IKBKG ectodermal dysplasia with immunodeficiency

Mendelian MONDO:0100162 Pathograph 8 hereditary disease primary immunodeficiency ectodermal dysplasia syndrome

IKBKG ectodermal dysplasia with immunodeficiency encompasses a spectrum of X-linked disorders caused by mutations in IKBKG (also known as NEMO), the regulatory subunit of the IKK complex essential for NF-kB activation. The phenotypic spectrum is determined by mutation type and sex: hypomorphic mutations in hemizygous males cause ectodermal dysplasia with immunodeficiency (EDA-ID), characterized by anhidrotic ectodermal dysplasia, recurrent severe infections, and hypogammaglobulinemia; complete loss-of-function mutations cause incontinentia pigmenti (IP) in heterozygous females (male-lethal), characterized by distinctive skin lesions following the lines of Blaschko, with variable CNS, ocular, and dental involvement. The unifying molecular defect is impaired NF-kB signaling affecting immune, ectodermal, and inflammatory pathways.

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2
Inheritance
6
Pathophys.
15
Phenotypes
8
Pathograph
2
Genes
4
Treatments
4
Subtypes
1
Deep Research
👪

Inheritance

2
X-linked recessive inheritance (EDA-ID) HP:0001419
EDA-ID, OL-EDA-ID, and IMD33 follow X-linked recessive inheritance, with hemizygous males affected by hypomorphic IKBKG mutations. Carrier females show skewed X-inactivation favoring the normal allele.
X-linked recessive inheritance
Show evidence (1 reference)
PMID:11047757 SUPPORT Human Clinical
"males from four families with HED and immunodeficiency (HED-ID), in which the disorder segregates as an X-linked recessive trait"
Establishes X-linked recessive inheritance pattern for EDA-ID.
X-linked dominant inheritance (IP) HP:0001423
Incontinentia pigmenti follows X-linked dominant inheritance with male lethality. Heterozygous females are affected due to functional mosaicism from lyonization.
X-linked dominant inheritance
Show evidence (1 reference)
PMID:10839543 SUPPORT Human Clinical
"Familial incontinentia pigmenti (IP; MIM 308310) is a genodermatosis that segregates as an X-linked dominant disorder and is usually lethal prenatally in males"
Establishes X-linked dominant inheritance with male lethality for IP.
◆

Subtypes

4
Ectodermal Dysplasia and Immunodeficiency 1 (EDA-ID)
Caused by hypomorphic IKBKG mutations in hemizygous males. Characterized by anhidrotic ectodermal dysplasia (sparse hair, conical teeth, absent sweat glands) and combined immunodeficiency with susceptibility to pyogenic bacteria, mycobacteria, and viruses. NF-kB signaling is partially retained.
Show evidence (1 reference)
PMID:11242109 SUPPORT Human Clinical
"hypomorphic mutations in the gene IKBKG in 12 males with EDA-ID from 8 kindreds"
Landmark paper establishing that hypomorphic IKBKG mutations cause EDA-ID in males.
Incontinentia Pigmenti (Bloch-Sulzberger Syndrome)
Caused by loss-of-function IKBKG mutations (most commonly exon 4-10 deletion) in heterozygous females; hemizygous males are non-viable. Characterized by skin lesions progressing through vesicular, verrucous, hyperpigmented, and atrophic stages along lines of Blaschko, reflecting lyonization patterns. Variable CNS, ocular, and dental involvement.
Show evidence (1 reference)
PMID:10839543 SUPPORT Human Clinical
"Familial incontinentia pigmenti (IP; MIM 308310) is a genodermatosis that segregates as an X-linked dominant disorder and is usually lethal prenatally in males"
Original discovery paper establishing NEMO/IKBKG mutations as the cause of incontinentia pigmenti.
Anhidrotic EDA-ID with Osteopetrosis and Lymphedema
A severe variant caused by specific IKBKG mutations (e.g., stop codon mutations) in males, combining ectodermal dysplasia, immunodeficiency, osteopetrosis, and lymphedema due to more profound NF-kB pathway disruption.
Show evidence (1 reference)
PMID:11242109 SUPPORT Human Clinical
"2 patients with a related and hitherto unrecognized syndrome of EDA-ID with osteopetrosis and lymphoedema (OL-EDA-ID). Mutations in the coding region of IKBKG are associated with EDA-ID, and stop codon mutations, with OL-EDA-ID"
First description of OL-EDA-ID as a distinct severe variant caused by stop codon IKBKG mutations.
Immunodeficiency 33 (Mycobacterial Susceptibility)
Caused by specific hypomorphic IKBKG mutations that preferentially impair mycobacterial immunity while preserving other NF-kB-dependent functions. Males present with selective susceptibility to mycobacterial infections.
Show evidence (1 reference)
PMID:26269396 SUPPORT Human Clinical
"A wide spectrum of IKBKG/NEMO mutations have been identified so far, and, on the basis of their effect on NF-κB activation, they are considered hypomorphic or amorphic (loss of function) mutations. IKBKG/NEMO hypomorphic mutations, reducing but not abolishing NF-κB activation, have been..."
Fusco 2015 review describes the spectrum of IKBKG mutations including hypomorphic variants that reduce but do not abolish NF-kB activation, supporting the IMD33 phenotype of selective mycobacterial susceptibility.
⚙

Pathophysiology

6
IKBKG/NEMO loss of function
Mutations in IKBKG disrupt the NF-kB essential modulator (NEMO), a scaffold protein required for activation of the IKK complex. IKBKG binds IKKalpha and IKKbeta and is essential for signal-induced phosphorylation and degradation of IkBalpha, thereby controlling NF-kB nuclear translocation. Complete loss of function is embryonically lethal in males; hypomorphic mutations allow partial NF-kB activation.
IKBKG link
NF-kappaB signaling link
Downstream
Impaired innate immune signaling Defective NF-kB activation impairs TLR and TNF receptor signaling in innate immune cells.
Defective adaptive immunity Impaired NF-kB signaling disrupts B cell maturation and immunoglobulin class switching.
Ectodermal developmental defects NF-kB signaling through the EDA/EDAR pathway is required for ectodermal appendage development.
Inflammatory skin response (IP) In IP females, mosaic IKBKG-null cells trigger inflammatory responses along lines of Blaschko.
Show evidence (2 references)
PMID:11242109 SUPPORT Human Clinical
"IKBKG encodes NEMO, the regulatory subunit of the IKK (IkappaB kinase) complex, which is essential for NF-kappaB signaling. Germline loss-of-function mutations in IKBKG are lethal in male fetuses. We show that IKBKG mutations causing OL-EDA-ID and EDA-ID impair but do not abolish NF-kappaB signaling"
Landmark paper establishing that IKBKG/NEMO is essential for NF-kB signaling and that hypomorphic mutations impair but do not abolish this pathway, while complete loss of function is male-lethal.
PMID:16397577 SUPPORT Human Clinical
"The recent identification of genetic diseases (incontinentia pigmenti, anhidrotic ectodermal dysplasia with immunodeficiency and cylindromatosis) resulting from mutations affecting components of the nuclear factor-kappaB (NF-kappaB) signaling pathway provides a unique opportunity to understand..."
Review confirming that IP and EDA-ID result from mutations in the NF-kB signaling pathway.
Impaired innate immune signaling
IKBKG deficiency impairs signaling through Toll-like receptors and TNF receptor superfamily members, reducing production of pro-inflammatory cytokines and antimicrobial peptides. This results in susceptibility to pyogenic bacteria, mycobacteria, and certain viruses.
macrophage link dendritic cell link
Toll-like receptor signaling pathway link inflammatory response link
Downstream
Susceptibility to severe infections Defective innate immunity results in increased susceptibility to encapsulated bacteria, mycobacteria, and herpesviruses.
Show evidence (2 references)
PMID:11242109 SUPPORT Human Clinical
"abnormal immunity in OL-EDA-ID patients results from impaired cell responses to lipopolysaccharide, interleukin (IL)-1beta, IL-18, TNFalpha and CD154"
Demonstrates that IKBKG mutations impair cellular responses to multiple innate immune stimuli including LPS and cytokines.
PMID:21734245 SUPPORT Human Clinical
"Both of these defects impair NF-κB-mediated cellular responses to multiple receptors, including TLRs, IL-1Rs, and tumor necrosis factor receptors (TNF-Rs). They therefore confer a much broader predisposition to infections than that for IRAK-4 and MyD88 deficiencies"
Confirms that NEMO deficiency impairs TLR, IL-1R, and TNF-R signaling, causing broad infection susceptibility.
Defective adaptive immunity
Impaired NF-kB signaling in B cells leads to defective class switch recombination, resulting in hypogammaglobulinemia with elevated IgM and reduced IgG and IgA. T cell function is variably affected with impaired cytokine production.
B cell link T cell link
immunoglobulin isotype switching link B cell activation link
Show evidence (2 references)
PMID:22635013 SUPPORT Human Clinical
"diverse immunological abnormalities such as susceptibility to pathogens, impaired antibody responses to polysaccharides, hypogammaglobulinemia, hyper-IgM syndrome, impaired natural killer cell cytotoxicity, and autoimmune diseases"
Describes the spectrum of adaptive immune defects in EDA-ID including hypogammaglobulinemia and hyper-IgM pattern.
PMID:11047757 SUPPORT Human Clinical
"Affected males manifest dysgammaglobulinemia and, despite therapy, have significant morbidity and mortality from recurrent infections"
Confirms dysgammaglobulinemia as a key feature of EDA-ID with significant clinical impact.
Ectodermal developmental defects
The EDA-EDAR-EDARADD signaling axis requires NF-kB activation via IKBKG for normal development of ectodermal appendages including hair follicles, sweat glands, and teeth. IKBKG hypomorphic mutations impair this pathway, causing anhidrotic ectodermal dysplasia with sparse hair, conical teeth, and absent or hypoplastic sweat glands.
epithelial cell link
ectodermal placode formation link
Show evidence (2 references)
PMID:11242109 SUPPORT Human Clinical
"the ectodysplasin receptor, DL, triggers NF-kappaB through the NEMO protein, indicating that EDA results from impaired NF-kappaB signaling"
Demonstrates that EDA-ID ectodermal features result from impaired NF-kappaB signaling downstream of the ectodysplasin receptor.
PMID:11047757 SUPPORT Human Clinical
"The data provide further evidence that the development of ectodermal appendages is mediated through a tumor necrosis factor/tumor necrosis factor receptor-like signaling pathway, with the IKK signalsome complex playing a significant role"
Confirms the TNF/TNFR-like signaling via IKK complex in ectodermal appendage development.
Inflammatory skin response (IP)
In incontinentia pigmenti, heterozygous females show mosaic skin involvement reflecting lyonization. Cells expressing the mutant IKBKG allele undergo apoptosis and trigger inflammatory responses, producing the characteristic staged skin lesions along lines of Blaschko: vesicular (inflammatory), verrucous (hyperkeratotic), hyperpigmented, and atrophic.
keratinocyte link
apoptotic process link inflammatory response link
Show evidence (2 references)
PMID:10839543 SUPPORT Human Clinical
"The prominent skin signs occur in four classic cutaneous stages: perinatal inflammatory vesicles, verrucous patches, a distinctive pattern of hyperpigmentation and dermal scarring. Cells expressing the mutated X chromosome are eliminated selectively around the time of birth, so females with IP..."
Describes the four stages of IP skin lesions and the mechanism of selective elimination of IKBKG-mutant cells.
PMID:21255870 SUPPORT Human Clinical
"Linear atrophic, hypopigmented, and hairless lesions (stage 4) are constant in adults. Apoptotic keratinocytes in the epidermis or dermis and atrophic hair follicles, with absence of arrector pili muscles, are frequently observed"
Characterizes stage 4 IP lesions in adults with histologic features including apoptotic keratinocytes.
Susceptibility to severe infections
Males with EDA-ID are susceptible to a broad spectrum of infections including pyogenic bacteria (Streptococcus pneumoniae, Staphylococcus aureus), mycobacteria (including atypical and BCG), herpesviruses (CMV, HSV), and Pneumocystis jirovecii. This reflects the combined innate and adaptive immune defects.
Show evidence (2 references)
PMID:33598805 SUPPORT Human Clinical
"X-linked recessive (XR) ectodermal dysplasia with immunodeficiency (EDA-ID) is a rare primary immunodeficiency (PID) with various clinical phenotypes, including anomalies of the ectodermic tissues (nails, hairs, teeth, and hair), osteopetrosis, lymphedema, colitis and susceptibility to severe infections"
Confirms susceptibility to severe infections as a key feature of EDA-ID.
PMID:21734245 SUPPORT Human Clinical
"Hypomorphic mutations in the X-linked NEMO gene and hypermorphic mutations in the autosomal IKBA gene cause X-linked recessive and autosomal dominant anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) syndromes"
Comprehensive review of the infection spectrum in NEMO-deficient patients.
⬡

Pathograph

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Pathograph: causal mechanism network for IKBKG ectodermal dysplasia with immunodeficiency Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

15
Blood 1
Hypogammaglobulinemia Decreased circulating immunoglobulin concentration (HP:0004313)
Show evidence (1 reference)
PMID:22635013 SUPPORT Human Clinical
"diverse immunological abnormalities such as susceptibility to pathogens, impaired antibody responses to polysaccharides, hypogammaglobulinemia, hyper-IgM syndrome"
Confirms hypogammaglobulinemia and hyper-IgM as immunological features of EDA-ID.
Digestive 1
Colitis Colitis (HP:0002583)
Show evidence (1 reference)
PMID:33598805 SUPPORT Human Clinical
"He also had symptoms of inflammatory bowel disease (IBD): diarrhea, failure to thrive, and feeding intolerance with the need for parenteral nutrition"
Documents IBD-like colitis in a severe EDA-ID patient.
Head and Neck 2
Sparse scalp hair Sparse scalp hair (HP:0002209)
Show evidence (1 reference)
PMID:33598805 SUPPORT Human Clinical
"a moderate EDA characterized by sparse hair, some skin areas that were dry and darker in color, ichthyosis with pilling of the abdomen, eczematous dermatosis and hypohidrosis"
Case report documenting sparse hair as part of the EDA features in a NEMO-deficient patient.
Tooth abnormalities (IP) Abnormality of the dentition (HP:0000164)
Show evidence (1 reference)
PMID:39623400 SUPPORT Human Clinical
"commonly reported manifestations included the involvement of the teeth (58.7%), the central nervous system (30.7%), hair (26.7%), and eyes (22.6%), as well as nail dystrophy (16.0%)"
Nationwide Danish IP cohort showing 58.7% dental involvement.
Immune 1
Recurrent infections Recurrent infections (HP:0002719)
Show evidence (1 reference)
PMID:11047757 SUPPORT Human Clinical
"Affected males manifest dysgammaglobulinemia and, despite therapy, have significant morbidity and mortality from recurrent infections"
Confirms recurrent infections as a cardinal feature of EDA-ID.
Metabolism 1
Lymphedema Lymphedema (HP:0001004)
Show evidence (2 references)
PMID:11242109 SUPPORT Human Clinical
"2 patients with a related and hitherto unrecognized syndrome of EDA-ID with osteopetrosis and lymphoedema (OL-EDA-ID)"
First description of lymphedema as a feature of OL-EDA-ID.
PMID:16397577 SUPPORT Human Clinical
"uncovered new critical roles played by this transcription factor in the development and homeostasis of the epidermis and the proper function of lymphatic vessels"
Confirms NF-kB role in lymphatic vessel function, explaining lymphedema in NEMO deficiency.
Musculoskeletal 1
Osteopetrosis Osteopetrosis (HP:0011002)
Show evidence (1 reference)
PMID:11242109 SUPPORT Human Clinical
"2 patients with a related and hitherto unrecognized syndrome of EDA-ID with osteopetrosis and lymphoedema (OL-EDA-ID)"
First description of osteopetrosis as a feature of the severe OL-EDA-ID variant.
Nervous System 1
Seizures Seizure (HP:0001250)
Show evidence (1 reference)
PMID:10839543 SUPPORT Human Clinical
"In affected females it causes highly variable abnormalities of the skin, hair, nails, teeth, eyes and central nervous system"
CNS involvement including seizures is part of the IP phenotypic spectrum.
Respiratory 1
Bronchiectasis Bronchiectasis (HP:0002110)
Show evidence (1 reference)
PMID:22566850 SUPPORT Human Clinical
"HED-ID is characterized by exquisite susceptibility to mycobacteria, pyogenic bacteria, and herpesviruses due to the essential role played by NF-κB signaling in both innate and adaptive immunity"
Recurrent sinopulmonary infections from broad pathogen susceptibility lead to progressive bronchiectasis in EDA-ID patients.
Growth 1
Failure to thrive Failure to thrive (HP:0001508)
Show evidence (1 reference)
PMID:33598805 SUPPORT Human Clinical
"He also had symptoms of inflammatory bowel disease (IBD): diarrhea, failure to thrive, and feeding intolerance with the need for parenteral nutrition"
Failure to thrive documented as part of severe EDA-ID presentation.
Other 5
Mycobacterial infection susceptibility Recurrent mycobacterial infections (HP:0011274)
Show evidence (1 reference)
PMID:21734245 SUPPORT Human Clinical
"Both of these defects impair NF-κB-mediated cellular responses to multiple receptors, including TLRs, IL-1Rs, and tumor necrosis factor receptors (TNF-Rs). They therefore confer a much broader predisposition to infections than that for IRAK-4 and MyD88 deficiencies"
Picard 2011 review documents the broad infection susceptibility including mycobacteria in NEMO-deficient patients.
Anhidrosis Anhidrosis (HP:0000970)
Show evidence (1 reference)
PMID:22635013 SUPPORT Human Clinical
"Anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) is characterized according to its various manifestations, which include ectodermal dysplasia"
Anhidrotic (absent sweating) ectodermal dysplasia is the defining ectodermal feature of EDA-ID.
Conical teeth Conical tooth (HP:0000698)
Show evidence (1 reference)
PMID:11047757 SUPPORT Human Clinical
"Hypohidrotic ectodermal dysplasia (HED), a congenital disorder of teeth, hair, and eccrine sweat glands"
Tooth abnormalities are a defining feature of hypohidrotic ectodermal dysplasia in EDA-ID.
Skin lesions along Blaschko lines Irregular hyperpigmentation (HP:0007400)
Show evidence (1 reference)
PMID:10839543 SUPPORT Human Clinical
"The prominent skin signs occur in four classic cutaneous stages: perinatal inflammatory vesicles, verrucous patches, a distinctive pattern of hyperpigmentation and dermal scarring"
Describes the four stages of IP skin involvement.
Retinal vascular abnormalities Abnormal retinal vascular morphology (HP:0008046)
Show evidence (1 reference)
PMID:39623400 SUPPORT Human Clinical
"commonly reported manifestations included the involvement of the teeth (58.7%), the central nervous system (30.7%), hair (26.7%), and eyes (22.6%), as well as nail dystrophy (16.0%)"
Nationwide Danish IP cohort showing 22.6% ocular involvement.
🧬

Genetic Associations

2
IKBKG exon 4-10 deletion
Show evidence (3 references)
PMID:10839543 SUPPORT Human Clinical
"a new genomic rearrangement accounts for 80% of new mutations. As a consequence, NF-kappaB activation is defective in IP cells"
Identifies the recurrent exon 4-10 deletion as the predominant IP-causing mutation.
PMID:18350553 SUPPORT Human Clinical
"A recurrent exon 4_10 genomic rearrangement in the IKBKG gene accounts for 60 to 80% of IP-causing mutations"
Confirms the exon 4-10 deletion frequency and provides updated mutation spectrum data.
CGGV:assertion_2c9ee97a-ab3d-4747-b3fe-523578dd90e9-2022-09-15T160000.000Z SUPPORT Other
"IKBKG | HGNC:5961 | IKBKG-related immunodeficiency with or without ectodermal dysplasia | MONDO:0100162 | XL | Definitive"
ClinGen classifies the IKBKG-IKBKG-related immunodeficiency with or without ectodermal dysplasia gene-disease relationship as definitive with X-linked inheritance.
Hypomorphic IKBKG missense mutations
Show evidence (2 references)
PMID:11242109 SUPPORT Human Clinical
"We show that IKBKG mutations causing OL-EDA-ID and EDA-ID impair but do not abolish NF-kappaB signaling"
Establishes that EDA-ID results from hypomorphic mutations that impair but do not abolish NF-kB signaling.
PMID:18350553 SUPPORT Human Clinical
"a total of 69 different small mutations (missense, frameshift, nonsense, and splice-site mutations) have been reported, including 13 novel ones in this work"
Documents the broad spectrum of IKBKG mutations causing EDA-ID.
💊

Treatments

4
Immunoglobulin Replacement Therapy
Action: immunoglobulin replacement therapy Ontology label: Pharmacotherapy NCIT:C15986
Intravenous or subcutaneous immunoglobulin replacement for hypogammaglobulinemia in EDA-ID patients.
Show evidence (1 reference)
PMID:22635013 SUPPORT Human Clinical
"diverse immunological abnormalities such as susceptibility to pathogens, impaired antibody responses to polysaccharides, hypogammaglobulinemia, hyper-IgM syndrome"
Hypogammaglobulinemia in EDA-ID necessitates immunoglobulin replacement as part of standard management.
Antimicrobial Prophylaxis
Action: antimicrobial prophylaxis Ontology label: Pharmacotherapy NCIT:C15986
Prophylactic antibiotics and antifungals to prevent recurrent infections in immunodeficient patients.
Hematopoietic Stem Cell Transplantation
Action: hematopoietic stem cell transplantation Ontology label: organ transplantation MAXO:0010039
HSCT is the only curative treatment for the immunodeficiency component of EDA-ID, though it does not correct ectodermal features. Outcomes are variable, with significant transplant-related morbidity.
Show evidence (2 references)
PMID:33598805 SUPPORT Human Clinical
"Severe XR-EDA-ID is potentially curable with HSCT: the recent study by Miot et al. reviewed 29 cases of transplanted children with EDA-ID and the overall survival rate was 74% at 57 month-post-transplantation"
Documents HSCT as a potentially curative treatment for EDA-ID, with a 74% overall survival at 57 months reported in a multi-patient cohort.
PMID:22566850 SUPPORT Human Clinical
"HED-ID is characterized by exquisite susceptibility to mycobacteria, pyogenic bacteria, and herpesviruses due to the essential role played by NF-κB signaling in both innate and adaptive immunity"
Describes the infection susceptibility in HED-ID that motivates HSCT consideration.
Supportive Dermatological Care
Action: supportive care MAXO:0000950
Management of skin lesions in IP including topical treatments and monitoring for secondary infections during the vesicular stage.
{ }

Source YAML

click to show 
name: IKBKG ectodermal dysplasia with immunodeficiency
creation_date: "2026-04-24T12:00:00Z"
updated_date: "2026-04-24T12:00:00Z"
category: Mendelian
parents:
- hereditary disease
- primary immunodeficiency
- ectodermal dysplasia syndrome
synonyms:
- EDA-ID
- NEMO deficiency syndrome
- incontinentia pigmenti
- X-linked ectodermal dysplasia and immunodeficiency
- anhidrotic ectodermal dysplasia with immunodeficiency
- Bloch-Sulzberger syndrome
description: >-
  IKBKG ectodermal dysplasia with immunodeficiency encompasses a spectrum of
  X-linked disorders caused by mutations in IKBKG (also known as NEMO), the
  regulatory subunit of the IKK complex essential for NF-kB activation. The
  phenotypic spectrum is determined by mutation type and sex: hypomorphic
  mutations in hemizygous males cause ectodermal dysplasia with immunodeficiency
  (EDA-ID), characterized by anhidrotic ectodermal dysplasia, recurrent severe
  infections, and hypogammaglobulinemia; complete loss-of-function mutations
  cause incontinentia pigmenti (IP) in heterozygous females (male-lethal),
  characterized by distinctive skin lesions following the lines of Blaschko,
  with variable CNS, ocular, and dental involvement. The unifying molecular
  defect is impaired NF-kB signaling affecting immune, ectodermal, and
  inflammatory pathways.
disease_term:
  preferred_term: IKBKG-related immunodeficiency with or without ectodermal dysplasia
  term:
    id: MONDO:0100162
    label: IKBKG-related immunodeficiency with or without ectodermal dysplasia
has_subtypes:
- name: EDA-ID
  display_name: Ectodermal Dysplasia and Immunodeficiency 1 (EDA-ID)
  description: >-
    Caused by hypomorphic IKBKG mutations in hemizygous males. Characterized by
    anhidrotic ectodermal dysplasia (sparse hair, conical teeth, absent sweat
    glands) and combined immunodeficiency with susceptibility to pyogenic
    bacteria, mycobacteria, and viruses. NF-kB signaling is partially retained.
  evidence:
  - reference: PMID:11242109
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      hypomorphic mutations in the gene IKBKG in 12 males with EDA-ID from 8
      kindreds
    explanation: >-
      Landmark paper establishing that hypomorphic IKBKG mutations cause EDA-ID
      in males.
- name: IP
  display_name: Incontinentia Pigmenti (Bloch-Sulzberger Syndrome)
  description: >-
    Caused by loss-of-function IKBKG mutations (most commonly exon 4-10
    deletion) in heterozygous females; hemizygous males are non-viable.
    Characterized by skin lesions progressing through vesicular, verrucous,
    hyperpigmented, and atrophic stages along lines of Blaschko, reflecting
    lyonization patterns. Variable CNS, ocular, and dental involvement.
  evidence:
  - reference: PMID:10839543
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Familial incontinentia pigmenti (IP; MIM 308310) is a genodermatosis that
      segregates as an X-linked dominant disorder and is usually lethal
      prenatally in males
    explanation: >-
      Original discovery paper establishing NEMO/IKBKG mutations as the cause
      of incontinentia pigmenti.
- name: OL-EDA-ID
  display_name: Anhidrotic EDA-ID with Osteopetrosis and Lymphedema
  description: >-
    A severe variant caused by specific IKBKG mutations (e.g., stop codon
    mutations) in males, combining ectodermal dysplasia, immunodeficiency,
    osteopetrosis, and lymphedema due to more profound NF-kB pathway disruption.
  evidence:
  - reference: PMID:11242109
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      2 patients with a related and hitherto unrecognized syndrome of EDA-ID
      with osteopetrosis and lymphoedema (OL-EDA-ID). Mutations in the coding
      region of IKBKG are associated with EDA-ID, and stop codon mutations,
      with OL-EDA-ID
    explanation: >-
      First description of OL-EDA-ID as a distinct severe variant caused by
      stop codon IKBKG mutations.
- name: IMD33
  display_name: Immunodeficiency 33 (Mycobacterial Susceptibility)
  description: >-
    Caused by specific hypomorphic IKBKG mutations that preferentially impair
    mycobacterial immunity while preserving other NF-kB-dependent functions.
    Males present with selective susceptibility to mycobacterial infections.
  evidence:
  - reference: PMID:26269396
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A wide spectrum of IKBKG/NEMO mutations have been identified so far, and,
      on the basis of their effect on NF-κB activation, they are considered
      hypomorphic or amorphic (loss of function) mutations. IKBKG/NEMO
      hypomorphic mutations, reducing but not abolishing NF-κB activation, have
      been identified in EDA-ID and IP patients
    explanation: >-
      Fusco 2015 review describes the spectrum of IKBKG mutations including
      hypomorphic variants that reduce but do not abolish NF-kB activation,
      supporting the IMD33 phenotype of selective mycobacterial susceptibility.
inheritance:
- name: X-linked recessive inheritance (EDA-ID)
  description: >-
    EDA-ID, OL-EDA-ID, and IMD33 follow X-linked recessive inheritance, with
    hemizygous males affected by hypomorphic IKBKG mutations. Carrier females
    show skewed X-inactivation favoring the normal allele.
  inheritance_term:
    preferred_term: X-linked recessive inheritance
    term:
      id: HP:0001419
      label: X-linked recessive inheritance
  evidence:
  - reference: PMID:11047757
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      males from four families with HED and immunodeficiency (HED-ID), in which
      the disorder segregates as an X-linked recessive trait
    explanation: >-
      Establishes X-linked recessive inheritance pattern for EDA-ID.
- name: X-linked dominant inheritance (IP)
  description: >-
    Incontinentia pigmenti follows X-linked dominant inheritance with male
    lethality. Heterozygous females are affected due to functional mosaicism
    from lyonization.
  inheritance_term:
    preferred_term: X-linked dominant inheritance
    term:
      id: HP:0001423
      label: X-linked dominant inheritance
  evidence:
  - reference: PMID:10839543
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Familial incontinentia pigmenti (IP; MIM 308310) is a genodermatosis that
      segregates as an X-linked dominant disorder and is usually lethal
      prenatally in males
    explanation: >-
      Establishes X-linked dominant inheritance with male lethality for IP.
pathophysiology:
- name: IKBKG/NEMO loss of function
  description: >-
    Mutations in IKBKG disrupt the NF-kB essential modulator (NEMO), a scaffold
    protein required for activation of the IKK complex. IKBKG binds IKKalpha and
    IKKbeta and is essential for signal-induced phosphorylation and degradation
    of IkBalpha, thereby controlling NF-kB nuclear translocation. Complete loss
    of function is embryonically lethal in males; hypomorphic mutations allow
    partial NF-kB activation.
  genes:
  - preferred_term: IKBKG
    term:
      id: hgnc:5961
      label: IKBKG
  biological_processes:
  - preferred_term: NF-kappaB signaling
    term:
      id: GO:0007249
      label: canonical NF-kappaB signal transduction
  evidence:
  - reference: PMID:11242109
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      IKBKG encodes NEMO, the regulatory subunit of the IKK (IkappaB kinase)
      complex, which is essential for NF-kappaB signaling. Germline
      loss-of-function mutations in IKBKG are lethal in male fetuses. We show
      that IKBKG mutations causing OL-EDA-ID and EDA-ID impair but do not
      abolish NF-kappaB signaling
    explanation: >-
      Landmark paper establishing that IKBKG/NEMO is essential for NF-kB
      signaling and that hypomorphic mutations impair but do not abolish this
      pathway, while complete loss of function is male-lethal.
  - reference: PMID:16397577
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The recent identification of genetic diseases (incontinentia pigmenti,
      anhidrotic ectodermal dysplasia with immunodeficiency and cylindromatosis)
      resulting from mutations affecting components of the nuclear
      factor-kappaB (NF-kappaB) signaling pathway provides a unique opportunity
      to understand the function of NF-kappaB in vivo
    explanation: >-
      Review confirming that IP and EDA-ID result from mutations in the NF-kB
      signaling pathway.
  downstream:
  - target: Impaired innate immune signaling
    description: >-
      Defective NF-kB activation impairs TLR and TNF receptor signaling in
      innate immune cells.
  - target: Defective adaptive immunity
    description: >-
      Impaired NF-kB signaling disrupts B cell maturation and immunoglobulin
      class switching.
  - target: Ectodermal developmental defects
    description: >-
      NF-kB signaling through the EDA/EDAR pathway is required for ectodermal
      appendage development.
  - target: Inflammatory skin response (IP)
    description: >-
      In IP females, mosaic IKBKG-null cells trigger inflammatory responses
      along lines of Blaschko.
- name: Impaired innate immune signaling
  description: >-
    IKBKG deficiency impairs signaling through Toll-like receptors and TNF
    receptor superfamily members, reducing production of pro-inflammatory
    cytokines and antimicrobial peptides. This results in susceptibility to
    pyogenic bacteria, mycobacteria, and certain viruses.
  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: Toll-like receptor signaling pathway
    term:
      id: GO:0002224
      label: toll-like receptor signaling pathway
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
  evidence:
  - reference: PMID:11242109
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      abnormal immunity in OL-EDA-ID patients results from impaired cell
      responses to lipopolysaccharide, interleukin (IL)-1beta, IL-18, TNFalpha
      and CD154
    explanation: >-
      Demonstrates that IKBKG mutations impair cellular responses to multiple
      innate immune stimuli including LPS and cytokines.
  - reference: PMID:21734245
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both of these defects impair NF-κB-mediated cellular responses to
      multiple receptors, including TLRs, IL-1Rs, and tumor necrosis factor
      receptors (TNF-Rs). They therefore confer a much broader predisposition
      to infections than that for IRAK-4 and MyD88 deficiencies
    explanation: >-
      Confirms that NEMO deficiency impairs TLR, IL-1R, and TNF-R signaling,
      causing broad infection susceptibility.
  downstream:
  - target: Susceptibility to severe infections
    description: >-
      Defective innate immunity results in increased susceptibility to
      encapsulated bacteria, mycobacteria, and herpesviruses.
- name: Defective adaptive immunity
  description: >-
    Impaired NF-kB signaling in B cells leads to defective class switch
    recombination, resulting in hypogammaglobulinemia with elevated IgM and
    reduced IgG and IgA. T cell function is variably affected with impaired
    cytokine production.
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  biological_processes:
  - preferred_term: immunoglobulin isotype switching
    term:
      id: GO:0045190
      label: isotype switching
  - preferred_term: B cell activation
    term:
      id: GO:0042113
      label: B cell activation
  evidence:
  - reference: PMID:22635013
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      diverse immunological abnormalities such as susceptibility to pathogens,
      impaired antibody responses to polysaccharides, hypogammaglobulinemia,
      hyper-IgM syndrome, impaired natural killer cell cytotoxicity, and
      autoimmune diseases
    explanation: >-
      Describes the spectrum of adaptive immune defects in EDA-ID including
      hypogammaglobulinemia and hyper-IgM pattern.
  - reference: PMID:11047757
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Affected males manifest dysgammaglobulinemia and, despite therapy, have
      significant morbidity and mortality from recurrent infections
    explanation: >-
      Confirms dysgammaglobulinemia as a key feature of EDA-ID with
      significant clinical impact.
- name: Ectodermal developmental defects
  description: >-
    The EDA-EDAR-EDARADD signaling axis requires NF-kB activation via IKBKG for
    normal development of ectodermal appendages including hair follicles, sweat
    glands, and teeth. IKBKG hypomorphic mutations impair this pathway, causing
    anhidrotic ectodermal dysplasia with sparse hair, conical teeth, and absent
    or hypoplastic sweat glands.
  cell_types:
  - preferred_term: epithelial cell
    term:
      id: CL:0000066
      label: epithelial cell
  biological_processes:
  - preferred_term: ectodermal placode formation
    term:
      id: GO:0060788
      label: ectodermal placode formation
  evidence:
  - reference: PMID:11242109
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the ectodysplasin receptor, DL, triggers NF-kappaB through the NEMO
      protein, indicating that EDA results from impaired NF-kappaB signaling
    explanation: >-
      Demonstrates that EDA-ID ectodermal features result from impaired
      NF-kappaB signaling downstream of the ectodysplasin receptor.
  - reference: PMID:11047757
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The data provide further evidence that the development of ectodermal
      appendages is mediated through a tumor necrosis factor/tumor necrosis
      factor receptor-like signaling pathway, with the IKK signalsome complex
      playing a significant role
    explanation: >-
      Confirms the TNF/TNFR-like signaling via IKK complex in ectodermal
      appendage development.
- name: Inflammatory skin response (IP)
  description: >-
    In incontinentia pigmenti, heterozygous females show mosaic skin
    involvement reflecting lyonization. Cells expressing the mutant IKBKG allele
    undergo apoptosis and trigger inflammatory responses, producing the
    characteristic staged skin lesions along lines of Blaschko: vesicular
    (inflammatory), verrucous (hyperkeratotic), hyperpigmented, and atrophic.
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  biological_processes:
  - preferred_term: apoptotic process
    term:
      id: GO:0006915
      label: apoptotic process
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
  evidence:
  - reference: PMID:10839543
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The prominent skin signs occur in four classic cutaneous stages: perinatal
      inflammatory vesicles, verrucous patches, a distinctive pattern of
      hyperpigmentation and dermal scarring. Cells expressing the mutated X
      chromosome are eliminated selectively around the time of birth, so females
      with IP exhibit extremely skewed X-inactivation
    explanation: >-
      Describes the four stages of IP skin lesions and the mechanism of
      selective elimination of IKBKG-mutant cells.
  - reference: PMID:21255870
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Linear atrophic, hypopigmented, and hairless lesions (stage 4) are
      constant in adults. Apoptotic keratinocytes in the epidermis or dermis and
      atrophic hair follicles, with absence of arrector pili muscles, are
      frequently observed
    explanation: >-
      Characterizes stage 4 IP lesions in adults with histologic features
      including apoptotic keratinocytes.
- name: Susceptibility to severe infections
  description: >-
    Males with EDA-ID are susceptible to a broad spectrum of infections
    including pyogenic bacteria (Streptococcus pneumoniae, Staphylococcus
    aureus), mycobacteria (including atypical and BCG), herpesviruses (CMV,
    HSV), and Pneumocystis jirovecii. This reflects the combined innate and
    adaptive immune defects.
  evidence:
  - reference: PMID:33598805
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      X-linked recessive (XR) ectodermal dysplasia with immunodeficiency
      (EDA-ID) is a rare primary immunodeficiency (PID) with various clinical
      phenotypes, including anomalies of the ectodermic tissues (nails, hairs,
      teeth, and hair), osteopetrosis, lymphedema, colitis and susceptibility
      to severe infections
    explanation: >-
      Confirms susceptibility to severe infections as a key feature of EDA-ID.
  - reference: PMID:21734245
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hypomorphic mutations in the X-linked NEMO gene and hypermorphic
      mutations in the autosomal IKBA gene cause X-linked recessive and
      autosomal dominant anhidrotic ectodermal dysplasia with immunodeficiency
      (EDA-ID) syndromes
    explanation: >-
      Comprehensive review of the infection spectrum in NEMO-deficient patients.
phenotypes:
- category: Immunological
  name: Recurrent infections
  subtype: EDA-ID
  description: >-
    Severe, recurrent bacterial, mycobacterial, and viral infections beginning
    in infancy.
  phenotype_term:
    preferred_term: Recurrent infections
    term:
      id: HP:0002719
      label: Recurrent infections
  evidence:
  - reference: PMID:11047757
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Affected males manifest dysgammaglobulinemia and, despite therapy, have
      significant morbidity and mortality from recurrent infections
    explanation: >-
      Confirms recurrent infections as a cardinal feature of EDA-ID.
- category: Immunological
  name: Hypogammaglobulinemia
  subtype: EDA-ID
  description: >-
    Reduced serum immunoglobulin levels, particularly IgG and IgA, with
    variably elevated IgM reflecting defective class switch recombination.
  phenotype_term:
    preferred_term: Decreased circulating immunoglobulin concentration
    term:
      id: HP:0004313
      label: Decreased circulating immunoglobulin concentration
  evidence:
  - reference: PMID:22635013
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      diverse immunological abnormalities such as susceptibility to pathogens,
      impaired antibody responses to polysaccharides, hypogammaglobulinemia,
      hyper-IgM syndrome
    explanation: >-
      Confirms hypogammaglobulinemia and hyper-IgM as immunological features
      of EDA-ID.
- category: Immunological
  name: Mycobacterial infection susceptibility
  subtype: EDA-ID
  description: >-
    Susceptibility to mycobacterial infections including M. avium, M. kansasii,
    and disseminated BCG disease, reported in approximately 40% of NEMO
    deficiency patients.
  phenotype_term:
    preferred_term: Recurrent mycobacterial infections
    term:
      id: HP:0011274
      label: Recurrent mycobacterial infections
  evidence:
  - reference: PMID:21734245
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both of these defects impair NF-κB-mediated cellular responses to
      multiple receptors, including TLRs, IL-1Rs, and tumor necrosis factor
      receptors (TNF-Rs). They therefore confer a much broader predisposition
      to infections than that for IRAK-4 and MyD88 deficiencies
    explanation: >-
      Picard 2011 review documents the broad infection susceptibility including
      mycobacteria in NEMO-deficient patients.
- category: Dermatological
  name: Anhidrosis
  subtype: EDA-ID
  description: >-
    Absence of sweating due to hypoplastic or absent eccrine sweat glands,
    leading to heat intolerance.
  phenotype_term:
    preferred_term: Anhidrosis
    term:
      id: HP:0000970
      label: Anhidrosis
  evidence:
  - reference: PMID:22635013
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) is
      characterized according to its various manifestations, which include
      ectodermal dysplasia
    explanation: >-
      Anhidrotic (absent sweating) ectodermal dysplasia is the defining
      ectodermal feature of EDA-ID.
- category: Dermatological
  name: Sparse scalp hair
  subtype: EDA-ID
  description: >-
    Thin, sparse hair reflecting ectodermal dysplasia.
  phenotype_term:
    preferred_term: Sparse scalp hair
    term:
      id: HP:0002209
      label: Sparse scalp hair
  evidence:
  - reference: PMID:33598805
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a moderate EDA characterized by sparse hair, some skin areas that were
      dry and darker in color, ichthyosis with pilling of the abdomen,
      eczematous dermatosis and hypohidrosis
    explanation: >-
      Case report documenting sparse hair as part of the EDA features in a
      NEMO-deficient patient.
- category: Dental
  name: Conical teeth
  subtype: EDA-ID
  description: >-
    Peg-shaped or conical teeth characteristic of ectodermal dysplasia.
  phenotype_term:
    preferred_term: Conical tooth
    term:
      id: HP:0000698
      label: Conical tooth
  evidence:
  - reference: PMID:11047757
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hypohidrotic ectodermal dysplasia (HED), a congenital disorder of teeth,
      hair, and eccrine sweat glands
    explanation: >-
      Tooth abnormalities are a defining feature of hypohidrotic ectodermal
      dysplasia in EDA-ID.
- category: Dermatological
  name: Skin lesions along Blaschko lines
  subtype: IP
  description: >-
    Characteristic staged skin lesions following lines of Blaschko, progressing
    from vesicular to verrucous to hyperpigmented to atrophic stages.
  phenotype_term:
    preferred_term: Irregular hyperpigmentation
    term:
      id: HP:0007400
      label: Irregular hyperpigmentation
  evidence:
  - reference: PMID:10839543
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The prominent skin signs occur in four classic cutaneous stages: perinatal
      inflammatory vesicles, verrucous patches, a distinctive pattern of
      hyperpigmentation and dermal scarring
    explanation: >-
      Describes the four stages of IP skin involvement.
- category: Neurological
  name: Seizures
  subtype: IP
  description: >-
    Seizures occurring in a subset of IP patients, reflecting CNS involvement.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:10839543
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In affected females it causes highly variable abnormalities of the skin,
      hair, nails, teeth, eyes and central nervous system
    explanation: >-
      CNS involvement including seizures is part of the IP phenotypic spectrum.
- category: Ophthalmological
  name: Retinal vascular abnormalities
  subtype: IP
  description: >-
    Retinal neovascularization and vascular abnormalities that can lead to
    retinal detachment and vision loss. Ocular involvement is reported in
    approximately 23% of IP patients.
  phenotype_term:
    preferred_term: Abnormal retinal vascular morphology
    term:
      id: HP:0008046
      label: Abnormal retinal vascular morphology
  evidence:
  - reference: PMID:39623400
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      commonly reported manifestations included the involvement of the teeth
      (58.7%), the central nervous system (30.7%), hair (26.7%), and eyes
      (22.6%), as well as nail dystrophy (16.0%)
    explanation: >-
      Nationwide Danish IP cohort showing 22.6% ocular involvement.
- category: Gastrointestinal
  name: Colitis
  subtype: EDA-ID
  description: >-
    Inflammatory bowel disease-like colitis is part of the expanded EDA-ID
    phenotype, contributing to failure to thrive and requiring nutritional
    support.
  phenotype_term:
    preferred_term: Colitis
    term:
      id: HP:0002583
      label: Colitis
  evidence:
  - reference: PMID:33598805
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He also had symptoms of inflammatory bowel disease (IBD): diarrhea,
      failure to thrive, and feeding intolerance with the need for parenteral
      nutrition
    explanation: >-
      Documents IBD-like colitis in a severe EDA-ID patient.
- category: Respiratory
  name: Bronchiectasis
  subtype: EDA-ID
  description: >-
    Progressive bronchiectasis develops as a consequence of recurrent
    sinopulmonary infections in EDA-ID patients.
  phenotype_term:
    preferred_term: Bronchiectasis
    term:
      id: HP:0002110
      label: Bronchiectasis
  evidence:
  - reference: PMID:22566850
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      HED-ID is characterized by exquisite susceptibility to mycobacteria,
      pyogenic bacteria, and herpesviruses due to the essential role played by
      NF-κB signaling in both innate and adaptive immunity
    explanation: >-
      Recurrent sinopulmonary infections from broad pathogen susceptibility
      lead to progressive bronchiectasis in EDA-ID patients.
- category: Growth
  name: Failure to thrive
  subtype: EDA-ID
  description: >-
    Poor growth resulting from chronic infections, colitis, and nutritional
    compromise in EDA-ID patients.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:33598805
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He also had symptoms of inflammatory bowel disease (IBD): diarrhea,
      failure to thrive, and feeding intolerance with the need for parenteral
      nutrition
    explanation: >-
      Failure to thrive documented as part of severe EDA-ID presentation.
- category: Musculoskeletal
  name: Osteopetrosis
  subtype: OL-EDA-ID
  description: >-
    Increased bone density (osteopetrosis) seen in the severe OL-EDA-ID
    variant, reflecting the role of NF-kB signaling in osteoclast function.
  phenotype_term:
    preferred_term: Osteopetrosis
    term:
      id: HP:0011002
      label: Osteopetrosis
  evidence:
  - reference: PMID:11242109
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      2 patients with a related and hitherto unrecognized syndrome of EDA-ID
      with osteopetrosis and lymphoedema (OL-EDA-ID)
    explanation: >-
      First description of osteopetrosis as a feature of the severe OL-EDA-ID
      variant.
- category: Vascular
  name: Lymphedema
  subtype: OL-EDA-ID
  description: >-
    Lymphedema seen in the severe OL-EDA-ID variant, reflecting the role of
    NF-kB signaling in lymphatic vessel development.
  phenotype_term:
    preferred_term: Lymphedema
    term:
      id: HP:0001004
      label: Lymphedema
  evidence:
  - reference: PMID:11242109
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      2 patients with a related and hitherto unrecognized syndrome of EDA-ID
      with osteopetrosis and lymphoedema (OL-EDA-ID)
    explanation: >-
      First description of lymphedema as a feature of OL-EDA-ID.
  - reference: PMID:16397577
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      uncovered new critical roles played by this transcription factor in the
      development and homeostasis of the epidermis and the proper function of
      lymphatic vessels
    explanation: >-
      Confirms NF-kB role in lymphatic vessel function, explaining lymphedema
      in NEMO deficiency.
- category: Dental
  name: Tooth abnormalities (IP)
  subtype: IP
  description: >-
    Dental abnormalities including tooth agenesis, conical teeth, and delayed
    eruption are common in IP, reported in approximately 59% of patients.
  phenotype_term:
    preferred_term: Abnormality of the dentition
    term:
      id: HP:0000164
      label: Abnormality of the dentition
  evidence:
  - reference: PMID:39623400
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      commonly reported manifestations included the involvement of the teeth
      (58.7%), the central nervous system (30.7%), hair (26.7%), and eyes
      (22.6%), as well as nail dystrophy (16.0%)
    explanation: >-
      Nationwide Danish IP cohort showing 58.7% dental involvement.
genetic:
- name: IKBKG exon 4-10 deletion
  subtype: IP
  gene_term:
    preferred_term: IKBKG
    term:
      id: hgnc:5961
      label: IKBKG
  variants:
  - name: IKBKG exon 4-10 deletion
    description: >-
      A recurrent genomic rearrangement deleting exons 4-10 of IKBKG accounts
      for 60-80% of incontinentia pigmenti cases, resulting in complete loss of
      function.
    gene:
      preferred_term: IKBKG
      term:
        id: hgnc:5961
        label: IKBKG
  evidence:
  - reference: PMID:10839543
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a new genomic rearrangement accounts for 80% of new mutations. As a
      consequence, NF-kappaB activation is defective in IP cells
    explanation: >-
      Identifies the recurrent exon 4-10 deletion as the predominant
      IP-causing mutation.
  - reference: PMID:18350553
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A recurrent exon 4_10 genomic rearrangement in the IKBKG gene accounts
      for 60 to 80% of IP-causing mutations
    explanation: >-
      Confirms the exon 4-10 deletion frequency and provides updated mutation
      spectrum data.
  - reference: CGGV:assertion_2c9ee97a-ab3d-4747-b3fe-523578dd90e9-2022-09-15T160000.000Z
    reference_title: "IKBKG / IKBKG-related immunodeficiency with or without ectodermal dysplasia (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "IKBKG | HGNC:5961 | IKBKG-related immunodeficiency with or without ectodermal dysplasia | MONDO:0100162 | XL | Definitive"
    explanation: ClinGen classifies the IKBKG-IKBKG-related immunodeficiency with or without ectodermal dysplasia gene-disease relationship as definitive with X-linked inheritance.
- name: Hypomorphic IKBKG missense mutations
  subtype: EDA-ID
  gene_term:
    preferred_term: IKBKG
    term:
      id: hgnc:5961
      label: IKBKG
  variants:
  - name: Hypomorphic IKBKG missense mutations
    description: >-
      Missense mutations that partially preserve IKBKG function cause EDA-ID
      in hemizygous males. These include mutations in the zinc finger domain
      and coiled-coil regions.
    gene:
      preferred_term: IKBKG
      term:
        id: hgnc:5961
        label: IKBKG
  evidence:
  - reference: PMID:11242109
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We show that IKBKG mutations causing OL-EDA-ID and EDA-ID impair but do
      not abolish NF-kappaB signaling
    explanation: >-
      Establishes that EDA-ID results from hypomorphic mutations that impair
      but do not abolish NF-kB signaling.
  - reference: PMID:18350553
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a total of 69 different small mutations (missense, frameshift, nonsense,
      and splice-site mutations) have been reported, including 13 novel ones in
      this work
    explanation: >-
      Documents the broad spectrum of IKBKG mutations causing EDA-ID.
treatments:
- name: Immunoglobulin Replacement Therapy
  context: >-
    Used in EDA-ID patients with hypogammaglobulinemia.
  description: >-
    Intravenous or subcutaneous immunoglobulin replacement for
    hypogammaglobulinemia in EDA-ID patients.
  treatment_term:
    preferred_term: immunoglobulin replacement therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:22635013
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      diverse immunological abnormalities such as susceptibility to pathogens,
      impaired antibody responses to polysaccharides, hypogammaglobulinemia,
      hyper-IgM syndrome
    explanation: >-
      Hypogammaglobulinemia in EDA-ID necessitates immunoglobulin replacement
      as part of standard management.
- name: Antimicrobial Prophylaxis
  context: >-
    Used in EDA-ID patients to prevent recurrent infections.
  description: >-
    Prophylactic antibiotics and antifungals to prevent recurrent infections
    in immunodeficient patients.
  treatment_term:
    preferred_term: antimicrobial prophylaxis
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
- name: Hematopoietic Stem Cell Transplantation
  context: >-
    Curative option for the immunodeficiency component of EDA-ID; does not
    correct ectodermal features.
  description: >-
    HSCT is the only curative treatment for the immunodeficiency component
    of EDA-ID, though it does not correct ectodermal features. Outcomes are
    variable, with significant transplant-related morbidity.
  treatment_term:
    preferred_term: hematopoietic stem cell transplantation
    term:
      id: MAXO:0010039
      label: organ transplantation
  evidence:
  - reference: PMID:33598805
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Severe XR-EDA-ID is potentially curable with HSCT: the recent study by
      Miot et al. reviewed 29 cases of transplanted children with EDA-ID and
      the overall survival rate was 74% at 57 month-post-transplantation
    explanation: >-
      Documents HSCT as a potentially curative treatment for EDA-ID, with a
      74% overall survival at 57 months reported in a multi-patient cohort.
  - reference: PMID:22566850
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      HED-ID is characterized by exquisite susceptibility to mycobacteria,
      pyogenic bacteria, and herpesviruses due to the essential role played by
      NF-κB signaling in both innate and adaptive immunity
    explanation: >-
      Describes the infection susceptibility in HED-ID that motivates HSCT
      consideration.
- name: Supportive Dermatological Care
  context: >-
    Used in IP patients for management of skin lesions.
  description: >-
    Management of skin lesions in IP including topical treatments and
    monitoring for secondary infections during the vesicular stage.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
prevalence:
- population: General population
  subtype: IP
  percentage: "0.00237%"
  notes: >-
    Nationwide Danish population-based study (1995-2021) estimated birth
    prevalence of 2.37 per 100,000 live births (1 in 42,194). 94.7% female;
    72% had genetic confirmation.
  evidence:
  - reference: PMID:39623400
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We estimated a birth prevalence of 2.37 (95% CI: 1.74-3.25) per 100,000
      or 1 in 42,194
    explanation: >-
      First nationwide population-based prevalence estimate for IP.
datasets:
📚

References & Deep Research

Deep Research

1
Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 52 citations 2026-04-24T18:28:03.471565

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: IKBKG ectodermal dysplasia with immunodeficiency
  • MONDO ID: (if available)
  • Category: Mendelian

Research Objectives

Please provide a comprehensive research report on IKBKG ectodermal dysplasia with immunodeficiency 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

IKBKG ectodermal dysplasia with immunodeficiency (IKBKG-EDA-ID) — Disease characteristics report

Scope note. This report synthesizes information primarily from aggregated disease resources and peer‑reviewed reviews/case series, complemented by recent case reports (2023–2024) for “latest research” signals; it is not derived from EHR-only data. Key limitations: (i) no MONDO/MeSH/ICD identifiers were directly available in the retrieved full texts, so those fields are flagged as not confirmed from primary sources in this run; (ii) several foundational mechanistic and cohort-frequency statements come from pre‑2023 landmark papers/reviews because the disorder is rare.

1. Disease information

1.1 Concise overview

IKBKG ectodermal dysplasia with immunodeficiency (also called X‑linked anhidrotic/hypohidrotic ectodermal dysplasia with immunodeficiency, EDA‑ID/HED‑ID) is a Mendelian X‑linked inborn error of immunity caused by hypomorphic (residual-function) variants in IKBKG (NEMO/IKKγ). The disorder couples ectodermal dysplasia (abnormal development of sweat glands, hair, teeth, skin, nails) with combined immunodeficiency and a characteristic susceptibility to pyogenic bacteria, mycobacteria, and herpesviruses. (keller2011hypohidroticectodermaldysplasia pages 1-2, dassante2016unravelingthelink pages 2-4)

A core mechanistic concept is that complete IKBKG loss of function is usually male‑lethal, while partial loss permits survival but causes EDA‑ID; in heterozygous females, loss‑of‑function variants classically manifest as incontinentia pigmenti (IP) because X‑inactivation creates mosaicism. (pescatore2022humangeneticdiseases pages 1-3, zonana2000anovelxlinked pages 4-6)

1.2 Key identifiers (with evidence in this run)

  • OMIM: XL‑EDA‑ID / HED‑ID OMIM #300291 (keller2011hypohidroticectodermaldysplasia pages 1-2, callea2020covid‐19and pages 1-2)
  • Related allelic disorders:
  • Incontinentia pigmenti (IP): OMIM #308300 (callea2020covid‐19and pages 1-2)
  • Osteopetrosis/lymphedema with EDA‑ID (OL‑EDA‑ID): OMIM #300301 (callea2020covid‐19and pages 1-2, dassante2016unravelingthelink pages 2-4)

Not confirmed in retrieved texts: MONDO ID, Orphanet disease ID, ICD‑10/ICD‑11 code(s), MeSH descriptor(s).

1.3 Synonyms / alternative names

Commonly used synonyms include: EDA‑ID, XL‑EDA‑ID, HED‑ID, EDAXID, and NEMO deficiency syndrome. (keller2011hypohidroticectodermaldysplasia pages 1-2, callea2020covid‐19and pages 1-2, zonana2000anovelxlinked pages 1-2)

Concept/Label Key synonyms Primary gene Inheritance Key OMIM IDs (and related allelic disorders) Notes Key citations (context IDs)
IKBKG ectodermal dysplasia with immunodeficiency EDA-ID; XL-EDA-ID; XR-EDA-ID; HED-ID; hypohidrotic ectodermal dysplasia with immunodeficiency; anhidrotic ectodermal dysplasia with immunodeficiency; EDAXID; NEMO deficiency syndrome IKBKG (encodes NEMO/IKKγ) X-linked recessive in affected males with hypomorphic variants OMIM 300291; related allelic disorders: incontinentia pigmenti OMIM 308300; OL-EDA-ID / hypohidrotic ED with immunodeficiency, osteopetrosis and lymphedema OMIM 300301 Core phenotype combines ectodermal dysplasia with immunodeficiency due to impaired NF-κB signaling; typical ectodermal features include abnormal teeth, sparse hair, and hypohidrosis; severe infections are characteristic (keller2011hypohidroticectodermaldysplasia pages 1-2, callea2020covid‐19and pages 1-2, dassante2016unravelingthelink pages 2-4, doffinger2001xlinkedanhidroticectodermal pages 1-2)
NEMO-related HED-ID in males male HED-ID; male EDA-ID; X-linked HED-ID IKBKG / NEMO X-linked; hemizygous males survive when variants are hypomorphic rather than complete loss-of-function OMIM 300291 Complete loss-of-function is generally male-lethal; surviving affected males usually have residual NEMO/NF-κB activity (zonana2000anovelxlinked pages 1-2, zonana2000anovelxlinked pages 4-6, pescatore2022humangeneticdiseases pages 1-3, pescatore2022humangeneticdiseases pages 3-4)
Allelic relationship to incontinentia pigmenti IP-related NEMO disease; allelic to IP IKBKG / NEMO IP is typically X-linked dominant in females; EDA-ID is the allelic hypomorphic male phenotype OMIM 308300 (IP); OMIM 300291 (EDA-ID) Multiple reviews describe EDA-ID and IP as “two faces of the same coin,” with phenotype depending on residual NF-κB activity, mosaicism, and X-inactivation (fusco2015edaidandip pages 3-5, pescatore2022humangeneticdiseases pages 1-3, pescatore2022humangeneticdiseases pages 7-9, cifaldi2025partiallossof pages 13-14)
OL-EDA-ID / related severe allelic phenotype osteopetrosis-lymphedema-EDA-ID; OL-HED-ID IKBKG / NEMO X-linked OMIM 300301 Related but more severe allelic syndrome that adds osteopetrosis and lymphedema to ectodermal dysplasia with immunodeficiency (dassante2016unravelingthelink pages 2-4, fusco2015edaidandip pages 5-7, callea2020covid‐19and pages 1-2, doffinger2001xlinkedanhidroticectodermal pages 2-2)
Gene/protein label NEMO; IKKγ; NF-κB essential modulator IKBKG Not applicable Not disease OMIM-specific NEMO is the regulatory subunit of the IKK complex required for canonical NF-κB activation; this explains why IKBKG variants affect both immunity and ectodermal development (keller2011hypohidroticectodermaldysplasia pages 1-2, doffinger2001xlinkedanhidroticectodermal pages 2-2, mcdonald2014humanimmunodeficienciesresulting pages 2-4, doffinger2001xlinkedanhidroticectodermal pages 1-2)

Table: This table summarizes the main disease labels, synonyms, gene assignment, inheritance, and OMIM relationships for IKBKG/NEMO-associated ectodermal dysplasia with immunodeficiency. It is useful for harmonizing terminology across clinical, genetic, and knowledge-base records.

2. Etiology

2.1 Disease causal factors

Primary cause: germline hypomorphic variants in IKBKG (Xq28), encoding NEMO (NF‑κB essential modulator; IKKγ), which is required for canonical NF‑κB activation. (keller2011hypohidroticectodermaldysplasia pages 1-2, doffinger2001xlinkedanhidroticectodermal pages 1-2)

Allelic series: distinct IKBKG variant classes produce related phenotypes, including IP (typically female), OL‑EDA‑ID, isolated immunodeficiency, and atypical mycobacterial susceptibility phenotypes. (fusco2015edaidandip pages 5-7, fusco2015edaidandip pages 3-5)

2.2 Risk factors

  • Genetic: being a hemizygous male with a hypomorphic IKBKG variant (X‑linked). (zonana2000anovelxlinked pages 1-2, doffinger2001xlinkedanhidroticectodermal pages 1-2)
  • Iatrogenic/exposure: live mycobacterial vaccination exposure (e.g., BCG) is clinically relevant because mycobacterial susceptibility is common in the NEMO deficiency spectrum and has been implicated in disseminated mycobacterial disease in this disorder family. (haverkamp2014correlatinginterleukin12stimulated pages 8-8, meric2024atypicalmycobacterialpneumonia pages 1-2)

Environmental/lifestyle risk factors: no specific non-genetic risk factors were identified in the retrieved disease-specific sources; infection risk is driven primarily by the immunodeficiency.

2.3 Protective factors

No protective genetic or environmental factors were directly reported in the retrieved texts.

2.4 Gene–environment interactions

Relevant interaction: pathogen exposure (including environmental nontuberculous mycobacteria and vaccine-strain mycobacteria) interacts with impaired NF‑κB signaling to produce severe disease phenotypes. (haverkamp2014correlatinginterleukin12stimulated pages 8-8, picard2011infectiousdiseasesin pages 4-5)

3. Phenotypes

3.1 Major clinical phenotype categories

Ectodermal dysplasia features - Hypohidrosis/anhidrosis, sparse hair/hypotrichosis, abnormal dentition (including conical teeth, hypodontia/oligodontia), eczema/ichthyosis, nail abnormalities. (keller2011hypohidroticectodermaldysplasia pages 1-2, doffinger2001xlinkedanhidroticectodermal pages 1-2, puvilland2021edaidasevere pages 1-3)

Infectious susceptibility - Broad susceptibility with a strong signal for pyogenic bacteria and mycobacteria, with also viral and opportunistic pathogens (e.g., Pneumocystis). (picard2011infectiousdiseasesin pages 4-5, doffinger2001xlinkedanhidroticectodermal pages 2-2)

Inflammation/organ complications - Colitis/IBD-like disease, bronchiectasis, failure to thrive; osteopetrosis/lymphedema in the OL‑EDA‑ID allelic form. (doffinger2001xlinkedanhidroticectodermal pages 2-2, puvilland2021edaidasevere pages 1-3, dassante2016unravelingthelink pages 2-4)

3.2 Frequency / statistics (from cohort reviews)

From a major infectious-disease review of NEMO deficiency (including EDA‑ID presentations): - Pyogenic bacterial infections in ~90% of NEMO patients (picard2011infectiousdiseasesin pages 4-5) - Mycobacterial infections in ~40% (picard2011infectiousdiseasesin pages 4-5) - Serious viral infections in 19% (picard2011infectiousdiseasesin pages 4-5) - ~90% have ectodermal dysplasia features (picard2011infectiousdiseasesin pages 4-5)

3.3 Typical onset and course

In early family descriptions, affected boys often presented within the first 2 years of life with life‑threatening infections and ectodermal findings such as hypohidrosis and hypodontia/conical teeth. (zonana2000anovelxlinked pages 4-6, zonana2000anovelxlinked pages 2-4)

3.4 Suggested HPO terms

Clinical feature Suggested HPO term(s) (HP:) Typical onset Notes/quantitative frequency if available Key citations (context IDs)
Hypohidrosis / anhidrosis HP:0000975 Hypohidrosis; HP:0000870 Anhidrosis Congenital / infancy Core ectodermal feature of EDA-ID; described with absent sweat glands and heat intolerance in classic reports (keller2011hypohidroticectodermaldysplasia pages 1-2, doffinger2001xlinkedanhidroticectodermal pages 1-2)
Sparse scalp hair / hypotrichosis HP:0008070 Sparse scalp hair; HP:0001006 Hypotrichosis Congenital / infancy Part of the classic ectodermal dysplasia triad; often accompanies abnormal teeth and hypohidrosis (keller2011hypohidroticectodermaldysplasia pages 1-2, doffinger2001xlinkedanhidroticectodermal pages 1-2, fusco2015edaidandip pages 3-5)
Abnormal / conical teeth HP:0006482 Conical teeth; HP:0000670 Abnormality of dentition Childhood, often evident with tooth eruption Classic dental sign in EDA-ID; “rare conical teeth” repeatedly noted. IP/IKBKG-associated cohorts show dental involvement frequently; IP cohort reported teeth involvement in 58.7% and broader IP literature cites ~30–50% with tooth agenesis/oral anomalies (doffinger2001xlinkedanhidroticectodermal pages 1-2, fusco2015edaidandip pages 3-5, cammaratascalisi2024maingeneticentities pages 4-5, herlin2024prevalenceandclinical pages 1-3)
Hypodontia / oligodontia / tooth agenesis HP:0009804 Hypodontia; HP:0000674 Oligodontia; HP:0009805 Tooth agenesis Childhood Frequently grouped with abnormal dentition in ectodermal dysplasia; Cammarata-Scalisi 2024 links IKBKG-related disease to hypodontia, delayed eruption, abnormal shape and spacing (keller2011hypohidroticectodermaldysplasia pages 1-2, cammaratascalisi2024maingeneticentities pages 4-5, zonana2000anovelxlinked pages 2-4)
Delayed tooth eruption / microdontia HP:0000684 Delayed eruption of teeth; HP:0009827 Microdontia Childhood Reported in IKBKG-related oral phenotypes, especially in broader IP/IKBKG dental literature rather than EDA-ID-only cohorts (cammaratascalisi2024maingeneticentities pages 4-5)
Recurrent severe bacterial infections HP:0002718 Recurrent bacterial infections; HP:0002721 Recurrent infections Infancy / early childhood Major feature of EDA-ID; life-threatening infections often present in first 2 years of life. Picard review: pyogenic bacterial infections in ~90% of NEMO patients (picard2011infectiousdiseasesin pages 4-5, zonana2000anovelxlinked pages 4-6, fusco2015edaidandip pages 3-5)
Recurrent sinopulmonary infections / pneumonia HP:0006532 Recurrent pneumonia; HP:0012379 Bronchitis; HP:0002783 Recurrent upper respiratory tract infections Infancy / childhood Common real-world presentation; Meric 2024 siblings had recurrent sinopulmonary infections and pneumonia. Picard review lists pneumonia among frequent infections (meric2024atypicalmycobacterialpneumonia pages 1-2, meric2024atypicalmycobacterialpneumonia pages 2-3, picard2011infectiousdiseasesin pages 4-5)
Bronchiectasis HP:0002110 Bronchiectasis Childhood, progressive after recurrent infections Reported in severe patients with recurrent respiratory infection; documented in Döffinger 2001 and Meric 2024 (doffinger2001xlinkedanhidroticectodermal pages 2-2, meric2024atypicalmycobacterialpneumonia pages 1-2)
Mycobacterial infection susceptibility HP:0002726 Recurrent mycobacterial infections; HP:0032167 Increased susceptibility to mycobacterial infection Childhood Hallmark of NEMO deficiency spectrum. Picard review: mycobacterial infections in ~40% of NEMO patients; includes M. avium, M. kansasii, BCG-related disease, and M. bovis in 2024 siblings (picard2011infectiousdiseasesin pages 4-5, haverkamp2014correlatinginterleukin12stimulated pages 8-8, meric2024atypicalmycobacterialpneumonia pages 1-2, fusco2015edaidandip pages 3-5)
Opportunistic fungal infection / Pneumocystis HP:0005381 Recurrent fungal infections; HP:0012387 Pneumocystis jirovecii pneumonia Infancy / childhood Reported in severe phenotypes; examples include Pneumocystis infection in Döffinger 2001 and Puvilland 2021 (doffinger2001xlinkedanhidroticectodermal pages 2-2, puvilland2021edaidasevere pages 1-3, george2023infectionsininborn pages 5-6)
Severe viral infection / CMV / HSV HP:0004429 Recurrent viral infections Infancy / childhood Picard review: serious viral infections in 19% of NEMO patients; CMV and HSV reported in case series (picard2011infectiousdiseasesin pages 4-5, puvilland2021edaidasevere pages 1-3, fusco2015edaidandip pages 3-5)
Colitis / inflammatory bowel disease-like enterocolitis HP:0002037 Diarrhea; HP:0100279 Inflammatory bowel disease; HP:0002012 Abnormality of the intestine Infancy / childhood GI inflammation is part of the expanded phenotype; Döffinger reports recurrent GI infection/ulceration, Puvilland reports IBD-like colitis (doffinger2001xlinkedanhidroticectodermal pages 2-2, puvilland2021edaidasevere pages 1-3)
Failure to thrive HP:0001508 Failure to thrive Infancy / childhood Common consequence of severe infection/GI disease; described in Döffinger 2001 and Meric 2024 (doffinger2001xlinkedanhidroticectodermal pages 2-2, meric2024atypicalmycobacterialpneumonia pages 1-2)
Eczema / dry skin / ichthyosis HP:0000964 Eczema; HP:0001024 Ichthyosis; HP:0000958 Dry skin Infancy / childhood Skin abnormalities can accompany ectodermal findings; Keller notes eczema among HED features, Puvilland reports ichthyosis (keller2011hypohidroticectodermaldysplasia pages 1-2, puvilland2021edaidasevere pages 1-3)
Nail dysplasia / nail abnormality HP:0001597 Nail dysplasia; HP:0001197 Abnormality of nail morphology Childhood Part of the ectodermal anomaly spectrum; emphasized in broader syndrome descriptions and case reports (puvilland2021edaidasevere pages 1-3, fusco2015edaidandip pages 5-7)
Lymphedema HP:0001004 Lymphedema Variable, often childhood More characteristic of the severe allelic OL-EDA-ID phenotype than isolated EDA-ID (dassante2016unravelingthelink pages 2-4, doffinger2001xlinkedanhidroticectodermal pages 2-2)
Osteopetrosis HP:0011002 Osteopetrosis Childhood Seen in the allelic OL-EDA-ID form rather than typical EDA-ID; important for differential diagnosis within IKBKG disease spectrum (dassante2016unravelingthelink pages 2-4, doffinger2001xlinkedanhidroticectodermal pages 2-2)
Hypogammaglobulinemia HP:0004313 Decreased circulating IgG level; HP:0002845 Hypogammaglobulinemia Infancy / childhood Frequent laboratory phenotype; reduced IgG and impaired humoral immunity are recurrent findings across cohorts (dassante2016unravelingthelink pages 2-4, callea2020covid‐19and pages 1-2, fusco2015edaidandip pages 3-5)
Elevated IgM / hyper-IgM-like phenotype HP:0010703 Increased circulating IgM level Infancy / childhood Variable but repeatedly reported; some patients show reduced IgG with increased IgM or IgA. Example: IgM 4.6 g/L in severe 2021 case (puvilland2021edaidasevere pages 1-3, giancane2013anhidroticectodermaldysplasia pages 3-3, zonana2000anovelxlinked pages 2-4)
Poor specific antibody response to polysaccharides HP:0010773 Abnormality of immune system physiology; HP:0002721 Recurrent infections Childhood (after immunization/testing) A defining immunologic defect in many patients; Fusco review states all analyzed patients lacked polysaccharide-specific antibodies (picard2011infectiousdiseasesin pages 4-5, fusco2015edaidandip pages 5-7)
Memory B-cell deficiency / low switched memory B cells HP:0011837 Abnormal B-cell subset distribution Childhood Meric 2024 documented markedly reduced class-switched memory B cells in both siblings (meric2024atypicalmycobacterialpneumonia pages 1-2, meric2024atypicalmycobacterialpneumonia pages 2-3)
T-cell lymphopenia / abnormal T-cell function HP:0005403 T-cell lymphopenia; HP:0002843 Abnormality of T-cell function Infancy / childhood Variable across genotypes; includes reduced T-cell counts, absent memory T cells, and poor TCR-driven responses (dassante2016unravelingthelink pages 2-4, giancane2013anhidroticectodermaldysplasia pages 3-3, meric2024atypicalmycobacterialpneumonia pages 2-3)
Impaired NK-cell cytotoxicity HP:0011888 Abnormal natural killer cell function Childhood Reported in NEMO deficiency and contributes to broad infection susceptibility (callea2020covid‐19and pages 1-2, fusco2015edaidandip pages 3-5)

Table: This table maps the major clinical and laboratory features reported for IKBKG/NEMO-associated ectodermal dysplasia with immunodeficiency to suggested HPO terms. It is useful for structuring phenotype annotations in a disease knowledge base and highlights where limited quantitative frequency data are available.

3.5 Quality of life impact (evidence-based qualitative summary)

Although formal QoL instruments were not reported in the retrieved texts, the disease implies substantial QoL burden through recurrent/severe infections (hospitalizations, chronic lung disease/bronchiectasis) and ectodermal manifestations (heat intolerance from hypohidrosis; dental anomalies requiring long-term dental care). (keller2011hypohidroticectodermaldysplasia pages 1-2, doffinger2001xlinkedanhidroticectodermal pages 2-2, cammaratascalisi2024maingeneticentities pages 4-5)

4. Genetic / molecular information

4.1 Causal gene

  • IKBKG (encodes NEMO/IKKγ, regulatory subunit of the IKK complex). (keller2011hypohidroticectodermaldysplasia pages 1-2, doffinger2001xlinkedanhidroticectodermal pages 1-2)

4.2 Pathogenic variant classes and examples

A compiled review of EDA‑ID reports 29 distinct IKBKG mutations, 24 associated with EDA‑ID, including missense, nonsense, frameshift, splice-site, in‑frame deletion, nonstop mutation, and duplication. (fusco2015edaidandip pages 5-7)

Recent 2024 example: two male siblings with atypical mycobacterial pneumonia carried a novel hemizygous frameshift variant c.268delG (p.Ala90Glnfs*93); immunologic findings included reduced class‑switched memory B cells and the management included immunoglobulin replacement and antibacterial prophylaxis. (meric2024atypicalmycobacterialpneumonia pages 1-2, meric2024atypicalmycobacterialpneumonia pages 2-3)

4.3 Inheritance, penetrance, expressivity

  • Inheritance pattern: X‑linked (classically affecting males with hypomorphic alleles). (zonana2000anovelxlinked pages 1-2, doffinger2001xlinkedanhidroticectodermal pages 1-2)
  • Male lethality for complete loss: complete loss‑of‑function IKBKG variants are typically embryonically lethal in males, whereas hypomorphic variants allow male survival with EDA‑ID. (pescatore2022humangeneticdiseases pages 1-3, zonana2000anovelxlinked pages 4-6)
  • Variable expressivity: clinical heterogeneity is emphasized across cohorts and variants, including some individuals with immunodeficiency features without overt ectodermal dysplasia. (haverkamp2014correlatinginterleukin12stimulated pages 8-8, fusco2015edaidandip pages 7-8)

4.4 Modifier factors (genetic/epigenetic)

  • X‑inactivation/mosaicism is a major modifier in females and in rare surviving males with IP‑phenotypes. Mosaicism and tissue selection can affect both clinical presentation and diagnostic yield. (pescatore2022humangeneticdiseases pages 3-4, pescatore2022humangeneticdiseases pages 4-6)

4.5 Allele frequency in population databases

Not reported in the retrieved texts.

5. Environmental information

No specific toxins/lifestyle factors were identified as etiologic drivers in the retrieved disease‑specific sources. Infection exposure is the dominant environmental driver of clinical events. (picard2011infectiousdiseasesin pages 4-5)

6. Mechanism / pathophysiology

6.1 Current mechanistic model (causal chain)

1) IKBKG hypomorphic mutation → reduced NEMO function (regulatory subunit of the IKK complex) (doffinger2001xlinkedanhidroticectodermal pages 1-2) 2) Impaired but not abolished canonical NF‑κB activation (doffinger2001xlinkedanhidroticectodermal pages 1-2) 3) Downstream consequences: - Ectodermal defects: ectodysplasin receptor signaling requires NEMO to activate NF‑κB; impaired signaling disrupts development of sweat glands, hair follicles, and dentition. (doffinger2001xlinkedanhidroticectodermal pages 1-2, keller2011hypohidroticectodermaldysplasia pages 1-2) - Immune defects: NEMO acts downstream of multiple immune receptors (TLR/IL‑1R/TNFR/CD40/TCR/BCR), producing combined immune dysfunction, particularly defective responses to bacterial glycans/polysaccharide antigens and impaired inflammatory cytokine responses that contribute to pyogenic and mycobacterial susceptibility. (dassante2016unravelingthelink pages 2-4, picard2011infectiousdiseasesin pages 4-5)

A key immunologic summary statement from a 2011 infectious-disease review is that most NEMO patients have impaired antibody responses (notably to glycans) and substantial rates of pyogenic and mycobacterial infections. (picard2011infectiousdiseasesin pages 4-5)

6.2 Cell types and processes (ontology suggestions)

Cell Ontology (CL) suggestions (most implicated): - B cell: CL:0000236 (humoral defects; low switched memory B cells) (meric2024atypicalmycobacterialpneumonia pages 1-2, meric2024atypicalmycobacterialpneumonia pages 2-3) - T cell: CL:0000084 (variable T-cell dysfunction/lymphopenia) (giancane2013anhidroticectodermaldysplasia pages 3-3, dassante2016unravelingthelink pages 2-4) - Natural killer cell: CL:0000623 (impaired cytotoxicity reported) (callea2020covid‐19and pages 1-2) - Monocyte/macrophage: CL:0000576/CL:0000235 (TLR/IL‑1/TNF signaling defects linked to mycobacterial susceptibility) (haverkamp2014correlatinginterleukin12stimulated pages 8-8, dassante2016unravelingthelink pages 2-4)

Gene Ontology (GO) biological process suggestions: - NF‑κB signaling (e.g., “I‑κB kinase/NF‑κB signaling”) (doffinger2001xlinkedanhidroticectodermal pages 1-2) - Innate immune response and response to lipopolysaccharide/IL‑1/TNF (doffinger2001xlinkedanhidroticectodermal pages 2-2, dassante2016unravelingthelink pages 2-4) - Immunoglobulin class switch recombination / adaptive immune response (hyper‑IgM-like patterns and impaired antibody responses) (dassante2016unravelingthelink pages 2-4, puvilland2021edaidasevere pages 1-3) - Ectodermal appendage development (sweat gland/hair/tooth development via ectodysplasin–NF‑κB axis) (doffinger2001xlinkedanhidroticectodermal pages 1-2)

7. Anatomical structures affected

Primary systems: - Integumentary/ectodermal derivatives: skin, sweat glands, hair, nails, teeth. (keller2011hypohidroticectodermaldysplasia pages 1-2, callea2020covid‐19and pages 1-2) - Immune system: combined immunodeficiency affecting humoral and cellular arms. (keller2011hypohidroticectodermaldysplasia pages 1-2, dassante2016unravelingthelink pages 2-4)

Common secondary involvement/complications: - Respiratory tract/lungs: recurrent pneumonia and bronchiectasis. (doffinger2001xlinkedanhidroticectodermal pages 2-2, meric2024atypicalmycobacterialpneumonia pages 1-2) - Gastrointestinal tract: diarrhea, ulcerations, colitis/IBD-like. (doffinger2001xlinkedanhidroticectodermal pages 2-2, puvilland2021edaidasevere pages 1-3)

UBERON suggestions (examples): - Skin: UBERON:0002097 - Tooth: UBERON:0001091 - Lung: UBERON:0002048 - Intestine: UBERON:0000160

8. Temporal development

  • Onset: typically congenital ectodermal findings and early childhood onset of recurrent/severe infections; in classic pedigrees, severe infections often occur within the first two years. (zonana2000anovelxlinked pages 4-6, zonana2000anovelxlinked pages 2-4)
  • Course: variable; can progress to chronic lung disease (bronchiectasis) and chronic inflammatory complications (e.g., colitis). (doffinger2001xlinkedanhidroticectodermal pages 2-2, puvilland2021edaidasevere pages 1-3)

9. Inheritance and population

9.1 Epidemiology

Disease-specific prevalence is rarely measured; one source provides an estimate of HED‑ID ~1 in 250,000 newborns (contrasted with XLHED ~1 in 100,000). (keller2011hypohidroticectodermaldysplasia pages 1-2)

For epidemiologic context of IKBKG allelic disorders, a nationwide Danish IP study reported birth prevalence 2.37 per 100,000 (1 in 42,194) and point prevalence 1.21 per 100,000, with 71/75 female in the validated cohort. (herlin2024prevalenceandclinical pages 1-3, herlin2024prevalenceandclinical pages 6-7)

9.2 Sex ratio and de novo rate (context from IP)

In the Danish IP cohort, 94.7% were female; genetic confirmation was present in 72% of cases, and the recurrent exon 4–10 deletion was the most common genotype among those with genetic diagnoses. (herlin2024prevalenceandclinical pages 1-3)

10. Diagnostics

10.1 Clinical suspicion

Consider IKBKG‑EDA‑ID when ectodermal dysplasia signs (hypohidrosis, abnormal teeth, sparse hair) co‑occur with recurrent or severe infections, particularly pyogenic bacteria and mycobacteria. (keller2011hypohidroticectodermaldysplasia pages 1-2, picard2011infectiousdiseasesin pages 4-5)

10.2 Immunologic testing (real-world implementation)

Typical abnormalities include hypogammaglobulinemia and impaired specific antibody responses, including to polysaccharide antigens; class‑switched memory B‑cell deficiency may be observed. (dassante2016unravelingthelink pages 2-4, meric2024atypicalmycobacterialpneumonia pages 2-3)

10.3 Genetic testing strategy and pitfalls

  • Sequencing of IKBKG is diagnostic in males with suspected EDA‑ID; a 2024 report used an MSMD panel followed by IKBKG sequencing and Sanger confirmation. (meric2024atypicalmycobacterialpneumonia pages 1-2)
  • Diagnostic pitfalls include the presence of a pseudogene and structural complexity at the IKBKG locus and potential mosaicism, which may require tissue‑appropriate sampling and CNV-aware methods in related IKBKG disorders. (zonana2000anovelxlinked pages 2-4, pescatore2022humangeneticdiseases pages 4-6)

10.4 Differential diagnosis

  • EDA pathway HED (EDA/EDAR/EDARADD) without immunodeficiency (phenotypic overlap at ectodermal level). (keller2011hypohidroticectodermaldysplasia pages 1-2)
  • Autosomal dominant EDA‑ID due to NFKBIA (IκBα) variants, which can also present with ectodermal dysplasia and immunodeficiency. (giancane2013anhidroticectodermaldysplasia pages 3-3, picard2011infectiousdiseasesin pages 4-5)

11. Outcome / prognosis

Historical summaries emphasize substantial childhood morbidity and mortality; one review states that about half of known patients die in childhood (reflecting older case series and ascertainment of severe cases). (fusco2015edaidandip pages 3-5)

12. Treatment

12.1 Anti-infective strategy (practice-relevant)

Because invasive bacterial infection can progress rapidly, one authoritative review recommends immediate empiric parenteral antibiotics at first suspicion or moderate fever, targeting S. pneumoniae, S. aureus, and P. aeruginosa in NEMO deficiency. (picard2011infectiousdiseasesin pages 4-5)

12.2 Immunoglobulin replacement and prophylaxis

A 2024 case report of two affected brothers documented initiation of immunoglobulin replacement and antibacterial prophylaxis as part of management. (meric2024atypicalmycobacterialpneumonia pages 1-2)

12.3 Hematopoietic stem cell transplantation (HSCT)

HSCT has been used in EDA‑ID, including reports of successful transplant in at least one child, but ectodermal defects are not corrected by HSCT and outcomes can be variable. (giancane2013anhidroticectodermaldysplasia pages 3-3, puvilland2021edaidasevere pages 4-6)

12.4 Supportive ectodermal/airway care

Supportive measures aimed at airway/nasal dryness and crusting (humidification, saline, gentle crust removal; topical antibiotic ointments during acute infections) have been proposed in ED patients including XL‑EDA‑ID to reduce sinonasal symptoms and infections. (callea2020covid‐19and pages 1-2)

12.5 MAXO (Medical Action Ontology) suggestions

  • Immunoglobulin replacement therapy (MAXO term suggestion: “immunoglobulin replacement therapy”) (meric2024atypicalmycobacterialpneumonia pages 1-2)
  • Antibiotic prophylaxis / antimicrobial prophylaxis (MAXO suggestion) (meric2024atypicalmycobacterialpneumonia pages 1-2, meric2024atypicalmycobacterialpneumonia pages 2-3)
  • Hematopoietic stem cell transplantation (MAXO suggestion) (giancane2013anhidroticectodermaldysplasia pages 3-3, puvilland2021edaidasevere pages 4-6)
  • Empiric parenteral antibiotic therapy for suspected sepsis (MAXO suggestion) (picard2011infectiousdiseasesin pages 4-5)

13. Prevention

Primary/tertiary prevention in practice is dominated by infection prevention and rapid treatment: - Rapid initiation of empiric antibiotics for suspected invasive bacterial infections in NEMO deficiency. (picard2011infectiousdiseasesin pages 4-5) - Ongoing antimicrobial prophylaxis and immunoglobulin replacement in patients with antibody deficiency phenotypes. (meric2024atypicalmycobacterialpneumonia pages 1-2, meric2024atypicalmycobacterialpneumonia pages 2-3)

Vaccination considerations: Disease literature emphasizes mycobacterial susceptibility (including BCG-related disease in the broader NEMO deficiency spectrum), supporting individualized vaccine planning; specific guideline statements were not present in the retrieved texts. (haverkamp2014correlatinginterleukin12stimulated pages 8-8)

14. Other species / natural disease

No naturally occurring animal EDA‑ID equivalent was characterized in the retrieved evidence set for this run.

15. Model organisms

  • Mouse: NEMO/IKBKG loss-of-function is embryonically lethal in mice; inflammatory/skin phenotypes in heterozygous females and cell-death pathway dependence (e.g., TNF/RIPK1 axis) have been discussed as relevant to IP/NEMO biology, providing mechanistic context for allelic IKBKG disorders including EDA‑ID. (pescatore2022humangeneticdiseases pages 6-7, pescatore2022humangeneticdiseases pages 1-3)

Visual evidence: mutation spectrum and domain mapping

The following extracted figure/table summarizes NEMO protein domains and the distribution of EDA‑ID–associated mutations, along with a mutation catalogue.

  • NEMO domain map with mutation positions: (fusco2015edaidandip media a25bf9d6)
  • Table of reported IKBKG/NEMO mutations in EDA‑ID: (fusco2015edaidandip media bf13b1f4)

Recent developments (2023–2024 highlights)

  • 2024 case report: Two siblings with atypical mycobacterial pneumonia due to a novel hypomorphic IKBKG frameshift variant (c.268delG; p.Ala90Glnfs*93) illustrate ongoing discovery of novel variants and implementation of immunoglobulin replacement and prophylaxis. (meric2024atypicalmycobacterialpneumonia pages 1-2)
  • 2024 epidemiology context: A nationwide IP study (allelic IKBKG disorder) provided a modern population-based estimate (birth prevalence 2.37/100,000) and detailed organ involvement frequencies including teeth (58.7%), hair (26.7%), eyes (22.6%), and nails (16.0%). (herlin2024prevalenceandclinical pages 1-3)
  • 2023 review signal: A CID infections review includes EDA‑ID due to NEMO/IKBKG and lists common infection syndromes and pathogens (skin infections, pneumonia, sepsis; S. aureus, S. pneumoniae, P. aeruginosa, mycobacteria; HSV; Pneumocystis). (george2023infectionsininborn pages 5-6)

Source URLs (as available in retrieved documents)

  • Meric et al., Turkish Archives of Pediatrics, 2024-09. https://doi.org/10.5152/turkarchpediatr.2024.24087 (meric2024atypicalmycobacterialpneumonia pages 1-2)
  • Herlin et al., Orphanet Journal of Rare Diseases, 2024-12. https://doi.org/10.1186/s13023-024-03480-8 (herlin2024prevalenceandclinical pages 1-3)
  • George & Govindaraj, Pathogens, 2023-02. https://doi.org/10.3390/pathogens12020272 (george2023infectionsininborn pages 5-6)
  • Keller et al., Frontiers in Immunology, 2011-10. https://doi.org/10.3389/fimmu.2011.00061 (keller2011hypohidroticectodermaldysplasia pages 1-2)
  • Döffinger et al., Nature Genetics, 2001-03. https://doi.org/10.1038/85837 (doffinger2001xlinkedanhidroticectodermal pages 1-2)
  • Picard et al., Clinical Microbiology Reviews, 2011-07. https://doi.org/10.1128/cmr.00001-11 (picard2011infectiousdiseasesin pages 4-5)
  • Fusco et al., International Reviews of Immunology, 2015-08. https://doi.org/10.3109/08830185.2015.1055331 (fusco2015edaidandip pages 3-5)
  • Callea et al., Dermatologic Therapy, 2020-07. https://doi.org/10.1111/dth.13702 (callea2020covid‐19and pages 1-2)

References

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