Phenotypic variability in patients with ADA2 deficiency due to identical homozygous R169Q mutations

Montfrans, JM van; Hartman, Esther A R; Braun, Kees P.J.; Hennekam, F. A. M.; Hak, A. Elisabeth; Nederkoorn, Paul J.; Westendorp, Willeke F.; Bredius, Robbert G. M.; Kollen, Wouter J.W.; Schölvinck, Elisabeth H.; Legger, G. Elizabeth; Meyts, Isabelle; Liston, Adrian; Giltay, Jacques C.; Haaften, Gijs van; Simons, G De Vries; Leavis, Helen L.; Nierkens, Stefan; Sanders, C. J. G.; Gijn, Mariëlle van

doi:10.1186/1546-0096-13-s1-o7

Cited by 36 publications

(96 citation statements)

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“…The spectrum of DADA2 phenotype is evolving as more atypical presentations have been reported recently. [7][8][9][10][11][12][13][15][16][17][18] Table 1 summarizes hematological manifestations that were reported in DADA2. In the present case, ALPS-like disorder was the main presentation with absence of signs of vasculitis, livedo reticularis, or stroke, causing a diagnostic challenge that was only resolved after obtaining exome sequencing result.…”

Section: Discussionmentioning

confidence: 99%

Deficiency of ADA2 mimicking autoimmune lymphoproliferative syndrome in the absence of livedo reticularis and vasculitis

Alsultan

Basher

Alqanatish

et al. 2017

Pediatric Blood & Cancer

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Adenosine deaminase-2 (ADA2) deficiency (DADA2) is associated with early onset polyarteritis nodosa and vasculopathy. Classic presentation includes livedo reticularis, vasculitis, and stroke. However, the phenotype and disease severity are variable. We present a 5-year-old female who presented with features that mimicked autoimmune lymphoproliferative syndrome (ALPS) in the absence of classic features of DADA2. Exome sequencing identified a novel homozygous splicing variant in ADA2 c.882-2A > G. Patient responded to anti- tumor necrosis factor medication and is in complete remission. Hematologists should be aware of various hematological presentations of DADA2, including ALPS-like disorder, that might lack vasculitis and livedo reticularis to prevent delay in initiating optimal therapy.

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Section: Discussionmentioning

confidence: 99%

Deficiency of ADA2 mimicking autoimmune lymphoproliferative syndrome in the absence of livedo reticularis and vasculitis

Alsultan

Basher

Alqanatish

et al. 2017

Pediatric Blood & Cancer

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“…1 In the severe spectrum of the disease are patients presenting with cranial nerve palsy, diplegia, paraplegia, peripheral polyneuropathy due to perineuritis, ataxia, sensorineural hearing loss, mononeuritis multiplex, labyrinthitis, neuromyelitis, encephalopathy and cerebral atrophy. 1,2,73,74,76,79,81,82 At the histology level, the brain lesions correspond to erythrocyte extravasation in brain parenchyma.…”

Section: Vasculitismentioning

confidence: 99%

“…For instance, the expressivity of one of the common founder mutations, p.R169Q, is extremely variable even in the families. 73 Patients homozygous for this mutation have variable age at presentation, intensity and spectrum of symptoms. There is another report on the variable disease penetrance in a large Iraqi family.…”

Section: The Ada 2 G Enementioning

confidence: 99%

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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“…Deficiency of adenosine deaminase-2 (ADA2) is a recently described autoinflammatory disorder with wide phenotypic variability. [96][97][98][99] ADA2 deficiency is caused by a mutation in the cat eye syndrome chromosome region candidate 1 gene (CECR1). Patients can present at any age and symptoms include cutaneous inflammatory disease, febrile episodes, aplastic anemia, autoimmune cytopenias, antibody deficiency, splenomegaly, and early-onset stroke.…”

Section: Ada2 Deficiencymentioning

confidence: 99%

“…Patients can present at any age and symptoms include cutaneous inflammatory disease, febrile episodes, aplastic anemia, autoimmune cytopenias, antibody deficiency, splenomegaly, and early-onset stroke. [96][97][98][99] HSCT appears to reverse the disease phenotype and is a therapeutic option for some patients. 100,101 Antitumor necrosis factor therapy (e.g., etanercept and infliximab) appears to be efficacious for the vasculitis in many of these patients and dramatic results have been reported.…”

Section: Ada2 Deficiencymentioning

confidence: 99%

Diagnosis and management of chronic and refractory immune cytopenias in children, adolescents, and young adults

Rotz

Ware

Kumar

2018

Pediatric Blood & Cancer

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Children, adolescents, and young adults with chronic refractory autoimmune cytopenias represent a rare but challenging group of patients, who are managed frequently by pediatric hematologists. Novel diagnostic tests and genomic discoveries are refining historical diagnoses of Evans syndrome and common variable immunodeficiency, while also elucidating the cellular and molecular basis for these disorders. Genetic characterization of chronic and refractory autoimmune cytopenias has led to targeted therapies with improved clinical outcomes and fewer off-target toxicities. In this review, we focus on the appropriate diagnostic workup, expanded genetic testing, and novel treatment opportunities that are available for these challenging patients.

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Phenotypic variability in patients with ADA2 deficiency due to identical homozygous R169Q mutations

Cited by 36 publications

References 0 publications

Deficiency of ADA2 mimicking autoimmune lymphoproliferative syndrome in the absence of livedo reticularis and vasculitis

Deficiency of ADA2 mimicking autoimmune lymphoproliferative syndrome in the absence of livedo reticularis and vasculitis

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

Diagnosis and management of chronic and refractory immune cytopenias in children, adolescents, and young adults

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