Alternative titles; symbols
SNOMEDCT: 724015007; ICD10CM: M04.8; ORPHA: 69126; DO: 0080519;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 15q24.3 | Pyogenic sterile arthritis, pyoderma gangrenosum, and acne | 604416 | Autosomal dominant | 3 | PSTPIP1 | 606347 |
A number sign (#) is used with this entry because of evidence that pyogenic sterile arthritis, pyoderma gangrenosum, and acne (PAPA) is caused by heterozygous mutation in the PSTPIP1 gene (606347) on chromosome 15q24.
Mutation in the PSTPIP1 gene can also cause autoinflammatory syndrome with cytopenia, hyperzincemia, and hypercalprotectinemia (AICZC; 601979).
Pyogenic sterile arthritis, pyoderma gangrenosum, and acne (PAPA) is a rare autosomal dominant autoinflammatory disease that typically presents with recurrent sterile, erosive arthritis in childhood, occurring spontaneously or after minor trauma, occasionally resulting in significant joint destruction. By puberty, joint symptoms tend to subside and cutaneous symptoms predominate, including pathergy, frequently with abscesses at the sites of injections, severe cystic acne, and recurrent nonhealing sterile ulcers, often diagnosed as pyoderma gangrenosum (summary by Demidowich et al., 2012).
Lindor et al. (1997) described a multigeneration family with transmission of an autosomal dominant disorder characterized by pyogenic arthritis, pyoderma gangrenosum, and severe cystic acne, which the authors designated 'PAPA syndrome.' Ten affected family members manifested variable expression of pauciarticular, nonaxial, destructive, corticosteroid-responsive arthritis that began in childhood; pyoderma gangrenosum; and severe cystic acne in adolescence and beyond. Other less commonly associated features included adult-onset insulin-dependent diabetes mellitus, proteinuria, abscess formation at the site of parenteral injections, and cytopenias attributable to sulfonamide medications. Genetic studies excluded linkage to the major histocompatibility complex.
Demidowich et al. (2012) studied 4 patients from 3 families with PAPA syndrome and mutation in the PSTPIP1 gene, including 2 brothers (patients 3 and 4) from a family with 7 affected individuals over 2 generations. In 3 patients (1, 2, and 3) disease onset occurred in infancy with pathergy or sterile abscesses after vaccination, followed by recurrent sterile arthritis; pyoderma gangrenosum (PG) and cystic acne developed later, in the first and second decades of life. Patient 4 experienced recurrent arthritis of the right ankle following a fracture at age 8 years, and developed cystic acne at age 12, but never had pathergy or PG. The brothers' 5 affected family members exhibited further phenotypic variability: their mother had arthritis and cystic acne; their maternal uncle had arthritis and PG; and 3 sibs had eczema of the neck, arms, and palms during adolescence, 2 of whom also had arthritis, and 1 of whom also experienced injection pathergy and cystic acne. Noting that PAPA syndrome is predominantly characterized by neutrophil dysfunction, the authors measured patient plasma levels of neutrophil granule proteins and found significant elevations compared to control levels; the acute-phase reactants C-reactive protein (CRP; 123260) and lipopolysaccharide-binding protein (LBP; 151990), and matrix metalloproteinase-9 (MMP9; 120361) were also significantly elevated.
Loffler et al. (2017) reported a 42-year-old German man with PAPA and mutation in the PSTPIP1 gene. The patient had onset of chronic arthritis at 8 years of age, with episodes of mono- or oligoarticular sterile effusions occurring about twice a year, primarily in the elbows and knees. Cell counts in synovial fluid were elevated over the years, with a mean leukocyte count of 64,000 per microliter and neutrophils predominating (85%). At age 15 he developed severe cystic acne, with large painful pustules in the nasolabial fold and axillae. Although pyoderma granulosum was not observed in this patient, his symptoms were believed to represent PAPA syndrome. A similarly affected cousin was reported, but no clinical or genetic information was available.
PASH Syndrome
Braun-Falco et al. (2012) reported 2 unrelated patients, a 34-year-old man of Russian descent (case 1) and a 44-year-old German man (case 2), with features similar to but distinct from PAPA syndrome. Both patients had pyoderma gangrenosum and severe cystic acne; neither experienced pyogenic arthritis but both had suppurative hidradenitis. The authors designated their phenotype as 'pyoderma gangrenosum, acne, and suppurative hidradenitis (PASH)' syndrome.
Duchatelet et al. (2015) studied 2 probands with PASH syndrome from multigeneration families showing intrafamilial variability. Patient 1 was a 23-year-old man who developed acne fulminans at age 14 years, followed by hidradenitis suppurativa (HS) of the buttocks and groin, and localized pyoderma granulosum of the sternum and thighs. His parents, a paternal aunt, and a paternal great-uncle all experienced moderate to severe acne. Patient 2 was a 37-year-old man who developed acne fulminans at age 19 years, followed by progressive HS of the axillae, buttocks, and groin, then localized PG on his chest and arms. A brother also had PASH syndrome with moderate HS, and their mother and maternal grandmother experienced moderate and transient HS and acne at puberty.
Saito et al. (2018) reported a 37-year-old Japanese woman with PASH and mutation in the PSTPIP1 gene. From age 18 years, she had severe acne on her back and lower legs, and suppurative hidradenitis in the axillae and groin. At age 25, she developed pyoderma gangrenosum on her legs. She had a increased leukocyte count with 74% neutrophils, and elevated CRP, IgG, and IgA levels. Her mother had acne and suppurative hidradenitis; the proband also had a sister with only severe acne, whereas another sister was asymptomatic.
Sonbol et al. (2018) reported a 42-year-old French man with PASH syndrome, who had active and scarring nodular acne on his face, neck, and upper back since puberty. At age 38, he began developing ulceronecrotic nodular lesions on the shoulders, abdomen, and legs that were consistent with pyoderma gangrenosum. In addition, at age 40 he had onset of recurrent abscesses at the body folds suggestive of hidradenitis suppurativa. Skin biopsy of an erythematopustular lesion on the right thigh showed an abundant perivascular and periadnexal inflammatory infiltrate in the dermis, primarily around the sweat glands and capillaries. The infiltrate was polymorphic, with few neutrophils and eosinophils. Another biopsy from an ulcerative lesion showed a deep skin ulcer with a dense inflammatory infiltrate associated with granulation tissue. The infiltrate was composed of lymphocytes, plasma cells, neutrophils, and eosinophils, in addition to histiocytes.
PAPASH Syndrome
Marzano et al. (2013) reported a 16-year-old girl of Moldavian descent who had pyogenic arthritis, pyoderma gangrenosum, acne, and hidradenitis suppurativa, and mutation in the PSTPIP1 gene. The authors designated the disorder PAPASH syndrome. The patient's symptoms began at age 14 years, with hidradenitis suppurativa and mild acne. She later developed lesions of pyoderma gangrenosum on the upper back, which left keloidal scars after healing. She also experienced arthralgias involving the nonaxial joints, with the shoulder, elbow, hands, and knees most severely affected. Intense neutrophilic inflammation of the synovia was documented.
Reviews
Cugno et al. (2017) reviewed the pyoderma gangrenosum (PG)-associated autoinflammatory syndromes designated PAPA, PASH, and PAPASH, noting that they share a common mechanism involving overactivation of innate immune system signaling pathways, causing dysregulation of neutrophil homeostasis that results in excessive skin inflammation, neutrophil-rich granulocyte infiltration, and tissue damage. These disorders are all associated with overexpression of interleukin-1 (see IL1A, 147760) and tumor necrosis factor-alpha (TNF; 191160), and the most effective treatments target those cytokines.
Yeon et al. (2000) used linkage mapping in a multigeneration family with PAPA syndrome, originally reported by Lindor et al. (1997), to locate the PAPAS gene on chromosome 15q (maximum 2-point lod score of 5.83 with recombination fraction = 0 at D15S206). Under the assumption of complete penetrance, haplotype analysis of recombination events defined a disease interval of 10 cM between D15S1023 and D15S979. They indicated that the gene is in the same region as the IL16 gene (603035) and the CRABP1 gene (180230) (incorrectly stated to be the CRABP2 gene), which map to 15q26.1 and 15q24, respectively.
In a 3-generation family in which 9 members had been diagnosed with juvenile idiopathic arthritis (604302), Wise et al. (2000) demonstrated linkage to chromosome 15q22-q24. In this family the disease was of very early onset and included episodic inflammation leading to eventual destruction of joints, muscle, and skin. The authors treated this disorder as a distinct clinical entity which they called familial recurrent arthritis (FRA). The proband in the family reported by Wise et al. (2000) presented at the age of 5 years with a history of recurrent joint swelling and cystic skin lesions since infancy. Arthritis was characteristically intermittent and migratory and led to the accumulation of sterile pyogenic material within the joint space if left untreated. It followed a monarticular pattern (rarely more than 1 joint affected during flares). It involved primarily the elbows, knees, and ankles, although small joints were occasionally affected. The father, 2 brothers (who were twins), a paternal aunt, and 2 cousins were also affected. The father reported that he had experienced marked improvement in the joint symptoms after puberty, with subsequent appearance of severe acne. In their discussion, Wise et al. (2000) stated that familial recurrent arthritis and PAPA syndrome are likely to be the same disorder. They pointed to a patient reported by Jacobs and Goetzl (1975) who may have had the same disorder, although no information was provided.
In affected individuals from 2 families with PAPA syndrome mapping to chromosome 15q, including family 'FRA1' studied by Wise et al. (2000) and the PAPA family originally described by Lindor et al. (1997), Wise et al. (2002) screened candidate genes and identified heterozygosity for missense mutations in the PSTPIP1 gene: an E250Q substitution (606347.0001) in family FRA1, and an A230T substitution (606347.0002) in 2 affected sisters from the original PAPA family. PSTPIP1 and its murine ortholog are adaptor proteins known to interact with PEST-type PTPs such as PTPN12 (600079). Yeast 2-hybrid assays demonstrated severely reduced binding between PTPN12 and the E250Q and A230T mutant proteins of PSTPIP1. Previous evidence supported the integral role of CD2BP1 (alternative symbol for PSTPIP1) and its interacting proteins in actin reorganization during cytoskeletal-mediated events. The authors hypothesized that the disease-causing mutations identified compromise physiologic signaling necessary for the maintenance of a proper inflammatory response.
In 4 patients from 3 families with PAPA, Demidowich et al. (2012) screened exons 10 and 11 of the PSTPIP1 gene and identified heterozygosity for the previously reported A230T mutation in patients 1, 3, and 4; patient 2 was heterozygous for the previously reported E250Q mutation. The 5 affected relatives of patients 3 and 4 were also heterozygous for A230T in PSTPIP1, as was 1 sib who remained asymptomatic at age 16 years. Given the variable expressivity and incomplete penetrance present within this family, the authors suggested that manifestations of PAPA syndrome might be broader than previously recognized, and prevalence of the disorder might be greater than previously thought.
In a 42-year-old German man with PAPA, Loffler et al. (2017) identified heterozygosity for the recurrent A230T mutation in the PSTPIP1 gene. Familial segregation of the variant was not reported.
Associations Pending Confirmation
---PAPASH Syndrome
In a 16-year-old girl of Moldavian descent with pyogenic arthritis, pyoderma gangrenosum, acne, and hidradenitis suppurativa, Marzano et al. (2013) analyzed exons 10 and 11 of the PSTPIP1 gene and identified heterozygosity for a missense mutation (E277D; 606347.0005). The authors designated the phenotype as 'PAPASH' syndrome and suggested that the genetic abnormality was likely to be closely related to the patient's clinical condition.
---PASH Syndrome
In a 29-year-old woman (patient 3) with severe hidradenitis suppurative from age 11 years, followed by severe acne and extensive pyoderma gangrenosum of the trunk and limbs (PASH syndrome), Duchatelet et al. (2015) sequenced the PSTPIP1 promoter and gene, and the candidate genes NCSTN (605254), PSENEN (607632), and PSEN1 (104311), and identified heterozygosity for an 8-bp deletion in the NCSTN gene (605254.0007). Because the patient was adopted, familial segregation could not be analyzed; the variant was not found in 434 in-house exomes or in the NHLBI Exome Sequencing Project database. The authors noted that patient 3 was also heterozygous for increased CCTG repeats in the PSTPIP1 promoter region, but stated that there was no evidence that this variation had any functional effect.
Marzano et al. (2017) analyzed a target panel of 10 autoinflammatory disease-associated genes in 7 patients with PASH and 13 patients with isolated pyoderma gangrenosum (PG). A wide range of mutations were found, involving all of the autoinflammatory genes tested to varying extents, including MEFV, NOD2, NRLP3, NLRP12, and PSTPIP1 in PASH patients. Noting an apparent excess of putatively damaging variants in patients with PASH compared to PG, the authors suggested that PASH and PG represent different phenotypes of a spectrum of polygenic autoinflammatory conditions.
In a 37-year-old Japanese woman with PASH, Saito et al. (2018) sequenced the PSTPIP1 gene and identified heterozygosity for a missense mutation in the PSTPIP1 gene (Y345C; 606347.0006). Her mother, who had acne and suppurative hidradenitis, and a sister with severe acne only, were also heterozygous for the Y345C variant, as was a sister who was asymptomatic. Thus this family showed both variable expressivity and incomplete penetrance. In a review of hidradenitis suppurativa and autoinflammatory syndromes, Maronese et al. (2024) designated the Y345C variant as a 'variant of unknown significance with pathogenic evidence' per the ACMG classification scheme.
Exclusion Studies
In a 34-year-old man of Russian descent (case 1) and a 44-year-old German man (case 2) with PASH syndrome, Braun-Falco et al. (2012) analyzed exons 1 to 15 of the PSTPIPl gene as well as the most commonly affected exons of the MEFV (608107), NLRP3 (606416), and TNFRSF1A (191190) genes, but did not identify any causative mutations. In the PSTPIP1 promoter region, an increased repetition of the CCTG microsatellite motif was present on 1 allele in both patients; however, the authors stated that the CCTG replications would likely have only a mild effect on the development of this distinct cutaneous inflammation.
In 2 unrelated men with PASH, Duchatelet et al. (2015) sequenced the PSTPIP1 promoter and gene, and the candidate genes NCSTN, PSENEN (607632), and PSEN1 (104311), but did not identify any mutations. The authors noted that patient 2 was heterozygous for increased CCTG repeats in the PSTPIP1 promoter region, but stated that there was no evidence that this variation had any functional effect.
In a 42-year-old French man with PASH, Sonbol et al. (2018) analyzed the PSTPIP1, NCSTN, PSENEN, or PSEN1 genes by Sanger sequencing of coding and flanking intronic regions but did not find any mutation. In addition, the proband was homozygous for the normal (CCTG)5 repeat in the PSTPIP1 promoter, with no increased number of CCTG repeats.
Holzinger et al. (2015) studied 14 patients with autoinflammatory syndrome with cytopenia, hyperzincemia, and hypercalprotectinemia (AICZC; 601979) and compared them to 11 patients with genetically confirmed PAPA syndrome. Noting that PSTPIP1-associated diseases show variable expressivity with a range of clinical phenotypes, the authors suggested a novel nomenclature for this group of related diseases, with the term 'PSTPIP1-associate inflammatory diseases (PAID)' as a new class, encompassing PAPA syndrome; pyogenic arthritis, pyoderma gangrenosum, acne, and hidradenitis suppurative (PAPASH syndrome); and AICZC. They suggested the term 'PSTPIP1-associated myeloid-related proteinemia inflammatory syndrome (PAMI)' for AICZC.
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Loffler, W., Lohse, P., Weihmayr, T., Widenmayer, W. Pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome: differential diagnosis of septic arthritis by regular detection of exceedingly high synovial cell counts. Infection 45: 395-402, 2017. [PubMed: 28251506] [Full Text: https://doi.org/10.1007/s15010-017-0996-1]
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Marzano, A. V., Damiani, G., Ceccherini, I., Berti, E., Gattorno, M., Cugno, M. Autoinflammation in pyoderma gangrenosum and its syndromic form (pyoderma gangrenosum, acne and suppurative hidradenitis). Brit. J. Derm. 176: 1588-1598, 2017. [PubMed: 27943240] [Full Text: https://doi.org/10.1111/bjd.15226]
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