Brief Report: Genotype, phenotype, and clinical course in five patients with PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum, and acne)

Abstract

Objective To describe the genotypes, phenotypes, immunophenotypes, and treatments of PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum, and acne), a rare autoinflammatory disease, in 5 patients. Methods Clinical information was gathered from medical records and through interviews with 5 patients from 4 kindreds. PSTPIP1 (CD2BP1) exon 10 and exon 11 sequencing was performed in each patient. Neutrophil granule content and cytokine levels were determined in plasma and stimulated peripheral blood mononuclear cells (PBMCs) from patients and controls. Results We identified 2 previously described PAPA syndrome–associated PSTPIP1 mutations, A230T and E250Q, and a novel change, E250K. Disease penetrance was incomplete, with variable expressivity. The cutaneous manifestations included pathergy, cystic acne, and pyoderma gangrenosum. Interleukin-1 (IL-1β) and circulating neutrophil granule enzyme levels were markedly elevated in patients compared to those in controls. PBMC stimulation studies demonstrated impaired production of IL-10 and enhanced production of granulocyte–macrophage colony-stimulating factor. Good resolution of pyoderma gangrenosum was achieved in 3 patients with tumor necrosis factor (TNFα) blockade treatment. Conclusion This analysis of 5 patients demonstrates that mutations in PSTPIP1 are incompletely penetrant and variably expressed in the PAPA syndrome. Neutrophil granule proteins are markedly elevated ex vivo and in the plasma, and elevated levels might be compatible with a diagnosis of PAPA syndrome. TNFα blockade appears to be effective in treating the cutaneous manifestations of PAPA syndrome.

Osteolytic Lesion in PAPA Syndrome Responding to Anti-interleukin 1 Treatment

“…The clinical manifestations of this disease are variable, and as observed in our present case, the penetrance of the mutations in the causative gene, PSTPIP1, might be variable in the context of the same family 2,3 .…”

“…In a study, Demidowich, et al reported the occurrence of an osteomyelitis in 1 patient belonging to a small cohort of patients with PAPA. However, a detailed description of radiological and histological findings was not available 3 .…”

A Case of Pyogenic Sterile Arthritis, Pyoderma Gangrenosum, and Acne(PAPA) Syndrome Accompanied by Nephrosclerosis, Splenomegaly and Intestinal Lesions

“…Typically, pyogenic sterile arthritis recurs in childhood and is often triggered by minor trauma. These symptoms tend to improve by adolescence, while the skin manifestations, pyoderma gangrenosum and severe cystic acne exacerbate instead [3,4]. The molecular mechanism by which mutation in the PSTPIP1 causes PAPA syndrome remains uncertain.…”

Autoinflammatory diseases in Pediatrics

“…1,2 Up to this date, three mutations related to this diseased have been identified in the CD2BP1 gene, responsible for synthesizing the CD2BP1 protein. 46 It has been proposed that the mutated protein has a higher binding affinity for the pyrin protein, thus leading to an increased susceptibility to inflammation. Clinical symptoms tend to respond to oral corticosteroids; however, corticosteroid-refractory patients have shown improvement with anti-IL-1 and TNFblockers.…”

“…Clinical symptoms tend to respond to oral corticosteroids; however, corticosteroid-refractory patients have shown improvement with anti-IL-1 and TNFblockers. 14,46,48 The PAPA syndrome is the most difficult autoinflammatory disease to manage from a clinical standpoint.…”