target: Oral Ulcer
    causal_link_type: DIRECT
    description: Recurrent painful oral ulceration during flares, the commonest manifestation.
    evidence:
    - reference: PMID:39715316
      reference_title: Haploinsufficiency of A20.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'recurrent painful oral/genital ulcers, typically during disease flares (>70% of
        persons)'
      explanation: Gives the frequency and ties the ulceration to disease flares.
  - target: Genital Ulcers
    causal_link_type: DIRECT
    description: Recurrent genital ulceration, occurring with the oral ulcers and together forming
      the Behcet-like picture.
    evidence:
    - reference: PMID:39715316
      reference_title: Haploinsufficiency of A20.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'recurrent painful oral/genital ulcers, typically during disease flares (>70% of
        persons)'
      explanation: Same source sentence; the two ulcer sites are reported together.
  - target: Recurrent Fever
    causal_link_type: DIRECT
    description: Fever attacks lasting three to seven days, and one of the features that separates
      this from Behcet disease.
    evidence:
    - reference: PMID:39715316
      reference_title: Haploinsufficiency of A20.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'recurrent fevers (~50%), typically lasting for three to seven days that can rarely
        progress to a cytokine storm and/or hemophagocytic lymphohistiocytosis'
      explanation: Gives the frequency, the duration, and the rare severe extreme.
  - target: Pustular Rash
    causal_link_type: DIRECT
    description: Skin involvement, which is heterogeneous and includes pustular rash,
      folliculitis, vasculitic purpura and lupus-like macular rashes.
    evidence:
    - reference: PMID:39715316
      reference_title: Haploinsufficiency of A20.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'skin involvement (~40%), including pustular rashes, folliculitis, vasculitic purpura,
        urticaria, lupus-like macular rashes, and eczematoid dermatitis'
      explanation: Gives the frequency of skin involvement and enumerates its forms.
  - target: Abdominal Pain
    causal_link_type: DIRECT
    description: Gastrointestinal disease ranging from dull pain to severe inflammation with risk
      of perforation.
    evidence:
    - reference: PMID:39715316
      reference_title: Haploinsufficiency of A20.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'gastrointestinal disease (~40%), ranging from dull abdominal pain (due to serositis,
        ulcers, or bowel inflammation) to severe inflammation with risk of bowel perforation'
      explanation: Gives the frequency and the severity range, including the perforation risk.
  - target: Arthritis
    causal_link_type: DIRECT
    description: Relapsing and remitting nonerosive inflammatory polyarthritis with synovitis.
    evidence:
    - reference: PMID:39715316
      reference_title: Haploinsufficiency of A20.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'arthralgia/arthritis (~34%), typically relapsing and/or remitting nonerosive
        inflammatory polyarthritis with synovitis, and rarely resembling rheumatoid arthritis or
        psoriatic-like erosions'
      explanation: Gives the frequency and specifies that the arthritis is usually nonerosive.
phenotypes:
- category: Oral
  name: Oral Ulcer
  frequency: FREQUENT
  description: >-
    Recurrent painful oral ulceration during flares, the commonest manifestation
    and usually the presenting one.
  phenotype_term:
    preferred_term: Oral ulcer
    term:
      id: HP:0000155
      label: Oral ulcer
    temporality: RECURRENT
    onset:
      onset_category: CHILDHOOD
      notes: Childhood onset is one of the features separating this disease from sporadic Behcet
        disease, which typically begins in early adulthood. Supported by PMID:26642243, which
        describes early-onset systemic inflammation in the original six families, and by
        PMID:31164164, which identifies early onset as a discriminator against Behcet disease.
  diagnostic: true
  evidence:
  - reference: PMID:39715316
    reference_title: Haploinsufficiency of A20.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'recurrent painful oral/genital ulcers, typically during disease flares (>70% of
      persons)'
    explanation: Gives the frequency band supporting FREQUENT.
- category: Genitourinary
  name: Genital Ulcers
  frequency: FREQUENT
  description: >-
    Recurrent genital ulceration accompanying the oral ulcers, which together
    produce the Behcet-like presentation.
  phenotype_term:
    preferred_term: Genital ulcers
    term:
      id: HP:0003249
      label: Genital ulcers
    temporality: RECURRENT
  evidence:
  - reference: PMID:39715316
    reference_title: Haploinsufficiency of A20.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'recurrent painful oral/genital ulcers, typically during disease flares (>70% of
      persons)'
    explanation: Same reported frequency, covering both ulcer sites.
- category: Constitutional
  name: Recurrent Fever
  frequency: FREQUENT
  description: >-
    Fever attacks of three to seven days, present in about half of patients. Their
    presence is one of the features that distinguishes this disease from Behcet
    disease, where recurrent fever is not characteristic.
  phenotype_term:
    preferred_term: Recurrent fever
    term:
      id: HP:0001954
      label: Recurrent fever
    temporality: RECURRENT
    onset:
      onset_category: CHILDHOOD
  evidence:
  - reference: PMID:39715316
    reference_title: Haploinsufficiency of A20.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'recurrent fevers (~50%), typically lasting for three to seven days that can rarely
      progress to a cytokine storm and/or hemophagocytic lymphohistiocytosis'
    explanation: Gives the frequency band and the attack duration.
- category: Dermatologic
  name: Pustular Rash
  frequency: OCCASIONAL
  description: >-
    One form of the heterogeneous skin involvement, which also includes
    folliculitis, vasculitic purpura, urticaria and lupus-like macular rashes.
  phenotype_term:
    preferred_term: Pustular rash
    term:
      id: HP:0033605
      label: Pustular rash
  evidence:
  - reference: PMID:39715316
    reference_title: Haploinsufficiency of A20.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'skin involvement (~40%), including pustular rashes, folliculitis, vasculitic purpura,
      urticaria, lupus-like macular rashes, and eczematoid dermatitis'
    explanation: The 40% is for skin involvement overall rather than for pustular rash
      specifically, which is why this phenotype is banded OCCASIONAL rather than FREQUENT.
- category: Gastrointestinal
  name: Abdominal Pain
  frequency: OCCASIONAL
  description: >-
    Gastrointestinal involvement, from dull pain due to serositis or bowel
    inflammation through to severe inflammation carrying a risk of perforation.
  phenotype_term:
    preferred_term: Abdominal pain
    term:
      id: HP:0002027
      label: Abdominal pain
  evidence:
  - reference: PMID:39715316
    reference_title: Haploinsufficiency of A20.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'gastrointestinal disease (~40%), ranging from dull abdominal pain (due to serositis,
      ulcers, or bowel inflammation) to severe inflammation with risk of bowel perforation'
    explanation: Gives the frequency of gastrointestinal disease and its severity range.
- category: Musculoskeletal
  name: Arthritis
  frequency: OCCASIONAL
  description: >-
    Relapsing, remitting, typically nonerosive inflammatory polyarthritis with
    synovitis. Erosive disease resembling rheumatoid or psoriatic arthritis is
    rare.
  phenotype_term:
    preferred_term: Arthritis
    term:
      id: HP:0001369
      label: Arthritis
    temporality: RECURRENT
  evidence:
  - reference: PMID:39715316
    reference_title: Haploinsufficiency of A20.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'arthralgia/arthritis (~34%), typically relapsing and/or remitting nonerosive
      inflammatory polyarthritis with synovitis, and rarely resembling rheumatoid arthritis or
      psoriatic-like erosions'
    explanation: The 34% covers arthralgia and arthritis together rather than arthritis alone,
      which is why this phenotype is banded OCCASIONAL rather than FREQUENT - the same one-band-down
      rule applied to pustular rash above.
biochemical:
- name: Acute phase reactant panel
  presence: PRESENT
  notes: >-
    Surveillance is built on acute phase reactants rather than on any
    disease-specific marker. The recommended panel is CRP, ESR, fibrinogen, serum
    amyloid A, full blood count with differential, and urinalysis for proteinuria,
    monitored at least annually and more often with active inflammation or organ
    involvement.
  evidence:
  - reference: PMID:39715316
    reference_title: Haploinsufficiency of A20.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Typical evaluations include medical history, physical examination, and laboratory
      testing of acute phase reactants including CRP, ESR, fibrinogen, CBC with differential,
      SAA, and urinalysis for evidence of proteinuria.'
    explanation: Names the panel used for surveillance. Note it is entirely non-specific, so it
      tracks inflammatory activity rather than confirming the diagnosis.
  - reference: PMID:39715316
    reference_title: Haploinsufficiency of A20.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Monitor at least annually by a rheumatologist, and more frequently for individuals
      with evidence of systemic inflammation and/or organ involvement.'
    explanation: Gives the monitoring interval and what shortens it.
genetic:
- name: TNFAIP3
  gene_term:
    preferred_term: TNFAIP3
    term:
      id: hgnc:11896
      label: TNFAIP3
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  association: Heterozygous Loss of Function
  notes: >-
    True haploinsufficiency. Nonsense variants, missense variants and whole-gene
    deletions all cause the disease, and a 236 kb deletion removing TNFAIP3
    entirely produces the same phenotype as a point mutation. That argues the
    mechanism is gene dosage rather than a dominant negative or gain-of-function
    protein. Missense alleles require functional demonstration before they can be
    called causal, which is what the NF-kappa-B reporter work in patient cells
    provides.
  evidence:
  - reference: PMID:31164164
    reference_title: "Haploinsufficiency of A20 caused by a novel nonsense variant or entire deletion of TNFAIP3\
      \ is clinically distinct from Behçet's disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'We identified c.1434C>A:p.(Cys478*) in one family and a 236 kb deletion at 6q23.3
      containing TNFAIP3 in another family.'
    explanation: Two very different alleles producing the same disease, which is the argument for
      a dosage mechanism.
  - reference: PMID:34808442
    reference_title: A novel missense mutation in TNFAIP3 causes haploinsufficiency of A20.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Herein, we reported a novel TNFAIP3 (c.1804A > T, p.T602S) variation, which has not
      been reported before.'
    explanation: A missense allele reported in a patient. Regraded from IN_VITRO on review - this
      sentence reports a clinical finding, and the paper is indexed as a case report.
  - reference: PMID:34808442
    reference_title: A novel missense mutation in TNFAIP3 causes haploinsufficiency of A20.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: 'Functional studies were performed in A20(c.1804A > T, p.T602S) patient-derived
      peripheral blood mononuclear cells (PBMCs) and THP-1 cell lines by lentivirus mediating
      stable over-expression of A20 and A20(c.1804A > T, p.T602S) to analyze the activity of NF-κB
      signaling pathway.'
    explanation: The genuinely in-vitro half of the same paper, split into its own item so the
      grading matches the sentence rather than the publication.
inheritance:
- name: Autosomal dominant
  description: >-
    Autosomal dominant, with familial occurrence being one of the features that
    distinguishes this disease from sporadic Behcet disease.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:29916847
    reference_title: Haploinsufficiency of A20 and other paediatric inflammatory disorders with mucosal
      involvement.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Patients may present with dominantly inherited, early-onset systemic inflammation
      and a Behçet-like disease, or a variety of autoinflammatory and autoimmune features.'
    explanation: States dominant inheritance together with the early onset that accompanies it.
  - reference: PMID:39715316
    reference_title: Haploinsufficiency of A20.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Many individuals diagnosed with HA20 have an affected parent; some individuals have
      the disorder as the result of a de novo TNFAIP3 pathogenic variant. Each child of an individual
      with HA20 has a 50% chance of inheriting the TNFAIP3 pathogenic variant.'
    explanation: Gives the transmission risk and records that de novo cases occur, which matters
      because familial occurrence is one of the discriminators against Behcet disease and a de
      novo case will not show it.
diagnosis:
- name: Distinguishing A20 haploinsufficiency from Behcet disease
  presence: PRESENT
  description: >-
    The central diagnostic problem. Patients present with recurrent oral and
    genital ulcers and are diagnosed and treated as Behcet disease; roughly half
    of reported cases had reached that diagnosis. A comparison of 54 patients with
    this disease against 520 Japanese Behcet patients identified the
    discriminating features: early onset, familial occurrence and recurrent fever.
    None of those is a laboratory test, so recognition depends on taking a family
    history and noticing the fever pattern.
  evidence:
  - reference: PMID:31164164
    reference_title: "Haploinsufficiency of A20 caused by a novel nonsense variant or entire deletion of TNFAIP3\
      \ is clinically distinct from Behçet's disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'A comparison of clinical features between HA20 patients and cohorts of BD patients
      revealed several critical features specific to HA20. These were early-onset, familial
      occurrence, recurrent fever attacks, gastrointestinal involvement, and infrequent ocular
      involvement.'
    explanation: The full discriminator list from a direct cohort comparison. Note the last item
      is a negative - ocular involvement is infrequent here, whereas it is characteristic of
      Behcet disease, so its absence is part of what separates them.
  - reference: PMID:31164164
    reference_title: "Haploinsufficiency of A20 caused by a novel nonsense variant or entire deletion of TNFAIP3\
      \ is clinically distinct from Behçet's disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Four HA20 patients in the two families presented with childhood-onset recurrent oral
      and genital ulcers and were initially diagnosed and treated as BD.'
    explanation: A concrete instance of the misdiagnosis this entry is warning about.
- name: Molecular genetic testing of TNFAIP3
  presence: PRESENT
  description: >-
    Diagnosis is molecular. Whole exome sequencing found the causal variants in
    the families described, and copy number analysis matters too, since whole-gene
    deletion is one of the mechanisms and would be missed by sequencing alone.
  evidence:
  - reference: PMID:31164164
    reference_title: "Haploinsufficiency of A20 caused by a novel nonsense variant or entire deletion of TNFAIP3\
      \ is clinically distinct from Behçet's disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Probands of these families were analyzed by whole exome sequencing (WES) and subsequent
      Sanger sequencing.'
    explanation: States the testing approach used to make the diagnosis in these families.
  - reference: PMID:39715316
    reference_title: Haploinsufficiency of A20.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'The diagnosis of HA20 is established in an individual by identification of either
      a heterozygous TNFAIP3 pathogenic variant (~95% of affected individuals) or a heterozygous
      deletion of 6q23 including TNFAIP3 (<5% of affected individuals) by molecular genetic
      testing.'
    explanation: Gives the two diagnostic routes with their relative yields. The under 5% deletion
      share is the practical reason sequence analysis alone is not sufficient - copy number must
      also be assessed.
treatments:
- name: Tumour Necrosis Factor Blockade
  therapeutic_modality: OTHER
  description: >-
    The most effective single class in the largest treatment series. In a Japanese
    national survey, molecular targeted drugs were given to 44.4% of patients and
    anti-TNF agents were effective in 59.5% of those treated. Note what that
    means: roughly forty per cent did not respond, so this is the best available
    option rather than a reliable one, and eleven patients failed to achieve
    control on their initial agent.
  treatment_term:
    preferred_term: biological therapy
    term:
      id: NCIT:C15187
      label: Biological Therapy
    therapeutic_agent:
    - preferred_term: infliximab
      term:
        id: NCIT:C1789
        label: Infliximab
    - preferred_term: adalimumab
      term:
        id: NCIT:C65216
        label: Adalimumab
    - preferred_term: etanercept
      term:
        id: NCIT:C2381
        label: Etanercept
  target_mechanisms:
  - target: Systemic Autoinflammation
    treatment_effect: INHIBITS
    description: Neutralises TNF, one of the proinflammatory cytokines whose expression rises
      when NF-kappa-B is unrestrained.
    evidence:
    - reference: PMID:40574834
      reference_title: 'Clinical characteristics and treatment strategies for A20 haploinsufficiency in Japan:
        a national epidemiological survey.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'Molecular target drugs (MTDs) were administered in 44.4% of patients, among which
        anti-tumor necrosis factor (TNF)-α agents showed efficacy in 59.5% of patients.'
      explanation: Gives both the proportion treated and the response rate, which together define
        how much of the disease this approach actually controls.
  evidence:
  - reference: PMID:40574834
    reference_title: 'Clinical characteristics and treatment strategies for A20 haploinsufficiency in Japan:
      a national epidemiological survey.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Seventy-two HA20 patients were identified in Japan. And, 54 patients from 37 unrelated
      families were analyzed in detail.'
    explanation: Establishes the size of the series behind the treatment figures, which is the
      largest available for this disease.
  - reference: PMID:40574834
    reference_title: 'Clinical characteristics and treatment strategies for A20 haploinsufficiency in Japan:
      a national epidemiological survey.'
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: 'The severity of A20 haploinsufficiency (HA20) varies, with no established clinical
      guidelines for treatment.'
    explanation: Recorded against any reading of the efficacy figure as a standard of care. The
      same survey states there are no established treatment guidelines.
  - reference: PMID:39715316
    reference_title: Haploinsufficiency of A20.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Supportive treatment: TNF inhibitors, the most used medications, directly target
      abnormal NF-κB signaling.'
    explanation: Names TNF inhibitors as the most used agents and states the mechanistic rationale
      - they act on the pathway this disease de-represses.
- name: Interleukin-1 Blockade
  therapeutic_modality: PROTEIN_REPLACEMENT
  description: >-
    A second-line option for patients not controlled by TNF blockade, which is a
    substantial group given the roughly forty per cent non-response rate.
    Anakinra is a recombinant IL-1 receptor antagonist; canakinumab and rilonacept
    are biologics against IL-1 beta. Described as effective in many individuals,
    which is not a rate.
  treatment_term:
    preferred_term: biological therapy
    term:
      id: NCIT:C15187
      label: Biological Therapy
    therapeutic_agent:
    - preferred_term: anakinra
      term:
        id: NCIT:C38717
        label: Anakinra
    - preferred_term: canakinumab
      term:
        id: NCIT:C80971
        label: Canakinumab
  target_mechanisms:
  - target: Systemic Autoinflammation
    treatment_effect: INHIBITS
    description: Neutralises IL-1 signalling, one cytokine output of the derepressed pathway.
    evidence:
    - reference: PMID:39715316
      reference_title: Haploinsufficiency of A20.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'In addition, IL-1 targeted therapy and JAK inhibitors are effective in many
        individuals.'
      explanation: States effectiveness for IL-1 targeted therapy. Note "many individuals" is not
        a rate, so this supports availability of the option rather than a quantified expectation.
  evidence:
  - reference: PMID:39715316
    reference_title: Haploinsufficiency of A20.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'The IL-1 receptor antagonist anakinra is considered relatively safe during pregnancy
      due to its extremely short half-life, although data are limited.'
    explanation: Names anakinra as an IL-1 receptor antagonist, which is the basis for the
      PROTEIN_REPLACEMENT modality on this entry rather than SMALL_MOLECULE, and records its
      pregnancy safety profile with the authors' own caveat.
- name: JAK Inhibition
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    The other second-line option, and a small-molecule class unlike IL-1 blockade.
    Contraindicated in pregnancy, which matters in a disease presenting in
    childhood and continuing through reproductive life.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: Systemic Autoinflammation
    treatment_effect: INHIBITS
    description: Acts downstream of the cytokine and interferon receptors engaged by the
      derepressed pathway.
    evidence:
    - reference: PMID:39715316
      reference_title: Haploinsufficiency of A20.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'In addition, IL-1 targeted therapy and JAK inhibitors are effective in many
        individuals.'
      explanation: States effectiveness for JAK inhibitors, with the same caveat that "many
        individuals" is not a quantified rate.
  evidence:
  - reference: PMID:39715316
    reference_title: Haploinsufficiency of A20.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'JAK inhibitors are contraindicated during pregnancy.'
    explanation: A hard contraindication, recorded because it constrains use in exactly the
      population this disease affects.
- name: Haematopoietic Stem Cell Transplantation
  therapeutic_modality: CELL_THERAPY
  description: >-
    Reserved for severe or refractory disease. It is the only listed option that
    addresses the mutant haematopoietic compartment itself rather than a cytokine
    downstream of it, and it is stated as something that may be considered rather
    than as established therapy.
  treatment_term:
    preferred_term: allogeneic stem cell transplantation
    term:
      id: NCIT:C201466
      label: Allogeneic Stem Cell Transplantation
  evidence:
  - reference: PMID:39715316
    reference_title: Haploinsufficiency of A20.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'In some instances of severe or refractory disease, hematopoietic stem cell
      transplantation may be considered.'
    explanation: States the indication and, in its own hedged phrasing, the strength of the
      recommendation.
references:
- reference: PMID:24242761
  title: "A20-mediated negative regulation of canonical NF-\u03baB signaling pathway."
- reference: PMID:25043000
  title: "Negative regulation of the NLRP3 inflammasome by A20 protects against arthritis."
- reference: PMID:26642243
  title: "Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early-onset autoinflammatory disease."
- reference: PMID:29916847
  title: "Haploinsufficiency of A20 and other paediatric inflammatory disorders with mucosal involvement."
- reference: PMID:31164164
  title: "Haploinsufficiency of A20 caused by a novel nonsense variant or entire deletion of TNFAIP3 is clinically distinct from Beh\u00e7et's disease."
- reference: PMID:34011076
  title: "Mutation analysis of the TNFAIP3 in A20 haploinsufficiency: A case report."
- reference: PMID:34808442
  title: "A novel missense mutation in TNFAIP3 causes haploinsufficiency of A20."
- reference: PMID:38451381
  title: "The Complexity of Being A20: From Biological Functions to Genetic Associations."
- reference: PMID:39715316
  title: "Haploinsufficiency of A20."
  tags:
  - GeneReviews
- reference: PMID:40574834
  title: "Clinical characteristics and treatment strategies for A20 haploinsufficiency in Japan: a national epidemiological survey."
animal_models:
- name: A20 myeloid-specific knockout mouse
  species: Mouse
  genotype: Tnfaip3 fl/fl LysM-Cre (A20 myel-KO)
  publication: PMID:25043000
  description: >-
    A conditional knockout deleting A20 in the myeloid lineage. It is the source
    of the inflammasome arm modelled in this entry, and it is a poor genetic match
    for the human disease, which is why that arm is graded HYPOTHETICAL.
  evidence:
  - reference: PMID:25043000
    reference_title: Negative regulation of the NLRP3 inflammasome by A20 protects against arthritis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: 'Myeloid-cell-specific deletion of the rheumatoid arthritis susceptibility gene
      A20/Tnfaip3 in mice (A20(myel-KO) mice) triggers a spontaneous erosive polyarthritis that
      resembles rheumatoid arthritis in patients.'
    explanation: Establishes the model and the phenotype it produces.
  modeled_mechanisms:
  - target: Inflammasome Derepression
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: >-
      Demonstrates that losing A20 derepresses the NLRP3 inflammasome and produces
      spontaneous arthritis that does not require TNF receptor 1, which is the
      evidence for a second arm beyond NF-kappa-B.
    limitations: >-
      Three mismatches against the human disease, and they run in the same
      direction. The mouse is a complete knockout, not haploinsufficiency. It is
      restricted to the myeloid lineage rather than germline. And the arthritis it
      produces is erosive, whereas the arthritis in this disease is typically
      nonerosive. The model therefore supports the existence of the pathway rather
      than its operation in patients.
    evidence:
    - reference: PMID:25043000
      reference_title: Negative regulation of the NLRP3 inflammasome by A20 protects against arthritis.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: 'Rheumatoid arthritis in A20(myel-KO) mice is not rescued by deletion of tumour
        necrosis factor receptor 1 (ref. 2).'
      explanation: The TNF receptor 1 independence is what argues for a second pathway rather
        than a purely TNF-driven one.
classifications:
  iuis_category:
    classification_value: autoinflammatory syndrome
    notes: >-
      Recorded because the disease is now classified as a complex inborn error of
      immunity rather than as a Behcet subtype, which is the reclassification this
      entry turns on. Assigned to the autoinflammatory syndrome category because
      that is the dominant presentation, though the phenotype also spans autoimmune
      features and the IUIS scheme does not let both be recorded here.
    evidence:
    - reference: PMID:38451381
      reference_title: 'The Complexity of Being A20: From Biological Functions to Genetic Associations.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'Originally described as an autosomal dominant form of Behcet''s disease, HA20 is
        now considered a complex inborn error of immunity with a broad spectrum of immunologic
        and clinical phenotypes.'
      explanation: States the classification as an inborn error of immunity directly.
disease_term:
  preferred_term: A20 haploinsufficiency
  term:
    id: MONDO:0100222
    label: A20 haploinsufficiency
notes: >-
  Why this entry is largely about a differential diagnosis. Roughly half of all
  reported cases had been diagnosed as Behcet disease before the genetic cause was
  found, and patients are treated as Behcet for years. The disease is separable,
  but only on features a clinician has to be looking for. A direct comparison of
  54 patients against 520 Behcet patients identified early onset, familial
  occurrence and recurrent fever as the discriminators. None of them is a
  laboratory finding. The diagnosis section is therefore written around that
  comparison rather than around a test.

  Loss of a brake, not gain of a signal. A20 terminates canonical NF-kappa-B
  signalling, so halving it removes negative regulation rather than adding drive.
  That is the most likely explanation for the phenotype's breadth: patients show
  autoinflammatory and autoimmune features together, across mucosa, skin, gut,
  joints, eye and liver, which is unusual for a monogenic disease and is what one
  would expect from de-restraining a pathway used by many stimuli rather than
  from a defect in one effector.

  Evidence for haploinsufficiency specifically, from two directions. The
  observational argument is that a nonsense variant and a 236 kb deletion removing
  the whole gene produce the same disease, and a deletion cannot act as a dominant
  negative. The experimental argument is stronger and comes from the original
  2016 description: truncated A20 proteins were tested for a dominant-negative
  effect in overexpression and did not show one. The disease is therefore about
  gene dosage, and both arguments are recorded rather than only the allele list.

  A correction to the draft. The first version of this entry did not cite the
  paper that described the disease. The 2016 report in six unrelated families is
  the source for the dominant-negative exclusion experiment, for the molecular
  detail that A20 acts through its deubiquitinase activity, and for the
  measurements in patient cells showing increased IkappaB-alpha degradation, p65
  nuclear translocation and cytokine output. All of that was reachable from the
  searches run, and its absence was a gap in my reading rather than in the
  literature. The deep-research job surfaced it.

  The inflammasome arm is graded HYPOTHETICAL and should stay that way until
  human evidence exists. A20 negatively regulates the NLRP3 inflammasome, and
  myeloid-specific A20 deletion in mice causes an erosive arthritis that persists
  without TNF receptor 1, which argues for a second pathway. But that is a
  complete knockout restricted to one lineage, not heterozygous loss in a whole
  organism, and the human arthritis in this disease is usually nonerosive. The
  mismatch is stated in the evidence explanation rather than left for a reader to
  notice.

  Frequency bands and how they were assigned. All five frequency values come from
  a single quoted sentence, reproduced in full under epidemiology so it can be
  checked directly. Where a reported percentage covers a category rather than the
  specific phenotype - skin involvement at 40% rather than pustular rash at 40% -
  the phenotype is banded one level lower and the reason is stated in its evidence
  explanation.

  On the treatment figure. Anti-TNF is the best available option and is not a
  reliable one. In the largest series, molecular targeted drugs were used in 44.4%
  of patients and anti-TNF was effective in 59.5% of those, so roughly forty per
  cent of treated patients did not respond and eleven failed their initial agent.
  The same survey states there are no established treatment guidelines, and that
  statement is carried as REFUTE evidence against reading the efficacy figure as a
  standard of care.

  A correction, review round 1. This section previously stated that IL-1, IL-6 and
  JAK-directed therapy and haematopoietic cell transplantation had no quotable
  outcome data in the cached references. That was false, and the contradicting
  sentences were in a file added by the same commit. The GeneReviews chapter
  states that IL-1 targeted therapy and JAK inhibitors are effective in many
  individuals and that transplantation may be considered in severe or refractory
  disease. Both are now modelled as treatments. The cause was that the chapter was
  mined only for its Clinical Characteristics section; its Diagnosis, Management
  and Genetic Counseling sections were not read, and they supplied the diagnostic
  yield split, the treatment options and the transmission risk that this entry now
  carries. Recorded rather than silently corrected, because prose describing what
  the repository contains is a factual claim and this one was wrong.

  Known extension points: uveitis and other ocular involvement; hepatic
  involvement including severe hepatitis progressing to cirrhosis; central nervous
  system vasculitis and the other neurologic manifestations; lymphoproliferation;
  the type I interferon signature described as a biomarker of disease activity;
  and the reported subset meeting criteria for systemic lupus erythematosus, which
  would make this a monogenic lupus as well as an autoinflammatory disease.

  Provenance. Curated from PubMed with a five-iteration OpenScientist
  deep-research job as a cross-check. Three of the ten cached references are full
  text rather than abstracts, and content_type was checked before writing.

📚

References & Deep Research

References

10

PMID:24242761

A20-mediated negative regulation of canonical NF-κB signaling pathway.

No top-level findings curated for this source.

PMID:25043000

Negative regulation of the NLRP3 inflammasome by A20 protects against arthritis.

No top-level findings curated for this source.

PMID:26642243

Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early-onset autoinflammatory disease.

No top-level findings curated for this source.

PMID:29916847

Haploinsufficiency of A20 and other paediatric inflammatory disorders with mucosal involvement.

No top-level findings curated for this source.

PMID:31164164

Haploinsufficiency of A20 caused by a novel nonsense variant or entire deletion of TNFAIP3 is clinically distinct from Behçet's disease.

No top-level findings curated for this source.

PMID:34011076

Mutation analysis of the TNFAIP3 in A20 haploinsufficiency: A case report.

No top-level findings curated for this source.

PMID:34808442

A novel missense mutation in TNFAIP3 causes haploinsufficiency of A20.

No top-level findings curated for this source.

PMID:38451381

The Complexity of Being A20: From Biological Functions to Genetic Associations.

No top-level findings curated for this source.

PMID:39715316

Haploinsufficiency of A20.

No top-level findings curated for this source.

PMID:40574834

Clinical characteristics and treatment strategies for A20 haploinsufficiency in Japan: a national epidemiological survey.

No top-level findings curated for this source.

Deep Research

1

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

Evaluations and curation notes (3)

Record notes

Why this entry is largely about a differential diagnosis. Roughly half of all reported cases had been diagnosed as Behcet disease before the genetic cause was found, and patients are treated as Behcet for years. The disease is separable, but only on features a clinician has to be looking for. A direct comparison of 54 patients against 520 Behcet patients identified early onset, familial occurrence and recurrent fever as the discriminators. None of them is a laboratory finding. The diagnosis section is therefore written around that comparison rather than around a test. Loss of a brake, not gain of a signal. A20 terminates canonical NF-kappa-B signalling, so halving it removes negative regulation rather than adding drive. That is the most likely explanation for the phenotype's breadth: patients show autoinflammatory and autoimmune features together, across mucosa, skin, gut, joints, eye and liver, which is unusual for a monogenic disease and is what one would expect from de-restraining a pathway used by many stimuli rather than from a defect in one effector. Evidence for haploinsufficiency specifically, from two directions. The observational argument is that a nonsense variant and a 236 kb deletion removing the whole gene produce the same disease, and a deletion cannot act as a dominant negative. The experimental argument is stronger and comes from the original 2016 description: truncated A20 proteins were tested for a dominant-negative effect in overexpression and did not show one. The disease is therefore about gene dosage, and both arguments are recorded rather than only the allele list. A correction to the draft. The first version of this entry did not cite the paper that described the disease. The 2016 report in six unrelated families is the source for the dominant-negative exclusion experiment, for the molecular detail that A20 acts through its deubiquitinase activity, and for the measurements in patient cells showing increased IkappaB-alpha degradation, p65 nuclear translocation and cytokine output. All of that was reachable from the searches run, and its absence was a gap in my reading rather than in the literature. The deep-research job surfaced it. The inflammasome arm is graded HYPOTHETICAL and should stay that way until human evidence exists. A20 negatively regulates the NLRP3 inflammasome, and myeloid-specific A20 deletion in mice causes an erosive arthritis that persists without TNF receptor 1, which argues for a second pathway. But that is a complete knockout restricted to one lineage, not heterozygous loss in a whole organism, and the human arthritis in this disease is usually nonerosive. The mismatch is stated in the evidence explanation rather than left for a reader to notice. Frequency bands and how they were assigned. All five frequency values come from a single quoted sentence, reproduced in full under epidemiology so it can be checked directly. Where a reported percentage covers a category rather than the specific phenotype - skin involvement at 40% rather than pustular rash at 40% - the phenotype is banded one level lower and the reason is stated in its evidence explanation. On the treatment figure. Anti-TNF is the best available option and is not a reliable one. In the largest series, molecular targeted drugs were used in 44.4% of patients and anti-TNF was effective in 59.5% of those, so roughly forty per cent of treated patients did not respond and eleven failed their initial agent. The same survey states there are no established treatment guidelines, and that statement is carried as REFUTE evidence against reading the efficacy figure as a standard of care. A correction, review round 1. This section previously stated that IL-1, IL-6 and JAK-directed therapy and haematopoietic cell transplantation had no quotable outcome data in the cached references. That was false, and the contradicting sentences were in a file added by the same commit. The GeneReviews chapter states that IL-1 targeted therapy and JAK inhibitors are effective in many individuals and that transplantation may be considered in severe or refractory disease. Both are now modelled as treatments. The cause was that the chapter was mined only for its Clinical Characteristics section; its Diagnosis, Management and Genetic Counseling sections were not read, and they supplied the diagnostic yield split, the treatment options and the transmission risk that this entry now carries. Recorded rather than silently corrected, because prose describing what the repository contains is a factual claim and this one was wrong. Known extension points: uveitis and other ocular involvement; hepatic involvement including severe hepatitis progressing to cirrhosis; central nervous system vasculitis and the other neurologic manifestations; lymphoproliferation; the type I interferon signature described as a biomarker of disease activity; and the reported subset meeting criteria for systemic lupus erythematosus, which would make this a monogenic lupus as well as an autoinflammatory disease. Provenance. Curated from PubMed with a five-iteration OpenScientist deep-research job as a cross-check. Three of the ten cached references are full text rather than abstracts, and content_type was checked before writing.

Review round 1: mine the three unread GeneReviews sections, correct a false notes claim, tag, narrow GO terms, fix evidence grading, add onset · 2026-09-09T15:13:17Z · View source

Response to review round 1 on PR #11525. All six items, none of which required fetching anything new. The sharpest finding is that a claim in notes was false, and the file contradicting it was added by the same commit. The section stated that IL-1, IL-6 and JAK-directed therapy and haematopoietic cell transplantation had no quotable outcome data in the cached references. The GeneReviews chapter says verbatim that IL-1 targeted therapy and JAK inhibitors are effective in many individuals and that transplantation may be considered in severe or refractory disease. Both are now modelled as treatments. The root cause is more useful than the individual error. The GeneReviews chapter has four sections and I mined one of them. Clinical Characteristics was read thoroughly, and every frequency band in the entry came from it. Diagnosis, Management and Genetic Counseling were not read at all, and between them they supplied the diagnostic yield split of roughly 95 percent sequence variants against under 5 percent 6q23 deletions, the treatment options above, and the 50 percent transmission risk with de novo occurrence. The de novo point matters specifically because familial occurrence is one of this entry's discriminators against Behcet disease and a de novo case will not show it. This is the fourth instance in this series of asserting that something was unavailable when it was present in a committed cache file. The previous three concerned full-text papers mined only at abstract level. This one is different in kind and worth distinguishing: the file was an abstract-only cache, but the abstract itself is sectioned, and I stopped at the first section. Checking content_type does not catch this. The check that would is reading a structured abstract to its end. Other items. The GeneReviews reference now carries tags GeneReviews, matching the convention used by other entries. Two GO bindings were narrowed from regulation to negative regulation, since the claim is specifically that a negative regulator is lost. An evidence item quoting a case-report sentence was regraded from IN_VITRO to HUMAN_CLINICAL, and the genuinely in-vitro sentence from the same paper was split into its own item so the grading matches the sentence rather than the publication. Structured onset was added to the two phenotypes that carry the Behcet discrimination argument, since early onset is the entry's central discriminator and had appeared only in prose. The reviewer also confirmed independently that the deep-research report's NCIT identifiers are wrong, with NCIT:C2707 resolving to DHEA Mustard rather than an IL-1 antagonist and NCIT:C142883 not resolving at all. None were used here, because identifiers in this entry are resolved against the local ontology databases rather than copied from the report. Validation: 45/45 snippets verified, term validation passes, qualifier terms pass, weighted compliance 100.0 percent, no mid-word truncations, no value/prose contradictions, one root, no orphan phenotypes, no dangling targets.

Create: A20 Haploinsufficiency MONDO:0100222 · 2026-09-09T13:32:56Z · View source

Created from PubMed literature with a five-iteration OpenScientist deep-research job as a cross-check, launched before writing so it ran in parallel. The entry is organised around a differential diagnosis rather than a mechanism, because that is where the clinical harm is. Roughly half of all reported cases had been diagnosed and treated as Behcet disease before the genetic cause was found. A direct comparison of 54 patients against 520 Japanese Behcet patients gives the discriminators: early onset, familial occurrence, recurrent fever attacks, gastrointestinal involvement, and infrequent ocular involvement. The last is a negative discriminator, since ocular involvement is characteristic of Behcet disease, and its absence is part of what separates them. None of these is a laboratory finding, so the diagnosis section is written around that comparison rather than around a test. The mechanism is loss of a brake rather than gain of a signal. A20 terminates canonical NF-kappa-B signalling through its deubiquitinase activity, so halving it de-restrains a pathway that many stimuli use. That is the most plausible account of the phenotype's unusual breadth for a monogenic disease, spanning mucosa, skin, gut, joints and liver with autoinflammatory and autoimmune features in the same patient. Haploinsufficiency is supported from two directions and both are now recorded. The observational argument is that a nonsense variant and a 236 kb whole-gene deletion produce the same disease, and a deletion cannot act as a dominant negative. The experimental argument is stronger: the 2016 description tested truncated A20 proteins for a dominant-negative effect in overexpression and did not find one. A gap in the draft, corrected before submission and recorded in notes. The first version did not cite the paper that described the disease. The 2016 report in six unrelated families is the source for the dominant-negative exclusion experiment, for the identification of deubiquitinase activity as the operative function, and for the measurements in patient cells showing increased IkappaB-alpha degradation, p65 nuclear translocation and raised cytokine expression. It was reachable from the searches I ran, so its absence was a gap in my reading rather than in the literature. The deep-research job surfaced it. The inflammasome arm is graded HYPOTHETICAL and should stay that way. It rests on a myeloid-specific complete knockout in mice producing an erosive arthritis independent of TNF receptor 1, which is a different genetic situation from heterozygous loss in humans, and the human arthritis in this disease is usually nonerosive. That mismatch is stated in the evidence explanation rather than left to be noticed. Treatment is recorded with its limits. Anti-TNF is the most effective single class at 59.5 percent efficacy among the 44.4 percent of patients given molecular targeted drugs, which means roughly forty percent of treated patients did not respond and eleven failed their initial agent. The same national survey states there are no established treatment guidelines, and that statement is carried as REFUTE evidence against reading the efficacy figure as a standard of care. Two checks were improved during this entry. The value-versus-prose check produced a false positive on the phrase "checked against it directly", the second such false positive from the word "against" used non-argumentatively; the prose was reworded, and a check that cries wolf is one people stop reading. More substantially, the truncation check was rewritten. The old version flagged any snippet not ending in terminal punctuation, which over-triggers on legitimate quotes of numbered sub-clauses from enumerated lists - eight false positives in this entry alone. The new version locates the snippet in the cached source and flags it only when the following character is a letter, which is an actual mid-word cut. It was verified against a synthetic case, firing on the truncated form and passing the complete one, and it found three genuine truncations here that the old heuristic had buried among the false positives. Validation: 38/38 snippets verified, term validation passes, qualifier terms pass, weighted compliance 100.0 percent, no mid-word truncations, no value/prose contradictions, one root, no orphan phenotypes, no dangling targets. Content_type was checked on all caches before writing.

OpenScientist ▸

Key Findings

openscientist-autonomous 26 citations 2026-09-09T09:25:51.877833

Key Findings

F001 — HA20 is an autosomal-dominant autoinflammatory disease caused by heterozygous LOF TNFAIP3 variants

The disease was originally described by Zhou et al. (2016) as arising from "high-penetrance heterozygous germline mutations in TNFAIP3, which encodes the NF-κB regulatory protein A20, in six unrelated families with early-onset systemic inflammation" (PMID: 26642243). The mechanism is haploinsufficiency rather than dominant-negative action: "Mutant, truncated A20 proteins are likely to act through haploinsufficiency because they do not exert a dominant-negative effect in overexpression experiments." A 2024 review reframes the condition beyond its Behçet-like origins: "Originally described as an autosomal dominant form of Behcet's disease, HA20 is now considered a complex inborn error of immunity with a broad spectrum of immunologic and clinical phenotypes" (PMID: 38451381). Evidence type: human clinical / genetic.

F002 — Mechanism: loss of A20 ubiquitin-editing activity drives NF-κB and NLRP3 inflammasome hyperactivation

A20 is a ubiquitin-editing enzyme that terminates NF-κB signaling. In patient cells, Zhou et al. showed "defective removal of Lys63-linked ubiquitin from TRAF6, NEMO and RIP1 after stimulation with tumor necrosis factor (TNF)," accompanied by increased IκBα degradation, nuclear translocation of NF-κB p65, and elevated NF-κB-dependent cytokines (PMID: 26642243). Steiner et al. (2018) confirmed that HA20 patients "display excessive ubiquitination and increased activity of NF-κB and of NLRP3 inflammasome activation" (PMID: 29846841). A parallel necroptosis branch operates through the zinc-finger 7 (ZnF7) ubiquitin-binding domain: "A20 prevents inflammasome-dependent arthritis by inhibiting macrophage necroptosis and that this function depends on its zinc finger 7 (ZnF7)" (PMID: 31086261) — notably, this anti-inflammatory function does not require A20's deubiquitinase catalytic activity. Evidence type: human clinical + model organism + in vitro.

F003 — Clinical spectrum: mucocutaneous ulcers dominate, with fever, GI inflammation, cytopenia, arthritis, and autoimmunity

The largest international multicenter cohort (He et al. 2026; n=185, 41 clinics, 7 countries; median age at onset 3.3 yr) reports: "Common clinical features were mucocutaneous involvement (80.5%), recurrent fever (63.3%), gastrointestinal symptoms (58.6%), cytopenia (56.6%), arthritis/arthralgia (46.7%), and recurrent infections (35.5%)" (PMID: 41692116). Hierarchical clustering "identified two major clusters, an autoinflammation-predominant phenotype and an autoimmune-predominant phenotype." An independent Italian series (De Nardi et al. 2026; n=17) found "oral aphthosis (88%), recurrent fever (53%), gastrointestinal inflammation (53%), autoimmunity (47%), genital ulcers (47%), neuropsychiatric symptoms (41%)," with early onset (<5 yr) associated with more lifetime neuropsychiatric involvement (p=0.004) (PMID: 42128528). Evidence type: human clinical.

Phenotype	He 2026 (n=185)	De Nardi 2026 (n=17)	Berteau 2018 (n=45)	Suggested HPO term
Oral/mucocutaneous ulcers	80.5%	88%	87% (oral)	HP:0000155 (Oral ulcer)
Genital ulcers	—	47%	67%	HP:0100728 (Genital ulcers)
Recurrent fever	63.3%	53%	62%	HP:0001954 (Recurrent fever)
GI inflammation	58.6%	53%	60% (abdominal)	HP:0002037 (Inflammation of the large intestine)
Cytopenia	56.6%	—	—	HP:0001875 (Neutropenia) / HP:0001873 (Thrombocytopenia)
Arthritis/arthralgia	46.7%	18%	42%	HP:0001369 (Arthritis)
Skin inflammation	—	12%	53%	HP:0000988 (Skin rash)
Neuropsychiatric	—	41%	—	HP:0000708 (Behavioral abnormality)
Recurrent infections	35.5%	—	—	HP:0002719 (Recurrent infections)

F004 — Treatment: HA20 is biologic-responsive; anti-TNF most effective, with IL-1/IL-6 blockade, JAK inhibitors, and HCT for refractory disease

A Japanese national survey (Shiraki 2025; 72 patients, 54 analyzed) found "Molecular target drugs (MTDs) were administered in 44.4% of patients, among which anti-tumor necrosis factor (TNF)-α agents showed efficacy in 59.5% of patients" (PMID: 40574834). Secondary failure (anti-drug antibodies, infusion reactions) was common, managed by switching agents, adding a JAK inhibitor/immunomodulator, or allogeneic HCT. A 2026 review confirms that HA20 and related monogenic conditions "are now recognized as biologic-responsive diseases" (PMID: 41620931). For refractory monogenic IBD phenotypes, "Monogenic IBDs include those that are refractory to traditional treatment and can be cured by allogeneic hematopoietic cell transplantation (HCT)" (PMID: 37899202), and HCT has been shown to ameliorate autoinflammation in HA20 (PMID: 34427832). Evidence type: human clinical.

Therapy	NCIT suggestion	Role in HA20	Key evidence
Anti-TNF (infliximab, adalimumab, etanercept)	NCIT:C2861 (TNF Inhibitor)	First-line targeted; ~60% efficacy	PMID: 40574834
IL-1 blockade (anakinra, canakinumab)	NCIT:C2707 (Interleukin-1 Antagonist)	Autoinflammation/inflammasome-driven disease	PMID: 41620931
IL-6 inhibition (tocilizumab)	NCIT:C165258 (IL-6 Inhibitor)	Refractory/systemic inflammation	PMID: 41620931
JAK inhibitors (baricitinib, tofacitinib, ruxolitinib)	NCIT:C142883 (JAK Inhibitor)	IFN-high/refractory disease	PMID: 31767699
Colchicine	NCIT:C819 (Colchicine)	Inconstant response (~24%)	PMID: 29890348
Allogeneic HCT	NCIT:C15431 (Allogeneic HSCT)	Curative for refractory disease	PMID: 34427832; PMID: 37899202

F005 — Diagnostic biomarkers: elevated type I IFN signature and IFN-γ-inducible chemokines mark disease activity and predict JAK-inhibitor response

De Nardi et al. found higher type 1 IFN signature (IS) levels in patients with active disease (p<0.01) and concluded "type 1 IS may represent a potential biomarker of disease activity in HA20," alongside evaluation of IFN-γ-inducible chemokines CXCL9/CXCL10 (PMID: 42128528). Schwartz et al. established that the "Type I interferon signature predicts response to JAK inhibition in haploinsufficiency of A20" (PMID: 31767699). Importantly, the signature can be elevated even in quiescent disease: "Half of the patients examined in this study, with undifferentiated inflammatory diseases, clinically quiescent A20 haploinsufficiency, or idiopathic pulmonary hemosiderosis, had an elevated type I IFN signature" (PMID: 36211342). Evidence type: human clinical.

F006 — Genetics: germline heterozygous LOF variants (truncating dominant, plus OTU/ZnF missense); phenotype spans autoinflammation to monogenic lupus

The international cohort revealed a "novel genetic architecture and phenotypic evolution" across 185 patients with pathogenic/likely-pathogenic TNFAIP3 variants (PMID: 41692116). Variant classes include truncating (nonsense, frameshift) variants causing haploinsufficiency, plus pathogenic missense variants in the catalytic OTU deubiquitinase domain — e.g., "a heterozygous c.608T>G (p.Leu203Arg) missense variant in TNFAIP3, located within the OTU domain" (PMID: 40719110) and c.1804A>T p.T602S causing over-activation of canonical NF-κB signaling (PMID: 34808442). A systematic review documented the lupus overlap: "Among all the 191 HA20 patients reported in the literature, we identified 16 patients (8.4%) with a compatible diagnosis of SLE," with frequent ANA/anti-dsDNA, renal (56.3%), cutaneous (81.3%), and musculoskeletal (56.3%) involvement (PMID: 39672252). Evidence type: human clinical / genetic + in vitro.

F007 — Organ involvement and gut dysbiosis: IBD-like GI inflammation, chronic liver disease, and altered gut microbiota

Elhani et al. (2026; 16 HA20 patients vs 22 controls) documented multi-organ pathology and microbiome changes: "The fecal microbiota of HA20 patients was characterized by marked alterations, including a reduction in microbial diversity and an increase in the pro-inflammatory bacterium Ruminococcus gnavus" (PMID: 41991504). The same study found that "Liver imaging revealed chronic liver disease in 3/5 patients, showing as liver dysmorphia and portal hypertension," with histology showing lymphoplasmocytic infiltrate of the GI tract and liver, impaired microbial bile-acid deconjugation/desulfation, and a shift of tryptophan metabolism toward the kynurenine pathway. Evidence type: human clinical + microbiome/metabolomic.

F008 — Model organisms: A20/Tnfaip3 mouse models recapitulate HA20

Cell-specific and domain-mutant mouse models reproduce major HA20 features. Myeloid-specific deletion produces arthritis: "Myeloid-cell-specific deletion of the rheumatoid arthritis susceptibility gene A20/Tnfaip3 in mice (A20(myel-KO) mice) triggers a spontaneous erosive polyarthritis that resembles rheumatoid arthritis in patients," and this "crucially relies on the Nlrp3 inflammasome and interleukin-1 receptor signalling" (PMID: 25043000). Intestinal models reproduce the IBD phenotype: "Combining IEC and myeloid A20 deletion induces ileitis and severe colitis" (PMID: 25267258). The ZnF7 ubiquitin-binding mutation alone causes arthritis (PMID: 31086261); additional cell-specific effects appear in airway club cells (PMID: 26815999), pancreatic β-cells, and enthesitis via STAT1 (PMID: 27551052). Evidence type: model organism.

F009 — Epidemiology & temporal course: rare, ubiquitous, female-predominant, early-childhood onset, chronic relapsing course

Berteau et al. (2018; systematic review of 45 cases) established key epidemiology: "sex ratio is inversed (one man for two women), first symptoms occur in early childhood (median age = 5.5 years; interquartile range: 1-10) instead of adulthood" (PMID: 29890348). HA20 "differs from classical BD because its geographical distribution is ubiquitous," and "response to colchicine in HA20 is inconstant (24%) unlike classical BD." The international cohort reports an even earlier median onset (3.3 yr) (PMID: 41692116). Evidence type: human clinical / epidemiological.

F010 — Prognosis & complications: chronic lifelong disease with autoimmune, vascular, and lymphoproliferative complications

HA20 predisposes to lymphoproliferation: "A20 haploinsufficiency disturbs immune homeostasis and drives the transformation of lymphocytes with permissive antigen receptors" (PMID: 39167656). Vasculitis is a recognized complication in which "type I interferon-enhanced autoimmune mechanisms and/or dysregulated adaptive immune responses have an important role in the development of immune-mediated endothelial dysfunction and vascular damage" (PMID: 40369133). Systemic autoimmunity complications include autoimmune cytopenias, thyroiditis, and lupus/glomerulonephritis (renal 56.3% in the SLE subset; PMID: 39672252). No formal survival/mortality statistics are established; most patients survive with chronic morbidity, though severe refractory disease, macrophage activation syndrome/HLH, and HCT-related risks contribute to mortality in a minority. Evidence type: human clinical.

F011 — HA20 is distinct from classic Behçet disease and from somatic TNFAIP3-driven lymphoma

HA20 differs from classical Behçet disease on multiple axes: "HA20 differs from classical BD because its geographical distribution is ubiquitous, sex ratio is inversed (one man for two women), first symptoms occur in early childhood" (PMID: 29890348); HLA-B51 is uncommon and colchicine response inconstant. Germline vs somatic TNFAIP3 lesions produce distinct diseases: "A20 germline variants are associated with a wide range of inflammatory diseases, while somatic mutations promote development of B cell lymphomas" (PMID: 38451381). Evidence type: human clinical / genetic.

Section-by-Section Disease Characterization

1. Disease Information

HA20 is a monogenic, autosomal-dominant systemic autoinflammatory disease (an inborn error of immunity) caused by haploinsufficiency of the ubiquitin-editing enzyme A20. It presents with early-onset, recurrent, Behçet-like inflammation and a broad autoinflammatory–autoimmune phenotypic spectrum.

Identifiers: MONDO:0100222; OMIM #616744 ("Autoinflammatory syndrome, familial, Behçet-like 1", AISBL1); Gene TNFAIP3 (OMIM *191163; HGNC:11896). Orphanet lists it under autoinflammatory syndromes. MeSH is best approximated by "Hereditary Autoinflammatory Diseases" (D056660). ICD-11 maps under immune dysregulation/autoinflammatory disorders (4A60 group).
Synonyms: Haploinsufficiency of A20; A20 haploinsufficiency; TNFAIP3 haploinsufficiency; Familial Behçet-like autoinflammatory syndrome 1 (AISBL1); autosomal-dominant familial Behçet disease.
Data source: Disease-level aggregated resources (OMIM, Orphanet) plus published patient cohorts and case series — not single-EHR-derived.

2. Etiology

Causal factor: Heterozygous germline LOF variants in TNFAIP3 (genetic; high penetrance) — F001, F006.
Genetic risk factors: The pathogenic variant itself is causal and dominant. Modifier genes and co-occurring autoinflammatory VUS may shape phenotype (mixed autoinflammatory disorders; PMID: 41191928).
Environmental risk factors: Not clearly established as disease-causing; however, infection/inflammatory triggers (TNF, LPS, IL-1β) provoke flares by engaging the very pathways A20 fails to restrain (F002). Gut dysbiosis (increased R. gnavus) is associated with the intestinal phenotype (F007) and may act as a gene–environment interface. Female sex is associated with higher prevalence (F009).
Protective factors: No validated genetic or environmental protective alleles reported for HA20 specifically. (Data not available.)
Gene–environment interaction: Loss of A20 lowers the threshold for NF-κB/inflammasome activation by microbial and cytokine stimuli, so environmental triggers (microbiota, infection) interact with the genetic lesion to precipitate flares (inferred from F002, F007, F008).

3. Phenotypes

See the frequency table under F003. Phenotype types span clinical signs (mucocutaneous ulcers, arthritis), symptoms (fever, abdominal pain), laboratory abnormalities (cytopenias, autoantibodies, elevated inflammatory markers/IFN signature), and behavioral/neuropsychiatric changes. Onset is typically pediatric (median 3.3–5.5 yr). Severity is variable, ranging from mild recurrent aphthosis to severe multi-organ disease and monogenic lupus. Progression is chronic-relapsing/episodic with lifelong activity. Quality-of-life impact is substantial through recurrent painful ulcers, chronic GI disease, arthritis, and treatment burden, though formal EQ-5D/SF-36 data specific to HA20 are not available.

4. Genetic / Molecular Information

Causal gene: TNFAIP3 (chromosome 6q23.3), encoding A20 (F001).
Variant classes: Truncating nonsense and frameshift variants (dominant, produce haploinsufficiency; F001) plus pathogenic missense variants in the catalytic OTU deubiquitinase domain (e.g., p.Leu203Arg; p.T602S) and zinc-finger domains (F006).
Classification: Pathogenic/likely-pathogenic per ACMG/AMP; truncating LOF in a haploinsufficient gene supports PVS1-level evidence. Rare missense variants require functional confirmation (NF-κB over-activation assays; F006).
Allele frequency: Pathogenic variants are private/ultra-rare and essentially absent from population databases (gnomAD), consistent with high-penetrance disease.
Origin: Germline (contrast with somatic TNFAIP3 mutations in B-cell lymphoma; F011).
Functional consequence: Loss of function / haploinsufficiency (no dominant-negative effect; F001).
Epigenetics / chromosomal abnormalities: No recurrent epigenetic signature or large-scale chromosomal abnormality is specific to HA20 (not applicable / data not available).

5. Environmental Information

No specific toxin, radiation, occupational, or infectious agent has been established as a primary cause. The gut microbiome is altered (reduced diversity, increased pro-inflammatory Ruminococcus gnavus, impaired bile-acid metabolism; F007), likely acting as a downstream/modifying environmental factor rather than a primary cause. Microbial and cytokine stimuli (LPS, TNF, IL-1β) trigger flares in vitro and in vivo (F002, F008).

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation):

A heterozygous germline LOF variant in TNFAIP3 leads to ~50% reduction in functional A20 protein (haploinsufficiency) — demonstrated (F001).
Reduced A20 results in impaired removal of Lys63-linked polyubiquitin from TRAF6, NEMO, and RIP1 after TNF/TLR stimulation, and impaired ZnF7-dependent ubiquitin binding — demonstrated (F002).
Excess K63-ubiquitination leads to increased IκBα degradation and nuclear translocation of NF-κB p65 — demonstrated (F002).
NF-κB hyperactivation results in transcription of pro-inflammatory cytokines (TNF, IL-6, IL-1β precursors) — demonstrated (F002).
Branch A (inflammasome): Loss of A20 restraint leads to NLRP3 inflammasome hyperactivation and mature IL-1β release — demonstrated in patient cells and mouse models (F002, F008).
Branch B (necroptosis): Loss of ZnF7 function leads to RIPK1/RIPK3-MLKL-dependent macrophage necroptosis and inflammasome-dependent arthritis — demonstrated in mice (F002, F008).
Branch C (interferon): Downstream signaling results in an elevated type I IFN signature and IFN-γ-inducible chemokines (CXCL9/CXCL10) — demonstrated as a biomarker (F005).
Sustained cytokine excess (TNF/IL-1β/IL-6/type I IFN) leads to chronic multi-organ inflammation: mucocutaneous ulcers, IBD-like gut inflammation, arthritis, cytopenias, vasculitis, and autoimmunity — demonstrated clinically (F003, F007, F010).
Immune dysregulation additionally leads to transformation of lymphocytes with permissive antigen receptors, contributing to autoimmunity and lymphoproliferation risk — demonstrated/inferred (F010).

Pathways & processes: NF-κB signaling (KEGG hsa04064; Reactome R-HSA-975138), NLRP3 inflammasome (GO:0072559), TNF signaling, type I IFN signaling, necroptosis (GO:0070266). Cellular processes: inflammation (GO:0006954), positive regulation of NF-κB (GO:0051092), inflammasome-mediated signaling, apoptosis/necroptosis, autophagy (A20–DEPTOR complex restrains inflammasome via autophagy; PMID: 29940800). Cell types (CL): macrophage (CL:0000235), monocyte (CL:0000576), intestinal epithelial cell (CL:0002563), neutrophil (CL:0000775), T cell (CL:0000084), B cell (CL:0000236). Suggested GO biological process: GO:0043123 (positive regulation of canonical NF-κB signal transduction); GO:0032611 (IL-1β production).

7. Anatomical Structures Affected

Primary organs/systems: skin and mucosa (oral, genital), gastrointestinal tract, joints, hematologic/immune system.
Secondary involvement: liver (chronic liver disease, portal hypertension — F007), blood vessels (vasculitis of all sizes — F010), kidney (glomerulonephritis in lupus subset — F006), CNS (neuropsychiatric — F003), eyes (uveitis), thyroid (autoimmune thyroiditis).
UBERON terms: oral mucosa (UBERON:0002424), skin (UBERON:0002097), large intestine (UBERON:0000059), small intestine/ileum (UBERON:0002116), liver (UBERON:0002107), synovial joint (UBERON:0002217), blood vessel (UBERON:0001981).
Tissue/cell level: epithelial (intestinal, mucosal), immune (myeloid, lymphoid), endothelial. CL terms as above.
Subcellular (GO CC): cytoplasm/cytosol (GO:0005829, site of A20 ubiquitin editing and NF-κB regulation), inflammasome complex (GO:0061702).
Lateralization: Bilateral/systemic; ulcers and arthritis are typically multifocal rather than lateralized.

8. Temporal Development

Onset: Congenital predisposition, clinical onset usually early childhood (median 3.3–5.5 yr; F009); onset pattern chronic/insidious with recurrent acute flares.
Progression: Chronic, relapsing-remitting/episodic course; lifelong. Rate variable. Early onset (<5 yr) associated with more lifetime neuropsychiatric involvement (F003).
Patterns: Treatment-induced remission achievable with biologics; spontaneous remissions uncommon. Early childhood is a critical window given cumulative organ damage.

9. Inheritance and Population

Epidemiology: Rare (ultra-rare); precise prevalence/incidence not established. Ubiquitous geographic distribution (F009, F011).
Inheritance: Autosomal dominant, high penetrance (F001), with variable expressivity even within families. De novo variants occur. Founder effects/consanguinity not central (dominant disease).
Penetrance: High but with intra-familial variable expressivity.
Sex ratio: Female-predominant, M:F ~1:2 (F009).
Carrier frequency: Not applicable (dominant, ultra-rare pathogenic alleles; largely absent from gnomAD).

10. Diagnostics

Genetic testing (definitive): Molecular confirmation of a pathogenic/likely-pathogenic TNFAIP3 variant via single-gene testing, autoinflammatory/immune-dysregulation gene panels, or whole-exome/whole-genome sequencing (F001, F006). Functional confirmation (NF-κB over-activation, ubiquitination assays) supports novel missense variants.
Laboratory/biomarkers: Elevated acute-phase reactants during flares; cytopenias; autoantibodies (ANA, anti-dsDNA in lupus-overlap); type I IFN signature and IFN-γ-inducible chemokines (CXCL9/CXCL10) as activity and therapy-selection biomarkers (F005).
Imaging/endoscopy: GI endoscopy shows ileocolonic ulcers (IBD-like); liver imaging may show dysmorphia/portal hypertension (F007).
Histopathology: Lymphoplasmocytic infiltrate of GI tract and liver (F007).
Clinical criteria & differential diagnosis: Distinguish from classic Behçet disease (ubiquitous distribution, early onset, inverted sex ratio, uncommon HLA-B51, inconstant colchicine response; F011) and from DADA2, monogenic IBD (IL-10/IL-10R, XIAP), FMF/periodic fevers, SAVI, VEXAS, monogenic lupus/ALPS (F011). Overlapping/mixed autoinflammatory presentations occur (PMID: 41191928; PMID: 39360366).
Screening: Cascade genetic testing of at-risk relatives after a proband variant is identified.

11. Outcome / Prognosis

Chronic, lifelong disease with substantial morbidity but generally survivable with modern biologic therapy. Complications: autoimmune cytopenias, IBD/chronic liver disease, vasculitis (F010), MAS/HLH, monogenic lupus with glomerulonephritis (F006), and predisposition to lymphocyte transformation/lymphoproliferation (F010). No formal survival/mortality statistics exist. Prognostic factors: age of onset (earlier → more neuropsychiatric involvement), disease cluster (autoinflammatory vs autoimmune), and type I IFN signature (activity/therapy response). Prognostic biomarker: type I IFN signature (F005).

12. Treatment

See the treatment table under F004. Strategy: control autoinflammation with targeted biologics, escalate for refractory disease, and reserve HCT for refractory monogenic-IBD/severe phenotypes. Personalized medicine: IFN-high patients preferentially respond to JAK inhibition (F005); anti-TNF is the most broadly effective class (F004). Colchicine is inconstantly effective (~24%; F009). Anti-drug antibody-mediated secondary failure is a common practical challenge (F004).

13. Prevention

No primary prevention exists for this monogenic disease. Prevention is centered on: genetic counseling for affected families (AD inheritance, 50% transmission risk, variable expressivity); prenatal/preimplantation genetic testing where a familial variant is known; cascade screening of relatives; and tertiary prevention (early biologic therapy to prevent cumulative organ damage, vigilance for autoimmune, vascular, and lymphoproliferative complications). Novel-variant identification has been proposed to enable prenatal diagnosis and reduce disease burden in newborns (PMID: 34808442).

14. Other Species / Natural Disease

Taxonomy/orthologs: Human TNFAIP3 (NCBI Gene 7128); mouse Tnfaip3 (NCBI Gene 21929). The gene and its NF-κB-regulatory function are evolutionarily conserved.
Natural disease: No well-characterized spontaneous HA20 equivalent in companion animals is documented (data not available). Disease is primarily modeled experimentally (Section 15).
Comparative biology: Cell-specific mouse deletions recapitulate distinct human phenotypes, demonstrating conserved mechanisms (F008).

15. Model Organisms

Type: Mammalian (mouse, Mus musculus), plus in vitro cell systems (THP-1 monocytes, patient PBMCs, iPSC-derived cells).
Genetic models: Germline Tnfaip3 knockout is perinatal-lethal with multi-organ inflammation; conditional/cell-specific knockouts (myeloid, intestinal epithelial, airway club cell, β-cell) and domain-specific knock-ins (ZnF7 mutant) are used (F008).
Phenotype recapitulation: Myeloid-specific KO → NLRP3/IL-1-dependent erosive polyarthritis (F008); IEC+myeloid KO → ileitis/severe colitis with dysbiosis (F008); ZnF7 mutant → arthritis (F008); myeloid KO → STAT1-dependent enthesitis (PMID: 27551052).
Limitations: Human HA20 is heterozygous haploinsufficiency, whereas most informative mouse models use complete cell-specific deletion; no single model captures the full multi-organ human spectrum.
Resources: MGI (Tnfaip3), IMPC, IMSR.

Mechanistic Model / Interpretation

 Germline heterozygous TNFAIP3 LOF variant
│  (haploinsufficiency, ~50% A20)   [F001]
▼
 Impaired removal of K63-Ub from TRAF6/NEMO/RIP1
 + impaired ZnF7 ubiquitin binding                [F002]
│
      ┌─────────┼───────────────────────────┐
      ▼         ▼                           ▼
 NF-κB p65   NLRP3 inflammasome      RIPK1/RIPK3-MLKL
 activation   hyperactivation         necroptosis (ZnF7)
   [F002]      → IL-1β  [F002/F008]     → arthritis [F008]
      │            │                         │
      └──────┬─────┴─────────────┬───────────┘
     ▼                    ▼
   TNF/IL-6/IL-1β excess    Type I IFN signature
             + CXCL9/CXCL10   [F005]
     │                    │
     └────────┬───────────┘
      ▼
   Chronic multi-organ inflammation & autoimmunity   [F003/F007/F010]
   (oral/genital ulcers, IBD, arthritis, cytopenia,
    vasculitis, monogenic lupus, lymphoproliferation)
      │
      ▼
  Therapeutic reversal by anti-TNF / IL-1 / IL-6 / JAK-i / HCT  [F004]

The unifying interpretation is that HA20 is a "de-repression" disease: A20 is a critical negative feedback brake on innate immune signaling, and losing half of it lowers the activation threshold across multiple downstream nodes (NF-κB, inflammasome, necroptosis, type I IFN). Because the lesion sits at a hub with several effector branches, the clinical phenotype is heterogeneous — patients partition into autoinflammation-predominant vs autoimmune-predominant clusters (F003) depending on which branch dominates. This directly rationalizes the therapeutic landscape: cytokine-directed biologics neutralize individual effector arms, anti-TNF works broadly because TNF sits both upstream and downstream of A20-regulated signaling, and JAK inhibition is best matched to IFN-high patients (F004, F005).

Evidence Base

PMID	Title (abbrev.)	Supports
26642243	LOF TNFAIP3 → early-onset autoinflammation (Zhou 2016)	F001, F002 (causal gene, haploinsufficiency, K63-Ub defect)
38451381	Complexity of being A20 (Karri 2024 review)	F001, F011 (IEI concept; germline vs somatic)
29846841	Relopathies update (Steiner 2018)	F002 (NF-κB + NLRP3 hyperactivation)
31086261	A20 ZnF7 prevents necroptosis/arthritis (Polykratis 2019)	F002, F008 (necroptosis branch)
41692116	International cohort n=185 (He 2026)	F003, F006 (frequencies, clusters, genetic architecture)
42128528	Italian case series (De Nardi 2026)	F003, F005 (frequencies; IFN biomarker)
40574834	Japan national survey (Shiraki 2025)	F004 (anti-TNF efficacy 59.5%)
41620931	Biologics in autoinflammatory disorders (Koga 2026)	F004 (biologic-responsive)
37899202	HCT for monogenic IBD (Kanegane 2023)	F004 (HCT curative for refractory)
34427832	HCT ameliorates HA20 autoinflammation (Shiraki 2021)	F004
31767699	IFN signature predicts JAK-i response (Schwartz 2020)	F004, F005
36211342	Type I IFN signatures (Miyamoto 2022)	F005 (IFN elevated even in quiescent HA20)
40719110	Novel OTU-domain missense (Potjewijd 2025)	F006 (p.Leu203Arg, STAT1/mTOR)
34808442	Novel missense p.T602S (Jiang 2022)	F006 (NF-κB over-activation; prenatal implication)
39672252	HA20 beyond SLE systematic review (Philip 2025)	F006 (8.4% meet SLE criteria)
41991504	Gut microbiota & intestinal phenotype (Elhani 2026)	F007 (dysbiosis, liver disease)
25043000	A20/NLRP3 & arthritis mouse (Vande Walle 2014)	F008 (myeloid-KO arthritis)
25267258	A20 intestinal homeostasis (Vereecke 2014)	F008 (ileitis/colitis model)
27551052	A20/STAT1 enthesitis (De Wilde 2017)	F008 (enthesitis branch)
26815999	A20 in lung club cells (Maelfait 2016)	F008 (airway-epithelial model)
29890348	HA20 vs Behçet review (Berteau 2018)	F009, F011 (epidemiology; distinction)
39167656	A20 & lymphocyte transformation (Schultheiss 2024)	F010 (lymphoproliferation risk)
40369133	Monogenic vasculitis (Gül 2025)	F010 (vasculitis, endothelial damage)
29940800	TNFAIP3–DEPTOR autophagy (AS monocytes)	Mechanism (autophagy restraint of inflammasome)
41191928	Mixed autoinflammatory disorders	Differential/overlap diagnosis

Limitations and Knowledge Gaps

No formal survival/mortality or population-level prevalence/incidence statistics exist for HA20; epidemiology derives from case series and systematic reviews, subject to ascertainment bias toward severe cases.
Genotype–phenotype correlation is incomplete. The two-cluster (autoinflammation vs autoimmune) framework is data-driven but the molecular determinants of cluster membership remain undefined.
Model-organism caveat: Most mechanistic mouse data use complete cell-specific deletion, not the heterozygous haploinsufficiency seen in patients; no single model captures the full human spectrum.
Microbiome/metabolomic findings (F007) are from a single small study (n=16) and require replication before causal claims about dysbiosis can be made.
Type I IFN biomarker utility is promising but not yet standardized or prospectively validated as a treatment-selection tool at scale.
Quality-of-life data specific to HA20 (EQ-5D/SF-36/PROMIS) are absent.
Prognostic modeling for lymphoproliferation/malignancy risk is qualitative; absolute risks are unknown.

Proposed Follow-up Experiments / Actions

Prospective natural-history registry with standardized organ-damage indices and QoL instruments to establish prevalence, mortality, and long-term outcomes.
Genotype–phenotype and multi-omics integration (single-cell transcriptomics of monocytes/T/B/NK cells) to define molecular determinants of the autoinflammatory vs autoimmune clusters and to nominate cluster-specific therapies.
Prospective validation of the type I IFN signature as a treatment-stratification biomarker (IFN-high → JAK inhibitor) in a controlled trial.
Microbiome replication and interventional studies (larger cohorts; assessment of whether modulating R. gnavus/bile-acid metabolism alters GI disease).
Heterozygous, patient-variant knock-in mouse and iPSC models that faithfully replicate haploinsufficiency (rather than full deletion) for mechanism and drug testing.
Systematic surveillance protocol for lymphoproliferation/malignancy and standardized long-term follow-up of HCT-treated patients.
Functional-assay framework for classifying novel TNFAIP3 missense VUS (NF-κB reporter, ubiquitination, STAT1/mTOR readouts) to support ACMG classification and cascade counseling.

Report compiled from 11 confirmed findings across 41 reviewed papers. Evidence types are annotated per finding (human clinical, model organism, in vitro, computational). All quoted text is drawn verbatim from the cited abstracts.

Artifacts

Citations

PMID:26642243
PMID:38451381
PMID:29846841
PMID:31086261
PMID:41692116
PMID:42128528
PMID:40574834
PMID:41620931
PMID:37899202
PMID:34427832
PMID:31767699
PMID:29890348
PMID:36211342
PMID:40719110
PMID:34808442
PMID:39672252
PMID:41991504
PMID:25043000
PMID:25267258
PMID:26815999
PMID:27551052
PMID:39167656
PMID:40369133
PMID:41191928
PMID:29940800
PMID:39360366

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Key Findings

F001 — HA20 is an autosomal-dominant autoinflammatory disease caused by heterozygous LOF TNFAIP3 variants

F002 — Mechanism: loss of A20 ubiquitin-editing activity drives NF-κB and NLRP3 inflammasome hyperactivation

F003 — Clinical spectrum: mucocutaneous ulcers dominate, with fever, GI inflammation, cytopenia, arthritis, and autoimmunity

F004 — Treatment: HA20 is biologic-responsive; anti-TNF most effective, with IL-1/IL-6 blockade, JAK inhibitors, and HCT for refractory disease

F005 — Diagnostic biomarkers: elevated type I IFN signature and IFN-γ-inducible chemokines mark disease activity and predict JAK-inhibitor response

F006 — Genetics: germline heterozygous LOF variants (truncating dominant, plus OTU/ZnF missense); phenotype spans autoinflammation to monogenic lupus

F007 — Organ involvement and gut dysbiosis: IBD-like GI inflammation, chronic liver disease, and altered gut microbiota

F008 — Model organisms: A20/Tnfaip3 mouse models recapitulate HA20

F009 — Epidemiology & temporal course: rare, ubiquitous, female-predominant, early-childhood onset, chronic relapsing course

F010 — Prognosis & complications: chronic lifelong disease with autoimmune, vascular, and lymphoproliferative complications

F011 — HA20 is distinct from classic Behçet disease and from somatic TNFAIP3-driven lymphoma

Section-by-Section Disease Characterization

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic / Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Mechanistic Model / Interpretation

Evidence Base

Limitations and Knowledge Gaps

Proposed Follow-up Experiments / Actions

Artifacts

Citations