Clinical characteristics.

Adenosine deaminase 2 deficiency (DADA2) is a complex systemic autoinflammatory disorder in which vasculopathy/vasculitis, dysregulated immune function, and/or hematologic abnormalities may predominate. Inflammatory features include intermittent fevers, rash (often livedo racemosa/reticularis), and musculoskeletal involvement (myalgia/arthralgia, arthritis, myositis). Vasculitis, which usually begins before age ten years, may manifest as early-onset ischemic (lacunar) and/or hemorrhagic strokes, or as cutaneous or systemic polyarteritis nodosa. Hypertension and hepatosplenomegaly are often found. More severe involvement may lead to progressive central neurologic deficits (dysarthria, ataxia, cranial nerve palsies, cognitive impairment) or to ischemic injury to the kidney, intestine, and/or digits. Dysregulation of immune function can lead to immunodeficiency or autoimmunity of varying severity; lymphadenopathy may be present and some affected individuals have had lymphoproliferative disease. Hematologic disorders may begin early in life or in late adulthood, and can include lymphopenia, neutropenia, pure red cell aplasia, thrombocytopenia, or pancytopenia. Of note, both interfamilial and intrafamilial phenotypic variability (e.g., in age of onset, frequency and severity of manifestations) can be observed; also, individuals with biallelic ADA2 pathogenic variants may remain asymptomatic until adulthood or may never develop clinical manifestations of DADA2.

Diagnosis/testing.

The diagnosis of DADA2 is established in a proband with suggestive clinical and laboratory findings and biallelic loss-of-function ADA2 pathogenic variants identified by molecular testing and/or low (<5% of normal) or undetectable ADA2 catalytic activity in plasma or serum.

Management.

Treatment of manifestations: Anti-tumor necrosis factor (TNF) agents (etanercept, adalimumab, golimumab, infliximab, certolizumab) are the drugs of choice for both symptomatic and asymptomatic individuals with biallelic ADA2 pathogenic variants. They prevent and eliminate manifestations of autoinflammatory disease / vasculitis, reduce the risk of ischemic stroke, reduce inflammatory burden, and relieve immunodeficiency, hepatosplenomegaly, and neutropenia. Anti-TNF agents also improve growth and development in affected children, and red blood cell and platelet counts; however, anti-TNF agents appear to have little effect in rescuing severe bone marrow abnormalities.

Surveillance: Routine monitoring of clinical and laboratory aspects of DADA2.

Agents/Circumstances to avoid: Antiplatelet medications including aspirin; anticoagulants (except in the presence of atrial fibrillation); and smoking, which may exacerbate peripheral arterial disease.

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk sibs of an affected individual in order to identify as early as possible those with biallelic ADA2 pathogenic variants who are currently symptomatic and would benefit from prompt initiation of treatment and those who are currently asymptomatic and would benefit from treatment with anti-TNF agents to reduce the risk of stroke.

Genetic counseling.

DADA2 is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier (heterozygote), and a 25% chance of being unaffected and not a carrier. Once the ADA2 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.

Suggestive Findings

Adenosine deaminase 2 deficiency (DADA2) should be suspected in individuals with clinical and laboratory findings of systemic autoinflammatory disease characterized by vasculitis, dysregulation of immune function, and hematologic abnormalities [Hashem et al 2017b, Lee 2018, Meyts & Aksentijevich 2018].

Establishing the Diagnosis

The diagnosis of DADA2 is established in a proband with suggestive findings by identification of biallelic loss-of-function ADA2 pathogenic variants on molecular testing (Table 1) and/or low (<5% of normal) or undetectable plasma ADA2 catalytic activity. Note: While both tests are diagnostic, molecular genetic testing is more widely available.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of DADA2 is broad, individuals with some of the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of DADA2 has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

Deficiency of adenosine deaminase 2 (DADA2) is a systemic autoinflammatory disorder in which the three major manifestations are vasculitis, dysregulation of immune function, and hematologic disease [Hashem et al 2017b, Lee 2018, Meyts & Aksentijevich 2018]. Other clinical features include neurologic, gastrointestinal, and musculoskeletal involvement. Severe manifestations (e.g., strokes or ischemic injuries to tissues and/or organs) can cause disability and/or be life threatening. Prior to the discovery of the molecular pathogenesis of DADA2 and adequate therapies, death before age 30 years was reported in 8% of affected individuals [Hashem et al 2017b, Meyts & Aksentijevich 2018].

Phenotypic variability that cannot be fully explained by the effect of pathogenic variants on protein function can be observed in the same family; for example, one sib may have have early-childhood onset of manifestations whereas another may have later-childhood onset. Affected individuals homozygous for the same founder variant have variability in age of onset and in frequency and severity of manifestations [Van Montfrans et al 2016]. In a large family of Iraqi descent, four adults homozygous for the same pathogenic variant were symptom free despite low ADA2 activity [Nanthapisal et al 2016].

Genotype-Phenotype Correlations

To date no genotype-phenotype correlations associating ADA2 pathogenic variants with the clinical presentation of DADA2 have been identified.

Studies of affected individuals in the two major founder populations in the Middle East and northern Europe could possibly offer insight into some genotype-phenotype correlations. See Table 3 for more details.

• The p.Gly47Arg founder variant, identified in 19 individuals of Georgian-Jewish ancestry and 15 individuals of Turkish ancestry, was associated with the clinical diagnosis of childhood-onset cutaneous polyarteritis nodosa (despite some clinical variability).
• The p.Arg169Gln founder variant identified in nine Dutch individuals was associated with significant variability in disease onset as well as frequency and severity of manifestations among affected sibs [Van Montfrans et al 2016]. Compared to the p.Gly47Arg variant, the cutaneous and visceral manifestations associated with the p.Arg169Gln variant in general were less severe, whereas neurologic and hematologic manifestations were more common.
• In a large family of Iraqi descent two affected and four unaffected members homozygous for the pathogenic missense variant p.Pro251Leu had low ADA2 activity irrespective of disease status, indicating variable expressivity of the clinical features of DADA2 [Nanthapisal et al 2016].

Prevalence

DADA2 is considered a rare disease; however, since its initial description in 2014, more than 170 affected individuals have been reported in the literature. Based on allele frequencies of in silico-predicted ADA2 damaging variants, the estimated prevalence of DADA2 could be as high as 4:100,000.

DADA2 prevalence is higher in populations with a high degree of consanguinity or in populations with founder variants. See Table 3.

• Most affected individuals from the Middle East are homozygous for the p.Gly47Arg founder variant. The highest carrier frequency for this variant is reported in the Georgian-Jewish population (1:10); the estimated carrier frequency of this variant in the Turkish population is about 1:500.
• The p.Arg169Gln founder variant has an estimated carrier frequency of 1:500 in northern European populations (Finnish, Dutch). The allele frequency is significantly lower in African, Latino, and Asian populations.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with adenosine deaminase 2 deficiency (DADA2), the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended.

• Complete physical examination with emphasis on:
  • Blood pressure and other vital signs, as systemic hypertension and/or fever are common.
  • Skin examination for evidence of livedo reticularis/racemosa, nodules, and Raynaud phenomenon. Severe involvement can include digital infarcts/gangrene or skin ulcerations.
  • Assessment for lymphadenopathy and hepatosplenomegaly.
  • Neurologic examination for evidence of prior or recent strokes.
• Ophthalmologic examination for vision loss, diplopia, retinal infarcts, optic nerve damage, uveitis, ptosis, strabismus, and nystagmus
• Electrocardiogram (ECG) for manifestations of portal hypertension, including prolonged QT interval
• Laboratory assessment
  • Complete blood count (CBC) with differential to detect anemia, lymphopenia, neutropenia, and/or thrombocytopenia
  • Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) as elevated levels may correlate with disease activity
  • Kidney and liver function tests
  • Quantitative serum immunoglobulins
  • PT/PTT to assess the risk of stroke in a patient who has not had a stroke OR to assess the risk of subsequent strokes in those who have had a stroke
  • Autoantibodies including antinuclear antibodies and lupus anticoagulant. Low titers are reported in 10% of patients, whereas high titers suggest other autoimmune diseases, such as systemic lupus erythematous.
  • Antineutrophilic cytoplasmic antibodies (ANCA) are usually absent; their presence suggests ANCA-related vasculitis.
  • Lymphocyte phenotyping. Failure to develop memory B-cells, a common finding, is evidence of a B-cell maturation defect that warrants further evaluation of the immune system (quantitative serum immunoglobulins, antibody response to vaccines, and history of severe and/or multiple infections). Failure to develop memory T-cells may be seen but is uncommon.
  • Antibody response to vaccines. Inadequate response suggests immune deficiency.
• Imaging assessment
  • Brain MRI in all patients, even those without overt neurologic manifestations, as a baseline given that small strokes can be clinically silent
  • Magnetic resonance angiography (MRA):
    • When brain MRI is abnormal, brain MRA (which is expected to be normal in persons with DADA2) can help differentiate the cause of stroke.
    • Abnormal peripheral MRA may suggest additional treatment options to improve vascular flow for cutaneous lesions (e.g., vascular insufficiency, infarcts, gangrene) or neurologic dysfunction, such as peripheral neuropathy).
  • Renal ultrasound examination to assess kidney size (which can be smaller due to poor vascularization and/or infarcts), function, and blood flow. Reported abnormalities that merit documentation before intiation of treatment include renal artery aneurysm and stenosis, renal infarcts (which may be silent), renal inflammation with dense lymphocytic infiltration, and glomerular scarring.
  • Abdominal ultrasound examination to provide baseline assessment of liver and spleen size and hepatic blood flow. Splenomegaly occurs in up to 30% of affected individuals, hepatomegaly in 20%.
  • FibroScan^® ultrasound examination (if available) to assess baseline hepatic elasticity (because early portal hypertension can be clinically silent)
• Other
  • When clinically indicated:
    • Skin biopsy in order to document vasculitis, or to investigate an atypical rash
    • Liver biopsy to assess cause of hepatomegaly and presence of hepatic steatosis and/or nodular regenerative sclerosis
  • Evaluation for manifestations of portal hypertension. If present, perform endoscopy to assess its extent.
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Surveillance

Suggested follow-up evaluations include the following:

• Complete physical examination (performed yearly or sooner if clinically indicated):
  • Blood pressure and other vital signs
  • Skin examination
  • Assessment for presence of lymphadenopathy and hepatosplenomegaly
  • Neurologic examination for evidence of prior or recent strokes
• Ophthalmologic examination for ptosis, abnormal eye movements, retinal infarcts, optic nerve damage
• ECG (if abnormal in the past). Note: Arterial hypertension, reported in 20% of patients, can lead to myocardial dysfunction.
• Laboratory assessment (performed yearly or sooner if clinically indicated):
  • CBC and differential
  • ESR and CRP
  • Kidney and liver function
  • Quantitative serum immunoglobulins
  • Lymphocyte phenotyping for evidence of a B-cell maturation defect
  • Additionally, follow-up evaluation of abnormal laboratory studies identified at earlier evaluations
• Imaging assessment (yearly or if clinically indicated):
  • Brain MRI if abnormal in the past or new symptoms or manifestations suggest brain involvement
  • Peripheral MRA if symptoms of peripheral arterial disease and/or neurologic dysfunction
  • Abdominal ultrasound examination to assess liver, spleen, and kidney size and hepatic blood flow
  • FibroScan^® ultrasound examination (if available) to assess hepatic elasticity for evidence of early portal hypertension
• Liver biopsy (if clinically indicated) is the most reliable way to diagnose diffuse hepatic disease (e.g., in the presence of portal hypertension).

Agents/Circumstances to Avoid

Avoid the following:

• Antiplatelet medications including aspirin
• Anticoagulation medications (except in the presence of atrial fibrillation)
• Smoking, which may exacerbate peripheral arterial disease

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk sibs of an affected individual in order to identify as early as possible those with biallelic ADA2 pathogenic variants who are currently symptomatic and would benefit from prompt initiation of treatment and those who are currently asymptomatic and would benefit from treatment with anti-TNF agents to reduce the risk of stroke.

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

Pregnancy Management

Information regarding the safety of use of anti-TNF agents during pregnancy is limited. One study evaluating use of anti-TNF agents in pregnant women with inflammatory bowel disease determined that these drugs can cross the placenta from the latter part of the second trimester of gestation, though they are low risk in the short term [Gisbert & Chaparro 2013].

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

Adenosine deaminase 2 deficiency (DADA2) is inherited in an autosomal recessive manner.

Parents of a proband

• The parents of an affected child are obligate heterozygotes (i.e., carriers of one ADA2 pathogenic variant).
• Heterozygotes (carriers) are asymptomatic and are not thought to be at risk of developing the disorder.

Sibs of a proband

• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not thought to be at risk of developing the disorder.

Offspring of a proband. Unless an individual with DADA2 has children with an affected individual or a carrier (see Prevalence), his/her offspring will be obligate heterozygotes (carriers) for a pathogenic variant in ADA2.

Other family members. Each sib of the proband’s parents is at a 50% risk of being a carrier of an ADA2 pathogenic variant.

Carrier (Heterozygote) Detection

Carrier testing for at-risk relatives requires prior identification of the ADA2 pathogenic variants in the family.

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.

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, 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, are carriers, or are at risk of being carriers.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown).

Prenatal Testing and Preimplantation Genetic Testing

Once the ADA2 pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

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

Molecular Pathogenesis

Humans express two enzymes, ADA1 (also referred to as ADA) (see Adenosine Deaminase Deficiency) and ADA2, which catalyze the deamination of adenosine and 2'-deoxyadenosine to inosine and deoxyinosine, respectively. Although homologous proteins that are considered isozymes, ADA1 and ADA2 differ substantially in structure, including the arrangement of the substrate-binding pocket in the catalytic center [Zavialov et al 2010b]. As a result, the affinity of ADA2 for adenosine is 100-fold lower than that of ADA1.

ADA1 is a largely intracellular protein, whereas ADA2 is a secreted protein. It has been postulated that ADA2 may control the level of extracellular adenosine (generated by stepwise dephosphorylation of extracellular ATP and AMP) and regulate a variety of biologic processes (through 4 distinct adenosine receptors expressed on many cells in the brain and immune and cardiovascular systems).

• Activation. Under stress conditions, hypoxia, ischemia, or inflammation, adenosine concentration increases due to excessive ATP breakdown.
• Signal termination. Adenosine signaling is terminated by adenosine uptake from the extracellular space towards the intracellular space through nucleoside transporters, followed by metabolic conversion in the presence of adenosine kinase (to AMP) or deaminase (to inosine). Thus, the deamination step is critical for regulation of many signaling pathways including immune responses.

Gene structure. ADA2 spans about 43,000 base pairs and comprises ten exons. The codon for translation initiation (p.1Met) is located in exon 2.

See Table A, Gene for a detailed summary of gene and protein information.

Pathogenic variants are loss of function. The majority of pathogenic variants are missense variants; however, nonsense and splice site variants as well as small and large deletions have also been reported. Pathogenic missense variants are located in different regions of the gene and do not cluster to a specific exon.

Normal gene product. ADA2 is a 59-kd monomer protein made up of 511 amino acids. It has four domains:

• Dimerization
• Catalytic
• Putative receptor binding
• Substrate binding

ADA2 forms a homodimer and localizes to the extracellular space where it may reduce the extracellular adenosine concentration.

ADA2 has four aspargine glycosylation sites at p.Asn127, p.Asn174, p.Asn185, and p.Asn378 [Zavialov et al 2010a]. Glycosylation plays an important role in ADA2 secretion by modulating ADA2 trafficking from the endoplasmic reticulum (ER) to the Golgi. Alteration of one consensus glycosylation sequence constituted by p.Thr129 and p.Asn127 has been shown to lead to ER retention and defective secretion of the abnormal ADA2 [Lee et al 2018].

ADA2 is predominately expressed in myeloid cells such as monocytes, macrophages, and dendritic cells. ADA2 is secreted by activated myeloid cells. Although it has been postulated that ADA2 decreases extracellular adenosine concentration at the sites of inflamed or tumor tissues, this has not been shown either in vitro or in vivo. Where measured, adenosine has not been elevated in the plasma of individuals with DADA2 [Van Eyck et al 2015], in contrast to the elevated levels found in individuals with ADA deficiency (see Adenosine Deaminase Deficiency). Numerous studies report elevated levels of ADA2 in the serum of individuals with HIV and chronic inflammatory diseases, as well as in tuberculous pleural effusions.

ADA2 has homology to so-called adenosine deaminase growth factors (ADGFs) identified in several insect species, fish, and frogs. Although ADA2 is found in many species, mice lack an ADA2 ortholog, which has hampered in vivo studies of ADA2 function. ADGFs may control tissue growth by modulating the level of extracellular adenosine [Zurovec et al 2002, Zavialov et al 2010a]. ADA2 also binds proteoglycans and adenosine receptors on immune cells, implying a role in cell signaling.

The role of ADA2 in multilineage hematopoiesis remains unclear. It is unknown if ADA2 plays additional roles in the development of bone marrow precursors or if the bone marrow failure in DADA2 may be related to inflammatory cell infiltration [Meyts & Aksentijevich 2018].

Abnormal gene product. Pathogenic missense variants are found in all protein domains and may affect protein secretion, dimerization or catalytic activity. Essentially, all pathogenic variants lead to decreased or complete loss of ADA2 protein expression and catalytic activity, one of the diagnostic features of DADA2. Lack of protein activity compromises several cellular processes that contribute to DADA2 pathogenesis (see Molecular Pathogenesis).

In ADA2 deficiency an imbalance between anti-inflammatory M2 and proinflammatory M1 macrophages may create a hyper-inflammatory environment that is damaging to blood vessels [Zhou et al 2014]. Another study showed that adenosine can induce formation of neutrophil extracellular traps and also identified circulating low-density granulocytes, suggesting that neutrophils further contribute to the inflammatory phenotype [Carmona-Rivera et al 2019]. Activated myeloid cells can inflict damage to endothelial cells, causing vasculopathy/vasculitis. This effect of the ADA2-deficient myeloid cells on endothelial cells can be reversed with treatment with anti-TNF agents (see Treatment of Manifestations).

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Author Notes

Natalia Sampaio Moura was a post-baccalaureate research fellow at the National Human Genome Research Institute, National Institutes of Health. Her work involves conducting genetic research studies and diagnostic sequencing of patients with autoinflammatory disorders including many patients with DADA2. She earned a Bachelor of Science degree with High Honors in the Cell Biology and Molecular Genetics department at the University of Maryland, College Park. Natalia is looking forward to starting medical school this year.

Dr Karyl Barron, a pediatric rheumatologist and immunologist, is the Deputy Director of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. She sees patients with autoinflammatory diseases at the National Institutes of Health where she has a large cohort of patients.

Dr Ivona Aksentijevich is an Associate Investigator in the National Human Genome Research Institute (NHGRI), National Institutes of Health. The laboratory focuses on identifying genes responsible for mediating inherited human disorders of inflammation. In addition to DADA2, autoinflammatory disorders identified by the laboratory include familial mediterranean fever (FMF), TNF receptor-associated periodic syndrome (TRAPS), neonatal-onset multisystem inflammatory disease (NOMID), autoinflammation PLCγ2-associated antibody deficiency (APLAID), deficiency of IL-1RN (DIRA), haploinsufficiency of A20 (HA20), and Otulin deficiency (otulipenia). The laboratory works to elucidate the mechanism of these genetic disorders in order to develop insights into possible targeted treatments. Dr Aksentijevich also runs a CLIA-certified diagnostic sequencing laboratory within the NHGRI.

Acknowledgments

We would like to acknowledge the GeneReviews Editors and Reviewers for their helpful advice and contributions to the development of this GeneReview chapter on ADA2.

Revision History

• 8 August 2019 (bp) Review posted live
• 18 April 2019 (ia) Original submission

Note: Pursuant to 17 USC Section 105 of the United States Copyright Act, the GeneReview "Adenosine Deaminase 2 Deficiency" is in the public domain in the United States of America.