D3.357 - Revealing an Underlying Inborn Error of Immunity in Pediatric Granulomatous Disease: A Case of STAT1 Loss-of-Function–Associated Mendelian Susceptibility to Mycobacterial Disease after BCG Vaccination

Granulomatous diseases in children present significant diagnostic challenges and may represent the initial manifestation of inborn errors of immunity (IEI). Mendelian susceptibility to mycobacterial disease (MSMD), caused by defects in the IL-12/IFN-γ signaling pathway, predisposes patients to infections with weakly virulent mycobacteria, including Bacillus Calmette–Guérin (BCG). Clinical, histopathological, and microbiological findings are often nonspecific, leading to misdiagnosis and delayed treatment, particularly in tuberculosis-endemic regions.

We report a detailed clinical, laboratory, histopathological, and genetic evaluation of a 2-year-old boy presenting with progressive granulomatous cutaneous lesions. Extensive immunological workup, microbiological cultures, PCR studies, imaging, and skin biopsies were performed. Due to atypical disease progression and temporal association with BCG vaccination, genetic analysis was pursued.

The patient initially received a presumptive diagnosis of leukocyte adhesion deficiency and multiple empiric antimicrobial and anti-inflammatory therapies without sustained improvement. Histopathology revealed mixed granulomatous inflammation with pseudoepitheliomatous hyperplasia, while all microbiological and PCR studies remained negative. Genetic testing ultimately identified a heterozygous autosomal dominant loss-of-function mutation in STAT1, confirming MSMD. Despite lack of microbiological confirmation, empiric antimycobacterial therapy combined with interferon-γ resulted in marked clinical improvement and disease stabilization.

This case highlights the critical importance of considering IEI, particularly MSMD, in children with atypical, refractory granulomatous disease. Strong clinical suspicion should prompt early genetic evaluation and initiation of targeted therapy, even in the absence of definitive microbiological evidence, to prevent disease progression, tissue destruction, and long-term complications.