J Rheum Dis.  2022 Oct;29(4):254-260. 10.4078/jrd.21.0046.

Adenosine Deaminase 2 Deficiency Caused by Biallele Variants Including Splicing Variant: The First Case in Korea

  • 1Department of Pediatrics, Seoul National University Hospital, Seoul, Korea
  • 2GENOME INSIGHT Inc., Korea
  • 3Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea
  • 4Hospital Medicine Center, Seoul National University Hospital, Seoul, Korea


Deficiency of adenosine deaminase 2 (DADA2) is an autoinflammatory disease caused by pathogenic variants of the ADA2 gene and has similar clinical features to polyarteritis nodosa (PAN). We, herein, report a case of DADA2 in Korea that was diagnosed in a patient with childhood-onset PAN. The patient had a truncal ataxia and facial palsy caused by thalamic infarction at 34 months of age. Livedo reticularis with Raynaud phenomenon and abdominal pain with fever were followed. Radiologic examination showed multiple infarctions in brain and kidney. She was diagnosed with PAN using skin biopsy and angiography. She had severe hemorrhagic strokes despite medical treatments. Her disease activity was controlled after adding a tumor necrosis factor-α inhibitor. Molecular analysis revealed compound heterozygous pathogenic variants of ADA2 gene. This is the first case of DADA2 in Korea. Genetic analysis for ADA2 gene should be considered in patients with childhood-onset PAN.


Polyarteritis nodosa; ADA2 deficiency; ADA2 gene; Deficiency of adenosine deaminase 2


  • Fig. 1 Skin manifestations and radiological findings. (A) The first magnetic resonance imaging (MRI) for brain revealed high signal intensity in diffusion weighted image (DWI), low signal intensity in apparent diffusion coefficient (ADC) on the right thalamus (yellow circle) which was conducted when the 1st neurologic symptoms; truncal ataxia, facial palsy with ptosis on the left side occurred. (B) Digital gangrene was observed on right 3rd finger. (C) Retiform purpura and livedo reticularis were shown on both lower legs with coldness. (D) Raynaud scan by 99mTc showed defects of digital blood flow on both hands, especially right the 2nd to 4th fingers and left 3rd and 4th fingers. (E) On computed tomography, several wedge-shaped focal, low attenuated lesions were observed in both kidneys and appeared to be infarctions. (F) Angiography showed multiple aneurysms in the superior mesenteric artery, inferior mesenteric artery, both renal, and splenic artery’s small branch. (G) The T2-weighted image of brain MRI showed a large amount of intracerebral hemorrhage which affects midline shifting and ventricular size at the age of 5 years.

  • Fig. 2 Main medical events and treatments. The patient had multiple infarctions including brain even though she received various immunosuppressive agents, but these events did not occur after tumor necrosis factor-α inhibitor (infliximab) therapy was commenced at the age of 13 years. The arrows indicate the administration of each drug. The horizontal arrow means a continuation of medication and the vertical arrow means pulse therapy. The administration method and dose of each drug are as follows. Prednisolone per oral (PO), Methylprednisolone pulse therapy intravenously (IV), Cyclophosphamide: pulse therapy IV and PO, Anticoagulant: low molecular heparin IV, warfarin PO, Azathioprine: PO, Lipo-Prostaglandin E1 (PGE-1-lipo): IV, Methotrexate: PO, Infliximab: IV, Intravenous immunoglobulin G.

  • Fig. 3 Results for genetic analysis. (A) The patient's pedigree. Compound heterozygous variants of ADA2 gene were inherited from her father (c753G>A, p.Pro251Pro) and mother (c.1069G>A, p.Ala357Thr), which lead to abnormal splicing and missense mutation, respectively (B). The patient has compound heterozygote variant exon 4 (c753G>A , p.Pro251Pro) and exon 7 (c.1069G>A, p.Ala357Thr). Integrative genomics viewer (IGV) for analysis of whole genome sequencing showed that these variants were inherited from her parents. (C) IGV for analysis of RNA sequencing showed retained intron, which was produced by non-decayed adenine. (D) Sashimi plot on IGV for RNA sequencing analysis showed mRNA splicing on patient and healthy control. Retained intron was observed on intron 4 in this patient. (E) Allele from her father has adenine on 753th nucleotide of the patient on DNA analysis. However, in RNA sequencing analysis, about 33% of adenine was decayed by nonsense-mediated mRNA decay (NMD) to reduce errors in gene expression and remnant 22% of adenine processes mRNA on RNA sequencing called retained intron.


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