Behçet's disease (BD) is an inflammatory disease mainly affecting men along the ancient Silk Route. In the present study we describe a Dutch family suffering from BD-like disease with extreme pathergic responses, but without systemic inflammation. Genetic assessment revealed a combination of the human leukocyte antigen (HLA)-B*51 risk-allele together with a rare heterozygous variant in the CSF2 gene (c.130A>C, p.N44H) encoding for granulocyte-macrophage colony-stimulating factor (GM-CSF) found by whole exome sequencing. We utilized an over-expression vector system in a human hepatocyte cell line to produce the aberrant variant of GM-CSF. Biological activity of the protein was measured by signal transducer and activator of transcription 5 (STAT-5) phosphorylation, a downstream molecule of the GM-CSF receptor, in wild-type peripheral mononuclear cells (PBMCs) using flow cytometry. Increased STAT-5 phosphorylation was observed in response to mutated GM-CSF when compared to the wild-type or recombinant protein. CSF2 p.N44H results in disruption of one of the protein's two N-glycosylation sites. Enzymatically deglycosylated wild-type GM-CSF also enhanced STAT-5 phosphorylation. The patient responded well to anti-tumor necrosis factor (TNF)-α treatment, which may be linked to the capacity of TNF-α to induce GM-CSF in phorbol 12-myristate 13-acetate (PMA)-treated PBMCs, while GM-CSF itself only induced dose-dependent interleukin (IL)-1Ra production. The identified CSF2 pathway could provide novel insights into the pathergic response of BD-like disease and offer new opportunities for personalized treatment.
Background To explore the clinical characteristics, treatment regimen, and prognosis of cardiac valvular involvement in pediatric Behcet's disease. Methods Retrospective analysis was conducted on the clinical data obtained from one pediatric patient suffering from Behcet's disease with cardiac valvular involvement. Present study also reviewed the literature related to cardiac involvement in pediatric Behcet's disease. Results The disease onset in the female patient was reported at the age of 3 years, with clinical symptoms, including apthous ulcers, fever, perianal ulcers, and erythema nodosum, accompanied by a significant increase in the inflammatory markers. Echocardiography indicated that aortic valve (AV) lesions, which were absent initially, developed later, gradually exacerbated. Initially, she was diagnosed as "infectious disease" and "systemic inflammatory response syndrome", and antibiotic therapy proved ineffective. After an accurate diagnosis of Behcet's disease, the patient was given glucocorticoids, immunosuppressants, and biologics, which resulted in the relief of the symptoms; however, cardiac valvular lesions continued to exacerbate. Subsequent treatment included medical treatment and surgical treatment, and the patient's condition was stable at follow-up. Conclusions Cardiac valvular lesions in pediatric Behcet's disease are rare with insidious onset, enhancing the propensity of misdiagnosis or missed diagnosis. Main manifestations include recurrent oral ulceration, skin lesions, and fever. Cardiac involvement may occur early, yet the symptoms are insidious, requiring comprehensive physical examination and close monitoring of echocardiography. Glucocorticoids combined with immunosuppressants are the primary therapy for cardiac involvement in Behcet's disease. When cardiac valvular damage and dysfunction are observed, treatment regimens can be jointly recommended by multidisciplinary consultation to conduct the surgical treatment on time.
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