Systemic juvenile idiopathic arthritis complicated with PSTPIP1 gene variant: A case report

Objective: Systemic Juvenile Idiopathic Arthritis (SJIA) is a subtype of childhood rheumatoid arthritis, with the main clinical manifestations of high fever, recurrent rash, and arthritis. At present, it is generally believed that it is caused by the interaction of gene and environmental factors and has complex genetic characteristics. We report a case of a 1-year and 4-month SJIA patient with heterozygous mutation in PSTPIP1, and we studied the literature on this gene and related autoinfl ammatory diseases.

Systemic Juvenile Idiopathic Arthritis (SJIA) is a subtype of childhood rheumatoid arthritis. Its clinical manifestations include relaxation and high fever, intermittent rash, and arthritis [1]. In addition to local joint manifestations, it is often accompanied by fatigue, enlargement of liver and spleen lymph nodes, serositis, and involvement of heart, liver, lung, kidney, and other organs [2]. PSTPIP1 gene (proline. Serine. Threonine. The variant of phosphatase binding protein 1 can cause PAPA syndrome, which has been previously reported in A230T, E250Q [3,4], and E250K [5] and involves mutation pathogenesis. The clinical manifestations of this disease are suppurative arthritis, pyodermatosis gangrene, and acne [6]. Here, we present a 1-year and 4-month SJIA case of SJIA associated with the PSTPIP1 variant.

Basic information
The patient is a 1-year and 4-month girl, admitted to our hospital because of the "repeatedly fever for 10 days, high fever with the hot peak of 40.2 , the thermal model is unknown, fever 1-2 times a day, the local hospital to" mezlocillin, oseltamivir treatment for 4 days, such as temperature control, and still had a fever again, accompanied by diarrhea, heat rash, there were no symptoms such as cough, conjunctival congestion, chapping of the lips, and rigid edema of hand and foot.
After reexamination, leukocytes and CRP were signifi cantly increased, and the patients were treated with infusion of "ceftriaxone ×5 days, azithromycin ×3 days" and propyl ball.
The symptoms did not improve, and they were transferred to our hospital for treatment. On admission, physical examination showed scattered miliary rash in the trunk, discoloration under pressure, enlarged lymph nodes in the neck, rhythm of heart, no murmur in the anterior heart area, no special auscultation of both lungs, no enlargement of liver and spleen, and no redness of joints. Auxiliary inspection: WBC, neutral ratio, CRP, ESR,

Laboratory results and treatments
The results of complete exon testing showed that the heterozygous mutation of PSTPIP1 gene C.1 l96T>C: P.v399A was paternal (Figure 1), but the clinical signifi cance of AGMG variation rating was unclear.
This child was given a high dose of methylprednisolone (30mg/kg×4 days) and gamma globulin (1g/kg×4 days). The fever symptoms were not improved signifi cantly, and the monitoring of erythrocyte rate, CRP, SF, cytokines, and other an autoinfl ammatory single gene syndrome characterized by infl ammation and seemingly unprovoked recurrent fever [12].
Arthritis and joint pain are common, and these clinical features overlap with the systemic form of juvenile idiopathic arthritis, but due to the small cohort sample size, further study is needed. PSTPIP1 mediates single-gene autoinfl ammatory diseases, the pathophysiological basis has not been fully defi ned. It can lead to IL-1 oversecretion in acute and chronic infl ammatory diseases, and this infl ammatory factor is also involved in the pathogenesis of SJIA [13,14]. We represented that clinical symptoms and laboratory indicators were signifi cantly improved after the application of immunosuppressive agents and biological agents in this case. Therefore, there may be the same immune pathway between SJIA and autoinfl ammatory single-gene diseases.

Conclusion
Immunosuppressive therapy and biological agents were effective for patients with PSTPIP1 gene variant this time.
Currently, there is a lack of cases and clinical studies confi rming a clear correlation between the autoinfl ammatory single gene variant and the onset of SJIA. However, according to this case report, there may be a broader susceptibility gene spectrum of SJIA. Further research is needed to identify undiscovered genetic abnormalities associated with these related diseases.
infl ammatory indicators were still signifi cantly increased, indicating disease activity. The child was treated with additional immunosuppressant cyclosporine, methotrexate, and the biological agent Tocilizumab (160mg), and the progressive body temperature was stable, besides, the rash subsided, and the infl ammatory indicators were normal. The parents of the child did not provide similar family history and denied any previous joint swelling and pain, morning stiffness, oral or nasal mucosal ulcers, facial redness, and Raynaud's phenomenon. Denying a family history of other rheumatic diseases, including SLE, scleroderma, or rheumatoid arthritis.
The child was subsequently treated with low-dose methylprednisolone (8mg/d), cyclosporine (0.5mL/d), methylaminopteryrin (5mg/qw), and monthly infusion of tocilizumab. The body temperature was stable, routine blood leukocytes, CRP, ESR, SF, and cytokines were normal without joint involvement. There was no disease activity in the followup of 15 months.

Research method
We searched WanFang database and Pubmed using the following search terms: JIA, juvenile idiopathic arthritis systemic type, PSTPIP1 gene. The included year was set from 1990 to 2021.

Search results and discussion
SJIA is a systemic infl ammatory disease, classifi ed as a category of juvenile idiopathic arthritis nowadays. The systemic infl ammation of SJIA has been proved to be related to the dysregulation of the innate immune system, suggesting that it may rather be part of the spectrum of autoinfl ammatory disorders. The pathogenesis of SJIA has been reported to be associated with multiple immunogenetics genes, such as HLA (human leukocyte antigen) gene [7], PTPN22 (protein tyrosine phosphatase non-receptor 22) gene, STAT4 (T lymphocyte signal transductor, and transcriptional activator 4) gene, TNF- (tumor necrosis factor A) and IL (interleukin) genes [8,9].
In the present case, we reported a case of SJIA patient with PSTPIP1 gene mutation. Some studies [10,11]indicated different clinical phenotypes from other PSTPIP1 mutation-induced diseases. According to Ellis JA, [11] et al. JIA was confi rmed to be related to SNP (single nucleic acid polymorphisms) of neighboring cl2orf30, c3orfI, PTPN22, STAT4, and TRAF1-C5 based on independent replication data of JIA susceptibility loci and identifi cation.
We also produced evidence supporting the replication of JIA with gene sites including AFF3, CD226, MBL2, PSTPIP1, and RANTES (CCL5). Day TG, [10] et al. using MassArray genotyping, analyzed 950 white British patients with JIA and 728 healthy people of the same race. The results showed that MEFV was signifi cantly correlated with 6 SNPs in JIA. Four loci, including NLRP3, NOD2, MEFV, and PSTPIP1, were found to be associated with 12 SNPs in the subgroup of patients with psoriasis JIA. The syndrome caused by these genes is collectively known as hereditary periodic fever syndrome (HPFS), which is