Definition
Cette maladie est associée à des mutations du gène TNFAIP3 codant la protéine A20. La présence d’une seule mutation peut causer la maladie.
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Elle est le plus souvent transmise par l’un des parents (on parle alors de transmission dominante); plus rarement, la mutation apparait de novo, c’est-à-dire chez le foetus lors de la conception.
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La protéine A20 régule l’immunité et permet de contrôler l’inflammation. Ainsi, en cas de mutation, il y a une inflammation exagérée dans le corps.
Epidemiology
It is a rare disease affecting around 200 patients worldwide.
Symptoms usually begin in childhood, in the first few months of life. Since it was first described in 2016, many patients are diagnosed in adulthood.
Genetic
A20 haploinsufficiency is a genetic disorder linked to a mutation in the TNFAIP3 gene causing dysfunction of the A20 protein.
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The presence of a single mutation can cause the disease. It is either transmitted in an autosomal dominant mode (the diseased gene is transmitted by one of the parents), or de novo (the diseased gene appeared in the child at the time of conception).
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Protein A20 is a protein that regulates immunity and helps control inflammation. Thus, in the event of a mutation, the abnormal protein leads to uncontrolled inflammation in the body.
Clinical
Most patients have frequent and painful mouth ulcers, and sometimes genital ulcers. Some have acne on the face and back, pseudofolliculitis or knots on the legs. Half of patients report episodes lasting a few days with fever.
Digestive problems such as diarrhoea, which may contain blood, are common. Joint pain and even arthritis may occur.
Symptoms of the disease may be continuous or transitory in the form of "flare-ups", interspersed with periods of little or no symptoms.
It is important to check for liver abnormalities.
The signs of A20 haploinsufficiency may vary from one person to another.
It is possible to have other immune diseases such as systemic lupus erythematosus, Hashimoto's thyroiditis or diabetes.
Diagnostic
Diagnosis is based on genetic analysis, which involves taking a blood sample to look for a mutation in the TNFAIP3 gene.
The referring doctor may suggest that family members undergo a consultation to identify other people with the disease.
There is no indication for genetic testing in people with no symptoms.
Evolution
Progression depends on the severity of the disease. It is a chronic disease.
No case of AA amyloidosis has been described to date.
Treatment and follow-up are coordinated by the expert physician in collaboration with the general practitioner, paediatrician and certain organ specialists, depending on the extent of the disease.
Treatment
The aim of treatment is to eliminate symptoms and allow patients to continue to lead a normal social and professional life. Treatment depends on the patient's symptoms.
Colchicine is usually proposed for mouth ulcers; sometimes biotherapies by injections under the skin or by infusion are necessary.
The referring doctor will reassess the need to continue treatment at each consultation; some patients do not receive any treatment at all.
Follow-up
Haploinsuffisance de A20
In the case of confirmed A20 haploinsufficiency, patients should be seen once or twice a year by a specialist who is used to following patients with this rare disease.
Inflammation should be monitored by measuring CRP in the blood every 6 months.
A haemogram should be taken at least once a year, and creatinine levels, liver function tests, urine sediment and proteinuria should be checked.
New article!
December 2023
A20 haploinsufficiency: A systematic review of 177 cases.
Inès Elhani, Quentin Riller, Guilaine Boursier, Véronique Hentgen, Frédéric Rieux Laucat, Sophie Georgin-Lavialle.
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PII: S0022-202X(23)03194-9
DOI: https://doi.org/10.1016/j.jid.2023.12.007
Reference: JID 4099
Summary:
Haploinsufficiency A20 (HA20) is an autoinflammatory disease caused by defective inactivation of the NF-κB pathway. We performed a systematic literature review of articles reporting patients with TNFAIP3 mutations between 2016 and August 2023 following PRISMA guidelines. Data from 177 patients from 65 articles were retrieved (108 women). The main features were: mucosal ulcers (n=129), fever (n=93) followed by gastrointestinal features (n=81), skin (n=76), autoimmunity (n=61) including thyroiditis (n=25) and lupus (n=16), and joint involvement (n=54). Five patients had died at the time of publication. In 54/63 patients, C9 reactive protein was significantly elevated during relapses, with a median of 51mg/L. The most commonly used treatments were corticosteroids and non-steroidal anti-inflammatory drugs (n=32), TNF blockers (n=29), colchicine (n=28) and methotrexate (n=14). TNFAIP3 variants affected the OTU domain in 92 cases and a zinc finger domain in 68 cases. Geographical origin, gender and type of variant had a significant impact on the phenotype. A better understanding of the broad HA20 phenotype could facilitate the diagnostic process. Much remains to be done to elucidate the pathogenesis and treatment in order to improve the outcome of HA20 patients.