title: Phenotypic variability in patients with ADA2 deficiency due to identical homozygous R169Q mutations.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors: Department of Pediatric Immunology and Infectious Diseases, j.vanmontfrans@umcutrecht.nl.
authors: Joris M
authors: JM
authors: Van Montfrans
authors: Department of Pediatric Immunology and Infectious Diseases.
authors: Esther A R
authors: EA
authors: Hartman
authors: Department of Child Neurology, Brain Center Rudolf Magnus.
authors: Kees P J
authors: KP
authors: Braun
authors: Department of Medical Genetics, University Medical Center Utrecht, Utrecht.
authors: Eric A M
authors: EA
authors: Hennekam
authors: Amsterdam Rheumatology and Immunology Center, Academic Medical Center.
authors: Elisabeth A
authors: EA
authors: Hak
authors: Department of Neurology, Academic Medical Center, Amsterdam.
authors: Paul J
authors: PJ
authors: Nederkoorn
authors: Department of Neurology, Academic Medical Center, Amsterdam.
authors: Willeke F
authors: WF
authors: Westendorp
authors: Department of Pediatrics, Leiden University Medical Center, Leiden.
authors: Robbert G M
authors: RG
authors: Bredius
authors: Department of Pediatrics, Leiden University Medical Center, Leiden.
authors: Wouter J W
authors: WJ
authors: Kollen
authors: Department of Pediatric Infectious Diseases, Rheumatology and Immunology, Beatrix Children's Hospital, University Medical Center Groningen, Groningen, The Netherlands.
authors: Elisabeth H
authors: EH
authors: Schölvinck
authors: Department of Pediatric Infectious Diseases, Rheumatology and Immunology, Beatrix Children's Hospital, University Medical Center Groningen, Groningen, The Netherlands.
authors: G Elizabeth
authors: GE
authors: Legger
authors: Department of Pediatrics, Department of Immunology and Microbiology, University Hospital Leuven, KU Leuven.
authors: Isabelle
authors: I
authors: Meyts
authors: VIB - KU Leuven Department of Microbiology and Immunology, Leuven, Belgium.
authors: Adrian
authors: A
authors: Liston
authors: Department of Medical Genetics, University Medical Center Utrecht, Utrecht.
authors: Klaske D
authors: KD
authors: Lichtenbelt
authors: Department of Medical Genetics, University Medical Center Utrecht, Utrecht.
authors: Jacques C
authors: JC
authors: Giltay
authors: Department of Medical Genetics, University Medical Center Utrecht, Utrecht.
authors: Gijs
authors: G
authors: Van Haaften
authors: Department of Medical Genetics, University Medical Center Utrecht, Utrecht.
authors: Gaby M
authors: GM
authors: De Vries Simons
authors: Department of Rheumatology and Clinical Immunology.
authors: Helen
authors: H
authors: Leavis
authors: Department of Dermatology, Division of Internal Medicine and Dermatology.
authors: Cornelis J G
authors: CJ
authors: Sanders
authors: Department of Pediatric Stem Cell Transplantation and.
authors: Marc B
authors: MB
authors: Bierings
authors: U-DAIR, Laboratory of Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: Stefan
authors: S
authors: Nierkens
authors: Department of Medical Genetics, University Medical Center Utrecht, Utrecht.
authors: Marielle E
authors: ME
authors: Van Gijn
mesh_terms: D000243:Adenosine Deaminase / Q000097:blood / Q000172:deficiency* / Q000235:genetics; D000361:Agammaglobulinemia / Q000188:drug therapy / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D018703:Founder Effect; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007223:Infant; D007231:Infant, Newborn; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood / Q000172:deficiency* / Q000235:genetics; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D016511:Severe Combined Immunodeficiency / Q000188:drug therapy / Q000235:genetics*
chemical_list: D007166:Immunosuppressive Agents; D036341:Intercellular Signaling Peptides and Proteins; C408373:ADA2 protein, human; D000243:Adenosine Deaminase
keywords: ADA2; CECR1; auto-inflammatory disease; early-onset stroke; genotype; livedo reticularis; phenotype; vasculitis