Plantar fibromatosis

Summary

Plantar fibromatosis (MONDO:0004684) is a disease with 2 cohort genes (2 GWAS associations across 1 studies) and 3 clinical trials.

At a glance

• Cohort genes: 2
• GWAS associations: 2
• Phenotypes (HPO): 5
• Clinical trials: 3

Clinical features

Signs & symptoms

Clinical features (HPO)

5 HPO clinical features (Orphanet curated; top 5 by frequency):

HPO ID	Term	Frequency
HP:0002829	Arthralgia	Very frequent (80-99%)
HP:0003401	Paresthesia	Very frequent (80-99%)
HP:0100679	Lack of skin elasticity	Very frequent (80-99%)
HP:0001482	Subcutaneous nodule	Frequent (30-79%)
HP:0009830	Peripheral neuropathy	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	plantar fibromatosis
Mondo ID	MONDO:0004684
EFO	EFO:1000481
MeSH	C537000
Orphanet	199251
DOID	DOID:8936
ICD-11	409482033
NCIT	C4680
SNOMED CT	13370002
UMLS	C0158360
MedGen	56385
GARD	0006873
MedDRA	10035154
Anatomy (UBERON)	UBERON:0008338
Is cancer (heuristic)	no

Also known as: Ledderhose’s disease · Lederhose disease · plantar fibromatosis · plantar part of pes superficial Fibromatosis · plantar part of pes superficial fibromatosis · superficial fibromatosis of plantar part of pes

Data availability: 2 GWAS associations (1 study).

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › cancer or benign tumor › neoplastic disease or syndrome › neoplasm › mesenchymal cell neoplasm › fibroblastic neoplasm › fibromatosis › superficial Fibromatosis › plantar fibromatosis

Related subtypes (5): palmar fibromatosis, familial Dupuytren contracture, Peyronie disease, calcified aponeurotic fibroma, infantile digital fibromatosis

Genetics & variants

GWAS landscape

2 GWAS associations across 1 studies. Top hits map to 1 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs62051384	2e-08	WWP2	T	1.07
chr5:118704153	3e-08		TGC	1.08

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST005558	Kim SK	2018	17,627	65,637	Two Genetic Variants Associated with Plantar Fascial Disorders.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	0
Tier 2: splice/UTR	0
Tier 3: regulatory	0
Tier 4: intronic/intergenic	2

MAF distribution

Bucket	Variants
common (>=0.05)	2
low_freq (0.01-0.05)	0
rare (<0.01)	0
unknown	0

Functional consequences

Consequence	Count
intron_variant	1
unknown	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs62051384	16	69825279	C>T	0.373	intron_variant	WWP2	2e-08	Tier 4: intronic/intergenic
chr5:118704153				0.322			3e-08	Tier 4: intronic/intergenic

Genes & proteins

Mendelian disease overlap and somatic drivers

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

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
WWP2	HGNC:16804	ENSG00000198373	O00308	NEDD4-like E3 ubiquitin-protein ligase WWP2	gwas
TNFAIP8	HGNC:17260	ENSG00000145779	O95379	Tumor necrosis factor alpha-induced protein 8	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
WWP2	NEDD4-like E3 ubiquitin-protein ligase WWP2	E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates.
TNFAIP8	Tumor necrosis factor alpha-induced protein 8	Acts as a negative mediator of apoptosis and may play a role in tumor progression.

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)
WWP2	Scaffold/PPI	no	2.3.2.26	C2_dom, HECT_dom, WW_dom
TNFAIP8	Other/Unknown	no		TNFAIP8-like, TNFAIP8_sf

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
ascending aorta	1
tendon of biceps brachii	1
tibia	1
cartilage tissue	1
epithelium of nasopharynx	1
nasopharynx	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
WWP2	279	ubiquitous	marker	tibia, tendon of biceps brachii, ascending aorta
TNFAIP8	255	ubiquitous	marker	cartilage tissue, epithelium of nasopharynx, nasopharynx

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
WWP2	4,978
TNFAIP8	491

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
WWP2	O00308	11

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TNFAIP8	O95379	89.83

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. 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
NOTCH3 Activation and Transmission of Signal to the Nucleus	1	237.9×	0.014	WWP2
PI Metabolism	1	178.4×	0.014	TNFAIP8
RHOU GTPase cycle	1	139.3×	0.014	WWP2
Phospholipid metabolism	1	100.2×	0.014	TNFAIP8
RHOJ GTPase cycle	1	100.2×	0.014	WWP2
Regulation of PTEN stability and activity	1	92.1×	0.014	WWP2
RHOQ GTPase cycle	1	90.6×	0.014	WWP2
Metabolism of lipids	1	15.8×	0.070	TNFAIP8
Metabolism	1	5.8×	0.165	TNFAIP8

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
extracellular transport	1	2808.7×	0.006	WWP2
negative regulation of potassium ion export across plasma membrane	1	1203.7×	0.007	WWP2
regulation of monoatomic ion transmembrane transport	1	366.4×	0.015	WWP2
negative regulation of Notch signaling pathway	1	216.1×	0.017	WWP2
symbiont entry into host cell	1	200.6×	0.017	WWP2
protein K63-linked ubiquitination	1	133.8×	0.018	WWP2
protein autoubiquitination	1	117.0×	0.018	WWP2
regulation of membrane potential	1	115.4×	0.018	WWP2
transcription by RNA polymerase II	1	35.3×	0.053	WWP2
positive regulation of apoptotic process	1	28.4×	0.059	TNFAIP8
proteasome-mediated ubiquitin-dependent protein catabolic process	1	26.1×	0.059	WWP2
protein ubiquitination	1	20.7×	0.068	WWP2
negative regulation of apoptotic process	1	17.4×	0.074	TNFAIP8
negative regulation of DNA-templated transcription	1	15.8×	0.076	WWP2
apoptotic process	1	14.3×	0.078	TNFAIP8
negative regulation of transcription by RNA polymerase II	1	8.9×	0.117	WWP2
positive regulation of transcription by RNA polymerase II	1	7.4×	0.130	WWP2

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
WWP2	0	0
TNFAIP8	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
WWP2	2.3.2.26	HECT-type E3 ubiquitin transferase

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	WWP2, TNFAIP8

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)
WWP2	0	—
TNFAIP8	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 3.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE3	2
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06151197	PHASE3	ACTIVE_NOT_RECRUITING	Study to Assess EN3835 in the Treatment of Plantar Fibromatosis (Also Known as Ledderhose Disease)
NCT05254457	PHASE3	COMPLETED	Long-Term Safety, Efficacy, and Durability of EN3835 in the Treatment and Retreatment of Plantar Fibromatosis
NCT05152173	PHASE2	COMPLETED	Efficacy, Safety, and Tolerability, of EN3835 vs Placebo in the Treatment of Plantar Fibromatosis