Ectodermal dysplasia and immune deficiency

Summary

Ectodermal dysplasia and immune deficiency (MONDO:0010293) is a disease with 2 cohort genes.

At a glance

• Prevalence: 1-9 / 1 000 000 (Europe) [Orphanet-validated]
• Cohort genes: 2
• Phenotypes (HPO): 34

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 1 000 000	0.2	Europe	Validated

Signs & symptoms

Clinical features (HPO)

34 HPO clinical features (Orphanet curated; top 34 by frequency):

HPO ID	Term	Frequency
HP:0000698	Conical tooth	Very frequent (80-99%)
HP:0000966	Hypohidrosis	Very frequent (80-99%)
HP:0000968	Ectodermal dysplasia	Very frequent (80-99%)
HP:0001508	Failure to thrive	Very frequent (80-99%)
HP:0001510	Growth delay	Very frequent (80-99%)
HP:0002718	Recurrent bacterial infections	Very frequent (80-99%)
HP:0008070	Sparse hair	Very frequent (80-99%)
HP:0010701	Abnormal immunoglobulin level	Very frequent (80-99%)
HP:0000403	Recurrent otitis media	Frequent (30-79%)
HP:0002028	Chronic diarrhea	Frequent (30-79%)
HP:0002037	Inflammation of the large intestine	Frequent (30-79%)
HP:0002728	Chronic mucocutaneous candidiasis	Frequent (30-79%)
HP:0005404	Increased B cell count	Frequent (30-79%)
HP:0011274	Recurrent mycobacterial infections	Frequent (30-79%)
HP:0033581	Absent peripheral lymph nodes in presence of infection	Frequent (30-79%)
HP:0100828	Increased T cell count	Frequent (30-79%)
HP:0000938	Osteopenia	Occasional (5-29%)
HP:0000964	Eczematoid dermatitis	Occasional (5-29%)
HP:0002720	Decreased circulating IgA level	Occasional (5-29%)
HP:0002850	Decreased circulating total IgM	Occasional (5-29%)
HP:0002960	Autoimmunity	Occasional (5-29%)
HP:0003212	Increased circulating IgE level	Occasional (5-29%)
HP:0003237	Increased circulating IgG level	Occasional (5-29%)
HP:0003496	Increased circulating IgM level	Occasional (5-29%)
HP:0004313	Decreased circulating antibody level	Occasional (5-29%)
HP:0004315	Decreased circulating IgG level	Occasional (5-29%)
HP:0008404	Nail dystrophy	Occasional (5-29%)
HP:0008872	Feeding difficulties in infancy	Occasional (5-29%)
HP:0010741	Pedal edema	Occasional (5-29%)
HP:0011108	Recurrent sinusitis	Occasional (5-29%)
HP:0020101	Invasive fungal infection	Occasional (5-29%)
HP:0031188	Genital edema	Occasional (5-29%)
HP:0031691	Severe viral infection	Occasional (5-29%)
HP:0040075	Hypopituitarism	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	ectodermal dysplasia and immune deficiency
Mondo ID	MONDO:0010293
MeSH	C536181
OMIM	300291
Orphanet	98813
DOID	DOID:0081077
NCIT	C118844
SNOMED CT	703525006
UMLS	C1846006
MedGen	375786
GARD	0009936
Is cancer (heuristic)	no

Also known as: anhidrotic ectodermal dysplasia with immune deficiency · anhidrotic ectodermal dysplasia with immunodeficiency · EDA-ID · HED-ID · hypohidrotic ectodermal dysplasia with immune deficiency · hypohidrotic ectodermal dysplasia with immunodeficiency

Data availability: 2 GenCC gene-disease records · 2 cell lines.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › immune system disorder › inborn error of immunity › ectodermal dysplasia and immune deficiency

Related subtypes (40): B cell deficiency, complement deficiency, phagocyte bactericidal dysfunction, trichohepatoenteric syndrome, hepatic veno-occlusive disease-immunodeficiency syndrome, immunodeficiency with defective T-cell response to interleukin 1, Say-Barber-Miller syndrome, familial isolated congenital asplenia, X-linked immunoneurologic disorder, immunodeficiency 33, immunodeficiency 47, combined immunodeficiency due to moesin deficiency, immunodeficiency, X-linked, with deficiency of 115,000 Dalton surface glycoprotein, properdin deficiency, X-linked, combined immunodeficiency with faciooculoskeletal anomalies, recurrent infections associated with rare immunoglobulin isotypes deficiency, immunodeficiency 28, autosomal recessive primary immunodeficiency with defective spontaneous natural killer cell cytotoxicity, immunodeficiency 37, immunodeficiency 39, BENTA disease, primary immunodeficiency with post-measles-mumps-rubella vaccine viral infection, immunodeficiency 49, chronic mucocutaneous candidiasis, hereditary hemophagocytic lymphohistiocytosis, immunoglobulin heavy chain deficiency, immuno-osseous dysplasia, lymphoproliferative syndrome, IL10-related early-onset inflammatory bowel disease, T-cell immunodeficiency with epidermodysplasia verruciformis, Aicardi-Goutieres syndrome, immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections-lymphopenia syndrome, inflammatory bowel disease-recurrent sinopulmonary infections syndrome, A20 haploinsufficiency, NK cell deficiency, T cell and NK cell immunodeficiency, dendritic cell deficiency, immunodysregulation with variable immunodeficiency and autoimmunity, immune dysregulation with immunodeficiency due to AIOLOS haploinsufficiency, STAT5 haploinsufficiency

Subtypes (2): ectodermal dysplasia and immunodeficiency 2, ectodermal dysplasia and immunodeficiency 1

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

No tiered GWAS variants or ClinVar records for this disease.

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 16 · Orphanet: 8 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
IKBKG	Definitive	X-linked	ectodermal dysplasia and immunodeficiency 1	12
NFKBIA	Definitive	Autosomal dominant	ectodermal dysplasia and immunodeficiency 2	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
IKBKG	Orphanet:464	Incontinentia pigmenti
IKBKG	Orphanet:69088	Hypohidrotic ectodermal dysplasia-immunodeficiency-osteopetrosis-lymphedema syndrome
IKBKG	Orphanet:699605	NEMO deleted exon 5 autoinflammatory syndrome
IKBKG	Orphanet:98813	Hypohidrotic ectodermal dysplasia with immunodeficiency
NFKBIA	Orphanet:150	Nasopharyngeal carcinoma
NFKBIA	Orphanet:251576	Gliosarcoma
NFKBIA	Orphanet:251579	Giant cell glioblastoma
NFKBIA	Orphanet:98813	Hypohidrotic ectodermal dysplasia with immunodeficiency

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
IKBKG	HGNC:5961	ENSG00000269335	Q9Y6K9	NF-kappa-B essential modulator	gencc
NFKBIA	HGNC:7797	ENSG00000100906	P25963	NF-kappa-B inhibitor alpha	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
IKBKG	NF-kappa-B essential modulator	Regulatory subunit of the IKK core complex which phosphorylates inhibitors of NF-kappa-B thus leading to the dissociation of the inhibitor/NF-kappa-B complex and ultimately the degradation of the inhibitor.
NFKBIA	NF-kappa-B inhibitor alpha	Inhibits the activity of dimeric NF-kappa-B/REL complexes by trapping REL (RELA/p65 and NFKB1/p50) dimers in the cytoplasm by masking their nuclear localization signals.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Scaffold/PPI	1	8.6×	0.225
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
IKBKG	Other/Unknown	no		NEMO_N, CC2-LZ_dom, NEMO_ZF
NFKBIA	Scaffold/PPI	no		Ankyrin_rpt, Ankyrin_rpt-contain_sf, NF-kappa-B_inhibitor

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
blood	1
granulocyte	1
spleen	1
lower lobe of lung	1
pericardium	1
vena cava	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
IKBKG	134	ubiquitous	marker	granulocyte, blood, spleen
NFKBIA	302	ubiquitous	marker	vena cava, pericardium, lower lobe of lung

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NFKBIA	6,991
IKBKG	4,981

Intra-cohort edges

A	B	Sources
IKBKG	NFKBIA	biogrid_interaction, string_interaction

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
IKBKG	Q9Y6K9	17
NFKBIA	P25963	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 91. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
IkBA variant leads to EDA-ID	2	1631.4×	3e-05	IKBKG, NFKBIA
SUMOylation of immune response proteins	2	951.7×	5e-05	IKBKG, NFKBIA
RIP-mediated NFkB activation via ZBP1	2	671.8×	6e-05	IKBKG, NFKBIA
TRAF6 mediated NF-kB activation	2	456.8×	1e-04	IKBKG, NFKBIA
Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells	2	356.9×	1e-04	IKBKG, NFKBIA
TAK1-dependent IKK and NF-kappa-B activation	2	300.5×	2e-04	IKBKG, NFKBIA
Activation of NF-kappaB in B cells	2	196.9×	3e-04	IKBKG, NFKBIA
FCERI mediated NF-kB activation	2	156.4×	5e-04	IKBKG, NFKBIA
CLEC7A (Dectin-1) signaling	2	142.8×	5e-04	IKBKG, NFKBIA
Downstream TCR signaling	2	128.3×	5e-04	IKBKG, NFKBIA
Interleukin-1 signaling	2	124.1×	5e-04	IKBKG, NFKBIA
Ub-specific processing proteases	2	53.1×	0.003	IKBKG, NFKBIA
IKBKB deficiency causes SCID	1	1903.3×	0.003	IKBKG
IKBKG deficiency causes anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) (via TLR)	1	1903.3×	0.003	IKBKG
SLC15A4:TASL-dependent IRF5 activation	1	951.7×	0.006	IKBKG
ZBP1(DAI) mediated induction of type I IFNs	1	519.1×	0.010	IKBKG
NF-kB is activated and signals survival	1	439.2×	0.010	NFKBIA
Diseases of Immune System	1	439.2×	0.010	IKBKG
Diseases associated with the TLR signaling cascade	1	439.2×	0.010	IKBKG
NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10	1	439.2×	0.010	IKBKG
Downstream signaling events of B Cell Receptor (BCR)	1	407.9×	0.010	IKBKG
IRAK1 recruits IKK complex	1	407.9×	0.010	IKBKG
IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation	1	407.9×	0.010	IKBKG
MAP3K8 (TPL2)-dependent MAPK1/3 activation	1	356.9×	0.010	IKBKG
Dengue virus modulates apoptosis	1	356.9×	0.010	NFKBIA
Regulation of NF-kappa B signaling	1	317.2×	0.011	IKBKG
TICAM1, RIP1-mediated IKK complex recruitment	1	300.5×	0.011	IKBKG
Modulation of host responses by IFN-stimulated genes	1	300.5×	0.011	IKBKG
JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1	1	259.6×	0.011	IKBKG
TCR signaling	1	248.3×	0.011	IKBKG

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
canonical NF-kappaB signal transduction	2	366.4×	3e-04	IKBKG, NFKBIA
negative regulation of canonical NF-kappaB signal transduction	2	172.0×	8e-04	IKBKG, NFKBIA
negative regulation of cholesterol transport	1	2106.5×	0.007	NFKBIA
nucleotide-binding oligomerization domain containing 1 signaling pathway	1	1685.2×	0.007	NFKBIA
establishment of vesicle localization	1	1203.7×	0.007	IKBKG
negative regulation of lipid storage	1	766.0×	0.007	NFKBIA
nucleotide-binding oligomerization domain containing 2 signaling pathway	1	766.0×	0.007	NFKBIA
response to muramyl dipeptide	1	702.2×	0.007	NFKBIA
negative regulation of macrophage derived foam cell differentiation	1	648.1×	0.007	NFKBIA
anoikis	1	648.1×	0.007	IKBKG
cellular response to cold	1	526.6×	0.007	NFKBIA
negative regulation of protein import into nucleus	1	468.1×	0.007	NFKBIA
negative regulation of myeloid cell differentiation	1	468.1×	0.007	NFKBIA
non-canonical NF-kappaB signal transduction	1	421.3×	0.007	NFKBIA
negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway	1	421.3×	0.007	IKBKG
interleukin-1-mediated signaling pathway	1	401.2×	0.007	NFKBIA
response to muscle stretch	1	383.0×	0.007	NFKBIA
positive regulation of T cell receptor signaling pathway	1	383.0×	0.007	IKBKG
B cell homeostasis	1	280.9×	0.008	IKBKG
positive regulation of ubiquitin-dependent protein catabolic process	1	280.9×	0.008	IKBKG
positive regulation of macroautophagy	1	263.3×	0.008	IKBKG
lipopolysaccharide-mediated signaling pathway	1	263.3×	0.008	NFKBIA
toll-like receptor 4 signaling pathway	1	263.3×	0.008	NFKBIA
response to exogenous dsRNA	1	263.3×	0.008	NFKBIA
negative regulation of Notch signaling pathway	1	216.1×	0.008	NFKBIA
negative regulation of cytokine production involved in inflammatory response	1	210.7×	0.008	NFKBIA
positive regulation of transcription by RNA polymerase II	2	14.9×	0.008	IKBKG, NFKBIA
B cell receptor signaling pathway	1	200.6×	0.009	NFKBIA
obsolete negative regulation of NF-kappaB transcription factor activity	1	179.3×	0.009	NFKBIA
tumor necrosis factor-mediated signaling pathway	1	165.2×	0.010	NFKBIA

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
IKBKG	0	0
NFKBIA	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
NFKBIA	48	Binding:48
IKBKG	38	Binding:30, Functional:8

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	IKBKG, NFKBIA

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
IKBKG	38	—
NFKBIA	48	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.