A Novel TNFAIP3 Truncating Variant in a Multigenerational Family with Haploinsufficiency of A20: Expanding the Disease Spectrum from Subclinical Inflammation to Autoimmune Endocrinopathy

Objectives To describe a 3-generation family carrying a novel TNFAIP3 truncating variant (p.Gly440*) and to highlight the wide clinical spectrum of Haploinsufficiency of A20 (HA20).

Methods We reviewed clinical histories and laboratory findings including genetic testing, in family members across 3 generations. Gene panel testing was performed by next-generation sequencing at the Hospital for Sick Children and variants were classified as per the American College of Medical Geneticists criteria.

Results The proband (grandmother), aged 71, was initially referred for unexplained and persistently elevated inflammatory markers (ESR 91mm/h, CRP 58-179mg/L). She had no symptoms of any inflammatory disease. Her son suffered from infant onset recurrent painful orogenital ulcers and arthritis, on a background of granuloma annulare and celiac disease. His inflammatory markers were also elevated (CRP 12-17 mg/L). The proband’s daughter was diagnosed in infancy with type 1 diabetes and died from an insulin overdose. Prior to this, she had a son who was also affected by infantile diabetes. Despite having no systemic inflammatory features, he also exhibited elevated CRP (10mg/L). Genetic analysis revealed a heterozygous TNFAIP3 variant, (c.1318G>T, p.Gly440*), in all 3 individuals. This variant was absent from healthy population databases. It has never been documented in the literature and was bioinformatically predicted to create a premature stop codon leading to an absent or dysfunctional A20 protein. As such, it was classified as Likely Pathogenic. The proband’s son was treated initially with colchicine with partial improvement, and later with apremilast, which completely eliminated any further mucocutaneous ulcerations.

Conclusion We report a novel truncating variant in TNFAIP3 causing HA20 in a multigenerational family. Our case series is in line with the current literature and demonstrates the phenotypic variability of HA20 even within the same family, ranging from silent inflammation to Behçet-like disease to organ-specific autoimmunity. Recognizing the variable expressivity and incomplete penetrance of HA20 is important for early diagnosis, screening of family members, and the use of targeted therapy in affected individuals.