Fever of unknown origin with rashes in early infancy is indicative of adenosine deaminase type 2 deficiency

Nihira, Hiroshi; Nakagawa, Kiyoshi; Izawa, Kazushi; Kawai, Takayuki; Yasumi, Takahiro; Nishikomori, Ryuta; Nambu, Mitsuhiko; Miyagawa‐Hayashino, Aya; Nomura, Takashi; Kabashima, Kenji; Ito, Moeko; Iwaki-Egawa, Sachiko; Sasahara, Yoji; Nakayama, Manabu; Heike, Toshio

doi:10.1080/03009742.2017.1324912

Cited by 13 publications

(9 citation statements)

References 6 publications

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“…The clinical presentation of patients with ADA2 deficiency is extremely variable. At present, over 170 patients have been reported with males and females equally affected . The disease onset is usually in childhood with 25% of patients presenting before age 1 year and the majority presenting prior to the age of 10 years.…”

Section: Human Ada2 Deficiency: An Expanding Clinical Phenotypementioning

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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Section: Human Ada2 Deficiency: An Expanding Clinical Phenotypementioning

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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“…22 The above mechanisms have led to the wide use of the IL-6R antagonist, TCZ, to treat fever of unknown origin in various inflammatory diseases, such as Still's disease and juvenile idiopathic arthritis, but seldom in SLE patients to date. [23][24][25] In a recent case report, a 41-year-old woman with refractory SLE who suffered from intractable high fever, massive pericarditis, macrophage activation syndrome, and glomerulonephritis showed dramatic improvement after TCZ therapy. 22 Likewise, a pilot study in 16 SLE patients and a trial in 15 SLE patients treated with TCZ showed better curative outcomes and significantly reduced levels of IgG and anti-dsDNA.…”

Section: Discussionmentioning

confidence: 99%

Tocilizumab therapy for persistent high-grade fever in systemic lupus erythematosus: two cases and a literature review

Chaoyi

Shrestha

et al. 2022

J Int Med Res

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Tocilizumab (TCZ) is a humanized immunoglobulin (Ig) G1 monoclonal antibody directed against the interleukin (IL)-6 receptor. We report on two patients with persistent high-grade fever and systemic lupus erythematosus (SLE) who were treated with TCZ. Two female Chinese patients presented with SLE and high-grade fever, with raised inflammatory markers including C-reactive protein, erythrocyte sedimentation rate, and IL-6, but no signs of opportunistic infections. Their fever and other symptoms responded poorly to broad-spectrum antibiotics, antifungals, antivirals, and glucocorticoids. They were both treated with TCZ. Their body temperatures returned to normal after treatment with TCZ, and other symptoms, including arthralgia, gradually improved. Both patients were followed-up and their conditions remained steady to date. TCZ may thus be an alternative treatment for patients with SLE and persistent high-grade fever who fail to respond to initial antibiotics and high-dose glucocorticoids.

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“…1,2,12,14 Recurrent fevers may lead to consideration of a periodic fever syndrome, especially of familial Mediterranean fever (FMF), in countries where FMF is a prevalent disease. 11,14,16 Skin manifestations of DADA2 include livedo reticularis, livedo racemosa, maculopapular rashes, erythema nodosum, Raynaud phenomenon, ulcers, and digital gangrene. [1][2][3] Nearly all of the cases described in the literature have one of these skin manifestations, with livedo reticularis being the most common.…”

Section: Discussionmentioning

confidence: 99%

Atypical phenotype of an old disease or typical phenotype of a new disease: deficiency of adenosine deaminase 2

Çakan¹,

Aktay-Ayaz²,

Karadağ³

et al. 2019

Turk J Pediatr

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phenotype of an old disease or typical phenotype of a new disease: deficiency of adenosine deaminase 2. Turk J Pediatr 2019; 61: 413-417. Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive autoinflammatory disorder caused by mutations in CECR1 (cat eye syndrome chromosome region, canditate 1) gene, which encodes the enzyme adenosine deaminase 2 necessary for endothelial cell survival and function. The diversity of the clinical phenotypes associated with DADA2 include polyarteritis nodosa-like vasculitic features, early-onset stroke, mild to severe immunodeficiency and cytopenias. The diagnosis of the disease may be difficult due to complex clinical phenotype. Herein, we present a case of DADA2 presenting with vasculitis, amarousis fugax, gastrointestinal bleeding and silent lacunar infarct successfully treated with etanercept.

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Fever of unknown origin with rashes in early infancy is indicative of adenosine deaminase type 2 deficiency

Cited by 13 publications

References 6 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

Tocilizumab therapy for persistent high-grade fever in systemic lupus erythematosus: two cases and a literature review

Atypical phenotype of an old disease or typical phenotype of a new disease: deficiency of adenosine deaminase 2

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