Le sindromi autoinfiammatorie: quando non è solo PFAPA

PFAPA (Periodic Fever, Aphthous Stomatitis, Pharyngitis and Adenitis) is the most common self-inflammatory disorder in children. The diagnosis of PFAPA is easy, based on Thomas criteria, and the prognosis is good. Differential diagnosis with hereditary periodic fever syndromes (Familial Mediterranean Fever, Mevalonate Kinase Deficiency, TRAPS and CAPS) should be considered only in the presence of red flags such as early onset, severe abdominal complaints, arthritis and severe rashes. Some patients may present distinct clinical entities with periodic fevers that neither meet PFAPA criteria nor hereditary periodic fever syndromes genotypes. Subjects with these “Undifferentiated Periodic Fever” may respond to glucocorticoids or colchicines or to anakinra in the most severe cases and still have an undetermined prognosis.

Atypical Familial Mediterranean Fever in a Japanese Boy with Heterozygous MEFV p.Ser503Cys Exon 5 Variant

Periodic fever syndromes are heterogeneous diseases. Familial Mediterranean fever (FMF) is one of the hereditary periodic fever diseases caused by a Mediterranean fever (MEFV) gene abnormality. FMF can be categorized as typical or atypical, based on clinical findings and genetic screening. Atypical FMF has a wide variation of clinical findings and disease-causing mutations of MEFV. Therefore, it is sometimes difficult to diagnose an unknown fever as FMF. To date, a large number of various typical and atypical FMF cases have been reported in Japan. Here, we describe a Japanese boy with heterozygous MEFV p.Ser503Cys exon 5 variant who developed periodic fever. He was treated with colchicine; a complete eradication of his fever and various accompanying symptoms have been subsequently achieved for more than a year. Given that there have been a few reports about patients with this variant, little is known about the genetic and phenotypic role of heterozygous MEFV p.Ser503Cys exon 5 variant. It is therefore imperative to consider atypical FMF as a differential diagnosis when a periodic fever is encountered. Furthermore, we suggest that it is worthwhile to integrate MEFV gene analysis with the potential effects of colchicine treatment in patients with periodic fever.

AB1069 CONSIDERATION OF YAO SYNDROME AS A DIFFERENTIAL DIAGNOSIS FOR HEREDITARY PERIODIC FEVER SYNDROMES

Background:Yao syndrome (YAOS, OMIM 617321), formerly termed nucleotide-binding oligomerization domain 2(NOD2)-associated autoinflammatory disease, is characterized by periodic fever, dermatitis, arthritis, and swelling of the distal extremities, as well as gastrointestinal and sicca-like symptoms. This disorder shares similar clinical phenotypes with hereditary periodic fever syndromes (HPFS) and thus can mimic one another.Objectives:This study aimed to exemplify by a comparison of YAOS vs familial Mediterranean fever (FMF).Methods:In this retrospective study, electronic medical records of a series of patients with YAOS were analyzed. All patients underwent genetic testing for periodic fever syndrome 6-gene panel (MEFV, TNFRSF1A, NLRP3, MVK, NLRP12 and NOD2).Results:All patients were Caucasian and had recurrent fever, patchy erythema, arthralgia, and gastrointestinal symptoms (Table 1). With negative DNA sequencing for MEFV, these patients were treated with colchicine for presumed FMF, with a good response in patient 2 and minimal or transient response in other two patients. Further genetic testing identified the NOD2 variants. Unlike HPFS, YAOS is generally sporadic and is mostly reported in adults; spongiotic dermatitis is common; YAOS is associated with the NOD2 variants, IVS8 + 158 in nearly all patients, IVS8 + 158/R702W in up to 30%, and IVS8 + 158/1007fs, G908R or other rarer NOD2 variants in some patients.Conclusion:YAOS can masquerade HPFS like FMF. Molecular analysis should cover NOD2 whole gene sequencing to help distinguish these diseases.References:[1]Yao Q, et al. Dermatitis as a characteristic phenotype of a new autoinflammatory disease associated with NOD2 mutations. J Am Acad Dermatol. 2013;68(4):624-31.Trueb B, et al. Coincidence of NOD2-Associated Autoinflammatory Disease (Yao Syndrome) and HCV Infection With Fatal Consequences: Interaction Between Genes and Environment. J Clin Rheumatol. 2018 Dec 28. doi: 10.1097/RHU.0000000000000963. [Epub ahead of print].China[2]Yao Q. Research letter: Effectiveness of canakinumab for the treatment of Yao syndrome patients. J Am Acad Dermatol. 2019.[3]Yao Q, Shen M, McDonald C, Lacbawan F, Moran R, Shen B. NOD2-associated autoinflammatory disease: a large cohort study. Rheumatology (Oxford). 2015;54(10):1904-12.[4]Yao Q, Shen B. A Systematic Analysis of Treatment and Outcomes of NOD2-Associated Autoinflammatory Disease. Am J Med. 2017;130(3):365 e13- e18.[5]McDonald C, et al. Alterations in nucleotide-binding oligomerization domain-2 expression, pathway activation, and cytokine production in Yao syndrome. Autoimmunity. 2018;51(2):53-61.Acknowledgments:The author is thankful to the statistician, Ms. Erin Taub for her help with making the table.Disclosure of Interests:None declared

Hereditary periodic fever syndromes

The hereditary periodic fever syndromes or hereditary autoinflammatory diseases are disorders of innate immunity that mostly present in childhood and are characterized by recurrent, self-limiting, seemingly unprovoked episodes of fever and systemic inflammation that occur in the absence of autoantibody production or identifiable infection. Disorders include (1) familial Mediterranean fever (FMF), due to mutations in the gene encoding pyrin; (2) tumour necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS), due to mutations in a gene for a TNF receptor; (3) mevalonate kinase deficiency and period fever (MKD), caused by mutations in the mevalonate kinase gene; and (4) the cryopyrin-associated periodic syndromes (CAPS), which include (a) familial cold urticarial syndrome, (b) Muckle–Wells syndrome, and (c) chronic infantile neurological, cutaneous, and articular syndrome. With advances in genetics, further syndromes are continually being recognized. These are all extremely rare and in the majority are only known to affect a handful of kindred or individuals. Diagnosis relies on recognition of suggestive clinical features that are almost always accompanied by a substantial acute phase response, and is supported by genetic testing. With the exception of FMF, which is a common disease in certain geographic areas, hereditary periodic fever syndromes are rare and easily overlooked in the differential diagnosis of recurrent fevers. Clinical features and management—attacks can be mild to debilitating and short to prolonged, while their most feared complication is AA amyloidosis. Effective therapies are available for some syndromes, for example: (1) FMF—daily prophylactic colchicine prevents clinical attacks and susceptibility to AA amyloidosis, (2) CAPS—treatment with anti-IL-1 agents produces rapid and often complete clinical and serological remission, and (3) TRAPS—anti-IL therapies are extremely effective.