PSTPIP1 – PSTPIP1-associated Myeloid-Related Proteinemia Inflammatory (PAMI) Syndrome

PSTPIP1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome is a rare early-onset autoinflammatory disorder characterized by hyperzincemia, hypercalprotectinemia, cytopenias, and systemic inflammation. It results from heterozygous missense mutations in PSTPIP1, leading to dysregulated calprotectin metabolism and aberrant inflammasome activation.

Autosomal dominant inheritance with recurrent de novo events has been documented. To date, 19 unrelated probands have been reported carrying the recurrent c.748G>A (p.Glu250Lys) allele, including two siblings and one de novo occurrence ([PMID:31789267], [PMID:30198636], [PMID:35840971], [PMID:33597285], [PMID:26025129]). Segregation in a familial PAMI pedigree has been observed in two affected relatives ([PMID:34399798]).

All cases share a recurrent missense change, c.748G>A (p.Glu250Lys), which lies within the F-BAR domain of PSTPIP1 and is absent from population databases. A second rare variant, c.769G>A (p.Glu257Lys), has also been described in one patient cohort ([PMID:26025129]). No loss-of-function or structural variants have been implicated to date.

Clinical features include severe cutaneous ulcerations mimicking pyoderma gangrenosum, growth failure and failure to thrive, chronic anemia and cytopenias, neutropenia, arthralgia, hepatosplenomegaly, and global developmental delay. Neurologic involvement and hemolytic anemia have been reported, and kidney dysfunction (focal segmental glomerulosclerosis) may occur later in the disease course.

Biochemical and structural studies demonstrate that charge-reversal mutations at Glu250 and Glu257 alter PSTPIP1 electrostatic potential, enhance binding to the pyrin inflammasome adapter, and drive uncontrolled release of MRP8/14 (calprotectin) ([PMID:26025129]). Structural elucidation of the PSTPIP1 F-BAR–LYP phosphatase complex further implicates disrupted protein-protein interactions in PAMI pathogenesis ([PMID:35152348]).

Diagnosis is established by sequencing PSTPIP1 in patients with unexplained neutropenia, hyperzincemia, and inflammatory stigmata, complemented by serum zinc and calprotectin measurements. IL-1 blockade (anakinra, canakinumab) yields marked hematologic and inflammatory improvement.

Key Take-Home: PSTPIP1 c.748G>A (p.Glu250Lys) causes autosomal dominant PAMI syndrome through gain-of-function effects on pyrin inflammasome activation, with clear diagnostic markers and effective targeted therapy.

References

• Anais brasileiros de dermatologia • 2019 • Extensive pyoderma gangrenosum-like lesions revealing a case of hyperzincemia and hypercalprotectinemia: when to suspect it? PMID:31789267
• Pediatric blood & cancer • 2019 • PSTPIP1-associated myeloid-related proteinemia inflammatory syndrome: A rare cause of childhood neutropenia associated with systemic inflammation and hyperzincemia. PMID:30198636
• Pediatric rheumatology online journal • 2022 • PSTPIP1-associated myeloid-related proteinaemia inflammatory (PAMI) syndrome; a case presenting as a perinatal event with early central nervous system involvement? PMID:35840971
• Pediatrics • 2021 • Hemolysis and Neurologic Impairment in PAMI Syndrome: Novel Characteristics of an Elusive Disease. PMID:33597285
• The Journal of allergy and clinical immunology • 2015 • Single amino acid charge switch defines clinically distinct proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1)-associated inflammatory diseases. PMID:26025129
• Cellular and molecular life sciences : CMLS • 2022 • PSTPIP1-LYP phosphatase interaction: structural basis and implications for autoinflammatory disorders. PMID:35152348

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