PAMI syndrome E83.2

PAMI syndrome (PAMI is the acronym for "PSTPIP1- associated myeloid-related proteinemia inflammatory syndrome") is a recently described, rare (<50 patients are known) inflammatory disorder formerly known as"hyperzincemia/hypercalprotectinemia syndrome (Hz/Hc)". It is an autoinflammatory disorder characterized by:

a chronic systemic imflammation caused by:

• cutaneous (severe recurrent pyoderma gangraenosum-like ulcers, including a positive pathergy phenomenon)
• osteoarticular manifestations
• Hepatosplenomegaly
• anemia and
• Neutropenia.

The clinical picture should be distinguished from PAPA syndrome (pyogenic arthritis-pyoderma gangrenosum-acne syndrome).

Prevalence: <1 / 1 000 000

This is caused by mutations (p.E250K and p.E257K) in the PSTPIP1 gene.

Infancy (age of onset: 13-30 months)

Clinical manifestations include:

• osteo-articular manifestations (80 %)
• skin lesions(pyoderma gangraenosum; pyoderma gangraenosum-like skin lesions; hidranitis suppurativa: 71 %)
• Splenomegaly (89 %)
• hepatomegaly (68 %)
• lymphadenopathy (42 %)
• growth disturbances (58 %)
• Hemorragic diasthesia with recurrent epistaxis and/or hematoma tendency (16%).

Mild to severe neutropenia and anemia (100%). Thrombocytopenia (42%). Signs of systemic inflammation (94%). Blood concentrations of zinc and MRP 8/14 (S100A8/A9) are significantly elevated.

Response to treatment varies, with no uniformly effective therapy. The most common treatment options are non-steroidal anti-inflammatory drugs, corticosteroids (n=9), anakinra (n=9), anti-TNF (n=6), and cyclosporine A (n=4)

Myeloid-related proteins (MRP) 8 (S100A8) and MRP14 (S100A9) are endogenous ligands of the Toll-like receptor (TLR) that are highly expressed in granulocytes, monocytes, and activated keratinocytes. Both proteins belong to the alarmin family, which are danger signals released in response to cellular stress or damage. Highly elevated serum concentrations of MRP8/14 complexes (calprotectin) have been found in patients with systemic juvenile idiopathic arthritis (SJIA) and familial Mediterranean fever (FMF; OMIM #249100).

1. Holzinger D et al. (2015) Single amino acid charge switch defines clinically distinct proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1)-associated inflammatory diseases. J Allergy Clin Immunol 136:1337-1345.
2. Hashmi SK et al (2019) PSTPIP1-associated myeloid-related proteinemia inflammatory syndrome: A rare cause of childhood neutropenia associated with systemic inflammation and hyperzincemia. Pediatr Blood Cancer 66:e27439.
3. Sampson B et al (2002) Hyperzincemia and hypercalprotectinemia: a new disorder of zinc metabolism. Lancet 360:1742-1745.
4. Xu XM et al (2021) PAMI syndrome: A rare cause that can be easily misdiagnosed. Am J Med Genet A 185:3074-3082.