Clinical phenotype and laboratory markers in patients affected by haploinsufficiency of A20 (HA20): a case series from two Italian centres

Introduction Haploinsufficiency of A20 (HA20) is a monogenic disease caused by heterozygous TNFAIP3 variants. Despite the marked clinical variability, no genotype–phenotype correlation or validated laboratory biomarkers have been identified so far. Neurobehavioural abnormalities have been reported in murine models, but their prevalence in humans remains unclear. Objectives To describe a cohort of patients with HA20 from two centres, evaluating age-related clinical variability; to assess the prevalence of neuropsychiatric symptoms; to explore the inflammatory profile of the patients, including interferon (IFN)-γ-inducible chemokines (CXCL9/10) and type 1 IFN signature (IS), as well as the therapies administered. Methods Clinical and laboratory data of 17 subjects from six families heterozygous for TNFAIP3 variants (American College of Medical Genetics and Genomics class 4–5) were retrospectively collected. Disease activity, treatments, CXCL9/10 and IS levels were collected. Continuous variables were expressed as medians (IQR). Age at onset was compared using the Kruskal-Wallis test, and groups were compared through the Wilcoxon test or Fisher’s exact test. Results Clinical manifestations included oral aphthosis (88%), recurrent fever (53%), gastrointestinal inflammation (53%), autoimmunity (47%), genital ulcers (47%), neuropsychiatric symptoms (41%), arthritis/tenosynovitis (18%) and skin inflammation (12%). Disease onset before 5 years of age was associated with a higher prevalence of neuropsychiatric symptoms during lifetime (p=0.004), whereas arthritis was more common in patients with later onset. The median age at onset differed significantly according to the type of clinical manifestation (p<0.001). Higher IS levels were found in patients with active disease (p<0.01). Conclusions HA20 shows marked clinical heterogeneity both between and within families. Clinical manifestations appear age-related and early disease onset was associated with increased neuropsychiatric involvement lifetime. Finally, type 1 IS may represent a potential biomarker of disease activity in HA20.