ESPE Abstracts

Background: STAT1 mutations can cause an extensive spectrum of disease, varying from severe bacterial and viral infections to mild disseminated mycobacterial disease, also chronic mucocutaneous candidiasis. Many patients present with autoimmune manifestations as type 1 diabetes, hypothyroidism and systemic lupus erythematosus. There are risks of cancers and cerebral aneurysms.

Aim: To present the clinical manifestations of STAT1 gain-of-function mutation.

Clinical case: We present a girl, born to a first normal pregnancy with uneventful family history. Since early infancy she suffered with obstructive lung infections and pneumonias, clinically resembling cystic fibrosis, accompanied with mildly elevated sweat chlorides. She developed bronchiectasias very early. At age of 3 years she was hospitalized for autoimmune hepatitis and chronic diarrhea. Cystic fibrosis was genetically excluded. Antifungal therapy was introduced for oral and nail moniliasis. At the age of 10 years autoimmune diabetes debuted with ketoacidosis. Severe autoimmune thyroiditis was established at the same time. Systemic therapy consisted of hormone replacement, antifungal and antimicrobial therapy. At the age of 13 years she revealed several episodes of autoimmune hemolytic anemia (1-2 times per year), which needed intermittent corticosteroid courses. She was genetically tested for AIRE gene defect to establish APECED syndrome without positive result. Through the years chronic lung infection worsened and at the age of 15 hemolytic anemia was transformed to syndrome of macrophageal activation. Lung infection progressed to lung abscesses and empyema that needed surgical interventions. She died at the age of 17 years.

Final genetic results: By using targeted next generation sequencing (Agilent custom capture v5.3/Illumina NextSeq500) at Exeter Molecular Genetic Laboratory we established de novo arisen missense mutation of STAT1 gene, Exon 14: c.1154C>T, p.(Thr385Met). This variant has been previously reported and is predicted to be pathogenic. This confirms a diagnosis of syndrome of immune dysregulation due to a gain-of-function variant in the STAT1 gene with CF-like and APECED-like clinical course, rather than IPEX–like one.

Conclusion: We report our first patient with autoimmune monogenic diabetes, multiple endocrinopathies and other autoimmune phenomena in combination with immune deficiency and CF-like lung disease due to pathogenic variant of the STAT1 gene. Complex clinical manifestation of reported patient with STAT1 mutation shows an extensive role of this gene in autoimmune, hematopoietic, gastrointestinal and pulmonary systems.