A Case Series of Adenosine Deaminase 2-deficient Patients Emphasizing Treatment and Genotype-phenotype Correlations

Batu, Ezgi Deniz; Karadağ, Ömer; Taşkıran, Ekim Z.; Kalyoncu, Umut; Aksentijevich, Ivona; Alikaşifoğlu, Mehmet; Özen, Seza

doi:10.3899/jrheum.150024

Cited by 83 publications

(77 citation statements)

References 8 publications

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“…While nephrogenic hypertension is rather common in this condition, in few patients focal glomerulosclerosis and renal amyloidosis have also been described [11]. Lung involvement with necrotising pneumonia (lethal) has been reported in one patient [11].…”

Section: Cecr1 Genementioning

confidence: 99%

“…Being DADA2 a vasculitis with a genetic basis, it has been proposed to group this disease in the vasculitis with a probable cause according to the Chapel Hill classification [11, 22]. …”

Section: Cecr1 Genementioning

confidence: 99%

“…The disease turned out to be lethal in seven out of the 65 patients by now described [1, 2, 6, 13, 14]: in three cases the severity of the visceral involvement was lethal [1, 2], two patients died for respiratory complications following intracranial haemorrhage [6, 13], while one patient developed necrotising pneumonia [1, 11]; finally one of the two patients carrying the homozygous deletion on 22.11.1 chromosome died for septic shock.…”

Section: Cecr1 Genementioning

confidence: 99%

“…Being an inflammatory condition, high doses of steroids are usually able to control the clinical manifestations [1, 2, 8, 9, 11, 12]. However, due to the severity of the condition, a steroid-dependence is often described.…”

Section: Cecr1 Genementioning

confidence: 99%

“…However, due to the severity of the condition, a steroid-dependence is often described. None of the most common immunosuppressive drugs (cyclophosphamide, azathioprine, methotrexate) was effective [1, 2, 6, 8, 11, 13]. …”

Section: Cecr1 Genementioning

confidence: 99%

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Monogenic polyarteritis: the lesson of ADA2 deficiency

et al. 2016

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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, mapped to chromosome 22q11.1, that encodes for the enzymatic protein adenosine deaminase 2 (ADA2). By now 19 different mutations in CECR1 gene have been detected.The pathogenetic mechanism of DADA2 is still unclear. ADA2 in a secreted protein mainly expressed by cells of the myeloid lineage; its enzymatic activity is higher in conditions of hypoxia, inflammation and oncogenesis. Moreover ADA2 is able to induce macrophages proliferation and differentiation; it’s deficiency is in fact associated with a reduction of anti-inflammatory macrophages (M2). The deficiency of ADA2 is also associated with an up-regulation of neutrophils-expressed genes and an increased secretion of pro-inflammatory cytokines. The mild immunodeficiency detected in many DADA2 patients suggests a role of this protein in the adaptive immune response; an increased mortality of B cells and a reduction in the number of memory B cells, terminally differentiated B cells and plasmacells has been described in many patients. The lack of the protein is associated with endothelium damage; however the function of this protein in the endothelial homeostasis is still unknown.From the clinical point of view, this disease is characterized by a wide spectrum of severity. Chronic or recurrent systemic inflammation with fever, elevation of acute phase reactants and skin manifestations (mainly represented by livedo reticularis) is the typical clinical picture. While in some patients the disease is mild and skin-limited, others present a severe, even lethal, disease with multi-organ involvement; the CNS involvement is rather common with ischemic or hemorrhagic strokes. In many patients not only the clinical picture but also the histopathologic features are undistinguishable from those of systemic polyarteritis nodosa (PAN). Of note, patients with an unusual phenotype, mainly dominated by clinical manifestations suggestive for an immune-disrective condition, have been described.Due to its rarity, the response to treatment of DADA2 is still anecdotal. While steroids can control the disease’s manifestations at high dosage, none of the common immunosuppressive drugs turned out to be effective. Biologic drugs have been used only in few patients, without a clear effectiveness; anti-TNF drugs are those associated to a better clinical response. Hematopoietic stem cells transplantation was effective in patients with a severe phenotype.

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Section: Cecr1 Genementioning

confidence: 99%

“…Being DADA2 a vasculitis with a genetic basis, it has been proposed to group this disease in the vasculitis with a probable cause according to the Chapel Hill classification [11, 22]. …”

Section: Cecr1 Genementioning

confidence: 99%

Section: Cecr1 Genementioning

confidence: 99%

Section: Cecr1 Genementioning

confidence: 99%

Section: Cecr1 Genementioning

confidence: 99%

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Monogenic polyarteritis: the lesson of ADA2 deficiency

et al. 2016

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ADA2 deficiency in a patient with Noonan syndrome‐like disorder with loose anagen hair: The co‐occurrence of two rare syndromes

Doğan

Şimşek‐Kiper

Taşkıran

et al. 2019

American J of Med Genetics Pt A

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Noonan syndrome-like disorder with loose anagen hair (NS/LAH) is one of the RASopathies, a group of clinically related developmental disorders caused by germline mutations in genes that encode components acting in the RAS/MAPK pathway. Among RASopathies, NS/LAH (OMIM 607721) is an extremely rare, multiple anomaly syndrome characterized by dysmorphic facial features similar to those observed in Noonan syndrome along with some distinctive ectodermal findings including easily pluckable, sparse, thin, and slow-growing hair. ADA2 deficiency (DADA2, OMIM 615688) is a monogenic autoinflammatory disorder caused by homozygous or compound heterozygous mutations in ADA2, with clinical features including recurrent fever, livedo racemosa, hepatosplenomegaly, and strokes as well as immune dysregulation. This is the first report of NS/LAH and ADA2 deficiency in the same individual. We report on a patient presenting with facial features, recurrent infections and ectodermal findings in whom both the clinical and molecular diagnoses of NS/LAH and ADA2 deficiency were established, respectively. K E Y W O R D SADA2, consanguinity, DADA2, Noonan syndrome-like disorder with loose anagen hair, SHOC2

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Deficiency of Adenosine Deaminase Type 2: A Description of Phenotype and Genotype in Fifteen Cases

Nanthapisal

Murphy

Omoyinmi

et al. 2016

Arthritis & Rheumatology

147

138

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Objective. To describe the clinical features, genotype, and treatment in a series of subjects with confirmed adenosine deaminase 2 (ADA2) deficiency.Methods. All symptomatic subjects were referred for genetic testing for suspected ADA2 deficiency; relatives of index cases were also screened. Demographic, clinical, and laboratory characteristics and treatments were recorded. Genetic analyses included whole-exome sequencing in 4 subjects and Sanger sequencing of CECR1 (the gene for cat eye syndrome chromosome region candidate 1) in all subjects. Assays for ADA2 enzyme activity and quantitative polymerase chain reaction analysis of CECR1 messenger RNA (mRNA) were also performed.Results. We identified 15 subjects with ADA2 deficiency, 5 of whom were asymptomatic (relatives of index cases; ages 5-42 years). Homozygous or compound heterozygous mutations in CECR1 were identified in all subjects. Phenotypic manifestations in the patients with symptomatic ADA2 deficiency included livedo racemosa (73.3%), neurologic involvement (53.3%), and immunodeficiency (46.7%). CECR1 mRNA expression in 8 subjects, including 5 who were presymptomatic, was significantly lower than in healthy controls (P 5 0.0016). Subjects with ADA2 deficiency (with or without symptoms) also had lower ADA2 enzyme activity compared to healthy pediatric controls (P < 0.0001) and patients with sporadic (nonfamilial) childhood polyarteritis nodosa (PAN) without CECR1 mutation (P 5 0.0108). Anti2tumor necrosis factor therapy was required in 9 of the 10 symptomatic subjects.Conclusion. The clinical manifestations of ADA2 deficiency ranged in severity from limited cutaneous involvement to severe multisystemic vasculitis; one-third of our cases (5 of 15) were currently asymptomatic, and required close monitoring. We recommend CECR1 screening for unaffected siblings of index cases, cases of familial vasculitis, and cases of PAN that is resistant to standard treatment.

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A Case Series of Adenosine Deaminase 2-deficient Patients Emphasizing Treatment and Genotype-phenotype Correlations

Cited by 83 publications

References 8 publications

Monogenic polyarteritis: the lesson of ADA2 deficiency

Monogenic polyarteritis: the lesson of ADA2 deficiency

ADA2 deficiency in a patient with Noonan syndrome‐like disorder with loose anagen hair: The co‐occurrence of two rare syndromes

Deficiency of Adenosine Deaminase Type 2: A Description of Phenotype and Genotype in Fifteen Cases

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