case_images: PMC11239428_01
case_images: (A) Patient abdominal CT scan. Homogeneous craniocaudal splenomegaly measuring 176 mm associated with increased diameter of splenic vascular structures and increased hepatic hilar vasculature. No evidence of free fluid. (B) Patient chest CT scan. Bilateral diffusely distributed nodules, including solid, subsolid, and ground-glass opacities, predominantly in the lung bases with the largest measuring 12 mm.
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case_images: PMC11239428_01_fped-12-1423858-g001.jpg
case_images: F1
case_images: Abdominal CT scan showed homogeneous splenomegaly (Figure 1A). Regarding pneumological assessment, chest CT scan showed bilateral diffusely distributed nodules, including solid, subsolid, and ground-glass opacities, predominantly in the lung bases (Figure 1B); pulmonary function tests revealed a mixed ventilatory incapacity and low diffusing carbon monoxide (DLCO); and bronchoalveolar lavage showed an abnormal cytological pattern with increased lymphocytes infiltration.
case_images: (A) Lung biopsy histology. (Upper left) Masson's trichrome stain (4x) peribronchiolar mononuclear inflammatory infiltrate; (Upper right) Hematoxylin and eosin (H&E) stain (10x) Interstitial expansion of lymphocytes and histiocytes; (Lower left and right) H&E stain (40x) Presence of poorly formed non-necrotizing granulomas. (B) Lung biopsy immunohistochemistry. (Upper left) (4x) CD3+ lymphocytes at the interstitial level; (Upper right) (4x) Aggregates of CD20+ lymphocytes; (Lower left and right) (40x) Kappa and lambda chains in similar proportions.
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case_images: PMC11239428_01_fped-12-1423858-g002.jpg
case_images: F2
case_images: Furthermore, lung biopsy was performed showing the presence of a tuberculoid-like necrotizing granuloma, in the superior lobe, and GLILD in the middle lobe (Figure 2A), and immunohistochemistry informed: negative EBERs and CMV, and positive CD3 and CD20 (Figure 2B).
case_images: (A) SOCS1 protein domains and locations of the variants. The kinase inhibitory region (KIR) functions as a pseudo-substrate that can inhibit the tyrosine kinase activity of JAK proteins. The SRC-homology 2 (SH2) domain binds the activation loop of the JAK proteins' catalytic domain. The SOCS box recruits the ubiquitin-transferase system and initiates the proteasomal degradation of JAK proteins. Mutations are described in the literature. Our patient's mutations are in red. (B) Pedigrees of the family with SOCS1 variants. Squares: males; circles: females; black: affected mutation carriers; gray: unaffected mutation carriers. WT, wild-type SOCS1 allele. (C) Sanger sequencing analysis. Sanger sequencing of the exon 1 of SOCS1 in the proband and his parents confirmed the maternal origin of: c.365G>A (p.G122E) and c.368C>A (p.P123H) in the same allele of SOCS1 gene. (D) STAT1 phosphorylation assay. Increased phosphorylation of monocytes (CD14+) after 15 min with IFN-gamma stimulation in the patient and his mother compared with a healthy control (HD).
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case_images: PMC11239428_01_fped-12-1423858-g003.jpg
case_images: F3
case_images: Two variants in SOCS1 were identified, NM_003745.2: c.[365G>A; 368C>A] p.[Gly122Glu; Pro123His], in the same allele, with no other clinically significant variants found (Figure 3A). Santa Cruz, USA), (CADD, University of Washington, USA)]. Sanger sequencing and familial segregation were performed confirming both variants in the patient, his mother, and two of his brothers (Figure 3B, C). Thereafter, we performed STAT-1 phosphorylation assay in the index case and his mother, which showed enhanced response of the JAK-STAT signaling pathway to IFN-gamma stimulus (Figure 3D).