Simon Lassman MBBS, Joel Reiter MD, Sigal Matza-Porges PhD, Yackov Berkun MD
STING-associated vasculopathy with onset in infancy (SAVI) is a rare monogenic type I interferonopathy that may present with heterogeneous clinical manifestations and mimic common inflammatory disorders of childhood. We report the first familial case of SAVI in Israel, affecting a father and daughter carrying an identical pathogenic gain-of-function TMEM173 variant. The daughter initially presented with features fulfilling criteria for rheumatoid factor-positive juvenile idiopathic arthritis (JIA), later developing growth failure and progressive interstitial lung disease. In contrast, the father developed adolescent-onset inflammatory arthritis, subsequently lung disease, and a severe infectious neurological complication during treatment. This case highlights marked intrafamilial phenotypic variability, the diagnostic challenges posed by atypical inflammatory arthritis and the importance of genetic testing in treatment-refractory or systemic disease. Our findings underscore both the benefits and limitations of JAK inhibition in SAVI, particularly with respect to pulmonary disease and growth outcomes.
Sigal Matza-Porges PhD, Oded Shamriz MD PhD
Inborn errors of immunity (IEI) are a heterogeneous group of monogenic disorders affecting immune function, associated with a broad clinical spectrum including recurrent infections and immune dysregulation consisting of poly-autoimmunity, multiple allergies, and malignancies. To date, more than 550 causative genes have been identified, with inheritance patterns that may be autosomal dominant, autosomal recessive, or X-linked. Pathogenic variants may result in loss-of-function, dominant-negative, or gain-of-function effects, leading to variable phenotypic presentations and, at times, incomplete penetrance. Despite advances in genomic technologies, a definitive molecular diagnosis is reached in only 30–35% of cases. Early and accurate genetic diagnosis is crucial for guiding targeted therapy and providing effective genetic counseling. This review presents an updated overview of IEI from the geneticist's perspective and offers a practical approach to the genetic evaluation and diagnosis of these conditions.