Chronic hepatic involvement in the clinical spectrum of A20 haploinsufficiency

Samuel Deshayes (1, 2) , Céline Bazille (1) , Elma El Khouri (3, 4) , Isabelle Kone-Paut (5) , Irina Giurgea (4, 6) , Sophie Georgin-Lavialle (3) , Nicolas Martin Silva (1) , Anaël Dumont (1, 2) , Isabelle Ollivier (1) , Serge Amselem (3, 4, 6) , Hubert Boysson (1, 2) , Achille Aouba (1, 2)

1 CHU Caen
2 UNICAEN - Université de Caen Normandie
3 SU - Sorbonne Université
4 U933 - Maladies génétiques d'expression pédiatrique
5 Hôpital Bicêtre [AP-HP, Le Kremlin-Bicêtre]
6 CHU Trousseau [APHP]

Background & aims: Secondary to tumour necrosis factor-alpha induced protein 3 (TNFAIP3) mutations, A20 haploinsufficiency (HA20) is a recently described autoinflammatory disease with clinical features similar to those of Behçet's and Crohn's diseases but with a constantly expanding clinical spectrum. Here, we describe HA20 liver involvement in three new patients from the same family. Methods: We retrospectively assessed clinical, biological and/or histological findings for eight patients over three generations of the same family with heterozygous mutations in the TNFAIP3 gene (c.259C > T, p.Arg87*). Results: The eight patients exhibited the following: aphthous ulcers (8/8, bipolar in 7), autoimmune features (6/8, including 5 with definitive autoimmune disease diagnoses, ie, type I diabetes, Hashimoto thyroiditis, pernicious anaemia, and/or 5 with antinuclear antibodies ≥320), pustulosis/folliculitis (5/8), abdominal pain (4/8), arthralgia (3/8), enlarged cervical lymph nodes (3/8) and pericarditis (1/8). In addition, three patients (twin sisters and their grandmother aged 23 and 70 years, respectively) exhibited persistent mild hepatic cytolysis associated with splenomegaly (n = 3), hepatomegaly (n = 1) and/or liver atrophy (n = 1) on echography. We could not detect any other causes of chronic liver diseases. Liver biopsies from three patients displayed hepatic fibrosis, hepatocyte injury and/or CD4+ /CD8+ T lymphocyte infiltration, and patterns of inflammatory cells and NLRP3 or NF-κB immunostaining differed from the predominant neutrophil infiltration observed in skin or some digestive tract biopsies. Conclusions: This study reinforces the dual involvement of innate and adaptive immunity in HA20 according to both acute and chronic injury and the organ involved and widens its clinical spectrum to include chronic hepatic involvement.

Mots clés: TNFAIP3; A20 haploinsufficiency; hepatic fibrosis; oral and genital aphthosis

Domaines: Génétique humaine; Sciences du Vivant [q-bio]

Samuel Deshayes, Céline Bazille, Elma El Khouri, Isabelle Kone-Paut, Irina Giurgea, et al.. Chronic hepatic involvement in the clinical spectrum of A20 haploinsufficiency. Liver International, 2021, 41 (8), pp.1894-1900. ⟨10.1111/liv.14935⟩. ⟨inserm-03798525⟩