PSTPIP1‐associated myeloid‐related proteinemia inflammatory syndrome: A rare cause of childhood neutropenia associated with systemic inflammation and hyperzincemia

Abstract

Neutropenia in pediatric patients can be due to a variety of disorders. We describe two patients who underwent extensive evaluation over many years for arthralgias and moderate neutropenia of unclear etiology. Genetic testing identified a pathogenic variant in PSTPIP1 (proline-serine-threonine phosphatase-interacting protein 1) in both patients. Markedly elevated inflammatory markers and zinc levels confirmed the rare diagnosis of PSTPIP1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome, tailoring treatment. Neutropenia is common in patients with PAMI syndrome. Unique mutations seen in PAMI syndrome may account for the specific phenotypic features of this disorder.

Actin Remodeling Defects Leading to Autoinflammation and Immune Dysregulation

“…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). Pyrin is the pivotal protein of the related inflammasome, a member of cytosolic multiprotein oligomers family responsible for the activation of inflammatory responses in human cells.…”

Phenotypic Associations of PSTPIP1 Sequence Variants in PSTPIP1-Associated Autoinflammatory Diseases

“…Over the years, PSTPIP1 variants have been identified in a broad spectrum of phenotypes such as in isolated PG (Nesterovitch et al, 2011), PG with acne and UC (Zeeli et al, 2015), PG, acne, and suppurative hidradenitis (SH) with (PAPASH) or without (PASH) pyogenic arthritis (Calderó n-Castrat et al, 2016;Cugno et al, 2017;Marzano et al, 2013) and PSTPIP1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome (Belelli et al, 2017;Hashmi et al, 2019;Holzinger et al, 2015;Klö tgen et al, 2018;Takagi et al, 2018). PAMI syndrome, also called hyperzincemia and/or hypercalprotectinemia, is characterized by early-onset chronic systemic inflammation, skin inflammation (i.e., skin ulcerations, abscesses, vesiculobullous lesions, or pustular lesions), arthralgia and/or arthritis, hepatosplenomegaly, pancytopenia, and failure to thrive (Holzinger et al, 2015).…”

Rare cases of PAMI syndrome in both father and son with the same missense mutation in PSTPIP1 gene and literature review

“…To our knowledge, there are 35 cases of PAMI syndrome that have been reported yet, and rarely families involved. [1][2][3][4][5][6][7][8][9][10][11][12][13] All of the 35 cases were reviewed to summarize the characteristics of PAMI syndrome, as shown in Table 1 (history and clinical symptoms of PAMI syndrome) and Table 2 (laboratory examination and treatment effect of PAMI syndrome). We found a family history in seven patients.…”

“…They also achieved sound effects. Based on the data in the literature, [1][2]5,9,[12][13] the response of PAMI is inconsistent with either anti-IL-1 or anti-TNF blockade, so we chose prednisone as the first-line treatment. The two patients have had a good reaction for prednisone combined with doxycycline in the three months of therapy.…”