Autoinflammatory Disorder IEIs (IUIS Table 7)

name: Autoinflammatory Disorder IEIs
display_name: Autoinflammatory Disorder IEIs (IUIS Table 7)
creation_date: "2026-08-20T00:00:00Z"
description: >-
  IUIS Table 7 — autoinflammatory disorders. These inborn errors of immunity
  drive sterile, antigen-independent inflammation through unrestrained innate
  signalling — inflammasome activation and IL-1beta release, constitutive type I
  interferon production, or dysregulated NF-kappaB — rather than through
  autoantibodies or autoreactive lymphocytes. The clinical signature is
  recurrent or continuous fever, rash, serositis and arthropathy with a raised
  acute-phase response and no identifiable infection or high-titre
  autoantibody.
grouping_basis:
- SHARED_MECHANISM
- SHARED_PHENOTYPE
grouping_rationale: >-
  Grouped on the IUIS Table 7 pattern of monogenic sterile innate inflammation.
  Members are kept as separate Disease entries because the deregulated innate
  circuit differs, and that difference is what determines treatment: CINCA is
  inflammasome/IL-1beta-driven and answers to IL-1 blockade, whereas COPA
  syndrome is a type I interferonopathy driven by failed STING retrieval and
  does not, and ADA2 deficiency is a secreted-enzyme defect treated with TNF
  blockade rather than either. Grouping them keeps the inflammasome, interferon
  and NF-kappaB arms of autoinflammation visible as siblings rather than
  collapsing them into a single "periodic fever" bucket. The grouping follows
  IUIS's own three-section split of Table 7, so it also carries members whose
  presentation is not a periodic fever at all — cherubism's jaw-restricted
  osteolysis, DITRA's pustular psoriasis, H syndrome's histiocytosis — which is
  the point: they share the innate-inflammatory mechanism, not the syndrome
  shape.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0019751
      label: autoinflammatory syndrome
    mapping_predicate: skos:broadMatch
    mapping_source: MONDO
    mapping_justification: >-
      IUIS Table 7 aligns with MONDO autoinflammatory syndrome
      (MONDO:0019751), but broadMatch rather than exactMatch: MONDO's class is
      phenotype-defined and admits non-monogenic and acquired autoinflammatory
      disease, whereas IUIS Table 7 is restricted to germline monogenic inborn
      errors. The MONDO term is therefore strictly wider than this grouping.
    consistency:
    - reference: MONDO
      consistent: CONSISTENT
      notes: >-
        Re-checked 2026-09-13 against the full member list with `runoak -i
        sqlite:obo:mondo descendants -p i MONDO:0019751`, which returns 128
        classes. Fifteen of the seventeen members resolve inside that set,
        including COPA syndrome, which MONDO carries as autoimmune interstitial
        lung disease-arthritis syndrome (MONDO:0014629). Two do not: A20
        haploinsufficiency (MONDO:0100222) and H syndrome (MONDO:0011273). Both
        are nonetheless IUIS Table 7 rows, so the divergence is MONDO's
        placement of those two classes rather than a membership error here, and
        it is exactly the kind of gap the broadMatch predicate leaves room for.
        Membership in this grouping is decided by the iuis_category criterion
        below, not by MONDO closure.
membership_criteria:
- description: >-
    A disorder belongs to IUIS Table 7 if it is a germline monogenic inborn
    error of immunity causing sterile, antigen-independent innate inflammation
    — via inflammasome/IL-1, type I interferon, or NF-kappaB dysregulation —
    rather than antibody- or lymphocyte-mediated autoimmunity.
  criteria_semantics: NECESSARY
  logic:
    criterion_predicate: HAS_CLASSIFICATION
    classification: "iuis_category:autoinflammatory syndrome"
    description: >-
      Assigned to IUIS Table 7 (autoinflammatory disorders) via
      classifications.iuis_category on the member Disease entry. Stated in the
      keyed `<slot>:<value>` form so the audit reads the structured
      classifications block.
members:
- member: A20 Haploinsufficiency
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      A20 is the ubiquitin-editing enzyme that switches NF-kappaB off downstream
      of TNF, IL-1 and Toll-like receptors, so haploinsufficiency leaves the
      brake only half applied and NF-kappaB output chronically raised. This is
      the NF-kappaB arm of Table 7 in its purest form, with no inflammasome
      sensor and no interferon signature to explain the phenotype. Clinically it
      presents as early-onset orogenital ulceration, uveitis and arthralgia, and
      it was first described as a dominantly inherited form of Behcet disease
      before being recognised as an inborn error of immunity.
    gene:
      preferred_term: TNFAIP3
      term:
        id: hgnc:11896
        label: TNFAIP3
- member: Aicardi-Goutieres Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The prototype of the type I interferonopathy arm, and the member where the
      lesion is in nucleic-acid housekeeping rather than in a receptor: defective
      clearance or mis-sensing of cytosolic DNA and RNA species leaves an
      endogenous ligand permanently available to the interferon-inducing sensors.
      That single mechanism is reached through nine different genes, which is why
      this entry is a lumped series rather than a single genotype. What
      distinguishes it clinically from every other Table 7 member is the target
      organ: intracranial calcification, leukodystrophy and chronic CSF
      lymphocytosis that mimic congenital infection, rather than fever and
      serositis.
    gene:
      preferred_term: TREX1
      term:
        id: hgnc:12269
        label: TREX1
- member: Blau Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Gain-of-function variants in the NOD2 nucleotide-binding domain drive
      constitutive NF-kappaB signalling from a cytosolic NOD-like receptor that,
      unlike NLRP3 and NLRP1, does not nucleate an inflammasome. The output is
      organised granuloma rather than an IL-1beta fever: the triad is
      granulomatous dermatitis, boggy synovitis with camptodactyly, and uveitis.
      This is also the member that has to be held apart from a common polygenic
      disease, since the NOD2 variants that raise Crohn disease risk are
      loss-of-function and sit in a different part of the protein.
    gene:
      preferred_term: NOD2
      term:
        id: hgnc:5331
        label: NOD2
- member: Cherubism
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Stabilising SH3BP2 variants leave the adaptor resistant to degradation, so
      macrophage and osteoclast NF-kappaB and TNF signalling run hot. Cherubism
      is the one Table 7 member whose inflammation is anatomically confined:
      symmetric osteolytic giant-cell lesions of the mandible and maxilla, with
      no fever, no serositis and no systemic acute-phase response. It is also the
      only one that characteristically regresses after puberty, so the natural
      history rather than the cytokine profile is what sets it apart from its
      siblings.
    gene:
      preferred_term: SH3BP2
      term:
        id: hgnc:10825
        label: SH3BP2
- member: CINCA Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Gain-of-function NLRP3 drives constitutive inflammasome assembly and
      excessive IL-1beta release — the inflammasome arm of Table 7, and its
      severe end: CINCA/NOMID is the most severe cryopyrin-associated periodic
      syndrome phenotype, with neonatal urticarial rash, chronic aseptic
      meningitis, sensorineural hearing loss and epiphyseal overgrowth.
    gene:
      preferred_term: NLRP3
      term:
        id: hgnc:16400
        label: NLRP3
- member: COPA Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Heterozygous COPA variants impair COPI-mediated retrograde Golgi-to-ER
      trafficking, so the SURF4 adapter fails to retrieve STING; STING
      accumulates and signals ligand-independently. The type I interferonopathy
      arm of Table 7, and the member that reaches autoinflammation through a
      housekeeping vesicular-transport defect rather than an immune sensor,
      presenting as interstitial lung disease with arthritis and
      autoantibodies.
    gene:
      preferred_term: COPA
      term:
        id: hgnc:2230
        label: COPA
- member: Deficiency of Adenosine Deaminase 2
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The only member whose defective product is a secreted enzyme rather than an
      intracellular sensor, adaptor or signalling node. Loss of extracellular
      adenosine deaminase activity, and of the growth-factor function of the same
      protein, skews monocytes toward a proinflammatory phenotype and
      destabilises endothelium, so the disease presents as medium-vessel
      vasculitis: livedo racemosa, early-onset lacunar and haemorrhagic stroke,
      and a polyarteritis-nodosa-like picture. It is also the Table 7 member most
      clearly separated by treatment, answering to TNF blockade rather than IL-1
      blockade, and it can add hypogammaglobulinaemia and marrow failure that
      overlap the antibody-deficiency and bone-marrow-failure tables.
    gene:
      preferred_term: ADA2
      term:
        id: hgnc:1839
        label: ADA2
- member: DNASE2 Deficiency
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The type I interferonopathy arm reached through a lysosomal nuclease rather
      than a cytosolic one: DNase II cannot digest the DNA of engulfed apoptotic
      cells and expelled erythroblast nuclei, so undegraded self DNA engages
      cGAS-STING. It is distinguished among the interferonopathy members by its
      neonatal haematologic onset, severe transfusion-dependent anemia,
      thrombocytopenia and hepatosplenomegaly from birth, which reflect DNase
      II's non-redundant role in definitive erythropoiesis, before the later
      membranoproliferative glomerulonephritis, liver fibrosis and deforming
      arthropathy. JAK inhibition is the mechanism-directed therapy.
    gene:
      preferred_term: DNASE2
      term:
        id: hgnc:2960
        label: DNASE2
- member: Familial Cold Autoinflammatory Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The mildest end of the NLRP3 cryopyrin-associated periodic syndrome
      spectrum, and the only member with an external physical trigger: attacks
      follow generalised cold exposure within about two hours, rather than
      arising unprovoked. Its mechanism is shared with Muckle-Wells syndrome and
      CINCA, so what separates the three is threshold and target tissue rather
      than pathway. The entry also carries the genetically distinct cold-urticarial
      and inflammasome-adjacent disorders caused by NLRP12, PLCG2 and NLRP1,
      which reach a similar phenotype through separate circuits.
    gene:
      preferred_term: NLRP3
      term:
        id: hgnc:16400
        label: NLRP3
- member: Familial Mediterranean Fever
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The archetypal inflammasome member, but built on pyrin rather than NLRP3:
      recessive loss-of-function MEFV variants remove the autoinhibition that
      normally keeps the pyrin inflammasome silent. Because pyrin is regulated
      through RhoA and the microtubule cytoskeleton, this is the member defined
      by colchicine responsiveness, which no other Table 7 disorder shares.
      Attacks are short, typically one to three days of fever with serositis,
      and the untreated long-term risk that distinguishes it is AA amyloidosis.
    gene:
      preferred_term: MEFV
      term:
        id: hgnc:6998
        label: MEFV
- member: H Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Loss of the equilibrative nucleoside transporter hENT3 disables nucleoside
      efflux from lysosomes and mitochondria in myeloid cells, and the resulting
      inflammation arrives as tissue histiocytic infiltration rather than as a
      circulating cytokine fever. That makes it the Table 7 member whose lesion
      is a transporter and whose read-out is a histiocytosis, with cutaneous
      hyperpigmentation, hypertrichosis and induration as the defining signs.
      SLC29A3 is allelic across a spectrum that also includes pigmented
      hypertrichotic dermatosis with insulin-dependent diabetes and Faisalabad
      histiocytosis, which IUIS records in the same row.
    gene:
      preferred_term: SLC29A3
      term:
        id: hgnc:23096
        label: SLC29A3
- member: Mevalonate Kinase Deficiency
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The only member that is simultaneously an inborn error of metabolism:
      biallelic MVK loss of function blocks the isoprenoid branch immediately
      downstream of mevalonate, and the resulting shortage of geranylgeranyl
      pyrophosphate leaves RhoA unprenylated, which releases pyrin. It therefore
      converges on the same pyrin inflammasome as familial Mediterranean fever
      while starting from a metabolic rather than an immune lesion, and IUIS
      itself records the link from the block to the inflammation as not fully
      resolved. Residual enzyme activity sets the phenotype on a continuous
      scale from hyper-IgD syndrome to mevalonic aciduria with neurological
      involvement, which none of the other members show.
    gene:
      preferred_term: MVK
      term:
        id: hgnc:7530
        label: MVK
- member: Muckle-Wells Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The intermediate rung of the NLRP3 spectrum, sharing its gain-of-function
      inflammasome mechanism with familial cold autoinflammatory syndrome and
      CINCA. It is distinguished from the former by attacks that are not
      cold-triggered and from the latter by the absence of neonatal central
      nervous system and epiphyseal disease. Its own defining late complications
      are progressive sensorineural hearing loss and AA amyloidosis, which is
      what makes early IL-1 blockade a disease-modifying rather than purely
      symptomatic treatment here.
    gene:
      preferred_term: NLRP3
      term:
        id: hgnc:16400
        label: NLRP3
- member: Proteasome-Associated Autoinflammatory Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Reaches the type I interferon arm through proteostasis failure rather than
      nucleic-acid sensing: loss-of-function defects in immunoproteasome subunits
      and proteasome assembly factors let ubiquitinated substrates accumulate,
      and the ensuing cell-intrinsic stress response drives chronic interferon
      signalling. That distinguishes it from Aicardi-Goutieres syndrome and SAVI,
      which start from a nucleic-acid ligand and a sensor respectively. The
      clinical signature is equally distinctive: annular violaceous plaques
      evolving to progressive lipodystrophy with joint contractures, a
      combination no other member produces.
    gene:
      preferred_term: PSMB8
      term:
        id: hgnc:9545
        label: PSMB8
- member: Psoriasis 14, Pustular
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Loss of the interleukin-36 receptor antagonist leaves IL-36 alpha, beta and
      gamma signalling unopposed on keratinocytes, which drives IL-8 release and
      massive neutrophil recruitment into the epidermis. The lesion is therefore
      an absent brake on an IL-1-family cytokine rather than an overactive
      sensor, the same logic IUIS applies to DIRA in the neighbouring row. What
      sets it apart from the rest of Table 7 is the compartment: recurrent
      sterile pustular flares confined largely to skin, rather than fever with
      serositis or vasculopathy.
    gene:
      preferred_term: IL36RN
      term:
        id: hgnc:15561
        label: IL36RN
- member: Spondyloenchondrodysplasia
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The only member that is both an interferonopathy and a skeletal dysplasia,
      because one enzyme serves both roles. Loss of tartrate-resistant acid
      phosphatase leaves osteopontin phosphorylated, which drives type I
      interferon through plasmacytoid dendritic cells, while the same enzyme loss
      disturbs the vertebral and metaphyseal growth plates and produces
      platyspondyly with enchondroma-like lesions. Clinically it adds prominent
      lupus-like autoimmunity and spastic paraparesis, so it sits at the
      intersection of the interferon arm and the bone nosology rather than
      cleanly inside either.
    gene:
      preferred_term: ACP5
      term:
        id: hgnc:124
        label: ACP5
- member: STING-Associated Vasculopathy with Onset in Infancy
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The gain of function is in the sensing adaptor itself: mutant STING adopts
      an active conformation and signals without ligand, so interferon induction
      no longer requires any accumulated nucleic acid. That makes SAVI the direct
      counterpart of COPA syndrome, which reaches the same STING node from the
      opposite direction by failing to retrieve it from the Golgi. What
      distinguishes SAVI clinically is the acral small-vessel vasculopathy, which
      can progress to ulceration and tissue loss, combined with early-onset
      interstitial lung disease.
    gene:
      preferred_term: TMEM173
      term:
        id: hgnc:27962
        label: STING1
- member: TNF Receptor-Associated Periodic Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Cysteine-disrupting TNFRSF1A variants cause the 55-kD TNF receptor to
      misfold and be retained in the endoplasmic reticulum instead of reaching
      the surface and being shed, so the primary lesion is protein folding and
      trafficking rather than inflammasome or interferon signalling. IUIS places
      it accordingly in the non-inflammasome section, even though the resulting
      phenotype is a periodic fever indistinguishable at first glance from the
      inflammasome members. Attack duration is the most useful bedside
      discriminator: episodes typically run one to three weeks rather than days,
      with migratory myalgia under an overlying rash and periorbital oedema.
    gene:
      preferred_term: TNFRSF1A
      term:
        id: hgnc:11916
        label: TNFRSF1A
notes: >-
  Created 2026-08-20 with two members (CINCA and COPA syndromes) to give the IUIS
  Table 7 disorders a place in the Inborn Errors of Immunity tree.

  Grown to seventeen members on 2026-09-13. Thirteen entries already curated in
  kb/disorders/ were classified against Table 7 in that pass, each with notes
  naming the table section and row and an evidence item quoting the row itself:
  Aicardi-Goutieres Syndrome, Deficiency of Adenosine Deaminase 2,
  Spondyloenchondrodysplasia and STING-Associated Vasculopathy with Onset in
  Infancy from section 1 (type I interferonopathies); Familial Mediterranean
  Fever, Mevalonate Kinase Deficiency and Familial Cold Autoinflammatory
  Syndrome from section 2 (defects affecting the inflammasome); and Blau
  Syndrome, Cherubism, H Syndrome, Proteasome-Associated Autoinflammatory
  Syndrome, Psoriasis 14 Pustular (the DITRA row) and TNF Receptor-Associated
  Periodic Syndrome from section 3 (non-inflammasome-related conditions). A20
  Haploinsufficiency and Muckle-Wells Syndrome were added at the same time: both
  already carried `classifications.iuis_category: autoinflammatory syndrome` but
  had never been listed here, so they were reachable by classification and not by
  grouping.

  This is not yet the whole of Table 7. IUIS prints 59 rows and counts 56
  disorders; seventeen of those now have a dismech entry in this grouping.
  Several further rows correspond to entries curated elsewhere in kb/disorders/
  under a different IUIS table and were deliberately left alone, notably
  X-linked reticulate pigmentary disorder (POLA1), which IUIS dual-lists in
  Tables 2 and 7 and which should not be reassigned by one table's reading
  alone.