X-linked hypohidrotic ectodermal dysplasia

Summary

X-linked hypohidrotic ectodermal dysplasia (MONDO:0010585) is a disease caused by EDA (GenCC Definitive), with 2 cohort genes and 14 clinical trials. Top therapeutic interventions include edi-200.

At a glance

• Prevalence: 1-9 / 1 000 000 (Europe) [Orphanet-validated]
• Causal gene: EDA (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 565
• Phenotypes (HPO): 14
• Clinical trials: 14

Clinical features

Epidemiology

Prevalence records

3 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000		Europe	Validated
Prevalence at birth	1-9 / 1 000 000	0.75	Europe	Validated
Point prevalence	1-5 / 10 000	12.7	Denmark	Not yet validated

Signs & symptoms

Clinical features (HPO)

14 HPO clinical features (Orphanet curated; top 14 by frequency):

HPO ID	Term	Frequency
HP:0000232	Everted lower lip vermilion	Very frequent (80-99%)
HP:0000457	Depressed nasal ridge	Very frequent (80-99%)
HP:0000684	Delayed eruption of teeth	Very frequent (80-99%)
HP:0000691	Microdontia	Very frequent (80-99%)
HP:0000966	Hypohidrosis	Very frequent (80-99%)
HP:0002231	Sparse body hair	Very frequent (80-99%)
HP:0008070	Sparse hair	Very frequent (80-99%)
HP:0010803	Everted upper lip vermilion	Very frequent (80-99%)
HP:0100840	Aplasia/Hypoplasia of the eyebrow	Very frequent (80-99%)
HP:0002007	Frontal bossing	Frequent (30-79%)
HP:0000822	Hypertension	Occasional (5-29%)
HP:0000830	Anterior hypopituitarism	Occasional (5-29%)
HP:0009882	Short distal phalanx of finger	Occasional (5-29%)
HP:0100651	Type I diabetes mellitus	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	X-linked hypohidrotic ectodermal dysplasia
Mondo ID	MONDO:0010585
OMIM	305100
Orphanet	181
DOID	DOID:0111664
ICD-11	941793098
SNOMED CT	239007005
UMLS	C0162359
MedGen	57890
GARD	0010427
Is cancer (heuristic)	no

Also known as: anhidrotic ectodermal dysplasia X-linked · Christ-Siemens-Touraine syndrome · ectodermal dysplasia 1, hypohidrotic, X-linked · ectodermal dysplasia 1, hypohidrotic, X-linked, X-linked recessive · hypohidrotic ectodermal dysplasia X-linked · hypohidrotic ectodermal dysplasia, X-linked · X-linked hypohidrotic ectodermal dysplasia · XHED

Data availability: 565 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › X-linked disease › X-linked hypohidrotic ectodermal dysplasia

Related subtypes (49): X-linked Opitz G/BBB syndrome, X-linked immunoneurologic disorder, X-linked adrenal hypoplasia congenita, X-linked lissencephaly with abnormal genitalia, X-linked severe congenital neutropenia, X-linked distal spinal muscular atrophy type 3, epilepsy, X-linked 1, with variable learning disabilities and behavior disorders, Aland island eye disease, X-linked erythropoietic protoporphyria, X-linked central congenital hypothyroidism with late-onset testicular enlargement, X-linked colobomatous microphthalmia-microcephaly-intellectual disability-short stature syndrome, X-linked acrogigantism due to Xq26 microduplication, Wiskott-Aldrich syndrome, X-linked Alport syndrome, X-linked mandibulofacial dysostosis, X-linked chondrodysplasia punctata, choroideremia, cone dystrophy, X-linked, with tapetal-like sheen, diabetes insipidus, nephrogenic, X-linked, Dyggve-Melchior-Clausen syndrome, X-linked, dyskeratosis congenita, X-linked, X-linked Ehlers-Danlos syndrome, epidermodysplasia verruciformis, X-linked, exudative vitreoretinopathy 2, X-linked, Aarskog-Scott syndrome, X-linked, hemophilia A, X-linked hydrocephalus with stenosis of the aqueduct of Sylvius, hyper-IgM syndrome type 1, X-linked lymphoproliferative syndrome, macular dystrophy, X-linked, X-linked Emery-Dreifuss muscular dystrophy, X-linked myotubular myopathy, X-linked lethal multiple pterygium syndrome, X-linked retinoschisis, spondyloepiphyseal dysplasia tarda, X-linked, X-linked cerebellar ataxia, adrenoleukodystrophy, Charcot-Marie-Tooth disease type X, X-linked dominant disease, X-linked recessive disease, X-linked hypophosphatemic rickets, X-linked sideroblastic anemia 1, X-linked deafness, X-linked cone-rod dystrophy, X-linked congenital stationary night blindness, X-linked congenital hemolytic anemia, X-linked complex neurodevelopmental disorder, X-linked intellectual disability, leukemia, acute, X-linked

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

ClinVar germline variants

565 retrieved; paginated sample, class counts are floors:

181 pathogenic, 167 likely benign, 72 likely pathogenic, 70 uncertain significance, 33 benign, 21 pathogenic/likely pathogenic, 19 conflicting classifications of pathogenicity, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1256048	NM_001399.5(EDA):c.[866G>C;868A>T]		Pathogenic	no assertion criteria provided
1068988	NM_001399.5(EDA):c.486_487insGGCCGGGCGCGGTGGCTCACGCCTGTAATCCCAGCACTTTGGGAGGCCGAGGCGGGTGGATCATGAGGTCAGGAGATCGAGACCATCCTGGCTAACAAGGTGAANNNNNNNNNNAAAAAAAAAAAAAAAAAAAAAAAAGAAGCAAAAGC (p.Asn163delinsGlyArgAlaArgTrpLeuThrProValIleProAlaLeuTrpGluAlaGluAlaGlyGlySerTer)	EDA	Pathogenic	criteria provided, single submitter
1070893	NM_001399.5(EDA):c.1A>G (p.Met1Val)	EDA	Pathogenic	criteria provided, single submitter
1070894	NM_001399.5(EDA):c.643G>T (p.Gly215Ter)	EDA	Pathogenic	criteria provided, single submitter
1070895	NM_001399.5(EDA):c.632C>G (p.Thr211Arg)	EDA	Pathogenic	criteria provided, single submitter
1070896	NM_001399.5(EDA):c.801A>G (p.Ser267=)	EDA	Pathogenic	criteria provided, single submitter
1071445	NM_001399.5(EDA):c.497del (p.Ala166fs)	EDA	Pathogenic	criteria provided, multiple submitters, no conflicts
1071552	NM_001399.5(EDA):c.213del (p.Glu71fs)	EDA	Pathogenic	criteria provided, single submitter
1071684	NM_001399.5(EDA):c.614_699del (p.Ile205fs)	EDA	Pathogenic	criteria provided, single submitter
1071925	NM_001399.5(EDA):c.441dup (p.Glu148Ter)	EDA	Pathogenic	criteria provided, single submitter
1072490	NM_001399.5(EDA):c.576_592del (p.Pro193fs)	EDA	Pathogenic	criteria provided, single submitter
1072863	NM_001399.5(EDA):c.1009G>T (p.Glu337Ter)	EDA	Pathogenic	criteria provided, single submitter
1072864	NM_001399.5(EDA):c.1067C>A (p.Ala356Asp)	EDA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076054	NM_001399.5(EDA):c.585_697del (p.Pro196fs)	EDA	Pathogenic	criteria provided, single submitter
1076088	NM_001399.5(EDA):c.223G>T (p.Glu75Ter)	EDA	Pathogenic	criteria provided, single submitter
1076565	NM_001399.5(EDA):c.216_220del (p.Gly73fs)	EDA	Pathogenic	criteria provided, single submitter
11031	NM_001399.5(EDA):c.181T>C (p.Tyr61His)	EDA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11033	NM_001399.5(EDA):c.67C>T (p.Gln23Ter)	EDA	Pathogenic	criteria provided, multiple submitters, no conflicts
11035	NM_001399.5(EDA):c.463C>T (p.Arg155Cys)	EDA	Pathogenic	criteria provided, multiple submitters, no conflicts
11036	NM_001399.5(EDA):c.466C>T (p.Arg156Cys)	EDA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11037	NM_001399.5(EDA):c.467G>A (p.Arg156His)	EDA	Pathogenic	criteria provided, multiple submitters, no conflicts
11039	NM_001399.5(EDA):c.671G>C (p.Gly224Ala)	EDA	Pathogenic	no assertion criteria provided
11040	NM_001399.5(EDA):c.1045G>A (p.Ala349Thr)	EDA	Pathogenic	criteria provided, multiple submitters, no conflicts
11041	NM_001399.5(EDA):c.183C>G (p.Tyr61Ter)	EDA	Pathogenic	criteria provided, single submitter
11042	EDA, 36-BP DEL, EX5	EDA	Pathogenic	no assertion criteria provided
11043	EDA, 1-BP DEL, EX6	EDA	Pathogenic	no assertion criteria provided
11045	NM_001399.5(EDA):c.1072C>G (p.Gln358Glu)	EDA	Pathogenic	criteria provided, single submitter
11046	NM_001399.5(EDA):c.573_574insT (p.Gly192fs)	EDA	Pathogenic	no assertion criteria provided
11047	NM_001399.5(EDA):c.912_913dup (p.Ser305fs)	EDA	Pathogenic	no assertion criteria provided
11048	NM_001399.5(EDA):c.1013C>T (p.Thr338Met)	EDA	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 3 · 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
EDA	Definitive	X-linked	X-linked hypohidrotic ectodermal dysplasia	7
EDA2R	Supportive	X-linked	X-linked hypohidrotic ectodermal dysplasia

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
EDA2R	Orphanet:181	X-linked hypohidrotic ectodermal dysplasia
EDA	Orphanet:181	X-linked hypohidrotic ectodermal dysplasia
EDA	Orphanet:99798	Oligodontia

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
EDA2R	HGNC:17756	ENSG00000131080	Q9HAV5	Tumor necrosis factor receptor superfamily member 27	gencc,clinvar
EDA	HGNC:3157	ENSG00000158813	Q92838	Ectodysplasin-A	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
EDA2R	Tumor necrosis factor receptor superfamily member 27	Receptor for EDA isoform A2, but not for EDA isoform A1.
EDA	Ectodysplasin-A	Cytokine which is involved in epithelial-mesenchymal signaling during morphogenesis of ectodermal organs.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
EDA2R	Other/Unknown	no		TNFR/NGFR_Cys_rich_reg, TNFR_27, TNFRSF27_N
EDA	Other/Unknown	no		TNF_dom, Tumour_necrosis_fac-like_dom, TNF_Ligand_Superfamily

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
olfactory bulb	1
stromal cell of endometrium	1
type B pancreatic cell	1
male germ line stem cell (sensu Vertebrata) in testis	1
oocyte	1
tongue squamous epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
EDA2R	157	ubiquitous	marker	olfactory bulb, type B pancreatic cell, stromal cell of endometrium
EDA	175	broad	marker	tongue squamous epithelium, male germ line stem cell (sensu Vertebrata) in testis, oocyte

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
EDA2R	842
EDA	792

Intra-cohort edges

A	B	Sources
EDA	EDA2R	string_interaction

Structural data

PDB: 1 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
EDA	Q92838	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
EDA2R	Q9HAV5	69.14

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
TNFs bind their physiological receptors	2	393.8×	6e-06	EDA2R, EDA

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
cytokine-mediated signaling pathway	2	130.6×	0.001	EDA2R, EDA
trachea gland development	1	4213.0×	0.002	EDA
positive regulation of canonical NF-kappaB signal transduction	2	72.6×	0.002	EDA2R, EDA
ectodermal cell differentiation	1	2106.5×	0.002	EDA2R
salivary gland cavitation	1	1685.2×	0.002	EDA
hair follicle placode formation	1	1685.2×	0.002	EDA
regulation of non-canonical NF-kappaB signal transduction	1	766.0×	0.004	EDA
pigmentation	1	351.1×	0.007	EDA
intrinsic apoptotic signaling pathway by p53 class mediator	1	290.6×	0.008	EDA2R
odontogenesis	1	263.3×	0.008	EDA
odontogenesis of dentin-containing tooth	1	150.5×	0.013	EDA
positive regulation of non-canonical NF-kappaB signal transduction	1	127.7×	0.014	EDA
epidermis development	1	105.3×	0.015	EDA2R
cell-matrix adhesion	1	81.8×	0.016	EDA
positive regulation of JNK cascade	1	81.8×	0.016	EDA2R
positive regulation of canonical Wnt signaling pathway	1	77.3×	0.016	EDA
canonical Wnt signaling pathway	1	76.6×	0.016	EDA
gene expression	1	39.9×	0.029	EDA
immune response	1	23.5×	0.046	EDA
positive regulation of gene expression	1	19.4×	0.054	EDA
cell differentiation	1	14.6×	0.068	EDA

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
EDA2R	0	0
EDA	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	EDA2R, EDA

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)
EDA2R	0	—
EDA	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 14.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	11
PHASE2	2
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04980638	PHASE2	RECRUITING	Intraamniotic Administrations of ER004 to Male Subjects With X-linked Hypohidrotic Ectodermal Dysplasia
NCT01775462	PHASE2	COMPLETED	Phase 2 Study to Evaluate Safety, Pharmacokinetics, Immunogenicity and Pharmacodynamics/Efficacy of EDI200 in Male Infants With X-Linked Hypohidrotic Ectodermal Dysplasia (XLHED)
NCT01564225	PHASE1	COMPLETED	A Phase 1, Open-label, Multicenter, Safety and Pharmacokinetic Study of EDI200
NCT07096206	Not specified	ACTIVE_NOT_RECRUITING	Characteristics and Impacts of X-linked Hypohidrotic Ectodermal Dysplasia (XLHED) in Boys: An Observational International Study
NCT01135888	Not specified	COMPLETED	Short Term Effects and Risks of Physical Exercise in Subjects With Hypohidrotic Ectodermal Dysplasia
NCT01308333	Not specified	COMPLETED	Investigation of Chronic Inflammatory Processes in Male Individuals With Hypohidrotic Ectodermal Dysplasia
NCT01342133	Not specified	COMPLETED	Sweat Duct Imaging in Mother/Newborn Dyads
NCT01398397	Not specified	COMPLETED	Medical Record Review of Hypohidrotic Ectodermal Dysplasia Clinical Phenotype
NCT01398813	Not specified	COMPLETED	X-Linked Hypohidrotic Ectodermal Dysplasia (XLHED) Carrier Outlook Toward Reproduction Survey
NCT01629927	Not specified	COMPLETED	Evaluation of Phenotypic and Genetic Properties in Male Subjects Affected By Hypohidrotic Ectodermal Dysplasia (ECP-012)
NCT01629940	Not specified	COMPLETED	Phenotypic and Genetic Properties in Males at Risk for X-linked Hypohidrotic Ectodermal Dysplasia: Evaluation of an Early Diagnosis Technology and Tests to Assess Nutritional Status
NCT01871714	Not specified	COMPLETED	Phenotypic Properties in Individuals Affected With XLHED
NCT01992289	Not specified	UNKNOWN	Extension Study of XLHED-Affected Male Subjects Treated With EDI200 in Protocol ECP-002
NCT02099552	Not specified	COMPLETED	Natural History and Outcomes in X-Linked Hypohidrotic Ectodermal Dysplasia

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
EDI-200	2	3