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Classifications

IUIS Category

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Inheritance

1

X-linked recessive inheritance (EDA-ID) HP:0001419

The classic immunodeficiency pedigrees show X-linked recessive inheritance. Heterozygous females may have mild ectodermal findings, IP, inflammatory manifestations or occasionally immunodeficiency; X-inactivation is not uniformly protective. Counseling must use the familial variant and observed phenotype rather than importing the usual male lethality of classic IP.

X-linked recessive inheritance

Show evidence (2 references)

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.

url:https://www.ncbi.nlm.nih.gov/books/NBK1112/ SUPPORT Human Clinical

"IKBKG ... Hypohidrotic ectodermal dysplasia w/immunodeficiency ... XL ... Sparse hair ... Hypohidrosis ... Hypodontia ... Impaired immune function w/risk for recurrent infections, hypogammaglobulinemia, T cell dysfunction"

The IKBKG differential row explicitly assigns X-linked inheritance; the separate EDA-specific counseling probabilities and classic-IP lethality are not used.

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Subtypes

3

Ectodermal Dysplasia and Immunodeficiency 1 (EDA-ID) MONDO:0020740

Hypomorphic IKBKG variants cause immune deficiency together with variable hair, tooth and sweat-gland abnormalities, predominantly in hemizygous males. The immune defects and infectious spectrum vary between variants and individuals.

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.

Anhidrotic EDA-ID with Osteopetrosis and Lymphedema MONDO:0010295

An immunodeficiency presentation with osteopetrosis and lymphedema, first described with IKBKG stop-codon variants. Neither skeletal nor lymphatic involvement is universal in NEMO deficiency; later cohorts contain additional genotypes.

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) MONDO:0010386

E315A and R319Q variants were identified in families with predominantly mycobacterial disease and selective impairment of CD40-dependent IL-12 production by antigen-presenting cells. B-cell switching was preserved. Minor dental findings and occasional invasive pyogenic infections mean the presentation is not absolutely restricted to mycobacteria.

Show evidence (2 references)

PMID:16818673 SUPPORT Human Clinical

"We report here mutations in the leucine zipper (LZ) domain of the NF-kappaB essential modulator (NEMO) gene in three unrelated kindreds with XR-MSMD."

Defines the primary families underlying the selective mycobacterial presentation.

PMID:16818673 SUPPORT In Vitro

"However, the CD40-dependent up-regulation of costimulatory molecules of dendritic cells and the proliferation and immunoglobulin class switch of B cells were normal."

Patient-cell assays distinguish this presentation from CD40-dependent B-cell switching defects.

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Discussions and Knowledge Gaps

5

How should immunodeficiency be distinguished from allelic IP and overlapping diagnoses?

INTERPRETATION OPEN ikbkg_allelic_scope

Attached to

pathophysiology#Impaired NEMO-dependent NF-kappaB activation

The assigned MONDO entity is IKBKG immunodeficiency. IP-only Blaschko lesions, retinal abnormalities, nonspecific IP dental findings and nail dystrophy are removed from the core phenotype set; the separate IP entry is unchanged. Seizures are retained only on new pre-HSCT evidence of an M. avium brain lesion. Hypomorphic variants can also produce IP in female relatives. The dual EDA/IKBKG families do not establish that every ectodermal feature, particularly their nail dystrophy, is attributable to NEMO alone. NEMO exon-5-deletion autoinflammation is another distinct allelic presentation, not evidence for a uniform loss-of-function mechanism.

Show evidence (2 references)

DOI:10.1086/316914 SUPPORT Human Clinical

"The molecular and clinical findings in these families establish HED-ID as a distinct X-linked recessive disorder. The phenotype and genetics (recessive vs. dominant) of HED-ID differ significantly from those of familial IP."

The primary families establish the disease boundary.

PMID:22566850 SUPPORT Other

"Thus in all three of the probands, it is difficult to attribute all of the clinical impact to one of the two mutant genes"

The authors explicitly limit attribution in the EDA/IKBKG dual diagnoses.

Which immune defects are shared and which depend on variant and assay?

INTERPRETATION OPEN ikbkg_variant_and_assay_scope

Attached to

pathophysiology#Impaired innate immune receptor responses pathophysiology#Impaired CD40-dependent B-cell maturation pathophysiology#Impaired CD40-dependent IL-12 and IFN-gamma cooperation

Patient-cell assays must retain their stimulus and genotype. C417 B-cell switching defects do not apply to E315A/R319Q B cells; c-Rel activation in the latter is delayed, not absent at every time point. The c.268delG family had no NF-kappaB functional assay, so the sequence alone does not demonstrate residual signaling. Normal lymphocyte counts or one normal response do not exclude immunodeficiency. Raw cytokine, proliferation and NK cytotoxicity assays are functional evidence, not extra causal clinical nodes.

Show evidence (1 reference)

PMID:16818673 SUPPORT In Vitro

"However, the CD40-dependent up-regulation of costimulatory molecules of dendritic cells and the proliferation and immunoglobulin class switch of B cells were normal."

The selective family assays preserve multiple CD40 outputs.

How should frequencies from compilations and transplant cohorts be interpreted?

INTERPRETATION OPEN ikbkg_cohort_ascertainment

Attached to

phenotypes#Hypogammaglobulinemia phenotypes#Impaired specific antibody response phenotypes#Recurrent infections phenotypes#Recurrent mycobacterial infections phenotypes#Severe cytomegalovirus infection has_subtypes#EDA-ID

Hanson combines reported patients with uneven testing and clinical ascertainment; denominators differ by feature. Its pneumococcal response text gives 72% for 13/16 whereas the table gives 81%, so no categorical frequency is inferred from that inconsistency. Miot is a severe HSCT-selected series with overlapping published cases, not an independent population sample. Pre-HSCT findings are separated from conditioning toxicity and post-HSCT complications; inconsistent patient IDs for vascular events preclude precise reassignment. Picard 2011 reports pyogenic bacterial infection in about 90%, mycobacterial infection in about 40%, serious viral infection in 19%, and aggregate ectodermal dysplasia in about 90% of the NEMO-deficient patients described at that time. These quantitative observations are retained here rather than discarded. The review describes up to 100 reported males and bases its NEMO infection tables on Hanson 2008 plus unpublished data, so it is not an independent population series. More importantly, its infection-occurrence estimates do not measure the narrower recurrent-infection phenotypes; the 19% viral composite includes HSV encephalitis, adenoviral gastroenteritis and CMV and is not a CMV-specific frequency. The approximately 90% ectodermal-dysplasia figure is not a frequency for each individual hair, dental or sweating abnormality. Although the numerical estimates fall within repository frequency bands, those bands would describe different endpoints from the phenotype entries. No categorical frequencies are transferred on that basis; observational study design alone is not the reason for declining them. These are NEMO-specific figures, not the separate IκBα cases.

Show evidence (8 references)

PMID:18851874 SUPPORT Human Clinical

"Hypogammaglobulinemia occurred in 24/41 (59%), but correlated with impaired CD40 signaling only in Zinc Finger mutations."

The feature-specific tested denominator limits frequency interpretation.

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC5609334/ SUPPORT Other

"As HSCT is generally considered only for the sickest patients, this may account for the high proportion of patients with ZF domain mutations in this cohort."

The authors explain transplant ascertainment.

DOI:10.1128/cmr.00001-11 SUPPORT Human Clinical

"Pyogenic bacterial infection was identified in about 90% of NEMO-deficient patients"

The review reports pyogenic infection occurrence among described NEMO-deficient cases; this does not give the frequency of the differently defined recurrent-infections endpoint.

+ 5 more references

Which remaining findings lack a sufficiently established causal route?

KNOWLEDGE GAP OPEN ikbkg_unresolved_clinical_attribution

Attached to

phenotypes#Frontal bossing phenotypes#Dry skin phenotypes#Ichthyosis phenotypes#Increased circulating IgA phenotypes#Decreased circulating IgM phenotypes#Decreased total T-cell count phenotypes#Intrauterine growth restriction phenotypes#Polyarticular arthritis phenotypes#Uveitis phenotypes#Autoimmune hemolytic anemia phenotypes#Autoimmune thrombocytopenia phenotypes#Hashimoto thyroiditis phenotypes#Neurodevelopmental delay phenotypes#Intracranial calcification phenotypes#Delayed umbilical cord separation phenotypes#Hyperpigmented skin

Elevated IgA and low IgM cannot be explained simply by a class-switch block; the authors leave low-IgM pathophysiology unresolved and discuss CD40-independent IgA as a hypothesis. Reduced T-cell counts in one c.268delG patient are not localized to a demonstrated survival or developmental defect. Dry skin, ichthyosis, pigment changes, autoimmune cytopenias, thyroiditis, arthritis and uveitis are documented, but the reviewed patient reports do not establish one common immune-dysregulation route; the Jurkat L153R apoptosis/A20 phenotype is not direct proof for each manifestation. Frontal bossing, prenatal growth restriction, developmental delay, intracranial calcification and delayed cord separation likewise have uncertain patient-specific attribution. These gaps concern causal attribution, not mere absence of a drawn intermediary. The supported epithelial, appendage, humoral and infection-consequence routes are already represented. The low-IgM, high-IgA and low-T-cell findings are laboratory observations, not clinical functional-assay readouts. Jain proposes CD40-independent synthesis to explain the presence of serum IgA despite failed cultured switching in a C417 patient; this does not establish why concentrations are elevated, especially in the distinct c.268delG family. Child hyperpigmentation is documented separately from maternal IP, without a proven pigmentary route.

Show evidence (3 references)

PMID:39540818 SUPPORT Other

"Although the pathophysiology remains unclear, normal and low IgM levels can be observed in patients with IKBKG mutations."

The source explicitly leaves the mechanism of low IgM unresolved.

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC5609334/ SUPPORT Other

"The pathogenesis of the inflammatory and infectious phenotypes remains more elusive."

The authors identify mechanistic uncertainty; the graph nevertheless retains the specific supported routes.

PMID:15578091 SUPPORT Other

"Taken together these observations suggest a CD40-independent mechanism for serum IgA in some patients with XHM-ED."

The proposal concerns preserved serum IgA synthesis in the C417 context, not a demonstrated mechanism for the magnitude of IgA elevation.

What is known about female manifestations and counseling?

INTERPRETATION OPEN ikbkg_female_exceptions

Attached to

inheritance#X-linked recessive inheritance (EDA-ID)

Female carriers are not uniformly asymptomatic or protected by skewed X-inactivation. Mild ectodermal findings, IP and immune or inflammatory manifestations occur. The recent adult female case developed infections after anti-TNF treatment, so it cannot establish that every infection or inflammatory comorbidity was caused solely by NEMO deficiency. Counseling should separate variant transmission from variable expression and should not apply classic-IP male lethality to all hypomorphic alleles.

Show evidence (3 references)

DOI:10.1086/316914 SUPPORT Human Clinical

"Female carriers had variable manifestations, ranging from normal dentition to minor degrees of hypodontia and conical teeth."

The original family observations refute a blanket asymptomatic-carrier claim.

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC5609334/ SUPPORT Human Clinical

"P6’s mother had recurrent bacterial infections."

A carrier mother in an immunodeficiency family had a clinical infectious phenotype.

PMID:39860371 SUPPORT Other

"Therefore, we cannot establish whether mycobacteriosis and pulmonary aspergillosis were secondary to the immunosuppression following infliximab treatment rather than resulting from the primary impairment of NF-κB signaling."

The authors explicitly retain the treatment-versus-intrinsic causal uncertainty in this female case.

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Pathophysiology

8

Impaired NEMO-dependent NF-kappaB activation

Hypomorphic IKBKG variants impair NEMO-dependent activation of the canonical NF-kappaB pathway. Residual activity, protein abundance and stimulus specificity vary. Exon 10 truncations as well as missense variants can retain function; preserved protein expression does not establish normal signaling.

IKBKG hgnc:5961

canonical NF-kappaB signal transduction GO:0007249

Downstream

Impaired innate immune receptor responses NEMO dysfunction can impair signal transmission from innate immune receptors; the affected receptor responses depend on the variant.

Impaired CD40-dependent B-cell maturation Selected zinc-finger variants impair CD40-mediated NF-kappaB signaling in B cells, compromising switching and antibody diversification.

Impaired CD40-dependent IL-12 and IFN-gamma cooperation The E315A/R319Q variants selectively impair the CD40/c-Rel cytokine branch in antigen-presenting cells; this is not generalized failure of all CD40 functions.

Impaired ectodermal appendage development Reduced NEMO-dependent signaling compromises the ectodysplasin receptor developmental program.

Impaired osteoclast maturation The authors attribute this uncommon nonhematopoietic manifestation to a NEMO-dependent developmental signaling pathway; direct patient-specific intermediates remain incompletely tested.

Impaired lymphatic developmental signaling The authors attribute this uncommon nonhematopoietic manifestation to a NEMO-dependent developmental signaling pathway; direct patient-specific intermediates remain incompletely tested.

Intestinal epithelial barrier dysfunction NEMO dysfunction may compromise epithelial integrity through altered NF-kappaB-dependent survival and antimicrobial programs. Human post-HSCT observations and epithelial knockout models support this provisional attribution.

Pneumocystis pneumonia The broad NEMO immunodeficiency predisposes to this opportunistic infection. The reviewed sources do not assign a single receptor or lymphocyte defect in the observed patient, so cellular intermediates remain unspecified.

Chronic mucocutaneous candidiasis The broad NEMO immunodeficiency predisposes to this opportunistic infection. The reviewed sources do not assign a single receptor or lymphocyte defect in the observed patient, so cellular intermediates remain unspecified.

Severe cytomegalovirus infection The broad NEMO immunodeficiency predisposes to this opportunistic infection. The reviewed sources do not assign a single receptor or lymphocyte defect in the observed patient, so cellular intermediates remain unspecified.

Eczematoid dermatitis A hematopoietic contribution to NEMO-associated eczema is supported by complete resolution after cord-blood transplantation in one c.1167insC patient and inflammatory-cell infiltrates in skin biopsies. This remains a qualified attribution, not proof that every dry or pigmented skin lesion has the same cause.

Show evidence (1 reference)

PMID:11242109 SUPPORT In Vitro

"We show that IKBKG mutations causing OL-EDA-ID and EDA-ID impair but do not abolish NF-kappaB signaling"

The functional experiments distinguish hypomorphic immunodeficiency variants from complete pathway abolition.

Impaired innate immune receptor responses

Responses to TNF, IL-1 and Toll-like receptor ligands are variably impaired in patient cells. This is a conditional pathway defect, not a claim that every response is absent in every IKBKG genotype. E315A/R319Q and other variants can preserve several tested innate responses.

Downstream

Recurrent infections Impaired innate activation contributes to susceptibility to invasive or recurrent infection in affected genotypes. Adaptive defects also contribute; this is not a unique receptor-pathogen mapping.

Recurrent pneumonia Impaired innate activation contributes to susceptibility to invasive or recurrent infection in affected genotypes. Adaptive defects also contribute; this is not a unique receptor-pathogen mapping.

Sepsis Impaired innate activation contributes to susceptibility to invasive or recurrent infection in affected genotypes. Adaptive defects also contribute; this is not a unique receptor-pathogen mapping.

Show evidence (1 reference)

PMID:18851874 SUPPORT In Vitro

"86% (6/7) patients had abnormal IL-1 signaling, and 64% (9/14) had abnormal TLR signaling"

Selected patient-cell assays show variable IL-1 and Toll-like receptor defects; denominators are tested subsets.

Impaired CD40-dependent B-cell maturation

C417R/C417Y patient B cells have impaired c-Rel activation, class-switch recombination and somatic hypermutation despite preserved induction of AID. This route explains a subset of humoral defects and is not transferred to E315A/R319Q patients with preserved B-cell CD40 responses.

Downstream

Hypogammaglobulinemia Defective terminal B-cell maturation provides a qualified explanation for this humoral finding in switching-defective genotypes. It is not established as the sole route in every individual contributing a clinical observation.

Decreased circulating IgG Defective terminal B-cell maturation provides a qualified explanation for this humoral finding in switching-defective genotypes. It is not established as the sole route in every individual contributing a clinical observation.

Decreased circulating IgA Defective terminal B-cell maturation provides a qualified explanation for this humoral finding in switching-defective genotypes. It is not established as the sole route in every individual contributing a clinical observation.

Increased circulating IgM Defective terminal B-cell maturation provides a qualified explanation for this humoral finding in switching-defective genotypes. It is not established as the sole route in every individual contributing a clinical observation.

Impaired specific antibody response Defective terminal B-cell maturation provides a qualified explanation for this humoral finding in switching-defective genotypes. It is not established as the sole route in every individual contributing a clinical observation.

Decreased class-switched memory B-cell proportion Defective terminal B-cell maturation provides a qualified explanation for this humoral finding in switching-defective genotypes. It is not established as the sole route in every individual contributing a clinical observation.

Decreased circulating IgE Defective terminal B-cell maturation provides a qualified explanation for this humoral finding in switching-defective genotypes. It is not established as the sole route in every individual contributing a clinical observation.

Show evidence (1 reference)

PMID:15578091 SUPPORT In Vitro

"Here we report that patient B cells are characterized by an absence of Ig somatic hypermutation (SHM) and defective class switch recombination (CSR) despite normal induction of activation-induced cytidine deaminase (AID) and Iepsilon-Cepsilon transcripts."

Functional studies in selected C417-mutant patient B cells establish impaired terminal maturation without an AID-expression deficiency.

Impaired CD40-dependent IL-12 and IFN-gamma cooperation

E315A/R319Q variants impair CD40-triggered cytokine production by monocytes and dendritic cells. Delayed c-Rel nuclear accumulation and reduced IL-12 lead to reduced T-cell IFN-gamma secretion. This is an antigen-presenting-cell defect, not an intrinsic IFN-gamma defect in the T cell; responses to live BCG and several other stimuli can remain intact.

Downstream

Recurrent mycobacterial infections Impaired CD40-dependent IL-12/IFN-gamma cooperation compromises control of mycobacteria in the E315A/R319Q families. Other NEMO variants and residual TNF defects can contribute through additional routes.

Show evidence (1 reference)

PMID:16818673 SUPPORT In Vitro

"However, the patients' monocytes presented an intrinsic defect in T cell-dependent IL-12 production, resulting in defective IFN-gamma secretion by T cells."

Patient coculture experiments localize the defect to monocyte-dependent IL-12 production and secondary IFN-gamma output.

Impaired ectodermal appendage development

Disrupted ectodysplasin/EDAR signaling through NEMO impairs development of hair, teeth and eccrine sweat glands. Clinical expression is variable, including individuals without overt ectodermal dysplasia. This pathway is distinct from inflammatory elimination of IKBKG-null cells in classic IP.

epithelial cell CL:0000066

ectodermal placode formation GO:0060788

Downstream

Anhidrosis Impaired ectodysplasin/NEMO-dependent appendage development provides the developmental explanation for this component. Expression varies between patients and the specific appendage-level steps were not measured in these families.

Hypohidrosis Impaired ectodysplasin/NEMO-dependent appendage development provides the developmental explanation for this component. Expression varies between patients and the specific appendage-level steps were not measured in these families.

Sparse scalp hair Impaired ectodysplasin/NEMO-dependent appendage development provides the developmental explanation for this component. Expression varies between patients and the specific appendage-level steps were not measured in these families.

Sparse eyebrows Impaired ectodysplasin/NEMO-dependent appendage development provides the developmental explanation for this component. Expression varies between patients and the specific appendage-level steps were not measured in these families.

Conical teeth Impaired ectodysplasin/NEMO-dependent appendage development provides the developmental explanation for this component. Expression varies between patients and the specific appendage-level steps were not measured in these families.

Hypodontia Impaired ectodysplasin/NEMO-dependent appendage development provides the developmental explanation for this component. Expression varies between patients and the specific appendage-level steps were not measured in these families.

Oligodontia Impaired ectodysplasin/NEMO-dependent appendage development provides the developmental explanation for this component. Expression varies between patients and the specific appendage-level steps were not measured in these families.

Show evidence (1 reference)

PMID:11242109 SUPPORT In Vitro

"We also show that the ectodysplasin receptor, DL, triggers NF-kappaB through the NEMO protein, indicating that EDA results from impaired NF-kappaB signaling."

The receptor signaling experiments connect ectodysplasin signaling to NEMO.

Impaired osteoclast maturation

The proposed skeletal route is reduced RANK/NF-kappaB-dependent osteoclast maturation and bone resorption. Human OL-EDA-ID observations and related NF-kappaB/RANK knockout models support the attribution, but the cited models do not directly measure osteoclast function for every patient variant.

Downstream

Osteopetrosis This source-supported pathway remains qualified by model translation or tissue-specific evidence; it is not merely an anatomical restatement of the clinical finding.

Show evidence (1 reference)

DOI:10.1086/316914 SUPPORT INDIRECT Model Organism

"Furthermore, a double p50/p52 knockout in mice blocks both B-cell and osteoclast maturation, the latter causing osteopetrosis"

The cited mouse experiments supply indirect support for the osteoclast route; they are not a NEMO patient assay.

Impaired lymphatic developmental signaling

Lymphedema in OL-EDA-ID has been attributed to impaired VEGFR3/NF-kappaB-dependent lymphatic development. This is a qualified pathway attribution based on the human syndrome and related signaling biology, not direct measurement of lymphatic vessel development in each affected person.

Downstream

Lymphedema This source-supported pathway remains qualified by model translation or tissue-specific evidence; it is not merely an anatomical restatement of the clinical finding.

Show evidence (1 reference)

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC5609334/ SUPPORT INDIRECT Other

"lymphedema from changes to the vascular endothelial growth factor-3 pathway"

The authors summarize the proposed nonhematopoietic lymphatic route.

Intestinal epithelial barrier dysfunction

An epithelial contribution to NEMO-associated colitis is supported by persistent or new colitis after HSCT, compartment-specific p65 staining in one patient biopsy, and intestinal epithelial knockout models. This is a qualified mechanism: infection, including CMV, can aggravate colitis and some patients improve after HSCT.

Downstream

Colitis This source-supported pathway remains qualified by model translation or tissue-specific evidence; it is not merely an anatomical restatement of the clinical finding.

Show evidence (1 reference)

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC5609334/ SUPPORT INDIRECT Human Clinical

"gut-infiltrating immune cells were strongly stained for nuclear p65, indicating normal NEMO function, whereas intestinal epithelial cells had no nuclear p65, suggesting the possible involvement of an intrinsic NF-κB signaling defect in intestinal epithelial cells."

The P7 gut biopsy provides a human tissue observation with a qualified epithelial interpretation; it does not prove a uniform cause of all colitis.

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Pathograph

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Phenotypes

49

Blood 12

Hypogammaglobulinemia Decreased circulating immunoglobulin concentration HP:0004313

Show evidence (2 references)

PMID:18851874 SUPPORT Human Clinical

"Hypogammaglobulinemia occurred in 24/41 (59%), but correlated with impaired CD40 signaling only in Zinc Finger mutations."

Reported in 24/41 evaluable individuals in the retrospective Hanson compilation; normal immunoglobulin levels also occur. The tested subset is not a population prevalence estimate.

url:https://www.ncbi.nlm.nih.gov/books/NBK1112/ SUPPORT Human Clinical

"IKBKG ... Hypohidrotic ectodermal dysplasia w/immunodeficiency ... XL ... Sparse hair ... Hypohidrosis ... Hypodontia ... Impaired immune function w/risk for recurrent infections, hypogammaglobulinemia, T cell dysfunction"

The GeneReviews differential table explicitly lists hypogammaglobulinemia for IKBKG-associated HED with immunodeficiency; frequencies and other-gene findings are not transferred.

Increased circulating IgM Increased circulating IgM level HP:0003496

Show evidence (2 references)

PMID:33598805 SUPPORT Human Clinical

"increased IgM levels at 4.6 g/L (0.26 −1), normal B cells differentiation and a slightly decreased of CD40L expression level."

Elevated IgM occurs in a subset; the Thr164Pro infant had 4.6 g/L. A hyper-IgM syndrome label does not establish elevated IgM in every patient.

DOI:10.1086/316914 SUPPORT Human Clinical

"Immunoglobulin levels at age 10 mo showed abnormally low levels of IgG (<200 mg/dl (normal range 294–1,069 mg/dl)), low-to-normal levels of IgA, and elevated levels of IgM (1,100 mg/dl (normal range 41–149 mg/dl))."

Family 1 carries C417R; the untreated IgM elevation supports the zinc-finger-associated humoral phenotype independently of the Thr164Pro infant.

Decreased circulating IgG Decreased circulating IgG concentration HP:0004315

Show evidence (1 reference)

DOI:10.1086/316914 SUPPORT Human Clinical

"Immunoglobulin levels at age 10 mo showed abnormally low levels of IgG (<200 mg/dl (normal range 294–1,069 mg/dl)), low-to-normal levels of IgA, and elevated levels of IgM (1,100 mg/dl (normal range 41–149 mg/dl))."

Low IgG was measured before replacement in original EDA-ID patients; values obtained during IVIG should not be interpreted as untreated concentrations.

Decreased circulating IgA Decreased circulating IgA concentration HP:0002720

Show evidence (2 references)

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC5609334/ SUPPORT Human Clinical

"16 ... P jirovecii ... CMV, rotavirus ... Low IgA"

Low IgA was reported before HSCT in patient P16; IgA can instead be elevated in other IKBKG genotypes.

PMID:15578091 SUPPORT Human Clinical

"IgM IgG IgA IgM IgG IgA XHM-ED1 552 991 <10"

Table 2 lists IgA below 10 mg/dL in the first three, serum columns for XHM-ED1; the serum reference interval is 51–375 mg/dL. These are human blood values during IVIG, not the later culture-supernatant columns.

Increased circulating IgA Increased circulating IgA concentration HP:0003261

Show evidence (1 reference)

PMID:39540818 SUPPORT Human Clinical

"Laboratory investigations revealed decreased serum IgM levels and increased IgA for his age."

Both brothers with c.268delG had increased IgA for age, despite low IgM. The mechanism is not assumed to be the same as a classical switching defect.

Decreased circulating IgM Decreased circulating total IgM HP:0002850

Show evidence (1 reference)

PMID:39540818 SUPPORT Human Clinical

"Laboratory investigations revealed decreased serum IgM levels and increased IgA for his age."

Both c.268delG brothers had low IgM; the authors state that the mechanism of this non-hyper-IgM presentation remains unclear.

Decreased class-switched memory B-cell proportion HP:0030388

Show evidence (2 references)

PMID:39540818 SUPPORT Human Clinical

"His class-switched B cell subset was decreased, with normal T and B cell counts."

The class-switched B-cell subset was reduced in both c.268delG brothers; P2 otherwise had normal T- and B-cell counts by the authors narrative.

PMID:15578091 SUPPORT Human Clinical

"absence of IgD –CD27+ B cells, which are typical memory B cells."

The C417 patient peripheral-blood analysis showed virtual absence of switched memory cells; this supports the maturation route independently of the later c.268delG family.

Decreased total T-cell count HP:0005403

Show evidence (1 reference)

PMID:39540818 SUPPORT Human Clinical

"Flow cytometric immunophenotyping revealed decreased T cells and increased B cells, predominantly naive, with a decreased switched memory subset."

T-cell reduction was reported in P1 of the c.268delG family. It is not generalized to all NEMO patients or to P2, whose narrative and borderline table value differ.

Autoimmune hemolytic anemia HP:0001890

Show evidence (1 reference)

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC5609334/ SUPPORT Human Clinical

"hemolytic autoimmune anemia for P12 and P21"

Reported before HSCT in the selected transplant cohort. This is an occurrence record, not an inferred prevalence or a proven cell-specific autoimmune mechanism.

Autoimmune thrombocytopenia HP:0001973

Show evidence (1 reference)

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC5609334/ SUPPORT Human Clinical

"immune thrombocytopenic purpura for P28"

Reported before HSCT in the selected transplant cohort. This is an occurrence record, not an inferred prevalence or a proven cell-specific autoimmune mechanism.

Hemophagocytosis HP:0012156

Show evidence (1 reference)

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC5609334/ SUPPORT Human Clinical

"P6 developed secondary hemophagocytic lymphohistiocytosis concomitantly with bacterial sepsis, which resolved with recovery from infection."

Secondary hemophagocytic lymphohistiocytosis occurred with bacterial sepsis in P6 and resolved as infection recovered.

Decreased circulating IgE Decreased circulating IgE concentration HP:0005479

Show evidence (1 reference)

PMID:15578091 SUPPORT Human Clinical

"defined by markedly dimin- ished serum levels of IgG and IgE and normal or elevated levels of serum IgM (Tables 1 and 2)."

Diminished serum IgE was part of the clinical definition in three C417-mutant patients. This is separate from failure of stimulated cultured B cells to secrete IgE.

Digestive 3

Colitis HP:0002583

Sequelae: Diarrhea Failure to thrive Feeding difficulties in infancy

Show evidence (1 reference)

PMID:33598805 SUPPORT Human Clinical

"However, the colitis was probably aggravated by the persistent CMV infection."

Inflammatory colitis is variably present and can persist after immune reconstitution. In the Thr164Pro infant, persistent CMV was a likely aggravating factor.

Diarrhea HP:0002014

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."

Reported among the inflammatory bowel symptoms of the Thr164Pro infant, requiring parenteral nutrition; CMV probably aggravated the colitis.

Feeding difficulties in infancy HP:0008872

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."

Reported among the inflammatory bowel symptoms of the Thr164Pro infant, requiring parenteral nutrition; CMV probably aggravated the colitis.

Endocrine 1

Hashimoto thyroiditis HP:0000872

Show evidence (1 reference)

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC5609334/ SUPPORT Human Clinical

"The following autoimmune additional features were observed: cytopenia (hemolytic autoimmune anemia for P12 and P21, and immune thrombocytopenic purpura for P28), lupus anticoagulant (asymptomatic, P22), and Hashimoto’s thyroiditis"

Reported before HSCT in the selected transplant cohort. This is an occurrence record, not an inferred prevalence or a proven cell-specific autoimmune mechanism.

Eye 1

Uveitis HP:0000554

Show evidence (1 reference)

PMID:39540818 SUPPORT Human Clinical

"At the age of 14, he developed polyarthritis and uveitis with negative autoantibodies but did not receive immunosuppressive treatment."

Observed at age 14 in P1 with c.268delG, before immunosuppressive treatment; the authors did not establish the specific inflammatory pathway.

Head and Neck 6

Sparse scalp hair HP:0002209

Show evidence (2 references)

DOI:10.1086/316914 SUPPORT Human Clinical

"He was noted to have reduced sweating, thin sparse scalp hair and eyebrows, and mild frontal bossing"

Sparse scalp hair occurs in EDA-ID, but normal scalp hair was also documented within the original families.

url:https://www.ncbi.nlm.nih.gov/books/NBK1112/ SUPPORT Human Clinical

"IKBKG ... Hypohidrotic ectodermal dysplasia w/immunodeficiency ... XL ... Sparse hair ... Hypohidrosis ... Hypodontia ... Impaired immune function w/risk for recurrent infections, hypogammaglobulinemia, T cell dysfunction"

The GeneReviews differential table explicitly lists sparse hair for IKBKG-associated HED with immunodeficiency; frequencies and other-gene findings are not transferred.

Conical teeth Conical tooth HP:0000698

Show evidence (1 reference)

DOI:10.1086/316914 SUPPORT Human Clinical

"He had conical-shaped incisors, hypodontia (missing four of his permanent teeth), and normal scalp hair"

Conical teeth occur in classic EDA-ID and can be a subtle developmental sign in selective mycobacterial presentations.

Hypodontia HP:0000668

Show evidence (2 references)

DOI:10.1086/316914 SUPPORT Human Clinical

"He had conical-shaped incisors, hypodontia (missing four of his permanent teeth), and normal scalp hair"

Four absent permanent teeth were documented in family 1 III-2. More extensive tooth agenesis in other patients is represented as oligodontia.

url:https://www.ncbi.nlm.nih.gov/books/NBK1112/ SUPPORT Human Clinical

"IKBKG ... Hypohidrotic ectodermal dysplasia w/immunodeficiency ... XL ... Sparse hair ... Hypohidrosis ... Hypodontia ... Impaired immune function w/risk for recurrent infections, hypogammaglobulinemia, T cell dysfunction"

The GeneReviews differential table explicitly lists hypodontia for IKBKG-associated HED with immunodeficiency; frequencies and other-gene findings are not transferred.

Oligodontia HP:0000677

Show evidence (1 reference)

DOI:10.1086/316914 SUPPORT Human Clinical

"Dental examination at age 12 years showed absence of seven teeth from his secondary dentition, on dental radiographs, as well as conical-shaped maxillary lateral incisors."

Seven missing permanent teeth were documented in family 1 III-1, supporting oligodontia rather than only nonspecific abnormal dentition.

Sparse eyebrows HP:0045075

Show evidence (1 reference)

DOI:10.1086/316914 SUPPORT Human Clinical

"He was noted to have reduced sweating, thin sparse scalp hair and eyebrows, and mild frontal bossing"

Sparse eyebrows were observed in family 4 III-1; the observation is case-scoped.

Frontal bossing HP:0002007

Show evidence (1 reference)

DOI:10.1086/316914 SUPPORT Human Clinical

"He was noted to have reduced sweating, thin sparse scalp hair and eyebrows, and mild frontal bossing"

Mild frontal bossing was described in family 4 III-1; no frequency or specific cranial mechanism is established.

Immune 10

Recurrent infections HP:0002719

Show evidence (1 reference)

DOI:10.1086/316914 SUPPORT Human Clinical

"Affected males manifest dysgammaglobulinemia and, despite therapy, have significant morbidity and mortality from recurrent infections."

Recurrent infections may be severe and continue despite immunoglobulin replacement. Organisms and onset vary; this is not universal infection in every genetically diagnosed infant.

Recurrent mycobacterial infections HP:0011274

Sequelae: Seizures

Show evidence (1 reference)

PMID:16818673 SUPPORT Human Clinical

"One of our patients with EM disease (II.4 in kindred A) also suffered from miliary tuberculosis in childhood, and two of our probands (P2 and P3) probably suffered from tuberculosis, as the sole infectious phenotype suggested by consistent histological results and strongly positive tuberculin skin tests."

Recurrent or disseminated mycobacterial disease occurs in classic EDA-ID and in selective E315A/R319Q presentations. The historical approximately 40% figure comes from selected reported cases. Presumed tuberculosis in two European probands lacked culture confirmation; M. bovis is in the tuberculosis complex.

Eczematoid dermatitis HP:0000964

Show evidence (2 references)

PMID:33598805 SUPPORT Human Clinical

"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"

Eczematous dermatitis occurs in NEMO deficiency and was observed in the Thr164Pro infant and in the pre-HSCT cohort.

url:https://oup.silverchair-cdn.com/article-minimal/6625140 SUPPORT INDIRECT Human Clinical

"We report a case of intractable eczematous eruption in a patient with EDA‐ID, which disappeared completely after allogenic transplantation of umbilical‐cord blood."

The c.1167insC case improved after hematopoietic replacement, supporting an immune-cell contribution to eczema by intervention. This is an indirect, single-case inference; the accessible publisher extract does not resolve individual immune intermediates.

Impaired specific antibody response HP:0012475

Show evidence (1 reference)

PMID:18851874 SUPPORT Human Clinical

"Defects in specific antibody production occurred in 64% (18/28)"

Defective specific antibody production was reported in 18/28 evaluated individuals in the retrospective compilation. Normal total immunoglobulin levels do not exclude this finding.

Recurrent pneumonia HP:0006532

Sequelae: Bronchiectasis Respiratory insufficiency

Show evidence (1 reference)

DOI:10.1086/316914 SUPPORT Human Clinical

"with recurrent infections and had repeated hospitalization for pneumonia and bacterial infections of both bone and soft tissues."

Recurrent pulmonary infections were documented in the original EDA-ID families.

Sepsis HP:0100806

Sequelae: Hemophagocytosis Acute respiratory distress syndrome

Show evidence (1 reference)

DOI:10.1086/316914 SUPPORT Human Clinical

"The proband's younger maternal half-brother (III-2) presented, at age 3 mo, with bacterial sepsis and meningitis."

Sepsis occurred before transplantation, including early bacterial sepsis in the original family 4; post-HSCT sepsis is not counted as an untreated baseline frequency.

Pneumocystis pneumonia Pneumocystis jirovecii pneumonia HP:0020102

Sequelae: Acute respiratory distress syndrome

Show evidence (1 reference)

PMID:33598805 SUPPORT Human Clinical

"Pneumocystosis was diagnosed by nasopharyngeal PCR and typical CT scans and was treated with corticosteroids and trimethoprim/sulfamethoxazole."

Pneumocystis pneumonia was diagnosed in the Thr164Pro infant using nasopharyngeal PCR and compatible CT findings.

Chronic mucocutaneous candidiasis HP:0002728

Show evidence (1 reference)

PMID:33598805 SUPPORT Human Clinical

"He had also recurrent muco-cutaneous Candidiasis."

Recurrent mucocutaneous candidiasis was reported in the Thr164Pro infant.

Acute respiratory distress syndrome HP:0033677

Show evidence (1 reference)

PMID:33598805 SUPPORT Human Clinical

"At 3 months, he presented with an acute respiratory distress syndrome with circulatory failure following a Staphylococcus aureus septicemia and pulmonary pneumocystosis."

At three months the Thr164Pro infant developed ARDS with circulatory failure during S. aureus septicemia and pulmonary pneumocystosis, before HSCT.

Severe cytomegalovirus infection HP:0031692

Sequelae: Colitis

Show evidence (1 reference)

PMID:33598805 SUPPORT Human Clinical

"Moreover, he had cytomegalovirus (CMV) viremia which was not controlled with Valganciclovir and Ganciclovir was introduced"

The Thr164Pro infant had prolonged CMV viremia before HSCT, requiring escalation from valganciclovir to ganciclovir; later post-HSCT infections are not used as baseline frequency evidence.

Integument 5

Anhidrosis HP:0000970

Show evidence (1 reference)

DOI:10.1086/316914 SUPPORT Human Clinical

"An inability to sweat had been noted since infancy, requiring lifelong cooling measures."

Complete inability to sweat was reported in affected males; other patients retain reduced sweating and are represented separately as hypohidrosis.

Hypohidrosis HP:0000966

Show evidence (2 references)

DOI:10.1086/316914 SUPPORT Human Clinical

"Similar to his brother, he had very low amounts of sweat on a quantitative sweat test."

Reduced sweating is distinct from complete anhidrosis; quantitative sweat testing in one original family showed very low sweat production.

url:https://www.ncbi.nlm.nih.gov/books/NBK1112/ SUPPORT Human Clinical

"IKBKG ... Hypohidrotic ectodermal dysplasia w/immunodeficiency ... XL ... Sparse hair ... Hypohidrosis ... Hypodontia ... Impaired immune function w/risk for recurrent infections, hypogammaglobulinemia, T cell dysfunction"

The GeneReviews differential table explicitly lists hypohidrosis for IKBKG-associated HED with immunodeficiency; frequencies and other-gene findings are not transferred.

Dry skin HP:0000958

Show evidence (1 reference)

PMID:33598805 SUPPORT Human Clinical

"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"

Dry skin was observed in the Thr164Pro infant.

Ichthyosis HP:0008064

Show evidence (1 reference)

PMID:33598805 SUPPORT Human Clinical

"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"

Abdominal ichthyosis was reported in the Thr164Pro infant.

Hyperpigmented skin Hyperpigmentation of the skin HP:0000953

Show evidence (1 reference)

PMID:33598805 SUPPORT Human Clinical

"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"

The Thr164Pro infant had darker skin areas; these are distinct from the maternal linear Blaschko pigmentation of IP.

Metabolism 1

Lymphedema HP:0001004

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)."

A subset manifestation, including OL-EDA-ID; neither finding is obligatory in IKBKG immunodeficiency.

Musculoskeletal 3

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)."

A subset manifestation, including OL-EDA-ID; neither finding is obligatory in IKBKG immunodeficiency.

Polyarticular arthritis HP:0005764

Show evidence (1 reference)

PMID:39540818 SUPPORT Human Clinical

"At the age of 14, he developed polyarthritis and uveitis with negative autoantibodies but did not receive immunosuppressive treatment."

Observed at age 14 in P1 with c.268delG, before immunosuppressive treatment; the authors did not establish the specific inflammatory pathway.

Intracranial calcification HP:0430048

Show evidence (1 reference)

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC5609334/ SUPPORT Human Clinical

"Subependymal calcifications on brain MRI."

The pre-HSCT P6 developmental-delay entry carried a footnote documenting subependymal calcifications on brain MRI.

Nervous System 2

Seizures HP:0001250

Show evidence (1 reference)

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC5609334/ SUPPORT Human Clinical

"Seizures ... M avium ... brain lesion), lupus anticoagulant"

One patient in the pre-HSCT cohort had seizures with an M. avium brain lesion. This replaces the former IP-derived assertion and does not imply a primary IKBKG epilepsy syndrome.

Neurodevelopmental delay HP:0012758

Show evidence (1 reference)

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC5609334/ SUPPORT Human Clinical

"c.1167-1168insC ... Switzerland ... HLH, developmental delay, ... MGUS"

Developmental delay was reported before HSCT in P6, together with subependymal calcifications. It is not attributed to the later post-HSCT VZV encephalitis or to IP.

Prenatal and Birth 1

Delayed umbilical cord separation HP:0032434

Show evidence (1 reference)

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC5609334/ SUPPORT Human Clinical

"c.1167_1168insC ... UK ... Delayed umbilical cord separation"

Reported before HSCT in P11; a specific NEMO-dependent leukocyte or tissue mechanism was not established.

Respiratory 2

Bronchiectasis HP:0002110

Show evidence (1 reference)

DOI:10.1086/316914 SUPPORT Human Clinical

"Despite therapy, he has had chronic lung infections with resultant bronchiectasis and pulmonary insufficiency."

Bronchiectasis is directly documented after chronic pulmonary infections, including in the original families and in patients without overt ectodermal dysplasia.

Respiratory insufficiency HP:0002093

Show evidence (1 reference)

DOI:10.1086/316914 SUPPORT Human Clinical

"Despite therapy, he has had chronic lung infections with resultant bronchiectasis and pulmonary insufficiency."

Pulmonary insufficiency was documented with bronchiectasis following chronic lung infections in an original EDA-ID patient.

Growth 2

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 occurred with inflammatory bowel symptoms and feeding intolerance in the Thr164Pro infant; it was also observed in the adolescent without ectodermal dysplasia.

Intrauterine growth restriction Intrauterine growth retardation HP:0001511

Show evidence (1 reference)

PMID:33598805 SUPPORT Human Clinical

"He was born healthy but with harmonious intrauterine growth restriction."

Intrauterine growth restriction was reported in the Thr164Pro infant. A specific prenatal growth mechanism was not established.

🧬

Genetic Associations

1

Hypomorphic IKBKG variants

Gene: IKBKG hgnc:5961 gene page

Show evidence (3 references)

CGGV:assertion_2c9ee97a-ab3d-4747-b3fe-523578dd90e9-2022-09-15T160000.000Z SUPPORT Other

ClinGen classifies the IKBKG-IKBKG-related immunodeficiency with or without ectodermal dysplasia gene-disease relationship as definitive with X-linked inheritance.

PMID:11242109 SUPPORT In Vitro

"We show that IKBKG mutations causing OL-EDA-ID and EDA-ID impair but do not abolish NF-kappaB signaling"

The functional experiments distinguish hypomorphic immunodeficiency variants from complete pathway abolition.

DOI:10.1086/316914 SUPPORT Human Clinical

"Mutations in families 2 and 4 produce a nonsense mutation at codon 391 (E391X) and a frameshift at codon 390, respectively, within the carboxy-terminal end of the 419-amino-acid protein."

The original immunodeficiency families include truncating variants, not only missense alleles.

Variants (1)

Hypomorphic IKBKG variants

Gene: IKBKG hgnc:5961

Missense, nonsense, frameshift and splice variants can cause immunodeficiency through residual or selectively impaired NEMO signaling. Variant class alone does not establish residual function or predict the full clinical phenotype.

💊

Medical Actions

4

Immunoglobulin Replacement Therapy

Action: immunoglobulin replacement therapy Ontology label: Pharmacotherapy NCIT:C15986

Agent: pooled donor immunoglobulin G NCIT:C2701

Immunoglobulin replacement is used when clinically significant humoral deficiency is present; it may not prevent all infections in NEMO deficiency.

Show evidence (1 reference)

DOI:10.1086/316914 SUPPORT Human Clinical

"He was begun on IVIG but still experienced hospitalizations because of recurrent bacterial infections."

A treated original patient illustrates both use and incomplete protection; this is not a controlled effectiveness estimate.

Antimicrobial Prophylaxis

Action: antimicrobial prophylaxis Ontology label: Pharmacotherapy NCIT:C15986

Agent: antibacterial and antimycobacterial prophylactic agents NCIT:C254

Antibacterial and pathogen-directed prophylaxis are individualized to immune defects and infection history; trimethoprim-sulfamethoxazole and antimycobacterial prophylaxis were used in the severe transplant cohort.

Show evidence (1 reference)

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC5609334/ SUPPORT Human Clinical

"Twenty-four patients received IVIG, and 22 received trimethoprim-sulfamethoxazole prophylaxis against bacterial infections. Ten patients received azithromycin or clarithromycin for prophylaxis against mycobacterial infection."

Describes actual pre-HSCT management in the selected cohort; it does not measure prophylactic efficacy.

Hematopoietic Stem Cell Transplantation

Action: hematopoietic stem cell transplantation Ontology label: Hematopoietic Cell Transplantation NCIT:C15431

Platform: Cell therapy

HSCT can correct major hematopoietic immune defects but has substantial risks and does not reliably resolve colitis or ectodermal abnormalities. In the 29-patient retrospective cohort, the Kaplan-Meier survival estimate was 74% at 108 months after transplantation; median follow-up among surviving children was 57 months. Preexisting mycobacterial infection and colitis showed poorer outcomes, but the subgroup comparisons were not statistically significant.

Show evidence (3 references)

PMID:28679735 SUPPORT Human Clinical

"The global survival rate after HSCT among NEMO-deficient children was 74% at a median follow-up after HSCT of 57 months (range, 4-108 months)."

The abstract pairs the survival estimate with median follow-up; Results identify the Kaplan-Meier time point as 108 months and the 57-month median as follow-up in survivors.

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC5609334/ SUPPORT Human Clinical

"Five of the 15 patients presenting with IBD before transplantation died after HSCT, 4 patients had persistent or intermittent colitis (P1, P5, P24, P29), and IBD symptoms disappeared in 6 patients."

Shows heterogeneous intestinal outcomes rather than an absolute inability of HSCT to improve colitis.

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC5609334/ SUPPORT Human Clinical

"The overall survival rate was 74% at 108 months after transplantation ... with a median follow-up of 57 months in surviving children (range, 4-108 months)."

The Results distinguish the survival-curve time point from the follow-up distribution among survivors.

Ectodermal supportive care

Action: supportive care Ontology label: Supportive Care NCIT:C15747

Cooling measures and early dental care address the ectodermal component. General HED GeneReviews care guidance is applied to shared ectodermal findings, not as NEMO-specific trial evidence or as evidence for the inheritance of EDA-ID.

Show evidence (2 references)

PMID:20301291 SUPPORT INDIRECT Other

"Access to an adequate water supply and a cool environment during hot weather."

General HED supportive-care advice is applicable to reduced sweating; this is expert management advice.

PMID:20301291 SUPPORT INDIRECT Other

"Early dental treatment; bonding of conical teeth; orthodontics as necessary;"

General HED dental advice applies to the shared tooth abnormalities, with disease-scope extrapolation explicit.

🔬

Diagnosis

1

Molecular and immune evaluation

IKBKG testing must distinguish the functional gene from its highly similar pseudogene. Immunologic evaluation is warranted when ectodermal dysplasia accompanies unusual infections, including when a separate EDA variant has already been identified. Normal immunoglobulin levels or absence of ectodermal findings does not exclude variant-specific NEMO immunodeficiency.

Show evidence (3 references)

PMID:33598805 SUPPORT Human Clinical

"This mutation was confirmed by Sanger method, with a long PCR using primers specific for IKBKG and excluding IKBKGP pseudogene"

The primary case demonstrates gene-specific confirmation despite the pseudogene.

PMID:22566850 SUPPORT Other

"Immunologic screening should be considered for all children with HED, and a thorough workup is essential if there is any abnormal pattern of infections."

The dual-diagnosis study recommends immunologic assessment; this is advice rather than an observed outcome.

url:https://www.ncbi.nlm.nih.gov/books/NBK1112/ SUPPORT Human Clinical

"IKBKG ... Hypohidrotic ectodermal dysplasia w/immunodeficiency ... XL ... Sparse hair ... Hypohidrosis ... Hypodontia ... Impaired immune function w/risk for recurrent infections, hypogammaglobulinemia, T cell dysfunction"

The GeneReviews differential table separates immunodeficient IKBKG disease from other genetic causes of HED and from IP.

📊

Prevalence

1

Newborns

Birth Prevalence 0.4 per 100,000 1–9 per 1,000,000 (births) EDA-ID

Historical HED-ID estimate quoted by Keller et al., approximately 1 in 250,000 newborns; this is not the IP birth prevalence and was not measured in the three dual-diagnosis families.

Show evidence (1 reference)

PMID:22566850 SUPPORT Human Clinical

"IKBKG is located on Xq28, and HED-ID occurs in approximately 1 in 250,000 newborns"

The paper repeats an earlier HED-ID estimate; its three EDA/IKBKG dual-diagnosis families do not constitute a population prevalence study.

{ }

Source YAML

click to show

name: IKBKG ectodermal dysplasia with immunodeficiency
creation_date: '2026-04-24T12:00:00Z'
category: Mendelian
parents:
- hereditary disease
- primary immunodeficiency
- ectodermal dysplasia syndrome
synonyms:
- EDA-ID
- NEMO deficiency syndrome
- X-linked ectodermal dysplasia and immunodeficiency
- anhidrotic ectodermal dysplasia with immunodeficiency
description: IKBKG-related immunodeficiency with or without ectodermal dysplasia is an X-linked disorder
  of NEMO-dependent NF-kappaB signaling. Hypomorphic variants produce variable immune defects, ranging
  from broad infection susceptibility with abnormal hair, teeth and sweating to predominantly mycobacterial
  disease without overt ectodermal dysplasia. Osteopetrosis, lymphedema and inflammatory bowel disease
  occur in subsets. Individual variants affect different receptor and cell-type responses; normal
  immunoglobulin concentrations or preserved responses in one assay do not exclude the disorder.
  Incontinentia pigmenti is a distinct allelic disease curated separately, although female manifestations
  and overlap can occur within immunodeficiency families.
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
classifications:
  iuis_category:
    classification_value: combined immunodeficiency with syndromic features
    notes: IUIS 2022 Table 2, subsection 7, places NEMO/IKBKG EDA-ID among combined immunodeficiencies
      with associated or syndromic features.
    evidence:
    - reference: PMID:35748970
      reference_title: 'Human Inborn Errors of Immunity: 2022 Update on the Classification from the
        International Union of Immunological Societies Expert Committee.'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: EDA-ID due to NEMO /IKBKG deficiency (ectodermal dysplasia, immune deficiency) IKBKG
        XL 300248
      explanation: The disease-specific row appears in Table 2 subsection 7; this is expert classification,
        not a patient measurement.
has_subtypes:
- name: EDA-ID
  display_name: Ectodermal Dysplasia and Immunodeficiency 1 (EDA-ID)
  subtype_term:
    preferred_term: ectodermal dysplasia and immunodeficiency 1
    term:
      id: MONDO:0020740
      label: ectodermal dysplasia and immunodeficiency 1
  description: Hypomorphic IKBKG variants cause immune deficiency together with variable hair, tooth
    and sweat-gland abnormalities, predominantly in hemizygous males. The immune defects and infectious
    spectrum vary between variants and individuals.
  evidence:
  - reference: PMID:11242109
    reference_title: X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by
      impaired NF-kappaB signaling.
    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: OL-EDA-ID
  display_name: Anhidrotic EDA-ID with Osteopetrosis and Lymphedema
  subtype_term:
    preferred_term: anhidrotic ectodermal dysplasia-immunodeficiency-osteopetrosis-lymphedema syndrome
    term:
      id: MONDO:0010295
      label: anhidrotic ectodermal dysplasia-immunodeficiency-osteopetrosis-lymphedema syndrome
  description: An immunodeficiency presentation with osteopetrosis and lymphedema, first described
    with IKBKG stop-codon variants. Neither skeletal nor lymphatic involvement is universal in NEMO
    deficiency; later cohorts contain additional genotypes.
  evidence:
  - reference: PMID:11242109
    reference_title: X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by
      impaired NF-kappaB signaling.
    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)
  subtype_term:
    preferred_term: immunodeficiency 33
    term:
      id: MONDO:0010386
      label: immunodeficiency 33
  description: E315A and R319Q variants were identified in families with predominantly mycobacterial
    disease and selective impairment of CD40-dependent IL-12 production by antigen-presenting cells.
    B-cell switching was preserved. Minor dental findings and occasional invasive pyogenic infections
    mean the presentation is not absolutely restricted to mycobacteria.
  evidence:
  - reference: PMID:16818673
    reference_title: X-linked susceptibility to mycobacteria is caused by mutations in NEMO impairing
      CD40-dependent IL-12 production.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We report here mutations in the leucine zipper (LZ) domain of the NF-kappaB essential
      modulator (NEMO) gene in three unrelated kindreds with XR-MSMD.
    explanation: Defines the primary families underlying the selective mycobacterial presentation.
  - reference: PMID:16818673
    reference_title: X-linked susceptibility to mycobacteria is caused by mutations in NEMO impairing
      CD40-dependent IL-12 production.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: However, the CD40-dependent up-regulation of costimulatory molecules of dendritic cells
      and the proliferation and immunoglobulin class switch of B cells were normal.
    explanation: Patient-cell assays distinguish this presentation from CD40-dependent B-cell switching
      defects.
inheritance:
- name: X-linked recessive inheritance (EDA-ID)
  description: The classic immunodeficiency pedigrees show X-linked recessive inheritance. Heterozygous
    females may have mild ectodermal findings, IP, inflammatory manifestations or occasionally immunodeficiency;
    X-inactivation is not uniformly protective. Counseling must use the familial variant and observed
    phenotype rather than importing the usual male lethality of classic IP.
  inheritance_term:
    preferred_term: X-linked recessive inheritance
    term:
      id: HP:0001419
      label: X-linked recessive inheritance
  evidence:
  - reference: PMID:11047757
    reference_title: A novel X-linked disorder of immune deficiency and hypohidrotic ectodermal dysplasia
      is allelic to incontinentia pigmenti and due to mutations in IKK-gamma (NEMO).
    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.
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1112/
    reference_title: Hypohidrotic Ectodermal Dysplasia - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: IKBKG ... Hypohidrotic ectodermal dysplasia w/immunodeficiency ... XL ... Sparse hair
      ... Hypohidrosis ... Hypodontia ... Impaired immune function w/risk for recurrent infections,
      hypogammaglobulinemia, T cell dysfunction
    explanation: The IKBKG differential row explicitly assigns X-linked inheritance; the separate
      EDA-specific counseling probabilities and classic-IP lethality are not used.
pathophysiology:
- name: Impaired NEMO-dependent NF-kappaB activation
  description: Hypomorphic IKBKG variants impair NEMO-dependent activation of the canonical NF-kappaB
    pathway. Residual activity, protein abundance and stimulus specificity vary. Exon 10 truncations
    as well as missense variants can retain function; preserved protein expression does not establish
    normal signaling.
  evidence:
  - &id001
    reference: PMID:11242109
    reference_title: X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by
      impaired NF-kappaB signaling.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: We show that IKBKG mutations causing OL-EDA-ID and EDA-ID impair but do not abolish
      NF-kappaB signaling
    explanation: The functional experiments distinguish hypomorphic immunodeficiency variants from
      complete pathway abolition.
  genes:
  - preferred_term: IKBKG
    term:
      id: hgnc:5961
      label: IKBKG
  biological_processes:
  - preferred_term: canonical NF-kappaB signal transduction
    term:
      id: GO:0007249
      label: canonical NF-kappaB signal transduction
  downstream:
  - target: Impaired innate immune receptor responses
    causal_link_type: DIRECT
    description: NEMO dysfunction can impair signal transmission from innate immune receptors; the
      affected receptor responses depend on the variant.
    evidence:
    - reference: PMID:18851874
      reference_title: Hypomorphic nuclear factor-kappaB essential modulator mutation database and
        reconstitution system identifies phenotypic and immunologic diversity.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: 86% (6/7) patients had abnormal IL-1 signaling, and 64% (9/14) had abnormal TLR signaling
      explanation: Selected patient-cell assays show variable IL-1 and Toll-like receptor defects;
        denominators are tested subsets.
  - target: Impaired CD40-dependent B-cell maturation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Selected zinc-finger variants impair CD40-mediated NF-kappaB signaling in B cells,
      compromising switching and antibody diversification.
    evidence:
    - reference: PMID:15578091
      reference_title: Specific NEMO mutations impair CD40-mediated c-Rel activation and B cell terminal
        differentiation.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Furthermore, we show that patient B cells stimulated with CD40 ligand are impaired
        in both p65 and c-Rel activation, and whereas addition of IL-4 can enhance p65 activity,
        c-Rel activity remains deficient.
      explanation: The cultured patient B-cell experiments support this variant-scoped signaling-to-maturation
        route.
  - target: Impaired CD40-dependent IL-12 and IFN-gamma cooperation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: The E315A/R319Q variants selectively impair the CD40/c-Rel cytokine branch in antigen-presenting
      cells; this is not generalized failure of all CD40 functions.
    evidence:
    - reference: PMID:16818673
      reference_title: X-linked susceptibility to mycobacteria is caused by mutations in NEMO impairing
        CD40-dependent IL-12 production.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: IL-12 production was also impaired as the result of a specific defect in NEMO- and
        NF-kappaB/c-Rel-mediated CD40 signaling after the stimulation of monocytes and dendritic
        cells by CD40L-expressing T cells and fibroblasts, respectively.
      explanation: Patient-cell experiments support the selective upstream mechanism.
  - target: Impaired ectodermal appendage development
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Reduced NEMO-dependent signaling compromises the ectodysplasin receptor developmental
      program.
    evidence:
    - reference: PMID:11242109
      reference_title: X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by
        impaired NF-kappaB signaling.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: We also show that the ectodysplasin receptor, DL, triggers NF-kappaB through the NEMO
        protein, indicating that EDA results from impaired NF-kappaB signaling.
      explanation: The receptor signaling experiments connect ectodysplasin signaling to NEMO.
  - target: Impaired osteoclast maturation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The authors attribute this uncommon nonhematopoietic manifestation to a NEMO-dependent
      developmental signaling pathway; direct patient-specific intermediates remain incompletely
      tested.
    evidence:
    - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC5609334/
      reference_title: Hematopoietic stem cell transplantation in 29 patients hemizygous for hypomorphic
        IKBKG/NEMO mutations - PMC
      supports: SUPPORT
      evidence_source: OTHER
      snippet: osteopetrosis from alterations to the receptor activator of NF-κB pathway.
      explanation: Disease-focused mechanistic synthesis supports the qualified developmental pathway.
      directness: INDIRECT
  - target: Impaired lymphatic developmental signaling
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The authors attribute this uncommon nonhematopoietic manifestation to a NEMO-dependent
      developmental signaling pathway; direct patient-specific intermediates remain incompletely
      tested.
    evidence:
    - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC5609334/
      reference_title: Hematopoietic stem cell transplantation in 29 patients hemizygous for hypomorphic
        IKBKG/NEMO mutations - PMC
      supports: SUPPORT
      evidence_source: OTHER
      snippet: lymphedema from changes to the vascular endothelial growth factor-3 pathway
      explanation: Disease-focused mechanistic synthesis supports the qualified developmental pathway.
      directness: INDIRECT
  - target: Intestinal epithelial barrier dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: NEMO dysfunction may compromise epithelial integrity through altered NF-kappaB-dependent
      survival and antimicrobial programs. Human post-HSCT observations and epithelial knockout models
      support this provisional attribution.
    evidence:
    - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC5609334/
      reference_title: Hematopoietic stem cell transplantation in 29 patients hemizygous for hypomorphic
        IKBKG/NEMO mutations - PMC
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: gut-infiltrating immune cells were strongly stained for nuclear p65, indicating normal
        NEMO function, whereas intestinal epithelial cells had no nuclear p65, suggesting the possible
        involvement of an intrinsic NF-κB signaling defect in intestinal epithelial cells.
      explanation: The P7 gut biopsy provides a human tissue observation with a qualified epithelial
        interpretation; it does not prove a uniform cause of all colitis.
      directness: INDIRECT
  - target: Pneumocystis pneumonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The broad NEMO immunodeficiency predisposes to this opportunistic infection. The
      reviewed sources do not assign a single receptor or lymphocyte defect in the observed patient,
      so cellular intermediates remain unspecified.
    evidence:
    - reference: DOI:10.1128/cmr.00001-11
      reference_title: Infectious Diseases in Patients with IRAK-4, MyD88, NEMO, or IκBα Deficiency
      supports: SUPPORT
      evidence_source: OTHER
      snippet: The broad and profound immunological phenotypes of patients with IκBα and NEMO deficiencies
        are responsible for their broad susceptibility to infections with invasive pyogenic bacteria
        (meningitis, sepsis, arthritis, osteomyelitis, and abscesses), environmental mycobacteria,
        and, to a lesser extent, parasites, viruses, and fungi.
      explanation: The disease review supports an immune-defect-to-infection attribution with unresolved
        individual intermediates.
      directness: INDIRECT
    - reference: PMID:33598805
      reference_title: 'EDA-ID: a Severe Clinical Presentation Associated with a New IKBKG Mutation.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Pneumocystosis was diagnosed by nasopharyngeal PCR and typical CT scans and was treated
        with corticosteroids and trimethoprim/sulfamethoxazole.
      explanation: Pneumocystis pneumonia was diagnosed in the Thr164Pro infant using nasopharyngeal
        PCR and compatible CT findings.
  - target: Chronic mucocutaneous candidiasis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The broad NEMO immunodeficiency predisposes to this opportunistic infection. The
      reviewed sources do not assign a single receptor or lymphocyte defect in the observed patient,
      so cellular intermediates remain unspecified.
    evidence:
    - reference: DOI:10.1128/cmr.00001-11
      reference_title: Infectious Diseases in Patients with IRAK-4, MyD88, NEMO, or IκBα Deficiency
      supports: SUPPORT
      evidence_source: OTHER
      snippet: The broad and profound immunological phenotypes of patients with IκBα and NEMO deficiencies
        are responsible for their broad susceptibility to infections with invasive pyogenic bacteria
        (meningitis, sepsis, arthritis, osteomyelitis, and abscesses), environmental mycobacteria,
        and, to a lesser extent, parasites, viruses, and fungi.
      explanation: The disease review supports an immune-defect-to-infection attribution with unresolved
        individual intermediates.
      directness: INDIRECT
    - reference: PMID:33598805
      reference_title: 'EDA-ID: a Severe Clinical Presentation Associated with a New IKBKG Mutation.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: He had also recurrent muco-cutaneous Candidiasis.
      explanation: Recurrent mucocutaneous candidiasis was reported in the Thr164Pro infant.
  - target: Severe cytomegalovirus infection
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The broad NEMO immunodeficiency predisposes to this opportunistic infection. The
      reviewed sources do not assign a single receptor or lymphocyte defect in the observed patient,
      so cellular intermediates remain unspecified.
    evidence:
    - reference: DOI:10.1128/cmr.00001-11
      reference_title: Infectious Diseases in Patients with IRAK-4, MyD88, NEMO, or IκBα Deficiency
      supports: SUPPORT
      evidence_source: OTHER
      snippet: The broad and profound immunological phenotypes of patients with IκBα and NEMO deficiencies
        are responsible for their broad susceptibility to infections with invasive pyogenic bacteria
        (meningitis, sepsis, arthritis, osteomyelitis, and abscesses), environmental mycobacteria,
        and, to a lesser extent, parasites, viruses, and fungi.
      explanation: The disease review supports an immune-defect-to-infection attribution with unresolved
        individual intermediates.
      directness: INDIRECT
    - reference: PMID:33598805
      reference_title: 'EDA-ID: a Severe Clinical Presentation Associated with a New IKBKG Mutation.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Moreover, he had cytomegalovirus (CMV) viremia which was not controlled with Valganciclovir
        and Ganciclovir was introduced
      explanation: The Thr164Pro infant had prolonged CMV viremia before HSCT, requiring escalation
        from valganciclovir to ganciclovir; later post-HSCT infections are not used as baseline frequency
        evidence.
  - target: Eczematoid dermatitis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: A hematopoietic contribution to NEMO-associated eczema is supported by complete
      resolution after cord-blood transplantation in one c.1167insC patient and inflammatory-cell
      infiltrates in skin biopsies. This remains a qualified attribution, not proof that every dry
      or pigmented skin lesion has the same cause.
    evidence:
    - reference: url:https://oup.silverchair-cdn.com/article-minimal/6625140
      reference_title: https://oup.silverchair-cdn.com/article-minimal/6625140
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: We report a case of intractable eczematous eruption in a patient with EDA‐ID, which
        disappeared completely after allogenic transplantation of umbilical‐cord blood.
      explanation: The c.1167insC case improved after hematopoietic replacement, supporting an immune-cell
        contribution to eczema by intervention. This is an indirect, single-case inference; the accessible
        publisher extract does not resolve individual immune intermediates.
      directness: INDIRECT
    - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC5609334/
      reference_title: Hematopoietic stem cell transplantation in 29 patients hemizygous for hypomorphic
        IKBKG/NEMO mutations - PMC
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Skin biopsy was performed in 8 patients, revealing spongiotic dermatitis with superficial
        perivascular inflammatory lymphocytes and eosinophil infiltrates.
      explanation: The selected cohort demonstrates a local inflammatory substrate; the biopsy alone
        does not identify the upstream immune-cell defect.
      directness: INDIRECT
- name: Impaired innate immune receptor responses
  description: Responses to TNF, IL-1 and Toll-like receptor ligands are variably impaired in patient
    cells. This is a conditional pathway defect, not a claim that every response is absent in every
    IKBKG genotype. E315A/R319Q and other variants can preserve several tested innate responses.
  evidence:
  - reference: PMID:18851874
    reference_title: Hypomorphic nuclear factor-kappaB essential modulator mutation database and
      reconstitution system identifies phenotypic and immunologic diversity.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: 86% (6/7) patients had abnormal IL-1 signaling, and 64% (9/14) had abnormal TLR signaling
    explanation: Selected patient-cell assays show variable IL-1 and Toll-like receptor defects;
      denominators are tested subsets.
  downstream:
  - target: Recurrent infections
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Impaired innate activation contributes to susceptibility to invasive or recurrent
      infection in affected genotypes. Adaptive defects also contribute; this is not a unique receptor-pathogen
      mapping.
    evidence:
    - reference: PMID:22566850
      reference_title: Hypohidrotic ectodermal dysplasia and immunodeficiency with coincident NEMO
        and EDA mutations.
      supports: SUPPORT
      evidence_source: OTHER
      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: The disease-focused background attributes broad infection susceptibility to NF-kappaB-dependent
        innate and adaptive immunity; it is an interpretive synthesis rather than a new assay.
      directness: INDIRECT
    - reference: DOI:10.1086/316914
      reference_title: A Novel X-Linked Disorder of Immune Deficiency and Hypohidrotic Ectodermal
        Dysplasia Is Allelic to Incontinentia Pigmenti and Due to Mutations in IKK-gamma (NEMO)
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Affected males manifest dysgammaglobulinemia and, despite therapy, have significant
        morbidity and mortality from recurrent infections.
      explanation: Recurrent infections may be severe and continue despite immunoglobulin replacement.
        Organisms and onset vary; this is not universal infection in every genetically diagnosed
        infant.
  - target: Recurrent pneumonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Impaired innate activation contributes to susceptibility to invasive or recurrent
      infection in affected genotypes. Adaptive defects also contribute; this is not a unique receptor-pathogen
      mapping.
    evidence:
    - reference: PMID:22566850
      reference_title: Hypohidrotic ectodermal dysplasia and immunodeficiency with coincident NEMO
        and EDA mutations.
      supports: SUPPORT
      evidence_source: OTHER
      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: The disease-focused background attributes broad infection susceptibility to NF-kappaB-dependent
        innate and adaptive immunity; it is an interpretive synthesis rather than a new assay.
      directness: INDIRECT
    - reference: DOI:10.1086/316914
      reference_title: A Novel X-Linked Disorder of Immune Deficiency and Hypohidrotic Ectodermal
        Dysplasia Is Allelic to Incontinentia Pigmenti and Due to Mutations in IKK-gamma (NEMO)
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: with recurrent infections and had repeated hospitalization for pneumonia and bacterial
        infections of both bone and soft tissues.
      explanation: Recurrent pulmonary infections were documented in the original EDA-ID families.
  - target: Sepsis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Impaired innate activation contributes to susceptibility to invasive or recurrent
      infection in affected genotypes. Adaptive defects also contribute; this is not a unique receptor-pathogen
      mapping.
    evidence:
    - reference: PMID:22566850
      reference_title: Hypohidrotic ectodermal dysplasia and immunodeficiency with coincident NEMO
        and EDA mutations.
      supports: SUPPORT
      evidence_source: OTHER
      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: The disease-focused background attributes broad infection susceptibility to NF-kappaB-dependent
        innate and adaptive immunity; it is an interpretive synthesis rather than a new assay.
      directness: INDIRECT
    - reference: DOI:10.1086/316914
      reference_title: A Novel X-Linked Disorder of Immune Deficiency and Hypohidrotic Ectodermal
        Dysplasia Is Allelic to Incontinentia Pigmenti and Due to Mutations in IKK-gamma (NEMO)
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The proband's younger maternal half-brother (III-2) presented, at age 3 mo, with bacterial
        sepsis and meningitis.
      explanation: Sepsis occurred before transplantation, including early bacterial sepsis in the
        original family 4; post-HSCT sepsis is not counted as an untreated baseline frequency.
- name: Impaired CD40-dependent B-cell maturation
  description: C417R/C417Y patient B cells have impaired c-Rel activation, class-switch recombination
    and somatic hypermutation despite preserved induction of AID. This route explains a subset of
    humoral defects and is not transferred to E315A/R319Q patients with preserved B-cell CD40 responses.
  evidence:
  - reference: PMID:15578091
    reference_title: Specific NEMO mutations impair CD40-mediated c-Rel activation and B cell terminal
      differentiation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Here we report that patient B cells are characterized by an absence of Ig somatic hypermutation
      (SHM) and defective class switch recombination (CSR) despite normal induction of activation-induced
      cytidine deaminase (AID) and Iepsilon-Cepsilon transcripts.
    explanation: Functional studies in selected C417-mutant patient B cells establish impaired terminal
      maturation without an AID-expression deficiency.
  downstream:
  - target: Hypogammaglobulinemia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Defective terminal B-cell maturation provides a qualified explanation for this humoral
      finding in switching-defective genotypes. It is not established as the sole route in every
      individual contributing a clinical observation.
    evidence:
    - reference: PMID:15578091
      reference_title: Specific NEMO mutations impair CD40-mediated c-Rel activation and B cell terminal
        differentiation.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Here we report that patient B cells are characterized by an absence of Ig somatic
        hypermutation (SHM) and defective class switch recombination (CSR) despite normal induction
        of activation-induced cytidine deaminase (AID) and Iepsilon-Cepsilon transcripts.
      explanation: Functional studies in selected C417-mutant patient B cells establish impaired
        terminal maturation without an AID-expression deficiency.
    - reference: PMID:18851874
      reference_title: Hypomorphic nuclear factor-kappaB essential modulator mutation database and
        reconstitution system identifies phenotypic and immunologic diversity.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Hypogammaglobulinemia occurred in 24/41 (59%), but correlated with impaired CD40 signaling
        only in Zinc Finger mutations.
      explanation: The selected compilation reported hypogammaglobulinemia in 24/41 evaluated individuals,
        with CD40 correlation confined to zinc-finger variants; this supports a qualified, variant-scoped
        humoral route rather than a universal association.
      directness: INDIRECT
  - target: Decreased circulating IgG
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Defective terminal B-cell maturation provides a qualified explanation for this humoral
      finding in switching-defective genotypes. It is not established as the sole route in every
      individual contributing a clinical observation.
    evidence:
    - reference: PMID:15578091
      reference_title: Specific NEMO mutations impair CD40-mediated c-Rel activation and B cell terminal
        differentiation.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Here we report that patient B cells are characterized by an absence of Ig somatic
        hypermutation (SHM) and defective class switch recombination (CSR) despite normal induction
        of activation-induced cytidine deaminase (AID) and Iepsilon-Cepsilon transcripts.
      explanation: Functional studies in selected C417-mutant patient B cells establish impaired
        terminal maturation without an AID-expression deficiency.
    - reference: PMID:18851874
      reference_title: Hypomorphic nuclear factor-kappaB essential modulator mutation database and
        reconstitution system identifies phenotypic and immunologic diversity.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Hypogammaglobulinemia occurred in 24/41 (59%), but correlated with impaired CD40 signaling
        only in Zinc Finger mutations.
      explanation: The clinical compilation limits the CD40-humoral association by variant class.
      directness: INDIRECT
    - reference: DOI:10.1086/316914
      reference_title: A Novel X-Linked Disorder of Immune Deficiency and Hypohidrotic Ectodermal
        Dysplasia Is Allelic to Incontinentia Pigmenti and Due to Mutations in IKK-gamma (NEMO)
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Immunoglobulin levels at age 10 mo showed abnormally low levels of IgG (<200 mg/dl
        (normal range 294–1,069 mg/dl)), low-to-normal levels of IgA, and elevated levels of IgM
        (1,100 mg/dl (normal range 41–149 mg/dl)).
      explanation: Low IgG was measured before replacement in original EDA-ID patients; values obtained
        during IVIG should not be interpreted as untreated concentrations.
  - target: Decreased circulating IgA
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Defective terminal B-cell maturation provides a qualified explanation for this humoral
      finding in switching-defective genotypes. It is not established as the sole route in every
      individual contributing a clinical observation.
    evidence:
    - reference: PMID:15578091
      reference_title: Specific NEMO mutations impair CD40-mediated c-Rel activation and B cell terminal
        differentiation.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Here we report that patient B cells are characterized by an absence of Ig somatic
        hypermutation (SHM) and defective class switch recombination (CSR) despite normal induction
        of activation-induced cytidine deaminase (AID) and Iepsilon-Cepsilon transcripts.
      explanation: Functional studies in selected C417-mutant patient B cells establish impaired
        terminal maturation without an AID-expression deficiency.
    - reference: PMID:18851874
      reference_title: Hypomorphic nuclear factor-kappaB essential modulator mutation database and
        reconstitution system identifies phenotypic and immunologic diversity.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Hypogammaglobulinemia occurred in 24/41 (59%), but correlated with impaired CD40 signaling
        only in Zinc Finger mutations.
      explanation: The clinical compilation limits the CD40-humoral association by variant class.
      directness: INDIRECT
    - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC5609334/
      reference_title: Hematopoietic stem cell transplantation in 29 patients hemizygous for hypomorphic
        IKBKG/NEMO mutations - PMC
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 16 ... P jirovecii ... CMV, rotavirus ... Low IgA
      explanation: Low IgA was reported before HSCT in patient P16; IgA can instead be elevated in
        other IKBKG genotypes.
    - reference: PMID:15578091
      reference_title: Specific NEMO mutations impair CD40-mediated c-Rel activation and B cell terminal
        differentiation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: IgM IgG IgA IgM IgG IgA XHM-ED1 552 991 <10
      explanation: Table 2 lists IgA below 10 mg/dL in the first three, serum columns for XHM-ED1;
        the serum reference interval is 51–375 mg/dL. These are human blood values during IVIG, not
        the later culture-supernatant columns.
  - target: Increased circulating IgM
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Defective terminal B-cell maturation provides a qualified explanation for this humoral
      finding in switching-defective genotypes. It is not established as the sole route in every
      individual contributing a clinical observation.
    evidence:
    - reference: PMID:15578091
      reference_title: Specific NEMO mutations impair CD40-mediated c-Rel activation and B cell terminal
        differentiation.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Here we report that patient B cells are characterized by an absence of Ig somatic
        hypermutation (SHM) and defective class switch recombination (CSR) despite normal induction
        of activation-induced cytidine deaminase (AID) and Iepsilon-Cepsilon transcripts.
      explanation: Functional studies in selected C417-mutant patient B cells establish impaired
        terminal maturation without an AID-expression deficiency.
    - reference: PMID:18851874
      reference_title: Hypomorphic nuclear factor-kappaB essential modulator mutation database and
        reconstitution system identifies phenotypic and immunologic diversity.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Hypogammaglobulinemia occurred in 24/41 (59%), but correlated with impaired CD40 signaling
        only in Zinc Finger mutations.
      explanation: The clinical compilation limits the CD40-humoral association by variant class.
      directness: INDIRECT
    - reference: PMID:33598805
      reference_title: 'EDA-ID: a Severe Clinical Presentation Associated with a New IKBKG Mutation.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: increased IgM levels at 4.6 g/L (0.26 −1), normal B cells differentiation and a slightly
        decreased of CD40L expression level.
      explanation: Elevated IgM occurs in a subset; the Thr164Pro infant had 4.6 g/L. A hyper-IgM
        syndrome label does not establish elevated IgM in every patient.
    - reference: DOI:10.1086/316914
      reference_title: A Novel X-Linked Disorder of Immune Deficiency and Hypohidrotic Ectodermal
        Dysplasia Is Allelic to Incontinentia Pigmenti and Due to Mutations in IKK-gamma (NEMO)
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Immunoglobulin levels at age 10 mo showed abnormally low levels of IgG (<200 mg/dl
        (normal range 294–1,069 mg/dl)), low-to-normal levels of IgA, and elevated levels of IgM
        (1,100 mg/dl (normal range 41–149 mg/dl)).
      explanation: Family 1 carries C417R; the untreated IgM elevation supports the zinc-finger-associated
        humoral phenotype independently of the Thr164Pro infant.
  - target: Impaired specific antibody response
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Defective terminal B-cell maturation provides a qualified explanation for this humoral
      finding in switching-defective genotypes. It is not established as the sole route in every
      individual contributing a clinical observation.
    evidence:
    - reference: PMID:15578091
      reference_title: Specific NEMO mutations impair CD40-mediated c-Rel activation and B cell terminal
        differentiation.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Here we report that patient B cells are characterized by an absence of Ig somatic
        hypermutation (SHM) and defective class switch recombination (CSR) despite normal induction
        of activation-induced cytidine deaminase (AID) and Iepsilon-Cepsilon transcripts.
      explanation: Functional studies in selected C417-mutant patient B cells establish impaired
        terminal maturation without an AID-expression deficiency.
    - reference: PMID:18851874
      reference_title: Hypomorphic nuclear factor-kappaB essential modulator mutation database and
        reconstitution system identifies phenotypic and immunologic diversity.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Hypogammaglobulinemia occurred in 24/41 (59%), but correlated with impaired CD40 signaling
        only in Zinc Finger mutations.
      explanation: The clinical compilation limits the CD40-humoral association by variant class.
      directness: INDIRECT
    - reference: PMID:18851874
      reference_title: Hypomorphic nuclear factor-kappaB essential modulator mutation database and
        reconstitution system identifies phenotypic and immunologic diversity.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Defects in specific antibody production occurred in 64% (18/28)
      explanation: Defective specific antibody production was reported in 18/28 evaluated individuals
        in the retrospective compilation. Normal total immunoglobulin levels do not exclude this
        finding.
  - target: Decreased class-switched memory B-cell proportion
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Defective terminal B-cell maturation provides a qualified explanation for this humoral
      finding in switching-defective genotypes. It is not established as the sole route in every
      individual contributing a clinical observation.
    evidence:
    - reference: PMID:15578091
      reference_title: Specific NEMO mutations impair CD40-mediated c-Rel activation and B cell terminal
        differentiation.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Here we report that patient B cells are characterized by an absence of Ig somatic
        hypermutation (SHM) and defective class switch recombination (CSR) despite normal induction
        of activation-induced cytidine deaminase (AID) and Iepsilon-Cepsilon transcripts.
      explanation: Functional studies in selected C417-mutant patient B cells establish impaired
        terminal maturation without an AID-expression deficiency.
    - reference: PMID:18851874
      reference_title: Hypomorphic nuclear factor-kappaB essential modulator mutation database and
        reconstitution system identifies phenotypic and immunologic diversity.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Hypogammaglobulinemia occurred in 24/41 (59%), but correlated with impaired CD40 signaling
        only in Zinc Finger mutations.
      explanation: The clinical compilation limits the CD40-humoral association by variant class.
      directness: INDIRECT
    - reference: PMID:39540818
      reference_title: Atypical Mycobacterial Pneumonia in 2 Siblings with a Novel Hypomorphic NEMO/IKBKG
        Mutation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: His class-switched B cell subset was decreased, with normal T and B cell counts.
      explanation: The class-switched B-cell subset was reduced in both c.268delG brothers; P2 otherwise
        had normal T- and B-cell counts by the authors narrative.
    - reference: PMID:15578091
      reference_title: Specific NEMO mutations impair CD40-mediated c-Rel activation and B cell terminal
        differentiation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: absence of IgD –CD27+ B cells, which are typical memory B cells.
      explanation: The C417 patient peripheral-blood analysis showed virtual absence of switched
        memory cells; this supports the maturation route independently of the later c.268delG family.
  - target: Decreased circulating IgE
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Defective terminal B-cell maturation provides a qualified explanation for this humoral
      finding in switching-defective genotypes. It is not established as the sole route in every
      individual contributing a clinical observation.
    evidence:
    - reference: PMID:15578091
      reference_title: Specific NEMO mutations impair CD40-mediated c-Rel activation and B cell terminal
        differentiation.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Here we report that patient B cells are characterized by an absence of Ig somatic
        hypermutation (SHM) and defective class switch recombination (CSR) despite normal induction
        of activation-induced cytidine deaminase (AID) and Iepsilon-Cepsilon transcripts.
      explanation: Functional studies in selected C417-mutant patient B cells establish impaired
        terminal maturation without an AID-expression deficiency.
    - reference: PMID:18851874
      reference_title: Hypomorphic nuclear factor-kappaB essential modulator mutation database and
        reconstitution system identifies phenotypic and immunologic diversity.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Hypogammaglobulinemia occurred in 24/41 (59%), but correlated with impaired CD40 signaling
        only in Zinc Finger mutations.
      explanation: The clinical compilation limits the CD40-humoral association by variant class.
      directness: INDIRECT
    - reference: PMID:15578091
      reference_title: Specific NEMO mutations impair CD40-mediated c-Rel activation and B cell terminal
        differentiation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: |-
        defined by markedly dimin-
        ished serum levels of IgG and IgE and normal or elevated levels
        of serum IgM (Tables 1 and 2).
      explanation: Diminished serum IgE was part of the clinical definition in three C417-mutant
        patients. This is separate from failure of stimulated cultured B cells to secrete IgE.
- name: Impaired CD40-dependent IL-12 and IFN-gamma cooperation
  description: E315A/R319Q variants impair CD40-triggered cytokine production by monocytes and dendritic
    cells. Delayed c-Rel nuclear accumulation and reduced IL-12 lead to reduced T-cell IFN-gamma
    secretion. This is an antigen-presenting-cell defect, not an intrinsic IFN-gamma defect in the
    T cell; responses to live BCG and several other stimuli can remain intact.
  evidence:
  - reference: PMID:16818673
    reference_title: X-linked susceptibility to mycobacteria is caused by mutations in NEMO impairing
      CD40-dependent IL-12 production.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: However, the patients' monocytes presented an intrinsic defect in T cell-dependent IL-12
      production, resulting in defective IFN-gamma secretion by T cells.
    explanation: Patient coculture experiments localize the defect to monocyte-dependent IL-12 production
      and secondary IFN-gamma output.
  downstream:
  - target: Recurrent mycobacterial infections
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Impaired CD40-dependent IL-12/IFN-gamma cooperation compromises control of mycobacteria
      in the E315A/R319Q families. Other NEMO variants and residual TNF defects can contribute through
      additional routes.
    evidence:
    - reference: PMID:16818673
      reference_title: X-linked susceptibility to mycobacteria is caused by mutations in NEMO impairing
        CD40-dependent IL-12 production.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: In conclusion, specific NEMO mutations may selectively target the CD40–NF-κB–c-Rel
        signaling pathway in monocytes and dendritic cells, preventing the production of sufficient
        quantities of IL-12 after T cell stimulation. This results in impaired IFN-γ–mediated immunity
        and predisposition to mycobacterial diseases
      explanation: The authors causal interpretation integrates the human pedigrees and patient-cell
        assays; it is not a claim of complete CD40 blockade.
    - reference: PMID:16818673
      reference_title: X-linked susceptibility to mycobacteria is caused by mutations in NEMO impairing
        CD40-dependent IL-12 production.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: One of our patients with EM disease (II.4 in kindred A) also suffered from miliary
        tuberculosis in childhood, and two of our probands (P2 and P3) probably suffered from tuberculosis,
        as the sole infectious phenotype suggested by consistent histological results and strongly
        positive tuberculin skin tests.
      explanation: Recurrent or disseminated mycobacterial disease occurs in classic EDA-ID and in
        selective E315A/R319Q presentations. The historical approximately 40% figure comes from selected
        reported cases. Presumed tuberculosis in two European probands lacked culture confirmation;
        M. bovis is in the tuberculosis complex.
- name: Impaired ectodermal appendage development
  description: Disrupted ectodysplasin/EDAR signaling through NEMO impairs development of hair, teeth
    and eccrine sweat glands. Clinical expression is variable, including individuals without overt
    ectodermal dysplasia. This pathway is distinct from inflammatory elimination of IKBKG-null cells
    in classic IP.
  evidence:
  - reference: PMID:11242109
    reference_title: X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by
      impaired NF-kappaB signaling.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: We also show that the ectodysplasin receptor, DL, triggers NF-kappaB through the NEMO
      protein, indicating that EDA results from impaired NF-kappaB signaling.
    explanation: The receptor signaling experiments connect ectodysplasin signaling to NEMO.
  conforms_to: eda_edar_nfkb_ectodermal_appendage#Failed Ectodermal Placode Formation
  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
  downstream:
  - target: Anhidrosis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Impaired ectodysplasin/NEMO-dependent appendage development provides the developmental
      explanation for this component. Expression varies between patients and the specific appendage-level
      steps were not measured in these families.
    evidence:
    - reference: DOI:10.1086/316914
      reference_title: A Novel X-Linked Disorder of Immune Deficiency and Hypohidrotic Ectodermal
        Dysplasia Is Allelic to Incontinentia Pigmenti and Due to Mutations in IKK-gamma (NEMO)
      supports: SUPPORT
      evidence_source: OTHER
      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: The authors developmental interpretation connects the shared appendage phenotype
        to IKK signaling.
      directness: INDIRECT
    - reference: DOI:10.1086/316914
      reference_title: A Novel X-Linked Disorder of Immune Deficiency and Hypohidrotic Ectodermal
        Dysplasia Is Allelic to Incontinentia Pigmenti and Due to Mutations in IKK-gamma (NEMO)
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: An inability to sweat had been noted since infancy, requiring lifelong cooling measures.
      explanation: Complete inability to sweat was reported in affected males; other patients retain
        reduced sweating and are represented separately as hypohidrosis.
  - target: Hypohidrosis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Impaired ectodysplasin/NEMO-dependent appendage development provides the developmental
      explanation for this component. Expression varies between patients and the specific appendage-level
      steps were not measured in these families.
    evidence:
    - reference: DOI:10.1086/316914
      reference_title: A Novel X-Linked Disorder of Immune Deficiency and Hypohidrotic Ectodermal
        Dysplasia Is Allelic to Incontinentia Pigmenti and Due to Mutations in IKK-gamma (NEMO)
      supports: SUPPORT
      evidence_source: OTHER
      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: The authors developmental interpretation connects the shared appendage phenotype
        to IKK signaling.
      directness: INDIRECT
    - reference: DOI:10.1086/316914
      reference_title: A Novel X-Linked Disorder of Immune Deficiency and Hypohidrotic Ectodermal
        Dysplasia Is Allelic to Incontinentia Pigmenti and Due to Mutations in IKK-gamma (NEMO)
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Similar to his brother, he had very low amounts of sweat on a quantitative sweat test.
      explanation: Reduced sweating is distinct from complete anhidrosis; quantitative sweat testing
        in one original family showed very low sweat production.
  - target: Sparse scalp hair
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Impaired ectodysplasin/NEMO-dependent appendage development provides the developmental
      explanation for this component. Expression varies between patients and the specific appendage-level
      steps were not measured in these families.
    evidence:
    - reference: DOI:10.1086/316914
      reference_title: A Novel X-Linked Disorder of Immune Deficiency and Hypohidrotic Ectodermal
        Dysplasia Is Allelic to Incontinentia Pigmenti and Due to Mutations in IKK-gamma (NEMO)
      supports: SUPPORT
      evidence_source: OTHER
      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: The authors developmental interpretation connects the shared appendage phenotype
        to IKK signaling.
      directness: INDIRECT
    - reference: DOI:10.1086/316914
      reference_title: A Novel X-Linked Disorder of Immune Deficiency and Hypohidrotic Ectodermal
        Dysplasia Is Allelic to Incontinentia Pigmenti and Due to Mutations in IKK-gamma (NEMO)
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: He was noted to have reduced sweating, thin sparse scalp hair and eyebrows, and mild
        frontal bossing
      explanation: Sparse scalp hair occurs in EDA-ID, but normal scalp hair was also documented
        within the original families.
  - target: Sparse eyebrows
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Impaired ectodysplasin/NEMO-dependent appendage development provides the developmental
      explanation for this component. Expression varies between patients and the specific appendage-level
      steps were not measured in these families.
    evidence:
    - reference: DOI:10.1086/316914
      reference_title: A Novel X-Linked Disorder of Immune Deficiency and Hypohidrotic Ectodermal
        Dysplasia Is Allelic to Incontinentia Pigmenti and Due to Mutations in IKK-gamma (NEMO)
      supports: SUPPORT
      evidence_source: OTHER
      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: The authors developmental interpretation connects the shared appendage phenotype
        to IKK signaling.
      directness: INDIRECT
    - reference: DOI:10.1086/316914
      reference_title: A Novel X-Linked Disorder of Immune Deficiency and Hypohidrotic Ectodermal
        Dysplasia Is Allelic to Incontinentia Pigmenti and Due to Mutations in IKK-gamma (NEMO)
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: He was noted to have reduced sweating, thin sparse scalp hair and eyebrows, and mild
        frontal bossing
      explanation: Sparse eyebrows were observed in family 4 III-1; the observation is case-scoped.
  - target: Conical teeth
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Impaired ectodysplasin/NEMO-dependent appendage development provides the developmental
      explanation for this component. Expression varies between patients and the specific appendage-level
      steps were not measured in these families.
    evidence:
    - reference: DOI:10.1086/316914
      reference_title: A Novel X-Linked Disorder of Immune Deficiency and Hypohidrotic Ectodermal
        Dysplasia Is Allelic to Incontinentia Pigmenti and Due to Mutations in IKK-gamma (NEMO)
      supports: SUPPORT
      evidence_source: OTHER
      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: The authors developmental interpretation connects the shared appendage phenotype
        to IKK signaling.
      directness: INDIRECT
    - reference: DOI:10.1086/316914
      reference_title: A Novel X-Linked Disorder of Immune Deficiency and Hypohidrotic Ectodermal
        Dysplasia Is Allelic to Incontinentia Pigmenti and Due to Mutations in IKK-gamma (NEMO)
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: He had conical-shaped incisors, hypodontia (missing four of his permanent teeth),
        and normal scalp hair
      explanation: Conical teeth occur in classic EDA-ID and can be a subtle developmental sign in
        selective mycobacterial presentations.
  - target: Hypodontia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Impaired ectodysplasin/NEMO-dependent appendage development provides the developmental
      explanation for this component. Expression varies between patients and the specific appendage-level
      steps were not measured in these families.
    evidence:
    - reference: DOI:10.1086/316914
      reference_title: A Novel X-Linked Disorder of Immune Deficiency and Hypohidrotic Ectodermal
        Dysplasia Is Allelic to Incontinentia Pigmenti and Due to Mutations in IKK-gamma (NEMO)
      supports: SUPPORT
      evidence_source: OTHER
      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: The authors developmental interpretation connects the shared appendage phenotype
        to IKK signaling.
      directness: INDIRECT
    - reference: DOI:10.1086/316914
      reference_title: A Novel X-Linked Disorder of Immune Deficiency and Hypohidrotic Ectodermal
        Dysplasia Is Allelic to Incontinentia Pigmenti and Due to Mutations in IKK-gamma (NEMO)
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: He had conical-shaped incisors, hypodontia (missing four of his permanent teeth),
        and normal scalp hair
      explanation: Four absent permanent teeth were documented in family 1 III-2. More extensive
        tooth agenesis in other patients is represented as oligodontia.
  - target: Oligodontia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Impaired ectodysplasin/NEMO-dependent appendage development provides the developmental
      explanation for this component. Expression varies between patients and the specific appendage-level
      steps were not measured in these families.
    evidence:
    - reference: DOI:10.1086/316914
      reference_title: A Novel X-Linked Disorder of Immune Deficiency and Hypohidrotic Ectodermal
        Dysplasia Is Allelic to Incontinentia Pigmenti and Due to Mutations in IKK-gamma (NEMO)
      supports: SUPPORT
      evidence_source: OTHER
      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: The authors developmental interpretation connects the shared appendage phenotype
        to IKK signaling.
      directness: INDIRECT
    - reference: DOI:10.1086/316914
      reference_title: A Novel X-Linked Disorder of Immune Deficiency and Hypohidrotic Ectodermal
        Dysplasia Is Allelic to Incontinentia Pigmenti and Due to Mutations in IKK-gamma (NEMO)
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Dental examination at age 12 years showed absence of seven teeth from his secondary
        dentition, on dental radiographs, as well as conical-shaped maxillary lateral incisors.
      explanation: Seven missing permanent teeth were documented in family 1 III-1, supporting oligodontia
        rather than only nonspecific abnormal dentition.
- name: Impaired osteoclast maturation
  description: The proposed skeletal route is reduced RANK/NF-kappaB-dependent osteoclast maturation
    and bone resorption. Human OL-EDA-ID observations and related NF-kappaB/RANK knockout models
    support the attribution, but the cited models do not directly measure osteoclast function for
    every patient variant.
  evidence:
  - reference: DOI:10.1086/316914
    reference_title: A Novel X-Linked Disorder of Immune Deficiency and Hypohidrotic Ectodermal Dysplasia
      Is Allelic to Incontinentia Pigmenti and Due to Mutations in IKK-gamma (NEMO)
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Furthermore, a double p50/p52 knockout in mice blocks both B-cell and osteoclast maturation,
      the latter causing osteopetrosis
    explanation: The cited mouse experiments supply indirect support for the osteoclast route; they
      are not a NEMO patient assay.
    directness: INDIRECT
  downstream:
  - target: Osteopetrosis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: This source-supported pathway remains qualified by model translation or tissue-specific
      evidence; it is not merely an anatomical restatement of the clinical finding.
    evidence:
    - reference: DOI:10.1086/316914
      reference_title: A Novel X-Linked Disorder of Immune Deficiency and Hypohidrotic Ectodermal
        Dysplasia Is Allelic to Incontinentia Pigmenti and Due to Mutations in IKK-gamma (NEMO)
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Furthermore, a double p50/p52 knockout in mice blocks both B-cell and osteoclast maturation,
        the latter causing osteopetrosis
      explanation: The cited mouse experiments supply indirect support for the osteoclast route;
        they are not a NEMO patient assay.
      directness: INDIRECT
    - reference: PMID:11242109
      reference_title: X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by
        impaired NF-kappaB signaling.
      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: A subset manifestation, including OL-EDA-ID; neither finding is obligatory in
        IKBKG immunodeficiency.
- name: Impaired lymphatic developmental signaling
  description: Lymphedema in OL-EDA-ID has been attributed to impaired VEGFR3/NF-kappaB-dependent
    lymphatic development. This is a qualified pathway attribution based on the human syndrome and
    related signaling biology, not direct measurement of lymphatic vessel development in each affected
    person.
  evidence:
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC5609334/
    reference_title: Hematopoietic stem cell transplantation in 29 patients hemizygous for hypomorphic
      IKBKG/NEMO mutations - PMC
    supports: SUPPORT
    evidence_source: OTHER
    snippet: lymphedema from changes to the vascular endothelial growth factor-3 pathway
    explanation: The authors summarize the proposed nonhematopoietic lymphatic route.
    directness: INDIRECT
  downstream:
  - target: Lymphedema
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: This source-supported pathway remains qualified by model translation or tissue-specific
      evidence; it is not merely an anatomical restatement of the clinical finding.
    evidence:
    - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC5609334/
      reference_title: Hematopoietic stem cell transplantation in 29 patients hemizygous for hypomorphic
        IKBKG/NEMO mutations - PMC
      supports: SUPPORT
      evidence_source: OTHER
      snippet: lymphedema from changes to the vascular endothelial growth factor-3 pathway
      explanation: The authors summarize the proposed nonhematopoietic lymphatic route.
      directness: INDIRECT
    - reference: PMID:11242109
      reference_title: X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by
        impaired NF-kappaB signaling.
      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: A subset manifestation, including OL-EDA-ID; neither finding is obligatory in
        IKBKG immunodeficiency.
- name: Intestinal epithelial barrier dysfunction
  description: 'An epithelial contribution to NEMO-associated colitis is supported by persistent
    or new colitis after HSCT, compartment-specific p65 staining in one patient biopsy, and intestinal
    epithelial knockout models. This is a qualified mechanism: infection, including CMV, can aggravate
    colitis and some patients improve after HSCT.'
  evidence:
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC5609334/
    reference_title: Hematopoietic stem cell transplantation in 29 patients hemizygous for hypomorphic
      IKBKG/NEMO mutations - PMC
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: gut-infiltrating immune cells were strongly stained for nuclear p65, indicating normal
      NEMO function, whereas intestinal epithelial cells had no nuclear p65, suggesting the possible
      involvement of an intrinsic NF-κB signaling defect in intestinal epithelial cells.
    explanation: The P7 gut biopsy provides a human tissue observation with a qualified epithelial
      interpretation; it does not prove a uniform cause of all colitis.
    directness: INDIRECT
  downstream:
  - target: Colitis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: This source-supported pathway remains qualified by model translation or tissue-specific
      evidence; it is not merely an anatomical restatement of the clinical finding.
    evidence:
    - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC5609334/
      reference_title: Hematopoietic stem cell transplantation in 29 patients hemizygous for hypomorphic
        IKBKG/NEMO mutations - PMC
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: gut-infiltrating immune cells were strongly stained for nuclear p65, indicating normal
        NEMO function, whereas intestinal epithelial cells had no nuclear p65, suggesting the possible
        involvement of an intrinsic NF-κB signaling defect in intestinal epithelial cells.
      explanation: The P7 gut biopsy provides a human tissue observation with a qualified epithelial
        interpretation; it does not prove a uniform cause of all colitis.
      directness: INDIRECT
    - reference: PMID:33598805
      reference_title: 'EDA-ID: a Severe Clinical Presentation Associated with a New IKBKG Mutation.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: However, the colitis was probably aggravated by the persistent CMV infection.
      explanation: Inflammatory colitis is variably present and can persist after immune reconstitution.
        In the Thr164Pro infant, persistent CMV was a likely aggravating factor.
phenotypes:
- name: Recurrent infections
  category: Immunological
  description: Recurrent infections may be severe and continue despite immunoglobulin replacement.
    Organisms and onset vary; this is not universal infection in every genetically diagnosed infant.
  phenotype_term:
    preferred_term: Recurrent infections
    term:
      id: HP:0002719
      label: Recurrent infections
  evidence:
  - reference: DOI:10.1086/316914
    reference_title: A Novel X-Linked Disorder of Immune Deficiency and Hypohidrotic Ectodermal Dysplasia
      Is Allelic to Incontinentia Pigmenti and Due to Mutations in IKK-gamma (NEMO)
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Affected males manifest dysgammaglobulinemia and, despite therapy, have significant
      morbidity and mortality from recurrent infections.
    explanation: Recurrent infections may be severe and continue despite immunoglobulin replacement.
      Organisms and onset vary; this is not universal infection in every genetically diagnosed infant.
- name: Hypogammaglobulinemia
  category: Immunological
  description: Reported in 24/41 evaluable individuals in the retrospective Hanson compilation; normal
    immunoglobulin levels also occur. The tested subset is not a population prevalence estimate.
  phenotype_term:
    preferred_term: Decreased circulating immunoglobulin concentration
    term:
      id: HP:0004313
      label: Decreased circulating immunoglobulin concentration
  evidence:
  - reference: PMID:18851874
    reference_title: Hypomorphic nuclear factor-kappaB essential modulator mutation database and
      reconstitution system identifies phenotypic and immunologic diversity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Hypogammaglobulinemia occurred in 24/41 (59%), but correlated with impaired CD40 signaling
      only in Zinc Finger mutations.
    explanation: Reported in 24/41 evaluable individuals in the retrospective Hanson compilation;
      normal immunoglobulin levels also occur. The tested subset is not a population prevalence estimate.
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1112/
    reference_title: Hypohidrotic Ectodermal Dysplasia - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: IKBKG ... Hypohidrotic ectodermal dysplasia w/immunodeficiency ... XL ... Sparse hair
      ... Hypohidrosis ... Hypodontia ... Impaired immune function w/risk for recurrent infections,
      hypogammaglobulinemia, T cell dysfunction
    explanation: The GeneReviews differential table explicitly lists hypogammaglobulinemia for IKBKG-associated
      HED with immunodeficiency; frequencies and other-gene findings are not transferred.
- name: Recurrent mycobacterial infections
  category: Immunological
  description: Recurrent or disseminated mycobacterial disease occurs in classic EDA-ID and in selective
    E315A/R319Q presentations. The historical approximately 40% figure comes from selected reported
    cases. Presumed tuberculosis in two European probands lacked culture confirmation; M. bovis is
    in the tuberculosis complex.
  phenotype_term:
    preferred_term: Recurrent mycobacterial infections
    term:
      id: HP:0011274
      label: Recurrent mycobacterial infections
  evidence:
  - reference: PMID:16818673
    reference_title: X-linked susceptibility to mycobacteria is caused by mutations in NEMO impairing
      CD40-dependent IL-12 production.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: One of our patients with EM disease (II.4 in kindred A) also suffered from miliary tuberculosis
      in childhood, and two of our probands (P2 and P3) probably suffered from tuberculosis, as the
      sole infectious phenotype suggested by consistent histological results and strongly positive
      tuberculin skin tests.
    explanation: Recurrent or disseminated mycobacterial disease occurs in classic EDA-ID and in
      selective E315A/R319Q presentations. The historical approximately 40% figure comes from selected
      reported cases. Presumed tuberculosis in two European probands lacked culture confirmation;
      M. bovis is in the tuberculosis complex.
  sequelae:
  - target: Seizures
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: The seizure attribution is limited to the patient with an M. avium brain lesion;
      cerebral infection is a known omitted intermediate, not an intrinsic NEMO epilepsy mechanism.
    evidence:
    - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC5609334/
      reference_title: Hematopoietic stem cell transplantation in 29 patients hemizygous for hypomorphic
        IKBKG/NEMO mutations - PMC
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Seizures ... M avium ... brain lesion), lupus anticoagulant
      explanation: One patient in the pre-HSCT cohort had seizures with an M. avium brain lesion.
        This replaces the former IP-derived assertion and does not imply a primary IKBKG epilepsy
        syndrome.
- name: Anhidrosis
  category: Dermatological
  description: Complete inability to sweat was reported in affected males; other patients retain
    reduced sweating and are represented separately as hypohidrosis.
  phenotype_term:
    preferred_term: Anhidrosis
    term:
      id: HP:0000970
      label: Anhidrosis
  evidence:
  - reference: DOI:10.1086/316914
    reference_title: A Novel X-Linked Disorder of Immune Deficiency and Hypohidrotic Ectodermal Dysplasia
      Is Allelic to Incontinentia Pigmenti and Due to Mutations in IKK-gamma (NEMO)
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: An inability to sweat had been noted since infancy, requiring lifelong cooling measures.
    explanation: Complete inability to sweat was reported in affected males; other patients retain
      reduced sweating and are represented separately as hypohidrosis.
- name: Sparse scalp hair
  category: Dermatological
  description: Sparse scalp hair occurs in EDA-ID, but normal scalp hair was also documented within
    the original families.
  phenotype_term:
    preferred_term: Sparse scalp hair
    term:
      id: HP:0002209
      label: Sparse scalp hair
  evidence:
  - reference: DOI:10.1086/316914
    reference_title: A Novel X-Linked Disorder of Immune Deficiency and Hypohidrotic Ectodermal Dysplasia
      Is Allelic to Incontinentia Pigmenti and Due to Mutations in IKK-gamma (NEMO)
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: He was noted to have reduced sweating, thin sparse scalp hair and eyebrows, and mild
      frontal bossing
    explanation: Sparse scalp hair occurs in EDA-ID, but normal scalp hair was also documented within
      the original families.
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1112/
    reference_title: Hypohidrotic Ectodermal Dysplasia - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: IKBKG ... Hypohidrotic ectodermal dysplasia w/immunodeficiency ... XL ... Sparse hair
      ... Hypohidrosis ... Hypodontia ... Impaired immune function w/risk for recurrent infections,
      hypogammaglobulinemia, T cell dysfunction
    explanation: The GeneReviews differential table explicitly lists sparse hair for IKBKG-associated
      HED with immunodeficiency; frequencies and other-gene findings are not transferred.
- name: Conical teeth
  category: Dental
  description: Conical teeth occur in classic EDA-ID and can be a subtle developmental sign in selective
    mycobacterial presentations.
  phenotype_term:
    preferred_term: Conical tooth
    term:
      id: HP:0000698
      label: Conical tooth
  evidence:
  - reference: DOI:10.1086/316914
    reference_title: A Novel X-Linked Disorder of Immune Deficiency and Hypohidrotic Ectodermal Dysplasia
      Is Allelic to Incontinentia Pigmenti and Due to Mutations in IKK-gamma (NEMO)
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: He had conical-shaped incisors, hypodontia (missing four of his permanent teeth), and
      normal scalp hair
    explanation: Conical teeth occur in classic EDA-ID and can be a subtle developmental sign in
      selective mycobacterial presentations.
- name: Colitis
  category: Gastrointestinal
  description: Inflammatory colitis is variably present and can persist after immune reconstitution.
    In the Thr164Pro infant, persistent CMV was a likely aggravating factor.
  phenotype_term:
    preferred_term: Colitis
    term:
      id: HP:0002583
      label: Colitis
  evidence:
  - reference: PMID:33598805
    reference_title: 'EDA-ID: a Severe Clinical Presentation Associated with a New IKBKG Mutation.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: However, the colitis was probably aggravated by the persistent CMV infection.
    explanation: Inflammatory colitis is variably present and can persist after immune reconstitution.
      In the Thr164Pro infant, persistent CMV was a likely aggravating factor.
  sequelae:
  - target: Diarrhea
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Inflammatory bowel disease, probably aggravated by CMV in the reported infant, produced
      these gastrointestinal and nutritional manifestations.
    evidence:
    - reference: PMID:33598805
      reference_title: 'EDA-ID: a Severe Clinical Presentation Associated with a New IKBKG Mutation.'
      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: The clinical narrative explicitly identifies this finding as an inflammatory bowel
        symptom; CMV is retained as a probable aggravating factor.
  - target: Failure to thrive
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Inflammatory bowel disease, probably aggravated by CMV in the reported infant, produced
      these gastrointestinal and nutritional manifestations.
    evidence:
    - reference: PMID:33598805
      reference_title: 'EDA-ID: a Severe Clinical Presentation Associated with a New IKBKG Mutation.'
      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: The clinical narrative explicitly identifies this finding as an inflammatory bowel
        symptom; CMV is retained as a probable aggravating factor.
  - target: Feeding difficulties in infancy
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Inflammatory bowel disease, probably aggravated by CMV in the reported infant, produced
      these gastrointestinal and nutritional manifestations.
    evidence:
    - reference: PMID:33598805
      reference_title: 'EDA-ID: a Severe Clinical Presentation Associated with a New IKBKG Mutation.'
      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: The clinical narrative explicitly identifies this finding as an inflammatory bowel
        symptom; CMV is retained as a probable aggravating factor.
- name: Bronchiectasis
  category: Respiratory
  description: Bronchiectasis is directly documented after chronic pulmonary infections, including
    in the original families and in patients without overt ectodermal dysplasia.
  phenotype_term:
    preferred_term: Bronchiectasis
    term:
      id: HP:0002110
      label: Bronchiectasis
  evidence:
  - reference: DOI:10.1086/316914
    reference_title: A Novel X-Linked Disorder of Immune Deficiency and Hypohidrotic Ectodermal Dysplasia
      Is Allelic to Incontinentia Pigmenti and Due to Mutations in IKK-gamma (NEMO)
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Despite therapy, he has had chronic lung infections with resultant bronchiectasis and
      pulmonary insufficiency.
    explanation: Bronchiectasis is directly documented after chronic pulmonary infections, including
      in the original families and in patients without overt ectodermal dysplasia.
- name: Failure to thrive
  category: Growth
  description: Failure to thrive occurred with inflammatory bowel symptoms and feeding intolerance
    in the Thr164Pro infant; it was also observed in the adolescent without ectodermal dysplasia.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:33598805
    reference_title: 'EDA-ID: a Severe Clinical Presentation Associated with a New IKBKG Mutation.'
    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 occurred with inflammatory bowel symptoms and feeding intolerance
      in the Thr164Pro infant; it was also observed in the adolescent without ectodermal dysplasia.
- name: Osteopetrosis
  category: Musculoskeletal
  description: A subset manifestation, including OL-EDA-ID; neither finding is obligatory in IKBKG
    immunodeficiency.
  phenotype_term:
    preferred_term: Osteopetrosis
    term:
      id: HP:0011002
      label: Osteopetrosis
  evidence:
  - reference: PMID:11242109
    reference_title: X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by
      impaired NF-kappaB signaling.
    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: A subset manifestation, including OL-EDA-ID; neither finding is obligatory in IKBKG
      immunodeficiency.
- name: Lymphedema
  category: Vascular
  description: A subset manifestation, including OL-EDA-ID; neither finding is obligatory in IKBKG
    immunodeficiency.
  phenotype_term:
    preferred_term: Lymphedema
    term:
      id: HP:0001004
      label: Lymphedema
  evidence:
  - reference: PMID:11242109
    reference_title: X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by
      impaired NF-kappaB signaling.
    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: A subset manifestation, including OL-EDA-ID; neither finding is obligatory in IKBKG
      immunodeficiency.
- name: Seizures
  category: Neurological
  description: One patient in the pre-HSCT cohort had seizures with an M. avium brain lesion. This
    replaces the former IP-derived assertion and does not imply a primary IKBKG epilepsy syndrome.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC5609334/
    reference_title: Hematopoietic stem cell transplantation in 29 patients hemizygous for hypomorphic
      IKBKG/NEMO mutations - PMC
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Seizures ... M avium ... brain lesion), lupus anticoagulant
    explanation: One patient in the pre-HSCT cohort had seizures with an M. avium brain lesion. This
      replaces the former IP-derived assertion and does not imply a primary IKBKG epilepsy syndrome.
- name: Hypohidrosis
  category: Dermatological
  description: Reduced sweating is distinct from complete anhidrosis; quantitative sweat testing
    in one original family showed very low sweat production.
  phenotype_term:
    preferred_term: Hypohidrosis
    term:
      id: HP:0000966
      label: Hypohidrosis
  evidence:
  - reference: DOI:10.1086/316914
    reference_title: A Novel X-Linked Disorder of Immune Deficiency and Hypohidrotic Ectodermal Dysplasia
      Is Allelic to Incontinentia Pigmenti and Due to Mutations in IKK-gamma (NEMO)
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Similar to his brother, he had very low amounts of sweat on a quantitative sweat test.
    explanation: Reduced sweating is distinct from complete anhidrosis; quantitative sweat testing
      in one original family showed very low sweat production.
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1112/
    reference_title: Hypohidrotic Ectodermal Dysplasia - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: IKBKG ... Hypohidrotic ectodermal dysplasia w/immunodeficiency ... XL ... Sparse hair
      ... Hypohidrosis ... Hypodontia ... Impaired immune function w/risk for recurrent infections,
      hypogammaglobulinemia, T cell dysfunction
    explanation: The GeneReviews differential table explicitly lists hypohidrosis for IKBKG-associated
      HED with immunodeficiency; frequencies and other-gene findings are not transferred.
- name: Hypodontia
  category: Dental
  description: Four absent permanent teeth were documented in family 1 III-2. More extensive tooth
    agenesis in other patients is represented as oligodontia.
  phenotype_term:
    preferred_term: Hypodontia
    term:
      id: HP:0000668
      label: Hypodontia
  evidence:
  - reference: DOI:10.1086/316914
    reference_title: A Novel X-Linked Disorder of Immune Deficiency and Hypohidrotic Ectodermal Dysplasia
      Is Allelic to Incontinentia Pigmenti and Due to Mutations in IKK-gamma (NEMO)
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: He had conical-shaped incisors, hypodontia (missing four of his permanent teeth), and
      normal scalp hair
    explanation: Four absent permanent teeth were documented in family 1 III-2. More extensive tooth
      agenesis in other patients is represented as oligodontia.
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1112/
    reference_title: Hypohidrotic Ectodermal Dysplasia - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: IKBKG ... Hypohidrotic ectodermal dysplasia w/immunodeficiency ... XL ... Sparse hair
      ... Hypohidrosis ... Hypodontia ... Impaired immune function w/risk for recurrent infections,
      hypogammaglobulinemia, T cell dysfunction
    explanation: The GeneReviews differential table explicitly lists hypodontia for IKBKG-associated
      HED with immunodeficiency; frequencies and other-gene findings are not transferred.
- name: Oligodontia
  category: Dental
  description: Seven missing permanent teeth were documented in family 1 III-1, supporting oligodontia
    rather than only nonspecific abnormal dentition.
  phenotype_term:
    preferred_term: Oligodontia
    term:
      id: HP:0000677
      label: Oligodontia
  evidence:
  - reference: DOI:10.1086/316914
    reference_title: A Novel X-Linked Disorder of Immune Deficiency and Hypohidrotic Ectodermal Dysplasia
      Is Allelic to Incontinentia Pigmenti and Due to Mutations in IKK-gamma (NEMO)
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Dental examination at age 12 years showed absence of seven teeth from his secondary
      dentition, on dental radiographs, as well as conical-shaped maxillary lateral incisors.
    explanation: Seven missing permanent teeth were documented in family 1 III-1, supporting oligodontia
      rather than only nonspecific abnormal dentition.
- name: Sparse eyebrows
  category: Dermatological
  description: Sparse eyebrows were observed in family 4 III-1; the observation is case-scoped.
  phenotype_term:
    preferred_term: Sparse eyebrow
    term:
      id: HP:0045075
      label: Sparse eyebrow
  evidence:
  - reference: DOI:10.1086/316914
    reference_title: A Novel X-Linked Disorder of Immune Deficiency and Hypohidrotic Ectodermal Dysplasia
      Is Allelic to Incontinentia Pigmenti and Due to Mutations in IKK-gamma (NEMO)
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: He was noted to have reduced sweating, thin sparse scalp hair and eyebrows, and mild
      frontal bossing
    explanation: Sparse eyebrows were observed in family 4 III-1; the observation is case-scoped.
- name: Frontal bossing
  category: Craniofacial
  description: Mild frontal bossing was described in family 4 III-1; no frequency or specific cranial
    mechanism is established.
  phenotype_term:
    preferred_term: Frontal bossing
    term:
      id: HP:0002007
      label: Frontal bossing
  evidence:
  - reference: DOI:10.1086/316914
    reference_title: A Novel X-Linked Disorder of Immune Deficiency and Hypohidrotic Ectodermal Dysplasia
      Is Allelic to Incontinentia Pigmenti and Due to Mutations in IKK-gamma (NEMO)
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: He was noted to have reduced sweating, thin sparse scalp hair and eyebrows, and mild
      frontal bossing
    explanation: Mild frontal bossing was described in family 4 III-1; no frequency or specific cranial
      mechanism is established.
- name: Dry skin
  category: Dermatological
  description: Dry skin was observed in the Thr164Pro infant.
  phenotype_term:
    preferred_term: Dry skin
    term:
      id: HP:0000958
      label: Dry skin
  evidence:
  - reference: PMID:33598805
    reference_title: 'EDA-ID: a Severe Clinical Presentation Associated with a New IKBKG Mutation.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 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: Dry skin was observed in the Thr164Pro infant.
- name: Ichthyosis
  category: Dermatological
  description: Abdominal ichthyosis was reported in the Thr164Pro infant.
  phenotype_term:
    preferred_term: Ichthyosis
    term:
      id: HP:0008064
      label: Ichthyosis
  evidence:
  - reference: PMID:33598805
    reference_title: 'EDA-ID: a Severe Clinical Presentation Associated with a New IKBKG Mutation.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 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: Abdominal ichthyosis was reported in the Thr164Pro infant.
- name: Eczematoid dermatitis
  category: Dermatological
  description: Eczematous dermatitis occurs in NEMO deficiency and was observed in the Thr164Pro
    infant and in the pre-HSCT cohort.
  phenotype_term:
    preferred_term: Eczematoid dermatitis
    term:
      id: HP:0000964
      label: Eczematoid dermatitis
  evidence:
  - reference: PMID:33598805
    reference_title: 'EDA-ID: a Severe Clinical Presentation Associated with a New IKBKG Mutation.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 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: Eczematous dermatitis occurs in NEMO deficiency and was observed in the Thr164Pro
      infant and in the pre-HSCT cohort.
  - reference: url:https://oup.silverchair-cdn.com/article-minimal/6625140
    reference_title: https://oup.silverchair-cdn.com/article-minimal/6625140
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We report a case of intractable eczematous eruption in a patient with EDA‐ID, which
      disappeared completely after allogenic transplantation of umbilical‐cord blood.
    explanation: The c.1167insC case improved after hematopoietic replacement, supporting an immune-cell
      contribution to eczema by intervention. This is an indirect, single-case inference; the accessible
      publisher extract does not resolve individual immune intermediates.
    directness: INDIRECT
- name: Increased circulating IgM
  category: Immunological
  description: Elevated IgM occurs in a subset; the Thr164Pro infant had 4.6 g/L. A hyper-IgM syndrome
    label does not establish elevated IgM in every patient.
  phenotype_term:
    preferred_term: Increased circulating IgM level
    term:
      id: HP:0003496
      label: Increased circulating IgM level
  evidence:
  - reference: PMID:33598805
    reference_title: 'EDA-ID: a Severe Clinical Presentation Associated with a New IKBKG Mutation.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: increased IgM levels at 4.6 g/L (0.26 −1), normal B cells differentiation and a slightly
      decreased of CD40L expression level.
    explanation: Elevated IgM occurs in a subset; the Thr164Pro infant had 4.6 g/L. A hyper-IgM syndrome
      label does not establish elevated IgM in every patient.
  - reference: DOI:10.1086/316914
    reference_title: A Novel X-Linked Disorder of Immune Deficiency and Hypohidrotic Ectodermal Dysplasia
      Is Allelic to Incontinentia Pigmenti and Due to Mutations in IKK-gamma (NEMO)
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Immunoglobulin levels at age 10 mo showed abnormally low levels of IgG (<200 mg/dl (normal
      range 294–1,069 mg/dl)), low-to-normal levels of IgA, and elevated levels of IgM (1,100 mg/dl
      (normal range 41–149 mg/dl)).
    explanation: Family 1 carries C417R; the untreated IgM elevation supports the zinc-finger-associated
      humoral phenotype independently of the Thr164Pro infant.
- name: Decreased circulating IgG
  category: Immunological
  description: Low IgG was measured before replacement in original EDA-ID patients; values obtained
    during IVIG should not be interpreted as untreated concentrations.
  phenotype_term:
    preferred_term: Decreased circulating IgG concentration
    term:
      id: HP:0004315
      label: Decreased circulating IgG concentration
  evidence:
  - reference: DOI:10.1086/316914
    reference_title: A Novel X-Linked Disorder of Immune Deficiency and Hypohidrotic Ectodermal Dysplasia
      Is Allelic to Incontinentia Pigmenti and Due to Mutations in IKK-gamma (NEMO)
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Immunoglobulin levels at age 10 mo showed abnormally low levels of IgG (<200 mg/dl (normal
      range 294–1,069 mg/dl)), low-to-normal levels of IgA, and elevated levels of IgM (1,100 mg/dl
      (normal range 41–149 mg/dl)).
    explanation: Low IgG was measured before replacement in original EDA-ID patients; values obtained
      during IVIG should not be interpreted as untreated concentrations.
- name: Decreased circulating IgA
  category: Immunological
  description: Low IgA was reported before HSCT in patient P16; IgA can instead be elevated in other
    IKBKG genotypes.
  phenotype_term:
    preferred_term: Decreased circulating IgA concentration
    term:
      id: HP:0002720
      label: Decreased circulating IgA concentration
  evidence:
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC5609334/
    reference_title: Hematopoietic stem cell transplantation in 29 patients hemizygous for hypomorphic
      IKBKG/NEMO mutations - PMC
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 16 ... P jirovecii ... CMV, rotavirus ... Low IgA
    explanation: Low IgA was reported before HSCT in patient P16; IgA can instead be elevated in
      other IKBKG genotypes.
  - reference: PMID:15578091
    reference_title: Specific NEMO mutations impair CD40-mediated c-Rel activation and B cell terminal
      differentiation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: IgM IgG IgA IgM IgG IgA XHM-ED1 552 991 <10
    explanation: Table 2 lists IgA below 10 mg/dL in the first three, serum columns for XHM-ED1;
      the serum reference interval is 51–375 mg/dL. These are human blood values during IVIG, not
      the later culture-supernatant columns.
- name: Increased circulating IgA
  category: Immunological
  description: Both brothers with c.268delG had increased IgA for age, despite low IgM. The mechanism
    is not assumed to be the same as a classical switching defect.
  phenotype_term:
    preferred_term: Increased circulating IgA concentration
    term:
      id: HP:0003261
      label: Increased circulating IgA concentration
  evidence:
  - reference: PMID:39540818
    reference_title: Atypical Mycobacterial Pneumonia in 2 Siblings with a Novel Hypomorphic NEMO/IKBKG
      Mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Laboratory investigations revealed decreased serum IgM levels and increased IgA for
      his age.
    explanation: Both brothers with c.268delG had increased IgA for age, despite low IgM. The mechanism
      is not assumed to be the same as a classical switching defect.
- name: Decreased circulating IgM
  category: Immunological
  description: Both c.268delG brothers had low IgM; the authors state that the mechanism of this
    non-hyper-IgM presentation remains unclear.
  phenotype_term:
    preferred_term: Decreased circulating total IgM
    term:
      id: HP:0002850
      label: Decreased circulating total IgM
  evidence:
  - reference: PMID:39540818
    reference_title: Atypical Mycobacterial Pneumonia in 2 Siblings with a Novel Hypomorphic NEMO/IKBKG
      Mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Laboratory investigations revealed decreased serum IgM levels and increased IgA for
      his age.
    explanation: Both c.268delG brothers had low IgM; the authors state that the mechanism of this
      non-hyper-IgM presentation remains unclear.
- name: Impaired specific antibody response
  category: Immunological
  description: Defective specific antibody production was reported in 18/28 evaluated individuals
    in the retrospective compilation. Normal total immunoglobulin levels do not exclude this finding.
  phenotype_term:
    preferred_term: Impaired specific antibody response
    term:
      id: HP:0012475
      label: Impaired specific antibody response
  evidence:
  - reference: PMID:18851874
    reference_title: Hypomorphic nuclear factor-kappaB essential modulator mutation database and
      reconstitution system identifies phenotypic and immunologic diversity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Defects in specific antibody production occurred in 64% (18/28)
    explanation: Defective specific antibody production was reported in 18/28 evaluated individuals
      in the retrospective compilation. Normal total immunoglobulin levels do not exclude this finding.
- name: Decreased class-switched memory B-cell proportion
  category: Immunological
  description: The class-switched B-cell subset was reduced in both c.268delG brothers; P2 otherwise
    had normal T- and B-cell counts by the authors narrative.
  phenotype_term:
    preferred_term: Decreased class-switched memory B cell proportion
    term:
      id: HP:0030388
      label: Decreased class-switched memory B cell proportion
  evidence:
  - reference: PMID:39540818
    reference_title: Atypical Mycobacterial Pneumonia in 2 Siblings with a Novel Hypomorphic NEMO/IKBKG
      Mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: His class-switched B cell subset was decreased, with normal T and B cell counts.
    explanation: The class-switched B-cell subset was reduced in both c.268delG brothers; P2 otherwise
      had normal T- and B-cell counts by the authors narrative.
  - reference: PMID:15578091
    reference_title: Specific NEMO mutations impair CD40-mediated c-Rel activation and B cell terminal
      differentiation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: absence of IgD –CD27+ B cells, which are typical memory B cells.
    explanation: The C417 patient peripheral-blood analysis showed virtual absence of switched memory
      cells; this supports the maturation route independently of the later c.268delG family.
- name: Decreased total T-cell count
  category: Immunological
  description: T-cell reduction was reported in P1 of the c.268delG family. It is not generalized
    to all NEMO patients or to P2, whose narrative and borderline table value differ.
  phenotype_term:
    preferred_term: Decreased total T cell count
    term:
      id: HP:0005403
      label: Decreased total T cell count
  evidence:
  - reference: PMID:39540818
    reference_title: Atypical Mycobacterial Pneumonia in 2 Siblings with a Novel Hypomorphic NEMO/IKBKG
      Mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Flow cytometric immunophenotyping revealed decreased T cells and increased B cells,
      predominantly naive, with a decreased switched memory subset.
    explanation: T-cell reduction was reported in P1 of the c.268delG family. It is not generalized
      to all NEMO patients or to P2, whose narrative and borderline table value differ.
- name: Recurrent pneumonia
  category: Respiratory
  description: Recurrent pulmonary infections were documented in the original EDA-ID families.
  phenotype_term:
    preferred_term: Recurrent pneumonia
    term:
      id: HP:0006532
      label: Recurrent pneumonia
  evidence:
  - reference: DOI:10.1086/316914
    reference_title: A Novel X-Linked Disorder of Immune Deficiency and Hypohidrotic Ectodermal Dysplasia
      Is Allelic to Incontinentia Pigmenti and Due to Mutations in IKK-gamma (NEMO)
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: with recurrent infections and had repeated hospitalization for pneumonia and bacterial
      infections of both bone and soft tissues.
    explanation: Recurrent pulmonary infections were documented in the original EDA-ID families.
  sequelae:
  - target: Bronchiectasis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: The original clinical report explicitly attributes bronchiectasis and pulmonary
      insufficiency to chronic lung infections.
    evidence:
    - reference: DOI:10.1086/316914
      reference_title: A Novel X-Linked Disorder of Immune Deficiency and Hypohidrotic Ectodermal
        Dysplasia Is Allelic to Incontinentia Pigmenti and Due to Mutations in IKK-gamma (NEMO)
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Despite therapy, he has had chronic lung infections with resultant bronchiectasis
        and pulmonary insufficiency.
      explanation: The patient narrative supports this pulmonary consequence of chronic infection.
  - target: Respiratory insufficiency
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: The original clinical report explicitly attributes bronchiectasis and pulmonary
      insufficiency to chronic lung infections.
    evidence:
    - reference: DOI:10.1086/316914
      reference_title: A Novel X-Linked Disorder of Immune Deficiency and Hypohidrotic Ectodermal
        Dysplasia Is Allelic to Incontinentia Pigmenti and Due to Mutations in IKK-gamma (NEMO)
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Despite therapy, he has had chronic lung infections with resultant bronchiectasis
        and pulmonary insufficiency.
      explanation: The patient narrative supports this pulmonary consequence of chronic infection.
- name: Sepsis
  category: Immunological
  description: Sepsis occurred before transplantation, including early bacterial sepsis in the original
    family 4; post-HSCT sepsis is not counted as an untreated baseline frequency.
  phenotype_term:
    preferred_term: Sepsis
    term:
      id: HP:0100806
      label: Sepsis
  evidence:
  - reference: DOI:10.1086/316914
    reference_title: A Novel X-Linked Disorder of Immune Deficiency and Hypohidrotic Ectodermal Dysplasia
      Is Allelic to Incontinentia Pigmenti and Due to Mutations in IKK-gamma (NEMO)
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The proband's younger maternal half-brother (III-2) presented, at age 3 mo, with bacterial
      sepsis and meningitis.
    explanation: Sepsis occurred before transplantation, including early bacterial sepsis in the
      original family 4; post-HSCT sepsis is not counted as an untreated baseline frequency.
  sequelae:
  - target: Hemophagocytosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The source identifies secondary HLH during bacterial sepsis with resolution during
      infection recovery; the cytokine sequence was not separately measured.
    evidence:
    - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC5609334/
      reference_title: Hematopoietic stem cell transplantation in 29 patients hemizygous for hypomorphic
        IKBKG/NEMO mutations - PMC
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: P6 developed secondary hemophagocytic lymphohistiocytosis concomitantly with bacterial
        sepsis, which resolved with recovery from infection.
      explanation: Secondary hemophagocytic lymphohistiocytosis occurred with bacterial sepsis in
        P6 and resolved as infection recovered.
  - target: Acute respiratory distress syndrome
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: ARDS occurred during simultaneous S. aureus septicemia and pneumocystosis. Each
      edge denotes a contributing infection in that episode, not a demonstration that either pathogen
      alone was sufficient.
    evidence:
    - reference: PMID:33598805
      reference_title: 'EDA-ID: a Severe Clinical Presentation Associated with a New IKBKG Mutation.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: At 3 months, he presented with an acute respiratory distress syndrome with circulatory
        failure following a Staphylococcus aureus septicemia and pulmonary pneumocystosis.
      explanation: At three months the Thr164Pro infant developed ARDS with circulatory failure during
        S. aureus septicemia and pulmonary pneumocystosis, before HSCT.
- name: Pneumocystis pneumonia
  category: Respiratory
  description: Pneumocystis pneumonia was diagnosed in the Thr164Pro infant using nasopharyngeal
    PCR and compatible CT findings.
  phenotype_term:
    preferred_term: Pneumocystis jirovecii pneumonia
    term:
      id: HP:0020102
      label: Pneumocystis jirovecii pneumonia
  evidence:
  - reference: PMID:33598805
    reference_title: 'EDA-ID: a Severe Clinical Presentation Associated with a New IKBKG Mutation.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Pneumocystosis was diagnosed by nasopharyngeal PCR and typical CT scans and was treated
      with corticosteroids and trimethoprim/sulfamethoxazole.
    explanation: Pneumocystis pneumonia was diagnosed in the Thr164Pro infant using nasopharyngeal
      PCR and compatible CT findings.
  sequelae:
  - target: Acute respiratory distress syndrome
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: ARDS occurred during simultaneous S. aureus septicemia and pneumocystosis. Each
      edge denotes a contributing infection in that episode, not a demonstration that either pathogen
      alone was sufficient.
    evidence:
    - reference: PMID:33598805
      reference_title: 'EDA-ID: a Severe Clinical Presentation Associated with a New IKBKG Mutation.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: At 3 months, he presented with an acute respiratory distress syndrome with circulatory
        failure following a Staphylococcus aureus septicemia and pulmonary pneumocystosis.
      explanation: At three months the Thr164Pro infant developed ARDS with circulatory failure during
        S. aureus septicemia and pulmonary pneumocystosis, before HSCT.
- name: Chronic mucocutaneous candidiasis
  category: Immunological
  description: Recurrent mucocutaneous candidiasis was reported in the Thr164Pro infant.
  phenotype_term:
    preferred_term: Chronic mucocutaneous candidiasis
    term:
      id: HP:0002728
      label: Chronic mucocutaneous candidiasis
  evidence:
  - reference: PMID:33598805
    reference_title: 'EDA-ID: a Severe Clinical Presentation Associated with a New IKBKG Mutation.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: He had also recurrent muco-cutaneous Candidiasis.
    explanation: Recurrent mucocutaneous candidiasis was reported in the Thr164Pro infant.
- name: Respiratory insufficiency
  category: Respiratory
  description: Pulmonary insufficiency was documented with bronchiectasis following chronic lung
    infections in an original EDA-ID patient.
  phenotype_term:
    preferred_term: Respiratory insufficiency
    term:
      id: HP:0002093
      label: Respiratory insufficiency
  evidence:
  - reference: DOI:10.1086/316914
    reference_title: A Novel X-Linked Disorder of Immune Deficiency and Hypohidrotic Ectodermal Dysplasia
      Is Allelic to Incontinentia Pigmenti and Due to Mutations in IKK-gamma (NEMO)
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Despite therapy, he has had chronic lung infections with resultant bronchiectasis and
      pulmonary insufficiency.
    explanation: Pulmonary insufficiency was documented with bronchiectasis following chronic lung
      infections in an original EDA-ID patient.
- name: Diarrhea
  category: Gastrointestinal
  description: Reported among the inflammatory bowel symptoms of the Thr164Pro infant, requiring
    parenteral nutrition; CMV probably aggravated the colitis.
  phenotype_term:
    preferred_term: Diarrhea
    term:
      id: HP:0002014
      label: Diarrhea
  evidence:
  - reference: PMID:33598805
    reference_title: 'EDA-ID: a Severe Clinical Presentation Associated with a New IKBKG Mutation.'
    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: Reported among the inflammatory bowel symptoms of the Thr164Pro infant, requiring
      parenteral nutrition; CMV probably aggravated the colitis.
- name: Feeding difficulties in infancy
  category: Gastrointestinal
  description: Reported among the inflammatory bowel symptoms of the Thr164Pro infant, requiring
    parenteral nutrition; CMV probably aggravated the colitis.
  phenotype_term:
    preferred_term: Feeding difficulties in infancy
    term:
      id: HP:0008872
      label: Feeding difficulties in infancy
  evidence:
  - reference: PMID:33598805
    reference_title: 'EDA-ID: a Severe Clinical Presentation Associated with a New IKBKG Mutation.'
    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: Reported among the inflammatory bowel symptoms of the Thr164Pro infant, requiring
      parenteral nutrition; CMV probably aggravated the colitis.
- name: Intrauterine growth restriction
  category: Growth
  description: Intrauterine growth restriction was reported in the Thr164Pro infant. A specific prenatal
    growth mechanism was not established.
  phenotype_term:
    preferred_term: Intrauterine growth retardation
    term:
      id: HP:0001511
      label: Intrauterine growth retardation
  evidence:
  - reference: PMID:33598805
    reference_title: 'EDA-ID: a Severe Clinical Presentation Associated with a New IKBKG Mutation.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: He was born healthy but with harmonious intrauterine growth restriction.
    explanation: Intrauterine growth restriction was reported in the Thr164Pro infant. A specific
      prenatal growth mechanism was not established.
- name: Polyarticular arthritis
  category: Musculoskeletal
  description: Observed at age 14 in P1 with c.268delG, before immunosuppressive treatment; the authors
    did not establish the specific inflammatory pathway.
  phenotype_term:
    preferred_term: Polyarticular arthritis
    term:
      id: HP:0005764
      label: Polyarticular arthritis
  evidence:
  - reference: PMID:39540818
    reference_title: Atypical Mycobacterial Pneumonia in 2 Siblings with a Novel Hypomorphic NEMO/IKBKG
      Mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: At the age of 14, he developed polyarthritis and uveitis with negative autoantibodies
      but did not receive immunosuppressive treatment.
    explanation: Observed at age 14 in P1 with c.268delG, before immunosuppressive treatment; the
      authors did not establish the specific inflammatory pathway.
- name: Uveitis
  category: Ophthalmological
  description: Observed at age 14 in P1 with c.268delG, before immunosuppressive treatment; the authors
    did not establish the specific inflammatory pathway.
  phenotype_term:
    preferred_term: Uveitis
    term:
      id: HP:0000554
      label: Uveitis
  evidence:
  - reference: PMID:39540818
    reference_title: Atypical Mycobacterial Pneumonia in 2 Siblings with a Novel Hypomorphic NEMO/IKBKG
      Mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: At the age of 14, he developed polyarthritis and uveitis with negative autoantibodies
      but did not receive immunosuppressive treatment.
    explanation: Observed at age 14 in P1 with c.268delG, before immunosuppressive treatment; the
      authors did not establish the specific inflammatory pathway.
- name: Autoimmune hemolytic anemia
  category: Hematological
  description: Reported before HSCT in the selected transplant cohort. This is an occurrence record,
    not an inferred prevalence or a proven cell-specific autoimmune mechanism.
  phenotype_term:
    preferred_term: Autoimmune hemolytic anemia
    term:
      id: HP:0001890
      label: Autoimmune hemolytic anemia
  evidence:
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC5609334/
    reference_title: Hematopoietic stem cell transplantation in 29 patients hemizygous for hypomorphic
      IKBKG/NEMO mutations - PMC
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: hemolytic autoimmune anemia for P12 and P21
    explanation: Reported before HSCT in the selected transplant cohort. This is an occurrence record,
      not an inferred prevalence or a proven cell-specific autoimmune mechanism.
- name: Autoimmune thrombocytopenia
  category: Hematological
  description: Reported before HSCT in the selected transplant cohort. This is an occurrence record,
    not an inferred prevalence or a proven cell-specific autoimmune mechanism.
  phenotype_term:
    preferred_term: Autoimmune thrombocytopenia
    term:
      id: HP:0001973
      label: Autoimmune thrombocytopenia
  evidence:
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC5609334/
    reference_title: Hematopoietic stem cell transplantation in 29 patients hemizygous for hypomorphic
      IKBKG/NEMO mutations - PMC
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: immune thrombocytopenic purpura for P28
    explanation: Reported before HSCT in the selected transplant cohort. This is an occurrence record,
      not an inferred prevalence or a proven cell-specific autoimmune mechanism.
- name: Hashimoto thyroiditis
  category: Endocrine
  description: Reported before HSCT in the selected transplant cohort. This is an occurrence record,
    not an inferred prevalence or a proven cell-specific autoimmune mechanism.
  phenotype_term:
    preferred_term: Hashimoto thyroiditis
    term:
      id: HP:0000872
      label: Hashimoto thyroiditis
  evidence:
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC5609334/
    reference_title: Hematopoietic stem cell transplantation in 29 patients hemizygous for hypomorphic
      IKBKG/NEMO mutations - PMC
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'The following autoimmune additional features were observed: cytopenia (hemolytic autoimmune
      anemia for P12 and P21, and immune thrombocytopenic purpura for P28), lupus anticoagulant (asymptomatic,
      P22), and Hashimoto’s thyroiditis'
    explanation: Reported before HSCT in the selected transplant cohort. This is an occurrence record,
      not an inferred prevalence or a proven cell-specific autoimmune mechanism.
- name: Hemophagocytosis
  category: Hematological
  description: Secondary hemophagocytic lymphohistiocytosis occurred with bacterial sepsis in P6
    and resolved as infection recovered.
  phenotype_term:
    preferred_term: Hemophagocytosis
    term:
      id: HP:0012156
      label: Hemophagocytosis
  evidence:
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC5609334/
    reference_title: Hematopoietic stem cell transplantation in 29 patients hemizygous for hypomorphic
      IKBKG/NEMO mutations - PMC
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: P6 developed secondary hemophagocytic lymphohistiocytosis concomitantly with bacterial
      sepsis, which resolved with recovery from infection.
    explanation: Secondary hemophagocytic lymphohistiocytosis occurred with bacterial sepsis in P6
      and resolved as infection recovered.
- name: Neurodevelopmental delay
  category: Neurological
  description: Developmental delay was reported before HSCT in P6, together with subependymal calcifications.
    It is not attributed to the later post-HSCT VZV encephalitis or to IP.
  phenotype_term:
    preferred_term: Neurodevelopmental delay
    term:
      id: HP:0012758
      label: Neurodevelopmental delay
  evidence:
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC5609334/
    reference_title: Hematopoietic stem cell transplantation in 29 patients hemizygous for hypomorphic
      IKBKG/NEMO mutations - PMC
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: c.1167-1168insC ... Switzerland ... HLH, developmental delay, ... MGUS
    explanation: Developmental delay was reported before HSCT in P6, together with subependymal calcifications.
      It is not attributed to the later post-HSCT VZV encephalitis or to IP.
- name: Intracranial calcification
  category: Neurological
  description: The pre-HSCT P6 developmental-delay entry carried a footnote documenting subependymal
    calcifications on brain MRI.
  phenotype_term:
    preferred_term: Intracranial calcification
    term:
      id: HP:0430048
      label: Intracranial calcification
  evidence:
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC5609334/
    reference_title: Hematopoietic stem cell transplantation in 29 patients hemizygous for hypomorphic
      IKBKG/NEMO mutations - PMC
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Subependymal calcifications on brain MRI.
    explanation: The pre-HSCT P6 developmental-delay entry carried a footnote documenting subependymal
      calcifications on brain MRI.
- name: Delayed umbilical cord separation
  category: Immunological
  description: Reported before HSCT in P11; a specific NEMO-dependent leukocyte or tissue mechanism
    was not established.
  phenotype_term:
    preferred_term: Delayed umbilical cord separation
    term:
      id: HP:0032434
      label: Delayed umbilical cord separation
  evidence:
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC5609334/
    reference_title: Hematopoietic stem cell transplantation in 29 patients hemizygous for hypomorphic
      IKBKG/NEMO mutations - PMC
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: c.1167_1168insC ... UK ... Delayed umbilical cord separation
    explanation: Reported before HSCT in P11; a specific NEMO-dependent leukocyte or tissue mechanism
      was not established.
- name: Decreased circulating IgE
  category: Immunological
  description: Diminished serum IgE was part of the clinical definition in three C417-mutant patients.
    This is separate from failure of stimulated cultured B cells to secrete IgE.
  phenotype_term:
    preferred_term: Decreased circulating IgE concentration
    term:
      id: HP:0005479
      label: Decreased circulating IgE concentration
  evidence:
  - reference: PMID:15578091
    reference_title: Specific NEMO mutations impair CD40-mediated c-Rel activation and B cell terminal
      differentiation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      defined by markedly dimin-
      ished serum levels of IgG and IgE and normal or elevated levels
      of serum IgM (Tables 1 and 2).
    explanation: Diminished serum IgE was part of the clinical definition in three C417-mutant patients.
      This is separate from failure of stimulated cultured B cells to secrete IgE.
- name: Hyperpigmented skin
  category: Dermatological
  description: The Thr164Pro infant had darker skin areas; these are distinct from the maternal linear
    Blaschko pigmentation of IP.
  phenotype_term:
    preferred_term: Hyperpigmentation of the skin
    term:
      id: HP:0000953
      label: Hyperpigmentation of the skin
  evidence:
  - reference: PMID:33598805
    reference_title: 'EDA-ID: a Severe Clinical Presentation Associated with a New IKBKG Mutation.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 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: The Thr164Pro infant had darker skin areas; these are distinct from the maternal
      linear Blaschko pigmentation of IP.
- name: Acute respiratory distress syndrome
  category: Respiratory
  description: At three months the Thr164Pro infant developed ARDS with circulatory failure during
    S. aureus septicemia and pulmonary pneumocystosis, before HSCT.
  phenotype_term:
    preferred_term: Acute respiratory distress syndrome
    term:
      id: HP:0033677
      label: Acute respiratory distress syndrome
  evidence:
  - reference: PMID:33598805
    reference_title: 'EDA-ID: a Severe Clinical Presentation Associated with a New IKBKG Mutation.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: At 3 months, he presented with an acute respiratory distress syndrome with circulatory
      failure following a Staphylococcus aureus septicemia and pulmonary pneumocystosis.
    explanation: At three months the Thr164Pro infant developed ARDS with circulatory failure during
      S. aureus septicemia and pulmonary pneumocystosis, before HSCT.
- name: Severe cytomegalovirus infection
  category: Immunological
  description: The Thr164Pro infant had prolonged CMV viremia before HSCT, requiring escalation from
    valganciclovir to ganciclovir; later post-HSCT infections are not used as baseline frequency
    evidence.
  phenotype_term:
    preferred_term: Severe cytomegalovirus infection
    term:
      id: HP:0031692
      label: Severe cytomegalovirus infection
  evidence:
  - reference: PMID:33598805
    reference_title: 'EDA-ID: a Severe Clinical Presentation Associated with a New IKBKG Mutation.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Moreover, he had cytomegalovirus (CMV) viremia which was not controlled with Valganciclovir
      and Ganciclovir was introduced
    explanation: The Thr164Pro infant had prolonged CMV viremia before HSCT, requiring escalation
      from valganciclovir to ganciclovir; later post-HSCT infections are not used as baseline frequency
      evidence.
  sequelae:
  - target: Colitis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Persistent CMV infection probably exacerbated colitis in the Thr164Pro infant. This
      is the authors’ case-specific clinical interpretation; the intervening tissue mechanisms were
      not demonstrated.
    evidence:
    - reference: PMID:33598805
      reference_title: 'EDA-ID: a Severe Clinical Presentation Associated with a New IKBKG Mutation.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: However, the colitis was probably aggravated by the persistent CMV infection.
      explanation: Supports a probable aggravating contribution of persistent CMV, not CMV as the
        sole or established cause of NEMO-associated colitis.
      directness: INDIRECT
genetic:
- name: Hypomorphic IKBKG variants
  gene_term:
    preferred_term: IKBKG
    term:
      id: hgnc:5961
      label: IKBKG
  variants:
  - name: Hypomorphic IKBKG variants
    description: Missense, nonsense, frameshift and splice variants can cause immunodeficiency through
      residual or selectively impaired NEMO signaling. Variant class alone does not establish residual
      function or predict the full clinical phenotype.
    gene:
      preferred_term: IKBKG
      term:
        id: hgnc:5961
        label: IKBKG
  evidence:
  - 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.
  - *id001
  - reference: DOI:10.1086/316914
    reference_title: A Novel X-Linked Disorder of Immune Deficiency and Hypohidrotic Ectodermal Dysplasia
      Is Allelic to Incontinentia Pigmenti and Due to Mutations in IKK-gamma (NEMO)
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Mutations in families 2 and 4 produce a nonsense mutation at codon 391 (E391X) and a
      frameshift at codon 390, respectively, within the carboxy-terminal end of the 419-amino-acid
      protein.
    explanation: The original immunodeficiency families include truncating variants, not only missense
      alleles.
treatments:
- name: Immunoglobulin Replacement Therapy
  context: Used in EDA-ID patients with hypogammaglobulinemia.
  description: Immunoglobulin replacement is used when clinically significant humoral deficiency
    is present; it may not prevent all infections in NEMO deficiency.
  treatment_term:
    preferred_term: immunoglobulin replacement therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: pooled donor immunoglobulin G
      term:
        id: NCIT:C2701
        label: Therapeutic Immune Globulin
  evidence:
  - reference: DOI:10.1086/316914
    reference_title: A Novel X-Linked Disorder of Immune Deficiency and Hypohidrotic Ectodermal Dysplasia
      Is Allelic to Incontinentia Pigmenti and Due to Mutations in IKK-gamma (NEMO)
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: He was begun on IVIG but still experienced hospitalizations because of recurrent bacterial
      infections.
    explanation: A treated original patient illustrates both use and incomplete protection; this
      is not a controlled effectiveness estimate.
- name: Antimicrobial Prophylaxis
  context: Used in EDA-ID patients to prevent recurrent infections.
  description: Antibacterial and pathogen-directed prophylaxis are individualized to immune defects
    and infection history; trimethoprim-sulfamethoxazole and antimycobacterial prophylaxis were used
    in the severe transplant cohort.
  treatment_term:
    preferred_term: antimicrobial prophylaxis
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: antibacterial and antimycobacterial prophylactic agents
      term:
        id: NCIT:C254
        label: Anti-Infective Agent
  evidence:
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC5609334/
    reference_title: Hematopoietic stem cell transplantation in 29 patients hemizygous for hypomorphic
      IKBKG/NEMO mutations - PMC
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Twenty-four patients received IVIG, and 22 received trimethoprim-sulfamethoxazole prophylaxis
      against bacterial infections. Ten patients received azithromycin or clarithromycin for prophylaxis
      against mycobacterial infection.
    explanation: Describes actual pre-HSCT management in the selected cohort; it does not measure
      prophylactic efficacy.
- name: Hematopoietic Stem Cell Transplantation
  context: Considered for severe immunodeficiency; decisions require individualized assessment.
  description: HSCT can correct major hematopoietic immune defects but has substantial risks and
    does not reliably resolve colitis or ectodermal abnormalities. In the 29-patient retrospective
    cohort, the Kaplan-Meier survival estimate was 74% at 108 months after transplantation; median
    follow-up among surviving children was 57 months. Preexisting mycobacterial infection and colitis
    showed poorer outcomes, but the subgroup comparisons were not statistically significant.
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: hematopoietic stem cell transplantation
    term:
      id: NCIT:C15431
      label: Hematopoietic Cell Transplantation
  evidence:
  - reference: PMID:28679735
    reference_title: Hematopoietic stem cell transplantation in 29 patients hemizygous for hypomorphic
      IKBKG/NEMO mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The global survival rate after HSCT among NEMO-deficient children was 74% at a median
      follow-up after HSCT of 57 months (range, 4-108 months).
    explanation: The abstract pairs the survival estimate with median follow-up; Results identify
      the Kaplan-Meier time point as 108 months and the 57-month median as follow-up in survivors.
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC5609334/
    reference_title: Hematopoietic stem cell transplantation in 29 patients hemizygous for hypomorphic
      IKBKG/NEMO mutations - PMC
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Five of the 15 patients presenting with IBD before transplantation died after HSCT,
      4 patients had persistent or intermittent colitis (P1, P5, P24, P29), and IBD symptoms disappeared
      in 6 patients.
    explanation: Shows heterogeneous intestinal outcomes rather than an absolute inability of HSCT
      to improve colitis.
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC5609334/
    reference_title: Hematopoietic stem cell transplantation in 29 patients hemizygous for hypomorphic
      IKBKG/NEMO mutations - PMC
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The overall survival rate was 74% at 108 months after transplantation ... with a median
      follow-up of 57 months in surviving children (range, 4-108 months).
    explanation: The Results distinguish the survival-curve time point from the follow-up distribution
      among survivors.
- name: Ectodermal supportive care
  context: Phenotype-directed care for sweating, skin and dental abnormalities in EDA-ID.
  description: Cooling measures and early dental care address the ectodermal component. General HED
    GeneReviews care guidance is applied to shared ectodermal findings, not as NEMO-specific trial
    evidence or as evidence for the inheritance of EDA-ID.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:20301291
    reference_title: Hypohidrotic Ectodermal Dysplasia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Access to an adequate water supply and a cool environment during hot weather.
    explanation: General HED supportive-care advice is applicable to reduced sweating; this is expert
      management advice.
    directness: INDIRECT
  - reference: PMID:20301291
    reference_title: Hypohidrotic Ectodermal Dysplasia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Early dental treatment; bonding of conical teeth; orthodontics as necessary;
    explanation: General HED dental advice applies to the shared tooth abnormalities, with disease-scope
      extrapolation explicit.
    directness: INDIRECT
prevalence:
- population: Newborns
  subtype: EDA-ID
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_9_PER_1000000
  rate_per_100000: 0.4
  notes: Historical HED-ID estimate quoted by Keller et al., approximately 1 in 250,000 newborns;
    this is not the IP birth prevalence and was not measured in the three dual-diagnosis families.
  evidence:
  - reference: PMID:22566850
    reference_title: Hypohidrotic ectodermal dysplasia and immunodeficiency with coincident NEMO
      and EDA mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: IKBKG is located on Xq28, and HED-ID occurs in approximately 1 in 250,000 newborns
    explanation: The paper repeats an earlier HED-ID estimate; its three EDA/IKBKG dual-diagnosis
      families do not constitute a population prevalence study.
datasets: null
discussions:
- discussion_id: ikbkg_allelic_scope
  kind: INTERPRETATION
  status: OPEN
  prompt: How should immunodeficiency be distinguished from allelic IP and overlapping diagnoses?
  rationale: The assigned MONDO entity is IKBKG immunodeficiency. IP-only Blaschko lesions, retinal
    abnormalities, nonspecific IP dental findings and nail dystrophy are removed from the core phenotype
    set; the separate IP entry is unchanged. Seizures are retained only on new pre-HSCT evidence
    of an M. avium brain lesion. Hypomorphic variants can also produce IP in female relatives. The
    dual EDA/IKBKG families do not establish that every ectodermal feature, particularly their nail
    dystrophy, is attributable to NEMO alone. NEMO exon-5-deletion autoinflammation is another distinct
    allelic presentation, not evidence for a uniform loss-of-function mechanism.
  attaches_to:
  - pathophysiology#Impaired NEMO-dependent NF-kappaB activation
  evidence:
  - reference: DOI:10.1086/316914
    reference_title: A Novel X-Linked Disorder of Immune Deficiency and Hypohidrotic Ectodermal Dysplasia
      Is Allelic to Incontinentia Pigmenti and Due to Mutations in IKK-gamma (NEMO)
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The molecular and clinical findings in these families establish HED-ID as a distinct
      X-linked recessive disorder. The phenotype and genetics (recessive vs. dominant) of HED-ID
      differ significantly from those of familial IP.
    explanation: The primary families establish the disease boundary.
  - reference: PMID:22566850
    reference_title: Hypohidrotic ectodermal dysplasia and immunodeficiency with coincident NEMO
      and EDA mutations.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Thus in all three of the probands, it is difficult to attribute all of the clinical
      impact to one of the two mutant genes
    explanation: The authors explicitly limit attribution in the EDA/IKBKG dual diagnoses.
- discussion_id: ikbkg_variant_and_assay_scope
  kind: INTERPRETATION
  status: OPEN
  prompt: Which immune defects are shared and which depend on variant and assay?
  rationale: Patient-cell assays must retain their stimulus and genotype. C417 B-cell switching defects
    do not apply to E315A/R319Q B cells; c-Rel activation in the latter is delayed, not absent at
    every time point. The c.268delG family had no NF-kappaB functional assay, so the sequence alone
    does not demonstrate residual signaling. Normal lymphocyte counts or one normal response do not
    exclude immunodeficiency. Raw cytokine, proliferation and NK cytotoxicity assays are functional
    evidence, not extra causal clinical nodes.
  attaches_to:
  - pathophysiology#Impaired innate immune receptor responses
  - pathophysiology#Impaired CD40-dependent B-cell maturation
  - pathophysiology#Impaired CD40-dependent IL-12 and IFN-gamma cooperation
  evidence:
  - reference: PMID:16818673
    reference_title: X-linked susceptibility to mycobacteria is caused by mutations in NEMO impairing
      CD40-dependent IL-12 production.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: However, the CD40-dependent up-regulation of costimulatory molecules of dendritic cells
      and the proliferation and immunoglobulin class switch of B cells were normal.
    explanation: The selective family assays preserve multiple CD40 outputs.
- discussion_id: ikbkg_cohort_ascertainment
  kind: INTERPRETATION
  status: OPEN
  prompt: How should frequencies from compilations and transplant cohorts be interpreted?
  rationale: Hanson combines reported patients with uneven testing and clinical ascertainment; denominators
    differ by feature. Its pneumococcal response text gives 72% for 13/16 whereas the table gives
    81%, so no categorical frequency is inferred from that inconsistency. Miot is a severe HSCT-selected
    series with overlapping published cases, not an independent population sample. Pre-HSCT findings
    are separated from conditioning toxicity and post-HSCT complications; inconsistent patient IDs
    for vascular events preclude precise reassignment.
    Picard 2011 reports pyogenic bacterial infection in about 90%, mycobacterial infection in
    about 40%, serious viral infection in 19%, and aggregate ectodermal dysplasia in about 90%
    of the NEMO-deficient patients described at that time. These quantitative observations are
    retained here rather than discarded. The review describes up to 100 reported males and bases
    its NEMO infection tables on Hanson 2008 plus unpublished data, so it is not an independent
    population series. More importantly, its infection-occurrence estimates do not measure the
    narrower recurrent-infection phenotypes; the 19% viral composite includes HSV encephalitis,
    adenoviral gastroenteritis and CMV and is not a CMV-specific frequency. The approximately 90%
    ectodermal-dysplasia figure is not a frequency for each individual hair, dental or sweating
    abnormality. Although the numerical estimates fall within repository frequency bands, those
    bands would describe different endpoints from the phenotype entries. No categorical
    frequencies are transferred on that basis; observational study design alone is not the
    reason for declining them. These are NEMO-specific figures, not the separate IκBα cases.
  attaches_to:
  - phenotypes#Hypogammaglobulinemia
  - phenotypes#Impaired specific antibody response
  - phenotypes#Recurrent infections
  - phenotypes#Recurrent mycobacterial infections
  - phenotypes#Severe cytomegalovirus infection
  - has_subtypes#EDA-ID
  evidence:
  - reference: PMID:18851874
    reference_title: Hypomorphic nuclear factor-kappaB essential modulator mutation database and
      reconstitution system identifies phenotypic and immunologic diversity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Hypogammaglobulinemia occurred in 24/41 (59%), but correlated with impaired CD40 signaling
      only in Zinc Finger mutations.
    explanation: The feature-specific tested denominator limits frequency interpretation.
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC5609334/
    reference_title: Hematopoietic stem cell transplantation in 29 patients hemizygous for hypomorphic
      IKBKG/NEMO mutations - PMC
    supports: SUPPORT
    evidence_source: OTHER
    snippet: As HSCT is generally considered only for the sickest patients, this may account for
      the high proportion of patients with ZF domain mutations in this cohort.
    explanation: The authors explain transplant ascertainment.
  - reference: DOI:10.1128/cmr.00001-11
    reference_title: Infectious Diseases in Patients with IRAK-4, MyD88, NEMO, or IκBα Deficiency
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Pyogenic bacterial infection was identified in about 90% of NEMO-deficient patients
    explanation: The review reports pyogenic infection occurrence among described NEMO-deficient cases;
      this does not give the frequency of the differently defined recurrent-infections endpoint.
  - reference: DOI:10.1128/cmr.00001-11
    reference_title: Infectious Diseases in Patients with IRAK-4, MyD88, NEMO, or IκBα Deficiency
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Mycobacterial infection was found in about 40% of NEMO-deficient patients (cellulitis,
      osteomyelitis, lymphadenitis, pneumonia, and disseminated infections)
    explanation: The approximately 40% estimate concerns any documented mycobacterial infection, not
      recurrence in the narrower HPO phenotype.
  - reference: DOI:10.1128/cmr.00001-11
    reference_title: Infectious Diseases in Patients with IRAK-4, MyD88, NEMO, or IκBα Deficiency
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Serious viral infection occurred in 19% of NEMO-deficient patients (herpes simplex virus
      encephalitis, severe adenoviral gastroenteritis, or severe cytomegalovirus infection)
    explanation: The 19% estimate pools three serious viral presentations and cannot be assigned to
      severe CMV infection alone.
  - reference: DOI:10.1128/cmr.00001-11
    reference_title: Infectious Diseases in Patients with IRAK-4, MyD88, NEMO, or IκBα Deficiency
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: about 90% of the NEMO-deficient patients described to date have EDA, with sparse hair,
      abnormal teeth (conical teeth, tooth agenesis), and hypohidrosis (a lack of sweating)
    explanation: The approximately 90% estimate is for the aggregate EDA phenotype, not each separately
      curated hair, dental or sweat-gland finding; the quoted clause explicitly selects NEMO-deficient
      patients.
  - reference: DOI:10.1128/cmr.00001-11
    reference_title: Infectious Diseases in Patients with IRAK-4, MyD88, NEMO, or IκBα Deficiency
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Up to 100 male patients with hypomorphic mutations ofNEMOhave been reported
    explanation: Defines the review-era reported-case context; this is not an independently sampled
      population denominator for every feature.
  - reference: DOI:10.1128/cmr.00001-11
    reference_title: Infectious Diseases in Patients with IRAK-4, MyD88, NEMO, or IκBα Deficiency
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Based on data from references12,19,29,39, and42(IκBα) and on reference25and unpublished
      data (NEMO).
    explanation: The infection-table footnotes identify the NEMO data as reference 25 (Hanson 2008)
      plus unpublished observations, separately from the IκBα sources. This is source-provenance information,
      not a new independent clinical cohort.
- discussion_id: ikbkg_unresolved_clinical_attribution
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: Which remaining findings lack a sufficiently established causal route?
  rationale: Elevated IgA and low IgM cannot be explained simply by a class-switch block; the authors
    leave low-IgM pathophysiology unresolved and discuss CD40-independent IgA as a hypothesis. Reduced
    T-cell counts in one c.268delG patient are not localized to a demonstrated survival or developmental
    defect. Dry skin, ichthyosis, pigment changes, autoimmune cytopenias, thyroiditis, arthritis
    and uveitis are documented, but the reviewed patient reports do not establish one common immune-dysregulation
    route; the Jurkat L153R apoptosis/A20 phenotype is not direct proof for each manifestation. Frontal
    bossing, prenatal growth restriction, developmental delay, intracranial calcification and delayed
    cord separation likewise have uncertain patient-specific attribution. These gaps concern causal
    attribution, not mere absence of a drawn intermediary. The supported epithelial, appendage, humoral
    and infection-consequence routes are already represented. The low-IgM, high-IgA and low-T-cell
    findings are laboratory observations, not clinical functional-assay readouts. Jain proposes CD40-independent
    synthesis to explain the presence of serum IgA despite failed cultured switching in a C417 patient;
    this does not establish why concentrations are elevated, especially in the distinct c.268delG
    family. Child hyperpigmentation is documented separately from maternal IP, without a proven pigmentary
    route.
  attaches_to:
  - phenotypes#Frontal bossing
  - phenotypes#Dry skin
  - phenotypes#Ichthyosis
  - phenotypes#Increased circulating IgA
  - phenotypes#Decreased circulating IgM
  - phenotypes#Decreased total T-cell count
  - phenotypes#Intrauterine growth restriction
  - phenotypes#Polyarticular arthritis
  - phenotypes#Uveitis
  - phenotypes#Autoimmune hemolytic anemia
  - phenotypes#Autoimmune thrombocytopenia
  - phenotypes#Hashimoto thyroiditis
  - phenotypes#Neurodevelopmental delay
  - phenotypes#Intracranial calcification
  - phenotypes#Delayed umbilical cord separation
  - phenotypes#Hyperpigmented skin
  evidence:
  - reference: PMID:39540818
    reference_title: Atypical Mycobacterial Pneumonia in 2 Siblings with a Novel Hypomorphic NEMO/IKBKG
      Mutation.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Although the pathophysiology remains unclear, normal and low IgM levels can be observed
      in patients with IKBKG mutations.
    explanation: The source explicitly leaves the mechanism of low IgM unresolved.
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC5609334/
    reference_title: Hematopoietic stem cell transplantation in 29 patients hemizygous for hypomorphic
      IKBKG/NEMO mutations - PMC
    supports: SUPPORT
    evidence_source: OTHER
    snippet: The pathogenesis of the inflammatory and infectious phenotypes remains more elusive.
    explanation: The authors identify mechanistic uncertainty; the graph nevertheless retains the
      specific supported routes.
  - reference: PMID:15578091
    reference_title: Specific NEMO mutations impair CD40-mediated c-Rel activation and B cell terminal
      differentiation.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Taken together these observations suggest a CD40-independent mechanism for serum IgA
      in some patients with XHM-ED.
    explanation: The proposal concerns preserved serum IgA synthesis in the C417 context, not a demonstrated
      mechanism for the magnitude of IgA elevation.
- discussion_id: ikbkg_female_exceptions
  kind: INTERPRETATION
  status: OPEN
  prompt: What is known about female manifestations and counseling?
  rationale: Female carriers are not uniformly asymptomatic or protected by skewed X-inactivation.
    Mild ectodermal findings, IP and immune or inflammatory manifestations occur. The recent adult
    female case developed infections after anti-TNF treatment, so it cannot establish that every
    infection or inflammatory comorbidity was caused solely by NEMO deficiency. Counseling should
    separate variant transmission from variable expression and should not apply classic-IP male lethality
    to all hypomorphic alleles.
  attaches_to:
  - inheritance#X-linked recessive inheritance (EDA-ID)
  evidence:
  - reference: DOI:10.1086/316914
    reference_title: A Novel X-Linked Disorder of Immune Deficiency and Hypohidrotic Ectodermal Dysplasia
      Is Allelic to Incontinentia Pigmenti and Due to Mutations in IKK-gamma (NEMO)
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Female carriers had variable manifestations, ranging from normal dentition to minor
      degrees of hypodontia and conical teeth.
    explanation: The original family observations refute a blanket asymptomatic-carrier claim.
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC5609334/
    reference_title: Hematopoietic stem cell transplantation in 29 patients hemizygous for hypomorphic
      IKBKG/NEMO mutations - PMC
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: P6’s mother had recurrent bacterial infections.
    explanation: A carrier mother in an immunodeficiency family had a clinical infectious phenotype.
  - reference: PMID:39860371
    reference_title: Partial Loss of NEMO Function in a Female Carrier with No Incontinentia Pigmenti.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Therefore, we cannot establish whether mycobacteriosis and pulmonary aspergillosis were
      secondary to the immunosuppression following infliximab treatment rather than resulting from
      the primary impairment of NF-κB signaling.
    explanation: The authors explicitly retain the treatment-versus-intrinsic causal uncertainty
      in this female case.
references:
- reference: DOI:10.1086/316914
  title: A Novel X-Linked Disorder of Immune Deficiency and Hypohidrotic Ectodermal Dysplasia Is
    Allelic to Incontinentia Pigmenti and Due to Mutations in IKK-gamma (NEMO)
- reference: PMID:18851874
  title: Hypomorphic nuclear factor-kappaB essential modulator mutation database and reconstitution
    system identifies phenotypic and immunologic diversity.
- reference: PMID:16818673
  title: X-linked susceptibility to mycobacteria is caused by mutations in NEMO impairing CD40-dependent
    IL-12 production.
- reference: PMID:15578091
  title: Specific NEMO mutations impair CD40-mediated c-Rel activation and B cell terminal differentiation.
- reference: PMID:33598805
  title: 'EDA-ID: a Severe Clinical Presentation Associated with a New IKBKG Mutation.'
- reference: PMID:39540818
  title: Atypical Mycobacterial Pneumonia in 2 Siblings with a Novel Hypomorphic NEMO/IKBKG Mutation.
- reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC5609334/
  title: Hematopoietic stem cell transplantation in 29 patients hemizygous for hypomorphic IKBKG/NEMO
    mutations - PMC
- reference: DOI:10.1128/cmr.00001-11
  title: Infectious Diseases in Patients with IRAK-4, MyD88, NEMO, or IκBα Deficiency
- reference: PMID:11242109
  title: X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-kappaB
    signaling.
- reference: PMID:22566850
  title: Hypohidrotic ectodermal dysplasia and immunodeficiency with coincident NEMO and EDA mutations.
- reference: PMID:39860371
  title: Partial Loss of NEMO Function in a Female Carrier with No Incontinentia Pigmenti.
- reference: PMID:20301291
  tags:
  - GeneReviews
  title: Hypohidrotic Ectodermal Dysplasia.
- reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1112/
  tags:
  - GeneReviews
  title: Hypohidrotic Ectodermal Dysplasia - GeneReviews® - NCBI Bookshelf
- reference: url:https://oup.silverchair-cdn.com/article-minimal/6625140
  title: https://oup.silverchair-cdn.com/article-minimal/6625140
diagnosis:
- name: Molecular and immune evaluation
  description: IKBKG testing must distinguish the functional gene from its highly similar pseudogene.
    Immunologic evaluation is warranted when ectodermal dysplasia accompanies unusual infections,
    including when a separate EDA variant has already been identified. Normal immunoglobulin levels
    or absence of ectodermal findings does not exclude variant-specific NEMO immunodeficiency.
  evidence:
  - reference: PMID:33598805
    reference_title: 'EDA-ID: a Severe Clinical Presentation Associated with a New IKBKG Mutation.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: This mutation was confirmed by Sanger method, with a long PCR using primers specific
      for IKBKG and excluding IKBKGP pseudogene
    explanation: The primary case demonstrates gene-specific confirmation despite the pseudogene.
  - reference: PMID:22566850
    reference_title: Hypohidrotic ectodermal dysplasia and immunodeficiency with coincident NEMO
      and EDA mutations.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Immunologic screening should be considered for all children with HED, and a thorough
      workup is essential if there is any abnormal pattern of infections.
    explanation: The dual-diagnosis study recommends immunologic assessment; this is advice rather
      than an observed outcome.
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1112/
    reference_title: Hypohidrotic Ectodermal Dysplasia - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: IKBKG ... Hypohidrotic ectodermal dysplasia w/immunodeficiency ... XL ... Sparse hair
      ... Hypohidrosis ... Hypodontia ... Impaired immune function w/risk for recurrent infections,
      hypogammaglobulinemia, T cell dysfunction
    explanation: The GeneReviews differential table separates immunodeficient IKBKG disease from
      other genetic causes of HED and from IP.

📚

References & Deep Research

References

14

DOI:10.1086/316914

A Novel X-Linked Disorder of Immune Deficiency and Hypohidrotic Ectodermal Dysplasia Is Allelic to Incontinentia Pigmenti and Due to Mutations in IKK-gamma (NEMO)

No top-level findings curated for this source.

PMID:18851874

Hypomorphic nuclear factor-kappaB essential modulator mutation database and reconstitution system identifies phenotypic and immunologic diversity.

No top-level findings curated for this source.

PMID:16818673

X-linked susceptibility to mycobacteria is caused by mutations in NEMO impairing CD40-dependent IL-12 production.

No top-level findings curated for this source.

PMID:15578091

Specific NEMO mutations impair CD40-mediated c-Rel activation and B cell terminal differentiation.

No top-level findings curated for this source.

PMID:33598805

EDA-ID: a Severe Clinical Presentation Associated with a New IKBKG Mutation.

No top-level findings curated for this source.

PMID:39540818

Atypical Mycobacterial Pneumonia in 2 Siblings with a Novel Hypomorphic NEMO/IKBKG Mutation.

No top-level findings curated for this source.

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC5609334/

Hematopoietic stem cell transplantation in 29 patients hemizygous for hypomorphic IKBKG/NEMO mutations - PMC

No top-level findings curated for this source.

DOI:10.1128/cmr.00001-11

Infectious Diseases in Patients with IRAK-4, MyD88, NEMO, or IκBα Deficiency

No top-level findings curated for this source.

PMID:11242109

X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-kappaB signaling.

No top-level findings curated for this source.

PMID:22566850

Hypohidrotic ectodermal dysplasia and immunodeficiency with coincident NEMO and EDA mutations.

No top-level findings curated for this source.

PMID:39860371

Partial Loss of NEMO Function in a Female Carrier with No Incontinentia Pigmenti.

No top-level findings curated for this source.

PMID:20301291

Hypohidrotic Ectodermal Dysplasia.

No top-level findings curated for this source.

url:https://www.ncbi.nlm.nih.gov/books/NBK1112/

Hypohidrotic Ectodermal Dysplasia - GeneReviews® - NCBI Bookshelf

No top-level findings curated for this source.

url:https://oup.silverchair-cdn.com/article-minimal/6625140

https://oup.silverchair-cdn.com/article-minimal/6625140

No top-level findings curated for this source.

Deep Research

1

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

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)

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Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

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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.)

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Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

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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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(doffinger2001xlinkedanhidroticectodermal pages 2-2): Rainer Döffinger, Asma Smahi, Christine Bessia, Frédéric Geissmann, Jacqueline Feinberg, Anne Durandy, Christine Bodemer, Sue Kenwrick, Sophie Dupuis-Girod, Stéphane Blanche, Philip Wood, Smail Hadj Rabia, Denis J. Headon, Paul A. Overbeek, Françoise Le Deist, Steven M. Holland, Kiran Belani, Dinakantha S. Kumararatne, Alain Fischer, Ralph Shapiro, Mary Ellen Conley, Eric Reimund, Hermann Kalhoff, Mario Abinun, Arnold Munnich, Alain Israël, Gilles Courtois, and Jean-Laurent Casanova. X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired nf-κb signaling. Nature Genetics, 27:277-285, Mar 2001. URL: https://doi.org/10.1038/85837, doi:10.1038/85837. This article has 992 citations and is from a highest quality peer-reviewed journal.
(mcdonald2014humanimmunodeficienciesresulting pages 2-4): Douglas R. McDonald and Raif S. Geha. Human immunodeficiencies resulting from defective nf-κb activation. ArXiv, pages 665-686, Jan 2014. URL: https://doi.org/10.1016/b978-0-12-405546-9.00033-9, doi:10.1016/b978-0-12-405546-9.00033-9. This article has 2 citations.
(haverkamp2014correlatinginterleukin12stimulated pages 8-8): Margje H. Haverkamp, Beatriz E. Marciano, David M. Frucht, Ashish Jain, Esther van de Vosse, and Steven M. Holland. Correlating interleukin-12 stimulated interferon-γ production and the absence of ectodermal dysplasia and anhidrosis (eda) in patients with mutations in nf-κb essential modulator (nemo). Journal of Clinical Immunology, 34:436-443, Feb 2014. URL: https://doi.org/10.1007/s10875-014-9998-2, doi:10.1007/s10875-014-9998-2. This article has 19 citations and is from a domain leading peer-reviewed journal.
(meric2024atypicalmycobacterialpneumonia pages 1-2): Zeynep Meric, Sezin Aydemir, Azer Kilic Baskan, Betul Gemici Karaaslan, Yasemin Kendir Demirkol, Ayse Ayzit Kilinc Sakalli, Ayca Kiykim, and Haluk Cokugras 1. Atypical mycobacterial pneumonia in 2 siblings with a novel hypomorphic nemo/ikbkg mutation. Turkish Archives of Pediatrics, 59:605-607, Sep 2024. URL: https://doi.org/10.5152/turkarchpediatr.2024.24087, doi:10.5152/turkarchpediatr.2024.24087. This article has 2 citations.
(picard2011infectiousdiseasesin pages 4-5): Capucine Picard, Jean-Laurent Casanova, and Anne Puel. Infectious diseases in patients with irak-4, myd88, nemo, or iκbα deficiency. Clinical Microbiology Reviews, 24:490-497, Jul 2011. URL: https://doi.org/10.1128/cmr.00001-11, doi:10.1128/cmr.00001-11. This article has 494 citations and is from a highest quality peer-reviewed journal.
(puvilland2021edaidasevere pages 1-3): Coline Bret Puvilland, Bertrand Boisson, Mathieu Fusaro, Jacinta Bustamante, Yves Bertrand, Antony Ceraulo, and Marie Ouachée-Chardin. Eda-id: a severe clinical presentation associated with a new ikbkg mutation. Journal of Clinical Immunology, 41:1099-1102, Feb 2021. URL: https://doi.org/10.1007/s10875-021-00992-x, doi:10.1007/s10875-021-00992-x. This article has 9 citations and is from a domain leading peer-reviewed journal.
(zonana2000anovelxlinked pages 2-4): Jonathan Zonana, Melissa E. Elder, Lynda C. Schneider, Seth J. Orlow, Celia Moss, Mahin Golabi, Stuart K. Shapira, Peter A. Farndon, Diane W. Wara, Stephanie A. Emmal, and Betsy M. Ferguson. A novel x-linked disorder of immune deficiency and hypohidrotic ectodermal dysplasia is allelic to incontinentia pigmenti and due to mutations in ikk-gamma (nemo). American journal of human genetics, 67 6:1555-62, Dec 2000. URL: https://doi.org/10.1086/316914, doi:10.1086/316914. This article has 603 citations and is from a highest quality peer-reviewed journal.
(cammaratascalisi2024maingeneticentities pages 4-5): Francisco Cammarata-Scalisi, Colin E. Willoughby, Jinia R. El-Feghaly, Antonio Cárdenas Tadich, Maykol Araya Castillo, Shadi Alkhatib, Marwa Abd Elsalam Elsherif, Rabab K. El-Ghandour, Riccardo Coletta, Antonino Morabito, and Michele Callea. Main genetic entities associated with tooth agenesis. Clinical oral investigations, 29 1:9, Dec 2024. URL: https://doi.org/10.1007/s00784-024-05941-7, doi:10.1007/s00784-024-05941-7. This article has 7 citations and is from a domain leading peer-reviewed journal.
(herlin2024prevalenceandclinical pages 1-3): Laura Krogh Herlin, Sigrun Alba Johannesdottir Schmidt, Trine H. Mogensen, and Mette Sommerlund. Prevalence and clinical characteristics of incontinentia pigmenti: a nationwide population-based study. Orphanet Journal of Rare Diseases, Dec 2024. URL: https://doi.org/10.1186/s13023-024-03480-8, doi:10.1186/s13023-024-03480-8. This article has 10 citations and is from a peer-reviewed journal.
(meric2024atypicalmycobacterialpneumonia pages 2-3): Zeynep Meric, Sezin Aydemir, Azer Kilic Baskan, Betul Gemici Karaaslan, Yasemin Kendir Demirkol, Ayse Ayzit Kilinc Sakalli, Ayca Kiykim, and Haluk Cokugras 1. Atypical mycobacterial pneumonia in 2 siblings with a novel hypomorphic nemo/ikbkg mutation. Turkish Archives of Pediatrics, 59:605-607, Sep 2024. URL: https://doi.org/10.5152/turkarchpediatr.2024.24087, doi:10.5152/turkarchpediatr.2024.24087. This article has 2 citations.
(george2023infectionsininborn pages 5-6): Kalpana George and Geeta Govindaraj. Infections in inborn errors of immunity with combined immune deficiency: a review. Pathogens, 12:272, Feb 2023. URL: https://doi.org/10.3390/pathogens12020272, doi:10.3390/pathogens12020272. This article has 20 citations.
(giancane2013anhidroticectodermaldysplasia pages 3-3): Gabriella Giancane, Simona Ferrari, Rita Carsetti, Paola Papoff, Metello Iacobini, and Marzia Duse. Anhidrotic ectodermal dysplasia: a new mutation. The Journal of allergy and clinical immunology, 132 6:1451-3, Dec 2013. URL: https://doi.org/10.1016/j.jaci.2013.05.034, doi:10.1016/j.jaci.2013.05.034. This article has 17 citations.
(fusco2015edaidandip pages 7-8): Francesca Fusco, Alessandra Pescatore, Matilde Immacolata Conte, Peppino Mirabelli, Mariateresa Paciolla, Elio Esposito, Maria Brigida Lioi, and Matilde Valeria Ursini. Eda-id and ip, two faces of the same coin: how the same ikbkg/nemo mutation affecting the nf-κb pathway can cause immunodeficiency and/or inflammation. International Reviews of Immunology, 34:445-459, Aug 2015. URL: https://doi.org/10.3109/08830185.2015.1055331, doi:10.3109/08830185.2015.1055331. This article has 118 citations and is from a peer-reviewed journal.
(pescatore2022humangeneticdiseases pages 4-6): Alessandra Pescatore, Ezia Spinosa, Carmela Casale, Maria Brigida Lioi, Matilde Valeria Ursini, and Francesca Fusco. Human genetic diseases linked to the absence of nemo: an obligatory somatic mosaic disorder in male. International Journal of Molecular Sciences, 23:1179, Jan 2022. URL: https://doi.org/10.3390/ijms23031179, doi:10.3390/ijms23031179. This article has 14 citations.
(herlin2024prevalenceandclinical pages 6-7): Laura Krogh Herlin, Sigrun Alba Johannesdottir Schmidt, Trine H. Mogensen, and Mette Sommerlund. Prevalence and clinical characteristics of incontinentia pigmenti: a nationwide population-based study. Orphanet Journal of Rare Diseases, Dec 2024. URL: https://doi.org/10.1186/s13023-024-03480-8, doi:10.1186/s13023-024-03480-8. This article has 10 citations and is from a peer-reviewed journal.
(puvilland2021edaidasevere pages 4-6): Coline Bret Puvilland, Bertrand Boisson, Mathieu Fusaro, Jacinta Bustamante, Yves Bertrand, Antony Ceraulo, and Marie Ouachée-Chardin. Eda-id: a severe clinical presentation associated with a new ikbkg mutation. Journal of Clinical Immunology, 41:1099-1102, Feb 2021. URL: https://doi.org/10.1007/s10875-021-00992-x, doi:10.1007/s10875-021-00992-x. This article has 9 citations and is from a domain leading peer-reviewed journal.
(pescatore2022humangeneticdiseases pages 6-7): Alessandra Pescatore, Ezia Spinosa, Carmela Casale, Maria Brigida Lioi, Matilde Valeria Ursini, and Francesca Fusco. Human genetic diseases linked to the absence of nemo: an obligatory somatic mosaic disorder in male. International Journal of Molecular Sciences, 23:1179, Jan 2022. URL: https://doi.org/10.3390/ijms23031179, doi:10.3390/ijms23031179. This article has 14 citations.
(fusco2015edaidandip media a25bf9d6): Francesca Fusco, Alessandra Pescatore, Matilde Immacolata Conte, Peppino Mirabelli, Mariateresa Paciolla, Elio Esposito, Maria Brigida Lioi, and Matilde Valeria Ursini. Eda-id and ip, two faces of the same coin: how the same ikbkg/nemo mutation affecting the nf-κb pathway can cause immunodeficiency and/or inflammation. International Reviews of Immunology, 34:445-459, Aug 2015. URL: https://doi.org/10.3109/08830185.2015.1055331, doi:10.3109/08830185.2015.1055331. This article has 118 citations and is from a peer-reviewed journal.
(fusco2015edaidandip media bf13b1f4): Francesca Fusco, Alessandra Pescatore, Matilde Immacolata Conte, Peppino Mirabelli, Mariateresa Paciolla, Elio Esposito, Maria Brigida Lioi, and Matilde Valeria Ursini. Eda-id and ip, two faces of the same coin: how the same ikbkg/nemo mutation affecting the nf-κb pathway can cause immunodeficiency and/or inflammation. International Reviews of Immunology, 34:445-459, Aug 2015. URL: https://doi.org/10.3109/08830185.2015.1055331, doi:10.3109/08830185.2015.1055331. This article has 118 citations and is from a peer-reviewed journal.

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OpenScientist Report

Classifications

Inheritance

Subtypes

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Prevalence

Source YAML

References & Deep Research

References

Deep Research

Disease Characteristics Research Template

Target Disease

Research Objectives

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Citation Requirements

Output Format

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

1. Disease information

1.1 Concise overview

1.2 Key identifiers (with evidence in this run)

1.3 Synonyms / alternative names

2. Etiology

2.1 Disease causal factors

2.2 Risk factors

2.3 Protective factors

2.4 Gene–environment interactions

3. Phenotypes

3.1 Major clinical phenotype categories

3.2 Frequency / statistics (from cohort reviews)

3.3 Typical onset and course

3.4 Suggested HPO terms

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

4. Genetic / molecular information

4.1 Causal gene

4.2 Pathogenic variant classes and examples

4.3 Inheritance, penetrance, expressivity

4.4 Modifier factors (genetic/epigenetic)

4.5 Allele frequency in population databases

5. Environmental information

6. Mechanism / pathophysiology

6.1 Current mechanistic model (causal chain)

6.2 Cell types and processes (ontology suggestions)

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

9.1 Epidemiology

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

10. Diagnostics

10.1 Clinical suspicion

10.2 Immunologic testing (real-world implementation)

10.3 Genetic testing strategy and pitfalls

10.4 Differential diagnosis

11. Outcome / prognosis

12. Treatment

12.1 Anti-infective strategy (practice-relevant)

12.2 Immunoglobulin replacement and prophylaxis

12.3 Hematopoietic stem cell transplantation (HSCT)

12.4 Supportive ectodermal/airway care

12.5 MAXO (Medical Action Ontology) suggestions