periodic fever , aphthous stomatitis , pharyngitis , and cervical adenitis ( pfapa )   syndrome belongs to the spectrum of autoinflammatory diseases characterized by spontaneous episodes of inflammation which are not accompanied by the usual hallmarks of autoimmunity  high - titer autoantibodies or autoreactive t - cells . in terms of symptomatology pfapa
is considered one of the periodic fever syndromes , but in regard of etiology it is categorized , along with behet 's disease and sjia ( systemic - onset juvenile idiopathic arthritis ) , as idiopathic disease .
many possible causative factors have been explored so far including infectious agents , immunological mechanisms , and genetic predisposition .
rare occurrence of pfapa in adults   and slight male predominance [ 36 ] absence of known autoreactive antibodies or t - cells [ 1 , 7 ] , as well as shortening of intervals between febrile attacks after corticosteroid - treatment [ 3 , 4 ] , speak highly against autoimmune - mediated disease .
rapid response to steroids [ 36 ] speaks against infection and for dysregulated inflammatory cytokine production .
while the occurrence of the disease in different geographical regions , among various ethnicities , might argue for an infectious vector with worldwide prevalence , studies so far have failed to identify any microbiological agent ( or agents ) potentially involved in pathogenesis of pfapa [ 3 , 11 , 12 ] . due to the lack of evidence of autoimmune or infectious cause
, pfapa has been considered an autoinflammatory disease , but the exact pathogenesis or genetic background remains unclear [ 9 , 1315 ] .
the purpose of this review is to provide up - to - date information considering etiology of pfapa syndrome , by summarizing what has been explored and established in this area so far .
pubmed , web of science , and scopus databases were searched for pertinent reports ; the last search update was performed on june 07 , 2015 .
the terms  pfapa  and  etiology or pathogenesis or pathophysiology  were used as the keywords .
two authors ( bk - g , amk ) independently screened all reports by title or abstract for eligibility .
the authors excluded comments , letters , reviews , and papers that did not study or report our outcomes of interest . if either of the reviewers considered the abstract potentially relevant , full - text articles were retrieved and then evaluated by both reviewers for their suitability for inclusion .
the following information was extracted from each study : the first author 's name , language , country , year of publication and patient 's characteristics ( including ethnicity and age ) , definition and numbers of cases and controls , laboratory methods , and outcomes .
the results were classified into three categories regarding three areas of interest : familial occurrence , genetic basis , and immunological mechanisms of pfapa .
contrary to the majority of periodic fever syndromes , which are hereditary monogenic disorders , genetic basis has not yet been established for pfapa , and for a long time it was regarded as a sporadic disease [ 1 , 4 , 8 , 16 ] .
familial occurrence was not mentioned in the reported series of pfapa patients [ 26 ] . however , within the last few years several cases of siblings [ 1721 ] including a case of siblings and their mother have been reported . in 2010
they interviewed 84 pfapa patients from 8 different countries and found positive family history for recurrent fever in 38 ( 45% ) of them . in 76% ( 29/38 ) of the cases ,
the recurrent fever met pfapa criteria in 12% ( 10/84 ) of the reported cases .
all 47 healthy children in the control group had negative family history of recurrent fever .
the limitations of the study are the following : a retrospective character of the study , a relatively small control group , potential mistakes deriving from relying on the respondent 's subjective knowledge and possibly an incomplete record of the diseases present in the family members . in another large comparative study (
130 pfapa patients , mostly italian ) positive family history was found only in 13.8% of cases . on the other hand , the result was similar in pfapa and hereditary recurrent fever syndromes such as fmf and mkd ( 13.8% , 14.3% , and 9.1% , resp . ) . nevertheless , comparing to pfapa ,
additionally , in the italian study genetic testing was performed in all pfapa patients to exclude hereditary periodic fever syndromes , while in cochard 's study monogenic autoinflammatory diseases were excluded mainly by clinical presentation ( genetic testing only in 20/84 patients ) . in a
lately reported single - center longitudinal study , positive family history ( recurrent fever and/or tonsillitis ) was found in 78% ( 50/64 ) of pfapa patients , which is the highest rate ever reported . however , a recent analysis of a large international web - based multicentre cohort showed lower ( 26.9% , 81/301 ) prevalence of positive family history in pfapa patients . in summary , recent findings strongly suggest that there is a familial tendency to pfapa but the level of evidence does not warrant definite conclusions .
nevertheless mutation of the gene was reported only in 1 patient with pfapa syndrome and the significance of this finding is still to be established . in the most recent report by di gioia
exome sequencing of 11 pfapa patients did not reveal any unique mutation that would be present in all the affected individuals , indicating that pfapa is not a monogenic condition .
since the clinical features of pfapa and hereditary periodic fever syndromes ( pfss ) are often overlapping , pfapa cohorts have been searched for the presence of mutations that are known to cause other pfss . 

were the first to report heterozygous variants of mefv ( a gene associated with familial mediterranean fever ) in patients with pfapa ; however all of those patients belonged to ethnicities with high frequency of carriers [ 4 , 8 ] .
dagan et al . found mefv variants ( m694v , v726a , or e148q ) in 28.1% ( 16/57 ) of pfapa patients from israel .
there was no control group , but the result is comparable to that of the general population in israel ( 3040% ) [ 26 , 27 ] . in a big prospective israeli study by berkun et al .
, mefv variants ( mostly m694v ) were identified in as much as 55.4% ( 65/124 ) of children with pfapa . however , according to the authors , due to a selection of bias reasons , the study should not be used to assess the prevalence of heterozygous mefv mutations in pfapa patients .
japanese authors ( taniuchi et al . ) reported frequency of mefv variants in pfapa patients of 65% ( 13/20 ) , which is higher than that in the aforementioned israeli studies [ 4 , 7 , 25 ] .
this might be due to differences in number of the included patients , their ethnicity , and selection method . in comparison to the control group ( 62 healthy volunteers )
the incidence of two mefv variants ( e148q - l110p and p369s - r408q ) was significantly higher in pfapa patients .
three of those variants ( e148q , p369s , and r408q ) along with three others ( a289v , i591 t , and k695r ) were also found in 8% ( 5/62 ) of children with pfapa in a recent report from slovenia . in a comprehensive genetic study by di gioia
the role of e148q variant is controversial , but it might have a functional effect on inflammasomes , macromolecular il-1-activating complexes , which have recently been associated with pfapa pathophysiology [ 9 , 1315 , 28 ] .
p369s and k695r are low - penetrant variants [ 29 , 30 ] and the function of the other variants remains unknown . in both taniuchi 's and berkun 's study ,
shorter duration of pfapa febrile attacks was found in patients with mefv mutations , compared to those without them [ 7 , 28 ] .
berkun et al . also observed lower rates of regular cyclic patterns and oral aphthae among the mefv carriers ( especially m694v ) . in a swiss study from 2013 variants of nlrp3a gene involved in caps
pathogenesis  were found in as much as 23% ( 12/57 ) of pfapa patients , which is a higher proportion than that in the general population [ 31 , 32 ] . nevertheless , a statistical analysis of single nlrp3 variants ( v198 m , r488k , and q703k ) proved significant difference for only one mutation ( r488k )   of limited significance .
v198 m variant , which is often associated with milder forms of caps , was recently shown not to cosegregate with pfapa .
the q703k variant was recently found in 14.5% ( 9/62 ) of pfapa patients as well as in 12% ( 12/100 ) healthy subjects from slovenia ( statistical significance has not been reached )   and in one of the 14 families studied by di gioia et al . .
this polymorphism has been recognized as a gain - of - function alteration leading to an overactive nlrp3 inflammasome and might play a role in pfapa pathogenesis .
the hitherto published data does not support the involvement of mutations associated with traps ( gene tnfrsf1a ) or mvd ( gene mvk ) in pfapa etiology [ 13 , 15 , 20 , 25 , 28 ] .
a mild low - penetrance , rather asymptomatic variant of tnfrsf1a ( r92q ) was found in 1 out of 50 israeli patients   and in 1 out of 57 cases from switzerland . in a recent study by di gioia
a rare mutation , that is usually associated with a mild form of traps ( r121q ) , was found in one of the families affected with pfapa .
recently published results of an exhaustive screening for mutation in genes responsible for hereditary recurrent fever syndromes   indicate that their involvement in pfapa etiology is very unlikely .
only a few rare variants were found , but their frequency in pfapa patients was similar to those observed in general population and some of these changes did not cosegregate with the phenotype . in summary , the absence of a clear monogenic trait indicates a heterogenous , polygenic , or complex inheritance of pfapa syndrome .
currently , there is no strong evidence to support the association between genes confirmative of hereditary pef 's and pfapa etiology .
tnfrsf1a or mvk mutations were sporadically reported in patients with pfapa and do not seem to be involved in the disease . most of the identified nlrp3 and mefv variants are low - penetrance mutations or benign polymorphisms and their relevance to pfapa pathogenesis is uncertain . as two mutations with a possible functional effect on the inflammasomes ( mefv e148q and nlrp3 q703k ) have been found in several pfapa cohorts , the role of inflammasome - related genes in pfapa pathogenesis can not be excluded .
it is not improbable that mefv and/or nlrp3 variants are involved in the pathogenesis of pfapa , since they are functionally linked to inflammatory reactions taking place during pfapa flares .
protein products of both of these genes regulate activation of caspase-1 , which processes proil-1 and proil-18 to mature forms [ 9 , 35 ] .
il-1 and il-18 are important mediators of the inflammatory response leading to fever , elevated acute - phase proteins , and neutrophilia .
it has been associated with the pathogenesis of the majority of hereditary periodic fever syndromes and recently also with pfapa syndrome , [ 1 , 9 , 14 , 15 , 3640 ] .
showed that fever attacks in 6 pfapa patients led to significant increase in serum concentrations of il-1 and other proinflammatory cytokines ( il-6 , ifn , and tnf- ) when compared to healthy controls ( 11 children ) .
brown et al . also reported increases in il-6 sera concentrations during pfapa flares , whereas levels of il-1 , tnf- , and ifn remain low .
similar results were presented in a norwegian study comparing 22 pfapa patients and 14 children with pneumonia . as the time after the onset of fever , in which sera were drawn , was the shortest in stojanov et al .
's study ( 612 hours ) , it was presumed that il-1 and tnf- peak early in the fever period and then quickly approach homeostatic levels .
this was not confirmed by kubota et al . , who found increased levels of il-1 and tnf- in blood collected from 9 pfapa patients within 96 hours from fever onset .
in a recent study among 33 patients from japan il-1 and tnf- were not elevated , while il-18 , il-6 , and ifn increased during pfapa febrile attacks .
two other studies failed to find elevated levels of il-1 in pfapa patients ; nevertheless , indirect evidence of the increased il-1 production during pfapa fever attacks was discovered [ 9 , 15 ] .
reported overexpression of il-1-related and inflammasome - related genes , increased sera concentrations of il-1-induced proinflammatory cytokines ( il-6 and g - csf ) , and , finally , prompt clinical response to il-1 receptor antagonist treatment ( anakinra ) in 5/5 pfapa patients .
kolly et al . found increased levels of caspase-1 and significantly higher secretion of il-1 by stimulated peripheral blood mononuclear cells during febrile episodes compared to afebrile periods .
increase in serum concentrations of il-18 was demonstrated in several studies [ 9 , 36 , 42 ] .
il-18 stimulates release of ifn that was also elevated in the serum of pfapa patients [ 9 , 36 , 40 , 42 ] as well as ifn inducible chemokines [ 9 , 15 , 40 ] .
elevated levels of il-1 , il-18 , il-6 , and ifn point to innate immunity dysregulation as the key pathomechanism of pfapa attacks .
the concept is advocated by other immunological aberrations during pfapa flares such as monocytosis , increased count [ 9 , 14 , 15 , 41 , 43 ] and characteristic features of neutrophils , increased secretion of proinflammatory chemokines ( ip10/cxcl10 , mig / cxcl9 ) [ 9 , 14 , 41 ] , and upregulated transcription of complement genes . increased neutrophil and monocyte counts during febrile episodes have been reported in several pfapa cohorts [ 9 , 14 , 15 , 41 , 43 ] .
furthermore , stojanov et al . found significant alteration of neutrophil functions during pfapa flares : diminished rates of spontaneous apoptosis , increased generation of intracellular nadph oxidase - derived ros ( reactive oxygen species ) , and signatures of priming such as granule mobilization and receptor upregulation of the cell surface .
chemokines are induced directly by early innate response mechanisms and under the influence of ifn .
they are strong chemoattractants of t - cells to the inflammation sites and may act as a link between innate and adaptive immune responses [ 9 , 14 , 41 ] , which in pfapa is mainly th1-driven [ 9 , 41 ] .
th1-induced elevation of ifn and cxcl10 levels [ 9 , 14 , 15 , 41 ] in the absence of the increased th2- and th17-cytokines   weighs heavily in favour of th1-type inflammatory response in pfapa .
the suppression of th2 type response is supported by low il-4 levels and low expression of il-4 gene in peripheral blood   and in the tonsils .
additionally , lack of eosinopenia has been linked to th2-driven inflammation [ 45 , 46 ] , whereas several studies reported eosinopenia in pfapa patients during febrile episodes [ 9 , 14 , 41 , 43 ] , which also argues in favour of th1-driven immune response in pfapa syndrome .
involvement of adaptive immunity in pfapa pathogenesis is indicated by fluctuations in t lymphocytes and increase in serum ifn levels during the attack periods [ 9 , 14 , 15 ] . a decrease in the number of circulating lymphocytes during pfapa flares
was found in several studies [ 9 , 14 , 15 , 41 ] , two of which reported a decrease in both cd4 + and cd8 + lymphocyte counts [ 9 , 41 ] .
as previously suggested , this may result from activation and recruitment of t - cells to peripheral tissues and is clinically reflected by tonsillitis and cervical adenitis [ 9 , 41 , 42 , 47 ] .
yamazaki et al . showed , that neutrophils and monocytes of pfapa patients ( n = 33 ) during attacks strongly expressed cd64 , an fc receptor , which might be upregulated by ifn , possibly from retention of activated t - cells in the periphery .
a study by petra et al . revealed increased levels of cd8 + t - cells , the transitional b cells , and naive stages of both the cd4 + and cd8 + t - cells in the tonsils from pfapa patients ( n = 10 ) , compared to tonsils from children with obstructive sleep apnea syndrome ( n = 10 ) .
the studies exploring pathophysiology of pfapa [ 9 , 14 , 15 , 36 , 4043 , 47 ] differed in terms of characteristics and size of the pfapa cohort , presence and type of control group , examined proteins , and laboratory methods .
most of them support the hypothesis of an abnormal , il-1 dependent innate immune response to an environmental trigger that leads to th1-driven inflammation , expressed by recruitment of t - cells to periphery . in summary
it shares some clinical and pathogenic features with monogenic recurrent fever syndromes ; however , studies have failed to identify its genetic basis .
possible involvement of mefv and nlrp mutations is in line with their functional connection to il-1 dependent innate inflammatory response , which might be involved in pfapa pathogenesis .
most autoinflammatory diseases derive from genetic variants of the innate immune system , and except for traps , all monogenic periodic syndromes belong to il-1-regulated autoinflammatory diseases .
however , the pathophysiology of pfapa syndrome seems to be more complex . inflammatory response in pfapa
is also driven by th1-type adaptive immune response , which also dominates in several autoimmune diseases , for example , hashimoto 's thyroiditis , grave 's disease , crohn 's disease , psoriasis , type 1 diabetes , and rheumatoid arthritis .
th1-driven immune response mainly develops following infections by viruses , intracellular bacteria , and parasites , while il-1 activation has been shown to be involved in bacterial , viral , and fungal infections .
the role of a viral or other infectious agents in pfapa etiology is unknown , though the hitherto published studies are pointing to collaboration of environmental and immunological factors in a genetically inclined individual .
despite recent advances in unravelling the molecular aspects of pfapa pathogenesis , there still seem to be more questions than answers .
areas for further research include identifying genes and microbiological factors involved in pfapa etiology , as well as the consequent exploration of immunological mechanisms that could improve diagnostic and treatment regimens for pfapa patients in the future .
 
 background . 
 pfapa syndrome is a chronic disease that is characterized by recurrent episodes of high fever , aphthous stomatitis , pharyngitis , and cervical adenitis . 
 knowledge regarding the etiology of pfapa is limited 
 . objectives . to provide up - to - date information considering etiology of pfapa syndrome , by summarizing what has been explored and established in this area so far . materials and methods . 
 pubmed , web of science , and scopus databases were searched for pertinent reports . 
 eventually 19 articles were selected . 
 the results were classified into categories regarding three areas of interest : familial occurrence , genetic basis , and immunological mechanisms of pfapa . 
 results . 
 recent findings suggest that there is a familial tendency to pfapa but the level of evidence does not warrant definite conclusions . 
 the absence of a clear monogenic trait indicates a heterogenous , polygenic , or complex inheritance of pfapa syndrome . as two mutations with a possible functional effect on the inflammasomes ( mefv e148q and nlrp3 q703k ) 
 have been found in several pfapa cohorts , the role of inflammasome - related genes in pfapa pathogenesis can not be excluded . 
 immunological mechanisms of pfapa involve an abnormal , il-1 dependent innate immune response to an environmental trigger , which leads to th1-driven inflammation expressed by recruitment of t - cells to the periphery . 
1. Introduction
2. Materials and Methods
3. Results and Discussion
4. Conclusions