Current review of pediatric Fas-associated death domain protein deficiency: expanding clinical and therapeutic perspectives.

Fas-associated death domain protein (FADD) deficiency is a rare inborn error of immunity characterized by dysregulated T-cell proliferation. The clinical spectrum and management of FADD deficiency in children remain incompletely described. This review aimed to synthesize patient-level observational evidence on clinical manifestations, immunological and genetic findings, and treatment outcomes of pediatric patients with FADD deficiency. A literature search was conducted of PubMed, the Cochrane Library, and Scopus from database inception to July 2, 2026, and reference lists of eligible articles were reviewed. Inclusion criterion was articles on human clinical studies of patients with FADD gene mutation. Eligibility screening and data extraction were performed independently. Ten articles describing 18 patients were included. The reported ancestries included South Asian (n=9), European (n=6), and East/Central Asian (n=1). Parental consanguinity was reported in 10 of 12 patients (83.3%). Median age at onset was 0.8 years. Major presentations were fever-related encephalopathy, lymphoproliferation, and invasive pneumococcal disease. Common features included liver dysfunction, seizures, and functional hyposplenism. Regarding immunophenotyping, double-negative T cells were elevated in 9 of 10 patients (90%). Elevated soluble FAS ligand and interleukin-10 levels and defective lymphocyte apoptosis were observed in all tested patients; most patients had elevated vitamin B12 levels. The most common pathogenic variant was c.350G>A, followed by c.315T>G. Six patients died (33%) at a median age of 0.8 years. Mortality was high among patients with invasive pneumococcal disease; no deaths were reported among those with a lymphoproliferative phenotype or among the 2 hematopoietic stem cell transplantation recipients. FADD deficiency ranges from early-onset fever-related encephalopathy and fulminant sepsis to lymphoproliferative phenotypes. This review emphasizes the importance of recognizing FADD deficiency in children presenting with recurrent febrile encephalopathy, liver dysfunction, and a history of consanguinity and highlights prompt genetic evaluation and hematopoietic stem cell transplantation as potential curative therapies.