Haploinsufficiency of A20 is a rare disease caused by mutations in the gene ''

TNFAIP3 Tumor necrosis factor, alpha-induced protein 3 or A20 is a protein that in humans is encoded by the ''TNFAIP3'' gene. This gene was identified as a gene whose expression is rapidly induced by the tumor necrosis factor (TNF). The protein encoded ...

''.Demir S, Sonmez HE, OZen S (2018) Vasculitis: Decade in Review. Curr Rheumatol Rev doi: 10.2174/1573397114666180726093731Aeschlimann FA, Batu ED, Canna SW, Go E, Gül A, Hoffmann P, Leavis HL, Ozen S, Schwartz DM, Stone DL, van Royen-Kerkof A, Kastner DL, Aksentijevich I, Laxer RM (2018) A20 haploinsufficiency (HA20): clinical phenotypes and disease course of patients with a newly recognised NF-kB-mediated autoinflammatory disease. Ann Rheum Dis 77(5):728-735 doi: 10.1136/annrheumdis-2017-212403 This gene is also known as A20.

Signs and symptoms

These are variable even within families. the main features are recurrent oral, genital and/or gastrointestinal ulcers, musculoskeletal and gastrointestinal complaints, cutaneous lesions, episodic fever and recurrent infections. The age on onset is also variable ranging from the first week of life to 29 years.Zheng C, Huang Y, Ye Z, Wang Y, Tang Z, Lu J, Wu J, Zhou Y, Wang L, Huang Z, Yang H, Xue A (2018) Infantile onset intractable inflammatory bowel disease due to novel heterozygous mutations in TNFAIP3 (A20). Inflamm Bowel Dis doi: 10.1093/ibd/izy165 The male:female ratio is 1:3.

Genetics

The TNFAIP3 gene is located on the long arm of chromosome 6 (6q23.3). Inheritance appears to be autosomal dominant with variable penetrance. It appears that two copies of this gene are required to avoid inflammatory features developing - hence the name haploinsufficiency.

Pathogenesis

The gene encodes a protein - Tumor necrosis factor alpha-induced protein 3 - which inhibits the pro inflammatory actions of

NF-κB Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a protein complex that controls transcription of DNA, cytokine production and cell survival. NF-κB is found in almost all animal cell types and is involved in cellular ...

. The protein encoded has both

ubiquitin Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Fo ...

ligation deubiquitinase activities and forms part of the ubiquitin editing protein complex. It is involved in several biochemical pathways the details of which are still under investigation.

Diagnosis

Diagnosis is made by sequencing the TNFAIP3 gene. The usual laboratory tests are consistent with non-specific inflammation. Antinuclear antibodies and anti-dsDNA antibodies may be positive. Biopsies show non specific inflammatory changes.

Differential diagnosis

The main differential diagnosis are

Behçet's disease Behçet's disease (BD) is a type of inflammatory disorder which affects multiple parts of the body. The most common symptoms include painful sores on the mucous membranes of the mouth and other parts of the body, inflammation of parts of the ey ...

and systemic lupus erythematosus.

Treatment

Response to

colchicine Colchicine is a medication used to treat gout and Behçet's disease. In gout, it is less preferred to NSAIDs or steroids. Other uses for colchicine include the management of pericarditis and familial Mediterranean fever. Colchicine is taken b ...

has been variable. Cytokine inhibitors - including the anti-IL6 receptor biologic

tocilizumab Tocilizumab, sold under the brand name Actemra among others, is an immunosuppressive drug, used for the treatment of rheumatoid arthritis, systemic juvenile idiopathic arthritis, a severe form of arthritis in children, and COVID19. It is a huma ...

- appear to be the most effective.Given the rarity of this condition, optimal management has not yet been definitely identified. Stem cell transplants have been given to saves lives.

History

This condition was first described in 2016.Zhou Q, Wang H, Schwartz DM, Stoffels M, Park YH, Zhang Y, Yang D, Demirkaya E, Takeuchi M, Tsai WL, Lyons JJ3, Yu X, Ouyang C, Chen C, Chin DT, Zaal K, Chandrasekharappa SC, P Hanson E, Yu Z, Mullikin JC, Hasni SA, Wertz IE, Ombrello AK, Stone DL, Hoffmann P, Jones A, Barham BK, Leavis HL, van Royen-Kerkof A, Sibley C, Batu ED, Gül A, Siegel RM, Boehm M, Milner JD, Ozen S, Gadina M, Chae J, Laxer RM, Kastner DL, Aksentijevich I (2016) Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early-onset autoinflammatory disease. Nat Genet 48(1):67-73 doi: 10.1038/ng.3459

References

{{Medical resources , DiseasesDB = , ICD10 = , ICD9 = , ICDO = , OMIM = 616744 , MedlinePlus = , eMedicineSubj = , eMedicineTopic = , MeshID = , GeneReviewsNBK = , GeneReviewsName = Genetic diseases and disorders Rare syndromes Autosomal dominant disorders