{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:43:56Z","timestamp":1787028236150,"version":"build-2736575974"},"reference-count":32,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2023,8,19]],"date-time":"2023-08-19T00:00:00Z","timestamp":1692403200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>PSTPIP1 (proline-serine-threonine phosphatase-interactive protein 1)-associated myeloid-related proteinemia inflammatory (PAMI) syndrome, previously known as Hyperzincemia\/Hypercalprotectinemia (Hz\/Hc) syndrome, is a recently described, rare auto-inflammatory disorder caused by specific deleterious variants in the PSTPIP1 gene (p.E250K and p.E257K). The disease is characterized by chronic systemic inflammation, cutaneous and osteoarticular manifestations, hepatosplenomegaly, anemia, and neutropenia. Increased blood levels of MRP 8\/14 and zinc distinguish this condition from other PSTPIP1-associated inflammatory diseases (PAID). The aim of this systematic review is to provide a comprehensive overview of the disease phenotype, course, treatment, and outcome based on reported cases. This systematic review adheres to the PRISMA guidelines (2020) for reporting. A literature search was performed in Embase, Medline, and Web of Science on 13 October 2022. The quality of the case reports and case series was assessed using the JBI checklists. Out of the 43 included patients with PAMI syndrome, there were 24 females and 19 males. The median age at onset was 3.9 years. The main clinical manifestations included anemia (100%), neutropenia (98%), cutaneous manifestations (74%), osteoarticular manifestations (72%), splenomegaly (70%), growth failure (57%), fever (51%), hepatomegaly (56%), and lymphadenopathy (39%). Systemic inflammation was described in all patients. Marked elevation of zinc and MRP 8\/14 blood levels were observed in all tested patients. Response to treatment varied and no consistently effective therapy was identified. The most common therapeutic options were corticosteroids (N = 30), anakinra (N = 13), cyclosporine A (N = 11), canakinumab (N = 6), and anti-TNF (N = 14). Hematopoietic stem cell transplantation has been recently reported to be successful in five patients. Our review highlights the key characteristics of PAMI syndrome and the importance of considering this disease in the differential diagnosis of patients presenting with early-onset systemic inflammation and cytopenia.<\/jats:p>","DOI":"10.3390\/genes14081655","type":"journal-article","created":{"date-parts":[[2023,8,21]],"date-time":"2023-08-21T01:38:31Z","timestamp":1692581911000},"page":"1655","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["PSTPIP1-Associated Myeloid-Related Proteinemia Inflammatory (PAMI) Syndrome: A Systematic Review"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-5992-9540","authenticated-orcid":false,"given":"Manel","family":"Mejbri","sequence":"first","affiliation":[{"name":"Pediatric Immuno-Rheumatology of Western Switzerland, Department Women-Mother-Child, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raffaele","family":"Renella","sequence":"additional","affiliation":[{"name":"Pediatric Hematology-Oncology Unit, Division of Pediatrics, Department Women-Mother-Child, Lausanne University Hospital, 1011 Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabio","family":"Candotti","sequence":"additional","affiliation":[{"name":"Division of Immunology and Allergy, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecile","family":"Jaques","sequence":"additional","affiliation":[{"name":"Medical Library, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8062-8820","authenticated-orcid":false,"given":"Dirk","family":"Holzinger","sequence":"additional","affiliation":[{"name":"Department of Pediatric Hematology-Oncology, University of Duisburg-Essen, 45147 Essen, Germany"},{"name":"Department of Applied Health Sciences, University of Applied Sciences Bochum, 44801 Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Hofer","sequence":"additional","affiliation":[{"name":"Pediatric Immuno-Rheumatology of Western Switzerland, Department Women-Mother-Child, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katerina","family":"Theodoropoulou","sequence":"additional","affiliation":[{"name":"Pediatric Immuno-Rheumatology of Western Switzerland, Department Women-Mother-Child, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,19]]},"reference":[{"key":"ref_1","first-page":"S28","article-title":"Neutropenia as a presenting feature of hyperzincemia due to mutation in proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1)","volume":"64","author":"Hashmi","year":"2017","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_2","first-page":"S113","article-title":"Haematological involvement associated with a mild autoinflammatory phenotype, in two patients carrying the E250K mutation of PSTPIP1","volume":"35","author":"Belelli","year":"2017","journal-title":"Clin. Exp. Rheumatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1337","DOI":"10.1016\/j.jaci.2015.04.016","article-title":"Single amino acid charge switch defines clinically distinct proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1)-associated inflammatory diseases","volume":"136","author":"Holzinger","year":"2015","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"105906","DOI":"10.1016\/j.ijsu.2021.105906","article-title":"The PRISMA 2020 statement: An updated guideline for reporting systematic reviews","volume":"88","author":"Page","year":"2021","journal-title":"Int. J. Surg."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1111\/j.1651-2227.2008.01092.x","article-title":"Hyperzincemia and hypercalprotectinemia: Unsuccessful treatment with tacrolimus","volume":"98","author":"Isidor","year":"2009","journal-title":"Acta Paediatr."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1080\/08035250500482255","article-title":"Effects of cyclosporine A in hyperzincaemia and hypercalprotectinaemia","volume":"95","author":"Sugiura","year":"2006","journal-title":"Acta Paediatr."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1097\/01.mph.0000179958.19524.9c","article-title":"Severe anemia and neutropenia associated with hyperzincemia and hypercalprotectinemia","volume":"27","author":"Fessatou","year":"2005","journal-title":"J. Pediatr. Hematol.\/Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1742","DOI":"10.1016\/S0140-6736(02)11683-7","article-title":"Hyperzincaemia and hypercalprotectinaemia: A new disorder of zinc metabolism","volume":"360","author":"Sampson","year":"2002","journal-title":"Lancet"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2022","DOI":"10.1002\/art.34332","article-title":"Brief report: Genotype, phenotype, and clinical course in five patients with PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum, and acne)","volume":"64","author":"Demidowich","year":"2012","journal-title":"Arthritis Rheum."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1186\/s13643-016-0384-4","article-title":"Rayyan\u2014A web and mobile app for systematic reviews","volume":"5","author":"Ouzzani","year":"2016","journal-title":"Syst. Rev."},{"key":"ref_11","unstructured":"(2023, August 14). The Joanna Briggs Institute Critical Appraisal Tools for Use in JBI Systematic Reviews Checklist for Case Reports. Available online: https:\/\/www.google.com.hk\/url?sa=t&rct=j&q=&esrc=s&source=web&cd=&ved=2ahUKEwi-9LO9kOCAAxVBcGwGHWJbAacQFnoECA4QAQ&url=https%3A%2F%2Fjbi.global%2Fsites%2Fdefault%2Ffiles%2F2019-05%2FJBI_Critical_Appraisal-Checklist_for_Case_Reports2017_0.pdf&usg=AOvVaw2Lu-IQRqxstRAOanORXSCG&opi=89978449."},{"key":"ref_12","unstructured":"(2023, August 14). The Joanna Briggs Institute Critical Appraisal Tools for Use in JBI Systematic Reviews Checklist for Case Series. Available online: https:\/\/www.google.com.hk\/url?sa=t&rct=j&q=&esrc=s&source=web&cd=&cad=rja&uact=8&ved=2ahUKEwi-9LO9kOCAAxVBcGwGHWJbAacQFnoECA8QAQ&url=https%3A%2F%2Fjbi.global%2Fsites%2Fdefault%2Ffiles%2F2019-05%2FJBI_Critical_Appraisal-Checklist_for_Case_Series2017_0.pdf&usg=AOvVaw3vdcMs9W_668l0pxCY_P0K&opi=89978449."},{"key":"ref_13","first-page":"977","article-title":"PSTPIP1-associated myeloid-related proteinemia inflammatory syndrome\/PAMI syndrome: Case report and review of the literature","volume":"78","author":"Mejbri","year":"2019","journal-title":"Ann. Rheum. Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"926087","DOI":"10.3389\/fimmu.2022.926087","article-title":"Strong inflammatory signatures in the neutrophils of PAMI syndrome","volume":"13","author":"Zheng","year":"2022","journal-title":"Front. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1186\/s12969-022-00707-5","article-title":"PSTPIP1-associated myeloid-related proteinaemia inflammatory (PAMI) syndrome; a case presenting as a perinatal event with early central nervous system involvement?","volume":"20","author":"Whiteside","year":"2022","journal-title":"Pediatr. Rheumatol. Online J."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1007\/s10875-022-01265-x","article-title":"PAMI Syndrome: Two Cases of an Autoinflammatory Disease with an ALPS-Like Phenotype","volume":"42","author":"Cox","year":"2022","journal-title":"J. Clin. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1186\/s12969-021-00636-9","article-title":"Clinical and genetic characteristics of PSTPIP1-associated myeloid-related proteinemia inflammatory syndrome","volume":"19","author":"Zhang","year":"2021","journal-title":"Pediatr. Rheumatol. Online J."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3074","DOI":"10.1002\/ajmg.a.62367","article-title":"PAMI syndrome: A rare cause that can be easily misdiagnosed","volume":"185","author":"Xu","year":"2021","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1186\/s12969-021-00617-y","article-title":"Immunological repertoire linked to PSTPIP1-associated myeloid-related inflammatory (PAMI) syndrome","volume":"19","author":"Terreri","year":"2021","journal-title":"Pediatr. Rheumatol. Online J."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Laberko, A., Burlakov, V., Maier, S., Abinun, M., Skinner, R., Kozlova, A., Suri, D., Lehmberg, K., M\u00fcller, I., and Balashov, D. (2021). HSCT is effective in patients with PSTPIP1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome. J. Allergy Clin. Immunol., 148.","DOI":"10.1016\/j.jaci.2020.11.043"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1111\/1346-8138.15706","article-title":"Rare cases of PAMI syndrome in both father and son with the same missense mutation in PSTPIP1 gene and literature review","volume":"48","author":"Huang","year":"2021","journal-title":"J. Dermatol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e20200784","DOI":"10.1542\/peds.2020-0784","article-title":"Hemolysis and Neurologic Impairment in PAMI Syndrome: Novel Characteristics of an Elusive Disease","volume":"147","author":"Guardo","year":"2021","journal-title":"Pediatrics"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"759092","DOI":"10.3389\/fmed.2021.759092","article-title":"Kidney Involvement in PSTPIP1 Associated Inflammatory Diseases (PAID): A Case Report and Review of the Literature","volume":"8","author":"Borgia","year":"2021","journal-title":"Front. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1016\/j.abd.2018.12.001","article-title":"Extensive pyoderma gangrenosum-like lesions revealing a case of hyperzincemia and hypercalprotectinemia: When to suspect it?","volume":"94","author":"Resende","year":"2019","journal-title":"Anais Brasileiros de Dermatologia"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e27439","DOI":"10.1002\/pbc.27439","article-title":"PSTPIP1-associated myeloid-related proteinemia inflammatory syndrome: A rare cause of childhood neutropenia associated with systemic inflammation and hyperzincemia","volume":"66","author":"Hashmi","year":"2019","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1007\/s10875-019-00646-z","article-title":"Autoinflammation Masquerading as Autoimmunity in an Adult with Heterozygous p.E250K PSTPIP1 Mutation","volume":"39","author":"Dai","year":"2019","journal-title":"J. Clin. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"982","DOI":"10.1111\/bjd.16136","article-title":"The expanding spectrum of clinical phenotypes associated with PSTPIP1 mutations: From PAPA to PAMI syndrome and beyond","volume":"178","author":"Beltraminelli","year":"2018","journal-title":"Br. J. Dermatol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.semarthrit.2015.02.012","article-title":"Novel PSTPIP1 gene mutation in a patient with pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome","volume":"45","author":"Lindwall","year":"2015","journal-title":"Semin. Arthritis Rheum."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1097\/BOR.0000000000000314","article-title":"Alarming consequences\u2014Autoinflammatory disease spectrum due to mutations in proline-serine-threonine phosphatase-interacting protein 1","volume":"28","author":"Holzinger","year":"2016","journal-title":"Curr. Opin. Rheumatol."},{"key":"ref_30","first-page":"S198","article-title":"Clinical, genetic and immunological characterization of a patient with the new pstpip1-associated autoinflammatory disease hyperzincemia with hypercalprotectinemia","volume":"34","author":"Sologuren","year":"2014","journal-title":"J. Clin. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.1007\/s00011-021-01479-6","article-title":"Analysis of five cases of monogenic lupus related to primary immunodeficiency diseases","volume":"70","author":"Su","year":"2021","journal-title":"Inflamm. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"565099","DOI":"10.3389\/fimmu.2020.565099","article-title":"Single-Center Overview of Pediatric Monogenic Autoinflammatory Diseases in the Past Decade: A Summary and Beyond","volume":"11","author":"Wang","year":"2020","journal-title":"Front. Immunol."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/14\/8\/1655\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:37:43Z","timestamp":1760128663000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/14\/8\/1655"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,19]]},"references-count":32,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2023,8]]}},"alternative-id":["genes14081655"],"URL":"https:\/\/doi.org\/10.3390\/genes14081655","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,19]]}}}