PSTPIP1-associated autoinflammatory syndrome

PSTPIP1-associated autoinflammatory syndrome, also called PSTPIP1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome, is a rare multi-system condition caused by anomalies in the proline-serine-threonine phosphatase interacting protein. Specific anomalies in the gene lead to constitutive activation of the pyrin inflammasome. Affected patients present with features of chronic systemic inflammation and cytopenia.

Patients typically present in childhood, though adulthood-onset disease is also described. Clinical features are highly variable. They include:

• cytopaenias, particularly anaemia and neutropaenia;
• cutaneous manifestations, such as erythematous rash;
• early-onset arthritis;
• lymphoproliferative features, such as hepatosplenomegaly;
• failure to thrive; and
• marked elevation of zinc, myeloid-related proteins (MRP)-8 and MRP14 blood levels (these are hallmarks of the condition).

Pleiotropy is seen in PSTPIP1, with deleterious variants in the gene noted to cause related syndromes:

• pyogenic sterile arthritis, pyoderma gangrenosum and acne (PAPA) syndrome; and
• pyoderma gangrenosum, acne and suppurative hidradenitis (PASH) syndrome.

These syndromes characteristically cause increased elevated IL-1β and neutrophil granule enzymes, with normal zinc and MRP8/14 levels.

PSTPIP1-associated autoinflammatory syndrome has been found in two particular deleterious heterozygous missense variants in PSTPIP1:

• c.748G>A, p.E250K; and
• c.769G>A, p.E257K.

Both variants cause a reversal in charge in the PSTPIP1 γ-domain, leading to an increase in pyrin binding and release of pro-inflammatory cytokines such as IL-1 and IL-6. PSTPIP1 E250K appears to have a milder phenotype, with a few episodes of arthritis. Variable penetrance has been noted in families, and clinical features are also heterogeneous between and within families.

Variant interpretation is challenging due to the spectrum of PSTPIP1-associated diseases and the presence of variants of uncertain significance (VUS). Only a minority of reported PSTPIP1 variants are clearly pathogenic; most are benign or VUS, necessitating careful clinical correlation and, when possible, functional validation.

PSTPIP1–associated autoinflammatory syndrome can be diagnosed following clinical evaluation of autoinflammatory symptoms with cytopaenias. Patients may have a family history of immunodeficiency.

Key diagnostic laboratory markers of increased blood levels of zinc and MRP8/14 distinguish this condition from other PSTPIP1-associated inflammatory conditions.

Genomic testing confirms the diagnosis and differentiates PSTPIP1-associated autoinflammatory syndrome caused by PSTPIP1 from other genetic causes of autoinflammation.

For information about testing, see ‘Child with a suspected autoinflammatory condition‘.

PSTPIP1-associated autoinflammatory syndrome may be identified before any symptoms appear; for example, through the Generation Study. Confirmation of the diagnosis will require referral to clinical immunology services or the National Amyloidosis Centre. Please refer to the local pathway for your region for this condition.

PSTPIP1-associated autoinflammatory syndrome has an autosomal dominant pattern of inheritance. Pathogenic genetic variants have a gain of function of the PSTPIP1 protein.

• Individuals affected by an autosomal dominant condition have one working copy of the gene, and one with a pathogenic variant.
• The chance of a child inheriting the gene with the variant from an affected parent is 1 in 2 (50%).
• Incomplete penetrance can occur (that is, not everyone who has the variant develops the disease).

If you are discussing genomics concepts with your patients, you may find it helpful to use the visual communication aids for genomics conversations.

PSTPIP1-associated autoinflammatory syndrome is a multi-system condition and requires specialised multidisciplinary care.

Initial management focuses on using corticosteroids in treatment of acute flares. In the long term, IL-1 targeted biologics, such as anakinra and canakinumab, are more effective at controlling symptoms. TNF-a inhibitors, such as infliximab, have also been used with good effect. Patients with isolated cytopaenias may respond to immunosuppressive agents, such as cyclosporin.

Haematopoietic stem cell transplantation (HSCT) has been recently reported to be successful, but should only be considered in more severe, treatment-refractory cases.

Patients require life-long monitoring, with regular assessment of inflammatory markers and monitoring for infections secondary to immunosuppression, as well as growth and development assessment.

PSTPIP1-associated autoinflammatory syndrome may be identified before any symptoms appear; for example, through the Generation Study. Management of these individuals may differ from those presenting symptomatically.

For clinicians

• OMIM: 601979 Autoinflammatory syndrome with cytopenia, hyperzincemia, and hypercalprotectinemia
• University College London Faculty of Medical Sciences: National Amyloidosis Centre

References:

• Holzinger D, Fassl SK, de Jager W and others. ‘Single amino acid charge switch defines clinically distinct proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1)-associated inflammatory diseases‘. The Journal of Allergy and Clinical Immunology 2015: volume 136, issue 5, pages 1,337–1,345. DOI: 10.1016/j.jaci.2015.04.016
• Mejbri M, Renella R, Candotti F and others. ‘PSTPIP1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome: A systematic review‘. Genes 2023: volume 14, issue 8, page 1,655. DOI: 10.3390/genes14081655

For patients

• Autoinflammatory UK