Papa syndrome L70.9 + L88 + M14.8

Lindor 1997

PAPA is an acronym that stands for"pyogenic arthritis, pyodermagangraenosum, severe acneconglobata". PAPA refers to a rare, congenital systemic disease characterized by recurrent arthritis in adolescence, (severe) acne vulgaris/conglobata in puberty, and recurrent pyoderma gangraenosum later in life.

Less commonly, inflammatory bowel disease (IBD) is associated.

The disease belongs to the group of hereditary autoinflammatory syndromes (see also immunodeficiencies primary /autoinflammatory diseases).

PAPA syndrome is caused by a heterozygous mutation in the PSTPIP1 gene(606347), which is located on chromosome 15q24. The mutation leads to defects in the"CD2 binding protein1", also known as "proline-serine-threonine phosphatase interacting protein". CD2 binding protein1, which is encoded by the PSTPIP1 gene, is part of an inflammatory cascade that plays an important role in other autoimmune diseases, such as Mediterranean fever and hyper-IgE syndrome. Mutated PSTPIP1 proteins have an increased ability to bind to pyrin.

The syndrome is to be distinguished from:

non-hereditary PASH syndrome(pyodermagangrenosum, acne, and suppurative hidradenitis) in which sterile pyogenic arthritis is absent.

PAMI syndrome (PSTPIP1- associated myeloid-related proteinemia inflammatory syndrome), which (like PAPA syndrome) is also caused by mutations in the PSTPIP1 gene.

TNF-alpha receptor antagonists were used with good success. Furthermore, there are reports of success with the use of IL-1 blockers, glucocorticoids and immunosuppressive drugs.

Lindor et al (1997) described a multigenerational family in which an autosomal dominant disorder was inherited, characterized by pyogenic arthritis, pyoderma gangrenosum, and severe cystic acne. Ten affected family members showed variable expression of pauciarticular, nonaxial, destructive, corticosteroid-responsive arthritis beginning in childhood, pyoderma gangrenosum, and severe cystic or necrotizing acne in adolescence and thereafter. Of note was a pathergy phenomenon. Other less common features were:

• Insulin-dependent diabetes mellitus (occurred in adulthood).
• Proteinuria
• Abscess formation at the site of parenteral injections and cytopenias (isomorphism) attributable to sulfonamide drugs.

In a family in which nine members had been diagnosed with juvenile idiopathic arthritis (604302), Wise et al. (2000) demonstrated linkage to chromosome 15q22-q24. In this family, the disease appeared very early and involved episodic inflammation that eventually led to destruction of joints, muscles, and skin. Characteristically, the arthritis was intermittent and migratory, leading to accumulation of sterile pyogenic material in the joint space if untreated. It followed a monarticular pattern (rarely more than 1 joint was affected during relapses). Elbows, knees, and ankles were primarily affected, but smaller joints were occasionally involved. The father, 2 brothers (twins), a paternal aunt, and 2 cousins were also affected. The father reported that the joint symptoms improved markedly after puberty, but a severe "acne-like" condition then developed.

1. Boursier G et al (2021) Phenotypic Associations of PSTPIP1 Sequence Variants in PSTPIP1-Associated Autoinflammatory Diseases. J Invest Dermatol 141:1141-1147.
2. Edrees AF et al (2002) Pyogenic arthritis, pyoderma gangraenosum and acne syndrome (PAPA syndrome) associated with hypogammoglobulinemia and elevated serum tumor necrosis factor-alpha löevels. J Clin Rheumatol 8: 273-275.
3. Jacobs JC et al (1975) Streaking leukocyte factor,' arthritis, and pyoderma gangrenosum. Pediatrics 56: 570-578.
4. Lindor NM et al (1997) A new autosomal dominant disorder of pyogenic sterile arthritis, pyoderma gangrenosum, and acne: PAPA syndrome. Mayo Clin Proc 72: 611-615.
5. Saito N et al (2018) Novel PSTPIP1 gene mutation in pyoderma gangrenosum, acne and suppurative hidradenitis syndrome. J Dermatol 45:e213-e214.
6. Renn CN et al (2007) Pyogenic arthritis, pyoderma gangraenosum, and acne syndrome (PAPA syndrome). Dermatologist 58: 383-384
7. Wise CA et al (2000) Localization of a gene for familial recurrent arthritis. Arthritis Rheum. 43: 2041-2045
8. Wise CA et al (2002) Mutations in CD2BP1 disrupt binding to PTP PEST and are responsible for PAPA syndrome, an autoinflammatory disorder. Hum Molec Genet 11: 961-969.
9. Yeon HB et al (2000) Pyogenic arthritis, pyoderma gangrenosum, and acne syndrome maps to chromosome 15q. Am J Hum Genet 66: 1443-1448.