Transient synovitis of the hip: Development and validation of a new diagnostic algorithm.

AIM: To develop and validate an algorithm to rapidly distinguish transient synovitis (TS) of the hip from differential diagnoses without additional tests. METHODS: This retrospective cohort study included all children admitted for non-traumatic limping in the emergency department at Lille University-Hospital between 2016 and 2020. The gold standard was a definitive diagnosis at follow-up visit. All variables associated with acute limping in children were analysed in univariate and multivariable analyses. An algorithm was then developed using recursive partitioning and validated internally on a subset of patients. RESULTS: There were 995 patients included (mean age 5.3 years; males 63%); 337 had a TS including 210 confirmed at follow-up visit and 354 another diagnosis. After multivariable analysis, the relevant variables for distinguishing between TS and differential diagnoses were: age 3-10 years, absence of fever, absence of local inflammation, sudden onset of limping on awakening. An algorithm combining these variables was developed (n = 297) and validated internally (n = 175) for children >12 months with limping for ≤10 days, with a specificity of 98.2% and a positive likelihood ratio of 19.6. No serious differential diagnoses were missed. CONCLUSION: Use of this algorithm enables the diagnosis of TS without additional tests and without missing serious differential diagnoses.

Mutations in COPA lead to abnormal trafficking of STING to the Golgi and interferon signaling.

Heterozygous missense mutations in coatomer protein subunit α, COPA, cause a syndrome overlapping clinically with type I IFN-mediated disease due to gain-of-function in STING, a key adaptor of IFN signaling. Recently, increased levels of IFN-stimulated genes (ISGs) were described in COPA syndrome. However, the link between COPA mutations and IFN signaling is unknown. We observed elevated levels of ISGs and IFN-α in blood of symptomatic COPA patients. In vitro, both overexpression of mutant COPA and silencing of COPA induced STING-dependent IFN signaling. We detected an interaction between COPA and STING, and mutant COPA was associated with an accumulation of ER-resident STING at the Golgi. Given the known role of the coatomer protein complex I, we speculate that loss of COPA function leads to enhanced type I IFN signaling due to a failure of Golgi-to-ER STING retrieval. These data highlight the importance of the ER-Golgi axis in the control of autoinflammation and inform therapeutic strategies in COPA syndrome.