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

Rheumatology (Oxford). 2016 May;55(5):902-10. doi: 10.1093/rheumatology/kev439. Epub 2016 Feb 10.


Objective: To determine the genotype-phenotype association in patients with adenosine deaminase-2 (ADA2) deficiency due to identical homozygous R169Q mutations inCECR1 METHODS: We present a case series of nine ADA2-deficient patients with an identical homozygous R169Q mutation. Clinical and diagnostic data were collected and available MRI studies were reviewed. We performed genealogy and haplotype analyses and measured serum ADA2 activity. ADA2 activity values were correlated to clinical symptoms.

Results: Age of presentation differed widely between the nine presented patients (range: 0 months to 8 years). The main clinical manifestations were (hepato)splenomegaly (8/9), skin involvement (8/9) and neurological involvement (8/9, of whom 6 encountered stroke). Considerable variation was seen in type, frequency and intensity of other symptoms, which included aplastic anaemia, acute myeloid leukaemia and cutaneous ulcers. Common laboratory abnormalities included cytopenias and hypogammaglobulinaemia. ADA2 enzyme activity in patients was significantly decreased compared with healthy controls. ADA2 activity levels tended to be lower in patients with stroke compared with patients without stroke. Genealogical studies did not identify a common ancestor; however, based on allele frequency, a North-West European founder effect can be noted. Three patients underwent haematopoietic cell transplantation, after which ADA2 activity was restored and clinical symptoms resolved.

Conclusion: This case series revealed large phenotypic variability in patients with ADA2 deficiency though they were homozygous for the same R169Q mutation inCECR1 Disease modifiers, including epigenetic and environmental factors, thus seem important in determining the phenotype. Furthermore, haematopoietic cell transplantation appears promising for those patients with a severe clinical phenotype.

Keywords: ADA2; CECR1; auto-inflammatory disease; early-onset stroke; genotype; livedo reticularis; phenotype; vasculitis.

Publication types

  • Multicenter Study

MeSH terms

  • Adenosine Deaminase / blood
  • Adenosine Deaminase / deficiency*
  • Adenosine Deaminase / genetics
  • Agammaglobulinemia / drug therapy
  • Agammaglobulinemia / genetics*
  • Child
  • Child, Preschool
  • Female
  • Founder Effect
  • Haplotypes
  • Homozygote
  • Humans
  • Immunosuppressive Agents / therapeutic use
  • Infant
  • Infant, Newborn
  • Intercellular Signaling Peptides and Proteins / blood
  • Intercellular Signaling Peptides and Proteins / deficiency*
  • Intercellular Signaling Peptides and Proteins / genetics
  • Male
  • Mutation*
  • Pedigree
  • Phenotype
  • Severe Combined Immunodeficiency / drug therapy
  • Severe Combined Immunodeficiency / genetics*


  • Immunosuppressive Agents
  • Intercellular Signaling Peptides and Proteins
  • ADA2 protein, human
  • Adenosine Deaminase

Supplementary concepts

  • Severe combined immunodeficiency due to adenosine deaminase deficiency