This article is part of the supplement: 7th Congress of International Society of Systemic Auto-Inflammatory Diseases (ISSAID)

Open Access Open Badges Meeting abstract

PW02-018 - Impact of PSTPIP1 mutaions on clinical phenotype

D Holzinger12*, P Lohse3, S Faßl1, J Austermann1, T Vogl1, W de Jager4, S Holland5, M Gattorno6, C Rodriguez-Gallego7, J Arostegui8, S Fessatou9, B Isidor10, K Ito11, H-J Epple12, J Bernstein13, M Jeng13, G Lionetti13, P Ong14, C Hinze15, B Sampson16, C Sunderkoetter17, D Foell2, J Chae18, A Ombrello18, J Brady18, I Aksentijevich18 and J Roth1

  • * Corresponding author: D Holzinger

Author Affiliations

1 Institute of Immunology, University Hospital Muenster, Germany

2 Department of Paediatric Rheumatology and Immunology, University Children´s Hospital Muenster, Muenster, Germany

3 Department of Clinical Chemistry Großhadern, University Munich, Munich, Germany

4 Department of Pediatric Immunology, University Medical Centre Utrecht, Utrecht, The Netherlands

5 National Institute of Allergy and Infectious Diseases, National Institute of Health, Bethesda, USA

6 2nd Division of Pediatrics , "G. Gaslini" Scientific Institute, Genova, Italy

7 Department of Immunology, Dr. Negrín University Hospital, Las Palmas de Gran Canaria, Spain

8 Immunology Department-CDB/IDIBAPS, Hospital Clinic, Barcelona, Spain

9 3rd Department of Pediatrics , Athens University Medical Faculty, Athens, Greece

10 Service de Génétique Médicale, Centre Hospitalo-Universitaire, Nantes, France

11 Department of Pediatrics and Neonatology, Nagoya City University, Nagoya, Japan

12 Department of Gastroenterology, Infectious Diseases and Rheumatology, Charité University Hospital Berlin, Berlin, Germany

13 Department of Pediatrics, Stanford University Medical Center, Stanford, LA, USA

14 Division of Clinical Immunology and Allergy, Children's Hospital Los Angeles, LA, USA

15 Deutsches Zentrum für Kinder- und Jugendrheumatologie, Garmisch-Patenkirchen, Germany

16 Department of Clinical Chemistry, Charing Cross Hospital, London, UK

17 Department of Dermatology, University Hospital Muenster, Muenster, Germany

18 National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institute of Health, Bethesda, USA

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Pediatric Rheumatology 2013, 11(Suppl 1):A158  doi:10.1186/1546-0096-11-S1-A158

The electronic version of this article is the complete one and can be found online at:

Published:8 November 2013

© 2013 Holzinger et al; licensee BioMed Central Ltd.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Hyperzincaemia and hypercalprotectinaemia (Hz/Hc), a rare condition within the spectrum of autoinflammatory diseases, is associated with hepatosplenomegaly, arthritis, anemia, cutaneous inflammation, and failure to thrive. So far, no genetic cause has been identified. While the clinical appearance is heterogeneous, all affected individuals present with extremely elevated MRP8/MRP14 (calprotectin) serum concentrations (0.9-12.0 g/l (normal range < 0.001 g/l)).


The clinical phenotype of 12 patients was characterized and compared to 11 patients with classical PAPA syndrome. Screening of candidate genes was performed to identify disease-causing mutations.


Serum concentrations of MRP8/14 complex were analyzed in 12 patients with Hz/Hc and compared to 11 PAPA patients. Candidate exons of these patients were sequenced. Cytokine profile of 12 patients with PSTPIP1 mutations was analyzed by mulitplex ELISA. MRP8/14 secretion from patient´s PBMCs was measured and activity of patient`s sera on monocytes evaluated. The clinical phenotype of all enrolled patients was characterized and compared.


Ten of twelve patients were heterozygous carriers of a glutamic acid 250 (GAG)→lysine (AAG)/p.Glu250Lys/E250K substitution and 1 patient of a glutamic acid 257 (GAG)→lysine (AAG)/p.Glu250Lys/E257K substitution in exon 11 of the PSTPIP1 gene. MRP8/MRP14 concentrations were extremely elevated in these patients (0.9-12 g/l) compared to eleven patients presenting with classical PAPA symptoms (0.02-0.35 g/l), whose levels again were significantly higher compared to normal controls. Cytokine profiling confirmed the heterogeneity of PSTPIP1 mutations with a distinct profile for the Hz/Hc phenotype. MRP8/14 hypersecretion was found in PBMCs of patients with PSTPIP1 mutations and the serum of patients with active disease showed co-stimulatory properties on monocytes activated with TLR-1 ligands.


The novel PSTPIP1 E250K and E275K mutations cause an autoinflammatory disorder known as hyperzincaemia and hypercalprotectinaemia. The disease causes a heterogeneous spectrum of symptoms that only partially overlaps with the presentation of the classical PAPA syndrome. Elevated MRP8/14 levels are a common hallmark and biomarker of disorders caused by mutations in the PSTPIP1 gene.

Disclosure of interest

None declared.