Combined Immunodeficiency with Syndromic Features IEIs (IUIS Table 2)

name: Combined Immunodeficiency with Syndromic Features IEIs
display_name: Combined Immunodeficiency with Syndromic Features IEIs (IUIS Table 2)
creation_date: "2026-06-13T00:00:00Z"
description: >-
  IUIS Table 2 — combined immunodeficiencies with associated or syndromic
  features. These IEIs combine T- and/or B-cell immunodeficiency with
  prominent developmental, craniofacial, ectodermal, hematologic, or
  multi-organ syndromic findings that are part of the recognized clinical
  spectrum.
grouping_basis:
- SHARED_MECHANISM
- SHARED_PHENOTYPE
grouping_rationale: >-
  Grouped on the IUIS Table 2 pattern: combined immunodeficiency plus
  syndromic features beyond infection susceptibility alone. Members are kept
  as separate Disease entries because the primary genetic lesion and
  extravascular phenotype differ (22q11.2 deletion vs DNMT3B/ICF vs SP110
  VODI vs NEMO/IKBKG ectodermal dysplasia). No MONDO mapping: IUIS Table 2
  has no MONDO grouping class (MONDO:0015133 is an obsolete phagocyte-defect
  orphan; ectodermal dysplasia and immune deficiency subsume only EDA-ID
  members). Criteria are NECESSARY and, since the 2026-08 iuis_category
  backfill of Table 2 entries, fully auditable against the classifications
  block of every member.
membership_criteria:
- description: >-
    A disorder belongs to IUIS Table 2 if it is an IEI with combined
    immunodeficiency and prominent associated syndromic features (craniofacial,
    cardiac, ectodermal, or hematologic) that define the clinical entity.
  criteria_semantics: NECESSARY
  logic:
    criterion_predicate: HAS_CLASSIFICATION
    classification: "iuis_category:combined immunodeficiency with syndromic features"
    description: >-
      Assigned to IUIS Table 2 (combined immunodeficiency with syndromic
      features) 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: 22q11.2 Deletion Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Hemizygous 22q11.2 deletion (TBX1 haploinsufficiency and contiguous
      genes) causes DiGeorge spectrum disease with thymic hypoplasia, T-cell
      deficiency, conotruncal heart defects, and hypocalcemia.
    gene:
      preferred_term: TBX1
      term:
        id: hgnc:11592
        label: TBX1
- member: Immunodeficiency-Centromeric Instability-Facial Anomalies Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      DNMT3B, ZBTB24, or CDCA7 defects cause DNA hypomethylation with
      centromeric instability, facial dysmorphism, and progressive combined
      immunodeficiency (ICF syndrome).
    gene:
      preferred_term: DNMT3B
      term:
        id: hgnc:2979
        label: DNMT3B
- member: Hepatic veno-occlusive disease-immunodeficiency syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic SP110 loss causes hepatic veno-occlusive disease with
      combined immunodeficiency and failure to control intracellular
      pathogens (VODI syndrome).
    gene:
      preferred_term: SP110
      term:
        id: hgnc:5401
        label: SP110
- member: IKBKG ectodermal dysplasia with immunodeficiency
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      X-linked NEMO (IKBKG) hypomorphic variants impair NF-kappaB signaling,
      causing ectodermal dysplasia with combined immunodeficiency and
      susceptibility to mycobacterial and pyogenic infections.
    gene:
      preferred_term: IKBKG
      term:
        id: hgnc:5961
        label: IKBKG
- member: Ectodermal Dysplasia and Immunodeficiency 2
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Autosomal recessive IKBA (NFKBIA) loss impairs NF-kappaB inhibitor
      function, causing ectodermal dysplasia with combined immunodeficiency
      (EDA-ID2) overlapping NEMO disease.
    gene:
      preferred_term: NFKBIA
      term:
        id: hgnc:7797
        label: NFKBIA
- member: Autosomal Dominant Hyper-IgE Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Heterozygous dominant-negative STAT3 poisons the obligate STAT3 dimer,
      collapsing transcriptional output across the IL-6/IL-11/IL-21/IL-23
      network. The immune arm (Th17 failure, cold staphylococcal abscesses,
      pneumatoceles, extreme IgE) is inseparable from a non-immune
      connective-tissue, skeletal, dental and vascular syndrome — the defining
      Table 2 pattern, and the anchor of the hyper-IgE subtable.
    gene:
      preferred_term: STAT3
      term:
        id: hgnc:11364
        label: STAT3
- member: Cartilage-hair hypoplasia
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic variants in RMRP, a non-coding RNA rather than a protein,
      disable the RNase MRP endoribonuclease. One RNA-folding lesion reaches
      four organ systems at once (pre-rRNA processing, cyclin B2 mRNA cleavage,
      TERT partnering, small-RNA silencing), giving the immuno-osseous Table 2
      pattern: metaphyseal chondrodysplasia and hypoplastic hair alongside
      combined immunodeficiency, anemia and a marked lymphoma excess.
    gene:
      preferred_term: RMRP
      term:
        id: hgnc:10031
        label: RMRP
- member: Immunoskeletal Dysplasia with Neurodevelopmental Abnormalities
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Hypomorphic biallelic EXTL3 alleles yield structurally aberrant heparan
      sulfate — longer chains, abnormal sulfation — rather than its absence.
      Because HS proteoglycans tune morphogen and cytokine signaling as
      co-receptors, one glycosyltransferase lesion is transduced in opposite
      directions by tissue, coupling spondyloepimetaphyseal dysplasia and
      neurodevelopmental disease to a T-cell-deficient combined
      immunodeficiency.
    gene:
      preferred_term: EXTL3
      term:
        id: hgnc:3518
        label: EXTL3
- member: Vici Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Loss of EPG5 blocks the late autophagosome-lysosome fusion step of
      macroautophagy. The immunodeficiency is one arm of a cardinal pentad
      (callosal agenesis, cataracts, oculocutaneous hypopigmentation,
      cardiomyopathy, combined immunodeficiency) — the only Table 2 member
      here whose syndromic breadth follows from a defect in a general
      catabolic pathway rather than a lymphocyte- or skeleton-specific one.
    gene:
      preferred_term: EPG5
      term:
        id: hgnc:29331
        label: EPG5
- member: STAT6 Gain-of-Function Disease
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Heterozygous gain-of-function STAT6 amplifies IL-4/IL-13 type-2 signaling,
      producing early-onset severe allergic dysregulation with extreme IgE — a
      hyper-IgE-like syndromic presentation that IUIS groups with
      dominant-negative STAT3 rather than with the Table 4 dysregulation
      disorders. The only member here whose defining lesion is excess rather
      than loss of cytokine signal transduction, and one of the ten Table 2
      entities newly recognized in the IUIS 2024 update.
    gene:
      preferred_term: STAT6
      term:
        id: hgnc:11368
        label: STAT6
- member: Wiskott-Aldrich syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      X-linked loss or dysfunction of WASp, the hematopoietic actin regulator,
      disrupts cytoskeletal remodeling in leukocytes and platelets at once.
      The result pairs combined immunodeficiency and immune dysregulation with
      microthrombocytopenia, bleeding and eczema — the anchor of the Table 2
      congenital-thrombocytopenia subtable — plus a marked lymphoid-malignancy
      excess.
    gene:
      preferred_term: WAS
      term:
        id: hgnc:12731
        label: WAS
- member: Ataxia-telangiectasia
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic ATM loss cripples the kinase that orchestrates the DNA
      double-strand-break response, yielding progressive cerebellar
      neurodegeneration, oculocutaneous telangiectasia, cellular
      radiosensitivity and high malignancy risk alongside a variable combined
      immunodeficiency. The prototype of the Table 2 DNA-repair-defect
      subtable, spanning a continuum from classic childhood-onset disease to
      later-onset variant A-T with residual kinase activity.
    gene:
      preferred_term: ATM
      term:
        id: hgnc:795
        label: ATM
- member: Nijmegen breakage syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      NBN (nibrin) defects disable the MRN double-strand-break sensor,
      producing chromosomal instability with delayed p53-mediated damage
      response and abnormal neurogenesis. Distinguished from its DNA-repair
      sibling ataxia-telangiectasia by progressive microcephaly and growth
      retardation rather than ataxia and telangiectasia, with
      immunodeficiency and marked lymphoma susceptibility.
    gene:
      preferred_term: NBN
      term:
        id: hgnc:7652
        label: NBN
- member: Bloom syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic BLM loss removes the RecQ helicase that dissolves
      homologous-recombination intermediates without crossover, causing
      hyper-recombination with markedly increased sister-chromatid exchange as
      the diagnostic cellular readout. Severe pre- and postnatal growth
      deficiency, photosensitive facial rash and striking early multi-cancer
      predisposition dominate a phenotype in which the immunodeficiency is
      comparatively mild.
    gene:
      preferred_term: BLM
      term:
        id: hgnc:1058
        label: BLM
- member: Purine nucleoside phosphorylase deficiency
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      An inborn error of the purine salvage pathway: without PNP,
      deoxyguanosine accumulates and is phosphorylated to dGTP, a
      substrate-toxicity chain that falls preferentially on T cells. The only
      classical metabolic-enzyme member here, coupling a T-cell-predominant
      combined immunodeficiency to neurological disease and autoimmunity.
    gene:
      preferred_term: PNP
      term:
        id: hgnc:7892
        label: PNP
- member: CHARGE syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Heterozygous loss of the CHD7 chromatin remodeler perturbs neural
      crest-driven organogenesis — coloboma, heart defects, choanal atresia,
      semicircular canal hypoplasia, ear anomalies — and can include thymic
      hypoplasia with a DiGeorge-like T-cell deficiency, placing this
      multiple-anomaly disorder beside 22q11.2 deletion in the
      thymic-defect arm of Table 2.
    gene:
      preferred_term: CHD7
      term:
        id: hgnc:20626
        label: CHD7
- member: Jacobsen Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      A contiguous-gene deletion of distal 11q (breakpoint at or telomeric to
      11q23.3), not a single-gene lesion: haploinsufficiency across the
      deleted segment produces growth retardation, psychomotor delay,
      characteristic facies and Paris-Trousseau thrombocytopenia attributed to
      FLI1 haploinsufficiency, with variable antibody deficiency. With
      22q11.2 deletion, one of the grouping's two chromosomal-deletion members
      carrying no single causal gene binding.
- member: Roifman-syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic RNU4ATAC mutations disable the U4atac snRNA of the minor
      (U12-dependent) spliceosome, impairing splicing of a subset of essential
      genes. Antibody deficiency with recurrent infections combines with
      spondyloepiphyseal dysplasia, growth retardation and intellectual
      disability — with cartilage-hair hypoplasia, one of the grouping's
      non-coding-RNA lesions.
    gene:
      preferred_term: RNU4ATAC
      term:
        id: hgnc:34016
        label: RNU4ATAC
- member: Loeys-Dietz Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Heterozygous mutations in TGF-beta signaling components (most commonly
      TGFBR1/TGFBR2) cause the connective-tissue triad of arterial tortuosity
      and aneurysms, hypertelorism, and bifid uvula or cleft palate. Its
      immune arm is allergic dysregulation — food allergy and eosinophilic
      gastrointestinal disease — making it the vasculopathy-dominant member
      whose Table 2 listing rests on TGF-beta-driven immune skewing rather
      than lymphopenia.
    gene:
      preferred_term: TGFBR1
      term:
        id: hgnc:11772
        label: TGFBR1
- member: Netherton syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      SPINK5 loss-of-function abolishes the serine-protease inhibitor LEKTI,
      unleashing kallikrein activity in the epidermis: congenital ichthyosis
      with bamboo-shaft hair, a defective skin barrier and prominent atopy.
      The grouping's skin-barrier member, where the syndromic surface disease
      rather than lymphocyte development carries the phenotype.
    gene:
      preferred_term: SPINK5
      term:
        id: hgnc:15464
        label: SPINK5
- member: Trichohepatoenteric Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic TTC37 (or SKIV2L) variants disable the SKI complex, a
      cytoplasmic RNA-exosome cofactor for mRNA surveillance — a housekeeping
      lesion rather than intestine-specific machinery. Intractable congenital
      diarrhea, woolly hair, facial dysmorphism and liver disease combine
      with antibody deficiency in the defining trichohepatoenteric triad.
    gene:
      preferred_term: TTC37
      term:
        id: hgnc:23639
        label: TTC37
- member: Hennekam lymphangiectasia-lymphedema syndrome 1
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic CCBE1 loss impairs VEGF-C-dependent lymphangiogenesis,
      producing generalized lymphatic dysplasia: intestinal lymphangiectasia
      with protein-losing enteropathy, peripheral and facial lymphedema, and
      intellectual disability. The immunodeficiency is attritional —
      hypogammaglobulinemia and lymphopenia from enteric loss of protein and
      lymphocytes rather than a lymphocyte-intrinsic defect.
    gene:
      preferred_term: CCBE1
      term:
        id: hgnc:29426
        label: CCBE1
- member: Hennekam lymphangiectasia-lymphedema syndrome 2
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic FAT4 mutations in the giant atypical cadherin reproduce the
      Hennekam lymphangiectasia-lymphedema triad in CCBE1-mutation-negative
      families, reaching the same generalized lymphatic dysplasia through
      planar-cell-polarity signaling rather than the VEGF-C maturation axis
      of the CCBE1 form.
    gene:
      preferred_term: FAT4
      term:
        id: hgnc:23109
        label: FAT4
- member: Kabuki Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Heterozygous KMT2D (less commonly KDM6A) variants impair epigenetic
      control of developmental gene expression, combining the characteristic
      facial gestalt, infantile hypotonia, intellectual disability and
      congenital heart disease with frequent humoral immune dysfunction and
      hypogammaglobulinemia — a chromatin-machinery member whose immune arm
      is B-cell rather than T-cell weighted.
    gene:
      preferred_term: KMT2D
      term:
        id: hgnc:7133
        label: KMT2D
- member: Wiedemann-Steiner Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Heterozygous KMT2A variants — usually de novo — disrupt the H3K4
      methyltransferase of the epigenetic machinery, giving developmental
      delay, hypertrichosis cubiti, growth restriction and characteristic
      facies with variably present immune findings. The sibling
      chromatin-disorder to Kabuki syndrome, distinguished by its
      hypertrichosis and milder, more variable immunodeficiency.
    gene:
      preferred_term: KMT2A
      term:
        id: hgnc:7132
        label: KMT2A
- member: Immunodeficiency 80 with or without Congenital Cardiomyopathy
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic hypomorphic MCM10 variants impair the essential activator of
      the CMG replicative helicase; replication stress falls on the NK
      compartment (absent terminally mature NK cells with CMV susceptibility)
      or the fetal heart (congenital restrictive cardiomyopathy). Listed by
      IUIS in the Table 2 DNA-repair subsection beside GINS1 deficiency,
      which it phenocopies — reclassified here from the former
      innate-immunity-defect reading on 2026-08-26.
    gene:
      preferred_term: MCM10
      term:
        id: hgnc:18043
        label: MCM10
- member: Schimke immuno-osseous dysplasia
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic SMARCAL1 loss removes the annealing helicase that restarts
      stalled replication forks; the resulting replication stress injures
      proliferative compartments selectively — growth-plate chondrocytes
      (spondyloepiphyseal dysplasia with short-trunk short stature),
      podocytes (steroid-resistant nephrotic syndrome) and lymphocytes
      (T-cell immunodeficiency). The grouping's immuno-osseous member
      alongside cartilage-hair hypoplasia, reached through genome maintenance
      rather than ribonucleoprotein biology.
    gene:
      preferred_term: SMARCAL1
      term:
        id: hgnc:11102
        label: SMARCAL1
- member: T-cell Immunodeficiency, Congenital Alopecia, and Nail Dystrophy
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Human nude SCID: biallelic FOXN1 loss prevents thymic epithelial cell
      differentiation, so no functional thymic microenvironment forms and
      athymia abolishes thymopoiesis. The same transcription factor acts in
      terminally differentiating skin epithelium, adding congenital alopecia
      and nail dystrophy — a two-organ lesion from one epithelial
      transcription factor, with the profoundest T-cell deficit in the
      grouping.
    gene:
      preferred_term: FOXN1
      term:
        id: hgnc:12765
        label: FOXN1
- member: ARPC1B Deficiency
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic ARPC1B loss removes the hematopoietically expressed isoform
      of the ARPC1 subunit of the Arp2/3 actin-branching complex, a lesion
      isoform redundancy cannot cover in blood cells. Thrombocytopenia with
      bleeding, eczema, recurrent infection, cutaneous vasculitis and raised
      IgA/IgE give a Wiskott-Aldrich-like actin defect reached one complex
      downstream of WASp.
    gene:
      preferred_term: ARPC1B
      term:
        id: hgnc:704
        label: ARPC1B
notes: >-
  Intentionally unmapped to MONDO. Audit with
  `uv run python scripts/grouping_mondo_gaps.py --grouping "Inborn"`.

  STAT6 Gain-of-Function Disease was reclassified from IUIS Table 4 to Table 2
  on 2026-08-20 and newly listed here: the IUIS 2024 update lists STAT6 (AD GOF)
  under combined immunodeficiencies with syndromic features, Table 2 subtable 1
  (PMID:41608114). Its allergic/type-2 phenotype had previously been read as a
  Table 4 signal. It had never been listed as a member of the Immune
  Dysregulation IEIs grouping — only its `iuis_category` carried the Table 4
  assignment — so this is a first listing, not a transfer between member lists.

  2026-08-29 membership sync: the member list was brought in line with the
  entries carrying `iuis_category: combined immunodeficiency with syndromic
  features` after the IUIS Table 2 classification backfill, growing from 10 to
  29 members (19 added: Wiskott-Aldrich, ataxia-telangiectasia, Nijmegen
  breakage, Bloom, PNP deficiency, CHARGE, Jacobsen, Roifman, Loeys-Dietz,
  Netherton, trichohepatoenteric, Hennekam 1 and 2, Kabuki, Wiedemann-Steiner,
  IMD80/MCM10, Schimke immuno-osseous dysplasia, FOXN1 nude SCID, and ARPC1B
  deficiency). IMD80 entered via its 2026-08-26 reclassification from `innate
  immunity defect` (the IUIS 2022 update lists MCM10 only in Table 2, beside
  GINS1 deficiency). Jacobsen syndrome is a contiguous-gene chromosomal
  deletion of distal 11q with no single causal gene, so its differentiating
  mechanism carries no gene binding (unlike 22q11.2 deletion, whose block
  names TBX1 as the major haploinsufficient driver).