title: Early-onset osteoarthritis, Charcot-Marie-Tooth like neuropathy, autoimmune features, multiple arterial aneurysms and dissections: an unrecognized and life threatening condition.
abstract: BACKGROUND
  Severe osteoarthritis and thoracic aortic aneurysms have recently been associated with mutations in the SMAD3 gene, but the full clinical spectrum is incompletely defined.
  
  
  METHODS
  All SMAD3 gene mutation carriers coming to our centre and their families were investigated prospectively with a structured panel including standardized clinical workup, blood tests, total body computed tomography, joint X-rays. Electroneuromyography was performed in selected cases.
  
  
  RESULTS
  Thirty-four SMAD3 gene mutation carriers coming to our centre were identified and 16 relatives were considered affected because of aortic surgery or sudden death (total 50 subjects). Aortic disease was present in 72%, complicated with aortic dissection, surgery or sudden death in 56% at a mean age of 45 years. Aneurysm or tortuosity of the neck arteries was present in 78%, other arteries were affected in 44%, including dissection of coronary artery. Overall, 95% of mutation carriers displayed either aortic or extra-aortic arterial disease. Acrocyanosis was also present in the majority of patients. Osteoarticular manifestations were recorded in all patients. Joint involvement could be severe requiring surgery in young patients, of unusual localization such as tarsus or shoulder, or mimicking crystalline arthropathy with fibrocartilage calcifications. Sixty eight percent of patients displayed neurological symptoms, and 9 suffered peripheral neuropathy. Electroneuromyography revealed an axonal motor and sensory neuropathy in 3 different families, very evocative of type II Charcot-Marie-Tooth (CMT2) disease, although none had mutations in the known CMT2 genes. Autoimmune features including Sjogren's disease, rheumatoid arthritis, Hashimoto's disease, or isolated autoantibodies- were found in 36% of patients.
  
  
  CONCLUSIONS
  SMAD3 gene mutations are associated with aortic dilatation and osteoarthritis, but also autoimmunity and peripheral neuropathy which mimics type II Charcot-Marie-Tooth.
authors.affiliation: INSERM U698, Hôpital Bichat, Paris, France.
authors.forename: Mélodie
authors.initials: M
authors.lastname: Aubart
authors.affiliation: AP-HP, Hôpital Bichat, Service de Médecine Interne, Hôpital Bichat, Paris, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Gobert
authors.affiliation: AP-HP, Service de Médecine Interne, Hôpital Pitié-Salpétrière, Paris, France.
authors.forename: Fleur
authors.initials: F
authors.lastname: Aubart-Cohen
authors.affiliation: INSERM U698, Hôpital Bichat, Paris, France; AP-HP, Hôpital Bichat, Centre de référence pour les syndromes de Marfan et apparentés, Service de Cardiologie, Paris, France; AP-HP, Hôpital Bichat, Service de Cardiologie, Paris, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Detaint
authors.affiliation: AP-HP Génétique moléculaire, Boulogne, France.
authors.forename: Nadine
authors.initials: N
authors.lastname: Hanna
authors.affiliation: AP-HP Génétique moléculaire, Boulogne, France.
authors.forename: Hyacintha
authors.initials: H
authors.lastname: d'Indya
authors.affiliation: AP-HP, Hôpital Bichat, Centre de référence pour les syndromes de Marfan et apparentés, Service de Cardiologie, Paris, France.
authors.forename: Janine-Sophie
authors.initials: JS
authors.lastname: Lequintrec
authors.affiliation: AP-HP, Hôpital Bichat, Centre de référence pour les syndromes de Marfan et apparentés, Service de Cardiologie, Paris, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Renard
authors.affiliation: AP-HP, Hôpital Bichat, Centre de référence pour les syndromes de Marfan et apparentés, Service de Cardiologie, Paris, France.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Vigneron
authors.affiliation: AP-HP, Hôpital Bichat, Service de Rhumatologie, Hôpital Bichat, Paris, France; Université Denis Diderot, Paris 7, UFR de Médecine, Paris, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Dieudé
authors.affiliation: Université Denis Diderot, Paris 7, UFR de Médecine, Paris, France; AP-HP, Hôpital Bichat, Service de Radiologie, Paris, France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Laissy
authors.affiliation: AP-HP, Hôpital Bichat, Service de Radiologie, Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Koch
authors.affiliation: AP-HP, Hôpital Bichat, Centre de référence pour les syndromes de Marfan et apparentés, Service de Cardiologie, Paris, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Muti
authors.affiliation: AP-HP, Hôpital Bichat, Centre de référence pour les syndromes de Marfan et apparentés, Service de Cardiologie, Paris, France.
authors.forename: Joelle
authors.initials: J
authors.lastname: Roume
authors.affiliation: AP-HP, Hôpital Bichat, Centre de référence pour les syndromes de Marfan et apparentés, Service de Cardiologie, Paris, France.
authors.forename: Veronica
authors.initials: V
authors.lastname: Cusin
authors.affiliation: Université Denis Diderot, Paris 7, UFR de Médecine, Paris, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Grandchamp
authors.affiliation: AP-HP, Hôpital Bichat, Centre de référence pour les syndromes de Marfan et apparentés, Service de Cardiologie, Paris, France; Université Versailles SQY, UFR des Sciences de la Santé, Guyancourt, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Gouya
authors.affiliation: AP-HP, Département de Génétique, Hôpital Pitié-Salpétrière, Paris, France.
authors.forename: Eric
authors.initials: E
authors.lastname: LeGuern
authors.affiliation: AP-HP, Hôpital Bichat, Service de Médecine Interne, Hôpital Bichat, Paris, France; Université Denis Diderot, Paris 7, UFR de Médecine, Paris, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Papo
authors.affiliation: AP-HP Génétique moléculaire, Boulogne, France; Université Versailles SQY, UFR des Sciences de la Santé, Guyancourt, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Boileau
authors.affiliation: INSERM U698, Hôpital Bichat, Paris, France; AP-HP, Hôpital Bichat, Centre de référence pour les syndromes de Marfan et apparentés, Service de Cardiologie, Paris, France; Université Denis Diderot, Paris 7, UFR de Médecine, Paris, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Jondeau
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000784:Aortic Dissection / Q000235:genetics*; D017545:Aortic Aneurysm, Thoracic / Q000235:genetics*; D001327:Autoimmune Diseases / Q000235:genetics*; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D003645:Death, Sudden; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010003:Osteoarthritis / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D051900:Smad3 Protein / Q000235:genetics*; D013577:Syndrome; D055815:Young Adult
chemical_list: D051900:Smad3 Protein