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Haploinsufficiency of A20 and other paediatric inflammatory disorders with mucosal involvement

Aeschlimann, Florence A.a; Laxer, Ronald M.b

doi: 10.1097/BOR.0000000000000532

Purpose of review This review aims at summarizing the current knowledge of A20 haploinsufficiency and other paediatric inflammatory disorders with mucosal involvement.

Recent findings A20 haploinsufficiency is a newly described autoinflammatory disease caused by loss-of-function mutations in TNFAIP3 that result in the activation of the nuclear factor (NF)-kB pathway. Patients may present with dominantly inherited, early-onset systemic inflammation and a Behçet-like disease, or a variety of autoinflammatory and autoimmune features. In Behçet disease, recent literature provides insights into genetic susceptibility and emerging treatment options; in addition, the first paediatric classification criteria were published. Recent advances in periodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome (PFAPA) suggest that the disease has a complex underlying genetic mechanism and in some cases is inherited in an autosomal dominant pattern with reduced penetrance phenotype in many family members. Activation of the pyrin inflammasome through the RoA signalling pathway uncovers an interesting molecular connection between hyperimmunoglobulinemia D syndrome and familial Mediterranean fever. The description of new monogenic types of inflammatory bowel disease (IBD) may provide novel insights into disease pathogenesis. Finally, recent studies highlighted the role of gut microorganisms and dysbiosis in IBD.

Summary Monogenic diseases such as A20 haploinsufficiency may help to advance our understanding of disease pathogenesis and to develop targeted therapies for more common, multifactorial disorders with mucosal inflammation.

aPediatric Immunology, Hematology and Rheumatology Unit, Hôpital Necker - Enfants Malades, Paris, France

bDivision of Rheumatology, Departments of Pediatrics and Medicine, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada

Correspondence to Dr Florence A. Aeschlimann, Pediatric Immunology, Hematology and Rheumatology Unit, Hôpital Necker – Enfants Malades, 149, rue de Sèvres, Paris 75015, France. Tel: +33 1 44 49 48 28; fax: +33 1 44 49 50 70; e-mail:

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