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  • Oral presentation
  • Open Access

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

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Pediatric Rheumatology201513 (Suppl 1) :O7

  • Published:


  • Acute Myeloid Leukemia
  • Hematopoietic Stem Cell Transplantation
  • Aplastic Anemia
  • Phenotypic Variability
  • Hematopoietic Cell Transplantation


Deficiency of adenosine deaminase-2 (ADA2) is a recently described autoinflammatory disorder with cutaneous inflammatory disease, febrile episodes, cytopenias, splenomegaly and early-onset stroke. Several homozygous and compound heterozygous mutations in CECR1 have been reported in these patients; however, pathogenesis is still poorly understood.


To determine the genotype - phenotype association in patients with ADA2 deficiency due to identical homozygous R169Q mutations in CECR1.


We performed a cohort study in nine patients diagnosed with ADA2 deficiency due to a homozygous R169Q mutation in the Netherlands and Belgium. Clinical and diagnostic data were collected from clinical files. We performed genealogy and haplotype analyses and measured serum ADA2 activity. ADA2 activity values were correlated to clinical symptoms.


Age of presentation differed widely between patients (range: 0 mths to 8 yrs). The main clinical manifestations were (hepato)splenomegaly (9/9); 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 anemia, acute myeloid leukemia and cutaneous ulcers. Common laboratory abnormalities included cytopenias and hypogammaglobulinemia. ADA2 enzyme activity in patients was significantly decreased compared to healthy controls (0.78 vs 5.41 IU/L, p < 0.0001). Within the patient cohort, ADA2 activity levels tended to be lower in patients with stroke compared to patients without stroke (0.30 vs 1.57 IU/L, p= 0.064). No common ancestor for all families could be detected by genealogy, however, based on allele frequency, a Dutch founder effect can be noted. Three patients underwent hematopoietic cell transplantation, after which ADA2 activity was restored and clinical symptoms resolved.


This study revealed large phenotypic variability in patients with ADA2 deficiency though they carried the same homozygous R169Q mutation in CECR1. Epigenetic and environmental factors thus seem important in the phenotype. A trend towards a relation between stroke risk and low ADA2 residual activity was seen. Furthermore, hematopoietic stem cell transplantation appears promising for those patients with a severe clinical phenotype.

Authors’ Affiliations

Pediatric Immunology and Infectious Diseases, University Medical Center Utrecht, Utrecht, Netherlands
University Medical Center Utrecht, Child Neurology, Utrecht, Netherlands
University Medical Center Utrecht, Medical Genetics, Utrecht, Netherlands
Academic Medical Center, Amsterdam Rheumatology and immunology Center, Amsterdam, Netherlands
Academic Medical Center, Neurology, Amsterdam, Netherlands
Leiden University Medical Center, Pediatrics, Leiden, Netherlands
University Medical Center Groningen, Paediatrics, Groningen, Netherlands
University Hospital Leuven, Paediatrics, Leuven, Belgium
University Hospital Leuven, Microbiology and Immunology, Leuven, Belgium
University Medical Center Utrecht, Rheumatology and Clinical Immunology, Utrecht, Netherlands
Laboratory of Translational Immunology, University Medical Center Utrecht, U-DAIR, Utrecht, Netherlands


© Van Montfrans et al. 2015

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.