Single amino acid charge switch defines clinically distinct proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1)-associated inflammatory diseases.

BACKGROUND: Hyperzincemia and hypercalprotectinemia (Hz/Hc) is a distinct autoinflammatory entity involving extremely high serum concentrations of the proinflammatory alarmin myeloid-related protein (MRP) 8/14 (S100A8/S100A9 and calprotectin). OBJECTIVE: We sought to characterize the genetic cause and clinical spectrum of Hz/Hc. METHODS: Proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1) gene sequencing was performed in 14 patients with Hz/Hc, and their clinical phenotype was compared with that of 11 patients with pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome. PSTPIP1-pyrin interactions were analyzed by means of immunoprecipitation and Western blotting. A structural model of the PSTPIP1 dimer was generated. Cytokine profiles were analyzed by using the multiplex immunoassay, and MRP8/14 serum concentrations were analyzed by using an ELISA. RESULTS: Thirteen patients were heterozygous for a missense mutation in the PSTPIP1 gene, resulting in a p.E250K mutation, and 1 carried a mutation resulting in p.E257K. Both mutations substantially alter the electrostatic potential of the PSTPIP1 dimer model in a region critical for protein-protein interaction. Patients with Hz/Hc have extremely high MRP8/14 concentrations (2045 ± 1300 µg/mL) compared with those with PAPA syndrome (116 ± 74 µg/mL) and have a distinct clinical phenotype. A specific cytokine profile is associated with Hz/Hc. Hz/Hc mutations altered protein binding of PSTPIP1, increasing interaction with pyrin through phosphorylation of PSTPIP1. CONCLUSION: Mutations resulting in charge reversal in the y-domain of PSTPIP1 (E→K) and increased interaction with pyrin cause a distinct autoinflammatory disorder defined by clinical and biochemical features not found in patients with PAPA syndrome, indicating a unique genotype-phenotype correlation for mutations in the PSTPIP1 gene. This is the first inborn autoinflammatory syndrome in which inflammation is driven by uncontrolled release of members of the alarmin family.

Insomnia and quality of life in children referred for limb pain.

OBJECTIVE: Children with limb pain have significantly diminished quality of life. Although this could result directly from the pain, we investigated the extent to which associated insomnia may contribute. METHODS: A consecutive series of pediatric rheumatology clinic patients (age 3-18 yrs) who presented for initial evaluation of limb pain were offered participation. Parents and children, as appropriate, completed the Pediatric Sleep Questionnaire and Pediatric Quality of Life Inventory (PedsQL 4.0). Validated measures of pain duration and current pain level were provided by the children. Subjects were judged to have substantial insomnia if they had at least 2 of the following symptoms: difficulty falling asleep at night, waking more than twice on average, trouble falling back to sleep, or waking in the morning feeling unrefreshed. Linear regression was used to model the total PedsQL 4.0 score on insomnia, pain duration, and pain level. RESULTS: Seventy-four subjects were recruited (47 girls, mean age 10 +/-3.9); 25 (33%) had juvenile idiopathic arthritis and 40 (54%) had insomnia. A low PedsQL 4.0 score was predicted by insomnia (p < 0.001), but not by pain duration or level (each p > 0.10). Neither pain level nor duration differed significantly between subjects with or without insomnia (each p > 0.10). CONCLUSION: Significant insomnia may affect half of the children who present to a pediatric rheumatology clinic for limb pain. Quality of life in this setting may depend more on insomnia than on current level or duration of pain.