title: Musculoskeletal manifestations of Fabry disease: A retrospective study.
abstract: OBJECTIVE
  Fabry disease is a rare X-linked metabolic disorder characterized by a deficiency in the enzyme alpha-galactosidase A. Both males and females can be affected. The main presenting symptom is pain in the extremities, whereas at a more advanced stage, the manifestations include hypertrophic cardiomyopathy, cardiac dysrhythmia, proteinuria, chronic kidney dysfunction, stroke, and hearing loss. When not diagnosed and treated, Fabry disease causes early death. No studies specifically designed to describe the musculoskeletal manifestations of Fabry disease are available.
  
  
  METHODS
  We conducted a single-center retrospective study of patients receiving follow-up at a Fabry disease referral center. We described the musculoskeletal manifestations and analyzed the differential diagnoses.
  
  
  RESULTS
  Our study included 40 patients belonging to 20 families, including 25 females with a mean age of 44.2 years (range, 20-76 years) and 15 males with a mean age of 40.1 years (range, 16-61 years). Mean age at the diagnosis of Fabry disease was 37.2 years (range, 7-71 years) in the females and 26.9 years (range, 9-51 years) in the males. Specific enzyme replacement therapy was given to 10 (40%) females and 12 (80%) males. Musculoskeletal manifestations were as follows: past or present pain in the extremities (13 females and 10 males), combined in some patients with vasomotor disorders in the extremities and telangiectasia; exercise intolerance (12 females and 12 males); osteoporotic fractures (2 brothers aged 45 and 44 years, respectively); osteoporosis (3 females, aged 57, 63, and 75 years, respectively), which contributed to death in the oldest patient; osteopenia (2 females aged 38 and 47 years, respectively; and 1 male aged 43 years); Charcot foot and lymphedema with serious infectious complications (4 males older than 40 years), with avascular osteonecrosis of the lower limbs in 2 cases; toe amputations (3 cases); bilateral lower-limb amputation (1 case); abnormally slender lower limbs (5 females and 8 males); acute gout (3 males with severe chronic kidney failure); and carpal tunnel syndrome (1 female and 1 male, both younger than 40 years). Mistaken diagnoses that were made at an early stage, contributing to delay the identification of Fabry disease, included rheumatic fever (2 females and 2 males), growing pains (2 males), pain with paralysis (1 female), chilblains of the lower limbs (1 female), and erythermalgia (1 female). In adulthood, the following mistaken diagnoses were made: Sjögren's syndrome and/or sicca syndrome (6 females), systemic sclerosis (1 male), dysautonomia (1 female), and familial Mediterranean fever (1 female).
  
  
  CONCLUSIONS
  The diagnosis of Fabry disease is usually delayed, due to confusion with more common disorders. Musculoskeletal manifestations may constitute the presenting symptoms. Past or present pain in the extremities is typical. Osteoporosis may develop early and become severe. Together with the family history, the presence of musculoskeletal manifestations can lead to the correct diagnosis by prompting alpha-galactosidase assays in males and genetic testing in females. Fabry disease is often responsible for musculoskeletal manifestations, of which the most common are pain in the extremities and osteoporosis. These manifestations can be inaugural and lead to diagnostic wanderings. They require specific treatment strategies.
authors.affiliation: Service de Rhumatologie, Médecine Interne, Site Diaconesses Croix St.-Simon, 125, rue d'Avron, 75020 Paris, France; Centre de Référence Maladies Lysosomales, Site Diaconesses Croix St.-Simon, 125, rue d'Avron, 75020 Paris, France; Inserm-UMRS 974, UPMC-équipe muscle inflammatoire/thérapies innovantes ciblées, 75013 Paris, France. Electronic address: olidove@hopital-dcss.org.
authors.forename: Olivier
authors.initials: O
authors.lastname: Lidove
authors.affiliation: Service de Rhumatologie, Médecine Interne, Site Diaconesses Croix St.-Simon, 125, rue d'Avron, 75020 Paris, France; Centre de Référence Maladies Lysosomales, Site Diaconesses Croix St.-Simon, 125, rue d'Avron, 75020 Paris, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Zeller
authors.affiliation: Service de Radiologie, 125, rue d'Avron, 75020 Paris, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Chicheportiche
authors.affiliation: Service de Rhumatologie, Médecine Interne, Site Diaconesses Croix St.-Simon, 125, rue d'Avron, 75020 Paris, France; Centre de Référence Maladies Lysosomales, Site Diaconesses Croix St.-Simon, 125, rue d'Avron, 75020 Paris, France.
authors.forename: Vanina
authors.initials: V
authors.lastname: Meyssonnier
authors.affiliation: Service de Rhumatologie, Médecine Interne, Site Diaconesses Croix St.-Simon, 125, rue d'Avron, 75020 Paris, France; Centre de Référence Maladies Lysosomales, Site Diaconesses Croix St.-Simon, 125, rue d'Avron, 75020 Paris, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Sené
authors.affiliation: Service de Rhumatologie, Médecine Interne, Site Diaconesses Croix St.-Simon, 125, rue d'Avron, 75020 Paris, France; Centre de Référence Maladies Lysosomales, Site Diaconesses Croix St.-Simon, 125, rue d'Avron, 75020 Paris, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Godot
authors.affiliation: Service de Rhumatologie, Médecine Interne, Site Diaconesses Croix St.-Simon, 125, rue d'Avron, 75020 Paris, France; Centre de Référence Maladies Lysosomales, Site Diaconesses Croix St.-Simon, 125, rue d'Avron, 75020 Paris, France.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Ziza
mesh_terms: D000328:Adult; D017677:Age Distribution; D000368:Aged; D018771:Arthralgia / Q000000981:diagnostic imaging / Q000453:epidemiology; D015210:Arthritis, Gouty / Q000175:diagnosis / Q000453:epidemiology; D015331:Cohort Studies; D015897:Comorbidity; D000795:Fabry Disease / Q000175:diagnosis* / Q000453:epidemiology*; D005260:Female; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D009140:Musculoskeletal Diseases / Q000175:diagnosis* / Q000453:epidemiology*; D010003:Osteoarthritis / Q000000981:diagnostic imaging / Q000453:epidemiology; D010024:Osteoporosis / Q000000981:diagnostic imaging / Q000453:epidemiology; D058866:Osteoporotic Fractures / Q000000981:diagnostic imaging / Q000453:epidemiology; D011379:Prognosis; D012189:Retrospective Studies; D018570:Risk Assessment; D012720:Severity of Illness Index; D017678:Sex Distribution; D015996:Survival Rate; D062606:Tertiary Care Centers; D055815:Young Adult
keywords: Acroparesthesia; Charcot foot; Early-onset osteoporosis; Fabry disease; Pain