Pachyonychia congenita

Summary

Pachyonychia congenita (MONDO:0016471) is a disease with 4 cohort genes and 12 clinical trials. The dominant Reactome pathway is Formation of the cornified envelope (4 cohort genes). Top therapeutic interventions include vehicle.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 4
• Phenotypes (HPO): 27
• Clinical trials: 12

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		1000	Worldwide	Validated
Point prevalence	<1 / 1 000 000	0.09	Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

27 HPO clinical features (Orphanet curated; top 27 by frequency):

HPO ID	Term	Frequency
HP:0000982	Palmoplantar keratoderma	Very frequent (80-99%)
HP:0007446	Palmoplantar blistering	Very frequent (80-99%)
HP:0008401	Onychogryposis of toenails	Very frequent (80-99%)
HP:0008404	Nail dystrophy	Very frequent (80-99%)
HP:0012514	Lower limb pain	Very frequent (80-99%)
HP:0030268	Hyperplastic callus formation	Very frequent (80-99%)
HP:0002745	Oral leukoplakia	Frequent (30-79%)
HP:0007410	Palmoplantar hyperhidrosis	Frequent (30-79%)
HP:0007490	Linear arrays of macular hyperkeratoses in flexural areas	Frequent (30-79%)
HP:0007502	Follicular hyperkeratosis	Frequent (30-79%)
HP:0010765	Palmar hyperkeratosis	Frequent (30-79%)
HP:0012035	Steatocystoma multiplex	Frequent (30-79%)
HP:0025245	Cutaneous cyst	Frequent (30-79%)
HP:0040036	Onychogryposis of fingernail	Frequent (30-79%)
HP:0100798	Fingernail dysplasia	Frequent (30-79%)
HP:0200040	Epidermoid cyst	Frequent (30-79%)
HP:0000695	Natal tooth	Occasional (5-29%)
HP:0001508	Failure to thrive	Occasional (5-29%)
HP:0001818	Paronychia	Occasional (5-29%)
HP:0006288	Advanced eruption of teeth	Occasional (5-29%)
HP:0011968	Feeding difficulties	Occasional (5-29%)
HP:0025248	Eruptive vellus hair cyst	Occasional (5-29%)
HP:0030766	Ear pain	Occasional (5-29%)
HP:0001596	Alopecia	Very rare (<1-4%)
HP:0001609	Hoarse voice	Very rare (<1-4%)
HP:0002098	Respiratory distress	Very rare (<1-4%)
HP:0030318	Angular cheilitis	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	pachyonychia congenita
Mondo ID	MONDO:0016471
MeSH	D053549
OMIM	167200
Orphanet	2309
DOID	DOID:0050449
ICD-11	1446983705
NCIT	C84986
UMLS	C0265334
MedGen	78556
GARD	0010753
NORD	1542
Is cancer (heuristic)	no

Also known as: congenital pachyonychia · pachyonychia congenita syndrome · pachyonychia congenita type 1 · PC

Data availability: 4 GenCC gene-disease records.

Disease family

An umbrella term covering 4 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › integumentary system disorder › skin disorder › keratosis › palmoplantar keratosis › hereditary palmoplantar keratoderma › focal palmoplantar keratoderma › pachyonychia congenita

Related subtypes (11): hereditary painful callosities, palmoplantar keratoderma-esophageal carcinoma syndrome, focal palmoplantar and gingival keratoderma, tyrosinemia type II, hypotrichosis-osteolysis-periodontitis-palmoplantar keratoderma syndrome, palmoplantar keratoderma, nonepidermolytic, focal 1, nail and teeth abnormalities-marginal palmoplantar keratoderma-oral hyperpigmentation syndrome, wooly hair-palmoplantar keratoderma syndrome, isolated focal non-epidermolytic palmoplantar keratoderma, focal palmoplantar keratoderma with joint keratoses, striate palmoplantar keratoderma

Subtypes (4): pachyonychia congenita 1, pachyonychia congenita 2, pachyonychia congenita 3, pachyonychia congenita 4

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: 33 · Orphanet: 7 · 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
KRT16	Strong	Autosomal dominant	pachyonychia congenita 1	10
KRT17	Strong	Autosomal dominant	pachyonychia congenita 2	9
KRT6A	Strong	Autosomal dominant	pachyonychia congenita 3	9
KRT6B	Strong	Autosomal dominant	pachyonychia congenita 4	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KRT16	Orphanet:2199	Epidermolytic palmoplantar keratoderma
KRT16	Orphanet:2309	Pachyonychia congenita
KRT16	Orphanet:448264	Isolated focal non-epidermolytic palmoplantar keratoderma
KRT17	Orphanet:2309	Pachyonychia congenita
KRT17	Orphanet:841	Sebocystomatosis
KRT6A	Orphanet:2309	Pachyonychia congenita
KRT6B	Orphanet:2309	Pachyonychia congenita

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
KRT16	HGNC:6423	ENSG00000186832	P08779	Keratin, type I cytoskeletal 16	gencc
KRT17	HGNC:6427	ENSG00000128422	Q04695	Keratin, type I cytoskeletal 17	gencc
KRT6A	HGNC:6443	ENSG00000205420	P02538	Keratin, type II cytoskeletal 6A	gencc
KRT6B	HGNC:6444	ENSG00000185479	P04259	Keratin, type II cytoskeletal 6B	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KRT16	Keratin, type I cytoskeletal 16	Epidermis-specific type I keratin that plays a key role in skin.
KRT17	Keratin, type I cytoskeletal 17	Type I keratin involved in the formation and maintenance of various skin appendages, specifically in determining shape and orientation of hair.
KRT6A	Keratin, type II cytoskeletal 6A	Epidermis-specific type I keratin involved in wound healing.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 4 · 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	4	1.8×	0.097

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KRT16	Other/Unknown	no		Keratin_I, IF_conserved, IF_rod_dom
KRT17	Other/Unknown	no		Keratin_I, IF_conserved, IF_rod_dom
KRT6A	Other/Unknown	no		Keratin_II, IF_conserved, Keratin_2_head
KRT6B	Other/Unknown	no		Keratin_II, IF_conserved, Keratin_2_head

Expression context

Cohort genes with no expression data: 0.

4 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gingiva	4
gingival epithelium	4
lower esophagus mucosa	2
squamous epithelium	1
cervix squamous epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KRT16	176	broad	marker	gingival epithelium, gingiva, lower esophagus mucosa
KRT17	224	broad	marker	gingival epithelium, gingiva, lower esophagus mucosa
KRT6A	187	broad	marker	gingiva, gingival epithelium, squamous epithelium
KRT6B	168	tissue_specific	marker	gingiva, gingival epithelium, cervix squamous epithelium

Protein interactions among cohort

Intra-cohort edges: 4.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KRT17	2,523
KRT16	2,175
KRT6A	2,160
KRT6B	1,692

Intra-cohort edges

A	B	Sources
KRT16	KRT6A	string_interaction
KRT16	KRT6B	string_interaction
KRT17	KRT6A	biogrid_interaction, intact
KRT17	KRT6B	string_interaction

Structural data

PDB: 1 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KRT6A	P02538	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
KRT17	Q04695	79.28
KRT16	P08779	74.26
KRT6B	P04259	69.76

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 4 evidence-associated genes (4 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 4 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	4	87.8×	6e-08	KRT16, KRT17, KRT6A, KRT6B
Keratinization	4	55.7×	2e-07	KRT16, KRT17, KRT6A, KRT6B
Developmental Biology	4	14.5×	3e-05	KRT16, KRT17, KRT6A, KRT6B
Developmental Lineage of Pancreatic Ductal Cells	1	57.1×	0.017	KRT17

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
intermediate filament organization	4	240.7×	4e-09	KRT16, KRT17, KRT6A, KRT6B
keratinization	4	234.1×	4e-09	KRT16, KRT17, KRT6A, KRT6B
morphogenesis of an epithelium	3	257.9×	7e-07	KRT16, KRT17, KRT6A
negative regulation of entry of bacterium into host cell	1	1404.3×	0.004	KRT6A
keratinocyte migration	1	601.9×	0.007	KRT16
positive regulation of hair follicle development	1	601.9×	0.007	KRT17
ectoderm development	1	300.9×	0.011	KRT6B
hair cycle	1	234.1×	0.013	KRT16
hair follicle morphogenesis	1	123.9×	0.021	KRT17
establishment of skin barrier	1	113.9×	0.021	KRT16
killing of cells of another organism	1	68.0×	0.030	KRT6A
keratinocyte differentiation	1	62.0×	0.030	KRT16
wound healing	1	56.9×	0.030	KRT6A
positive regulation of translation	1	56.9×	0.030	KRT17
positive regulation of cell growth	1	45.8×	0.034	KRT17
epithelial cell differentiation	1	43.9×	0.034	KRT17
antimicrobial humoral immune response mediated by antimicrobial peptide	1	40.5×	0.035	KRT6A
cytoskeleton organization	1	33.2×	0.039	KRT16
defense response to Gram-positive bacterium	1	31.9×	0.039	KRT6A
negative regulation of cell migration	1	27.9×	0.042	KRT16
inflammatory response	1	9.4×	0.117	KRT16
positive regulation of cell population proliferation	1	8.4×	0.119	KRT6A
innate immune response	1	8.4×	0.119	KRT16
cell differentiation	1	7.3×	0.131	KRT6A

Therapeutics

Drugs indicated for this disease

0 approved, 1 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Sirolimus	Phase 3 (in late-stage trials)

Drug target analysis

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

Druggability breadth: 0 of 4 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
KRT16	0	0
KRT17	0	0
KRT6A	0	0
KRT6B	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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	4	KRT16, KRT17, KRT6A, KRT6B

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
KRT16	0	—
KRT17	0	—
KRT6A	0	—
KRT6B	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 12.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE1	5
PHASE3	3
Not specified	2
PHASE2/PHASE3	1
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05643872	PHASE3	RECRUITING	A Study Evaluating the Safety and Pharmacokinetics of QTORIN Rapamycin 3.9% Anhydrous Gel in the Treatment of Adults With Pachyonychia Congenita
NCT03920228	PHASE2/PHASE3	COMPLETED	Phase 2/3 Study Evaluating the Safety and Efficacy of PTX-022 in Treatment of Adults With Pachyonychia Congenita
NCT04520750	PHASE3	COMPLETED	VALO-2: Study Evaluating the Safety and Efficacy of PTX022 in the Treatment of Adults With Pachyonychia Congenita
NCT05180708	PHASE3	COMPLETED	A Multicenter, Phase 3 Randomized, Double-Blind, Vehicle-Controlled Study Evaluating the Safety and Efficacy of QTORIN 3.9% Rapamycin Anhydrous Gel in the Treatment of Pachyonychia Congenita
NCT06545695	PHASE1/PHASE2	NOT_YET_RECRUITING	Epidermal Growth Factor Receptor Inhibition for Keratinopathies
NCT00716014	PHASE1	COMPLETED	Study of TD101, a Small Interfering RNA (siRNA) Designed for Treatment of Pachyonychia Congenita
NCT02152007	PHASE1	COMPLETED	Topical Sirolimus for the Treatment of Pachyonychia Congenita (PC)
NCT02592954	PHASE1	COMPLETED	Effect of Broccoli Sprout Extract on Keratinocyte Differentiation in Normal Skin
NCT05435638	PHASE1	COMPLETED	Study Designed to Evaluate Safety and Efficacy of 1% Topical Formulation of KM-001 on Type 1 Punctate Palmoplantar Keratoderma or Pachyonychia Congenita Diseases
NCT05956314	PHASE1	COMPLETED	Assessment of KM-001 - Safety, Tolerability, and Efficacy in Patients With PPPK1 or PC
NCT02321423	Not specified	RECRUITING	International Pachyonychia Congenita Research Registry
NCT01382511	Not specified	UNKNOWN	Simvastatin Treatment of Pachyonychia Congenita

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
VEHICLE	0	1