Epidermolytic palmoplantar keratoderma, 1

Summary

Epidermolytic palmoplantar keratoderma, 1 (MONDO:0007758) is a disease caused by KRT9 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: 1-9 / 100 000 (Ireland) [Orphanet-validated]
• Causal gene: KRT9 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 23
• Phenotypes (HPO): 15

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	4.4	Ireland	Validated

Signs & symptoms

Clinical features (HPO)

15 HPO clinical features (Orphanet curated; top 15 by frequency):

HPO ID	Term	Frequency
HP:0000962	Hyperkeratosis	Very frequent (80-99%)
HP:0000972	Palmoplantar hyperkeratosis	Very frequent (80-99%)
HP:0001217	Clubbing	Frequent (30-79%)
HP:0001220	Interphalangeal joint contracture of finger	Frequent (30-79%)
HP:0001231	Abnormal fingernail morphology	Frequent (30-79%)
HP:0007447	Diffuse palmoplantar kyperkeratosis	Frequent (30-79%)
HP:0010765	Palmar hyperkeratosis	Frequent (30-79%)
HP:0025092	Epidermal acanthosis	Frequent (30-79%)
HP:0032541	Knuckle pad	Frequent (30-79%)
HP:0000975	Hyperhidrosis	Occasional (5-29%)
HP:0008066	Abnormal blistering of the skin	Occasional (5-29%)
HP:0010829	Impaired temperature sensition	Occasional (5-29%)
HP:0010830	Impaired tactile sensation	Occasional (5-29%)
HP:0012385	Camptodactyly	Occasional (5-29%)
HP:0025114	Hypergranulosis	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	epidermolytic palmoplantar keratoderma, 1
Mondo ID	MONDO:0007758
OMIM	144200
Orphanet	2199
DOID	DOID:0070552
NCIT	C84693
SNOMED CT	399955009
GARD	0002826
Is cancer (heuristic)	no

Also known as: diffuse erythrodermic palmoplantar keratoderma, VC6rner type · diffuse erythrodermic palmoplantar keratoderma, Voerner type · diffuse erythrodermic palmoplantar keratoderma, Vörner type · epidermolytic palmoplantar keratoderma of VC6rner · epidermolytic palmoplantar keratoderma of Voerner · epidermolytic palmoplantar keratoderma of Vörner · EPPK · hyperkeratosis palmoplantar localised epidermolytic · hyperkeratosis palmoplantar localized epidermolytic · hyperkeratosis, localised epidermolytic · palmoplantar keratoderma, epidermolytic

Data availability: 23 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › integumentary system disorder › skin disorder › keratosis › palmoplantar keratosis › hereditary palmoplantar keratoderma › diffuse palmoplantar keratoderma › epidermolytic palmoplantar keratoderma, 1

Related subtypes (31): autosomal dominant palmoplantar keratoderma and congenital alopecia, dermatopathia pigmentosa reticularis, Clouston syndrome, palmoplantar keratoderma-deafness syndrome, palmoplantar keratoderma-hereditary motor and sensory neuropathy syndrome, keratosis palmaris et plantaris-clinodactyly syndrome, Bart-Pumphrey syndrome, Naegeli-Franceschetti-Jadassohn syndrome, palmoplantar keratoderma-sclerodactyly syndrome, autosomal recessive palmoplantar keratoderma and congenital alopecia, Schöpf-Schulz-Passarge syndrome, hereditary palmoplantar keratoderma, Gamborg-Nielsen type, Papillon-Lefevre disease, Haim-Munk syndrome, mal de Meleda, odonto-onycho-dermal dysplasia, palmoplantar keratoderma, Bothnian type, diffuse nonepidermolytic palmoplantar keratoderma, loricrin keratoderma, skin fragility-woolly hair-palmoplantar keratoderma syndrome, Curly hair - acral keratoderma - caries syndrome, CEDNIK syndrome, palmoplantar keratoderma-XX sex reversal-predisposition to squamous cell carcinoma syndrome, corneal intraepithelial dyskeratosis-palmoplantar hyperkeratosis-laryngeal dyskeratosis syndrome, hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome, palmoplantar keratoderma, Nagashima type, erythrokeratodermia variabilis, diffuse palmoplantar keratoderma with painful fissures, KID syndrome, diffuse palmoplantar keratoderma - acrocyanosis syndrome, hearing loss with skin disease

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

23 retrieved; paginated sample, class counts are floors:

9 uncertain significance, 9 pathogenic, 3 pathogenic/likely pathogenic, 1 likely pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
2997	NM_000226.4(KRT9):c.487C>T (p.Arg163Trp)	KRT9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2998	NM_000226.4(KRT9):c.515A>C (p.Gln172Pro)	KRT9	Pathogenic	no assertion criteria provided
2999	NM_000226.4(KRT9):c.481A>T (p.Asn161Tyr)	KRT9	Pathogenic	no assertion criteria provided
3001	NM_000226.4(KRT9):c.488G>A (p.Arg163Gln)	KRT9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3002	NM_000226.4(KRT9):c.469A>G (p.Met157Val)	KRT9	Pathogenic	criteria provided, multiple submitters, no conflicts
3003	NM_000226.4(KRT9):c.482A>G (p.Asn161Ser)	KRT9	Pathogenic	criteria provided, multiple submitters, no conflicts
3004	NM_000226.4(KRT9):c.503T>C (p.Leu168Ser)	KRT9	Pathogenic	no assertion criteria provided
3005	NM_000226.4(KRT9):c.478C>G (p.Leu160Val)	KRT9	Pathogenic	no assertion criteria provided
3007	NM_000226.4(KRT9):c.511G>A (p.Val171Met)	KRT9	Pathogenic	no assertion criteria provided
3008	NM_000226.4(KRT9):c.478C>T (p.Leu160Phe)	KRT9	Pathogenic	no assertion criteria provided
3009	NM_000226.4(KRT9):c.482A>T (p.Asn161Ile)	KRT9	Pathogenic	no assertion criteria provided
3237488	NM_000226.4(KRT9):c.488G>T (p.Arg163Leu)	KRT9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3000	NM_000226.4(KRT9):c.483T>A (p.Asn161Lys)	KRT9	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3006	NM_000226.4(KRT9):c.470T>C (p.Met157Thr)	KRT9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2970040	NM_000226.4(KRT9):c.980G>A (p.Arg327His)	KRT9	Uncertain significance	criteria provided, multiple submitters, no conflicts
323128	NM_000226.4(KRT9):c.1096A>G (p.Ser366Gly)	KRT9	Uncertain significance	criteria provided, multiple submitters, no conflicts
3382072	NM_000226.4(KRT9):c.1282C>T (p.Gln428Ter)	KRT9	Uncertain significance	criteria provided, single submitter
3581942	NM_000226.4(KRT9):c.1795A>C (p.Ser599Arg)	KRT9	Uncertain significance	criteria provided, single submitter
3891543	NM_000226.4(KRT9):c.170G>A (p.Ser57Asn)	KRT9	Uncertain significance	criteria provided, single submitter
3891544	NM_000226.4(KRT9):c.170G>T (p.Ser57Ile)	KRT9	Uncertain significance	criteria provided, single submitter
3891545	NM_000226.4(KRT9):c.1647_1712del (p.His550_Gly571del)	KRT9	Uncertain significance	criteria provided, single submitter
4277594	NM_000226.4(KRT9):c.494C>T (p.Ala165Val)	KRT9	Uncertain significance	criteria provided, single submitter
66155	NM_000226.4(KRT9):c.484T>C (p.Ser162Pro)	KRT9	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · 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
KRT9	Definitive	Autosomal dominant	epidermolytic palmoplantar keratoderma, 1	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KRT9	Orphanet:2199	Epidermolytic palmoplantar keratoderma

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
KRT9	HGNC:6447	ENSG00000171403	P35527	Keratin, type I cytoskeletal 9	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KRT9	Keratin, type I cytoskeletal 9	May serve an important special function either in the mature palmar and plantar skin tissue or in the morphogenetic program of the formation of these tissues.

Protein-family classification

Druggable: 0 · Difficult: 0 · 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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KRT9	Other/Unknown	no		Keratin_I, IF_conserved, IF_rod_dom

Expression context

Cohort genes with no expression data: 0.

Breadth distribution (Bgee present_calls)

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

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	1
penis	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KRT9	59	tissue_specific	yes	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, penis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KRT9	1,635

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
KRT9	P35527	66.43

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Formation of the cornified envelope	1	87.8×	0.027	KRT9
Keratinization	1	55.7×	0.027	KRT9
Developmental Biology	1	14.5×	0.069	KRT9

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
skin development	1	443.5×	0.007	KRT9
morphogenesis of an epithelium	1	343.9×	0.007	KRT9
intermediate filament organization	1	240.7×	0.007	KRT9
epidermis development	1	210.7×	0.007	KRT9
epithelial cell differentiation	1	175.5×	0.007	KRT9
spermatogenesis	1	35.2×	0.028	KRT9

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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
KRT9	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	1	KRT9

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
KRT9	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.