Extending the Clinical Phenotype of Adenosine Deaminase 2 Deficiency

Ben-Ami, Tal; Revel‐Vilk, Shoshana; Brooks, Rebecca; Shaag, Avraham; Hershfield, Michael S.; Kelly, Susan J.; Ganson, Nancy J.; Kfir‐Erenfeld, Shlomit; Weintraub, Michael; Elpeleg, Orly; Berkun, Yackov; Stepensky, Polina

doi:10.1016/j.jpeds.2016.06.058

Cited by 92 publications

(90 citation statements)

References 20 publications

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“…In the past couple of years, it has become increasingly clear that cytopenia is an important disease manifestation and sometimes the initial presenting feature in DADA2. PRCA was first described by Hashem et al and Ben‐Ami et al and later confirmed with additional reports . Some patients were diagnosed with Diamond Blackfan‐like anemia (DBA).…”

Section: Human Ada2 Deficiency: An Expanding Clinical Phenotypementioning

confidence: 62%

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Human adenosine deaminase 2 deficiency: A multi‐faceted inborn error of immunity

Moens

Hershfield

Arts

et al. 2018

Immunological Reviews

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Human adenosine deaminase 1 deficiency was described in the 1970s to cause severe combined immunodeficiency. The residual adenosine deaminase activity in these patients was attributed to adenosine deaminase 2. Human adenosine deaminase type 2 deficiency (DADA2), due to biallelic deleterious mutations in the ADA2 gene, is the first described monogenic type of small‐ and medium‐size vessel vasculitis. The phenotype of DADA2 also includes lymphoproliferation, cytopenia, and variable degrees of immunodeficiency. The physiological role of ADA2 is still enigmatic hence the pathophysiology of the condition is unclear. Preliminary data showed that in the absence of ADA2, macrophage differentiation is skewed to a pro‐inflammatory M1 subset, which is detrimental for endothelial integrity. The inflammatory phenotype responds well to anti‐TNF therapy with etanercept and that is the first‐line treatment for prevention of severe vascular events including strokes. The classic immunosuppressive drugs are not successful in controlling the disease activity. However, hematopoietic stem cell transplantation (HSCT) has been shown to be a definitive cure in DADA2 patients who present with a severe cytopenia. HSCT can also cure the vascular phenotype and is the treatment modality for patients’ refractory to anti‐cytokine therapies. In this review, we describe what is currently known about the molecular mechanisms of DADA2. Further research on the pathophysiology of this multifaceted condition is needed to fine‐tune and steer future therapeutic strategies.

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Section: Human Ada2 Deficiency: An Expanding Clinical Phenotypementioning

confidence: 62%

“…Some patients were diagnosed with Diamond Blackfan‐like anemia (DBA). Anemia in DADA2 is not always accompanied by inflammation . Importantly, unlike typical DBA due to mutations in ribosomal proteins or GATA1, there is no increase of ADA1 in red blood cell.…”

Section: Human Ada2 Deficiency: An Expanding Clinical Phenotypementioning

confidence: 92%

Human adenosine deaminase 2 deficiency: A multi‐faceted inborn error of immunity

Moens

Hershfield

Arts

et al. 2018

Immunological Reviews

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“…103 A complex immunological phenotype is seen in PLCγ2-associated antibody deficiency and immune dysregulation (PLAID) and autoinflammation and PLAID (APLAID), caused by mutations in PLCG2. The presence of autoinflammation in patients with evidence of autoimmunity and/or immunodeficiency highlights that the divide between the innate and adaptive immune system is not strict.…”

Section: Immunological Overlapmentioning

confidence: 99%

Monogenic autoinflammatory disorders: beyond the periodic fever

Moghaddas

2020

Internal Medicine Journal

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The past two decades have seen an exponential increase in the number of monogenic autoinflammatory disorders described, coinciding with improved genetic sequencing techniques. This group of disorders has evolved to be heterogeneous and certainly more complex than the original four ‘periodic fever syndromes’ caused by innate immune over‐activation. This review aims to provide an update on the classic periodic fever syndromes as well as introducing the broadening spectrum of clinical features seen in more recently described conditions.

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“…In a subsequent study of 48 cases with polyarteritis nodosa associated with livedo reticularis and/or strokes, Gattorno et al performed Sanger sequencing of CECR1 and determined that 15 cases harboured homozygous or compound heterozygous mutations [88]. Since the time of the original description, there has been an expansion of the clinical phenotype of cases with DADA2, from cytopaenias and pure red cell aplasia [89], to lymphoproliferative disease [90–92], and combined immune deficiency, as well as common variable immune deficiency (CVID) [93]. Indeed, a cohort study of 181 cases with antibody deficiency diagnosed 11 individuals with mutation and enzyme activity confirmed DADA2 [94].…”

Section: Classificationmentioning

confidence: 99%

The classification, genetic diagnosis and modelling of monogenic autoinflammatory disorders

Moghaddas

Masters

2018

Clinical Science

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Monogenic autoinflammatory disorders are an increasingly heterogeneous group of conditions characterised by innate immune dysregulation. Improved genetic sequencing in recent years has led not only to the discovery of a plethora of conditions considered to be ‘autoinflammatory’, but also the broadening of the clinical and immunological phenotypic spectra seen in these disorders. This review outlines the classification strategies that have been employed for monogenic autoinflammatory disorders to date, including the primary innate immune pathway or the dominant cytokine implicated in disease pathogenesis, and highlights some of the advantages of these models. Furthermore, the use of the term ‘autoinflammatory’ is discussed in relation to disorders that cross the innate and adaptive immune divide. The utilisation of next-generation sequencing (NGS) in this population is examined, as are potential in vivo and in vitro methods of modelling to determine pathogenicity of novel genetic findings. Finally, areas where our understanding can be improved are highlighted, such as phenotypic variability and genotype–phenotype correlations, with the aim of identifying areas of future research.

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Extending the Clinical Phenotype of Adenosine Deaminase 2 Deficiency

Cited by 92 publications

References 20 publications

Human adenosine deaminase 2 deficiency: A multi‐faceted inborn error of immunity

Human adenosine deaminase 2 deficiency: A multi‐faceted inborn error of immunity

Monogenic autoinflammatory disorders: beyond the periodic fever

The classification, genetic diagnosis and modelling of monogenic autoinflammatory disorders

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