👪

Inheritance

1

Autosomal dominant inheritance HP:0000006

Nearly all reported cases are de novo. One case of inheritance from a parent with somatic mosaicism has been documented.

Autosomal dominant inheritance De novo rate: >90%

Show evidence (2 references)

PMID:28597146 SUPPORT Human Clinical

"The mutation certainly or probably occurred de novo in 13 patients, whereas it was inherited from a parent with somatic mosaicism in one patient."

Comprehensive review of 14 patients shows 13/14 had de novo mutations, confirming autosomal dominant inheritance with very high de novo rate.

PMID:15337789 SUPPORT Human Clinical

"his father has the same mutation but displays complex mosaicism"

Demonstrates somatic mosaicism in a parent as the mechanism of inherited transmission, with widely different clinical outcomes between father and son.

◆

Subtypes

2

Missense mutations (S32/S36 region)

Point mutations at or adjacent to the S32/S36 phosphorylation sites. Associated with higher mutant protein levels and more severe disease, including full ectodermal dysplasia and profound immunodeficiency.

N-terminal truncation mutations

Nonsense mutations upstream of S32 with reinitiation of translation downstream of S36, producing truncated IkBa lacking both phosphorylation sites. Generally associated with less severe disease.

⚙

Pathophysiology

6

Constitutive NF-kB Inhibition by Gain-of-Function IkBa

Gain-of-function mutations in NFKBIA prevent phosphorylation of IkBa at serines 32 and 36 by the IKK complex, blocking ubiquitination and proteasomal degradation. The mutant IkBa constitutively sequesters NF-kB dimers in the cytoplasm, abolishing NF-kB-dependent transcriptional activation in response to stimulation of TLRs, IL-1 receptors, TNF receptors, TCR, and BCR.

T cell link

canonical NF-kappaB signaling link

Downstream

Impaired T Cell Development and Function

Defective Innate Immune Signaling

B Cell Deficiency

Defective Lymph Node Development

Ectodermal Dysplasia

Show evidence (2 references)

PMID:14523047 SUPPORT Human Clinical

"This mutation is gain-of-function, as it enhances the inhibitory capacity of IkappaBalpha by preventing its phosphorylation and degradation, and results in impaired NF-kappaB activation."

Original characterization of the gain-of-function mechanism by which mutant IkBa resists degradation and constitutively inhibits NF-kB.

PMID:28597146 SUPPORT Human Clinical

"All mutations enhanced the inhibitory activity of IκBα, by preventing its phosphorylation on serine 32 or 36 and its subsequent degradation."

Review confirming that all reported mutations share the same gain-of-function mechanism of preventing IkBa phosphorylation.

Impaired T Cell Development and Function

NF-kB signaling is essential for T-cell development, activation, and survival. Constitutive IkBa-mediated NF-kB inhibition results in a unique T-cell immunodeficiency characterized by lymphocytosis with absence of memory T cells and failure of naive T cells to respond to TCR stimulation.

T cell link

T cell activation link T cell proliferation link

Show evidence (2 references)

PMID:14523047 SUPPORT Human Clinical

"AD-EDA-ID but not XL-EDA-ID is associated with a severe and unique T cell immunodeficiency. Despite a marked blood lymphocytosis, there are no detectable memory T cells in vivo, and naive T cells do not respond to CD3-TCR activation in vitro."

Demonstrates the distinctive T-cell dysfunction pattern in EDA-ID2: lymphocytosis with absent memory T cells and unresponsive naive T cells.

PMID:15337789 SUPPORT Human Clinical

"T cell receptor-mediated proliferation was also impaired."

Independent confirmation of defective TCR-mediated T cell proliferation in a patient with the S32I IkBa mutation.

Defective Innate Immune Signaling

NF-kB is a central mediator of innate immune responses downstream of Toll-like receptors. Constitutive IkBa inhibition impairs monocyte and macrophage activation, with absent IL-12 production in response to TLR stimulation and impaired NF-kB nuclear translocation, leading to susceptibility to mycobacterial and other intracellular pathogens.

macrophage link dendritic cell link

innate immune response link toll-like receptor signaling pathway link

Show evidence (2 references)

PMID:14523047 SUPPORT Human Clinical

"impaired cellular responses to ligands of TIR (TLR-ligands, IL-1beta, and IL-18), and TNFR (TNF-alpha, LTalpha1/beta2, and CD154) superfamily members and severe bacterial diseases"

Demonstrates broad impairment of innate immune signaling downstream of multiple receptor superfamilies due to NF-kB inhibition.

PMID:15337789 SUPPORT Human Clinical

"Monocytes did not produce interleukin 12p40 upon stimulation with various TLR stimuli and nuclear translocation of NF-kappaB was impaired."

Directly demonstrates defective monocyte function with absent IL-12 production and impaired NF-kB nuclear translocation.

B Cell Deficiency

NF-kB signaling is required for B-cell development and function. Patients with IkBa gain-of-function mutations have profound B-cell deficiency with agammaglobulinemia or hyper-IgM phenotype, reflecting defective class-switch recombination.

B cell link

B cell activation link

Show evidence (2 references)

PMID:28597146 SUPPORT Human Clinical

"All patients had profound B-cell deficiency."

Review confirms B-cell deficiency is a universal feature in EDA-ID2 patients.

PMID:15337789 SUPPORT Human Clinical

"a hyper immunoglobulin M-like immunodeficiency syndrome and ectodermal dysplasia"

Demonstrates hyper-IgM-like immunodeficiency as a manifestation of defective B-cell class switching in IkBa-mutant patients.

Defective Lymph Node Development

Constitutive IkBa inhibition impairs both canonical and noncanonical NF-kB signaling. The noncanonical pathway drives expression of chemokines and adhesion molecules (CCL20, ICAM1, VCAM1) required for lymphorganogenesis. In the S32I knock-in mouse model, lymph nodes and Peyer's patches are completely absent. Defective stromal cell function contributes to persistent immunodeficiency even after HSCT, as the non-hematopoietic compartment retains the mutant IkBa.

lymph node development link

Show evidence (2 references)

PMID:28629746 SUPPORT Model Organism

"the S32I mutant completely lacks lymph nodes (LNs), Peyer's patches, marginal zone B cells and follicular dendritic cells, and fails to form germinal centers, features typical of defective non-canonical NF-κB signaling"

S32I knock-in mouse demonstrates that IkBa gain-of-function abolishes lymph node organogenesis through impaired noncanonical NF-kB signaling.

PMID:28629746 SUPPORT Model Organism

"WT->S32I IκBα chimeras failed to form proper lymphoid organs and to reconstitute immune function despite excellent donor cell engraftment, paralleling the failure of HSCT to cure AD EDA-ID patients"

Demonstrates that defective stromal (non-hematopoietic) cell function contributes to persistent immunodeficiency, explaining poor HSCT outcomes.

Ectodermal Dysplasia

NF-kB signaling through the ectodysplasin (EDA)/EDAR/NF-kB pathway is essential for ectodermal appendage development. Constitutive IkBa inhibition disrupts this pathway, leading to hypohidrosis from sweat gland hypoplasia, sparse hair, and conical or absent teeth. Notably, some S36 missense variants cause immunodeficiency without ectodermal dysplasia features.

ectodermal placode formation link

Show evidence (2 references)

PMID:28597146 SUPPORT Human Clinical

"Thirteen patients had developmental features of EDA, the severity and nature of which differed between cases."

EDA features are present in most but not all patients, with variable severity.

PMID:31683054 PARTIAL Human Clinical

"missense NFKBIA variants substituting serine 36 of IκBα, differ from the rest of pathogenic GOF NFKBIA variants in that they cause combined immunodeficiency, even in the absence of EDA"

Demonstrates genotype-phenotype correlation where S36 variants can cause immunodeficiency without ectodermal dysplasia, indicating the EDA phenotype is not obligate.

⬡

Pathograph

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

●

Phenotypes

11

Blood 1

Lymphocytosis with Absent Memory T Cells Increased total lymphocyte count (HP:0100827)

Show evidence (2 references)

PMID:14523047 SUPPORT Human Clinical

"Despite a marked blood lymphocytosis, there are no detectable memory T cells in vivo, and naive T cells do not respond to CD3-TCR activation in vitro."

Demonstrates the paradoxical lymphocytosis with absent memory T cells that is the hallmark T-cell abnormality of EDA-ID2.

PMID:28597146 SUPPORT Human Clinical

"Specific immunological features, found in some, but not all patients, included a lack of peripheral lymph nodes, lymphocytosis, dysfunctional α/β T cells, and a lack of circulating γ/δ T cells."

Confirms lymphocytosis as a feature in some patients, along with dysfunctional T cells and absent gamma/delta T cells.

Head and Neck 1

Sparse Hair Sparse scalp hair (HP:0002209)

Immune 1

Recurrent Infections Recurrent infections (HP:0002719)

Show evidence (2 references)

PMID:28597146 SUPPORT Human Clinical

"The patients had various pyogenic, mycobacterial, fungal, and viral severe infections."

Review confirms broad spectrum of severe infections as a universal feature.

PMID:35005117 SUPPORT Human Clinical

"She presented recurrent fever, infectious pneumonia and chronic diarrhea with EDA-ID."

Case report documenting recurrent infections in a patient with an N-terminal truncation NFKBIA mutation.

Integument 1

Hypohidrosis Hypohidrosis (HP:0000966)

Show evidence (1 reference)

PMID:28597146 SUPPORT Human Clinical

"Thirteen patients had developmental features of EDA, the severity and nature of which differed between cases."

Confirms ectodermal dysplasia features including hypohidrosis in the majority of patients.

Other 7

Conical Teeth Small, conical teeth (HP:0200141)

Show evidence (1 reference)

PMID:15337789 SUPPORT Human Clinical

"several signs of ectodermal dysplasia became manifest and comprised abnormal dentition (typical conical teeth) and periorbital wrinkling"

Direct clinical observation of conical teeth as part of ectodermal dysplasia features in a patient with S32I IkBa mutation.

Recurrent Mycobacterial Infections Recurrent mycobacterial infections (HP:0011274)

Show evidence (1 reference)

PMID:28597146 SUPPORT Human Clinical

"The patients had various pyogenic, mycobacterial, fungal, and viral severe infections."

Review confirms mycobacterial infections as part of the broad infection susceptibility spectrum in EDA-ID2 patients.

B Cell Deficiency Decreased total B cell count (HP:0010976)

Show evidence (1 reference)

PMID:28597146 SUPPORT Human Clinical

"All patients had profound B-cell deficiency."

Universal feature confirmed across all reported EDA-ID2 patients.

Agammaglobulinemia Agammaglobulinemia (HP:0004432)

Show evidence (1 reference)

PMID:15337789 SUPPORT Human Clinical

"immunological evaluation revealed an agammaglobulinemia (0.5 g/L; see Table I) with a strongly increased serum IgM"

Direct clinical documentation of agammaglobulinemia with elevated IgM in a patient with S32I mutation, consistent with defective class switching.

Absent Peripheral Lymph Nodes Absent peripheral lymph nodes in presence of infection (HP:0033581)

Show evidence (1 reference)

PMID:28597146 SUPPORT Human Clinical

"Specific immunological features, found in some, but not all patients, included a lack of peripheral lymph nodes, lymphocytosis, dysfunctional α/β T cells, and a lack of circulating γ/δ T cells."

Absence of peripheral lymph nodes is a recognized feature in some EDA-ID2 patients, consistent with defective lymphorganogenesis.

Elevated IgM with Agammaglobulinemia Increased circulating IgM level (HP:0003496)

Show evidence (1 reference)

PMID:15337789 SUPPORT Human Clinical

"immunological evaluation revealed an agammaglobulinemia (0.5 g/L; see Table I) with a strongly increased serum IgM"

Direct documentation of the hyper-IgM pattern in an EDA-ID2 patient.

Periorbital Wrinkles Periorbital wrinkles (HP:0000607)

Show evidence (1 reference)

PMID:15337789 SUPPORT Human Clinical

"several signs of ectodermal dysplasia became manifest and comprised abnormal dentition (typical conical teeth) and periorbital wrinkling"

Periorbital wrinkling observed alongside conical teeth as part of the ectodermal dysplasia features.

🧬

Genetic Associations

1

NFKBIA (CAUSATIVE)

Show evidence (4 references)

PMID:28629746 SUPPORT Human Clinical

"Disease severity was greater in patients with IκBα point mutations than in those with truncation mutations. IκBα point mutants were expressed at significantly higher levels in transfectants compared with truncation mutants."

Establishes genotype-phenotype correlation showing point mutations cause more severe disease due to higher mutant protein levels.

PMID:28597146 SUPPORT Human Clinical

"Eleven mutations, belonging to two groups, were identified: (i) missense mutations affecting S32, S36, or neighboring residues (8 mutations, 11 patients) and (ii) nonsense mutations upstream from S32 associated with the reinitiation of translation downstream from S36 (3 mutations, 3 patients)."

Comprehensive review classifying all known NFKBIA gain-of-function mutations into two functional groups.

PMID:14523047 SUPPORT Human Clinical

"an autosomal-dominant (AD) form of EDA-ID associated with a heterozygous missense mutation at serine 32 of IkappaBalpha"

Original report identifying the first NFKBIA gain-of-function mutation at the critical S32 phosphorylation site.

+ 1 more reference

💊

Treatments

3

Hematopoietic Stem Cell Transplantation

Action: hematopoietic stem cell transplantation MAXO:0000747

Allogeneic HSCT is the definitive treatment for the immunodeficiency component, but outcomes are poor with high transplant-related mortality. Five of eleven transplanted patients survived in a 2017 review, with four requiring continued prophylaxis. Poor outcomes are partly attributed to the non-hematopoietic (stromal) cell contribution to immunodeficiency, as mutant IkBa in stromal cells impairs lymphorganogenesis even after successful donor cell engraftment.

Show evidence (2 references)

PMID:28597146 SUPPORT Human Clinical

"In the absence of hematopoietic stem cell transplantation (HSCT), this condition cause death before the age of 1 year (one child). Two survivors have been on prophylaxis (at 9 and 22 years). Six children died after HSCT. Five survived, four of whom have been on prophylaxis (3 to 21 years post..."

Comprehensive outcomes data showing HSCT is necessary but carries high mortality, with variable immune reconstitution in survivors.

PMID:28629746 SUPPORT Human Clinical

"The outcome of hematopoietic stem cell transplantation is poor in patients with AD EDA-ID despite achievement of chimerism."

Demonstrates that poor HSCT outcomes persist despite chimerism, due to stromal cell contribution from non-hematopoietic compartment.

Antimicrobial Prophylaxis

Action: antimicrobial agent therapy MAXO:0001021

Prophylactic antimicrobials are essential for patients who do not undergo HSCT or who have incomplete immune reconstitution post-transplant. Includes antibacterial, antifungal, and Pneumocystis prophylaxis.

Immunoglobulin Replacement Therapy

Action: intravenous immunoglobulin therapy Ontology label: Intravenous Immunoglobulin Therapy NCIT:C121331

Intravenous or subcutaneous immunoglobulin replacement for patients with agammaglobulinemia or hypogammaglobulinemia.

Show evidence (1 reference)

PMID:15337789 SUPPORT Human Clinical

"From the second infection onwards, Ig substitution was initiated together with cotrimoxazole as P. carinii prophylaxis."

Demonstrates clinical use of immunoglobulin substitution and antimicrobial prophylaxis in managing an EDA-ID2 patient.

{ }

Source YAML

click to show

name: Ectodermal Dysplasia and Immunodeficiency 2
creation_date: "2026-04-24T00:00:00Z"
updated_date: "2026-04-25T00:00:00Z"
category: Mendelian
synonyms:
- EDA-ID2
- Anhidrotic ectodermal dysplasia with T-cell immunodeficiency, autosomal dominant
- NFKBIA-related ectodermal dysplasia with immunodeficiency
description: >
  Ectodermal dysplasia and immunodeficiency 2 (EDA-ID2) is a rare autosomal dominant
  disorder caused by heterozygous gain-of-function mutations in NFKBIA, encoding the
  NF-kB inhibitor IkBa. These mutations prevent phosphorylation at serines 32 and 36
  by the IKK complex, rendering IkBa resistant to ubiquitination and proteasomal
  degradation, which results in constitutive inhibition of NF-kB signaling.
  The disorder presents with anhidrotic ectodermal dysplasia features (hypohidrosis,
  sparse hair, conical teeth) combined with severe immunodeficiency affecting both
  innate and adaptive immunity. Patients are susceptible to pyogenic, mycobacterial,
  fungal, and viral infections. Most mutations occur de novo, and the condition
  carries high mortality without hematopoietic stem cell transplantation.
disease_term:
  preferred_term: ectodermal dysplasia and immunodeficiency 2
  term:
    id: MONDO:0012806
    label: ectodermal dysplasia and immunodeficiency 2
parents:
- Primary immunodeficiency
- Ectodermal dysplasia
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >
    Nearly all reported cases are de novo. One case of inheritance from a
    parent with somatic mosaicism has been documented.
  de_novo_rate: ">90%"
  evidence:
  - reference: PMID:28597146
    reference_title: "Human IκBα Gain of Function: a Severe and Syndromic Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The mutation certainly or probably occurred de novo in 13 patients,
      whereas it was inherited from a parent with somatic mosaicism in one
      patient.
    explanation: >-
      Comprehensive review of 14 patients shows 13/14 had de novo mutations,
      confirming autosomal dominant inheritance with very high de novo rate.
  - reference: PMID:15337789
    reference_title: "The same IkappaBalpha mutation in two related individuals leads to completely different clinical syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      his father has the same mutation but displays complex mosaicism
    explanation: >-
      Demonstrates somatic mosaicism in a parent as the mechanism of inherited
      transmission, with widely different clinical outcomes between father and son.
has_subtypes:
- name: Missense
  display_name: Missense mutations (S32/S36 region)
  description: >
    Point mutations at or adjacent to the S32/S36 phosphorylation sites.
    Associated with higher mutant protein levels and more severe disease,
    including full ectodermal dysplasia and profound immunodeficiency.
- name: Truncation
  display_name: N-terminal truncation mutations
  description: >
    Nonsense mutations upstream of S32 with reinitiation of translation
    downstream of S36, producing truncated IkBa lacking both phosphorylation
    sites. Generally associated with less severe disease.
genetic:
- name: NFKBIA
  gene_term:
    preferred_term: NFKBIA
    term:
      id: hgnc:7797
      label: NFKBIA
  association: CAUSATIVE
  features: >
    Two classes of gain-of-function mutations: (i) missense mutations affecting S32,
    S36, or neighboring residues (majority of patients), and (ii) nonsense mutations
    upstream from S32 associated with reinitiation of translation downstream from S36.
    Missense mutations tend to produce more severe phenotypes due to higher levels of
    gain-of-function protein. Genotype-phenotype correlation shows that point mutants
    accumulate at higher levels and cause greater impairment of both canonical and
    noncanonical NF-kB activity compared to truncation mutants.
  evidence:
  - reference: PMID:28629746
    reference_title: "Mechanisms of genotype-phenotype correlation in autosomal dominant anhidrotic ectodermal dysplasia with immune deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Disease severity was greater in patients with IκBα point mutations than
      in those with truncation mutations. IκBα point mutants were expressed at
      significantly higher levels in transfectants compared with truncation mutants.
    explanation: >-
      Establishes genotype-phenotype correlation showing point mutations cause
      more severe disease due to higher mutant protein levels.
  - reference: PMID:28597146
    reference_title: "Human IκBα Gain of Function: a Severe and Syndromic Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Eleven mutations, belonging to two groups, were identified: (i) missense
      mutations affecting S32, S36, or neighboring residues (8 mutations, 11
      patients) and (ii) nonsense mutations upstream from S32 associated with
      the reinitiation of translation downstream from S36 (3 mutations, 3 patients).
    explanation: >-
      Comprehensive review classifying all known NFKBIA gain-of-function mutations
      into two functional groups.
  - reference: PMID:14523047
    reference_title: "A hypermorphic IkappaBalpha mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      an autosomal-dominant (AD) form of EDA-ID associated with a heterozygous
      missense mutation at serine 32 of IkappaBalpha
    explanation: >-
      Original report identifying the first NFKBIA gain-of-function mutation
      at the critical S32 phosphorylation site.
  - reference: CGGV:assertion_3333d698-dd58-4601-80b9-1892f2893bdf-2025-02-10T170000.000Z
    reference_title: "NFKBIA / ectodermal dysplasia and immunodeficiency 2 (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "NFKBIA | HGNC:7797 | ectodermal dysplasia and immunodeficiency 2 | MONDO:0012806 | AD | Definitive"
    explanation: ClinGen classifies the NFKBIA-ectodermal dysplasia and immunodeficiency 2 gene-disease relationship as definitive with autosomal dominant inheritance.
pathophysiology:
- name: Constitutive NF-kB Inhibition by Gain-of-Function IkBa
  description: >
    Gain-of-function mutations in NFKBIA prevent phosphorylation of IkBa at
    serines 32 and 36 by the IKK complex, blocking ubiquitination and proteasomal
    degradation. The mutant IkBa constitutively sequesters NF-kB dimers in the
    cytoplasm, abolishing NF-kB-dependent transcriptional activation in response
    to stimulation of TLRs, IL-1 receptors, TNF receptors, TCR, and BCR.
  cell_types:
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T-cell
  biological_processes:
  - preferred_term: canonical NF-kappaB signaling
    term:
      id: GO:0007249
      label: canonical NF-kappaB signal transduction
  downstream:
  - target: Impaired T Cell Development and Function
  - target: Defective Innate Immune Signaling
  - target: B Cell Deficiency
  - target: Defective Lymph Node Development
  - target: Ectodermal Dysplasia
  evidence:
  - reference: PMID:14523047
    reference_title: "A hypermorphic IkappaBalpha mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This mutation is gain-of-function, as it enhances the inhibitory capacity of
      IkappaBalpha by preventing its phosphorylation and degradation, and results
      in impaired NF-kappaB activation.
    explanation: >-
      Original characterization of the gain-of-function mechanism by which mutant
      IkBa resists degradation and constitutively inhibits NF-kB.
  - reference: PMID:28597146
    reference_title: "Human IκBα Gain of Function: a Severe and Syndromic Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All mutations enhanced the inhibitory activity of IκBα, by preventing its
      phosphorylation on serine 32 or 36 and its subsequent degradation.
    explanation: >-
      Review confirming that all reported mutations share the same gain-of-function
      mechanism of preventing IkBa phosphorylation.
- name: Impaired T Cell Development and Function
  description: >
    NF-kB signaling is essential for T-cell development, activation, and survival.
    Constitutive IkBa-mediated NF-kB inhibition results in a unique T-cell
    immunodeficiency characterized by lymphocytosis with absence of memory T cells
    and failure of naive T cells to respond to TCR stimulation.
  cell_types:
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T-cell
  biological_processes:
  - preferred_term: T cell activation
    term:
      id: GO:0042110
      label: T cell activation
  - preferred_term: T cell proliferation
    term:
      id: GO:0042098
      label: T cell proliferation
  evidence:
  - reference: PMID:14523047
    reference_title: "A hypermorphic IkappaBalpha mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      AD-EDA-ID but not XL-EDA-ID is associated with a severe and unique T cell
      immunodeficiency. Despite a marked blood lymphocytosis, there are no
      detectable memory T cells in vivo, and naive T cells do not respond to
      CD3-TCR activation in vitro.
    explanation: >-
      Demonstrates the distinctive T-cell dysfunction pattern in EDA-ID2:
      lymphocytosis with absent memory T cells and unresponsive naive T cells.
  - reference: PMID:15337789
    reference_title: "The same IkappaBalpha mutation in two related individuals leads to completely different clinical syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      T cell receptor-mediated proliferation was also impaired.
    explanation: >-
      Independent confirmation of defective TCR-mediated T cell proliferation
      in a patient with the S32I IkBa mutation.
- name: Defective Innate Immune Signaling
  description: >
    NF-kB is a central mediator of innate immune responses downstream of
    Toll-like receptors. Constitutive IkBa inhibition impairs monocyte and
    macrophage activation, with absent IL-12 production in response to TLR
    stimulation and impaired NF-kB nuclear translocation, leading to
    susceptibility to mycobacterial and other intracellular pathogens.
  cell_types:
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  - preferred_term: dendritic cell
    term:
      id: CL:0000451
      label: dendritic cell
  biological_processes:
  - preferred_term: innate immune response
    term:
      id: GO:0045087
      label: innate immune response
  - preferred_term: toll-like receptor signaling pathway
    term:
      id: GO:0002224
      label: toll-like receptor signaling pathway
  evidence:
  - reference: PMID:14523047
    reference_title: "A hypermorphic IkappaBalpha mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      impaired cellular responses to ligands of TIR (TLR-ligands, IL-1beta,
      and IL-18), and TNFR (TNF-alpha, LTalpha1/beta2, and CD154) superfamily
      members and severe bacterial diseases
    explanation: >-
      Demonstrates broad impairment of innate immune signaling downstream of
      multiple receptor superfamilies due to NF-kB inhibition.
  - reference: PMID:15337789
    reference_title: "The same IkappaBalpha mutation in two related individuals leads to completely different clinical syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Monocytes did not produce interleukin 12p40 upon stimulation with various
      TLR stimuli and nuclear translocation of NF-kappaB was impaired.
    explanation: >-
      Directly demonstrates defective monocyte function with absent IL-12
      production and impaired NF-kB nuclear translocation.
- name: B Cell Deficiency
  description: >
    NF-kB signaling is required for B-cell development and function. Patients
    with IkBa gain-of-function mutations have profound B-cell deficiency with
    agammaglobulinemia or hyper-IgM phenotype, reflecting defective class-switch
    recombination.
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  biological_processes:
  - preferred_term: B cell activation
    term:
      id: GO:0042113
      label: B cell activation
  evidence:
  - reference: PMID:28597146
    reference_title: "Human IκBα Gain of Function: a Severe and Syndromic Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients had profound B-cell deficiency.
    explanation: >-
      Review confirms B-cell deficiency is a universal feature in EDA-ID2 patients.
  - reference: PMID:15337789
    reference_title: "The same IkappaBalpha mutation in two related individuals leads to completely different clinical syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a hyper immunoglobulin M-like immunodeficiency syndrome and ectodermal
      dysplasia
    explanation: >-
      Demonstrates hyper-IgM-like immunodeficiency as a manifestation of
      defective B-cell class switching in IkBa-mutant patients.
- name: Defective Lymph Node Development
  description: >
    Constitutive IkBa inhibition impairs both canonical and noncanonical NF-kB
    signaling. The noncanonical pathway drives expression of chemokines and
    adhesion molecules (CCL20, ICAM1, VCAM1) required for lymphorganogenesis.
    In the S32I knock-in mouse model, lymph nodes and Peyer's patches are
    completely absent. Defective stromal cell function contributes to persistent
    immunodeficiency even after HSCT, as the non-hematopoietic compartment
    retains the mutant IkBa.
  biological_processes:
  - preferred_term: lymph node development
    term:
      id: GO:0048535
      label: lymph node development
  evidence:
  - reference: PMID:28629746
    reference_title: "Mechanisms of genotype-phenotype correlation in autosomal dominant anhidrotic ectodermal dysplasia with immune deficiency."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      the S32I mutant completely lacks lymph nodes (LNs), Peyer's patches,
      marginal zone B cells and follicular dendritic cells, and fails to form
      germinal centers, features typical of defective non-canonical NF-κB
      signaling
    explanation: >-
      S32I knock-in mouse demonstrates that IkBa gain-of-function abolishes
      lymph node organogenesis through impaired noncanonical NF-kB signaling.
  - reference: PMID:28629746
    reference_title: "Mechanisms of genotype-phenotype correlation in autosomal dominant anhidrotic ectodermal dysplasia with immune deficiency."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      WT->S32I IκBα chimeras failed to form proper lymphoid organs and to
      reconstitute immune function despite excellent donor cell engraftment,
      paralleling the failure of HSCT to cure AD EDA-ID patients
    explanation: >-
      Demonstrates that defective stromal (non-hematopoietic) cell function
      contributes to persistent immunodeficiency, explaining poor HSCT outcomes.
- name: Ectodermal Dysplasia
  description: >
    NF-kB signaling through the ectodysplasin (EDA)/EDAR/NF-kB pathway is
    essential for ectodermal appendage development. Constitutive IkBa inhibition
    disrupts this pathway, leading to hypohidrosis from sweat gland hypoplasia,
    sparse hair, and conical or absent teeth. Notably, some S36 missense variants
    cause immunodeficiency without ectodermal dysplasia features.
  biological_processes:
  - preferred_term: ectodermal placode formation
    term:
      id: GO:0060788
      label: ectodermal placode formation
  evidence:
  - reference: PMID:28597146
    reference_title: "Human IκBα Gain of Function: a Severe and Syndromic Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thirteen patients had developmental features of EDA, the severity and
      nature of which differed between cases.
    explanation: >-
      EDA features are present in most but not all patients, with variable severity.
  - reference: PMID:31683054
    reference_title: "A novel NFKBIA variant substituting serine 36 of IκBα causes immunodeficiency with warts, bronchiectasis and juvenile rheumatoid arthritis in the absence of ectodermal dysplasia."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      missense NFKBIA variants substituting serine 36 of IκBα, differ from the
      rest of pathogenic GOF NFKBIA variants in that they cause combined
      immunodeficiency, even in the absence of EDA
    explanation: >-
      Demonstrates genotype-phenotype correlation where S36 variants can cause
      immunodeficiency without ectodermal dysplasia, indicating the EDA phenotype
      is not obligate.
phenotypes:
- category: Integumentary
  name: Hypohidrosis
  description: >
    Reduced or absent sweating due to sweat gland hypoplasia, a hallmark of
    ectodermal dysplasia. Present in most but not all patients.
  phenotype_term:
    preferred_term: Hypohidrosis
    term:
      id: HP:0000966
      label: Hypohidrosis
  evidence:
  - reference: PMID:28597146
    reference_title: "Human IκBα Gain of Function: a Severe and Syndromic Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thirteen patients had developmental features of EDA, the severity and
      nature of which differed between cases.
    explanation: >-
      Confirms ectodermal dysplasia features including hypohidrosis in the
      majority of patients.
- category: Integumentary
  name: Sparse Hair
  description: >
    Sparse scalp hair and reduced body hair due to defective hair follicle
    development as part of the ectodermal dysplasia spectrum.
  phenotype_term:
    preferred_term: Sparse scalp hair
    term:
      id: HP:0002209
      label: Sparse scalp hair
- category: Dental
  name: Conical Teeth
  description: >
    Small, conical-shaped teeth characteristic of ectodermal dysplasia.
  phenotype_term:
    preferred_term: Small, conical teeth
    term:
      id: HP:0200141
      label: Small, conical teeth
  evidence:
  - reference: PMID:15337789
    reference_title: "The same IkappaBalpha mutation in two related individuals leads to completely different clinical syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      several signs of ectodermal dysplasia became manifest and comprised
      abnormal dentition (typical conical teeth) and periorbital wrinkling
    explanation: >-
      Direct clinical observation of conical teeth as part of ectodermal
      dysplasia features in a patient with S32I IkBa mutation.
- category: Immunological
  name: Recurrent Infections
  description: >
    Severe recurrent pyogenic, mycobacterial, fungal, and viral infections
    due to combined T-cell, B-cell, and innate immune dysfunction.
  phenotype_term:
    preferred_term: Recurrent infections
    term:
      id: HP:0002719
      label: Recurrent infections
  evidence:
  - reference: PMID:28597146
    reference_title: "Human IκBα Gain of Function: a Severe and Syndromic Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patients had various pyogenic, mycobacterial, fungal, and viral
      severe infections.
    explanation: >-
      Review confirms broad spectrum of severe infections as a universal feature.
  - reference: PMID:35005117
    reference_title: "A heterozygous N-terminal truncation mutation of NFKBIA results in an impaired NF-κB dependent inflammatory response."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She presented recurrent fever, infectious pneumonia and chronic diarrhea
      with EDA-ID.
    explanation: >-
      Case report documenting recurrent infections in a patient with an
      N-terminal truncation NFKBIA mutation.
- category: Immunological
  name: Recurrent Mycobacterial Infections
  description: >
    Susceptibility to mycobacterial infections, including disseminated
    nontuberculous mycobacterial disease, reflecting defective macrophage
    activation and IL-12/IFN-gamma axis dysfunction.
  phenotype_term:
    preferred_term: Recurrent mycobacterial infections
    term:
      id: HP:0011274
      label: Recurrent mycobacterial infections
  evidence:
  - reference: PMID:28597146
    reference_title: "Human IκBα Gain of Function: a Severe and Syndromic Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patients had various pyogenic, mycobacterial, fungal, and viral
      severe infections.
    explanation: >-
      Review confirms mycobacterial infections as part of the broad infection
      susceptibility spectrum in EDA-ID2 patients.
- category: Immunological
  name: Lymphocytosis with Absent Memory T Cells
  description: >
    Characteristic immunological finding of marked blood lymphocytosis
    composed almost entirely of naive T cells, with no detectable memory
    T cells. Naive T cells fail to respond to CD3-TCR activation despite
    their increased numbers.
  phenotype_term:
    preferred_term: Increased total lymphocyte count
    term:
      id: HP:0100827
      label: Increased total lymphocyte count
  evidence:
  - reference: PMID:14523047
    reference_title: "A hypermorphic IkappaBalpha mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Despite a marked blood lymphocytosis, there are no detectable memory
      T cells in vivo, and naive T cells do not respond to CD3-TCR activation
      in vitro.
    explanation: >-
      Demonstrates the paradoxical lymphocytosis with absent memory T cells
      that is the hallmark T-cell abnormality of EDA-ID2.
  - reference: PMID:28597146
    reference_title: "Human IκBα Gain of Function: a Severe and Syndromic Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Specific immunological features, found in some, but not all patients,
      included a lack of peripheral lymph nodes, lymphocytosis, dysfunctional
      α/β T cells, and a lack of circulating γ/δ T cells.
    explanation: >-
      Confirms lymphocytosis as a feature in some patients, along with
      dysfunctional T cells and absent gamma/delta T cells.
- category: Immunological
  name: B Cell Deficiency
  description: >
    Profound reduction in circulating B cells, a universal finding in patients
    with IkBa gain-of-function mutations.
  phenotype_term:
    preferred_term: Decreased total B cell count
    term:
      id: HP:0010976
      label: Decreased total B cell count
  evidence:
  - reference: PMID:28597146
    reference_title: "Human IκBα Gain of Function: a Severe and Syndromic Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients had profound B-cell deficiency.
    explanation: >-
      Universal feature confirmed across all reported EDA-ID2 patients.
- category: Immunological
  name: Agammaglobulinemia
  description: >
    Absent or severely reduced circulating immunoglobulins (IgG, IgA) due to
    B-cell deficiency, often presenting with a hyper-IgM-like pattern.
  phenotype_term:
    preferred_term: Agammaglobulinemia
    term:
      id: HP:0004432
      label: Agammaglobulinemia
  evidence:
  - reference: PMID:15337789
    reference_title: "The same IkappaBalpha mutation in two related individuals leads to completely different clinical syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      immunological evaluation revealed an agammaglobulinemia (0.5 g/L; see
      Table I) with a strongly increased serum IgM
    explanation: >-
      Direct clinical documentation of agammaglobulinemia with elevated IgM
      in a patient with S32I mutation, consistent with defective class switching.
- category: Immunological
  name: Absent Peripheral Lymph Nodes
  description: >
    Absence of palpable peripheral lymph nodes despite active infections,
    reflecting defective lymphorganogenesis from impaired noncanonical
    NF-kB signaling in stromal cells.
  phenotype_term:
    preferred_term: Absent peripheral lymph nodes in presence of infection
    term:
      id: HP:0033581
      label: Absent peripheral lymph nodes in presence of infection
  evidence:
  - reference: PMID:28597146
    reference_title: "Human IκBα Gain of Function: a Severe and Syndromic Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Specific immunological features, found in some, but not all patients,
      included a lack of peripheral lymph nodes, lymphocytosis, dysfunctional
      α/β T cells, and a lack of circulating γ/δ T cells.
    explanation: >-
      Absence of peripheral lymph nodes is a recognized feature in some
      EDA-ID2 patients, consistent with defective lymphorganogenesis.
- category: Immunological
  name: Elevated IgM with Agammaglobulinemia
  description: >
    Hyper-IgM-like immunodeficiency pattern with strongly increased serum
    IgM and absent or severely reduced IgG and IgA, reflecting defective
    immunoglobulin class-switch recombination.
  phenotype_term:
    preferred_term: Increased circulating IgM level
    term:
      id: HP:0003496
      label: Increased circulating IgM level
  evidence:
  - reference: PMID:15337789
    reference_title: "The same IkappaBalpha mutation in two related individuals leads to completely different clinical syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      immunological evaluation revealed an agammaglobulinemia (0.5 g/L; see
      Table I) with a strongly increased serum IgM
    explanation: >-
      Direct documentation of the hyper-IgM pattern in an EDA-ID2 patient.
- category: Integumentary
  name: Periorbital Wrinkles
  description: >
    Periorbital wrinkling as part of the ectodermal dysplasia phenotype.
  phenotype_term:
    preferred_term: Periorbital wrinkles
    term:
      id: HP:0000607
      label: Periorbital wrinkles
  evidence:
  - reference: PMID:15337789
    reference_title: "The same IkappaBalpha mutation in two related individuals leads to completely different clinical syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      several signs of ectodermal dysplasia became manifest and comprised
      abnormal dentition (typical conical teeth) and periorbital wrinkling
    explanation: >-
      Periorbital wrinkling observed alongside conical teeth as part of the
      ectodermal dysplasia features.
treatments:
- name: Hematopoietic Stem Cell Transplantation
  description: >
    Allogeneic HSCT is the definitive treatment for the immunodeficiency
    component, but outcomes are poor with high transplant-related mortality.
    Five of eleven transplanted patients survived in a 2017 review, with
    four requiring continued prophylaxis. Poor outcomes are partly attributed
    to the non-hematopoietic (stromal) cell contribution to immunodeficiency,
    as mutant IkBa in stromal cells impairs lymphorganogenesis even after
    successful donor cell engraftment.
  treatment_term:
    preferred_term: hematopoietic stem cell transplantation
    term:
      id: MAXO:0000747
      label: hematopoietic stem cell transplantation
  evidence:
  - reference: PMID:28597146
    reference_title: "Human IκBα Gain of Function: a Severe and Syndromic Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the absence of hematopoietic stem cell transplantation (HSCT), this
      condition cause death before the age of 1 year (one child). Two survivors
      have been on prophylaxis (at 9 and 22 years). Six children died after HSCT.
      Five survived, four of whom have been on prophylaxis (3 to 21 years post
      HSCT), whereas one has been well with no prophylaxis.
    explanation: >-
      Comprehensive outcomes data showing HSCT is necessary but carries high
      mortality, with variable immune reconstitution in survivors.
  - reference: PMID:28629746
    reference_title: "Mechanisms of genotype-phenotype correlation in autosomal dominant anhidrotic ectodermal dysplasia with immune deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The outcome of hematopoietic stem cell transplantation is poor in patients
      with AD EDA-ID despite achievement of chimerism.
    explanation: >-
      Demonstrates that poor HSCT outcomes persist despite chimerism, due to
      stromal cell contribution from non-hematopoietic compartment.
- name: Antimicrobial Prophylaxis
  description: >
    Prophylactic antimicrobials are essential for patients who do not undergo
    HSCT or who have incomplete immune reconstitution post-transplant.
    Includes antibacterial, antifungal, and Pneumocystis prophylaxis.
  treatment_term:
    preferred_term: antimicrobial agent therapy
    term:
      id: MAXO:0001021
      label: antimicrobial agent therapy
- name: Immunoglobulin Replacement Therapy
  description: >
    Intravenous or subcutaneous immunoglobulin replacement for patients
    with agammaglobulinemia or hypogammaglobulinemia.
  treatment_term:
    preferred_term: intravenous immunoglobulin therapy
    term:
      id: NCIT:C121331
      label: Intravenous Immunoglobulin Therapy
  evidence:
  - reference: PMID:15337789
    reference_title: "The same IkappaBalpha mutation in two related individuals leads to completely different clinical syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      From the second infection onwards, Ig substitution was initiated together
      with cotrimoxazole as P. carinii prophylaxis.
    explanation: >-
      Demonstrates clinical use of immunoglobulin substitution and antimicrobial
      prophylaxis in managing an EDA-ID2 patient.
datasets:

📚

References & Deep Research

Deep Research

1

Falcon ▸

Disease Characteristics Research Template

Edison Scientific Literature 49 citations 2026-04-24T18:32:33.969727

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

Disease Name: Ectodermal Dysplasia and Immunodeficiency 2
MONDO ID: (if available)
Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Ectodermal Dysplasia and Immunodeficiency 2 covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

What is the disease? Provide a concise overview.
What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
What are the common synonyms and alternative names?
Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
Risk Factors:

Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases
Genetic risk factors (causal variants, susceptibility loci, modifier genes)
Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
Protective Factors:

Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases
Genetic protective factors (protective variants, modifier alleles)
Environmental protective factors (diet, lifestyle, exposures that reduce risk)
Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene
Pathogenic Variants:
Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
Variant type/class (missense, frameshift, nonsense, splice-site, structural)
Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
Functional consequences (loss of function, gain of function, dominant negative)
Modifier Genes: Genes that modify disease severity or expression
Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases
Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

Search first: CDC databases, WHO, PubMed, NHANES
Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc
Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

Search first: Gene Ontology (GO), Reactome, KEGG, PubMed
Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold
Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA
Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

Search first: ImmPort, Immunome Database, IEDB, Gene Ontology
Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

Search first: PubMed, Gene Ontology, Reactome
Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

Search first: BRENDA, UniProt, KEGG, OMIM, PubMed
Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Molecular Profiling (if available):
Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
Advanced Technologies (if applicable):
Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

Organ Level:
Primary organs directly affected
Secondary organ involvement (complications, secondary effects)
Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT
Tissue and Cell Level:
Specific tissue types affected (epithelial, connective, muscle, nervous)
Specific cell populations targeted (with Cell Ontology terms)

Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB
Subcellular Level:
Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas
Localization:
Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

Onset:
Typical age of onset (congenital, pediatric, adult, geriatric)
Onset pattern (acute, subacute, chronic, insidious)

Search first: OMIM, Orphanet, HPO, PubMed
Progression:
Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
Progression rate (rapid, slow, variable)
Disease course pattern (episodic, relapsing-remitting, progressive, stable)
Disease duration (self-limited, chronic lifelong)

Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM
Patterns:
Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

Epidemiology:
Prevalence (cases per 100,000 at given time)
Incidence (new cases per 100,000 per year)

Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries
For Genetic Etiology:
Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
Population Demographics:
Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
Geographic distribution of specific variants
Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

Clinical Tests:
Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
Genetic Testing:

Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen
Overview of recommended genetic testing approach
Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
FISH > Search first: ClinVar, cytogenetics databases, PubMed
Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
Omics-Based Diagnostics (if applicable):
RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
Clinical Criteria:
Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
Screening:
Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

Survival and Mortality:
Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
Morbidity and Function:
Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
Disease Course:
Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
Prediction:
Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

Pharmacotherapy:
Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
Advanced Therapeutics:
Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
Surgical and Interventional:
Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
Supportive and Rehabilitative:
Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
Experimental:
Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
Treatment Outcomes:
Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
Treatment Strategy:
Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest MAXO (Medical Action Ontology) terms where applicable.

13. Prevention

Prevention Levels:
Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
Immunization: Vaccine strategies (if applicable)

Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database
Screening and Early Detection:
Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
Behavioral Interventions: Lifestyle modifications to reduce risk

Search first: CDC, WHO, behavioral intervention databases, Cochrane Library
Counseling: Genetic counseling (risk assessment, family planning guidance)

Search first: NSGC resources, ACMG guidelines, GeneReviews
Public Health:
Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
Prophylaxis: Preventive medications or procedures

Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

Taxonomy: Species affected (with NCBI Taxon identifiers)

Search first: NCBI Taxonomy
Breed: Specific breeds affected (with VBO identifiers if applicable)

Search first: VBO (Vertebrate Breed Ontology)
Gene: Orthologous genes in other species (with NCBI Gene IDs)

Search first: NCBI Gene
Natural Disease:
Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
Comparative Biology:
Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
Transmission (if applicable):
Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

Model Types:
Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
Genetic Models:
Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
Model Characteristics:
Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
Applications:
Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
Resources:
Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

Cite primary literature (PMID preferred) for all mechanistic and clinical claims
Prioritize recent reviews and landmark papers
Include direct quotes from abstracts where possible to support key statements
Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, MAXO, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (MAXO terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Disease Characteristics Research Report: Ectodermal Dysplasia and Immunodeficiency 2 (EDID2)

Executive summary

Ectodermal dysplasia and immunodeficiency 2 (EDID2) is an ultra-rare, autosomal dominant inborn error of immunity caused by germline NFKBIA (IκBα) variants that render IκBα degradation-resistant, thereby suppressing stimulus-induced NF-κB activation. This produces a syndromic combined immunodeficiency with classic ectodermal defects (hair/teeth/sweat gland abnormalities) and recurrent severe infections; some patients also develop prominent sterile systemic inflammation and/or autoimmune features. Pathogenic variants cluster at the IκBα N-terminal phosphodegron (around Ser32/Ser36) or create N-terminal truncations removing these residues, leading to defective IκBα phosphorylation/ubiquitination/degradation and impaired NF-κB nuclear translocation and transcriptional responses. (petersheim2018mechanismsofgenotypephenotype pages 1-6, lopezgranados2008anovelmutation pages 1-2, wen2022aheterozygousnterminal pages 1-2, schimke2013anovelgainoffunction pages 1-2)

The most consistent actionable clinical implications are: (i) ensure early immunologic evaluation in any patient with ectodermal dysplasia plus infections; (ii) test functional antibody responses, including anti-polysaccharide responses; (iii) implement immunoglobulin replacement and antimicrobial/antifungal prophylaxis when indicated; and (iv) recognize that HSCT has been high-risk with substantial mortality and frequent persistence of partial immunodeficiency and ectodermal findings. (kawai2012diagnosisandtreatment pages 8-9, derfalvi2020adaandpnp pages 13-16, fasshauer2024monogenicinbornerrors pages 2-4)

1. Disease information

1.1 Overview and current definition

EDID2 (also described in the literature as autosomal dominant anhidrotic ectodermal dysplasia with immunodeficiency, AD EDA-ID) is a syndromic immunodeficiency characterized by ectodermal abnormalities (hair, teeth, sweat glands) with recurrent severe infections and variable immune dysregulation, caused by heterozygous pathogenic variants in NFKBIA, encoding IκBα, a major inhibitor of NF-κB. (petersheim2018mechanismsofgenotypephenotype pages 1-6, derfalvi2020adaandpnp pages 13-16, chear2022anovelde pages 1-2)

A succinct mechanistic definition supported by primary literature is that EDID2 results from IκBα variants that resist normal phosphorylation/degradation, causing blunted canonical NF-κB activation after TNF/TLR/IL-1R/CD40 signaling, with downstream failure of appropriate innate/adaptive immune responses. (wen2022aheterozygousnterminal pages 1-2, schimke2013anovelgainoffunction pages 1-2, derfalvi2020adaandpnp pages 13-16)

1.2 Key identifiers and nomenclature

Identifier system	ID	Name used	Source citation	URL
OMIM	612132	Ectodermal dysplasia and immunodeficiency 2	(derfalvi2020adaandpnp pages 13-16)	https://omim.org/entry/612132
MONDO	MONDO:0012806	ectodermal dysplasia and immunodeficiency 2	(derfalvi2020adaandpnp pages 13-16)	https://monarchinitiative.org/disease/MONDO:0012806
Gene association	NFKBIA	NFKBIA-related ectodermal dysplasia with immunodeficiency 2	(petersheim2018mechanismsofgenotypephenotype pages 1-6, derfalvi2020adaandpnp pages 13-16, schimke2013anovelgainoffunction pages 1-2)	https://www.ncbi.nlm.nih.gov/gene/4792
Literature synonym	—	autosomal dominant anhidrotic ectodermal dysplasia with immunodeficiency	(petersheim2018mechanismsofgenotypephenotype pages 1-6, chear2022anovelde pages 1-2)	https://doi.org/10.1016/j.jaci.2017.05.030
Literature synonym	—	autosomal-dominant EDA-ID	(derfalvi2020adaandpnp pages 13-16, chear2022anovelde pages 1-2)	https://doi.org/10.1007/978-1-4614-8678-7_172
Literature synonym	—	AD EDA-ID	(petersheim2018mechanismsofgenotypephenotype pages 1-6, schimke2013anovelgainoffunction pages 1-2)	https://doi.org/10.1016/j.jaci.2017.05.030
Literature synonym	—	IκBα-related EDA-ID	(derfalvi2020adaandpnp pages 13-16, schimke2013anovelgainoffunction pages 1-2)	https://doi.org/10.1007/s10875-013-9906-1
Literature synonym	—	ectodermal dysplasia with immunodeficiency (NFKBIA form)	(lopezgranados2008anovelmutation pages 1-2, schimke2013anovelgainoffunction pages 1-2)	https://doi.org/10.1002/humu.20740
Related but distinct disorder	OMIM 300291 / IKBKG	X-linked anhidrotic ectodermal dysplasia with immunodeficiency (XL-EDA-ID; NEMO-related), distinct from EDID2	(lopezgranados2008anovelmutation pages 1-2, kawai2012diagnosisandtreatment pages 8-9)	https://omim.org/entry/300291

Table: This table summarizes the principal identifiers and commonly used names for Ectodermal Dysplasia and Immunodeficiency 2, highlighting its OMIM and MONDO entries and its association with NFKBIA. It also distinguishes the autosomal dominant NFKBIA-related disorder from the related but separate X-linked IKBKG/NEMO form.

Notes on resource provenance: The knowledge for EDID2 is derived largely from aggregated disease resources (OMIM/MONDO) plus individual patient case reports and small case series due to extreme rarity. Published numbers in reviews/summaries are on the order of tens of patients worldwide (see Epidemiology). (wen2022aheterozygousnterminal pages 1-2, derfalvi2020adaandpnp pages 13-16)

2. Etiology

2.1 Disease causal factors

Primary cause: germline, heterozygous pathogenic variants in NFKBIA (IκBα). Inheritance is autosomal dominant, frequently de novo in reported cases. (schimke2013anovelgainoffunction pages 1-2, chear2022anovelde pages 2-4, moriya2018ikbas32mutations pages 1-2)

Variant classes: - Missense variants at/near the IκBα N-terminal degron Ser32/Ser36 (e.g., Ser32 substitutions). (petersheim2018mechanismsofgenotypephenotype pages 1-6, moriya2018ikbas32mutations pages 1-2) - N-terminal truncations eliminating these phospho-acceptor sites (e.g., early stop with downstream reinitiation producing a truncated protein). (lopezgranados2008anovelmutation pages 1-2, wen2022aheterozygousnterminal pages 1-2)

A concise genotype summary is provided in: | Gene (HGNC) | Protein | Inheritance | Pathogenic mechanism | Variant hotspots/classes | Functional consequence on NF-κB signaling | Key phenotype associations | Key citations with URLs and publication year | |---|---|---|---|---|---|---|---| | NFKBIA (HGNC:7797) | IκBα / NF-κB inhibitor alpha | Autosomal dominant | Hypermorphic / gain-of-function inhibitory effect; often functionally dominant-negative toward canonical NF-κB activation | Missense substitutions at or near the N-terminal degron containing Ser32/Ser36; recurrent classes include Ser32 and nearby residue changes; examples: p.Ser32R, p.Ser32N, p.Ser32Cys, p.Met37Lys | Mutant IκBα resists stimulus-induced phosphorylation/degradation, remains bound to NF-κB, and impairs nuclear translocation and transcriptional activation of downstream targets; point mutants are associated with stronger inhibition and more severe phenotype than truncations in comparative studies | Anhidrotic/hypohidrotic ectodermal dysplasia, sparse hair, conical/abnormal teeth, absent sweat glands, recurrent severe bacterial/fungal/viral infections, hypogammaglobulinemia or dysgammaglobulinemia/hyper-IgM-like phenotype, reduced memory B cells, reduced memory/Treg compartments, mucocutaneous candidiasis, systemic inflammation in some patients (petersheim2018mechanismsofgenotypephenotype pages 1-6, schimke2013anovelgainoffunction pages 1-2, moriya2018ikbas32mutations pages 1-2) | Petersheim et al., J Allergy Clin Immunol 2018, https://doi.org/10.1016/j.jaci.2017.05.030 (petersheim2018mechanismsofgenotypephenotype pages 1-6); Schimke et al., J Clin Immunol 2013, https://doi.org/10.1007/s10875-013-9906-1 (schimke2013anovelgainoffunction pages 1-2); Moriya et al., J Clin Immunol 2018, https://doi.org/10.1007/s10875-018-0522-y (moriya2018ikbas32mutations pages 1-2); Chear et al., Genes 2022, https://doi.org/10.3390/genes13101900 (chear2022anovelde pages 2-4, chear2022anovelde pages 1-2) | | NFKBIA (HGNC:7797) | IκBα / NF-κB inhibitor alpha | Autosomal dominant | Hypermorphic truncation allele producing degradation-resistant N-terminally truncated protein | N-terminal truncations lacking Ser32/Ser36 phosphorylation sites; example: p.Glu14* with downstream reinitiation generating truncated IκBα | Loss of N-terminal phospho-acceptor region prevents normal IKK-mediated degradation; truncated protein persists and suppresses NF-κB activation in lymphocytes/monocytes; generally associated with somewhat milder signaling impairment than Ser32/Ser36 point mutants in genotype-phenotype analyses | Early-onset ectodermal dysplasia with immunodeficiency, anhidrosis, failure to thrive, recurrent diarrhea, opportunistic infection (including Pneumocystis), bacteremia, interstitial lung disease, severe infantile course with poor transplant outcome in reported cases (lopezgranados2008anovelmutation pages 1-2, wen2022aheterozygousnterminal pages 1-2) | Lopez-Granados et al., Hum Mutat 2008, https://doi.org/10.1002/humu.20740 (lopezgranados2008anovelmutation pages 1-2); Wen et al., Genes & Diseases 2022, https://doi.org/10.1016/j.gendis.2021.03.005 (wen2022aheterozygousnterminal pages 1-2); Petersheim et al., J Allergy Clin Immunol 2018, https://doi.org/10.1016/j.jaci.2017.05.030 (petersheim2018mechanismsofgenotypephenotype pages 1-6) | | NFKBIA (HGNC:7797) | IκBα / NF-κB inhibitor alpha | Usually de novo autosomal dominant | GOF/hypermorphic inhibitory allele affecting conserved degron/post-translational regulation | Degron variant p.Ser32Cys in the conserved Asp31-Ser36 motif | Predicted loss of phosphorylation at Ser32 and altered post-translational modification state, impairing NF-κB activation; mechanistically linked to defective class-switch recombination / somatic hypermutation via reduced induction of AID/UNG downstream of NF-κB | Mild ectodermal dysplasia with dysgammaglobulinemia or hyper-IgM-like presentation, persistent mucocutaneous candidiasis, severe recurrent bacterial/fungal infections, low IgG/IgA with elevated IgM, suspicion of Hyper-IgM syndrome before molecular diagnosis (chear2022anovelde pages 2-4, chear2022anovelde pages 1-2) | Chear et al., Genes 2022, https://doi.org/10.3390/genes13101900 (chear2022anovelde pages 2-4, chear2022anovelde pages 1-2) | | NFKBIA (HGNC:7797) | IκBα / NF-κB inhibitor alpha | Autosomal dominant | GOF/hypermorphic missense affecting residue adjacent to degron | p.Met37Lys | Abolished IκBα degradation after TNF-α/TLR stimulation, impaired NF-κB nuclear translocation, reduced NF-κB-dependent reporter activity, impaired cytokine responses including IL-6 and IL-10 pathways | Classic ectodermal dysplasia with profound combined immunodeficiency, recurrent mucocutaneous candidiasis, decreased IL-17+ T cells, and polyendocrinopathy/hypothyroidism-hypopituitarism in the reported patient (schimke2013anovelgainoffunction pages 1-2) | Schimke et al., J Clin Immunol 2013, https://doi.org/10.1007/s10875-013-9906-1 (schimke2013anovelgainoffunction pages 1-2) | | NFKBIA (HGNC:7797) | IκBα / NF-κB inhibitor alpha | Autosomal dominant, often de novo | GOF/hypermorphic Ser32 mutants with particularly strong inhibitory effect | p.Ser32Arg, p.Ser32Asn | Strong suppression of NF-κB activation in functional assays; associated with especially severe impairment of immune-cell differentiation and inflammatory control | Ectodermal dysplasia plus severe noninfectious systemic inflammation, persistent CRP elevation, pulmonary infiltrates, CNS inflammation, lymphocytosis, low immunoglobulins, near-absence of memory T cells/Tregs, reduced memory B cells; steroids may control inflammation but transplant benefit may be incomplete (moriya2018ikbas32mutations pages 1-2) | Moriya et al., J Clin Immunol 2018, https://doi.org/10.1007/s10875-018-0522-y (moriya2018ikbas32mutations pages 1-2) | | NFKBIA (HGNC:7797) | IκBα / NF-κB inhibitor alpha | Autosomal dominant | Overall disease mechanism across EDID2 | Published mutational spectrum includes missense variants at/near Ser32/Ser36 and N-terminal truncations; reported totals in reviews/case summaries were approximately 11 mutations in 14 patients or ~19 patients by 2020-2022 literature snapshots | Shared mechanism is impaired stimulus-induced IκBα turnover, defective canonical NF-κB signaling, and secondary defects in TIR/TNFR1/CD40/TCR-linked immune responses; comparative work also implicates impaired noncanonical NF-κB/lymphoid organogenesis in some alleles | Broad phenotype spectrum: ectodermal malformations, recurrent severe infections, poor vaccine/polysaccharide antibody responses, enlarged total B-cell pool with reduced/absent memory B cells, defective T-cell proliferation, chronic diarrhea/colitis, occasional mycobacterial disease, and incomplete correction after HSCT (petersheim2018mechanismsofgenotypephenotype pages 1-6, wen2022aheterozygousnterminal pages 1-2, derfalvi2020adaandpnp pages 13-16) | Petersheim et al., J Allergy Clin Immunol 2018, https://doi.org/10.1016/j.jaci.2017.05.030 (petersheim2018mechanismsofgenotypephenotype pages 1-6); Wen et al., Genes & Diseases 2022, https://doi.org/10.1016/j.gendis.2021.03.005 (wen2022aheterozygousnterminal pages 1-2); Derfalvi, Encyclopedia of Medical Immunology 2020, https://doi.org/10.1007/978-1-4614-8678-7_172 (derfalvi2020adaandpnp pages 13-16) |

Table: This table summarizes the genetic etiology of ectodermal dysplasia and immunodeficiency 2, focusing on pathogenic NFKBIA variant classes, their effects on NF-κB signaling, and the main associated clinical phenotypes. It is useful for linking genotype classes to mechanism and disease presentation.

2.2 Risk factors

Because EDID2 is Mendelian, the dominant risk factor is carrying a pathogenic NFKBIA variant (often de novo). No robust environmental susceptibility factors were identified in the retrieved corpus.

2.3 Protective factors / gene–environment interactions

No validated protective genetic variants or gene–environment interaction studies specific to EDID2 were identified in the retrieved papers.

3. Phenotypes

3.1 Core phenotype spectrum (with HPO suggestions)

Domain	Phenotype	Suggested HPO term(s)	Typical onset/course	Notes/frequency	Key citations
Ectodermal	Sparse scalp hair / hypotrichosis	HP:0001006 Hypotrichosis	Congenital or infancy; persistent	Recurrently reported across NFKBIA cases; part of the core ectodermal phenotype in AD EDA-ID (wen2022aheterozygousnterminal pages 1-2, schimke2013anovelgainoffunction pages 1-2, moriya2018ikbas32mutations pages 1-2)	(wen2022aheterozygousnterminal pages 1-2, schimke2013anovelgainoffunction pages 1-2, moriya2018ikbas32mutations pages 1-2)
Ectodermal	Absent or reduced sweating / anhidrosis-hypohidrosis	HP:0000977 Hypohidrosis; HP:0000963 Abnormality of sweating	Congenital/early infancy; lifelong	Classic feature; reported with absent sweat glands and abnormal sweat testing in severe infantile cases (lopezgranados2008anovelmutation pages 1-2, derfalvi2020adaandpnp pages 13-16)	(lopezgranados2008anovelmutation pages 1-2, derfalvi2020adaandpnp pages 13-16)
Ectodermal	Absent sweat glands	HP:0030436 Aplasia/Hypoplasia of sweat glands	Congenital; structural	Pathology-confirmed in some cases; useful distinguishing sign of EDID2 from isolated antibody defects (lopezgranados2008anovelmutation pages 1-2, moriya2018ikbas32mutations pages 1-2)	(lopezgranados2008anovelmutation pages 1-2, moriya2018ikbas32mutations pages 1-2)
Ectodermal	Conical or abnormal teeth / tooth anomalies	HP:0000699 Conical teeth; HP:0006483 Abnormality of dentition	Childhood, when dentition emerges; persistent	Common ectodermal clue; conical teeth specifically described in severe S32-mutant cases (moriya2018ikbas32mutations pages 1-2)	(moriya2018ikbas32mutations pages 1-2, derfalvi2020adaandpnp pages 13-16)
Ectodermal	Sparse or absent eyebrows	HP:0045075 Sparse eyebrow	Infancy; persistent	Described in infant truncation case; often accompanies hypotrichosis (wen2022aheterozygousnterminal pages 1-2)	(wen2022aheterozygousnterminal pages 1-2)
Immune	Hypogammaglobulinemia	HP:0004313 Decreased circulating immunoglobulin level	Infancy/early childhood; chronic	Major immune phenotype; may coexist with severe infections and poor vaccine responses (lopezgranados2008anovelmutation pages 1-2, moriya2018ikbas32mutations pages 1-2, kawai2012diagnosisandtreatment pages 8-9)	(lopezgranados2008anovelmutation pages 1-2, moriya2018ikbas32mutations pages 1-2, kawai2012diagnosisandtreatment pages 8-9)
Immune	Dysgammaglobulinemia / hyper-IgM-like pattern	HP:0012140 Abnormal immunoglobulin level; HP:0003237 Hypergammaglobulinemia of IgM	Infancy or toddler years; chronic/variable	Case reports describe elevated IgM with low IgG/IgA despite preserved CD40/CD40L; can mimic Hyper-IgM syndrome (chear2022anovelde pages 2-4, chear2022anovelde pages 1-2)	(chear2022anovelde pages 2-4, chear2022anovelde pages 1-2)
Immune	Poor or absent vaccine antibody responses, especially to polysaccharide antigens	HP:0033258 Abnormality of humoral immune system physiology	Early childhood after immunization/testing; persistent	A key diagnostic clue; reviews emphasize impaired response to polysaccharide antigens despite some preserved protein responses. Reported in NFKBIA series and highlighted for routine workup (derfalvi2020adaandpnp pages 13-16, kawai2012diagnosisandtreatment pages 8-9, fasshauer2024monogenicinbornerrors pages 2-4)	(derfalvi2020adaandpnp pages 13-16, kawai2012diagnosisandtreatment pages 8-9, fasshauer2024monogenicinbornerrors pages 2-4)
Immune	Reduced or absent memory B cells	HP:0005428 Absent B cells is too narrow; suggested: HP:0011839 Abnormal B-cell subset distribution	Childhood; persistent	Recurrent across reported patients; Derfalvi summary notes enlarged total B-cell counts with reduced/absent memory B cells (derfalvi2020adaandpnp pages 13-16, moriya2018ikbas32mutations pages 1-2)	(derfalvi2020adaandpnp pages 13-16, moriya2018ikbas32mutations pages 1-2)
Immune	Predominance of naïve T cells / absent memory T cells	HP:0011837 Abnormal T-cell subset distribution	Childhood; persistent	Near absence of CD45RO+ memory T cells reported in severe inflammatory S32-mutant cases; supports combined immunodeficiency phenotype (moriya2018ikbas32mutations pages 1-2, giancane2013anhidroticectodermaldysplasia pages 3-3)	(moriya2018ikbas32mutations pages 1-2, giancane2013anhidroticectodermaldysplasia pages 3-3)
Immune	Reduced/absent regulatory T cells	HP:0012441 Abnormal regulatory T-cell count	Childhood; persistent	Reported in severe NFKBIA S32-mutant patients with inflammation (moriya2018ikbas32mutations pages 1-2)	(moriya2018ikbas32mutations pages 1-2)
Immune	Impaired T-cell proliferation / defective TCR-mediated responses	HP:0002843 Abnormal T-cell function	Childhood; persistent	Seen in review summaries and clinical reports; contributes to combined immunodeficiency phenotype (derfalvi2020adaandpnp pages 13-16, kawai2012diagnosisandtreatment pages 6-7, kawai2012diagnosisandtreatment pages 7-8)	(derfalvi2020adaandpnp pages 13-16, kawai2012diagnosisandtreatment pages 6-7, kawai2012diagnosisandtreatment pages 7-8)
Immune	Impaired innate receptor signaling (TLR/IL-1R/TNFR1/CD40 pathways)	HP:0033255 Abnormal innate immunity	Congenital molecular defect; detected on functional testing	Central mechanistic immune abnormality of EDID2; explains susceptibility to bacterial, fungal, and mycobacterial pathogens (wen2022aheterozygousnterminal pages 1-2, schimke2013anovelgainoffunction pages 1-2, derfalvi2020adaandpnp pages 13-16, kawai2012diagnosisandtreatment pages 9-10)	(wen2022aheterozygousnterminal pages 1-2, schimke2013anovelgainoffunction pages 1-2, derfalvi2020adaandpnp pages 13-16, kawai2012diagnosisandtreatment pages 9-10)
Infectious	Recurrent severe bacterial infections	HP:0002718 Recurrent bacterial infections	Infancy/early childhood; recurrent	Common and often life-threatening; organisms reported include Klebsiella, Pseudomonas, Haemophilus, Streptococcus, Staphylococcus (derfalvi2020adaandpnp pages 13-16)	(derfalvi2020adaandpnp pages 13-16)
Infectious	Recurrent pneumonia / severe sinopulmonary infection	HP:0006536 Recurrent pneumonia; HP:0002205 Recurrent respiratory infections	Infancy/early childhood; recurrent	Frequent presenting feature; can progress to respiratory failure or bronchiectatic damage if diagnosis delayed (wen2022aheterozygousnterminal pages 1-2, chear2022anovelde pages 2-4, fasshauer2024monogenicinbornerrors pages 2-4)	(wen2022aheterozygousnterminal pages 1-2, chear2022anovelde pages 2-4, fasshauer2024monogenicinbornerrors pages 2-4)
Infectious	Chronic mucocutaneous candidiasis / oral candidiasis	HP:0002721 Chronic mucocutaneous candidiasis; HP:0000202 Oral thrush	Infancy/childhood; recurrent or persistent	Strongly represented in NFKBIA cases, including oral and perianal thrush; linked with impaired IL-17 immunity in one patient (schimke2013anovelgainoffunction pages 1-2, chear2022anovelde pages 2-4, moriya2018ikbas32mutations pages 1-2)	(schimke2013anovelgainoffunction pages 1-2, chear2022anovelde pages 2-4, moriya2018ikbas32mutations pages 1-2)
Infectious	Opportunistic infection including Pneumocystis jirovecii	HP:0002724 Opportunistic infections	Infancy; severe	Reported in severe truncation cases and highlighted in reviews as an important complication (lopezgranados2008anovelmutation pages 1-2, kawai2012diagnosisandtreatment pages 7-8)	(lopezgranados2008anovelmutation pages 1-2, kawai2012diagnosisandtreatment pages 7-8)
Infectious	Mycobacterial susceptibility / BCG disease	HP:0002728 Mycobacterial infection, recurrent	Infancy/childhood; risk after BCG exposure	Reported in some AD EDA-ID patients and emphasized in reviews; relevant to vaccine decisions and prophylaxis (derfalvi2020adaandpnp pages 13-16, kawai2012diagnosisandtreatment pages 9-10, derfalvi2020adaandpnp pages 16-17)	(derfalvi2020adaandpnp pages 13-16, kawai2012diagnosisandtreatment pages 9-10, derfalvi2020adaandpnp pages 16-17)
Inflammatory	Persistent fever and elevated inflammatory markers	HP:0001945 Fever; HP:0011227 Elevated C-reactive protein level	Infancy/childhood; episodic or chronic	Some NFKBIA mutants, especially Ser32 substitutions, show severe noninfectious systemic inflammation with high CRP and leukocytosis (moriya2018ikbas32mutations pages 1-2)	(moriya2018ikbas32mutations pages 1-2)
Inflammatory	Skin rash / erythema	HP:0000988 Skin rash; HP:0001047 Erythema	Early infancy; persistent or relapsing	Seen in inflammatory presentations; may precede systemic manifestations (moriya2018ikbas32mutations pages 1-2)	(moriya2018ikbas32mutations pages 1-2)
Inflammatory	Pulmonary inflammatory infiltrates / consolidations	HP:0002209 Pulmonary infiltrates	Infancy/childhood; relapsing or persistent	Described in severe inflammatory S32-mutant disease and infectious pneumonia presentations (moriya2018ikbas32mutations pages 1-2, wen2022aheterozygousnterminal pages 1-2)	(moriya2018ikbas32mutations pages 1-2, wen2022aheterozygousnterminal pages 1-2)
Inflammatory	CNS inflammation / seizures / MRI lesions	HP:0001250 Seizure; HP:0012638 Abnormality of CNS white matter	Infancy/childhood; severe episodic	Reported in severe S32-mutant disease with steroid-responsive brain inflammation (moriya2018ikbas32mutations pages 1-2)	(moriya2018ikbas32mutations pages 1-2)
GI	Chronic diarrhea	HP:0002028 Chronic diarrhea	Infancy; persistent or recurrent	Common presenting problem in severe infantile cases; may accompany infections or inflammatory bowel disease–like manifestations (lopezgranados2008anovelmutation pages 1-2, wen2022aheterozygousnterminal pages 1-2)	(lopezgranados2008anovelmutation pages 1-2, wen2022aheterozygousnterminal pages 1-2)
GI	Colitis / enterocolitis	HP:0002037 Inflammatory abnormality of the intestine	Childhood; chronic/relapsing	Reported in EDA-ID reviews; may respond to corticosteroids, and can persist despite HSCT in broader EDA-ID experience (kawai2012diagnosisandtreatment pages 8-9, kawai2012diagnosisandtreatment pages 9-10, kawai2012diagnosisandtreatment pages 10-11)	(kawai2012diagnosisandtreatment pages 8-9, kawai2012diagnosisandtreatment pages 9-10, kawai2012diagnosisandtreatment pages 10-11)
GI	Failure to thrive	HP:0001508 Failure to thrive	Infancy; progressive if untreated	Reported in severe infantile truncation case with recurrent infection and diarrhea (lopezgranados2008anovelmutation pages 1-2)	(lopezgranados2008anovelmutation pages 1-2)
Endocrine	Polyendocrinopathy / hypopituitarism / hypothyroidism	HP:0000820 Abnormality of the thyroid gland; HP:0000837 Hypopituitarism; HP:0003117 Polyendocrine abnormality	Childhood; chronic	Not universal, but important expansion of phenotype in p.M37K case with profound immunodeficiency and reduced IL-17+ T cells (schimke2013anovelgainoffunction pages 1-2)	(schimke2013anovelgainoffunction pages 1-2)
Epidemiology / spectrum	Reported case burden in literature	HP:0000007 Autosomal dominant inheritance	Ultra-rare; congenital Mendelian disease	Literature snapshots report approximately 14 patients with 11 mutations (2020 summary) and ~19 reported patients by 2022, indicating extreme rarity and likely ascertainment from case reports/series rather than registries (derfalvi2020adaandpnp pages 13-16, wen2022aheterozygousnterminal pages 1-2)	(derfalvi2020adaandpnp pages 13-16, wen2022aheterozygousnterminal pages 1-2)

Table: This table summarizes the reported clinical and immunologic spectrum of NFKBIA-related ectodermal dysplasia and immunodeficiency 2, with suggested HPO mappings, typical onset, and practical notes from key case reports and reviews. It is useful for disease knowledge base curation and phenotype-driven diagnostic recognition.

Key phenotype themes supported by primary literature: - Ectodermal dysplasia: hypotrichosis/sparse hair, abnormal or conical teeth, and reduced or absent sweating/sweat glands. (lopezgranados2008anovelmutation pages 1-2, moriya2018ikbas32mutations pages 1-2) - Immunodeficiency: hypogammaglobulinemia or dysgammaglobulinemia/hyper-IgM-like patterns, poor vaccine responses, reduced memory B cells, and in some patients profound T-cell subset abnormalities (absent memory T cells, reduced Tregs). (chear2022anovelde pages 2-4, moriya2018ikbas32mutations pages 1-2, derfalvi2020adaandpnp pages 13-16) - Infectious susceptibility: recurrent severe bacterial infections (including invasive disease), pneumonia, chronic mucocutaneous candidiasis, opportunistic infections including Pneumocystis, and occasional mycobacterial disease (including in the broader EDA-ID spectrum). (lopezgranados2008anovelmutation pages 1-2, derfalvi2020adaandpnp pages 13-16, kawai2012diagnosisandtreatment pages 7-8) - Inflammation/immune dysregulation: a subset—especially with Ser32 variants—can have severe noninfectious systemic inflammation (persistent CRP elevation, CNS inflammation) that is steroid-responsive but may recur after transplantation with mixed chimerism. (moriya2018ikbas32mutations pages 1-2) - Endocrinopathy (subset): polyendocrinopathy/hypothyroidism/hypopituitarism reported in at least one NFKBIA GOF case. (schimke2013anovelgainoffunction pages 1-2)

3.2 Quality-of-life impact

Direct validated QoL instrument data (e.g., SF-36/EQ-5D) were not found in the retrieved corpus. However, case reports and reviews describe prolonged hospitalizations, recurrent severe infections, chronic prophylaxis/IVIG dependence, and persistent ectodermal manifestations, all of which strongly imply substantial QoL burden. (chear2022anovelde pages 2-4, derfalvi2020adaandpnp pages 13-16)

4. Genetic/molecular information

4.1 Causal gene

NFKBIA (HGNC:7797), encoding IκBα. (petersheim2018mechanismsofgenotypephenotype pages 1-6, schimke2013anovelgainoffunction pages 1-2)

4.2 Pathogenic variants and functional consequences

Mechanistically, IKK-mediated phosphorylation of IκBα at Ser32/Ser36 normally triggers ubiquitination and proteasomal degradation; EDID2 variants interfere with this step and lead to persistent inhibition of NF-κB. (wen2022aheterozygousnterminal pages 1-2, derfalvi2020adaandpnp pages 13-16)

Genotype–phenotype correlation: Petersheim et al. report that point mutants accumulate at higher levels than truncations and are associated with greater clinical severity and larger deficits in both canonical and non-canonical NF-κB pathway readouts in stimulated patient fibroblasts. (petersheim2018mechanismsofgenotypephenotype pages 1-6)

4.3 Molecular pathway mapping (ontology suggestions)

Canonical NF-κB signaling (Reactome/KEGG concept); suggested GO biological process terms:
GO:0043122 “regulation of I-kappaB kinase/NF-kappaB signaling”
GO:0038061 “NIK/NF-kappaB signaling” (for the noncanonical component implicated in lymphoid organogenesis phenotypes)

Cell types (Cell Ontology suggestions) implicated by functional assays and phenotype: - CL:0000542 “lymphocyte” (broad) - CL:0000236 “B cell”; CL:0000084 “T cell”; CL:0000623 “natural killer cell” - CL:0000451 “dendritic cell” (based on TLR-driven cytokine defects and mouse DC subset changes)

5. Environmental information

No EDID2-specific environmental toxin/lifestyle risk literature was identified in the retrieved corpus. Infectious exposures (e.g., respiratory pathogens; Candida; and in some contexts live mycobacterial exposure such as BCG) are clinically important because of heightened susceptibility. (derfalvi2020adaandpnp pages 13-16, kawai2012diagnosisandtreatment pages 9-10)

6. Mechanism / pathophysiology

6.1 Causal chain (trigger → pathway defect → phenotype)

Germline NFKBIA variant produces a degradation-resistant IκBα (by disrupting the Ser32/Ser36 phosphodegron or deleting it). (lopezgranados2008anovelmutation pages 1-2, wen2022aheterozygousnterminal pages 1-2)
Impaired IκBα turnover prevents normal NF-κB nuclear translocation and NF-κB-dependent transcription after TNF/TLR/IL-1R/CD40 stimulation. (schimke2013anovelgainoffunction pages 1-2, chear2022anovelde pages 2-4)
Downstream consequences include:
Innate immune defects (blunted cytokine production to TLR ligands; impaired IL-1R/TLR4 activation). (wen2022aheterozygousnterminal pages 1-2, schimke2013anovelgainoffunction pages 1-2)
Humoral immune failure (poor specific antibody responses, impaired responses to polysaccharide vaccines/antigens; memory B-cell defects). (derfalvi2020adaandpnp pages 13-16, kawai2012diagnosisandtreatment pages 8-9)
Combined immune deficiency features (abnormal T-cell subset distribution and T-cell functional defects in severe cases). (moriya2018ikbas32mutations pages 1-2, giancane2013anhidroticectodermaldysplasia pages 3-3)
Clinical manifestations: recurrent severe infections, opportunistic infections, chronic candidiasis, ectodermal dysplasia, and (in some) systemic inflammation/autoimmunity. (derfalvi2020adaandpnp pages 13-16, moriya2018ikbas32mutations pages 1-2)

6.2 Mechanistic evidence from functional studies

Schimke et al. report an NFKBIA GOF variant with “abolished IκB-α degradation after TNF-α and TLR stimulation” and impaired NF-κB activation with broad cytokine defects, consistent with hypermorphic inhibition. (schimke2013anovelgainoffunction pages 1-2)
Wen et al. describe impaired NF-κB translocation and defective IL-1R/TLR4 pathway activation in a truncation case. (wen2022aheterozygousnterminal pages 1-2)

6.3 Molecular profiling / omics

EDID2-specific systematic transcriptomic/proteomic/metabolomic cohort studies were not found in the retrieved corpus; existing evidence is largely pathway-functional (cytokine readouts, reporter assays, immunoblotting). (petersheim2018mechanismsofgenotypephenotype pages 1-6, schimke2013anovelgainoffunction pages 1-2)

7. Anatomical structures affected

Primary tissues/organs: - Ectodermal appendages: hair follicles (hypotrichosis), teeth (conical/abnormal dentition), eccrine sweat glands (hypoplasia/aplasia). (lopezgranados2008anovelmutation pages 1-2, moriya2018ikbas32mutations pages 1-2) - Immune system: secondary lymphoid tissues (functional impairment; in model organism, absent lymph nodes/Peyer’s patches and disorganized spleen). (mooster2015defectivelymphoidorganogenesis pages 2-3)

UBERON suggestions: - UBERON:0002106 “spleen”; UBERON:0000029 “lymph node”; UBERON:0001085 “Peyer’s patch”; UBERON:0001003 “skin”; UBERON:0000970 “tooth”; UBERON:0001820 “sweat gland”.

8. Temporal development

Onset: commonly infancy/early childhood, with ectodermal features often congenital and immunologic/infectious manifestations presenting early (including severe pneumonia, diarrhea, candidiasis, sepsis). (lopezgranados2008anovelmutation pages 1-2, wen2022aheterozygousnterminal pages 1-2, chear2022anovelde pages 2-4)

Course/progression: recurrent severe infections and chronic immune dysfunction; a subset with Ser32 variants can have persistent inflammatory disease requiring immunosuppression. (moriya2018ikbas32mutations pages 1-2)

9. Inheritance and population

9.1 Inheritance

Autosomal dominant; many reported cases are de novo. (schimke2013anovelgainoffunction pages 1-2, moriya2018ikbas32mutations pages 1-2)

9.2 Epidemiology

No robust prevalence/incidence estimates specific to EDID2 were identified in the retrieved corpus. Available quantitative information is limited to case-count snapshots in reviews/case series summaries: - A 2020 summary describes “14 patients with 11 mutations” (literature to that point). (derfalvi2020adaandpnp pages 13-16) - A 2022 report notes ~19 reported patients and distribution of variant classes (point mutants at/near S32/S36; truncations; mosaic). (wen2022aheterozygousnterminal pages 1-2)

These figures reflect published case ascertainment rather than population-based prevalence.

10. Diagnostics

10.1 Recommended diagnostic approach (tests + rationale)

Category	Specific action	Rationale / what it detects	Real-world implementation notes	Outcome data / statistics when available	Key citations with URLs and publication years
Diagnostic test	Quantitative immunoglobulins (IgG, IgA, IgM)	Detects hypogammaglobulinemia or dysgammaglobulinemia/hyper-IgM-like patterns reported in EDID2	Basic first-line immune workup in infants/children with ectodermal dysplasia plus recurrent infection; abnormalities may be variable, so normal total IgG does not exclude disease (derfalvi2020adaandpnp pages 13-16, chear2022anovelde pages 2-4, kawai2012diagnosisandtreatment pages 7-8)	Low Ig levels reported in severe NFKBIA cases; hyper-IgM-like phenotype also described (chear2022anovelde pages 2-4, moriya2018ikbas32mutations pages 1-2)	Derfalvi 2020 https://doi.org/10.1007/978-1-4614-8678-7_172; Chear et al. 2022 https://doi.org/10.3390/genes13101900; Kawai et al. 2012 https://doi.org/10.2332/allergolint.12-rai-0446 (derfalvi2020adaandpnp pages 13-16, chear2022anovelde pages 2-4, kawai2012diagnosisandtreatment pages 7-8)
Diagnostic test	Vaccine antibody titers, including protein antigens	Assesses functional humoral immunity and specific antibody production	Should be part of routine workup because EDID2 can show absent/poor specific antibodies even when some quantitative immunoglobulins are preserved (kawai2012diagnosisandtreatment pages 6-7, derfalvi2020adaandpnp pages 13-16)	Poor or absent vaccine antibody responses repeatedly reported in summaries of AD EDA-ID (derfalvi2020adaandpnp pages 13-16)	Kawai et al. 2012 https://doi.org/10.2332/allergolint.12-rai-0446; Derfalvi 2020 https://doi.org/10.1007/978-1-4614-8678-7_172 (kawai2012diagnosisandtreatment pages 6-7, derfalvi2020adaandpnp pages 13-16)
Diagnostic test	Polysaccharide response testing (e.g., pneumococcal polysaccharide antibodies pre/post vaccination)	Detects impaired IgG response to polysaccharide antigens, a key clue in NF-κB-pathway IEI	Particularly important because basic workup may miss monogenic IEI with normal total IgG but defective anti-polysaccharide responses; recommended even when protein vaccine responses are preserved (kawai2012diagnosisandtreatment pages 8-9, fasshauer2024monogenicinbornerrors pages 2-4)	2024 review emphasizes that delayed diagnosis without anti-polysaccharide testing can lead to irreversible damage such as bronchiectasis (fasshauer2024monogenicinbornerrors pages 2-4)	Kawai et al. 2012 https://doi.org/10.2332/allergolint.12-rai-0446; Fasshauer et al. 2024 https://doi.org/10.3389/fped.2024.1386959 (kawai2012diagnosisandtreatment pages 8-9, fasshauer2024monogenicinbornerrors pages 2-4)
Diagnostic test	Lymphocyte subset immunophenotyping, including memory B cells, memory T cells, Tregs, NK cells	Defines combined immunodeficiency phenotype and immune dysregulation	Useful because EDID2 often shows enlarged total B-cell counts with reduced/absent memory B cells, naïve-predominant T-cell compartments, reduced Tregs, and sometimes NK defects (derfalvi2020adaandpnp pages 13-16, moriya2018ikbas32mutations pages 1-2, kawai2012diagnosisandtreatment pages 6-7)	Severe S32-mutant cases showed near absence of memory T cells and Tregs plus reduced memory B cells (moriya2018ikbas32mutations pages 1-2)	Derfalvi 2020 https://doi.org/10.1007/978-1-4614-8678-7_172; Moriya et al. 2018 https://doi.org/10.1007/s10875-018-0522-y; Kawai et al. 2012 https://doi.org/10.2332/allergolint.12-rai-0446 (derfalvi2020adaandpnp pages 13-16, moriya2018ikbas32mutations pages 1-2, kawai2012diagnosisandtreatment pages 6-7)
Diagnostic test	T-cell proliferation / TCR-mediated functional assays	Detects defective adaptive cellular signaling downstream of NF-κB	Recommended when recurrent/opportunistic infections or inflammatory features suggest combined immunodeficiency; abnormalities may help distinguish EDID2 from isolated ectodermal dysplasia (kawai2012diagnosisandtreatment pages 6-7, derfalvi2020adaandpnp pages 13-16, giancane2013anhidroticectodermaldysplasia pages 3-3)	Impaired T-cell responses are a recurrent feature in reported series/reviews (derfalvi2020adaandpnp pages 13-16, giancane2013anhidroticectodermaldysplasia pages 3-3)	Kawai et al. 2012 https://doi.org/10.2332/allergolint.12-rai-0446; Derfalvi 2020 https://doi.org/10.1007/978-1-4614-8678-7_172; Giancane et al. 2013 https://doi.org/10.1016/j.jaci.2013.05.034 (kawai2012diagnosisandtreatment pages 6-7, derfalvi2020adaandpnp pages 13-16, giancane2013anhidroticectodermaldysplasia pages 3-3)
Diagnostic test	Innate signaling assays (TLR, IL-1R, TNFR1, CD40 pathways; cytokine readouts)	Detects the pathway-level defect caused by degradation-resistant IκBα and impaired NF-κB activation	Helpful when diagnosis is uncertain or phenotype is atypical; can show defective IL-1R/TLR4 signaling and reduced cytokine induction after stimulation (wen2022aheterozygousnterminal pages 1-2, schimke2013anovelgainoffunction pages 1-2, kawai2012diagnosisandtreatment pages 9-10)	Functional defects documented in case reports include impaired IL-6 secretion and defective NF-κB nuclear translocation (schimke2013anovelgainoffunction pages 1-2)	Wen et al. 2022 https://doi.org/10.1016/j.gendis.2021.03.005; Schimke et al. 2013 https://doi.org/10.1007/s10875-013-9906-1; Kawai et al. 2012 https://doi.org/10.2332/allergolint.12-rai-0446 (wen2022aheterozygousnterminal pages 1-2, schimke2013anovelgainoffunction pages 1-2, kawai2012diagnosisandtreatment pages 9-10)
Diagnostic test	Genetic confirmation with NFKBIA sequencing, targeted panel, WES	Confirms EDID2 and identifies variant class (Ser32/Ser36-adjacent missense vs N-terminal truncation)	NGS/WES is especially useful when phenotype mimics Hyper-IgM syndrome or when ectodermal findings are subtle; de novo variants are common (chear2022anovelde pages 2-4, chear2022anovelde pages 1-2)	2022 review/case notes ~13 distinct NFKBIA mutations reported; 2022 truncation review mentions ~19 patients reported (chear2022anovelde pages 1-2, wen2022aheterozygousnterminal pages 1-2)	Chear et al. 2022 https://doi.org/10.3390/genes13101900; Wen et al. 2022 https://doi.org/10.1016/j.gendis.2021.03.005 (chear2022anovelde pages 2-4, chear2022anovelde pages 1-2, wen2022aheterozygousnterminal pages 1-2)
Management	Early empiric intravenous antibiotics for suspected serious infection	Addresses high risk of rapid progression/sepsis in immunodeficient patients	Reviews emphasize prompt treatment because some patients may not mount robust fever or CRP responses; threshold for treatment should be low (kawai2012diagnosisandtreatment pages 8-9)	No response-rate statistics given, but recommendation is strong due to recurrent life-threatening infections (kawai2012diagnosisandtreatment pages 8-9)	Kawai et al. 2012 https://doi.org/10.2332/allergolint.12-rai-0446 (kawai2012diagnosisandtreatment pages 8-9)
Management	Immunoglobulin replacement (IVIG or SCIG)	Replaces deficient antibody function and compensates for poor vaccine/polysaccharide responses	Recommended for most/all AD EDA-ID patients with antibody dysfunction; used long term in real-world case management (kawai2012diagnosisandtreatment pages 8-9, derfalvi2020adaandpnp pages 13-16)	In Derfalvi summary, 2 non-HSCT patients remained on IVIG; among 5 HSCT survivors, 4 had ongoing partial immunodeficiency requiring IVIG (derfalvi2020adaandpnp pages 13-16)	Kawai et al. 2012 https://doi.org/10.2332/allergolint.12-rai-0446; Derfalvi 2020 https://doi.org/10.1007/978-1-4614-8678-7_172 (kawai2012diagnosisandtreatment pages 8-9, derfalvi2020adaandpnp pages 13-16)
Management	TMP-SMX (co-trimoxazole) prophylaxis	Reduces risk of recurrent bacterial infection and Pneumocystis	Strongly recommended in EDA-ID reviews; also used in individual NFKBIA cases alongside IVIG (kawai2012diagnosisandtreatment pages 8-9, chear2022anovelde pages 2-4)	Case-level use documented in 2022 NFKBIA patient receiving co-trimoxazole prophylaxis (chear2022anovelde pages 2-4)	Kawai et al. 2012 https://doi.org/10.2332/allergolint.12-rai-0446; Chear et al. 2022 https://doi.org/10.3390/genes13101900 (kawai2012diagnosisandtreatment pages 8-9, chear2022anovelde pages 2-4)
Management	Antifungal prophylaxis / treatment	Addresses frequent Candida and other fungal infections	Strongly recommended because chronic mucocutaneous candidiasis and invasive fungal disease are recurrent features; itraconazole was used in practice (kawai2012diagnosisandtreatment pages 8-9, chear2022anovelde pages 2-4)	Individual case used itraconazole prophylaxis with IVIG and co-trimoxazole (chear2022anovelde pages 2-4)	Kawai et al. 2012 https://doi.org/10.2332/allergolint.12-rai-0446; Chear et al. 2022 https://doi.org/10.3390/genes13101900 (kawai2012diagnosisandtreatment pages 8-9, chear2022anovelde pages 2-4)
Management	Antimycobacterial surveillance and caution with BCG exposure	Detects/prevents mycobacterial disease related to impaired CD40/IL-12/NF-κB signaling	Periodic surveillance is advised in EDA-ID because mycobacterial susceptibility is well recognized; live mycobacterial exposure warrants caution (kawai2012diagnosisandtreatment pages 8-9, kawai2012diagnosisandtreatment pages 9-10, derfalvi2020adaandpnp pages 16-17)	One non-HSCT patient in summary received anti-TB therapy plus IFN-γ and antibiotics (derfalvi2020adaandpnp pages 13-16)	Kawai et al. 2012 https://doi.org/10.2332/allergolint.12-rai-0446; Derfalvi 2020 https://doi.org/10.1007/978-1-4614-8678-7_172 (kawai2012diagnosisandtreatment pages 8-9, kawai2012diagnosisandtreatment pages 9-10, derfalvi2020adaandpnp pages 13-16, derfalvi2020adaandpnp pages 16-17)
Management	Corticosteroids for severe inflammation or colitis	Suppresses noninfectious systemic inflammation linked to NF-κB dysregulation	Used successfully for inflammatory colitis in EDA-ID and for severe systemic/CNS inflammation in NFKBIA Ser32-mutant cases (kawai2012diagnosisandtreatment pages 8-9, moriya2018ikbas32mutations pages 1-2)	In Moriya 2018, systemic corticosteroids were effective for controlling severe inflammatory symptoms (moriya2018ikbas32mutations pages 1-2)	Kawai et al. 2012 https://doi.org/10.2332/allergolint.12-rai-0446; Moriya et al. 2018 https://doi.org/10.1007/s10875-018-0522-y (kawai2012diagnosisandtreatment pages 8-9, moriya2018ikbas32mutations pages 1-2)
Management	Anti-TNF therapy for refractory colitis/inflammation	Targets inflammatory bowel disease–like or cytokine-driven manifestations	Has been used in EDA-ID, but reviews warn it may increase risk of mycobacterial infection; should be considered only with careful infectious risk assessment (kawai2012diagnosisandtreatment pages 9-10)	No EDID2-specific success rate provided; caution emphasized more strongly than efficacy claims (kawai2012diagnosisandtreatment pages 9-10)	Kawai et al. 2012 https://doi.org/10.2332/allergolint.12-rai-0446 (kawai2012diagnosisandtreatment pages 9-10)
Management / advanced therapy	Hematopoietic stem cell transplantation (HSCT)	Attempts immune reconstitution for severe combined immunodeficiency phenotype	Real-world outcomes are mixed to poor; engraftment difficulties, infectious mortality, and persistence of ectodermal features are major issues; should be considered high-risk and individualized (petersheim2018mechanismsofgenotypephenotype pages 1-6, kawai2012diagnosisandtreatment pages 8-9, derfalvi2020adaandpnp pages 13-16)	Derfalvi summary: 11 HSCT recipients, 6 deaths post-HSCT; among 5 surviving “successful” HSCT cases, all retained ectodermal phenotype and 4 had persistent partial immunodeficiency on IVIG (derfalvi2020adaandpnp pages 13-16). Petersheim also notes poor outcomes despite chimerism (petersheim2018mechanismsofgenotypephenotype pages 1-6)	Petersheim et al. 2018 https://doi.org/10.1016/j.jaci.2017.05.030; Kawai et al. 2012 https://doi.org/10.2332/allergolint.12-rai-0446; Derfalvi 2020 https://doi.org/10.1007/978-1-4614-8678-7_172 (petersheim2018mechanismsofgenotypephenotype pages 1-6, kawai2012diagnosisandtreatment pages 8-9, derfalvi2020adaandpnp pages 13-16)
Outcome / prognosis	Long-term monitoring for persistent immune deficiency and non-hematopoietic disease burden	Captures residual antibody deficiency, inflammatory disease, and persistent ectodermal manifestations	Even after transplant or stabilization, ongoing follow-up is needed for IVIG dependence, infection surveillance, GI inflammation, and supportive ectodermal care (derfalvi2020adaandpnp pages 13-16, kawai2012diagnosisandtreatment pages 10-11)	Historical prognosis is poor in severe cases; Kawai review cites poor survival in broader EDA-ID experience, and Derfalvi data show substantial HSCT mortality (kawai2012diagnosisandtreatment pages 6-7, derfalvi2020adaandpnp pages 13-16)	Derfalvi 2020 https://doi.org/10.1007/978-1-4614-8678-7_172; Kawai et al. 2012 https://doi.org/10.2332/allergolint.12-rai-0446 (kawai2012diagnosisandtreatment pages 6-7, derfalvi2020adaandpnp pages 13-16, kawai2012diagnosisandtreatment pages 10-11)

Table: This table summarizes clinically relevant diagnostic tests, real-world management practices, and reported outcomes for NFKBIA-related ectodermal dysplasia and immunodeficiency 2. It is useful for translating case-report and review evidence into a practical disease knowledge base entry.

Key diagnostic principle (2024 development): Fasshauer et al. emphasize that many monogenic IEIs may initially have normal total IgG but impaired IgG response to polysaccharide antigens, and that failure to measure anti-polysaccharide antibodies can delay diagnosis and allow irreversible damage such as bronchiectasis. (fasshauer2024monogenicinbornerrors pages 2-4)

10.2 Differential diagnosis

Important differentials include: - X-linked EDA-ID due to IKBKG/NEMO (overlapping ectodermal phenotype and NF-κB-pathway immunodeficiency). (kawai2012diagnosisandtreatment pages 8-9) - Classical Hyper-IgM syndromes (e.g., CD40L deficiency): NFKBIA patients may have hyper-IgM-like immunoglobulin patterns but can have preserved CD40/CD40L expression; genetic testing distinguishes. (chear2022anovelde pages 2-4)

11. Outcome / prognosis

Outcomes vary by variant class and severity. Available quantitative outcome data include HSCT experiences summarized in a 2020 reference source: - In a reported series summarized by Derfalvi, 11 patients underwent HSCT and 6 died post-HSCT (causes included sepsis and other severe complications). Among 5 surviving HSCT cases, all retained ectodermal phenotype and 4 had ongoing partial immunodeficiency requiring IVIG. (derfalvi2020adaandpnp pages 13-16)

Kawai et al. (2012) also highlight mixed/poor HSCT outcomes and transplant complications in the broader EDA-ID spectrum and emphasize the need for improved HSCT strategies. (kawai2012diagnosisandtreatment pages 8-9)

12. Treatment

12.1 Real-world management

Immunoglobulin replacement (IVIG/SCIG): recommended for most/all AD EDA-ID patients due to impaired antibody responses (particularly polysaccharide responses). (kawai2012diagnosisandtreatment pages 8-9, derfalvi2020adaandpnp pages 13-16)
Antimicrobial prophylaxis: Kawai et al. strongly recommend co-trimoxazole and antifungal prophylaxis given frequent Candida and Pneumocystis infections; case-level real-world use (co-trimoxazole + itraconazole) is documented in an NFKBIA patient. (kawai2012diagnosisandtreatment pages 8-9, chear2022anovelde pages 2-4)
Inflammation control: systemic corticosteroids can be effective for severe noninfectious inflammation (including CNS inflammation) and colitis within the broader EDA-ID spectrum. (moriya2018ikbas32mutations pages 1-2, kawai2012diagnosisandtreatment pages 8-9)
Anti-TNF therapy: reported for inflammatory colitis in EDA-ID, but authors caution it may increase mycobacterial infection risk. (kawai2012diagnosisandtreatment pages 9-10)
HSCT: considered in severe combined immunodeficiency phenotypes but is high-risk with significant mortality and frequent incomplete immune correction and persistence of ectodermal defects. (petersheim2018mechanismsofgenotypephenotype pages 1-6, derfalvi2020adaandpnp pages 13-16)

MAXO suggestions (examples): - MAXO:0000747 “immunoglobulin replacement therapy” - MAXO:0000775 “antibacterial prophylaxis” - MAXO:0000776 “antifungal prophylaxis” - MAXO:0000180 “hematopoietic stem cell transplantation” - MAXO:0000016 “glucocorticoid therapy”

12.2 Clinical trials

A clinicaltrials.gov search for ectodermal dysplasia + immunodeficiency retrieved general PID observational studies/registries, but no EDID2-specific interventional trials were identified among the retrieved trials. (No EDID2-specific NCT IDs available in retrieved set.)

13. Prevention

Because EDID2 is a Mendelian disorder, prevention focuses on: - Genetic counseling (autosomal dominant; frequently de novo but familial transmission is possible). - Secondary/tertiary prevention via early immunologic recognition and infection prevention (IVIG, prophylaxis, rapid antibiotics, avoidance of high-risk live exposures such as BCG where relevant to NF-κB-pathway immunodeficiency). (kawai2012diagnosisandtreatment pages 8-9, derfalvi2020adaandpnp pages 16-17)

14. Other species / natural disease

No naturally occurring EDID2-like disease in non-human species was identified in the retrieved corpus.

15. Model organisms

A mechanistically faithful model exists:

15.1 Mouse knock-in model (IκBα S32I)

Mooster et al. generated a heterozygous IκBα S32I knock-in mouse, a mutation identified in a human ED-ID/AD EDA-ID patient. The mice exhibit: - Ectodermal abnormalities (including hair/teeth and eccrine gland defects). - Profound secondary lymphoid organogenesis defects (absence of lymph nodes and Peyer’s patches; disorganized spleen lacking follicles and follicular dendritic cells). - Functional innate cytokine response defects to TLR ligands and impaired adhesion molecule induction. These data support the concept that EDID2 can include both canonical NF-κB signaling failure and disruption of lymphoid organogenesis programs relevant to humoral immunity. (mooster2015defectivelymphoidorganogenesis pages 2-3, mooster2015defectivelymphoidorganogenesis pages 3-4)

Key abstract quotes (supporting evidence)

Kawai et al. 2012 (review abstract): “Two genes responsible for EDA-ID have been identified: … NEMO for X-linked EDA-ID … and IκBα for autosomal-dominant EDA-ID (AD-EDA-ID). Both genes are involved in NF-κB activation, such that mutations or related defects cause impaired NF-κB signaling.” (Published 2012-01; https://doi.org/10.2332/allergolint.12-rai-0446) (kawai2012diagnosisandtreatment pages 8-9)
Chear et al. 2022 (abstract): “The variant analysis demonstrated a novel missense mutation in NFKBIA … The mutation occurred at the six degrons (Asp31-Ser36) in IκBα…” (Published 2022-10; https://doi.org/10.3390/genes13101900) (chear2022anovelde pages 2-4)

Limitations of this report

Orphanet/ICD/MeSH identifiers were not retrievable from the current tool context; OMIM and MONDO identifiers were captured reliably.
2023–2024 primary publications specifically focused on EDID2 (NFKBIA) were sparse in the retrieved corpus; the strongest 2024 “recent development” applicable to EDID2 is improved emphasis on anti-polysaccharide antibody testing for monogenic IEI detection (Frontiers in Pediatrics 2024). (fasshauer2024monogenicinbornerrors pages 2-4)
No EDID2-specific prevalence estimates or standardized QoL outcome studies were identified.

References

(petersheim2018mechanismsofgenotypephenotype pages 1-6): Daniel Petersheim, Michel J. Massaad, Saetbyul Lee, Alessia Scarselli, Caterina Cancrini, Kunihiko Moriya, Yoji Sasahara, Arjan C. Lankester, Morna Dorsey, Daniela Di Giovanni, Liliana Bezrodnik, Hidenori Ohnishi, Ryuta Nishikomori, Kay Tanita, Hirokazu Kanegane, Tomohiro Morio, Erwin W. Gelfand, Ashish Jain, Elizabeth Secord, Capucine Picard, Jean-Laurent Casanova, Michael H. Albert, Troy R. Torgerson, and Raif S. Geha. Mechanisms of genotype-phenotype correlation in autosomal dominant anhidrotic ectodermal dysplasia with immune deficiency. Journal of Allergy and Clinical Immunology, 141:1060-1073.e3, Mar 2018. URL: https://doi.org/10.1016/j.jaci.2017.05.030, doi:10.1016/j.jaci.2017.05.030. This article has 27 citations and is from a highest quality peer-reviewed journal.
(lopezgranados2008anovelmutation pages 1-2): Eduardo Lopez-Granados, Jeffrey E. Keenan, Matthew C. Kinney, Harvey Leo, Neal Jain, Chi A. Ma, Ralph Quinones, Erwin W. Gelfand, and Ashish Jain. A novel mutation in nfkbia/ikba results in a degradation‐resistant n‐truncated protein and is associated with ectodermal dysplasia with immunodeficiency. Human Mutation, 29:861-868, Jun 2008. URL: https://doi.org/10.1002/humu.20740, doi:10.1002/humu.20740. This article has 109 citations and is from a domain leading peer-reviewed journal.
(wen2022aheterozygousnterminal pages 1-2): Wen Wen, Li Wang, Mengyue Deng, Yue Li, Xuemei Tang, Huawei Mao, and Xiaodong Zhao. A heterozygous n-terminal truncation mutation of nfkbia results in an impaired nf-κb dependent inflammatory response. Genes & Diseases, 9:176-186, Jan 2022. URL: https://doi.org/10.1016/j.gendis.2021.03.005, doi:10.1016/j.gendis.2021.03.005. This article has 7 citations.
(schimke2013anovelgainoffunction pages 1-2): Lena F. Schimke, Nikolaus Rieber, Stacey Rylaarsdam, Otávio Cabral-Marques, Nicholas Hubbard, Anne Puel, Laura Kallmann, Stephanie Anover Sombke, Gundula Notheis, Hans-Peter Schwarz, Birgit Kammer, Tomas Hökfelt, Reinald Repp, Capucine Picard, Jean-Laurent Casanova, Bernd H. Belohradsky, Michael H. Albert, Hans D. Ochs, Ellen D. Renner, and Troy R. Torgerson. A novel gain-of-function ikba mutation underlies ectodermal dysplasia with immunodeficiency and polyendocrinopathy. Journal of Clinical Immunology, 33:1088-1099, May 2013. URL: https://doi.org/10.1007/s10875-013-9906-1, doi:10.1007/s10875-013-9906-1. This article has 72 citations and is from a domain leading peer-reviewed journal.
(kawai2012diagnosisandtreatment pages 8-9): Tomoki Kawai, Ryuta Nishikomori, and Toshio Heike. Diagnosis and treatment in anhidrotic ectodermal dysplasia with immunodeficiency. Allergology international : official journal of the Japanese Society of Allergology, 61 2:207-17, Jan 2012. URL: https://doi.org/10.2332/allergolint.12-rai-0446, doi:10.2332/allergolint.12-rai-0446. This article has 82 citations.
(derfalvi2020adaandpnp pages 13-16): Beata Derfalvi. Ada and pnp deficiency. Encyclopedia of Medical Immunology, pages 4-9, Jan 2020. URL: https://doi.org/10.1007/978-1-4614-8678-7_172, doi:10.1007/978-1-4614-8678-7_172. This article has 0 citations.
(fasshauer2024monogenicinbornerrors pages 2-4): Maria Fasshauer, Sarah Dinges, Olga Staudacher, Mirjam Völler, Anna Stittrich, Horst von Bernuth, Volker Wahn, and Renate Krüger. Monogenic inborn errors of immunity with impaired igg response to polysaccharide antigens but normal igg levels and normal igg response to protein antigens. Frontiers in Pediatrics, Jun 2024. URL: https://doi.org/10.3389/fped.2024.1386959, doi:10.3389/fped.2024.1386959. This article has 3 citations.
(chear2022anovelde pages 1-2): Chai Teng Chear, Bader Abdul Kader El Farran, Marina Sham, Kavetha Ramalingam, Lokman Mohd Noh, Intan Hakimah Ismail, Mei Yee Chiow, Mohd Farid Baharin, Adiratna Mat Ripen, and Saharuddin Bin Mohamad. A novel de novo nfkbia missense mutation associated to ectodermal dysplasia with dysgammaglobulinemia. Genes, 13:1900, Oct 2022. URL: https://doi.org/10.3390/genes13101900, doi:10.3390/genes13101900. This article has 8 citations.
(chear2022anovelde pages 2-4): Chai Teng Chear, Bader Abdul Kader El Farran, Marina Sham, Kavetha Ramalingam, Lokman Mohd Noh, Intan Hakimah Ismail, Mei Yee Chiow, Mohd Farid Baharin, Adiratna Mat Ripen, and Saharuddin Bin Mohamad. A novel de novo nfkbia missense mutation associated to ectodermal dysplasia with dysgammaglobulinemia. Genes, 13:1900, Oct 2022. URL: https://doi.org/10.3390/genes13101900, doi:10.3390/genes13101900. This article has 8 citations.
(moriya2018ikbas32mutations pages 1-2): Kunihiko Moriya, Yoji Sasahara, Hidenori Ohnishi, Tomoki Kawai, and Hirokazu Kanegane. Ikba s32 mutations underlie ectodermal dysplasia with immunodeficiency and severe noninfectious systemic inflammation. Journal of Clinical Immunology, 38:543-545, Jun 2018. URL: https://doi.org/10.1007/s10875-018-0522-y, doi:10.1007/s10875-018-0522-y. This article has 14 citations and is from a domain leading peer-reviewed journal.
(giancane2013anhidroticectodermaldysplasia pages 3-3): Gabriella Giancane, Simona Ferrari, Rita Carsetti, Paola Papoff, Metello Iacobini, and Marzia Duse. Anhidrotic ectodermal dysplasia: a new mutation. The Journal of allergy and clinical immunology, 132 6:1451-3, Dec 2013. URL: https://doi.org/10.1016/j.jaci.2013.05.034, doi:10.1016/j.jaci.2013.05.034. This article has 17 citations.
(kawai2012diagnosisandtreatment pages 6-7): Tomoki Kawai, Ryuta Nishikomori, and Toshio Heike. Diagnosis and treatment in anhidrotic ectodermal dysplasia with immunodeficiency. Allergology international : official journal of the Japanese Society of Allergology, 61 2:207-17, Jan 2012. URL: https://doi.org/10.2332/allergolint.12-rai-0446, doi:10.2332/allergolint.12-rai-0446. This article has 82 citations.
(kawai2012diagnosisandtreatment pages 7-8): Tomoki Kawai, Ryuta Nishikomori, and Toshio Heike. Diagnosis and treatment in anhidrotic ectodermal dysplasia with immunodeficiency. Allergology international : official journal of the Japanese Society of Allergology, 61 2:207-17, Jan 2012. URL: https://doi.org/10.2332/allergolint.12-rai-0446, doi:10.2332/allergolint.12-rai-0446. This article has 82 citations.
(kawai2012diagnosisandtreatment pages 9-10): Tomoki Kawai, Ryuta Nishikomori, and Toshio Heike. Diagnosis and treatment in anhidrotic ectodermal dysplasia with immunodeficiency. Allergology international : official journal of the Japanese Society of Allergology, 61 2:207-17, Jan 2012. URL: https://doi.org/10.2332/allergolint.12-rai-0446, doi:10.2332/allergolint.12-rai-0446. This article has 82 citations.
(derfalvi2020adaandpnp pages 16-17): Beata Derfalvi. Ada and pnp deficiency. Encyclopedia of Medical Immunology, pages 4-9, Jan 2020. URL: https://doi.org/10.1007/978-1-4614-8678-7_172, doi:10.1007/978-1-4614-8678-7_172. This article has 0 citations.
(kawai2012diagnosisandtreatment pages 10-11): Tomoki Kawai, Ryuta Nishikomori, and Toshio Heike. Diagnosis and treatment in anhidrotic ectodermal dysplasia with immunodeficiency. Allergology international : official journal of the Japanese Society of Allergology, 61 2:207-17, Jan 2012. URL: https://doi.org/10.2332/allergolint.12-rai-0446, doi:10.2332/allergolint.12-rai-0446. This article has 82 citations.
(mooster2015defectivelymphoidorganogenesis pages 2-3): Jana L. Mooster, Severine Le Bras, Michel J. Massaad, Haifa Jabara, Juhan Yoon, Claire Galand, Balthasar A. Heesters, Oliver T. Burton, Hamid Mattoo, John Manis, and Raif S. Geha. Defective lymphoid organogenesis underlies the immune deficiency caused by a heterozygous s32i mutation in iκbα. The Journal of Experimental Medicine, 212:185-202, Feb 2015. URL: https://doi.org/10.1084/jem.20140979, doi:10.1084/jem.20140979. This article has 36 citations.
(mooster2015defectivelymphoidorganogenesis pages 3-4): Jana L. Mooster, Severine Le Bras, Michel J. Massaad, Haifa Jabara, Juhan Yoon, Claire Galand, Balthasar A. Heesters, Oliver T. Burton, Hamid Mattoo, John Manis, and Raif S. Geha. Defective lymphoid organogenesis underlies the immune deficiency caused by a heterozygous s32i mutation in iκbα. The Journal of Experimental Medicine, 212:185-202, Feb 2015. URL: https://doi.org/10.1084/jem.20140979, doi:10.1084/jem.20140979. This article has 36 citations.

Ask OpenScientist

OpenScientist Report

Inheritance

Subtypes

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Treatments

Source YAML

References & Deep Research

Deep Research

Disease Characteristics Research Template

Target Disease

Research Objectives

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

Citation Requirements

Output Format

Disease Characteristics Research Report: Ectodermal Dysplasia and Immunodeficiency 2 (EDID2)

Executive summary

1. Disease information

1.1 Overview and current definition

1.2 Key identifiers and nomenclature

2. Etiology

2.1 Disease causal factors

2.2 Risk factors

2.3 Protective factors / gene–environment interactions

3. Phenotypes

3.1 Core phenotype spectrum (with HPO suggestions)

3.2 Quality-of-life impact

4. Genetic/molecular information

4.1 Causal gene

4.2 Pathogenic variants and functional consequences

4.3 Molecular pathway mapping (ontology suggestions)

5. Environmental information

6. Mechanism / pathophysiology

6.1 Causal chain (trigger → pathway defect → phenotype)

6.2 Mechanistic evidence from functional studies

6.3 Molecular profiling / omics

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

9.1 Inheritance

9.2 Epidemiology

10. Diagnostics

10.1 Recommended diagnostic approach (tests + rationale)

10.2 Differential diagnosis

11. Outcome / prognosis

12. Treatment

12.1 Real-world management

12.2 Clinical trials

13. Prevention

14. Other species / natural disease

15. Model organisms

15.1 Mouse knock-in model (IκBα S32I)

Key abstract quotes (supporting evidence)

Limitations of this report