CARD8 encodes the caspase recruitment domain-containing protein 8, a negative regulator of the NLRP3 inflammasome and a modulator of innate immune signaling. Although not yet formally classified among inborn errors of immunity (IEIs), emerging evidence suggests a potential role of CARD8 variants in autoinflammatory syndromes and immune dysregulation.
We describe three unrelated patients from different families with variable phenotypes involving autoinflammation and immune dysregulation.
Patient 1: A 15-year-old female with an IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked)-like phenotype, including alopecia universalis, growth retardation, pubertal delay, and elevated serum IL-18 levels. A heterozygous frameshift variant in CARD8 (c.40delG, p.Glu14fs) was identified.
Patient 2: A 3-year-old male presenting with neonatal lupus-like rash, severe atopic dermatitis, refractory autoimmune cytopenias, persistent hepatitis, and total villous atrophy on intestinal biopsy (Marsh 3b). A heterozygous frameshift variant (c.68dupG, p.Ser24fs) was detected.
Patient 3: A 42-year-old female with adult-onset CVID (common variable immunodeficiency)-like phenotype, including recurrent pneumonia, chronic diarrhea, and persistent hypogammaglobulinemia requiring immunoglobulin replacement. A heterozygous missense variant (c.1093A>C, p.Met365Leu) was identified.
These cases illustrate the broad clinical spectrum associated with CARD8 variants, ranging from severe early-onset autoinflammatory disease to adult-onset humoral immunodeficiency. The presence of elevated IL-18 and multi-organ involvement supports dysregulated inflammasome activation as a key pathogenic mechanism. Importantly, heterozygous variants may result in incomplete penetrance and variable expressivity, complicating diagnosis and counseling.
CARD8 mutations should be considered in patients presenting with unexplained autoinflammation, immune dysregulation, or CVID-like phenotypes. Recognition of this spectrum may facilitate earlier diagnosis, appropriate therapeutic interventions targeting IL-1/IL-18 pathways, and genetic counseling for affected families.
