Disseminated Tuberculosis and Chronic Mucocutaneous Candidiasis in a Patient with a Gain-of-Function Mutation in Signal Transduction and Activator of Transcription 1

In humans, recessive loss of function mutations in STAT1 are associated with mycobacterial and viral infections, whereas gain of function (GOF) mutations in STAT1 are associated with a type of primary immunodeficiency related mainly, but not exclusively, to chronic mucocutaneous candidiasis (CMC). We studied and established a molecular diagnosis in a pediatric patient with mycobacterial infections, associated with CMC. The patient, daughter of a non-consanguineous mestizo Mexican family had axillary adenitis secondary to BCG vaccination and was cured with resection of the abscess at one-year old. At four years of age, she had a supraclavicular abscess with acid-fast staining bacilli identified in the soft tissue and bone, with clinical signs of disseminated infection and a positive Gene-X-pert test, which responded to anti-mycobacterial drugs. Laboratory tests of the IL-12/IFN-γ circuit showed a higher production of IL-12p70 in the whole blood from the patient compared to healthy controls, when stimulated with BCG and BCG + IFN-γ. The whole blood of the patient produced 35% less IFN-γ compared to controls assessed by ELISA and flow cytometry, but IL-17 producing T cells from patient were almost absent in PBMC stimulated with PMA plus ionomycin. STAT-1 was hyperphosphorylated at tyrosine 701 in response to IFN-γ and α, as demonstrated by flow cytometry and western blotting in fresh blood mononuclear cells and in Epstein-Barr virus lymphoblastoid cell lines (EBV-LCL); phosphorylation of STAT-1 in EBV-LCL from the patient was resistant to inhibition by staurosporine, but sensitive to ruxolitinib, a Jak phosphorilation inhibitor. Genomic DNA sequencing showed a de novo mutation in STAT1 in cells from the patient, absent in her parents and brother; a known T385M missense mutation in the DNA-binding domain of the transcription factor was identified and it is a GOF mutation. Therefore, GOF mutations in STAT1 can induce susceptibility not only to fungal but also to mycobacterial infections, by mechanisms to be determined.