Papillon-Lefevre disease

Summary

Papillon-Lefevre disease (MONDO:0009490) is a disease caused by CTSC (GenCC Definitive), with 1 cohort gene and 5 clinical trials.

At a glance

• Prevalence: 1-9 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: CTSC (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 473
• Phenotypes (HPO): 29
• Clinical trials: 5

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000	0.25	Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

29 HPO clinical features (Orphanet curated; top 29 by frequency):

HPO ID	Term	Frequency
HP:0000164	Abnormality of the dentition	Very frequent (80-99%)
HP:0000166	Severe periodontitis	Very frequent (80-99%)
HP:0000230	Gingivitis	Very frequent (80-99%)
HP:0000704	Periodontitis	Very frequent (80-99%)
HP:0000972	Palmoplantar hyperkeratosis	Very frequent (80-99%)
HP:0000982	Palmoplantar keratoderma	Very frequent (80-99%)
HP:0001231	Abnormal fingernail morphology	Very frequent (80-99%)
HP:0006308	Atrophy of alveolar ridges	Very frequent (80-99%)
HP:0006323	Premature loss of primary teeth	Very frequent (80-99%)
HP:0009804	Tooth agenesis	Very frequent (80-99%)
HP:0200039	Pustule	Very frequent (80-99%)
HP:0001581	Recurrent skin infections	Frequent (30-79%)
HP:0001597	Abnormality of the nail	Frequent (30-79%)
HP:0002205	Recurrent respiratory infections	Frequent (30-79%)
HP:0002514	Cerebral calcification	Frequent (30-79%)
HP:0008404	Nail dystrophy	Frequent (30-79%)
HP:0011132	Chronic furunculosis	Frequent (30-79%)
HP:0100838	Recurrent cutaneous abscess formation	Frequent (30-79%)
HP:0000998	Hypertrichosis	Occasional (5-29%)
HP:0001053	Hypopigmented skin patches	Occasional (5-29%)
HP:0001073	Cigarette-paper scars	Occasional (5-29%)
HP:0001166	Arachnodactyly	Occasional (5-29%)
HP:0002230	Generalized hirsutism	Occasional (5-29%)
HP:0002231	Sparse body hair	Occasional (5-29%)
HP:0002797	Osteolysis	Occasional (5-29%)
HP:0002860	Squamous cell carcinoma	Occasional (5-29%)
HP:0002861	Melanoma	Occasional (5-29%)
HP:0008069	Neoplasm of the skin	Occasional (5-29%)
HP:0100523	Liver abscess	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Papillon-Lefevre disease
Mondo ID	MONDO:0009490
MeSH	D010214
OMIM	245000
Orphanet	678
DOID	DOID:3389
NCIT	C84992
SNOMED CT	40158001
UMLS	C0030360
MedGen	45306
GARD	0003100
NORD	1552
Is cancer (heuristic)	no

Also known as: hyperkeratosis palmoplantaris with periodontosis · Keratoris palmoplantaris with periodontopathia · keratosis palmoplantar - periodontopathy · keratosis palmoplantar-periodontopathy syndrome · palmar-plantar hyperkeratosis and concomitant periodontal destruction · palmoplantar keratoderma with periodontosis · PALS · Papillon Lefèvre Syndrome · PAPILLON-Lefevre syndrome · PLS

Data availability: 473 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › skeletal system disorder › periodontal disorder › Papillon-Lefevre disease

Related subtypes (3): gingival disorder, periodontitis, regional odontodysplasia

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

473 retrieved; paginated sample, class counts are floors:

201 likely benign, 141 uncertain significance, 70 pathogenic, 19 conflicting classifications of pathogenicity, 17 benign, 13 likely pathogenic, 9 pathogenic/likely pathogenic, 3 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
634988	NM_001814.6(CTSC):c.[1211delA;190_191insA]		Pathogenic	no assertion criteria provided
634989	NM_001814.6(CTSC):c.[716A>G;757+1G>A]		Pathogenic	no assertion criteria provided
1075099	NM_001814.6(CTSC):c.-55C>A	CTSC	Pathogenic	criteria provided, multiple submitters, no conflicts
1351279	NM_001814.6(CTSC):c.555dup (p.Thr186fs)	CTSC	Pathogenic	criteria provided, single submitter
1352166	NM_001814.6(CTSC):c.783del (p.Phe261fs)	CTSC	Pathogenic	criteria provided, single submitter
139654	NM_001814.6(CTSC):c.1056del (p.Phe351_Tyr352insTer)	CTSC	Pathogenic	no assertion criteria provided
139656	NM_001814.6(CTSC):c.815G>A (p.Arg272His)	CTSC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1398717	NM_001814.6(CTSC):c.570C>G (p.Tyr190Ter)	CTSC	Pathogenic	criteria provided, single submitter
1424145	NM_001814.6(CTSC):c.268C>T (p.Gln90Ter)	CTSC	Pathogenic	criteria provided, single submitter
1455525	NM_001814.6(CTSC):c.754C>T (p.Gln252Ter)	CTSC	Pathogenic	criteria provided, single submitter
1457970	NC_000011.9:g.(?88045475)(88071056_?)del	CTSC	Pathogenic	criteria provided, single submitter
1506173	NC_000011.9:g.(?88040961)(88042398_?)del	CTSC	Pathogenic	criteria provided, single submitter
1687330	NM_001814.6(CTSC):c.526A>T (p.Lys176Ter)	CTSC	Pathogenic	criteria provided, single submitter
1932647	NM_001814.6(CTSC):c.672dup (p.Gln225fs)	CTSC	Pathogenic	criteria provided, single submitter
1993744	NM_001814.6(CTSC):c.889+1G>A	CTSC	Pathogenic	criteria provided, single submitter
2137217	NM_001814.6(CTSC):c.1015C>T (p.Arg339Cys)	CTSC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2137218	NM_001814.6(CTSC):c.757G>A (p.Ala253Thr)	CTSC	Pathogenic	criteria provided, single submitter
2137219	NM_001814.6(CTSC):c.587T>C (p.Leu196Pro)	CTSC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2137220	NM_001814.6(CTSC):c.319-1G>A	CTSC	Pathogenic	criteria provided, multiple submitters, no conflicts
2152122	NM_001814.6(CTSC):c.401G>A (p.Trp134Ter)	CTSC	Pathogenic	criteria provided, single submitter
2160925	NM_001814.6(CTSC):c.189dup (p.Val64fs)	CTSC	Pathogenic	criteria provided, single submitter
2167619	NM_001814.6(CTSC):c.566_572del (p.Thr189fs)	CTSC	Pathogenic	criteria provided, single submitter
2193005	NM_001814.6(CTSC):c.748C>T (p.Arg250Ter)	CTSC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2446400	NM_001814.6(CTSC):c.622_628del (p.His208fs)	CTSC	Pathogenic	criteria provided, single submitter
2921412	NM_001814.6(CTSC):c.725del (p.Gly242fs)	CTSC	Pathogenic	criteria provided, single submitter
2921800	NM_001814.6(CTSC):c.201C>A (p.Tyr67Ter)	CTSC	Pathogenic	criteria provided, single submitter
2921926	NM_001814.6(CTSC):c.606dup (p.Arg203Ter)	CTSC	Pathogenic	criteria provided, single submitter
2922681	NM_001814.6(CTSC):c.328G>T (p.Glu110Ter)	CTSC	Pathogenic	criteria provided, single submitter
2925487	NM_001814.6(CTSC):c.1286G>A (p.Trp429Ter)	CTSC	Pathogenic	criteria provided, single submitter
2925490	NM_001814.6(CTSC):c.555G>A (p.Trp185Ter)	CTSC	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 2 · 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
CTSC	Definitive	Autosomal recessive	Papillon-Lefevre disease	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CTSC	Orphanet:2342	Haim-Munk syndrome
CTSC	Orphanet:678	Papillon-Lefèvre syndrome

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
CTSC	HGNC:2528	ENSG00000109861	P53634	Dipeptidyl peptidase 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CTSC	Dipeptidyl peptidase 1	Thiol protease.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Protease	1	36.6×	0.027

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CTSC	Protease	yes	3.4.14.1	Pept_cys_AS, Peptidase_C1A_C, Peptidase_C1A

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
epithelium of nasopharynx	1
nasopharynx	1
palpebral conjunctiva	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CTSC	285	ubiquitous	marker	palpebral conjunctiva, epithelium of nasopharynx, nasopharynx

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CTSC	2,733

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CTSC	P53634	18

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 14. 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
Cargo concentration in the ER	1	335.9×	0.031	CTSC
COPII-mediated vesicle transport	1	163.1×	0.031	CTSC
ER to Golgi Anterograde Transport	1	132.8×	0.031	CTSC
Transport to the Golgi and subsequent modification	1	102.9×	0.031	CTSC
MHC class II antigen presentation	1	89.2×	0.031	CTSC
Asparagine N-linked glycosylation	1	60.1×	0.039	CTSC
Membrane Trafficking	1	37.1×	0.050	CTSC
Vesicle-mediated transport	1	34.8×	0.050	CTSC
Adaptive Immune System	1	29.8×	0.052	CTSC
Innate Immune System	1	25.5×	0.055	CTSC
Neutrophil degranulation	1	23.1×	0.055	CTSC
Post-translational protein modification	1	19.2×	0.061	CTSC
Immune System	1	13.0×	0.081	CTSC
Metabolism of proteins	1	12.4×	0.081	CTSC

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
obsolete positive regulation of proteolysis involved in protein catabolic process	1	4213.0×	0.001	CTSC
positive regulation of microglial cell activation	1	2106.5×	0.001	CTSC
negative regulation of myelination	1	1872.4×	0.001	CTSC
T cell mediated cytotoxicity	1	1123.5×	0.002	CTSC
positive regulation of apoptotic signaling pathway	1	581.1×	0.003	CTSC
obsolete proteolysis involved in protein catabolic process	1	526.6×	0.003	CTSC
immune response	1	47.1×	0.024	CTSC
proteolysis	1	34.2×	0.029	CTSC

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
CTSC	OSIMERTINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CTSC	3	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
OSIMERTINIB	4	CTSC
CANERTINIB	3	CTSC
BRENSOCATIB	3	CTSC

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
CTSC	107	Binding:106, ADMET:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CTSC	3.4.14.1	dipeptidyl-peptidase I

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
CTSC	107

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

3 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.

Compound	Max phase	Cohort target (bioactivity)
OSIMERTINIB	4	CTSC
CANERTINIB	3	CTSC
BRENSOCATIB	3	CTSC

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CTSC
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 5.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	5

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05271435	Not specified	ACTIVE_NOT_RECRUITING	Digital Tools for Assessment of Motor Functions and Falls in ALS
NCT05966038	Not specified	RECRUITING	ALS/MND Natural History Study Data Repository
NCT01116934	Not specified	COMPLETED	Cytokines in Papillon-Lefèvre Syndrome
NCT01459302	Not specified	WITHDRAWN	Genetic Study of Familial and Sporadic ALS/Motor Neuron Disease, Miyoshi Myopathy and Other Neuromuscular Disorders
NCT06408727	Not specified	TEMPORARILY_NOT_AVAILABLE	Intermediate Expanded Access Protocol CNMAu8.EAP04