Medical Genetics · PSTPIP1-Associated Inflammatory Disease (PAMI Syndrome)

The Biology and Genetics of PAMI

At a Glance

PAMI is a rare genetic inflammatory disorder linked to PSTPIP1 variants. Abnormal immune signaling can produce very high serum calprotectin and zinc, low blood counts, and skin ulcers; diagnosis requires genetic results interpreted with the clinical picture.

The transition from the name HZ/HCP to PAMI syndrome reflects a major shift in how doctors understand this condition. It moved from being defined just by high zinc levels to being recognized as a genetic disorder of the innate immune system. Understanding the proposed biology behind PAMI can help you advocate for the specific tests and specialists needed.

The Genetics: A “Charge-Reversal” Change

At the heart of PAMI is a mutation in the PSTPIP1 gene ^[1]^[2].

In the majority of reported PAMI cases, the variation occurs at one of two specific locations on the gene: p.E250K or p.E257K ^[3]^[4]. (Other rare variants, such as p.N236K, have also been reported).

The Proposed Science: These are called “charge-reversing” mutations. Reversing the electrical charge of the protein at these spots alters how it interacts with other proteins. Specifically, current models suggest it increases interaction with a protein called pyrin ^[5]^[6].

The Biology: The Inflammasome Model

When the mutated PSTPIP1 protein binds too tightly to pyrin, it is believed to trigger the assembly of the pyrin-inflammasome in white blood cells (specifically neutrophils and macrophages) ^[5]^[7].

In this model, the dysregulated inflammasome activates the processing and release of powerful inflammatory chemicals:

Cytokine Release: The cells release excessive amounts of IL-1β and IL-18, which signal the body to create a fever and drive systemic inflammation ^[6]^[7].
The Calprotectin Elevation: The cells also release massive amounts of MRP8/14, also known as calprotectin ^[8]^[4]. This protein is an alarmin, meaning its job is to alert the rest of the immune system ^[9].

The Zinc Connection: Calprotectin naturally binds to zinc. Because there is so much calprotectin in the blood of patients with PAMI, it retains zinc there, causing the hyperzincemia (high zinc) that gave the condition its original name ^[8]^[4].

Confirming the Diagnosis

Because PAMI is so rare, diagnosis requires interpreting genetic results alongside the full clinical picture. A single test is never definitively diagnostic on its own ^[4].

PSTPIP1 Sequencing: A clinical genetics laboratory must interpret a pathogenic or likely pathogenic variant in the context of the patient’s symptoms. A “variant of uncertain significance” does not establish PAMI ^[1]^[10]. Parental testing is often useful for counseling and inheritance determination.
Serum Calprotectin (MRP8/14): In PAMI, calprotectin levels in the blood (not the stool) are often markedly elevated. For example, while children with a similar condition called PAPA syndrome might have levels around 116 μg/mL, children with PAMI often have levels exceeding 2,000 μg/mL ^[3].
Serum Zinc: Elevated zinc levels are characteristic, but they are not unique to PAMI ^[4]^[11].

Distinguishing PAMI from Similar Conditions

PAMI is frequently confused with other conditions because its symptoms—like skin ulcers or low blood counts—are seen in many diseases.

Condition	Distinguishing Factors
PAPA Syndrome	PAMI causes low blood counts (neutropenia) and much higher zinc/calprotectin levels than PAPA ^[3]^[12].
Nutritional Zinc/Copper Issues	High zinc can also be caused by supplements, occupational exposure, or lab contamination, which can lead to copper deficiency and low blood counts. Do not start or stop zinc or copper supplements without medical guidance ^[4]^[13].
Inflammatory Bowel Disease (IBD)	While IBD also uses calprotectin as a marker, it is usually measured in the stool (fecal calprotectin) rather than in the blood ^[11]^[14].

Understanding these differences ensures that the patient undergoes a full clinician-led evaluation, which may include reviewing supplements, checking copper/ceruloplasmin, and interpreting genetic findings ^[13].

Common questions in this guide

What is PAMI syndrome?

PAMI, or PSTPIP1-associated inflammatory disease, is a rare genetic disorder that causes ongoing inflammation. Changes in the PSTPIP1 gene can overactivate immune cells, leading to very high blood calprotectin and zinc, fever, skin ulcers, or low blood counts.

How do PSTPIP1 changes affect the immune system in PAMI?

Certain PSTPIP1 changes may make the protein bind more strongly to pyrin, a protein involved in immune activation. This can trigger an inflammatory complex in white blood cells and increase release of IL-1β, IL-18, and MRP8/14, also called calprotectin.

Is calprotectin in blood or stool used to evaluate PAMI?

PAMI is associated with markedly high calprotectin in the blood, measured as serum MRP8/14. Stool calprotectin is more commonly used when evaluating intestinal inflammation such as inflammatory bowel disease, so the sample type matters.

Does a high zinc level confirm PAMI?

No. High zinc can also result from supplements, occupational exposure, or laboratory contamination, and it may contribute to copper deficiency and low blood counts. Clinicians usually interpret zinc with symptoms, serum calprotectin, copper and ceruloplasmin results, and genetic testing.

What genetic test is used to diagnose PAMI?

A clinical genetics laboratory can sequence PSTPIP1 and assess whether a variant is pathogenic or likely pathogenic. The result must be interpreted with the person's clinical findings; a variant of uncertain significance alone does not establish PAMI. Testing parents may help clarify inheritance.

How is PAMI different from PAPA syndrome?

Both conditions can cause inflammatory symptoms and skin ulcers, but PAMI is more often associated with neutropenia and much higher serum zinc and calprotectin levels. Because the conditions can overlap, clinicians use the full clinical picture, laboratory results, and genetic testing rather than one measurement alone.

Get notified when new evidence is published on Hyperzincemia and hypercalprotectinemia.

We monitor PubMed for new peer-reviewed studies on this topic and email a short summary when something meaningful changes.

References (14)

1
Phenotypic Associations of PSTPIP1 Sequence Variants in PSTPIP1-Associated Autoinflammatory Diseases.
Boursier G, Piram M, Rittore C, et al.
The Journal of investigative dermatology 2021; (141(5)):1141-1147 doi:10.1016/j.jid.2020.08.028.
PMID: 33218716
2
PSTPIP1-LYP phosphatase interaction: structural basis and implications for autoinflammatory disorders.
Manso JA, Marcos T, Ruiz-Martín V, et al.
Cellular and molecular life sciences : CMLS 2022; (79(2)):131 doi:10.1007/s00018-022-04173-w.
PMID: 35152348
3
Single amino acid charge switch defines clinically distinct proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1)-associated inflammatory diseases.
Holzinger D, Fassl SK, de Jager W, et al.
The Journal of allergy and clinical immunology 2015; (136(5)):1337-45.
PMID: 26025129
4
PSTPIP1-Associated Myeloid-Related Proteinemia Inflammatory (PAMI) Syndrome: A Systematic Review.
Mejbri M, Renella R, Candotti F, et al.
Genes 2023; (14(8)) doi:10.3390/genes14081655.
PMID: 37628706
5
Autoinflammatory disease and severe neutropenia due to de novo variant of PSTPIP1 with increased binding to pyrin.
Cook S, Nomula K, Cross CE, et al.
Journal of human immunity 2026; (2(2)):e20250201 doi:10.70962/jhi.20250201.
PMID: 42007463
6
Strong inflammatory signatures in the neutrophils of PAMI syndrome.
Zheng W, Fan X, Yang Z, et al.
Frontiers in immunology 2022; (13()):926087 doi:10.3389/fimmu.2022.926087.
PMID: 36203570
7
Recent Insights in Pyrin Inflammasome Activation: Identifying Potential Novel Therapeutic Approaches in Pyrin-Associated Autoinflammatory Syndromes.
Wouters F, Bogie J, Wullaert A, van der Hilst J
Journal of clinical immunology 2023; (44(1)):8 doi:10.1007/s10875-023-01621-5.
PMID: 38129719
8
Alarming consequences - autoinflammatory disease spectrum due to mutations in proline-serine-threonine phosphatase-interacting protein 1.
Holzinger D, Roth J
Current opinion in rheumatology 2016; (28(5)):550-9 doi:10.1097/BOR.0000000000000314.
PMID: 27464597
9
Extensive pyoderma gangrenosum-like lesions revealing a case of hyperzincemia and hypercalprotectinemia: when to suspect it?
Resende LO, Jorge MFS, Schmitt JV
Anais brasileiros de dermatologia 2019; (94(6)):713-716 doi:10.1016/j.abd.2018.12.001.
PMID: 31789267
10
Hemolysis and Neurologic Impairment in PAMI Syndrome: Novel Characteristics of an Elusive Disease.
Del Borrello G, Guardo D, Micalizzi C, et al.
Pediatrics 2021; (147(3)) doi:10.1542/peds.2020-0784.
PMID: 33597285
11
A Case Study of PSTPIP1-Associated Myeloid-Related Proteinemia Inflammatory Syndrome Masquerading as Inflammatory Bowel Disease.
Rodsaward P, Kiattikunrat K, Tangnuntachai N, et al.
Inflammatory intestinal diseases 2026; (11(1)):300-306 doi:10.1159/000553249.
PMID: 42559525
12
Kidney Involvement in PSTPIP1 Associated Inflammatory Diseases (PAID): A Case Report and Review of the Literature.
Borgia P, Papa R, D'Alessandro M, et al.
Frontiers in medicine 2021; (8()):759092 doi:10.3389/fmed.2021.759092.
PMID: 34778321
13
PAMI syndrome: A rare cause that can be easily misdiagnosed.
Xu XM, Huang H, Ding F, et al.
American journal of medical genetics. Part A 2021; (185(10)):3074-3082 doi:10.1002/ajmg.a.62367.
PMID: 34047005
14
Comparison of Fecal Calprotectin with Different Endoscopic Scores in the Assessment of Ulcerative Colitis (UC) Activity and Its Utility in Differentiating IBS from IBD.
Acharya K, Bhardwaj V, Chuahan I, et al.
Euroasian journal of hepato-gastroenterology 2023; (13(2)):120-123 doi:10.5005/jp-journals-10018-1411.
PMID: 38222953

This page is for informational purposes only and does not constitute medical advice. A clinical geneticist and treating team should interpret your genetic, zinc, and serum calprotectin results.

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