Clinical characteristics.

Haploinsufficiency of A20 (HA20), a complex immune dysregulation disease, is characterized by recurrent systemic immune dysfunction (i.e., inflammation and/or immune deficiency). The most common manifestations and their frequency include: (1) recurrent painful oral/genital ulcers, typically during disease flares (>70% of persons); (2) recurrent fevers (~50%), typically lasting for three to seven days that can rarely progress to a cytokine storm and/or hemophagocytic lymphohistiocytosis; (3) skin involvement (~40%), including pustular rashes, folliculitis, vasculitic purpura, urticaria, lupus-like macular rashes, and eczematoid dermatitis; (4) gastrointestinal disease (~40%), ranging from dull abdominal pain (due to serositis, ulcers, or bowel inflammation) to severe inflammation with risk of bowel perforation; and (5) arthralgia/arthritis (~34%), typically relapsing and/or remitting nonerosive inflammatory polyarthritis with synovitis, and rarely resembling rheumatoid arthritis or psoriatic-like erosions. Other less common but significant findings include lymphoproliferation, most often lymphadenopathy; liver involvement, including severe hepatitis that if untreated can progress to cirrhosis and liver failure; neurologic disease including central nervous system vasculitis/vasculopathy (manifesting as severe headaches and cognitive changes) and in some individuals transient ischemic attacks. Other findings include aseptic meningitis, mononeuritis multiplex, chronic inflammatory demyelinating polyradiculoneuropathy, and/or peripheral neuropathy.

HA20 demonstrates both variable expressivity (i.e., different systems may be involved simultaneously and/or over time in an affected individual) and intrafamilial variability (i.e., variability in clinical presentation among affected individuals within the same immediate or extended family).

Diagnosis/testing.

The diagnosis of HA20 is established in an individual by identification of either a heterozygous TNFAIP3 pathogenic variant (~95% of affected individuals) or a heterozygous deletion of 6q23 including TNFAIP3 (<5% of affected individuals) by molecular genetic testing.

Management.

Supportive treatment: TNF inhibitors, the most used medications, directly target abnormal NF-κB signaling. In addition, IL-1 targeted therapy and JAK inhibitors are effective in many individuals. Corticosteroids, colchicine, methotrexate, azathioprine, thalidomide, mycophenolate, phosphodiesterase-4 inhibitors, and calcineurin inhibitors may also be useful. In some instances of severe or refractory disease, hematopoietic stem cell transplantation may be considered.

Surveillance: Monitor at least annually by a rheumatologist, and more frequently for individuals with evidence of systemic inflammation and/or organ involvement. Typical evaluations include medical history, physical examination, and laboratory testing of acute phase reactants including CRP, ESR, fibrinogen, CBC with differential, SAA, and urinalysis for evidence of proteinuria. Low threshold for evaluation of subclinical inflammation by relevant subspecialists, such as gastroenterologist for inflammatory bowel disease-like symptoms, neurologist for aseptic meningitis, and ophthalmologist for symptoms of ocular inflammation.

Agents/circumstances to avoid: For individuals managed with continuous biologic agents, consideration should be given to whether live attenuated versus non-live vaccines should be administered. Because data are limited on the effect of live attenuated vaccines, risks/benefits should be considered before receiving any live vaccinations.

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual to identify as early as possible those who would benefit from an initial evaluation similar to that of a symptomatic individual and prompt initiation of treatment and/or scheduled routine surveillance.

Pregnancy management: Maternal medications should be discussed with a health care provider ideally prior to conception or as soon as a pregnancy has been recognized. Colchicine is generally considered safe during pregnancy; however, data are limited. Information regarding the safety of the use of TNF inhibitors in human pregnancy is limited. Per the American College of Rheumatology guidelines for general populations, the use of anti-TNF agents is recommended for women with active disease, with consideration of weaning such medication during the third trimester if maternal remission has been achieved to decrease placental transfer to the fetus. The IL-1 receptor antagonist anakinra is considered relatively safe during pregnancy due to its extremely short half-life, although data are limited. JAK inhibitors are contraindicated during pregnancy.

Genetic counseling.

HA20 is inherited in an autosomal dominant manner. Many individuals diagnosed with HA20 have an affected parent; some individuals have the disorder as the result of a de novo TNFAIP3 pathogenic variant. Each child of an individual with HA20 has a 50% chance of inheriting the TNFAIP3 pathogenic variant. Once the TNFAIP3 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

HA20 should be suspected in probands with the following clinical and laboratory findings and family history.

Clinical findings

• All individuals
  • Mean age of onset is 7 years (range: 1st week of life to age 39 years) [Yu et al 2020]
    Note: Because of variable expressivity, manifestations during early childhood may not have been reported to a health care professional due to their mildness and minimal effect on quality of life, or due to social barriers (i.e., genital ulcers).
  • Relapsing/remitting disease course characterized by unprovoked episodes of acute or chronic immune dysregulation
• Common (present in ≥15% of individuals)
  • Episodic fever
  • Recurrent painful ulcers/abscesses, including oral (~68%), genital (~37%), perianal, cutaneous, and gastrointestinal (~39%; sometimes diagnosed as Crohn disease or inflammatory bowel disease-related arthritis, can lead to bowel obstruction)
  • Arthralgia/polyarthritis, including polyarticular juvenile idiopathic arthritis and erosive arthritis (~34%)
  • Cutaneous lesions, including folliculitis-like rashes, acne, and dermal abscesses, psoriasis, erythema nodosum, and immunoglobulin A vasculitis (Henoch-Schonlein purpura) (~42%)
  • Lymphadenopathy (25%-30%)
  • Autoimmune cytopenias (~20%)
• Less common (present in ≤15% of individuals)
  • Chronic hepatic involvement, including hepatitis, hepatomegaly, and/or liver fibrosis (15%)
  • Autoimmune thyroiditis (~14%)
  • Neurologic involvement, including chronic inflammatory demyelinating polyradiculoneuropathy, neuropathy, and central nervous system vasculitis (~12%)
  • Vasculopathy, including vasculitis, coronary vasculitis, or arterial aneurysms (~11%)
  • Ocular inflammation, including severe treatment-resistant anterior uveitis, retinal vasculitis with chorioretinal scarring, and macular fibrosis (~9%)
  • Recurrent upper respiratory infections and/or lower respiratory infections (~9%)
  • Diabetes mellitus type 1 (~4%)
  • Autoimmune lymphoproliferative syndrome (1%)
  • Cardiac involvement, including pericardial effusion and/or pericarditis
  • Pulmonary nodules, pleuritis, and/or interstitial lung disease
  • Lupus nephritis and/or nephrotic syndrome
  • Secondary hemophagocytic lymphohistiocytosis and/or macrophage activation syndrome
  • Pernicious anemia
  • Hypogammaglobulinemia
  • Common variable immunodeficiency

Laboratory findings

• Elevated acute phase reactants (erythrocyte sedimentation rate, C-reactive protein, lactate dehydrogenase, serum ferritin concentration), especially during flares
  Note: These may be normal in individuals with findings that are more like an autoimmune disease and less like an autoinflammatory disease.
• Fluctuating or sustained presence of various autoantibodies (e.g., rheumatoid factor, antinuclear antibodies, antiphospholipid antibodies, antithyroid antibodies, and antiplatelet antibodies); sometimes high titers
• Abnormal (reduced or elevated) leukocyte, neutrophil, or lymphocyte counts
• Reduced hemoglobin and/or platelet counts (especially during flares)
• Total immunoglobulins (IgG, IgM, IgA) can be elevated or reduced
• Reduced responses (i.e., antibody titers) to diphtheria and tetanus vaccinations
• Elevated transaminases (AST, ALT), especially during relapses
• Elevated fecal calprotectin
• Proteinuria or positive urine sediment (i.e., red blood cell / white blood cell casts)

Family history is consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of HA20 is established in an individual by identification of one of the following on molecular genetic testing (see Table 1):

• A heterozygous TNFAIP3 pathogenic (or likely pathogenic) variant (95% of affected individuals)
• A heterozygous deletion of 6q23 including TNFAIP3 (<5% of affected individuals) [Franco-Jarava et al 2018, Shimizu et al 2021, Endo et al 2022, Elhani et al 2023]

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a heterozygous TNFAIP3 variant of uncertain significance does not establish or exclude the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel), chromosomal microarray analysis, and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas comprehensive genomic testing does not.

• A multigene panel for inborn errors of immunity, autoimmune lymphoproliferative syndrome, immunodeficiency, autoinflammation or periodic fever syndrome that includes TNFAIP3 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including TNFAIP3) that cannot be detected by sequence analysis.
  For an introduction to CMA click here. More detailed information for clinicians ordering genetic tests can be found here.
• Comprehensive genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most used; genome sequencing is also possible. To date, the majority of reported TNFAIP3 pathogenic variants (e.g., missense, nonsense) are within the coding region and are likely to be identified on exome sequencing. Of note, several splicing variants beyond the canonical splice site have been identified [Kadowaki et al 2021, Similuk et al 2022].
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

Haploinsufficiency of A20 (HA20), a complex immune dysregulation disease, is characterized by recurrent systemic immune dysfunction (inflammation and/or immune deficiency). HA20 demonstrates both variable expressivity (i.e., in an affected individual, different systems may be involved simultaneously and/or over time) and intrafamilial variability (i.e., variability in clinical presentation among affected individuals within the same immediate or extended family).

To date, more than 180 individuals from 97 families have been identified with HA20 [Elhani et al 2023, Karri et al 2024]. The following description of the phenotypic features associated with this condition is based on these reports.

Oral/genital ulcers, the most common manifestation of HA20, are recurrent and usually present during flares. Whereas oral ulcers are more common than genital ulcers and may be present in individuals who do not have genital ulcers, presence of genital ulcers in the absence of oral ulcers is less common. Both oral and genital ulcers can be quite painful and can cause scarring. Some individuals also may develop gastrointestinal ulcers. Although HA20 can mimic Behçet disease, affected individuals may have atypical features or not fully meet the international criteria for Behçet disease.

Recurrent fevers, present in many individuals, typically last for three to seven days and do not have a clear periodicity; however, there is variability between individuals. Rarely, recurrent febrile episodes can progress to cytokine storm and/or secondary hemophagocytic lymphohistiocytosis (HLH) / macrophage activation syndrome (MAS) [Elhani et al 2023, Karri et al 2024]. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are not always elevated.

Skin rash is highly variable and can include pustular rashes, folliculitis, vasculitic purpura, urticaria, and macular rashes. Up to 40% of individuals can develop an eczematoid dermatitis that does not always correlate with flares of disease activity [Schwartz et al 2021].

Gastrointestinal disease ranges from dull abdominal pain (caused by serositis, gastrointestinal ulcers, small bowel inflammation, or inflammatory colitis) to severe inflammation with risk of bowel perforation [Karri et al 2024]. Biopsies may resemble Crohn disease or may include nonspecific lymphoid aggregates.

Arthralgia/arthritis is most often relapsing and/or remitting nonerosive inflammatory polyarthritis with synovitis. Arthritis can be symmetric or asymmetric and may involve the axial joints. Although joint inflammation is usually nonerosive, in some individuals arthritis can be erosive and resemble psoriatic-like erosions or rheumatoid arthritis.

Lymphoproliferation most often presents as lymphadenopathy. Although affected individuals can rarely experience autoimmune lymphoproliferative syndrome-like disease (i.e., expansion of double-negative T cells and lymphoma), the exact link between these conditions and HA20 remains unclear.

Liver disease, including severe hepatitis, may be an underrecognized manifestation of HA20. If untreated, this can progress to cirrhosis and liver failure.

Neurologic disease. Central nervous system vasculitis/vasculopathy can manifest as severe headaches and cognitive changes; some individuals experience transient ischemic attacks. Other findings include aseptic meningitis, mononeuritis multiplex, chronic inflammatory demyelinating polyradiculoneuropathy, and/or peripheral neuropathy.

Hematologic involvement. Cytopenias can include pancytopenia, immune thrombocytopenic purpura, autoimmune hemolytic anemia, autoimmune neutropenia, or lymphopenia. Leukocytosis and neutrophilia can also be seen.

Endocrine involvement. Both autoimmune thyroid disease and diabetes mellitus type 1 can be seen.

Less common findings in HA20 can include the following:

• Kidney involvement. Membranous nephropathy can resemble class V lupus nephritis with a "full house" (positive for IgA, IgG, IgM, C3, and C1Q) pattern of immunofluorescence.
• Pericarditis and coronary vasculitis/vasculopathy
• Immunodeficiency, most commonly recurrent infections that may also be diagnosed as common variable immunodeficiency. Five percent of individuals have had humoral deficiency (i.e., low IgG, IgA, IgM).
• Ocular inflammation, a rare manifestation, can present as uveitis, scleritis, episcleritis, and/or retinal vasculitis. Dry eye disease is also reported.
• Lung inflammation can include pulmonary nodules, pleuritis, or interstitial lung disease.
• Other rare phenotypes known to be associated with germline pathogenic variants in TNFAIP3 (but not discussed in this GeneReview) include premature ovarian insufficiency, dental abnormalities, atrophic gastritis, and others. However, the association between some of these phenotypes and HA20 is not entirely clear. A full list of phenotypes described in association with A20 can be found in Elhani et al [2023] and Karri et al [2024].

Intrafamilial variability is considerable among family members who have the same TNFAIP3 pathogenic variant; interfamilial variability is considerable among unrelated individuals who have the same TNFAIP3 pathogenic variant.

Prognosis. With proper management the prognosis for HA20 is good; life expectancy is not expected to be significantly decreased. However, as with many monogenic complex immune deregulatory diseases, treatment is refractory and even fatalities have been reported [Elhani et al 2023].

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified. While it appears that TNFAIP3 pathogenic missense variants (compared to loss-of-function variants) might correlate with milder disease with reduced penetrance, more research is needed.

Penetrance

Most individuals with pathogenic variants in TNFAIP3 have at least some manifestations of HA20. However, due to variable expressivity manifestations may go unrecognized or be subclinical.

Nomenclature

Because HA20 can mimic Behçet disease, it was originally identified as a monogenic Behçet disease (see Differential Diagnosis).

Prevalence

To date ~200 individuals with HA20 have been reported; however, prevalence is unknown.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with HA20 (i.e., an individual with either a TNFAIP3 pathogenic variant or a heterozygous deletion of 6q23 including TNFAIP3), the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

There is no cure for HA20. In addition to use of a variety of biologic agents under the care of a rheumatologist, other supportive treatments can improve quality of life, maximize function, and reduce complications.

Biologic agents. Tumor necrosis factor (TNF) inhibitors, the most used medications for management of manifestations of HA20, directly target abnormal nuclear factor kappa B (NF-κB) signaling. Note: Affected individuals may have severe, paradoxical reactions associated with anti-TNF monoclonal antibodies.

In addition, interleukin-1 (IL-1) therapy and Janus kinase (JAK) inhibitors are effective in many individuals.

Corticosteroids, colchicine, methotrexate, azathioprine, thalidomide, mycophenolate, phosphodiesterase-4 inhibitors, and calcineurin inhibitors may also be useful. For more information on these medications from the American College of Rheumatology, see rheumatology.org/patients/treatments.

Hematopoietic stem cell transplantation (HSCT). In some instances of severe or refractory disease, HSCT may be considered. Family members considering stem cell donation should be tested for the family-specific TNFAIP3 pathogenic variant.

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the following evaluations are recommended.

• Rheumatologic features (see Table 2) should be monitored at least annually by a rheumatologist, and more frequently for individuals with evidence of systemic inflammation and/or organ involvement (typically including medical history, physical examination, and laboratory testing of acute phase reactants including CRP, ESR, fibrinogen, CBC with differential, SAA if available, and urinalysis for evidence of proteinuria).
• A low threshold for evaluation of subclinical inflammation by relevant subspecialists should be maintained:
  • Gastroenterologist for inflammatory bowel disease-like symptoms
  • Neurologist for aseptic meningitis
  • Ophthalmologist for symptoms of ocular inflammation
  • Endocrinologist for symptoms of thyroid disease, diabetes mellitus type 1
  • Nephrologist for manifestations of nephritis
  • Hematologist for manifestations of hematologic features
  • Neurologist for chronic inflammatory demyelinating polyradiculoneuropathy / encephalitis
  • Immunologist for immunodeficiency
  • Cardiologist for coronary vasculitis

Agents/Circumstances to Avoid

Vaccines. For individuals managed with continuous biologic agents, the American College of Rheumatology recommends against administration of live attenuated vaccines, unless medications can be paused for at least one dosing interval (typically 1-4 weeks) prior to AND following vaccination; however, shorter hold times can be considered if vaccination is critical [Bass et al 2023].

Note: Because many individuals with HA20 may not be able to tolerate prolonged cessation of continuous biologic therapy, risks/benefits should be considered before receiving any live vaccinations.

Evaluation of Relatives at Risk

For early diagnosis and treatment. It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual to identify as early as possible those who would benefit from evaluation (see Evaluations Following Initial Diagnosis) and prompt initiation of treatment and/or surveillance.

For hematopoietic stem cell donation. When HSCT is considered, family members considering stem cell donation should be tested for the family-specific TNFAIP3 pathogenic variant.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Maternal medications should be discussed with a health care provider ideally prior to conception or as soon as a pregnancy has been recognized.

Information regarding adverse outcomes due to the use of TNF inhibitors in human pregnancy is limited; to date, no pattern of birth anomalies with any of the TNF inhibitor medications has been reported. Per the American College of Rheumatology guidelines [Sammaritano et al 2020], the use of anti-TNF agents in rheumatic diseases is recommended for women with active disease, with consideration of weaning such medication during the third trimester to decrease placental transfer to the fetus if maternal remission has been achieved. However, as with any medication treatment during pregnancy, discussion of the risks versus benefits of such treatment between the affected individual and their health care provider is encouraged [De Felice & Kane 2021].

Information regarding the safety of the use of IL-1 inhibitors in human pregnancy is limited; to date, no pattern of birth anomalies in humans have been reported with IL-1 or IL-1R inhibitor medication classes. These medications are often continued during pregnancy; it is recommended that clinicians discuss risks and benefits with affected individuals.

Colchicine, azathioprine, and hydroxychloroquine are generally continued during pregnancy; however, it is recommended that clinicians discuss risks and benefits with affected individuals.

Mycophenolate, methotrexate, and thalidomide are all known human teratogens and should be avoided during pregnancy. Less information is available for JAK inhibitors, although these are generally also avoided during pregnancy due to concerns about potential embryo disruption in animal models.

The use of corticosteroids during human pregnancy has been associated with an increased risk of cleft lip with or without cleft palate and growth restriction in exposed fetuses; however, the risks and benefits of treatment should be weighed carefully, as uncontrolled inflammation may also have risks [Odufalu et al 2022].

See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Haploinsufficiency of A20 (HA20) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Many individuals diagnosed with HA20 have an affected parent.
• Some individuals diagnosed with HA20 have the disorder as the result of a de novo TNFAIP3 pathogenic variant.
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members, intrafamilial variability, reduced penetrance, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, de novo occurrence of a TNFAIP3 pathogenic variant in the proband cannot be confirmed unless molecular genetic testing has demonstrated that neither parent has the TNFAIP3 pathogenic variant.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
    * A parent with somatic and gonadal mosaicism for a TNFAIP3 pathogenic variant may be mildly/minimally affected.

Sibs of a proband. The risk to the sibs of the proband depends on the clinical/genetic status of the proband's parents:

• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Intrafamilial variability is considerable among family members who have the same TNFAIP3 pathogenic variant; affected family members may have different disease manifestations and severity.
• If the TNFAIP3 pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism [Rahbari et al 2016].
• If the parents have not been tested for the TNFAIP3 pathogenic variant but appear to be clinically unaffected, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for HA20 because of the possibility of reduced penetrance or variable expressivity (manifestations may go unrecognized or be subclinical) in a heterozygous parent and the possibility of parental gonadal mosaicism.

Offspring of a proband. Each child of an individual with HA20 has a 50% chance of inheriting the TNFAIP3 pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the TNFAIP3 pathogenic variant, the parent's family members may be at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Predictive testing for at-risk asymptomatic family members requires prior identification of the germline TNFAIP3 pathogenic variant in the family.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

Prenatal Testing and Preimplantation Genetic Testing

Once the TNFAIP3 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

TNFAIP3 encodes tumor necrosis factor alpha-induced protein 3 (TNFAIP3; also known as A20), which regulates signaling pathways critical for inflammation, proliferation, and cellular homeostasis including TNF, NF-κB, necroptosis, inflammasome activation, JNK signaling, and JAK-STAT signaling.

Mechanism of disease causation. Haploinsufficiency

TNFAIP3-specific laboratory technical considerations. The majority of TNFAIP3 pathogenic variants are frameshift, nonsense, or splice-site variants or deletions.

Although a few missense variants have been described, their segregation in families is not clear, leading to speculation that they may be associated with milder disease.

Missense variants should be evaluated with functional assays to confirm pathogenicity [El Khouri et al 2023]. Such assays may include ectopic overexpression of wild type vs mutated A20 in cell lines and measurement of TNF-induced NF-κB activation, or measurement of A20 expression in patient cells and mutation-negative controls (preferably family controls) [Zhou et al 2016, Kadowaki et al 2021].

Author Notes

Daniella M Schwartz ([email protected]) is actively involved in the treatment of and clinical research regarding individuals with haploinsufficiency of A20 (HA20). She would be happy to communicate with persons who have any questions regarding diagnosis or treatment of HA20 or other considerations.

Natalie Deuitch ([email protected]) and Ivona Aksentijevich (vog.hin.smain.bra@iitneska) are also interested in hearing from clinicians treating families affected by autoinflammatory disorders in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders.

Contact any of the authors to inquire about review of TNFAIP3 variants of uncertain significance.

Acknowledgments

We would like to thank the patients and their families for helping us to better understand this condition.

Revision History

• 19 December 2024 (bp) Review posted live
• 8 April 2024 (nd) Original submission

Literature Cited

• Bass AR, Chakravarty E, Akl EA, Bingham CO, Calabrese L, Cappelli LC, Johnson SR, Imundo LF, Winthrop KL, Arasaratnam RJ, Baden LR, Berard R, Bridges SL, Jr., Cheah JTL, Curtis JR, Ferguson PJ, Hakkarinen I, Onel KB, Schultz G, Sivaraman V, Smith BJ, Sparks JA, Vogel TP, Williams EA, Calabrese C, Cunha JS, Fontanarosa J, Gillispie-Taylor MC, Gkrouzman E, Iyer P, Lakin KS, Legge A, Lo MS, Lockwood MM, Sadun RE, Singh N, Sullivan N, Tam H, Turgunbaev M, Turner AS, Reston J. 2022 American College of Rheumatology guideline for vaccinations in patients with rheumatic and musculoskeletal diseases. Arthritis Care Res (Hoboken). 2023;75:449-64. [PMC free article: PMC10291822] [PubMed: 36597813]
• De Felice KM, Kane S. Safety of anti-TNF agents in pregnancy. J Allergy Clin Immunol. 2021;148:661-7. [PubMed: 34489011]
• Elhani I, Riller Q, Boursier G, Hentgen V, Rieux-Laucat F, Georgin-Lavialle S. A20 haploinsufficiency: a systematic review of 177 cases. J Invest Dermatol. 2023;S0022-202X:03194-9. [PubMed: 38128752]
• El Khouri E, Diab F, Louvrier C, Assrawi E, Daskalopoulou A, Nguyen A, Piterboth W, Deshayes S, Desdoits A, Copin B, Dastot Le Moal F, Karabina SA, Amselem S, Aouba A, Giurgea I. A critical region of A20 unveiled by missense TNFAIP3 variations that lead to autoinflammation. Elife. 2023;12:e81280. [PMC free article: PMC10284599] [PubMed: 37342083]
• Endo Y, Funakoshi Y, Koga T, Ohashi H, Takao M, Miura K, Yoshiura KI, Matsumoto T, Moriuchi H, Kawakami A. Large deletion in 6q containing the TNFAIP3 gene associated with autoimmune lymphoproliferative syndrome. Clin Immunol. 2022;235:108853. [PubMed: 34520861]
• Franco-Jarava C, Wang H, Martin-Nalda A, Alvarez SD, García-Prat M, Bodet D, García-Patos V, Plaja A, Rudilla F, Rodriguez-Sureda V, García-Latorre L, Aksentijevich I, Colobran R, Soler-Palacín P. TNFAIP3 haploinsufficiency is the cause of autoinflammatory manifestations in a patient with a deletion of 13Mb on chromosome 6. Clin Immunol. 2018;191:44-51. [PubMed: 29572183]
• Kadowaki S, Hashimoto K, Nishimura T, Kashimada K, Kadowaki T, Kawamoto N, Imai K, Okada S, Kanegane H, Ohnishi H. Functional analysis of novel A20 variants in patients with atypical inflammatory diseases. Arthritis Res Ther. 2021;23:52. [PMC free article: PMC7866758] [PubMed: 33549127]
• Karri U, Harasimowicz M, Carpio Tumba M, Schwartz DM. The complexity of being A20: from biological functions to genetic associations. J Clin Immunol. 2024;44:76. [PubMed: 38451381]
• Lv Q, Li Y, Wei Q, Xiang T, Guan W, Gong Y, Zeng Q, Zhang X, Wang Y, Shi Y, Liu H, Xu H, Sun L. Autoinflammatory syndromes mimicking Behçet's disease with gastrointestinal involvement: a retrospective analysis. Clin Exp Rheumatol. 2024;42:2076-85. [PubMed: 39360366]
• Odufalu FD, Long M, Lin K, Mahadevan U, Crohn's PIft, Colitis Foundation Clinical Research Alliance recruited patients for their respective centers for participant e. Exposure to corticosteroids in pregnancy is associated with adverse perinatal outcomes among infants of mothers with inflammatory bowel disease: results from the PIANO registry. Gut. 2022;71:1766-72. [PubMed: 34686575]
• Rahbari R, Wuster A, Lindsay SJ, Hardwick RJ, Alexandrov LB, Turki SA, Dominiczak A, Morris A, Porteous D, Smith B, Stratton MR, Hurles ME, et al. Timing, rates and spectra of human germline mutation. Nat Genet. 2016;48:126-33. [PMC free article: PMC4731925] [PubMed: 26656846]
• Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405-24. [PMC free article: PMC4544753] [PubMed: 25741868]
• Sammaritano LR, Bermas BL, Chakravarty EE, Chambers C, Clowse MEG, Lockshin MD, et al. 2020 American College of Rheumatology guideline for the management of reproductive health in rheumatic and musculoskeletal diseases. Arthritis Rheumatol. 2020;72:529-56. [PubMed: 32090480]
• Schwartz DM, Kitakule MM, Dizon BL, Gutierrez-Huerta C, Blackstone SA, Burma AM, Son A, Deuitch N, Rosenzweig S, Komarow H, Stone DL, Jones A, Nehrebecky M, Hoffmann P, Romeo T, de Jesus AA, Alehashemi S, Garg M, Torreggiani S, Montealegre Sanchez GA, Honer K, Souto Adeva G, Barron KS, Aksentijevich I, Ombrello AK, Goldbach-Mansky R, Kastner DL, Milner JD, Frischmeyer-Guerrerio P. Systematic evaluation of nine monogenic autoinflammatory diseases reveals common and disease-specific correlations with allergy-associated features. Ann Rheum Dis. 2021;80:788-95. [PMC free article: PMC8380268] [PubMed: 33619160]
• Shimizu M, Matsubayashi T, Ohnishi H, Nakama M, Izawa K, Honda Y, Nishikomori R. Haploinsufficiency of A20 with a novel mutation of deletion of exons 2-3 of TNFAIP3. Mod Rheumatol. 2021;31:493-7. [PubMed: 32011208]
• Similuk MN, Yan J, Ghosh R, Oler AJ, Franco LM, Setzer MR, Kamen M, Jodarski C, DiMaggio T, Davis J, Gore R, Jamal L, Borges A, Gentile N, Niemela J, Lowe C, Jevtich K, Yu Y, Hullfish H, Hsu AP, Hong C, Littel P, Seifert BA, Milner J, Johnston JJ, Cheng X, Li Z, Veltri D, Huang K, Kaladi K, Barnett J, Zhang L, Vlasenko N, Fan Y, Karlins E, Ganakammal SR, Gilmore R, Tran E, Yun A, Mackey J, Yazhuk S, Lack J, Kuram V, Cao W, Huse S, Frank K, Fahle G, Rosenzweig S, Su Y, Hwang S, Bi W, Bennett J, Myles IA, De Ravin SS, Fuss I, Strober W, Bielekova B, Almeida de Jesus A, Goldbach-Mansky R, Williamson P, Kumar K, Dempsy C, Frischmeyer-Guerrerio P, Fisch R, Bolan H, Metcalfe DD, Komarow H, Carter M, Druey KM, Sereti I, Dropulic L, Klion AD, Khoury P, O' Connell EM, Holland-Thomas NC, Brown T, McDermott DH, Murphy PM, Bundy V, Keller MD, Peng C, Kim H, Norman S, Delmonte OM, Kang E, Su HC, Malech H, Freeman A, Zerbe C, Uzel G, Bergerson JRE, Rao VK, Olivier KN, Lyons JJ, Lisco A, Cohen JI, Lionakis MS, Biesecker LG, Xirasagar S, Notarangelo LD, Holland SM, Walkiewicz MA. Clinical exome sequencing of 1000 families with complex immune phenotypes: toward comprehensive genomic evaluations. J Allergy Clin Immunol. 2022;150:947-54. [PMC free article: PMC9547837] [PubMed: 35753512]
• Stenson PD, Mort M, Ball EV, Chapman M, Evans K, Azevedo L, Hayden M, Heywood S, Millar DS, Phillips AD, Cooper DN. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting. Hum Genet. 2020;139:1197-207. [PMC free article: PMC7497289] [PubMed: 32596782]
• Tsuchida N, Kirino Y, Soejima Y, Onodera M, Arai K, Tamura E, Ishikawa T, Kawai T, Uchiyama T, Nomura S, Kobayashi D, Taguri M, Mitsuhashi S, Mizuguchi T, Takata A, Miyake N, Nakajima H, Miyatake S, Matsumoto N. Haploinsufficiency of A20 caused by a novel nonsense variant or entire deletion of TNFAIP3 is clinically distinct from Behçet's disease. Arthritis Res Ther. 2019;21:137. [PMC free article: PMC6549368] [PubMed: 31164164]
• Yu MP, Xu XS, Zhou Q, Deuitch N, Lu MP. Haploinsufficiency of A20 (HA20): updates on the genetics, phenotype, pathogenesis and treatment. World J Pediatr. 2020;16:575-84. [PubMed: 31587140]
• Zhou Q, Wang H, Schwartz DM, Stoffels M, Park YH, Zhang Y, Yang D, Demirkaya E, Takeuchi M, Tsai WL, Lyons JJ, Yu X, Ouyang C, Chen C, Chin DT, Zaal K, Chandrasekharappa SC, Hanson EP, 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. Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early-onset autoinflammatory disease. Nat Genet. 2016;48:67-73. [PMC free article: PMC4777523] [PubMed: 26642243]