Delayed diagnosis of STAT1 gain-of-function variant in a patient with multiple endocrine autoimmunity and recurrent fungal infections.

Abstract

Summary: This case report describes a 54-year-old woman with multiple endocrine autoimmune pathologies and recurrent mucocutaneous Candida spp. infections that were inappropriately attributed to her glycemic control. Following an allergic reaction over four decades later, the patient was referred to clinical immunology. The combination of persistent Candida infections, autoimmune endocrinopathies, and a positive family history prompted investigation for an inborn error of immunity (IEI). Genetic testing revealed a novel, missense mutation in STAT1. Functional analysis confirmed enhanced STAT1 protein phosphorylation, confirming a gain-of-function phenotype that explained her infectious and autoimmune manifestations. She was started on the JAK inhibitor, ruxolitinib, with clinical improvement. This case underscores the shared molecular mechanisms between IEIs and autoimmune endocrinopathies and highlights the importance of early recognition of IEI in patients with unusual or treatment-refractory infections alongside autoimmune disease. Endocrinologists and primary care providers may be the first to encounter such patients and should consider referral for immunologic and genetic evaluation. Early diagnosis can reduce long-term morbidity and open the door to targeted therapies that address the root cause of immune dysregulation.

Learning points: Persistent mucocutaneous candidiasis in patients with autoimmune endocrinopathies warrants evaluation for underlying IEI: while candidiasis is common in individuals with diabetes, recurrent or treatment-refractory infections - particularly in the presence of additional autoimmune conditions - should prompt consideration of IEI, including STAT1 gain-of-function mutations. Autoimmunity and immunodeficiency represent overlapping spectra of immune dysregulation: genetic syndromes such as STAT1 GOF may manifest with both autoimmune endocrinopathies and increased susceptibility to fungal infections, underscoring the importance of a unifying diagnostic approach to seemingly disparate clinical features. Early referral to clinical immunology and genetic testing can enable timely diagnosis and targeted therapy: early recognition of IEI allows for disease-modifying treatment, such as JAK inhibition, which may alleviate infectious susceptibility and autoimmune manifestations, ultimately reducing morbidity and improving the quality of life. A thorough family history can provide critical diagnostic clues in cases of immune dysregulation: subtle patterns of autoimmunity or recurrent infections in family members - particularly in non-consanguineous pedigrees - may indicate heritable immunologic disorders and should inform the clinical threshold for pursuing genetic evaluation.