To present a case with STAT1 gain-of-function (GoF) mutations absent of chronic mucocutaneous candidiasis (CMC) and to discuss the use of unanalyzed data from genetic panel testing.
The male patient initially had stomatitis at age 3 and experienced sepsis-like symptoms at age 4. During his school-age years, he repeatedly had fevers 4 to 5 times a year, each episode lasting 7 to 10 days. At age 13, he developed ileocecal enteritis two times; while antibiotics were not effective, glucocorticoid (GC) showed marked response. Considering the possibilities of autoinflammatory diseases such as familial Mediterranean fever, he was treated with low-dose GC, colchicine, and adalimumab. At age 14, he suffered from Pneumocystis jirovecii pneumonia, Cryptococcus neoformans fungemia/meningitis, and herpes zoster, successively. A chest CT scan revealed bronchiectasis. After age 18, he hemoptysed several times. He was diagnosed with STAT1 GoF by genetic testing at age 19. Elevated antinuclear antibodies (x 640, speckled pattern) were detected at age 13, and a proteome-wide antibody array analysis (HuPEX) identified 176 kinds of autoantibodies. Though most had unknown clinical significance, anti-PSME3 (anti-Ki) antibody has been reported as an autoantibody associated with Sicca syndrome in male systemic lupus erythematosus (SLE) patients. Our patient did not have dry symptoms; however, inflammatory cell infiltration was observed in some small salivary glands.
In this case, autoinflammatory-like symptoms emerged in early childhood and autoimmune symptoms and susceptibility to infectious diseases became apparent from around adolescence. Ultimately, a heterozygous p.R274Q mutation was identified in the STAT1 gene, and he was diagnosed with STAT1 GoF, but no CMC symptoms were observed throughout the clinical course. For cases difficult to diagnose clinically, we believe that genetic testing should be actively pursued to facilitate early diagnosis. The genetic testing for hereditary autoinflammatory diseases (conducted by Kazusa DNA Research Institute), which is covered by health insurance, provides results for about 10 target genes. However, in the background, sequencing data for more than 242 genes is obtained using next-generation sequencers and stored without analysis. We have successfully established definitive diagnoses through the secondary analysis of these unused data.
We reported a case of STAT1 GoF without CMC. Genetic analysis has a crucial role in the diagnosis of inborn errors of immunity. Promoting the secondary use of unanalyzed data could lead to enhanced diagnostic rates.
