Pyogenic arthritis-pyoderma gangrenosum-acne syndrome

Summary

Pyogenic arthritis-pyoderma gangrenosum-acne syndrome (MONDO:0011462) is a disease caused by PSTPIP1 (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: PSTPIP1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 694
• Phenotypes (HPO): 15

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		53	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0001061	Acne	Very frequent (80-99%)
HP:0001369	Arthritis	Very frequent (80-99%)
HP:0001376	Limitation of joint mobility	Very frequent (80-99%)
HP:0001945	Fever	Very frequent (80-99%)
HP:0012378	Fatigue	Very frequent (80-99%)
HP:0200039	Pustule	Very frequent (80-99%)
HP:0200042	Skin ulcer	Very frequent (80-99%)
HP:0002716	Lymphadenopathy	Frequent (30-79%)
HP:0002829	Arthralgia	Frequent (30-79%)
HP:0010702	Increased circulating antibody level	Frequent (30-79%)
HP:0000093	Proteinuria	Occasional (5-29%)
HP:0012649	Increased inflammatory response	Occasional (5-29%)
HP:0100280	Crohn’s disease	Occasional (5-29%)
HP:0100614	Myositis	Occasional (5-29%)
HP:0100651	Type I diabetes mellitus	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	pyogenic arthritis-pyoderma gangrenosum-acne syndrome
Mondo ID	MONDO:0011462
MeSH	C536253
OMIM	604416
Orphanet	69126
DOID	DOID:0080519
NCIT	C119055
SNOMED CT	724015007
UMLS	C1858361
MedGen	346801
GARD	0009176
Is cancer (heuristic)	no

Also known as: familial recurrent arthritis · FRA · fra · PAPA · papa · papa syndrome · Papas · pyogenic arthritis, pyoderma gangrenosum and acne · pyogenic arthritis, pyoderma gangrenosum, and severe cystic acne

Data availability: 694 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › immune system disorder › pyogenic arthritis-pyoderma gangrenosum-acne syndrome

Related subtypes (46): hypersensitivity reaction disease, immune system cancer, immune system organ benign neoplasm, bone marrow disorder, thymus gland disorder, inborn error of immunity, leukocyte disorder, psoriasis, spondyloarthropathy, aggressive insulitis, benign insulitis, inflammatory bowel disease, autoimmune disease, TNF receptor 1-associated periodic fever syndrome, epidermodysplasia verruciformis, Vici syndrome, proteosome-associated autoinflammatory syndrome, hyperimmunoglobulinemia D with periodic fever, transcobalamin II deficiency, granulomatosis with polyangiitis, autosomal recessive osteopetrosis 7, graft versus host disease, congenital sideroblastic anemia-B-cell immunodeficiency-periodic fever-developmental delay syndrome, Roifman syndrome, cryopyrin-associated periodic syndrome, anti-HLA hyperimmunization, acquired immunodeficiency, erythroderma desquamativum, autoinflammatory syndrome with pyogenic bacterial infection and amylopectinosis, familial Mediterranean fever, 22q11.2 deletion syndrome, T-cell large granular lymphocyte leukemia, twin to twin transfusion syndrome, immunodeficiency disease, immunoproliferative disorder, cytokine receptor deficiency, immunodeficiency-related disorder, phagocytic cell dysfunction, thrombocytopenic purpura, lymphoid system disorder, immune reconstitution inflammatory syndrome, growth hormone insensitivity with immune dysregulation 1, autosomal recessive, cytokine release syndrome, early-onset autoimmunity-autoinflammation-immunodeficiency syndrome, CADINS disease, autoinflammation, panniculitis, and dermatosis syndrome

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

600 retrieved; paginated sample, class counts are floors:

273 uncertain significance, 230 likely benign, 41 benign/likely benign, 36 conflicting classifications of pathogenicity, 18 benign, 2 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
4434	NM_003978.5(PSTPIP1):c.748G>C (p.Glu250Gln)	PSTPIP1	Pathogenic	criteria provided, single submitter
4435	NM_003978.5(PSTPIP1):c.688G>A (p.Ala230Thr)	PSTPIP1	Pathogenic	criteria provided, multiple submitters, no conflicts
1044940	NM_003978.5(PSTPIP1):c.605G>A (p.Arg202Gln)	PSTPIP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1121319	NM_003978.5(PSTPIP1):c.516+3G>A	PSTPIP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1139987	NM_003978.5(PSTPIP1):c.987G>A (p.Ala329=)	PSTPIP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1289029	NM_003978.5(PSTPIP1):c.765G>A (p.Thr255=)	PSTPIP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1540389	NM_003978.5(PSTPIP1):c.768G>T (p.Leu256=)	PSTPIP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1661285	NM_003978.5(PSTPIP1):c.429A>T (p.Thr143=)	PSTPIP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1694144	NM_003978.5(PSTPIP1):c.1062G>A (p.Gln354=)	PSTPIP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1694151	NM_003978.5(PSTPIP1):c.537G>A (p.Gln179=)	PSTPIP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1989844	NM_003978.5(PSTPIP1):c.1037C>A (p.Thr346Lys)	PSTPIP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2157042	NM_003978.5(PSTPIP1):c.228C>T (p.Ser76=)	PSTPIP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
242299	NM_003978.5(PSTPIP1):c.37T>G (p.Cys13Gly)	PSTPIP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
242302	NM_003978.3(PSTPIP1):c.517_518delAG	PSTPIP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
242306	NM_003978.5(PSTPIP1):c.1208G>A (p.Gly403Glu)	PSTPIP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
242307	NM_003978.5(PSTPIP1):c.1213C>T (p.Arg405Cys)	PSTPIP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
245930	NM_003978.5(PSTPIP1):c.1221C>A (p.Phe407Leu)	PSTPIP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
246329	NM_003978.5(PSTPIP1):c.355-16C>G	PSTPIP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
246332	NM_003978.5(PSTPIP1):c.882G>A (p.Pro294=)	PSTPIP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2472880	NM_003978.5(PSTPIP1):c.1058T>C (p.Ile353Thr)	PSTPIP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
317170	NM_003978.5(PSTPIP1):c.59C>T (p.Thr20Met)	PSTPIP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
317176	NM_003978.5(PSTPIP1):c.555C>T (p.Thr185=)	PSTPIP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
317177	NM_003978.5(PSTPIP1):c.586G>A (p.Ala196Thr)	PSTPIP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
317178	NM_003978.5(PSTPIP1):c.629G>A (p.Arg210Gln)	PSTPIP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
317181	NM_003978.5(PSTPIP1):c.856A>G (p.Asn286Asp)	PSTPIP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
317183	NM_003978.5(PSTPIP1):c.1054G>A (p.Glu352Lys)	PSTPIP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
317188	NM_003978.5(PSTPIP1):c.1145C>T (p.Ala382Val)	PSTPIP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
317189	NM_003978.5(PSTPIP1):c.1248T>C (p.Leu416=)	PSTPIP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
378437	NM_003978.5(PSTPIP1):c.488C>T (p.Ala163Val)	PSTPIP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
391240	NM_003978.5(PSTPIP1):c.837C>G (p.Pro279=)	PSTPIP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · 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
PSTPIP1	Definitive	Autosomal dominant	pyogenic arthritis-pyoderma gangrenosum-acne syndrome	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PSTPIP1	Orphanet:251523	Hyperzincemia and hypercalprotectinemia
PSTPIP1	Orphanet:69126	PAPA syndrome

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
PSTPIP1	HGNC:9580	ENSG00000140368	O43586	Proline-serine-threonine phosphatase-interacting protein 1	gencc,clinvar
SCAMP2	HGNC:10564	ENSG00000140497	O15127	Secretory carrier-associated membrane protein 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PSTPIP1	Proline-serine-threonine phosphatase-interacting protein 1	Involved in regulation of the actin cytoskeleton.
SCAMP2	Secretory carrier-associated membrane protein 2	Functions in post-Golgi recycling pathways.

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)
PSTPIP1	Scaffold/PPI	no		FCH_dom, SH3_domain, AH/BAR_dom_sf
SCAMP2	Other/Unknown	no		SCAMP

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
granulocyte	1
leukocyte	1
monocyte	1
lower esophagus mucosa	1
mucosa of transverse colon	1
rectum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PSTPIP1	179	broad	marker	granulocyte, monocyte, leukocyte
SCAMP2	288	ubiquitous	marker	rectum, mucosa of transverse colon, lower esophagus mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PSTPIP1	2,508
SCAMP2	1,190

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PSTPIP1	O43586	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SCAMP2	O15127	77.30

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 2 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
The NLRP3 inflammasome	1	671.8×	0.002	PSTPIP1
Purinergic signaling in leishmaniasis infection	1	423.0×	0.002	PSTPIP1

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
post-Golgi vesicle-mediated transport	1	526.6×	0.015	SCAMP2
exocytosis	1	75.9×	0.053	SCAMP2
endocytosis	1	47.6×	0.056	PSTPIP1
protein transport	1	21.9×	0.067	SCAMP2
inflammatory response	1	18.9×	0.067	PSTPIP1
cell adhesion	1	18.7×	0.067	PSTPIP1
innate immune response	1	16.8×	0.067	PSTPIP1
signal transduction	1	8.0×	0.121	PSTPIP1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PSTPIP1	0	0
SCAMP2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SCAMP2	1	Binding:1

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	PSTPIP1, SCAMP2

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)
PSTPIP1	0	—
SCAMP2	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.