Published online September 28, 2009
PEDIATRICS Vol. 124 No. 4 October 2009, pp. e721-e728 (doi:10.1542/peds.2009-0088)

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ARTICLE

Differentiating PFAPA Syndrome From Monogenic Periodic Fevers

Marco Gattorno, MD^a,b, Roberta Caorsi, MD^a,b, Antonella Meini, MD^c, Marco Cattalini, MD^c, Silvia Federici, MD^a,b, Francesco Zulian, MD^d, Elisabetta Cortis, MD^e, Giuseppina Calcagno, MD^f, Alberto Tommasini, MD^g, Rita Consolini, MD^h, Gabriele Simonini, MDⁱ, Maria Antonietta Pelagatti, MD^a,b, Maurizia Baldi, PhD^j, Isabella Ceccherini, PhD^k, Alessandro Plebani, MD^c, Joost Frenkel, MD^l, Maria Pia Sormani, PhD^m and Alberto Martini, MD^a,b

^a Pediatric Unit II
^k Laboratory of Molecular Genetics, Giannina Gaslini Institute, Genoa, Italy
^b Department of Pediatrics
^m Biostatistics Unit, Department of Health Sciences, University of Genoa, Genoa, Italy
^c Department of Pediatrics, Pediatric Immunology and Rheumatology Unit, Spedali Civili and University of Brescia, Brescia, Italy
^d Department of Pediatrics, University of Padua, Padua, Italy
^e Department of Medicine, Division of Rheumatology, Pediatric Hospital of the Child Jesus, Rome, Italy
^f Department of Medical and Surgical Pediatric Sciences, Section of Pediatric Rheumatology, Hospital Worker University Gaetano Martino, Messina, Italy
^g Department of Pediatrics, Scientific Institute for Treatment and Research Burlo Garofolo, University of Trieste, Trieste, Italy
^h Department of Reproductive Medicine and Development, University of Pisa, Pisa, Italy
ⁱ Department of Pediatrics, Rheumatology Unit, Anna Meyer Children's Hospital and University of Florence, Florence, Italy
^j Department of Human Genetics, Galliera Hospital, Genoa, Italy
^l Department of General Pediatrics, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, Netherlands

OBJECTIVES: To analyze whether there were clinical differences between genetically positive and negative patients fulfilling periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome criteria and to test the accuracy of the Gaslini diagnostic score for identifying patients with PFAPA syndrome with higher probabilities of carrying relevant mutations in genes associated with periodic fevers.

METHODS: Complete clinical and genetic information was available for 393 children with periodic fever; 82 had positive genetic test results, 75 had incomplete genetic test results, and 236 had negative results for MVK, TNFRSF1A, and MEFV mutations. Current diagnostic criteria for PFAPA syndrome were applied.

RESULTS: Of 393 children, 210 satisfied PFAPA syndrome criteria; 43 carried diagnostic mutations (mevalonate kinase deficiency: n = 33; tumor necrosis factor receptor-associated periodic syndrome: n = 3; familial Mediterranean fever: n = 7), 37 displayed low-penetrance mutations or incomplete genotypes, and 130 demonstrated negative genetic testing results. Genetically positive patients had higher frequencies of abdominal pain and diarrhea (P < .001), vomiting (P = .006), and cutaneous rash and arthralgia (P = .01). Genetically negative patients had a higher frequency of exudative pharyngitis (P = .010). Genetically undetermined patients showed the same pattern of symptom frequency as genetically negative patients. The Gaslini diagnostic score was able to identify 91% of genetically positive patients correctly, with a global accuracy of 66%.

CONCLUSION: The Gaslini diagnostic score represents a useful tool to identify patients meeting PFAPA syndrome criteria and at low risk of carrying relevant mutations in genes associated with periodic fevers.

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Key Words: periodic fever • aphthous stomatitis • pharyngitis • and cervical adenitis syndrome • classification • diagnostic score • molecular analysis

Abbreviations: PFAPA—periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis • FMF—familial Mediterranean fever • TNF—tumor necrosis factor • TRAPS—tumor necrosis factor receptor-associated periodic syndrome • MKD—mevalonate kinase deficiency

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Accepted May 29, 2009.

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