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Cat Eye Syndrome Chromosome Region 1 (CECR1) gene and Adenosine Deaminase 2 (ADA2) protein with the mutations by now detected
Source publication
The deficiency of Adenosine Deaminase 2 (DADA2) is a new autoinflammatory disease characterised by an early onset vasculopathy with livedoid skin rash associated with systemic manifestations, CNS involvement and mild immunodeficiency.
This condition is secondary to autosomal recessive mutations of CECR1 (Cat Eye Syndrome Chromosome Region 1) gene,...
Contexts in source publication
Context 1
... mutations detected in CECR1 gene so far are 19, with a different prevalence according to patient's ethni- city (Table 1, Fig. 1) [1][2][3][4][5][6][7][8][9][10][11][12][13]. The G47R mutation has been detected in homozygous state in all patients of Georgian Jewish and Turkish origin. Based on the results of the molecular analysis performed in 246 healthy do- nors of Georgian Jewish origin, the estimated frequency of this mutation in this population is 10 % [2]. ...
Context 2
... mutations so far detected affect the Signal peptide (n = 2), the 5' untranslated region (n = 1), the dimerization domain (n = 4), the putative receptor bind- ing (n = 1) and the catalytic domain (n = 11) ( Table 1, Fig. 1) [1][2][3][4][5][6][7][8][9][10][11][12][13]. Moreover two patients with a homozy- gous deletion on 22.11.1 chromosome (encompassing CECR1 gene) have been recently described ...
Citations
... Il decorso clinico può essere cronico o caratterizzato da ricorrenti riacutizzazioni dell'infiammazione sistemica, durante le quali sono state descritte le manifestazioni cliniche più gravi (1). ...
... Finora sono stati utilizzati diversi trattamenti nei pazienti con diagnosi di DADA2, inclusi steroidi, ciclofosfamide, azatioprina e metotrexato, ma i trattamenti più promettenti sono le terapie anti-TNF (etanercept, adalimumab e infliximab). Per massimizzare l'efficacia delle terapie con anti-TNF e prevenire le conseguenze gravi della patologia, il trattamento dovrebbe essere avviato al momento della diagnosi (1,10,17,18). Per questo motivo una diagnosi precoce è fondamentale per indirizzare il prima possibile i pazienti verso un trattamento efficace e per prevenire le gravi complicanze della malattia. ...
Diagnostic workflow for Adenosine Deaminase-2 Deficiency (DADA2): a proposal Deficiency of Adenosine deaminase 2 (DADA2) is a monogenic autoinflammatory disease caused by homozygous or compound heterozygous mutations in the ADA2 gene (formerly CECR1 Cat Eye Syndrome Chromosome Region 1). Clinical manifestations of DADA2 are highly variable and include systemic inflammation with fever, early stroke, vasculopathy, immune dysregulation (hypogammaglobulinemia, lymphoproliferation, increased rate of infections), and hematologic abnormalities (pure red cell aplasia, bone marrow failure, cytopenias). The most promising treatments are anti-TNF inhibitors, the only drugs that can prevent the serious consequences of the disease. Early diagnosis is therefore critical. DADA2 can be diagnosed by genetic analysis or functional tests (biochemical diagnosis) that allow the enzyme activity to be assayed. At the Giannina Gaslini Institute, a children's hospital in Italy, a method based on liquid chromatography coupled with tandem mass spectrometry has been developed to measure enzyme activity. A diagnostic workflow is adopted at the institute that involves the assay of ADA2 activity followed by genetic confirmation when the biochemical test is altered.
... A central role has recently been attributed to the dysregulation of the interferon (IFN) axis (both type I and II). Elevated levels of IFNγ have been found in the plasma of DADA2 patients, which could lead to proinflammatory macrophage differentiation (M1) and the release of tumor necrosis factor α (TNFα) (22). Additionally, an increase in immature CD56 + natural killer (NK) cells, known as regulatory NK cells, characterized by low cytotoxicity but high production of cytokines including TNFα, was found in DADA2 patients. ...
... The ability of B cells to undergo immunoglobulin class switches is impaired, and the response to various stimuli by naïve B cells is reduced. From a phenotypic point of view, all of this translates into hypogammaglobulinemia and an increased risk of infection (21,22). ...
Adenosine deaminase 2 deficiency (DADA2) is a rare monogenic vasculopathy caused by loss-of-function homozygous or compound heterozygous mutations in ADA2, formerly CECR1 (cat eye syndrome chromosome region 1) gene. The DADA2 phenotype is widely heterogeneous, and patients may present with fever, weight loss, livedo reticularis/racemosa, digital ischemia, cutaneous ulceration, peripheral neuropathy, abdominal pain, bowel perforation, and portal or nephrogenic hypertension. More specific manifestations include early-onset ischemic or hemorrhagic stroke, mild immunodeficiency and hypogammaglobinemia, cytopenia, and vision disturbances. Herein, we present the case of a young male with vasculitis associated with DADA2. The presence of HLA-B51 and the clinical features of this patient raised the question of similarities between ADA2 deficiency, Behçet’s disease, and NOD2-associated diseases. Treatment of this rare monogenic disease is challenging and based on small case series. The long-term experience of this patient proved the difficulties of prednisone tapering and the lack of satisfactory therapeutic strategies.
... On the other hand, we observed significant negative correlations between serum ADA2 activity and proinflammatory phenotype reflected by increased levels of circulating adhesion molecules, TNFα concentration, and TNFα/IL10 ratio, which is assumed as an independent predictor for coronary artery disease. It was demonstrated previously that ADA2 is crucial for M2 monocyte/macrophage polarization and, hence, its decreased activity may be related to the disturbed proportion of circulating monocyte subtypes [36,37]. Furthermore, we observed a trend to lower platelet count in post-COVID patients, which may also be connected with higher level of serum TNFα. ...
Endothelial cells are a preferential target for SARS-CoV-2 infection. Previously, we have reported that vascular adenosine deaminase 1 (ADA1) may serve as a biomarker of endothelial activation and vascular inflammation, while ADA2 plays a critical role in monocyte and macrophage function. In this study, we investigated the activities of circulating ADA isoenzymes in patients 8 weeks after mild COVID-19 and related them to the parameters of inflammation and microvascular/endothelial function. Post-COVID patients revealed microvascular dysfunction associated with the changes in circulating parameters of endothelial dysfunction and inflammatory activation. Interestingly, serum total ADA and ADA2 activities were diminished in post-COVID patients, while ADA1 remained unchanged in comparison to healthy controls without a prior diagnosis of SARS-CoV-2 infection. While serum ADA1 activity tended to positively correspond with the parameters of endothelial activation and inflammation, sICAM-1 and TNFα, serum ADA2 activity correlated with IL-10. Simultaneously, post-COVID patients had lower circulating levels of ADA1-anchoring protein, CD26, that may serve as an alternative receptor for virus binding. This suggests that after the infection CD26 is rather maintained in cell-attached form, enabling ADA1 complexing. This study points to the possible role of ADA isoenzymes in cardiovascular complications after mild COVID-19.
... Clinical manifestations include autoinflammatory response syndrome, recurrent stroke, vasculitis similar to nodular arteritis, and immunodeficiency [33]. Small and medium arterial vascular lesions are the main clinical features of DADA2, coronary arteries can be affected, and patients may develop coronary aneurysms [34]. Studies have found that transgenic expression of ADA2 in mice can lead to abnormal cardiac development [35]. ...
Introduction
Autoinflammatory diseases (AIDs) constitute several disorders that are characterized by the presence of recurrent episodes of unprovoked inflammation due to dysregulated innate immune system in the absence of autoantibodies or infections. Most of them have a strong genetic background, with mutations in single genes involved in inflammation referred to monogenic AIDs. In this article, we will review the cardiac manifestations in various monogenic AIDs.
Areas covered
Various cardiac manifestations can be seen in various monogenic AIDs, including pericarditis, valvular diseases, coronary diseases, cardiomyopathies, and pulmonary hypertension, especially in Familial Mediterranean fever (FMF).
Expert commentary
Monogenic AIDs can manifest a variety of cardiac lesions, the most common of which is pericardial effusion, which may be local pericardial inflammation secondary to systemic inflammatory responses. While, the pathogenesis and incidence are still unclear. More research is still needed to explore the relationship between monogenic AIDs and cardiac damage for better understanding these diseases.
... Thus, the onset of neurological manifestations is in line with the onset of DADA2 manifestations in general (7 years), although adult-onset is possible. The late onset can lead to misdiagnosis; therefore, differential diagnosis of DADA2 is obligatory in every case of PAN [48]. ...
Deficiency of human adenosine deaminase type 2 (DADA2) is a complex systemic autoinflammatory disorder characterized by vasculopathy, immune dysregulation, and hematologic abnormalities. The most notable neurological manifestations of DADA2 are strokes that can manifest with various neurological symptoms and are potentially fatal. However, neurological presentations can be diverse. We here present a review of the neurological manifestations of DADA2 to increase clinical awareness of DADA2 as the underlying diagnosis. We reviewed all published cases of DADA2 from 1 January 2014 until 19 July 2022 found via PubMed. A total of 129 articles describing the clinical features of DADA2 were included in the analysis. Six hundred twenty-eight patients diagnosed with DADA2 were included in the review. 50.3% of patients had at least signs of one reported neurological event, which was the initial or sole manifestation in 5.7% and 0.6%, respectively. 77.5% of patients with neurological manifestations had at least signs of one cerebrovascular accident, with lacunar strokes being the most common and 35.9% of them having multiple stroke episodes. There is a remarkable predilection for the brain stem and deep gray matter, with 37.3% and 41.6% of ischemic strokes, respectively. Other neurological involvement included neuropathies, focal neurological deficits, ophthalmological findings, convulsions, and headaches. In summary, neurological manifestations affect a significant proportion of patients with DADA2, and the phenotype is broad. Neurological manifestations can be the first and single manifestation of DADA2. Therefore, stroke, encephalitis, posterior reversible encephalopathy syndrome, mononeuropathy and polyneuropathy, and Behçet’s disease-like presentations should prompt the neurologist to exclude DADA2, especially but not only in childhood.
... Since two patients from the same family with the same mutation in similar environmental conditions have different phenotypic clinical findings (3), it is important to investigate epigenetic modifications and develop treatment options for this disorder in the future. It has initially been recognized as a monogenic vasculitis syndrome that manifests with fevers, vasculitis disorders, and mild immunodeficiency (2,9). It is caused by biallelic hypomorphic/loss of function mutations in the ADA2 gene that encodes the ADA2 protein (5). ...
... Antineutrophilic cytoplasmic antibody (ANCA) negative vasculopathy begins earlier than 10 years of age and ranges from livedo racemosa / reticularis to early onset polyarteritis nodosa (PAN) or nonspecific eruptions on the skin and life-threatening ischemic and/or hemorrhagic stroke (1,7). Vasculitis and inflammation can affect many organs, explaining the intestinal, hepatological, and renal manifestations (9). Other than simple livedo racemosa in case 2, there was no other symptoms or signs related to vasculopathy/vasculitis in either sibling. ...
Deficiency of adenosine deaminase 2 (DADA2) is a childhood-onset disease known with pleiotropic clinical manifestations due to a monogenic form of systemic vasculopathy. Although the clinical spectrum of DADA2, linked to biallelic mutations in the ADA2 gene, has significantly expanded since 2014, approximately 200 cases have been reported thus far. In this report, two siblings are presented to draw attention to an unreported mutation of DADA2 and different phenotypic features of the same missense type homozygous mutation, p.Ser50Leu (c.149C>T). Next-generation sequencing demonstrated an autosomal recessive inherited missense type p.Ser50Leu (c.149C>T) variant homozygous mutation in the ADA-2 gene. The index patient is a 10-year-old Iraqi citizen boy who was referred to us with a complaint of anemia. The patient still needed blood transfusions after 2 hematopoietic stem cell transplantations. His older brother was an 11-year-old boy who presented to the emergency with a history of recurrent lung infections since 7 years of age. Considering the genotype-phenotype relationship from literature data, although vasculitis and low ADA2 activity are defined in cases with missense mutations, immuno-hematological manifestations are remarkable in our patients rather than vasculitic manifestations. While bone marrow failure findings e.g., anemia, neutropenia, etc. are reported to be seen in the 5th and 6th decades of life, those were predominant clinical features in our patients despite their younger age. DADA2 should also be kept in mind in cases of otherwise unexplained cytopenia, especially when associated with panhypogammaglobulinaemia and bone marrow hypocellularity, irrespective of the age of the patient at presentation.
... Recurrent non-infectious fever, as presented by our patient, emerges as the most frequent autoinflammatory manifestation (51.8% of DADA2 patients) (5). Neutropenia have been mostly reported in frequencies around 15%, and even within hematologic phenotype, predominant neutropenia is very uncommon (12,13). A recent Saudi cohort of 21 patients from 14 families, however, encountered neutropenia in 76% of patients and described hematological phenotype as predominant; nevertheless, it is noteworthy that mild neutropenia is a common clinical problem in that region (14). ...
... A recent Saudi cohort of 21 patients from 14 families, however, encountered neutropenia in 76% of patients and described hematological phenotype as predominant; nevertheless, it is noteworthy that mild neutropenia is a common clinical problem in that region (14). Oral aphthous lesions are an uncommon finding in overall DADA2 patients (12,13,15). ...
Deficiency of adenosine deaminase 2 (DADA2), first reported in 2014, is a disease with great phenotypic variability, which has been increasingly reported. Therapeutic response depends on the phenotype. We present a case of an adolescent with recurrent fever, oral aphthous ulcers, and lymphadenopathy from 8 to 12 years of age and subsequently presented with symptomatic neutropenia. After the diagnosis of DADA2, therapy with infliximab was started, but after the second dose, she developed leukocytoclastic vasculitis and showed symptoms of myopericarditis. Infliximab was switched to etanercept, with no relapses. Despite the safety of tumor necrosis factor alpha inhibitors (TNFi), paradoxical adverse effects have been increasingly reported. The differential diagnosis between disease new-onset manifestations of DADA2 and side effects of TNFi can be challenging and warrants further clarification.
... Episodes of fever and systemic symptoms, vasculitis features such as the notable sign of recurrent strokes, skin manifestations (most commonly livedo racemosa/reticularis), hypertension, hematologic manifestations, and immunologic dysregulations are among the most common signs and symptoms. Besides the mentioned symptoms, our patients manifested oral ulcers, genital ulcers, myalgia, and headache, which are also reported in the literature, albeit less commonly [10,[12][13][14]. Lee et al. suggested categorizing DADA2 patients into three major groups: vasculitis, bone marrow failure (BMF), and PRCA [15]. They performed a literature review and found 100 cases of vasculitis, the most common presentation of DADA2, and 52 cases of BMF or PRCA. ...
... ADA2 enzyme is a protein encoded by the ADA2 gene and is composed of four domains: signal peptide, a dimerization domain, catalytic domain, and putative receptor binding domain. The most common disease variant, p.Gly47Arg (p.G47R), is located in the dimerization domain [13,19]. Ozen et al. surveyed the clinical and molecular differences between two groups of DADA2 patients: 14 in the PAN-like group and 10 in the DBA-like group. ...
... The mutations found in DADA patients are less commonly heterozygous. However, no correlation has been found between heterozygosity and the phenotype [10,13]. Likewise, our two patients with heterozygous mutations of G47R, who were brother and sister, did not show distinct manifestations in comparison with the rest of the patients of the PAN-like group. ...
Background
Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive autoinflammatory disease caused by mutations in the ADA2 gene. DADA2 has a broad spectrum of clinical presentations. Apart from systemic manifestations, we can categorize most of the signs and symptoms of DADA2 into the three groups of vasculitis, hematologic abnormalities, and immunologic dysregulations. The most dominant vasculitis features are skin manifestations, mostly in the form of livedo racemosa/reticularis, and early onset ischemic or hemorrhagic strokes. Hypogammaglobulinemia that is found in many cases of DADA2 brings immunodeficiencies into the differential diagnosis. Cytopenia, pure red cell aplasia (PRCA), and bone marrow failure (BMF) are the hematologic abnormalities commonly found in DADA.
Case presentation
We introduce eleven patients with DADA2 diagnosis, including two brothers and sisters, one set of twin sisters, and one father and his daughter and son. Ten patients (91%) had consanguineous parents. All the patients manifested livedo racemose/reticularis. Ten patients (91%) reported febrile episodes, and seven (64%) had experienced strokes. Only one patient had hypertension. Two of the patients (11%) presented decreased immunoglobulin levels. One of the patients presented with PRCA. Except for the PRCA patient with G321E mutation, all of our patients delivered G47R mutation, the most common mutation in DADA2 patients. Except for one patient who unfortunately passed away before the diagnosis was made and proper treatment was initiated, the other patients’ symptoms are currently controlled; two of the patients presented with mild symptoms and are now being treated with colchicine, and the eight others responded well to anti-TNFs. The PRCA patient still suffers from hematologic abnormalities and is a candidate for a bone marrow transplant.
Conclusions
Considering the manifestations and the differential diagnoses, DADA2 is not merely a rheumatologic disease, and introducing this disease to hematologists, neurologists, and immunologists is mandatory to initiate prompt and proper treatment. The efficacy of anti-TNFs in resolving the symptoms of DADA2 patients have been proven, but not for those with hematologic manifestations. Similarly, they were effective in controlling the symptoms of our cohort of patients, except for the one patient with cytopenia.
... 14 ADA2 deficiency is characterized by increased susceptibility to livedo reticularis. 68 Ichthyosis and trichorrhexis invaginatum are seen in Netherton syndrome. 11 Necrotizing granulomatous skin ulcerations similar to granulomatous polyangiitis can be diagnosed in patients with major histocompatibility complex (MHC) I deficiency. ...
... 32 Patients with ADA2 deficiency can manifest increased susceptibility to CNS involvement in the form of ischemic or hemorrhagic strokes. 68 Central nervous system (CNS) vasculitis is noticed in XLP. 49 Spontaneous CNS candidiasis is reported in CARD9 deficiency. ...
Inborn errors of immunity (IEI) comprise a group of about 490 genetic disorders that lead to aberrant functioning or the development of distinct immune system components. So far, a broad spectrum of IEI-related manifestations has been noted in the literature. Due to overlapping signs and symptoms of IEI, physicians face challenges in appropriately diagnosing and managing affected individuals. The last decade has witnesses improving in the molecular diagnosis of IEI patients. As a result, it can be the mainstay of diagnostic algorithms, prognosis, and possibly therapeutic interventions in patients with IEI. Furthermore, reviewing IEI clinical complications demonstrates that the manifestations and severity of the symptoms depend on the involved gene that causes the disease and its penetrance. Although several diagnostic criteria have been used for IEI, not every patient can be explored in the same way. As a result of the failure to consider IEI diagnosis and the variety of diagnostic capabilities and laboratory facilities in different regions, undiagnosed patients are increasing. On the other hand, early diagnosis is an almost essential element in improving the quality of life in IEI patients. Since there is no appropriate guideline for IEI diagnosis in different organs, focusing on the clues in the patient's chief complaint and physical exams can help physicians narrow their differential diagnosis. This article aims to provide a practical guide for IEI diagnosis based on the involved organ. We hope to assist clinicians in keeping IEI diagnosis in mind and minimizing possible related complications due to delayed diagnosis.
... The main skin finding associated with the gene segment involving CES is a livedoid rash stemming from a deficiency of adenosine deaminase 2 (DADA2) or Sneddon syndrome [12]. DADA2 results from autosomal recessive mutations of the CECR1 (Cat Eye Syndrome Chromosome Region 1) gene found on chromosome 22q11.1, ...
... but it is a separate autoinflammatory disease characterized by immunodeficiencies, systemic inflammation, and early-onset stroke, which were not seen in our patient. The skin manifestations in DADA2 are livedo racemosa, a bluish net-like discoloration with no papules, painful cutaneous nodules, and erythematous papules [12]. ...
Cat eye syndrome (CES), also known as Schmid-Fraccaro syndrome, is a complex genetic syndrome with a highly variable phenotype that includes ocular coloboma, anal atresia, preauricular skin tags and pits, heart defects, kidney malformations, dysmorphic facial features, and mild to moderate intellectual disability. We describe a case of a 23-year-old male with a past medical history of CES with short stature, mild learning disability, and some dysmorphic facial features who presented with recurrent pruritus and rashes and had mild liver dysfunction. Furthermore, the patient did not have the classic presentation of CES but a clinically milder expression of the phenotypes. Abnormalities in the abdominal ultrasound prompted an ultrasound-guided liver biopsy, which showed bile ductular proliferation with mild portal inflammation composed of lymphocytes and plasma cells, and bridging fibrosis. The patient's labs showed elevated immunoglobulins with the highest increase observed in IgG, along with negative antinuclear antibodies (ANA), negative anti-mitochondrial antibody, and negative hepatitis A/B/C but a weak positive anti-smooth muscle antibody (ASMA). These findings indicated that the patient most likely had autoimmune hepatitis (AIH) or an overlap syndrome with primary sclerosing cholangitis (PSC). The patient was initially treated with steroids and antihistamines for pruritus, which led to some clinical improvement. After dermatological evaluation, the patient was diagnosed with atopic dermatitis and was recently started on a dupilumab 600 mg loading dose and would continue with biweekly dupilumab 300 mg injections. This dermatological finding may require additional examination and can be a unique presentation in patients with CES. This case illustrates that even patients with milder CES expression can experience intense dermatological complications if not effectively managed. CES is a multifactorial disease that requires intervention from multiple specialists. Therefore, primary care physicians must be aware of the potential complications of CES and make adequate referrals to closely monitor patients' symptoms.
