Next-generation screening of a panel of genes associated with periodic fever syndromes in patients with Familial Mediterranean Fever and their clinical characteristics

Autoinflammatory diseases (AIDs) represent a rare and heterogeneous group of disorders characterized by recurrent episodes of inflammation and a broad range of clinical manifestations. The most common symptoms involve recurrent fevers, musculoskeletal symptoms, and serositis; however, AIDs can also lead to life-threatening complications, such as macrophage activation syndrome (MAS) and systemic AA amyloidosis. Typical monogenic periodic fever syndromes include cryopyrin-associated periodic fever syndrome (CAPS), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency/hyper IgD syndrome (MKD/HIDS), and familial Mediterranean fever (FMF). However, a number of other clinical entities, such as systemic juvenile idiopathic arthritis (sJIA), adult-onset Still’s disease (AOSD), Kawasaki disease (KD) and idiopathic recurrent pericarditis (IRP), display similar phenotypical and immunological features to AIDs. All these diseases are pathophysiologicaly characterized by dysregulation of the innate immune system and the central pathogenic role is attributed to the IL-1 cytokine family (IL-1α, IL-1β, IL-1Ra, IL-18, IL-36Ra, IL-36α, IL-37, IL-36β, IL-36g, IL-38, and IL-33). Therefore, reasonable therapeutic approaches aim to inhibit these cytokines and their pathways. To date, several anti-IL-1 therapies have evolved. Each drug differs in structure, mechanism of action, efficacy for the treatment of selected diseases, and side effects. Most of the available data regarding the efficacy and safety of IL-1 inhibitors are related to anakinra, canakinumab, and rilonacept. Other promising therapeutics, such as gevokizumab, tadekinig alfa, and tranilast are currently undergoing clinical trials. In this review, we provide sophisticated and up-to-date insight into the therapeutic uses of different IL-1 inhibitors in monogenic periodic fever syndromes.

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Periodic fever syndromes: a patient diagnosed with recurrent Kawasaki disease

Cardiology in the Young ◽

10.1017/s1047951120001444 ◽

2020 ◽

Vol 30 (7) ◽

pp. 1009-1011

Author(s):

Sena Turk ◽

Derya Aydin ◽

Eser Dogan ◽

Erturk Levent ◽

Necil Kutukculer

Keyword(s):

Kawasaki Disease ◽

Periodic Fever ◽

Periodic Fever Syndromes ◽

System Disease ◽

Rheumatologic Diseases ◽

Coronary Artery Involvement ◽

Fever Syndromes ◽

Mediterranean Fever ◽

Systemic Onset ◽

Children Under 5

AbstractKawasaki disease, known as mucocutaneous lymph node syndrome, is a multi-system disease of unknown aetiology that occurs in young children under 5 years of age. The recurrence rate of Kawasaki disease is as rare as 1–3%. Especially in cases with coronary artery involvement, recurrent Kawasaki disease should be investigated in terms of underlying rheumatologic diseases such as periodic fever syndromes, microscopic polyangiitis, polyarteritis nodosa, and systemic-onset juvenile arthritis. In this study, we report homozygote mutations in mevalonate kinase and familial Mediterranean fever genes in a recurrent Kawasaki disease with coronary dilatation.

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Pathogenesis of familial periodic fever syndromes or hereditary autoinflammatory syndromes

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00504.2006 ◽

2007 ◽

Vol 292 (1) ◽

pp. R86-R98 ◽

Cited By ~ 92

Author(s):

Anna Simon ◽

Jos W. M. van der Meer

Keyword(s):

Periodic Fever ◽

Innate Immune ◽

Tnf Receptor ◽

Inherited Disorders ◽

Autoinflammatory Syndromes ◽

General Hypothesis ◽

Periodic Fever Syndromes ◽

Fever Syndromes ◽

Mediterranean Fever ◽

Pyogenic Arthritis

Familial periodic fever syndromes, otherwise known as hereditary autoinflammatory syndromes, are inherited disorders characterized by recurrent episodes of fever and inflammation. The general hypothesis is that the innate immune response in these patients is wrongly tuned, being either too sensitive to very minor stimuli or turned off too late. The genetic background of the major familial periodic fever syndromes has been unraveled, and through research into the pathophysiology, a clearer picture of the innate immune system is emerging. After an introduction on fever, interleukin-1β and inflammasomes, which are involved in the majority of these diseases, this manuscript offers a detailed review of the pathophysiology of the cryopyrin-associated periodic syndromes, familial Mediterranean fever, the syndrome of pyogenic arthritis, pyoderma gangrenosum and acne, Blau syndrome, TNF-receptor-associated periodic syndrome and hyper-IgD and periodic fever syndrome. Despite recent major advances, there are still many questions to be answered regarding the pathogenesis of these disorders.

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

Case Reports in Pediatrics ◽

10.1155/2021/6650226 ◽

2021 ◽

Vol 2021 ◽

pp. 1-6

Author(s):

Tomonobu Sato ◽

Shunichiro Takezaki ◽

Takeru Goto ◽

Shinichi Ishikawa ◽

Kazumi Oura ◽

...

Keyword(s):

Familial Mediterranean Fever ◽

Periodic Fever ◽

Mefv Gene ◽

Colchicine Treatment ◽

Clinical Findings ◽

Hereditary Periodic Fever ◽

Fever Syndromes ◽

Mediterranean Fever ◽

Accompanying Symptoms

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.

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Le sindromi autoinfiammatorie: quando non è solo PFAPA

Medico e Bambino ◽

10.53126/meb40221 ◽

2021 ◽

Vol 40 (4) ◽

pp. 221-225

Author(s):

ALBERTO TOMMASINI ◽

LOREDANA LEPORE

Keyword(s):

Periodic Fever ◽

Mevalonate Kinase Deficiency ◽

Inflammatory Disorder ◽

Mevalonate Kinase ◽

Red Flags ◽

Periodic Fever Syndromes ◽

Hereditary Periodic Fever Syndromes ◽

Hereditary Periodic Fever ◽

Fever Syndromes ◽

Mediterranean Fever

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.

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Familial Mediterranean Gene (MEFV) Mutation in Parents of Children with Familial Mediterranean Fever: What Are the Exceptions?

International Journal of Inflammation ◽

10.1155/2018/1902791 ◽

2018 ◽

Vol 2018 ◽

pp. 1-6 ◽

Cited By ~ 1

Author(s):

Leila Shahbaznejad ◽

Sayed-Reza Raeeskarami ◽

Raheleh Assari ◽

Abbas Shakoori ◽

Hamidreza Azhideh ◽

...

Keyword(s):

Familial Mediterranean Fever ◽

Periodic Fever ◽

Mefv Gene ◽

Cross Sectional Study ◽

Compound Heterozygote ◽

Mefv Mutation ◽

Cross Sectional ◽

Fever Syndromes ◽

History Of ◽

Mediterranean Fever

Objectives. Familial Mediterranean Fever (FMF) is one of the most prevalent periodic fever syndromes; MEFV, the responsible gene for the disease, is in the short arm of chromosome16. In the considerable count of the FMF patients, only one mutation is found in the MEFV and parents, who were the obligatory carriers for that mutation, were asymptomatic. The aim of this study was to evaluate these asymptomatic parents in regard to mutation in MEFV gene and similarity between parents and offspring patients. Methods. In this cross-sectional study, asymptomatic parents of FMF patients enrolled the study were referred to periodic fever clinic or pediatric rheumatology clinic of Tehran University of Medical Sciences. The patients should have at least one mutation in MEFV gene and none of them had any family history of autoinflammatory disease. Twelve mutations in MEFV gene were assessed in the parents by Vienna Lab FMF Strip Assay kit by MAS PCR/Reverse hybridization. Results. Forty-three patients and their parents participated in the study. Sixty-three percent (27) of patients were male. Onset of disease symptoms in 31 patients (72%) was before 4 years of old. Nine (21%) of the patients had homozygote, 16 (37%) compound heterozygote, and 17(40%) heterozygote for MEFV mutation; there was a case of complex alleles mutations (2%). M694V/M694V in 4 patients (9%) was the most homozygote genotype, and M694V/R761H in 4 (9%) and E148Q in 7 (16%) were the most compound heterozygote and heterozygote genotype, respectively. M694V, M680I, and E148Q were the most mutation in the parents. Overall, 41 patients had mutations similar to their parents’ mutation, except 2 whose parents had no mutation, but a patient did. Conclusion. It seems that occurrence of new mutations in offspring is not prevalent among FMF patients and there are other reasons for different clinical presentation in similar mutation carriers. On the other hand, in ethnicities with high prevalence of FMF, new mutation in descendant may occur, infrequently.

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Familial Periodic Fever Syndromes Erupt on Skin

Skin & Allergy News ◽

10.1016/s0037-6337(07)70719-2 ◽

2007 ◽

Vol 38 (9) ◽

pp. 36-37

Author(s):

HEIDI SPLETE

Keyword(s):

Periodic Fever ◽

Periodic Fever Syndromes ◽

Fever Syndromes

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