The expanding spectrum of clinical phenotypes associated with PSTPIP1 mutations: from PAPA to PAMI syndrome and beyond

Abstract

DEAR EDITOR, Mutations in the PSTPIP1 gene, encoding prolineserine-threonine phosphatase-interactive protein 1, were first identified in an autosomal dominant syndrome called PAPA, associated with pyogenic sterile arthritis, pyoderma gangrenosum (PG) and cystic acne. 1,2We report a patient with an autoinflammatory syndrome called PSTPIP1-associated myeloid-related proteinaemia inflammatory (PAMI) syndrome. 3 A 23-year-old man had a 3-year-history of skin ulcerations. During childhood he exhibited anaemia (81 g L À1 ), neutropenia (0.3 g L À1 ), mild thrombocytopenia and hepatosplenomegaly. Presence of anaemia and of recurrent infections prompted a bone marrow biopsy, which showed evidence for disturbed myelopoiesis beyond the promyelocyte-myelocyte level. From the age of 7 years he developed relapsing sterile osteomyelitis affecting the left talus, tibia and fibula. In his adolescence he had relapsing sterile arthritis of one knee and elbow.

Actin Remodeling Defects Leading to Autoinflammation and Immune Dysregulation

“…Heterozygous GoF mutation of the PSTPIP1 gene causes the pyogenic sterile arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome and the PSTPIP1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome (no. 21 in Table 1 and Figure 1) (106,107). PAMI syndrome is caused by variants that substantially alter electrostatic properties of the PSTPIP1 critical region for auto-inhibiting dimerization, resulting in a GoF mutant protein that constitutively activates the underlying Pyrin inflammasome (108).…”

PAMI syndrome: A rare cause that can be easily misdiagnosed

“…It is believed that E250K and E257K variants of PSTPIP1 result in PAMI syndrome. Overall, 17 and 2 cases of PAMI syndrome have been associated with E250K and E257K, respectively, most of which were found to be de novo mutations (Belelli et al, 2017;Hashmi et al, 2019;Holzinger et al, 2015;Klötgen et al, 2018 (Belelli et al, 2017;Hashmi et al, 2019;Holzinger et al, 2015;Klötgen et al, 2018) (Table 2). At early disease stage, when PAMI syndrome is dominated by some common clinical manifestations, such as arthritis, blood system involvement, and cutaneous lesions, it can be easily misdiagnosed.…”

“…PAMI syndrome is often confused with PAPA syndrome because some patients may present with an overlapping phenotype. In addition to neutropenia, anemia, thrombocytopenia, hepatosplenomegaly, and hyperzincaemia/hypercalprotectinemia, a case of PAMI syndrome reported in 2018 also had all the characteristics of PAPA syndrome (Klötgen et al, 2018). Not only neutropenia is believed to be highly associated with PAMI syndrome, but it can also be distinguished from PAPA syndrome by significantly high serum zinc and calprotectin levels (Holzinger et al, 2015).…”

“…Later on, in 2015, Holzinger et al (Holzinger et al, 2015) reported that mutations in PSTPIP1 (NP_003969.2) were the real cause of hyperzincemia/hypercalprotectinemia, and officially named this disorder as PSTPIP1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome. Patients with PAMI syndrome experience a persistent early onset inflammatory disease characterized by recurrent infections, arthritis, anemia, cutaneous inflammation, growth failure, hepatosplenomegaly, and lymphadenopathy, along with extremely high plasma concentrations of zinc and calprotectin, elevated C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), neutropenia, and thrombocytopenia (Hashmi et al, 2019;Klötgen et al, 2018).…”

Single-Center Overview of Pediatric Monogenic Autoinflammatory Diseases in the Past Decade: A Summary and Beyond

“…We also diagnosed two patients of PSTPIP1-associated inflammatory diseases (PAID), a dominantly inherited disease that can be subtyped into pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome, PSTPIP1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome, and other PAPA-like syndromes (22). Both patients had skin rash, arthritis, persistent systemic inflammation, hepatosplenomegaly, pancytopenia, and growth retardation, which matched the typical phenotypes of PAMI.…”