title: ADA2 deficiency: case report of a new phenotype and novel mutation in two sisters.
abstract: The objective of this paper is to: describe the phenotype compound heterozygote for mutations in CECR1 in two children. We describe the clinical and immunological phenotype, including the assessment of ADA2 activity, cytokine expression, interferon-stimulated and neutrophil-stimulated gene signatures, and the results of CECR1 sequencing. The first patient presented with intermittent fever, cutaneous vasculitis, myalgia and muscle inflammation on MRI leading to a provisional diagnosis of periarteritis nodosa. Subsequently, two cerebral lacunar lesions were identified following a brain stroke. Clinical features improved on anti-tumour necrosis factor therapy. The first patient's sister demonstrated early-onset, long-lasting anaemia with mild biological inflammation; at the ages of 3 and 5 years, she had presented 2 acute, transient neurological events with lacunar lesions on MRI. CECR1 sequencing identified both sisters to be compound heterozygous for a p.Tyr453Cys mutation and a previously undescribed deletion of exon 7. ADA2 activity was reduced by 50%. Neutrophil-stimulated genes were not overexpressed, but interferon-stimulated genes were. The expression of a panel of other cytokine transcripts was not significantly altered. In conclusion, searching for CECR1 mutation or assessing ADA2 activity should be considered in patients with an atypical presentation of inflammatory disease.
authors.affiliation: Pediatric Immunology-Hematology and Rheumatology Unit, Institut Imagine, Hôpital Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris, Paris, France; Transversal Unit of Allergology and Rheumatology, CHRU Tours, Tours, France.
authors.forename: F
authors.initials: F
authors.lastname: Uettwiller
authors.affiliation: Laboratory of Rare and Autoinflammatory Genetic Diseases , CHRU , Montpellier , France.
authors.forename: G
authors.initials: G
authors.lastname: Sarrabay
authors.affiliation: INSERM UMR 1163, Laboratory of Neurogenetics and Neuroinflammation, Institut Imagine, Hôpital Necker, Paris Descartes-Sorbonne Paris Cité University , Paris , France.
authors.forename: M P
authors.initials: MP
authors.lastname: Rodero
authors.affiliation: Manchester Centre for Genomic Medicine, Institute of Human Development Faculty of Medical and Human Sciences, Manchester Academic Health Sciences Centre, University of Manchester , Manchester , UK.
authors.forename: G I
authors.initials: GI
authors.lastname: Rice
authors.affiliation: Inserm U930, CNRS 2448, Tours, France; Service Neuropédiatrie et Handicaps, CHRU de Tours, Tours, France.
authors.forename: E
authors.initials: E
authors.lastname: Lagrue
authors.affiliation: Pediatric Emergency Unit , CHRU Tours , Tours , France.
authors.forename: Y
authors.initials: Y
authors.lastname: Marot
authors.affiliation: Pediatric Neurology Department , National Referral Center for Neuro-Inflammatory Diseases in Children, Hôpitaux Universitaires Paris Sud, Assistance Publique-Hôpitaux de Paris and UMR 1184, Center for Immunology of viral infections and autoimmune diseases, University Paris Sud , Le Kremlin-Bicêtre , France.
authors.forename: K
authors.initials: K
authors.lastname: Deiva
authors.affiliation: Laboratory of Rare and Autoinflammatory Genetic Diseases , CHRU , Montpellier , France.
authors.forename: I
authors.initials: I
authors.lastname: Touitou
authors.affiliation: INSERM UMR 1163, Laboratory of Neurogenetics and Neuroinflammation, Institut Imagine, Hôpital Necker, Paris Descartes-Sorbonne Paris Cité University, Paris, France; Manchester Centre for Genomic Medicine, Institute of Human Development Faculty of Medical and Human Sciences, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, UK.
authors.forename: Y J
authors.initials: YJ
authors.lastname: Crow
authors.affiliation: Pediatric Immunology-Hematology and Rheumatology Unit , Institut Imagine, Hôpital Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris , Paris , France.
authors.forename: P
authors.initials: P
authors.lastname: Quartier
keywords: Fever Syndromes; Inflammation; Systemic vasculitis