Joris M Van Montfrans1, Esther A R Hartman2, Kees P J Braun3, Eric A M Hennekam4, Elisabeth A Hak5, Paul J Nederkoorn6, Willeke F Westendorp6, Robbert G M Bredius7, Wouter J W Kollen7, Elisabeth H Schölvinck8, G Elizabeth Legger8, Isabelle Meyts9, Adrian Liston10, Klaske D Lichtenbelt4, Jacques C Giltay4, Gijs Van Haaften4, Gaby M De Vries Simons4, Helen Leavis11, Cornelis J G Sanders12, Marc B Bierings13, Stefan Nierkens14, Marielle E Van Gijn4. 1. Department of Pediatric Immunology and Infectious Diseases, j.vanmontfrans@umcutrecht.nl. 2. Department of Pediatric Immunology and Infectious Diseases. 3. Department of Child Neurology, Brain Center Rudolf Magnus. 4. Department of Medical Genetics, University Medical Center Utrecht, Utrecht. 5. Amsterdam Rheumatology and Immunology Center, Academic Medical Center. 6. Department of Neurology, Academic Medical Center, Amsterdam. 7. Department of Pediatrics, Leiden University Medical Center, Leiden. 8. Department of Pediatric Infectious Diseases, Rheumatology and Immunology, Beatrix Children's Hospital, University Medical Center Groningen, Groningen, The Netherlands. 9. Department of Pediatrics, Department of Immunology and Microbiology, University Hospital Leuven, KU Leuven. 10. VIB - KU Leuven Department of Microbiology and Immunology, Leuven, Belgium. 11. Department of Rheumatology and Clinical Immunology. 12. Department of Dermatology, Division of Internal Medicine and Dermatology. 13. Department of Pediatric Stem Cell Transplantation and. 14. U-DAIR, Laboratory of Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
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. 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.
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-deficientpatients 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.
Authors: Oskar Schnappauf; Qing Zhou; Natalia Sampaio Moura; Amanda K Ombrello; Drew G Michael; Natalie Deuitch; Karyl Barron; Deborah L Stone; Patrycja Hoffmann; Michael Hershfield; Carolyn Applegate; Hans T Bjornsson; David B Beck; P Dane Witmer; Nara Sobreira; Elizabeth Wohler; John A Chiorini; The American Genome Center; Clifton L Dalgard; Nih Intramural Sequencing Center; Daniel L Kastner; Ivona Aksentijevich Journal: J Clin Immunol Date: 2020-07-08 Impact factor: 8.317