Periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis syndrome in children: a brief literature review / Síndrome da febre periódica, estomatite aftosa, faringite e adenite em crianças: uma breve revisão de literatura

ABSTRACT Objective: To describe clinical, diagnostic and therapeutic characteristics of the periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome. Data source: Literature review in the PubMed database by using specific descriptors to identify all articles published in the English language in the last three years; 38 articles were found. After performing selection of titles and abstract analysis, 13 out of the 38 articles were fully read. Relevant studies found in the references of the reviewed articles were also included. Data synthesis: The PFAPA syndrome (Periodic Fever, Aphthous Stomatitis, Pharyngitis and cervical Adenitis) is a medical condition grouped among the periodic fever syndromes. The etiology is uncertain, but possibly multifactorial, and its symptoms are accompanied by recurrent febrile episodes although weight and height development are preserved. It is a self-limiting disease of benign course with remission of two to three years without significant interference in the patient's overall development. Treatment consists of three pillars: interruption of febrile episodes, increase in the interval between episodes, and remission. Conclusions: Despite several attempts to establish more sensitive and specific criteria, the diagnosis of PFAPA syndrome is still clinical and reached by exclusion, based on the modified Marshall's criteria. The most common pharmacological options for treatment include prednisolone and betamethasone; colchicine may be used as prophylaxis, and surgical treatment with tonsillectomy can be considered in selected cases.

RESUMO Objetivo: Descrever as características clínicas, diagnósticas e de tratamento da síndrome de febre periódica, estomatite aftosa, faringite e adenite (PFAPA). Fontes de dados: Revisão de literatura na base de dados PubMed, feita por meio de descritores específicos para identificar todos os artigos publicados em língua inglesa nos últimos três anos. Dos 38 artigos encontrados, foram encaminhados para leitura integral 13 publicações após seleção de títulos e análise de abstract. Estudos relevantes encontrados nas referências dos artigos revisados também foram incluídos. Síntese dos dados: A PFAPA é traduzida do inglês periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis. Caracterizada por etiologia ainda incerta e possivelmente multifatorial, seus sintomas são acompanhados por episódios recorrentes de febre associados a um desenvolvimento pôndero-estatural preservado. É uma doença autolimitada de curso benigno, com remissão em dois a três anos, sem interferências significativas no desenvolvimento do paciente pediátrico. O tratamento consiste em três pilares: interrupção da crise febril, aumento do intervalo entre crises e remissão. Conclusões: Apesar de várias tentativas de estabelecer critérios atuais mais sensíveis e específicos, o diagnóstico da síndrome PFAPA ainda é clínico e de exclusão com base nos critérios de Marshall modificados. As opções farmacológicas mais utilizadas para o tratamento são a prednisolona e betametasona; colchicina pode ser utilizada como profilaxia e o tratamento cirúrgico com tonsilectomia pode ser considerado em casos selecionados.

O estado da arte das síndromes autoinflamatórias associadas à criopirina / The state of the art of cryopyrin-associated periodic syndromes

As síndromes autoinflamatórias associadas à criopirina (CAPS) compreendem um grupo espectral de doenças raras autoinflamatórias. Todas estas doenças estão relacionadas ao inflamassoma NLRP3, sendo que de 50-60% dos pacientes apresentam mutações ao longo do gene NLRP3. Clinicamente, febre recorrente associada à urticária neutrofílica e outros sintomas sistêmicos são o grande marco clínico, comum a todo o espectro. O bloqueio da interleucina-1 trouxe grande alívio ao tratamento destas desordens, mas variações na resposta clínica podem ser observadas, principalmente nos espectros mais graves. Neste trabalho os autores trazem uma revisão do estado da arte das doenças autoinflamatórias CAPS. Foi realizado levantamento de literatura e, ao final, 49 artigos restaram como base para construção do texto final. O trabalho traz de forma narrativa os principais pontos relacionados a imunofisiopatologia, manifestação clínica, diagnóstico, tratamento, complicações e novas armas diagnósticas, e terapia gênica.

Cryopyrin-associated periodic syndromes (CAPS) comprise a spectrum of rare autoinflammatory disorders. They are all related to the NLRP3 inflammasome, and 50-60% of the patients harbor mutations along the NLRP3 gene. Clinically, recurrent fever associated with neutrophilic urticaria and other systemic symptoms are a hallmark of all the disorders in the spectrum. Biologic drugs that can block interleukin-1 were a milestone for the treatment of such rare diseases, although variability in clinical response to this therapeutic intervention were observed, especially in those affected by severe phenotypes. In this paper, the authors provide a state-of-the-art review of CAPS. A literature search was performed and, finally, 49 articles remained for the construction of the final manuscript. The article presents a narrative review focused on the topics related to immune pathophysiology, clinical manifestations, diagnosis, treatment, complications and new therapeutic options, and gene therapy.

Atualizando e expandindo o universo de: "Uma nova classe de doenças ­ doenças autoinflamatórias" / Updating and expanding the universe of: "A new class of diseases ­ autoinflammatory disorders"

As síndromes autoinflamatórias são doenças raras, genéticas de envolvimento prioritário da imunidade inata. Avanços nas técnicas de sequenciamento genético permitiram dissecar os genes envolvidos nestas doenças, continuamente organizando o quebra-cabeça genético e fisiopatológico de tais desordens. Este artigo revisa os últimos achados genéticos com seus respectivos fenótipos, código OMIM e ORPHA. Além disso, sugere cautela na triagem clínica e na indicação de métodos restritivos de sequenciamentos genéticos.

Autoinflammatory diseases comprise a group of rare, genetic disorders with priority involvement of innate immunity. Advances in genetic sequencing techniques allowed genetic dissection of genes involved in these diseases, with continuous organization of the genetic and pathophysiologic puzzle of these disorders. This article reviews the most recent genetic findings linked to respective phenotypes and OMIM and ORPHA codes. Moreover, it suggests caution in clinical screening and genetic sequencing indication with restrictive genetic panels.

Síndrome de Hiper IgD: espectros clínicos, achados genéticos e condutas terapêuticas / Hyper-IgD syndrome: clinical spectrum, genetic findings, and therapeutic approaches

A deficiência de mevalonato quinase (MVK; MIM #142680; ORPHA #343) é uma doença genética, espectral, rara, associadas a mutações ao longo do gene MVK causando distúrbios na síntese do colesterol, que culminam em: inflamação sistêmica com febre, adenopatia, sintomas abdominais e outros achados clínicos. Enquanto no polo leve da doença os achados mais comuns são febres recorrentes com linfadenopatia, no polo mais grave adiciona-se o acometimento do sistema nervoso central (meningites assépticas, vasculites e atraso do desenvolvimento neuropsicomotor) e do sistema hematopoiético (síndrome de ativação macrofágica). Apesar de inúmeras terapêuticas, os bloqueadores da interleucina-1 ainda são os únicos medicamentos capazes de controlar a doença e de impedir a evolução para amiloidose. Os estudos atuais visam tentar novos tratamentos, como o transplante de células-tronco hematopoiéticas, ou mesmo a terapia gênica.

Mevalonate kinase deficiency (MVK; MIM #142680; ORPHA #343) is a rare spectral genetic disorder linked to mutations along the MVK gene leading to impaired cholesterol synthesis, clinically observed as systemic inflammation with fever, adenopathy, abdominal manifestations, and other clinical findings. While on mild forms recurrent fever with lymphadenopathy is commonly observed, severe forms add to that neurological (aseptic meningitis, vasculitis, and neuropsychomotor developmental delay) and hematopoietic involvement (macrophage activation syndrome). Despite of several therapeutic approaches, blocking interleukin-1 is the only effective method to control the disease and prevent the development of systemic amyloidosis. Ongoing studies aim to test new treatments, such as hematopoietic stem cell transplantation and gene therapy.

A report of clinical characteristics of 2 Chinese pedigrees with haploinsufficiency of A20 and literature review / 中华儿科杂志

Objective@#To summarize the clinical characteristics of patients with haploinsufficiency of A20 (HA20).@*Methods@#The clinical manifestations, laboratory examinations, treatment, outcome and genetic analysis of 4 cases with HA20 hospitalized in Peking Union Medical College Hospital were analysed.Further literature review was done after searching articles in PubMed and Wangfang databases with the key words "HA20" "A20 haploinsufficiency" "TNFAIP3" up to the date of September 2019.@*Results@#The 4 patients were a father and a daughter, as well as a mother and a daughter. Their phenotypes were quite variable, but all of them have been suffering from recurrent oral ulcer since childhood. Elevation of C-reactive protein (13-33 mg/L) and erythrocyte sedimentation rate (21-60 mm/1h) were found in these 4 patients, and there was positive antinuclear antibody in proband 1.The father in pedigree 1 and the 2 patients in pedigrees 2 have been diagnosed with Behçet disease and the proband 1 with undifferentiated connective tissue disease. The 2 patients in pedigree 1 have developed Hashimoto′s thyroiditis. After gene sequencing analysis, it was found that all the 4 patients have heterozygous nonsense mutations in TNFAIP3 gene, that is, c.811C>T, p.R271X in pedigree 1 and c.133C>T, p.R45X in pedigree 2.The diagnosis of HA20 was eventually established when sequencing results and their clinical manifestations were both compatible with this disease.A total of 21 articles were retrieved, all in English, with a total of 91 cases from 39 families (including the 4 cases reported in this paper). HA20 was reported more often in female (57, 64.8%). Most patients develop symptoms from childhood, but as many as 53.4% (47 cases) are not correctly diagnosed until adulthood. Oral ulcers, genital ulcers, periodic fever, gastrointestinal symptoms, rashes, and arthritis are the primary manifestations.Hashimoto′s thyroiditis is the most common autoimmune diseases that HA20 patients coexist with. Laboratory tests were characterized by significantly elevated inflammatory markers and low to moderate titers of autoantibodies in some patients.Most HA20 patients were reported to have nonsense mutations or shift mutations of TNFAIP3 gene, which leads to truncation of A20 protein, and only a small number of patients have missense mutation. In terms of treatment, anti-TNF treatment and anti-interleukin 1 is believed to be an effective and the most optimal therapy. The treatment effect is variable and requires long term observations.@*Conclusions@#The clinical phenotypes of HA20 are complex. For patients with both autoinflammatory and autoimmune characteristics, family history should be inquired in detail and gene sequencing should be performed if necessary.

Autoinflammatory diseases accompanied by vasculitis / 中华皮肤科杂志

Autoinflammatory diseases are a group of inherited disorders characterized by dysregulation of the immune system,periodic fever and reccurrence of inflammation.The common rashes of autoinflammatory diseases include acne,pyoderma gangrenosum,erysipelas,urticaria,ichthyosis,pustulosis,while vasculitis is rare.This review summarizes autoinflammatory diseases accompanied by vasculitis.Familial Mediterranean fever mainly manifests as small-and medium-vessel vasculitis such as Henoch-Sch(o)nlein purpura and polyarteritis nodosa,while large-vessel vasculitis is common in Blau syndrome.Small-and medium-artery vasculitis can occur in patients with deficiency of adenosine deaminase 2 as well,so it should be differentiated from polyarteritis nodosa in clinical practice.Stimulator of interferon gene-associated vasculopathy with onset in infancy mainly presents as cutaneous small-vessel vasculitis and vasculopathy.

Clinical and genetic analysis of 11 cases with periodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome / 中华儿科杂志

Objective@#To investigate the clinical, inflammatory and genetic characteristics of cases with periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome.@*Methods@#Clinical and inflammatory manifestations and gene sequencing of 11 cases with PFAPA were retrospectively analyzed. Inflammatory markers including white blood cell (WBC) , C reactive protein (CRP) , and serum amyloid A (SAA) were compared between febrile period and intermittent period. Fifteen normal children were taken as healthy controls. The levels of plasma inflammatory cytokines including interleukin(IL)1β, IL-6, IL-17, tumor necrosis factor(TNF)-α, interferon (IFN)-γ, and granulocyte-colony stimulating factor(G-CSF) were compared between febrile period and intermittent period with paired-sample t test, and compared between febrile cases and healthy controls with independent t test.@*Results@#A total of 11 cases (7 females and 4 males) were included. The median onset age was 24 (3-60) months, and the median age of diagnosis was 69 (11-151) months. The median febrile duration was 4 (1-8) days, and the intermittent period lasted 1 to 8 weeks. All the cases had periodic fever and pharyngitis/tonsillitis, 7 of whom had combined lymphadenitis, and 5 of whom suffered from oral ulcers. Compared to intermittent-period-status,WBC ((14.7±4.1) ×109/L vs. (8.4±1.9) ×109/L, P<0.05), CRP((24.2±21.1) vs. (3.3±2.1)mg/L, P<0.05), SAA ((136.4±47.7) vs. (7.1±1.1)mg/L, P<0.05) were significantly elevated in febrile period. Compared to intermittent-period-status and healthy controls, plasma levels of IL-6 ((38±10) vs. (8±4) and (8±5)ng/L, t=6.514 and 6.830 respectively, P<0.05), IFN-γ ((132±43) vs.(49±21) and (53±21)ng/L, t=4.069 and 4.276 respectively, P<0.05), G-CSF ((403±12) vs. (175±90) and (121±49)ng/L, t=4.219 and 9.047 respectively, P<0.05) were significantly higher in febrile period, while no differences were found in levels of IL-1β, IL-17 and TNF-α. Gene sequencing found MEFV gene heterozygous variation in 8 cases.@*Conclusions@#PFAPA often manifests as periodic fever, pharyngitis, tonsillitis, aphthous stomatitis and adenitis. Gene sequencing analysis, detection of inflammation markers and cytokines could help with the diagnose of this disease.

Uma nova classe de doenças: doenças autoinflamatórias / A new class of diseases: autoinflammatory diseases

As doenças autoinflamatórias sistêmicas são um grupo de doenças raras recentemente descritas, mas que vêm ganhando espaço no cenário clínico. Caracterizam-se por alterações da imunidade inata, portanto sem a presença de linfócito T autorreator ou autoanticorpo, e que respondem ao bloqueio de uma única citocina. Esta revisão tem como objetivo analisar a base imunofisiológica destas doenças e descrever brevemente cada uma delas com suas características clínicas mais importantes.

Systemic autoinflammatory diseases are a group of rare diseases only recently described but rapidly growing in importance in the clinical setting. They are characterized by innate immunity impairment, i.e., absence of autoreactive T lymphocytes or autoantibodies, and respond to individual cytokine blockade. The objective of this review was to analyze the immunophysiological basis of these diseases and to briefly describe each of them along with their most relevant clinical characteristics.

Skin symptoms as diagnostic clue for autoinflammatory diseases

ABSTRACT Autoinflammatory disorders are immune-mediated diseases with increased production of inflammatory cytokines and absence of detectable autoantibodies. They course with recurrent episodes of systemic inflammation and fever is the most common symptom. Cutaneous manifestations are prevalent and important to diagnosis and early treatment of the syndromes. The purpose of this review is to emphasize to dermatologists the skin symptoms present in these syndromes in order to provide their early diagnosis.

Inflammasomes and dermatology

Abstract: Inflammasomes are intracellular multiprotein complexes that comprise part of the innate immune response. Since their definition, inflammasome disorders have been linked to an increasing number of diseases. Autoinflammatory diseases refer to disorders in which local factors lead to the activation of innate immune cells, causing tissue damage when in the absence of autoantigens and autoantibodies. Skin symptoms include the main features of monogenic inflammasomopathies, such as Cryopyrin-Associated Periodic Syndromes (CAPS), Familial Mediterranean Fever (FMF), Schnitzler Syndrome, Hyper-IgD Syndrome (HIDS), PAPA Syndrome, and Deficiency of IL-1 Receptor Antagonist (DIRA). Concepts from other pathologies have also been reviewed in recent years, such as psoriasis, after the recognition of a combined contribution of innate and adaptive immunity in its pathogenesis. Inflammasomes are also involved in the response to various infections, malignancies, such as melanoma, autoimmune diseases, including vitiligo and lupus erythematosus, atopic and contact dermatitis, acne, hidradenitis suppurativa, among others. Inhibition of the inflammasome pathway may be a target for future therapies, as already occurs in the handling of CAPS, through the introduction of IL-1 inhibitors. This study presents a literature review focusing on the participation of inflammasomes in skin diseases.

Descripción de un caso de fiebre mediterránea familiar / Family Mediterranean Fever - case description

RESUMEN: Arch Med Interna 2013 - 35(3):101-104 La fiebre mediterránea familiar es una enfermedad autosómica recesiva, causada por mutaciones en el gen MEFV, el cual codifica una proteína denominada pirina. Esta proteína interviene en la formación del inflamasoma que estimula la activación de la IL-1β a través de la activación de la caspasa-1. Esta proteína tendría un efecto inhibitorio sobre la activación de la IL-1 β, por lo que las mutaciones de pérdida de función de ésta causarían una regulación en más de la inflamación. Forma parte de los síndromes hereditarios de fiebre periódica, caracterizados por episodios inflamatorios recurrentes autolimitados que cursan con fiebre, poliserositis, sinovitis y manifestaciones cutáneas. Es más frecuente en determinados grupos étnicos como es el caso que se presenta en este trabajo, se considera de interés por la dificultad en su diagnóstico. Es opinión de los autores que esta enfermedad es subdiagnosticada en Uruguay.

ABSTRACT: Arch Med Interna 2013 - 35(3):101-104 Familial Mediterranean fever is an autosomal recessive disease caused by mutations in the gene MEFV, which encodes a protein called pirin. This protein is involved in the formation of stimulating inflamasome activation of IL-1β through activation of caspase-1. This protein would have an inhibitory effect on activation of IL-1β, so loss of function mutations cause an up-regulation of the inflammatory response. It is part of the hereditary periodic fever syndromes which characterized by recurrent episodes of fever, polyserositis, synovitis, and cutaneous manifestations. 
It is more common in certain ethnic groups such as this case, which is presented because of the difficulty in its diagnosis. It is the opinion of the authors that this disease is underdiagnosed in Uruguay.

Extensive Thrombosis in a Patient with Familial Mediterranean Fever, Despite Hyperimmunoglobulin D State in Serum: First Adult Case in Korea

Familial Mediterranean fever (FMF) is an autosomal recessive disease characterized by recurrent episodes of fever accompanied by peritonitis, pleuritis, arthritis, or erysipelas-like erythema. It is known to occur mainly among Mediterranean and Middle Eastern populations such as non-Ashkenazi Jews, Arabs, Turks, and Armenians. FMF is not familiar to clinicians beyond this area and diagnosing FMF can be challenging. We report a 22-yr old boy who presented with fever, arthalgia and abdominal pain. He had a history of recurrent episodes of fever associated with arthalgia which would subside spontaneously or by antipyretics. Autosomal recessive periodic fever syndromes were suspected. Immunoglobulin D (IgD) level in the serum was elevated and DNA analysis showed complex mutations (p.Glu148Gln, p.Pro369Ser, p.Arg408Gln) in the MEFV gene. 3D angio computed tomography showed total thrombosis of splenic vein with partial thrombosis of proximal superior mesenteric vein, main portal vein and intrahepatic both portal vein. This is a case of FMF associated with multiple venous thrombosis and elevated IgD level. When thrombosis is associated with elevated IgD, FMF should be suspected. This is the first adult case reported in Korea.