Clinical Guidance

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.

Source: GeneReviews — "Haploinsufficiency of A20"

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.

Source: GeneReviews — "Haploinsufficiency of A20"

Diagnostic Criteria

No consensus diagnostic criteria for haploinsufficiency of A20 (HA20) have been published.

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)

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).

Source: GeneReviews — "Haploinsufficiency of A20"

Differential Diagnosis

Monogenic disorders of interest in the differential diagnosis of haploinsufficiency of A20 (HA20) are listed in . Table 3. Monogenic Disorders of Interest in the Differential Diagnosis of Haploinsufficiency of A20

Management Guidelines

No clinical practice guidelines for haploinsufficiency of A20 (HA20) have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with HA20 and similar disorders.

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 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 4.

Haploinsufficiency of A20: Recommended Evaluations Following Initial Diagnosis

System/Concern | Evaluation | Comment

Rheumatologic

| History physical exam for signs/symptoms of systemic inflammation, fevers, serositis/pain, joint involvement | Consider referral to rheumatologist to initiate biologic therapies .

Assessment of inflammatory markers (serum CRP ESR), CBC w/differential, autoantibody titers (ANA, ANCA, CCP3, RF) | Imaging of abdomen to assess for splenomegaly /or hepatomegaly should also be considered if there are findings of or suspected spleen or liver enlargement on physical exam.

Immunologic

| Assessment for immune dysfunction or immunodeficiency | • Quantitative blood immunoglobulins (IgG, IgA, IgM)

• Vaccine-specific responses (tetanus, diphtheria)

• T/B/NK cell counts

Skin | Full skin exam | • To assess for rashes

• Consider dermatology consultation for mgmt.

Source: GeneReviews — "Haploinsufficiency of A20"

Clinical Guidance

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 . 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.

Source: GeneReviews — "Haploinsufficiency of A20"

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.

Source: GeneReviews — "Haploinsufficiency of A20"

Surveillance Guidelines

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

• Rheumatologic features 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

Source: GeneReviews — "Haploinsufficiency of A20"