case_images: PMC11747594_01
case_images: Clinical history. (A) Timeline of clinical course, radiological features, and management from birth until 5 years old. (B) Genogram of the two patients with unaffected parents. : male (affected); : male (unaffected); : female (affected); : female (unaffected).
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case_images: The patient otherwise remained well and had satisfactory growth parameters, with no fever, chronic respiratory symptoms, unusual environmental exposures, or challenges in accessing healthcare since birth ( Figure 1A ). Further assessment with MRI of the brain and bone scan revealed disseminated osteomyelitis involving the skull, left zygoma and right posterior fourth rib ( Figure 1B ).
case_images: Cytokine response test. Cytokine response levels produced by blood mononuclear cells when stimulated by agents listed on the x-axis, in the production of (A) interferon-gamma (IFN-gamma), (B) tumor necrosis factor-alpha (TNF-alpha), and (C) interleukin 12 (IL-12), respectively. Levels in patient's father (control sample) shown in gray. Each bar represents an individual's single assay result; hence, statistical comparison was non-applicable.
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case_images: In the cytokine response assay ( Supplementary Material ), there was normal response in the production of IFN-gamma to IL-12 with or without phytohemagglutinin (PHA) or lipopolysaccharide (LPS) for both siblings ( Figure 2A ). However, the two siblings had reduced production of tumor necrosis factor alpha (TNF-alpha) with IFN-gamma stimulation, which normalized with the addition of LPS ( Figure 2B ). These findings were supportive of IFN-gamma response defect, such as IFN-gamma receptor deficiency and STAT1 deficiency due to markedly reduced interleukin-12 (IL-12) p40 and p70 production in response to IFN-gamma stimulation of peripheral blood mononuclear cells (PBMCs), which was more obvious in response to combined lipopolysaccharide (LPS) and IFN-gamma ( Figure 2C ).
case_images: STAT1 S710F mutation. (A) Gamma-activated sequence (GAS) reporter assay with human cells completely lacking STAT1 (U3C cells) that transiently express wild-type (WT) or mutant STAT1 were subjected to a GAS reporter assay. Both the S710F (mutation in our patients) and Y701C (known loss-of-function mutation) STAT1 mutants exhibited reduced GAS activation, whereas the R274Q (known gain-of-function mutation) mutant resulted in increased GAS activation upon IFN-gamma stimulation. This GAS reporter assay confirmed that the two siblings had a STAT1 loss-of-function mutation. The bar graphs display the means with standard errors. (B) STAT1 protein with the mutation site S710F (red); activation of STAT1 by phosphorylation at Y701 (blue).
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case_images: IFN-gamma ( Figure 3A ). In contrast, the R274Q mutant, a known gain-of-function mutation found in patients with chronic mucocutaneous candidiasis, showed excess GAS activation in response to IFN-gamma.
case_images: Serial X-rays of left forearm during treatment. (A) 1 month, (B) 3 months, (C) 8 months, (D) 12 months, and (E) 19 months (immediately prior to discontinuation of the anti-tuberculosis medications) showing progressive radiological disease improvement, with near full recovery and remodeling towards the end of the treatment. (F) X-ray of the left forearm 2 years after treatment completion, with full bone remodeling.
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case_images: There was clinical and radiological recovery of osteomyelitis for patient 1 ( Figure 4 ).