title: The impact of fever/hyperthermia in the diagnosis of Fabry: A retrospective analysis.
abstract: BACKGROUND
  Fabry disease (FD) is an X-linked lysosomal storage disorder caused by a deficiency of alpha-galactosidase A enzyme, which leads to the accumulation of its substrate, the globotriaosylceramide or Gb3, in many organs and tissues. Main clinical manifestations of FD are neuropathic pain, angiokeratomas, proteinuria and renal failure, left ventricular hypertrophy and stroke. Fever is also a possible symptom at the onset of the disease during childhood and adolescence, but it is frequently misdiagnosed, causing a delay in FD diagnosis.
  
  
  METHODS
  We retrospectively analysed the medical records in our series of 58 Fabry patients, focusing on the proportion of patients who exhibited fever as the main symptom at the onset of FD in order to evaluate the diagnostic delay in these patients.
  
  
  RESULTS
  In our series, we found a significant proportion of patients with a history of fevers at the beginning of their medical history (20.7%; 12/58). 83% of patients with fever also exhibited acroparesthesias (10/12). Inflammatory markers were elevated in few of those cases (2/12). The mean diagnostic delay was 15.6±SD 12.8years.
  
  
  CONCLUSIONS
  Fever emerged to be common as part of the FD clinical spectrum and it significantly contributed to the diagnostic delay encountered with this rare disease. Furthermore, our retrospective analysis indicated that FD patients commonly exhibit episodes of fever in association with other symptoms suggestive of FD (such as episodic pain crisis, acroparesthesias, hypo/anhydrosis, heat intolerance, fatigue and gastrointestinal distress). A careful analysis of the medical history in patients suffering fever could lead to an early and correct FD diagnosis. We believe that fever/hyperthermia, acroparesthesias and angiokeratoma should be considered for inclusion in the algorithm for Intermittent Fever of Unknown Origin (FUO) in order to improve the recognition of FD.
authors.affiliation: Periodic Fever Research Centre, A. Gemelli Policlinic, Catholic University of the Sacred Heart, Rome, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Verrecchia
authors.affiliation: Department of Dermatology Saint Mary's Hospital, Imperial College NHS Trust, London, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Zampetti
authors.affiliation: Department of Paediatric Sciences, A. Gemelli Policlinic, Rome, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Antuzzi
authors.affiliation: Department of Paediatric Sciences, A. Gemelli Policlinic, Rome, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Ricci
authors.affiliation: Laboratory for Molecular and Cell Biology of Neurologic and Metabolic Disorders, Paediatric Neurology Unit and Laboratories, Meyer Children's Hospital, Florence, Italy; Department of NEUROFARBA, University of Florence, Florence, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Ferri
authors.affiliation: Laboratory for Molecular and Cell Biology of Neurologic and Metabolic Disorders, Paediatric Neurology Unit and Laboratories, Meyer Children's Hospital, Florence, Italy; Department of NEUROFARBA, University of Florence, Florence, Italy.
authors.forename: Amelia
authors.initials: A
authors.lastname: Morrone
authors.affiliation: Department of Dermatology, University of Parma, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Feliciani
authors.affiliation: Vita-Salute San Raffaele University, Milan, Italy; Unit of Medicine and Clinical Immunology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Dagna
authors.affiliation: Periodic Fever Research Centre, A. Gemelli Policlinic, Catholic University of the Sacred Heart, Rome, Italy. Electronic address: raffaele.manna@policlinicogemelli.it.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Manna
mesh_terms: D000794:Angiokeratoma / Q000209:etiology*; D002648:Child; D002675:Child, Preschool; D057210:Delayed Diagnosis; D003967:Diarrhea / Q000209:etiology; D004415:Dyspepsia / Q000209:etiology; D000795:Fabry Disease / Q000150:complications* / Q000175:diagnosis; D005221:Fatigue / Q000209:etiology; D005260:Female; D005335:Fever of Unknown Origin / Q000209:etiology*; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000209:etiology; D007007:Hypohidrosis / Q000209:etiology; D008297:Male; D010292:Paresthesia / Q000209:etiology*; D012189:Retrospective Studies; D012878:Skin Neoplasms / Q000209:etiology*
keywords: Early onset; Fabry disease; Fever; Fever of unknown origin