the innate immune system acts as an immunosurveillance keeper that discriminates among healthy host tissue , cellular debris , apoptotic cells , chromatin - modifiers , and transcription factors , mediating detection of infectious agents and instructing the adaptive immune response ; the discovery and recent characterization of danger - sensing molecules of the innate immunity have revealed that immunologic homeostasis relies on a complex and highly integrated system of cells , complement , and defense factors with complementary specificity and action . systemic autoinflammatory diseases ( saids ) are a growing cluster of heterogeneous disorders , characterized by apparently inexplicable recurrence of multiorgan inflammation in the absence of autoreactive t - lymphocytes and autoantibodies , involving the innate immune system ; all these diseases are caused by a lack of regulation in the inflammasome , a large intracellular multiprotein platform , that plays a crucial role in innate immunity , leading to overproduction of proinflammatory cytokines , such as interleukin ( il)-1 and tumor necrosis factor ( tnf)- , and to a pathological delay in the turning off of inflammatory responses . a brief summary of saids described in this review can be found in table 1 . the main subgroup of saids includes different hereditary periodic fever syndromes ( hpfs ) , sharing a common clinical background characterized by recurrent fever attacks and inflammation involving different sites , such as skin , serosal membranes , joints , gastrointestinal tube , or central nervous system . aa amyloidosis is their most serious long - term complication , with an overall prevalence ranging from 2 to 25% of cases . hpfs include familial mediterranean fever , associated with homozygosity or compound heterozygosity in the mefv gene located on chromosome 16p13.3 , encoding a 781-amino acid length protein , named pyrin ( also known as marenostrin ) , which is mainly expressed in polymorphonuclear cells and monocytes ; mevalonate kinase deficiency syndrome , also known as hyperimmunoglobulinemia - d syndrome , caused by homozygosity or compound heterozygosity for disease - causing mutations in the mvk gene , which has been localized to chromosome 12q24 and encodes for mevalonate kinase , a cytosolic enzyme involved in the cholesterol and isoprenoid biosynthesis pathway ; tnf receptor - associated periodic syndrome , related to mutations in the soluble tnf receptor superfamily member 1a gene on chromosome 12p13 ; and finally the family of cryopyrin - associated periodic syndrome , which in turn includes familial cold urticaria syndrome ( fcas ) , muckle - wells syndrome ( mws ) and chronic infantile neurological cutaneous and articular syndrome ( cincas ) , all caused by mutations in the nlrp3 gene , located on chromosome 1 , which encodes for the cryopyrin protein [ 2 , 4 ] . familial mediterranean fever and mevalonate kinase deficiency syndrome are transmitted by autosomal recessive inheritance , while inheritance is autosomal dominant for tnf receptor - associated periodic syndrome and cryopyrin - associated periodic syndrome . generally speaking , genes associated with hpfs encode proteins involved in the regulation , activation , and/or deactivation of the inflammatory response , and disease flares usually alternate with symptom - free intervals of variable duration , characterized by entire wellbeing and complete normalization of acute phase reactants . familial mediterranean fever ( fmf ) is paradigmatic among hpfs and is characterized by recurrent acute fever episodes lasting from 1 to 3 days , in its most classic phenotype , arthritis , erysipelas - like erythema , and polyserositis presenting with abdominal and/or thoracic pain . muscular and skeletal involvement is frequent , often as recurrent simple myalgia or arthralgia , while approximately 30% of fmf patients complain of arthritides , especially affecting large joints , which are rarely erosive but may even persist for several days after fever resolution [ 7 , 8 ] . more than 60% of patients have a disease onset before age 10 and 98% before age 30 [ 9 , 10 ] . fmf is common in populations of mediterranean ancestry and has traditionally been considered an autosomal - recessive disease , caused by mutations in the mefv gene . among almost 300 mutations discovered in the mefv gene so far , five mutations ( m694v , v726a , m680i , m694i , and e148q ) are the most frequent in the classically affected populations ( armenians , arabs , jews , and turks ) . adult - onset fmf seems to be genetically related to heterozygosity and low - penetrance mutations , although these patients often experience a milder disease course , with clinical features similar to those found in younger patients , except for a lower rate of arthritis and erysipelas - like rash . diagnosis of fmf relies on the tel hashomer clinical criteria , based on recurrent episodes of fever and serosal inflammation ( manifested by nonspecific signs , such as sterile peritonitis and/or pleurisy ) and clinical efficacy of daily oral administration of colchicine . however , oligosymptomatic adult - onset patients may not fulfill diagnostic criteria , and in these cases genetic testing is useful in making a definite diagnosis [ 13 , 14 ] . genetic diagnosis of fmf can be certified if two mutations are identified on both of a patient 's chromosomes , but many patients may have only one mutation or do not display any mutation at all . given the high carrier frequency of mefv mutations and the lower - than - expected prevalence of the disease , it seems possible that other alleles could modify inflammatory signals initiated by mutant pyrin . thus , fmf may not be a simple monogenic inflammatory disease , and the fmf phenotype may occur in patients with only one mefv mutation in the presence of other permissive alleles or environmental factors ; genome - wide association studies might help confirming the polygenic influences on the clinical expression of fmf [ 15 , 16 ] . occasional reports of autosomal dominant fmf have also been associated with the compound pyrin variant e148q / m694i encoded on a single allele ( revealed in independent indian and turkish kindreds ) and heterozygosity for the simple deletion mutation encoding pyrin m694 ( in three unrelated british families ) . standard therapy for the prevention of acute fmf attacks and also fmf - related amyloidosis is colchicine ; febrile attacks are generally prevented by colchicine administration in most patients [ 19 , 20 ] . valid therapeutic alternatives are anti - il-1 agents in unresponder or noncompliant patients [ 21 , 22 ] . 
 mevalonate kinase deficiency syndrome ( mkd ) usually starts in the first year of life and is characterized by lifelong recurrent fever episodes , typically ranging from 3 to 7 days . the most frequent symptoms reported during febrile attacks , sometimes precipitated by vaccination , infections , emotional stress , trauma , or surgery , are abdominal pain , diarrhea , vomiting , arthralgia , lymphadenopathy , heterogeneous skin lesions , and aphthous ulcers . the disease is caused by different mvk mutations , which elicit clinical signs ranging from the milder hyperimmunoglobulinemia - d syndrome ( hids ) to its most severe expression , named however , autoinflammatory attacks in hids can even be complicated by macrophage activation syndrome . another recently - reported potential complication of mkd is retinitis pigmentosa , characterized by night blindness and peripheral vision loss , which can occur as a result of specific mvk mutations with mild systemic symptoms . using genome - wide exon sequencing technologies have also found mvk mutations in patients with disseminated superficial actinic porokeratosis , a severe rare chronic cutaneous disorder with high genetic heterogeneity , which causes hyperkeratosis and noncontagious dry itchy lesions worsened by sun exposure ; mevalonate might have a role in regulating calcium - induced keratinocyte differentiation and protecting keratinocytes from apoptosis induced by ultraviolet radiations . as regards diagnosis of mkd , patients might display increased serum igd concentrations in every period of life , both febrile and interfebrile , while urinary concentration of mevalonic acid is increased only during febrile flares . genetic testing remains essential for a definite confirmation [ 28 , 29 ] . to date , no single therapy has been found to be effective in the totality of mkd patients . most of them use nonsteroidal anti - inflammatory drugs during febrile attacks , showing only limited benefit . based on the pathophysiology of mkd , statins were thought to be useful although they resulted ineffective in the majority of cases [ 24 , 30 ] . many patients get better with corticosteroids , especially when given in high doses at the beginning of an attack . however , when recurrent inflammatory attacks are very close , chronic high dose corticosteroid administration might lead to multiple side effects , such as early - onset osteoporosis . in these cases , anti - tnf- and anti - il-1 agents are reasonable therapeutic alternatives , though with variable results , confirming the complex and still unraveled cytokine dysregulation in mkd . noteworthy , the nitrogen - containing bisphosphonate alendronate has been reported to bring about an unexpected remission of all symptoms and laboratory abnormalities in a mkd patient . 
 tumor necrosis factor receptor - associated periodic syndrome ( traps ) is the most protean entity among hpfs in terms of age of disease onset , frequency , length , and severity of inflammatory attacks . clinical features of traps include prolonged recurrent fever episodes with periorbital edema , migratory erythematous plaques with underlying myalgia , arthralgia , and serous membranes inflammation ; pericardial involvement has been also reported as the only manifestation of traps , mimicking autoimmune disorders [ 3243 ] . although recurrent pericarditis is the most frequent cardiovascular manifestation , traps mutations seem also to be responsible for early - onset atherosclerosis , thrombosis , and acute myocardial infarction [ 44 , 45 ] . traps heterogeneity is probably linked to the wide spectrum of tnfrsf1a mutations , affecting the interaction between tnf and its two transmembrane receptors ( tnfr ) , characterized by four cysteine - rich extracellular domains , in a wide range of cell types . in physiological circumstances , tnfr extracellular domains can be cleaved , generating soluble receptor fragments that may function as natural tnf - antagonists . the majority of tnfrsfa1 mutations affect the extracellular domain of tnfr , leading to changes in the three - dimensional structure of the ectodomains or alterations in ligand - independent tnfr assembly , with accumulation of the mutated receptors in the endoplasmic reticulum , final activation of proinflammatory signals , and prolonged survival of the activated inflammatory cells . altered receptor cleavage ( the  shedding hypothesis  ) was evaluated initially to be a key - process in traps , but this has not been demonstrated in many causing - disease tnfrsf1a mutations . in particular , r92q is considered to be a low - penetrance mutation leading to later disease presentation , shorter - lasting febrile episodes , less frequent occurrence of rash and abdominal pain , and even potential spontaneous resolution . genome - wide association studies have also identified the r92q mutation as a genetic risk factor for multiple sclerosis and a susceptibility locus for vascular thrombosis in behet 's disease , atherosclerosis , and other inflammatory phenomena [ 47 , 48 ] . the average age of traps onset is around 3 years ; however , adult onset of traps , up to the sixtieth decade , has been described as well and related to low - penetrance mutations . patients with adult - onset traps may be characterized by a phenotype that also mimics fmf in the duration of inflammatory attacks , that is , less than 1 week . diagnosis of traps relies both on a compatible clinical phenotype and identification of a tnfrsf1a mutation . results of treatment are highly variable in traps ; a few patients gain some symptomatic relief from high - dose nonsteroidal anti - inflammatory drugs , while colchicine and different immunomodulators such as cyclosporine and thalidomide produce poor benefit . inflammatory attacks are often responsive to corticosteroid administration , but patients may become prone to metasteroidal comorbidities . furthermore , corticosteroids do not seem to provide complete protection from the risk of developing reactive amyloidosis . etanercept has been proven to induce a good disease control , although in some cases it gradually loses efficacy [ 45 , 5254 ] . noteworthy , infliximab and adalimumab may paradoxically induce a typical acute inflammatory attack in traps patients for reasons only partially understood [ 54 , 55 ] . on the contrary , anti - il-1 agents are reasonable treatment options in order to prevent disease relapses both in the short- and long - term [ 21 , 22 , 56 ] . cryopyrin - associated periodic syndrome ( caps ) includes a spectrum of apparently distinct inflammatory disorders of increasing severity : fcas , mws , and cincas , all caused by nlrp3 mutations , though the molecular basis for this distinction is still not well - understood [ 4 , 29 , 36 ] . fcas is characterized by fever , urticaria - like rash , fatigue , arthralgia , myalgia , headache , and conjunctivitis , which usually appear after exposure to cold . in addition to the clinical features seen in fcas , mws is also characterized by sensorineural hearing loss . as regards cincas , also called  neonatal onset multisystem inflammatory disease ,  this is the most severe caps phenotype , characterized by diffuse subcontinuous neutrophilic urticaria - like erythema without pruritus occurring within a few days after birth , distinctive arthropathy with knee and patella deformity , chronic aseptic meningitis combined with ocular involvement ( in terms of conjunctivitis , uveitis , retinopathy , and optic nerve atrophy , potentially causing blindness ) , bilateral sensorineural hearing loss , and progressive mental retardation . the extent of organ damage and permanent disability varies considerably among patients with fcas , mws , and cincas . although caps are regularly marked by onset of symptoms during early infancy or childhood [ 59 , 60 ] , a case series of patients presenting with adult onset fcas - like symptoms and carrying the low - penetrance q703k mutation in the nlrp3 gene has recently been described . consistent with caps pathogenesis , linked to the constitutively increased inflammasome activity and chronic oversecretion of il-1 , lifelong treatment with il-1 blocking therapies is the most logical option to control organ disease and damage ; different strategies to block il-1 have been used in clinical trials , all characterized by dramatic success in bringing down episodes of fever , urticaria - like rash , joint pain , and elevations in acute - phase reactants . stabilization of the central nervous system inflammation with il-1 antagonists has been sustained after several years of treatment even in cinca patients [ 62 , 63 ] , and il-1 blocking therapies have also permitted to prevent long - term development of systemic amyloidosis [ 21 , 22 ] . the severity gradient of clinical signs from fcas to cincas may be a consequence of the amount of il-1 production , which could also explain the substantially higher doses of il-1 blocking therapy needed to control inflammation in patients with cincas . about 30 to 50% of patients who present caps clinical picture , responding impressively to il-1 blocking agents , are negative for any mutations in the nlrp3 gene . recent reports have shown the presence of somatic mosaicism in circulating leukocytes and epithelial cells of such  mutation - negative  patients ; the extent to which mosaicism in mutation - negative cases can account for caps phenotype is a lively field of investigation . key - points and discriminating factors suggesting the diagnosis of specific hpfs included in systemic autoinflammatory diseases ( saids ) are listed as follows :  self - limited febrile attacks with localized symptoms ( abdominal or thoracic pain , joint pain , rash , migratory muscular involvement , and periorbital edema ) ;  recurrent serositis ;  family history of similar attacks in horizontal or vertical distribution ;  peculiar ethnic origin ;  response to colchicine or corticosteroids ;  positive genetic test.although hpfs are the best - known clinical entities among saids , in recent years numerous other less - known and still rarely identified disorders have been included in this emerging chapter of medicine . figure 2 shows a schematic representation of the main pathophysiologic mechanisms involved in the less frequently diagnosed saids , revealing that mutated proteins cooperate in the regulation of the inflammasome activity , activating a proinflammatory cascade with il-1 and tnf- as prominent cytokines . self - limited febrile attacks with localized symptoms ( abdominal or thoracic pain , joint pain , rash , migratory muscular involvement , and periorbital edema ) ; family history of similar attacks in horizontal or vertical distribution ; peculiar ethnic origin ; response to colchicine or corticosteroids ; positive genetic test . nlrp12-associated autoinflammatory disorder ( nlrp12-ad ) is a rare autosomal - dominant condition , firstly observed in two families originating from guadeloupe , who presented a nonsense mutation in the nlrp12 gene , situated at the locus 19q13.4 , encoding the monarch-1 protein , which is mainly expressed in monocytes and is involved in the activation of nf-b protein complex via canonical and noncanonical pathways [ 65 , 66 ] . disease onset usually occurs in the first year of life with recurrent high fevers and other inflammatory symptoms , mostly evoked by exposure to cold : urticaria - like skin rash , polyarthritis or arthralgia , myalgia , and headache . figure 3 represents an example of cold induced urticaria - like rash in a patient affected with nlrp12-ad . currently , nlrp12-ad treatment is empirical and based on the severity of clinical manifestations . corticosteroids and antihistamines during wintertime may bring about a good clinical response in the less severe cases ; in addition , satisfactory therapeutic effects have been obtained with nonsteroidal anti - inflammatory drugs [ 67 , 68 ] . it should be also noted that in a recent study two nlrp12-ad patients underwent anakinra treatment with only initial clinical improvement . based on this evidence , it was deduced that other proinflammatory cytokines , such as tnf- and il-6 , could have a pathogenic role , suggesting the use of anti - tnf- and anti - il-6 drugs as potential alternative treatments . blau syndrome ( bs ) , first reported in 1985 as  juvenile systemic granulomatosis ,  is a rare autosomal - dominant disease caused by nod2/card15 gene mutations ; the gene was individuated in 2001 on the locus 16q12.1 - 13 , which also contains the genetic susceptibility region for crohn 's disease and early - onset sarcoidosis ( eos ) [ 70 , 71 ] , and codifies for nod2 , a sensor of bacterial antigens which induces nf-b activation . originally , bs was considered a separate entity from eos , but it has been demonstrated that many individuals with eos also present nod2/card15 mutations . for this reason , researchers have proposed distinguishing the familiar form , definitely named bs , from sporadic forms , which are called eos [ 73 , 74 ] . the disease can be observed in caucasians and also in asians and afro - americans ; in most patients the onset is around the 3rd-4th year of age with joint and skin granulomatous inflammatory signs ; eye involvement usually develops later , between ages 7 and 12 [ 7681 ] . symmetrical polyarthritis with effusion in the little joints is the most common manifestation , frequently leading to finger deformities and ankylosis [ 82 , 83 ] . more than 90% of patients have variable skin rashes , although ichthyosis - like changes are the most commonly observed . eye involvement , generally in the form of recurrent panuveitis , and often evolving towards chorioretinitis , glaucoma , and cataract , is the most significant danger in bs [ 8486 ] . moreover , the disease can also be revealed by granulomatous inflammatory processes affecting kidneys , liver , heart , and brain [ 8790 ] . the presence of nonnecrotizing granulomas on synovial or skin biopsy should require the individuation of nod2/card15 mutations . treatment of bs remains controversial ; the prolonged administration of corticosteroids and immunosuppressant agents ( methotrexate and cyclosporine ) has led to variable results . eye involvement usually responds adequately to low - dose corticosteroids during nonacute periods , while higher doses are required in acute attacks . biological agents such as infliximab or anakinra may be additional therapeutic choices , although in vitro studies seem to demonstrate that bs is not associated with il-1 oversecretion [ 80 , 91 ] . it is also interesting to note that a pilot study conducted on two patients with the sporadic form of eos / bs showed that thalidomide mitigated granulomatous inflammation through a specific interference with differentiation of monocytes and inhibition of nf-b . this syndrome ( named also phid syndrome ) is an autosomal - recessive autoinflammatory disorder due to mutations in the slc29a3 gene , which codifies the human equilibrative nucleoside transporter-3 ( hent3 ) , regulating apoptosis and macrophage recruitment . several studies have demonstrated that phid inflammatory response is related to nf-b activation and cytokine overproduction . the clinical onset is in early childhood with pigmented skin lesions , hypertrichosis , and insulin - dependent diabetes mellitus without any autoantibodies . other symptoms may include short stature , delayed puberty , and exocrine pancreatic insufficiency [ 94 , 95 ] . recently , phid syndrome has also been associated with lipodystrophy , abnormal distribution of perivisceral fat , scleroderma - like skin modifications , and cardiomyopathy resulting from chronic inflammation , resistant to anti - tnf- and anti - il-1 therapy . in regard to treatment , adalimumab and anakinra have produced little benefit in controlling systemic inflammation of phid syndrome , while new therapeutic horizons might derive from the use of agents acting directly against macrophages , such as etoposide . the ubiquitin - proteasome system participates in the qualitative control and degradation of different proteins , also playing an active role in cell cycle regulation , dna repair , and signal transduction mechanisms [ 96 , 97 ] . a dysregulated proteolytic activity in the proteasome is associated with numerous syndromes , sharing different features of saids . in particular , mutations in the psmb8 gene , located at the locus 6p21 and codifying the inducible subunit  type-8 ( psmb8 ) of the proteasome , have been identified as the cause of nakajo - nishimura syndrome [ 99101 ] , recently redefined as  japanese autoinflammatory syndrome with lipodystrophy    and known in western countries as joint contractures , muscle atrophy , and panniculitis - induced lipodystrophy syndrome  ( or jmp ) [ 103 , 104 ] . this group of disorders also includes candle , standing for  chronic atypical neutrophilic dermatitis with lipodystrophy and elevated temperature ,  syndrome [ 105107 ] . 
 nakajo - nishimura syndrome ( nns ) is a very rare disorder starting in infancy with pernio - like rashes during the first cold months , gradually evolving into lipodystrophy mainly in the face and upper extremities and remittent fevers , firstly described in 1939 in japan [ 99 , 100 , 108 ] ; a distinct homozygous psmb8 mutation encoding the proteasome 5i subunit has been identified as its genetic cause , leading to reduced proteolytic activity and accumulation of ubiquitin proteins . as regards treatment , skin lesions regress with high - dose corticosteroids but tend to reappear when they are tapered . the use of corticosteroids has no effect , however , on lipodystrophy , and even worsens central obesity , while biological agents , such as anti - tnf- and anti - il-1 , might be working alternatives . although nns has been assumed to be found exclusively in japan , a similar syndrome related to psmb8 mutations has been reported from foreign countries and named jmp [ 103 , 110 ] . candle syndrome has been also described as distinct from nns , though determined by missense mutations of the same psmb8 gene and other proteasome - associated genes ; it starts during the first year of life with recurrent fevers as high as 42c , lymphadenopathy , arthralgia , purplish eyelid edema , abnormal growth of lips , and progressive lipodystrophy . interferon- is the key - molecule in candle syndrome , and a clinical trial is in progress to test the use of baricitinib , janus kinase jak1 and jak2 inhibitor , to deregulate interferon production and allow corticosteroid dose reduction . saids presenting with nonbacterial pyogenic manifestations include pyogenic arthritis , pyoderma gangrenosum and acne ( papa ) syndrome , deficiency of the il-1-receptor antagonist , deficiency of the il-36 receptor antagonist , majeed syndrome , and chronic recurrent multifocal osteomyelitis . 
 papa syndrome ( papas ) is an autosomal - dominant condition caused by mutations in the pstpip1 gene , situated at the locus 15q24-q25.1 , which codifies the cd2-binding protein 1 ( cd2bp1 ) , enclosed in the pyrin - mediated inflammatory pathway . in the case of a pstpip1 mutation , the cd2bp1-pyrin link is facilitated ; hence , the percentage of cd2bp1 binding to pyrin is higher , determining a proinflammatory state . papas starts in the first or second decade and is characterized by sterile pyogenic pauciarticular arthritis , cystic acne , ulcerative lesions occurring on the lower extremities , and pyogenic abscesses at the injection sites ; cultures from the synovial liquid and skin lesions are characteristically negative . corticosteroid therapy brings about inconstant success , while anti - tnf- ( etanercept , infliximab ) and anti - il-1 ( anakinra ) agents usually give positive results in corticosteroid - resistant patients [ 116118 ] . recently , two patients have been described with manifestations similar to papa syndrome but without joint involvement ; in both cases , there was also the presence of hidradenitis suppurativa in the armpits . although these patients did not bear any pstpip1 mutations , they presented cctg microsatellites repetitions in the promoter region of the pstpip1 gene ; this condition , characterized by the triad of pyoderma gangrenosum , acne , and hidradenitis suppurativa , has been distinguished from the  classic  papas and identified with the acronym pash ( pyoderma gangrenosum , acne , and suppurativa hidradenitis ) syndrome . deficiency of the il-1-receptor antagonist ( dira ) is an autosomal - recessive disorder secondary to homozygous missense and nonsense loss - of - function mutations in the il1rn gene , located on the long arm of chromosome 2 , which codifies the il-1 receptor antagonist , physiologically antagonizing the effect of the proinflammatory cytokines il-1 and il-1. aksentijevich et al . identified il1rn mutations in 9 individuals , all displaying an abnormal function of the il-1 receptor antagonist protein and leading to uninhibited signaling of il-1 . this condition starts at birth and is characterized by multifocal osteomyelitis , periostitis with heterotopic nuclei of ossification , pustular , and/or ichthyosis skin lesions . patients with dira respond only partially to high - dose corticosteroids , while anti - il-1 treatment with anakinra appears the most obvious and effective therapy , which gives rapid and prolonged clinical remission . a recently reported disease has been named with the acronym ditra , standing for deficiency of the il-36 receptor antagonist , as it depends on mutations in the il36r gene , located on chromosome 2 , which encodes the il-36 receptor antagonist , predominantly expressed in keratinocytes but not in fibroblasts and endothelial cells , having the role of inhibiting the activation of nf-b . clinical manifestations , occasionally triggered by viral or bacterial infections , as pustulous skin lesions , high fever ( until 4042c ) , arthralgia , glossitis with  geographic tongue ,  and asthenia , arise during infancy . to date , there are no consolidated therapies for the cure of this pathology ; however , acitretin , an oral retinoid usually used for psoriasis and hidradenitis suppurativa , has been effective in most patients , while corticosteroids , methotrexate , cyclosporine , or anakinra can give diverse results in terms of efficacy . majeed syndrome is a rare autosomal recessive clinical entity , first identified in 1989 , caused by mutations in the lpin2 gene , localized on the short arm of chromosome 18 , which codifies the lipin-2 protein , expressed in liver , kidney , gastrointestinal tract , lymphatic tissue , and bone marrow . lipin-2 regulates proinflammatory signals determined by saturated fatty acids , and its mutated variant leads to chronic recurrent multifocal osteomyelitis , congenital dyserythropoietic anemia , and neutrophilic dermatosis , usually around the second year of life [ 127 , 128 ] . skin lesions start with erythematosus papules and well - defined painful plaques all over the body , often resembling sweet 's syndrome or psoriasis . considering the rarity of the syndrome , treatment is still empirical , nonsteroidal anti - inflammatory drugs may be useful , while corticosteroids can be used for short periods to control both osteomyelitis and skin signs . recently , some authors have described a significant radiological improvement after administration of anakinra and canakinumab in majeed syndrome , while the lack of response to anti - tnf- agents ( etanercept ) in these same patients suggests the presence of yet - to - be - clarified pathogenetic mechanisms . described for the first time by giedion et al . in 1972 , and manifesting with autoinflammatory attacks predominantly affecting the metaphysis and epiphysis of long bones , each attack is characterized by severe bone pain , increased osteoclastic activity , and bone remodeling . the average onset age is around 10 years , and females are more frequently affected than males . the sites most often involved are shinbones , followed by pelvis , proximal femora , clavicles , and heels . permanent physical invalidity , bone deformities , or limb dysmetria might result from untreated or overlooked crmo . different bone pathologies require a strict differential diagnosis , such as infections ( septic osteomyelitis , typical , and atypical mycobacterial infections ) , neoplasms ( malignant primitive bone tumors , osteoid osteoma , leukemias / lymphomas ) , metabolic disorders , osteopetrosis , and other saids ( as papas ) . the fact that individuals from the same family may be affected by crmo suggests a genetic susceptibility to the disease combined with heterogeneous polygenic influences [ 133 , 134 ] . there is no gold - standard treatment for crmo , which has long been based on nonsteroidal anti - inflammatory drugs , like indomethacin and glucocorticoids , which must be limited to the short - term , especially in adolescents , due to the risk of side effects impacting growth [ 135 , 136 ] . their efficacy was first reported in 2004   and confirmed by several clinical studies published later . tnf- antagonists have also been employed with good results in the few crmo patients refractory to bisphosphonates and nonsteroidal anti - inflammatory drugs . the increasingly accessible genetic investigation techniques currently available have led to and probably will continue to deliver the identification of a greater number of rare genetic diseases belonging to the web of saids . the discovery of new disorders involving the innate immunity system and specifically related to inflammasome dysfunction , accompanied by intensive molecular and clinical research activity , will increase our knowledge in the basic mechanisms of inflammation . in the end , genotype - phenotype correlations will help us in the most proper evaluation of genetic tests on one hand and in the individuation of diagnostic pathways and adequate therapies on the other .
the innate immune system is involved in the pathophysiology of systemic autoinflammatory diseases ( saids ) , an enlarging group of disorders caused by dysregulated production of proinflammatory cytokines , such as interleukin-1 and tumor necrosis factor- , in which autoreactive t - lymphocytes and autoantibodies are indeed absent . 
 a widely deranged innate immunity leads to overactivity of proinflammatory cytokines and subsequent multisite inflammatory symptoms depicting various conditions , such as hereditary periodic fevers , granulomatous disorders , and pyogenic diseases , collectively described in this review . 
 further research should enhance our understanding of the genetics behind saids , unearth triggers of inflammatory attacks , and result in improvement for their diagnosis and treatment .