Abstract
Fever of unknown origin (FUO) is a rather rare clinical syndrome representing a major diagnostic challenge. The occurrence of more than three febrile attacks with fever-free intervals of variable duration during 6 months of observation has recently been proposed as a subcategory of FUO, Recurrent FUO (RFUO). A substantial number of patients with RFUO have auto-inflammatory genetic fevers, but many patients remain undiagnosed. We hypothesize that this undiagnosed subgroup may be comprised of, at least in part, a number of rare genetic febrile diseases such as Fabry disease. We aimed to identify key features or potential diagnostic clues for Fabry disease as a model of rare genetic febrile diseases causing RFUO, and to develop diagnostic guidelines for RFUO, using Fabry disease as an example of inserting other rare diseases in the existing FUO algorithms. An international panel of specialists in recurrent fevers and rare diseases, including internists, infectious disease specialists, rheumatologists, gastroenterologists, nephrologists, and medical geneticists convened to review the existing diagnostic algorithms, and to suggest recommendations for arriving at accurate diagnoses on the basis of available literature and clinical experience. By combining specific features of rare diseases with other diagnostic considerations, guidelines have been designed to raise awareness and identify rare diseases among other causes of FUO. The proposed guidelines may be useful for the inclusion of rare diseases in the diagnostic algorithms for FUO. A wide spectrum of patients will be needed to validate the algorithm in different clinical settings.
Similar content being viewed by others
Abbreviations
- α-GAL:
-
α-Galactosidase enzyme
- CAPS:
-
Cryopyrin-associated periodic syndrome
- CRP:
-
C-reactive protein
- FCAS:
-
Familial cold urticaria (or familial cold auto-inflammatory syndrome
- FD:
-
Fabry disease
- FDG-PET:
-
Fluorodeoxyglucose-positron emission tomography
- FMF:
-
Familial Mediterranean fever
- FUO:
-
Fever of unknown origin
- HIDS:
-
Hyper IgD syndrome
- IPRAFUO:
-
International Panel for RAre recurrent FUO
- LSDs:
-
Lysosomal storage disorders
- MKD:
-
Mevalonate kinase deficiency
- NOMID:
-
Neonatal onset multisystem inflammatory disease or chronic infantile neurologic, cutaneous, and articular syndrome
- PDC:
-
Potential diagnostic clues
- PFAPA:
-
Periodic fever, aphthous stomatitis, pharyngitis (cervical) adenitis
- RFUO:
-
Recurrent fever of unknown origin
- SAA:
-
Serum amyloid A
- TIA:
-
Transient ischemic attack
- TRAPS:
-
Tumor necrosis factor receptor-1-associated periodic syndrome
References
Petersdorf RG, Beeson PB (1961) Fever of unexplained origin: report on 100 cases. Medicine (Baltimore) 40:1–30
Durack DT, Street AC (1991) Fever of unknown origin—re-examined and redefined. Curr Clin Top Infect Dis 11:35–51
Knockaert DC, Vanderschueren S, Blockmans D (2003) Fever of unknown origin in adults: 40 years on. J Intern Med 253(3):263–275
Knockaert DC (2007) Recurrent fevers of unknown origin. Infect Dis Clin N Am 21:1189–1211
Knockaert DC, Vanneste LJ, Bobbaers HJ (1993) Recurrent or episodic fever of unknown origin: review of 45 cases and survey of the literature. Medicine 72(3):184–196
Baldovino S, Moliner AM, Taruscio D, Daina E, Roccatello D (2016) Rare diseases in Europe: from a wide to a local perspective. Isr Med Assoc J 18(6):359–363
Chao CT, Yang CC, Kao TW (2012) Fabry disease: a rare cause of fever of unknown origin. Am J Kidney Dis 59(1):161–162
Marchesoni CL, Roa N, Pardal AM, Neumann P, Cáceres G, Martínez P, Kisinovsky I, Bianchi S, Tarabuso AL, Reisin RC (2010) Misdiagnosis in Fabry disease. J Pediatr 156(5):828–831
Lidove O, Kaminsky P, Hachulla E, Leguy-Seguin V, Lavigne C, Marie I, Maillot F, Serratrice C, Masseau A, Chérin P, Cabane J (2012) Noel E; FIMeD investigators. Fabry disease ‘The New Great Imposter’: results of the French Observatoire in Internal Medicine Departments (FIMeD). Clin Genet 81(6):571–577
Verrecchia E, Zampetti A, Antuzzi D, Ricci R, Ferri L, Morrone A, Feliciani C, Dagna L, Manna R (2016) The impact of fever/hyperthermia in the diagnosis of Fabry: a retrospective analysis. Eur J Intern Med 32:26–30
Mehta A, Hughes DA (2002) Fabry Disease. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, Bird TD, Ledbetter N, Mefford HC, Smith RJH, Stephens K (eds) GeneReviews® [Internet]. University of Washington, Seattle; 1993–2017 (updated 2017 Jan 5)
Schiffmann R, Ries M (2016) Fabry disease: a disorder of childhood onset. Pediatr Neurol 64:10–20
Seydelmann N, Wanner C, Störk S, Ertl G (2015) Weidemann F Fabry disease and the heart. Best Pract Res Clin Endocrinol Metab 29(2):195–204
van der Tol L, Smid BE, Poorthuis BJ, Biegstraaten M, Deprez RH, Linthorst GE et al (2014) A systematic review on screening for Fabry disease: prevalence of individuals with genetic variants of unknown significance. J Med Genet 51:1–9
Reisin R, Perrin A, García-Pavía P (2017) Time delays in the diagnosis and treatment of Fabry disease. Int J Clin Pract 71(1). doi:10.1111/ijcp.12914
Thomas AS, Mehta AB (2013) Difficulties and barriers in diagnosing Fabry disease: what can be learnt from the literature? Expert Opin Med Diagn 7(6):589–599
Tabak F, Mert A, Celik AD, Ozaras R, Altiparmak MR, Ozturk R, Aktuglu Y (2003) Fever of unknown origin in Turkey. Infection 31(6):417–420
Bleeker-Rovers CP, Vos FJ, de Kleijn EM, Mudde AH, Dofferhoff TS, Richter C, Smilde TJ, Krabbe PF, Oyen WJ, van der Meer JW (2007) A prospective multicenter study on fever of unknown origin: the yield of a structured diagnostic protocol. Medicine (Baltimore) 86(1):26–38
Nicolotti N, Cattel C, Gualano M, Soriano A, Manna R, Boccia S (2013) A retrospective analysis of 3156 admissions with fever of unknown origin in a large Italian hospital. Epidemiology, Biostatistics and Public Health. (Dicembre): pe8776-1-pe8776-7 (Available at: ebph.it/article/download/8776/8221)
Wolf H, Graninger W (2003) Cost-effectiveness in diagnosis of patients with long-standing fever. Wien Med Wochenschr 153(9–10):202–207
Pisani A, Visciano B, Imbriaco M, Di Nuzzi A, Mancini A, Marchetiello C, Riccio E (2014) The kidney in Fabry’s disease. Clin Genet 86(4):301–309
Mignani R, Gallieni M, Feriozzi S, Pisani A, Marziliano N, Morrone A (2015) The nephropathy in the Anderson–Fabry disease: new recommendations for the diagnosis, the follow-up and the therapy. G Ital Nefrol 32(4)
Debette S, Germain DP (2014) Neurologic manifestations of inherited disorders of connective tissue. Handb Clin Neurol 119:565–576
Biegstraaten M, Linthorst GE, van Schaik IN, Hollak CE (2013) Fabry disease: a rare cause of neuropathic pain. Curr Pain Headache Rep 17(10):365
Davey PG (2014) Fabry disease: a survey of visual and ocular symptoms. Clin Ophthalmol 8:1555–1560
Hagège AA, Germain DP (2015) Adult patients with Fabry disease: what does the cardiologist need to know? Heart 101(12):916–918
Zampetti A, Orteu CH, Antuzzi D, Bongiorno MR, Manco S, Gnarra M, Morrone A, Cardinali G, Kovacs D, Aspite N, Linder D, Parini R (2012) Feliciani C; Interdisciplinary Study Group on Fabry Disease (ISGF). Angiokeratoma: decision-making aid for the diagnosis of Fabry disease. Br J Dermatol 166(4):712–720
Germain DP (2010) Fabry disease. Orphanet J Rare Dis 5:30
Morrone A, Cavicchi C, Bardelli T, Antuzzi D, Parini R, Di Rocco M, Feriozzi S, Gabrielli O, Barone R, Pistone G, Spisni C, Ricci R, Zammarchi E (2003) Fabry disease: molecular studies in Italian patients and X inactivation analysis in manifesting carriers. J Med Genet 40(8):e103
Echevarria L, Benistan K, Toussaint A, Dubourg O, Hagege AA, Eladari D, Jabbour F, Beldjord C, De Mazancourt P, Germain DP (2016) X-chromosome inactivation in female patients with Fabry disease. Clin Genet 89(1):44–54
Acknowledgements
The authors wish to thank Sanofi Genzyme, and particularly Cecilia Traversa, for the support offered in organizing the meeting of the board. The Board coordinator, with Genzyme medical direction, selected the participants based on objective clinical experience criteria and a number of scientific publications related to FUO and Fabry disease in national and international journals.
Author information
Authors and Affiliations
Consortia
Contributions
RM conceived of the study, and participated in its design and coordination and helped to draft the manuscript. AV participated in the design of study, helped to draft the manuscript and revised it. EV, RC, SF, GG, AG, DL, AM, HO, AP, ER and LD participated in the design of study, and helped to draft the manuscript. All authors read and approved the final manuscript.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Statement of human and animal rights
This article does not contains any study with human participants or animals performed by any of the authors.
Informed consent
None.
Appendix
Appendix
Rights and permissions
About this article
Cite this article
Manna, R., Cauda, R., Feriozzi, S. et al. Recommendations for the inclusion of Fabry disease as a rare febrile condition in existing algorithms for fever of unknown origin. Intern Emerg Med 12, 1059–1067 (2017). https://doi.org/10.1007/s11739-017-1704-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11739-017-1704-y