Haploinsufficiency of A20

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 pathogenic variant (~95% of affected individuals) or a heterozygous deletion of 6q23 including (<5% of affected individuals) by molecular genetic testing.

MANAGEMENT

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. 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. 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. 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. 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 pathogenic variant. Each child of an individual with HA20 has a 50% chance of inheriting the pathogenic variant. Once the pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.