A Mendelian Mimic of Jaccoud’s Arthropathy

Objective. To define the molecular basis of a multisystem phenotype with progressive musculoskeletal disease of the hands and feet, including camptodactyly, subluxation, and tendon rupture, reminiscent of Jaccoud’s arthropathy. Methods. We identified 2 families segregating an autosomal-dominant phenotype encompassing musculoskeletal disease and variable additional features, including psoriasis, dental abnormalities, cardiac valve involvement, glaucoma, and basal ganglia calcification. We measured the expression of interferon (IFN)–stimulated genes in the peripheral blood and skin, and undertook targeted Sanger sequencing of the IFIH1 gene encoding the cytosolic double-stranded RNA (dsRNA) sensor melanoma differentiation–associated protein 5 (MDA-5). We also assessed the functional consequences of IFIH1 gene variants using an in vitro IFNb reporter assay in HEK 293T cells. Results. We recorded an up-regulation of type I IFN–induced gene transcripts in all 5 patients tested and identified a heterozygous gain-of-function mutation in IFIH1 in each family, resulting in different substitutions of the threonine residue at position 331 of MDA-5. Both of these variants were associated with increased IFNb expression in the absence of exogenous dsRNA ligand, consistent with constitutive activation of MDA-5. Conclusion. These cases highlight the significant musculoskeletal involvement that can be associated with mutations in MDA-5, and emphasize the value of testing for up-regulation of IFN signaling as a marker of the underlying molecular lesion. Our data indicate that both SingletonMerten syndrome and neuroinflammation described in the Dr. Ehmke’s work was supported by the Clinician Scientist Program funded by the Charit e–Universit€atsmedizin Berlin and the Berlin Institute of Health. Dr. Crow’s work was supported by the European Research Council (grant GA309449) and a state subsidy managed by the National Research Agency, France (Investments for the Future grant ANR-10-IAHU-01). Luciana Martins de Carvalho, MD, PhD, Fl avio Falc€ao L. Souza, MD, Marcello H. Nogueira-Barbosa, MD, PhD, Virg ınia Ferriani, MD, PhD, Paulo Louzada-Junior, MD, PhD, Wilson Marques Jr., MD, PhD, Charles M. Lourenço, MD, PhD: Ribeir~ao Preto Medical School, University of S~ao Paulo, S~ao Paulo, Brazil; Gonza Ngoumou, MD, Nikolaus Deigendesch, MD, PhD, Denise Horn, MD, Tilmann Kallinich, MD, Werner Stenzel, MD: Charit e–Universit€atsmedizin Berlin, Berlin, Germany; Ji Woo Park: Boston College, Chestnut Hill, Massachusetts; Nadja Ehmke, MD: Charit e–Universit€atsmedizin Berlin and Berlin Institute of Health, Berlin, Germany; Naoki Kitabayashi, BSc: INSERM UMR 1163, Laboratory of Neurogenetics and Neuroinflammation and Paris Descartes University, Sorbonne Paris Cit e, Institut Imagine, Paris, France; Isabelle Melki, MD: INSERM UMR 1163, Laboratory of Neurogenetics and Neuroinflammation, Paris Descartes University, Sorbonne Paris Cit e, Institut Imagine, Hôpital Robert Debr e, AP-HP Paris, and Hôpital NeckerEnfants Malades, AP-HP Paris, Paris, France; Andreas Tzschach, MD: Technische Universit€at Dresden, Dresden, Germany; Sun Hur, PhD: Harvard Medical School, Boston, Massachusetts; Gillian I. Rice, PhD: University of Manchester, Manchester Academic Health Science Centre, Manchester, UK; Yanick J. Crow, MD, PhD: INSERM UMR 1163, Laboratory of Neurogenetics and Neuroinflammation, Paris Descartes University, Sorbonne Paris Cit e, Institut Imagine, and Hôpital Necker Enfants Malades, AP-HP Paris, Paris, France, and University of Manchester, Manchester Academic Health Science Centre, Manchester, UK. Drs. de Carvalho, Ngoumou, and Ehmke and Mr. Park contributed equally to this work. Address correspondence to Yanick J. Crow, MD, PhD, Institut Imagine, Laboratory of Neurogenetics and Neuroinflammation, 24 Boulevard du Montparnasse, Paris 75015, France. E-mail: yanickcrow@mac.com. Submitted for publication March 16, 2017; accepted in revised form June 8, 2017.