Familial Mediterranean fever (FMF; OMIM*249100) is an ancient disease but was only described as a clinical entity as recently as 1945 [220] and it was given the name FMF in 1958 [98]. FMF is the most common of the hereditary autoinflammatory diseases worldwide and prevalence of FMF has been estimated to be 1 in 250 to 1 in 500 among non-Ashkenazi Jews and 1 in 1000 in the Turkish population. The disease is mainly found in populations from the eastern Mediterranean area (especially non-Ashkenazi Jews, Armenians, Turks and Arabs). FMF can be found in other ethnic groups around the Mediterranean Sea but at a lower incidence [7, 133, 135]. It has been proposed that the only possible explanation for the high frequency of MEFV mutations in populations in the eastern Mediterranean area is that heterozygous carriers have a survival advantage compared to non-carrier, possibly due to an increased resistance to an undetermined infection [157]. The disease is uncommon in other ethnic populations. However, a clinical understanding of the disease has become increasingly important in other parts of the world, partly due to emigration from the eastern Mediterranean area. The disease usually presents in children or adolescents, 50 % has onset before the age of 10 years and 90 % before the age of 20 years.

FMF is an autosomal recessive inherited disease caused by mutation in the MEditerranean FeVer (MEFV) gene (OMIM*608107) on chromosome 16. FMF was the first of the autoinflammatory diseases where a gene defect could be found (1997) [78, 112]. Initially, five mutations were described and they are still the most frequent (80–90 %). Thus far more than 300 variants have been described mostly encoding substitutions (fmf.​igh.​cnrs.​fr/​ISSAID/​infevers/​). Mutations in both alleles are found in only 2/3 of clinically classic cases. The reason for this is not known but mutations in another gene or in the promoter region could be explanations. MEFV codes for a protein, pyrin (“relation to fever”) also called marenostrin (“our sea”), which is mainly expressed in granulocytes, monocytes and synovial fibroblasts. The structure and function of pyrin have not yet been characterized in detail, although it is clearly of importance for regulation of the innate immune system and subtle abnormalities of leucocyte function have been reported in FMF. The putative 781 amino acid protein has sequence homologies with a number of proteins of apparently disparate function and cellular localization. Recent work suggests that pyrin is not primarily a nuclear protein, but interacts via its N-terminal death domain with microtubules and the actin cytoskeleton, consistent with a role in directed cell migration and by the C-terminal domain to activate IL-1β and NF-κB. There are two possible mechanisms for this action of pyrin (Fig. 7.2). In the sequestration hypothesis it is believed that native pyrin has an inhibitory effect on the cryopyrin (NLRP3) inflammasome by competitive binding of ASC and pro-caspase-1 as well as binding of caspase-1 [37, 184]. The pyrin inflammasome hypothesis suggests that pyrin can form an inflammasome by binding to ASC and another adaptor protein in order to cleave pro-caspase-1 and activate IL-1β [35].

Members of the death-domain superfamily play important roles in the assembly and activation of apoptotic and inflammatory complexes through homotypic protein-protein interactions. Proteins with pyrin domains are involved in inflammation, apoptosis, and NF-κB signaling and have been implicated in pathways in CAPS as well. A recent study indicates that pyrin is activated by pathogen-mediated modifications of Rho GTPases, a small G protein that is induced by toxins from bacteria like Clostridium difficile, Vibrio parahemolyticus and C. botulinum [260]. This mechanism may explain the survival advantage of individuals that are heterozygous for MEFV in the eastern Mediterranean area.

The symptoms of FMF are self-limiting (12–72 h) recurring attacks of fever and serositis. The most frequent manifestation besides fever is peritonitis (80 %). The abdominal pain can resemble appendicitis and 40 % patients undergo laparoscopy before the FMF diagnosis is made. Pleuritis is seen in about 15–30 % of the patients [209] and is usually one-sided with painful breathing. Acute arthritis is also common, usually affecting one or a few large joints (ankle, knee, hip or the sacro-iliac joints). The arthritis is usually non-erosive but it may in rare cases be chronic and erosive. Pericarditis and orchitis can also occur but are rare. An erysipelas-like erythema during attacks is seen in about 25 % of pediatric patients [180]. The erythema is often associated with arthritis and is usually located between the knee and ankle, on the dorsum of the foot, or in the ankle region (Fig. 7.3). Polyarteritis nodosa and Henoch-Schonlein purpura are associated with FMF [243].

There is a short but marked inflammatory response during an attack indicated by an increase in CRP, ESR and serum amyloid A protein (SAA). Studies have shown that subclinical inflammation is common between attacks [65, 138], which might also affect the patients’ quality of life [177].

The main risk of FMF is development of renal AA amyloidosis, which may lead to end-stage renal failure. SAA is the precursor of amyloid deposits in FMF. SAA levels rise during attacks and usually normalize in attack-free periods [244]. However, in a significant proportion of patients, SAA levels are not normalized [65, 138]. The level of increased SAA with which there is no risk for development of amyloidosis has not been established. The MEFV mutation M694V and the SAA1 genotype are risk factors for amyloidosis [34, 85, 147, 265]. Interestingly, the country of residence is for unknown reasons an independent risk factor with the highest risk for those in Armenia, Turkey or Arabic countries [242]. Analysis of SAA might be a tool in diagnosing as well as monitoring FMF [17]. Patients with amyloidosis as the presenting or only manifestation of disease (phenotype II) exist but are uncommon [13, 243].

Pyrin-associated autoinflammation with neutrophilic dermatosis (PAAND) is an extremely rare autosomal dominant disease [156]. The disease is distinct from FMF, but is caused by a mutation in MEFV. Manifestations include episodes of fever, dermatitis, arthralgia, myalgia and myositis.

The diagnosis is made on the basis of clinical criteria. The Tel Hashomer criteria [148] are often used to make the diagnosis (Table 7.2). A set of criteria for childhood FMF has been proposed [261] (Table 7.3). However, these criteria have shortcomings, especially in countries with a low prevalence of FMF were the specificity is limited [131]. The diagnosis should be considered in patients with ethnicity from the eastern Mediterranean with recurrent inflammatory episodes. A diagnostic trial with colchicine treatment is part of the investigation in patients with atypical symptoms. Genetic investigation can in atypical cases verify the diagnosis but a negative mutation analysis cannot rule out the disease since MEFV positive mutations in both alleles are only seen in 2/3 of patients with classical FMF.

The disease is treated prophylactically with life long colchicine [59, 90, 267]. Most patients will be symptom-free and the risk of amyloidosis is reduced from 25–40 % to less than 1 %. However, colchicine is not effective in acute attacks. Children usually need a higher dose per kilogram than adults do [123]. Colchicine can sometimes, especially in higher doses, give gastrointestinal side effects. A temporary reduction in the colchicine dose and reduced intake of lactose can relieve the gastrointestinal symptoms. Cohort studies suggest that colchicine in pregnancy is safe and should be continued. Failure to respond to colchicine should prompt a careful review of compliance but cytokine (mostly IL-1 and to a lesser extent TNF) inhibitors have been used with success in therapy resistant cases [30, 37, 94, 167, 179, 211]. Acute FMF attacks can be treated with non-steroid anti-inflammatory drugs (NSAID). Corticosteroids do not have an effect on the classical manifestations but are effective in protracted myalgia, a rare vasculitic complication of FMF [140]. Arthritis that becomes chronic can be treated as juvenile idiopathic arthritis or rheumatoid arthritis.

Hyperimmunoglobulinemia D and periodic fever syndrome (HIDS, OMIM*260920) was defined in 1984 [248] and was given its name because of increased IgD and periodic fever. Mevalonic aciduria (MVA, OMIM*251170) is a more severe disease with mental retardation and dysmorphic features in addition to similar symptoms as for hyperimmunoglobulinemia D and periodic fever syndrome (HIDS). It later turned out that both diseases are caused by a defect in the same enzyme (mevalonate kinase). The name mevalonate kinase deficiency (MKD) is now used for the both diseases, but is most often used to describe the periodic fever syndrome historically known as HIDS. MKD is an uncommon inborn error of the cholesterol biosynthesis. There are only a few hundred and less than one hundred patients known with HIDS and MVA, respectively. Most patients with HIDS are from Europe, in particular from the Netherlands and France. A common founder of the most frequent variant V377I may explain this geographical bias [222].

MKD is autosomal recessive inherited and caused by a mutation in the mevalonate kinase (MVK) gene (OMIM*251170) located on chromosome 12 [61, 107]. The mutation leads to reduced activity of mevalonate kinase. This enzyme is part of the cholesterol, farnesyl and isoprenoid biosynthetic pathway (Fig. 7.4). In MVA, mevalonate kinase activity is almost zero [104] and in HIDS 1–10 % of normal levels [61, 107] resulting in an accumulation of mevalonic acid. In MVA mevalonic acid is continuously very high, while in HIDS it is normal between attacks and increases only moderately during attacks. There are about 60 known disease-causing mutations (http://​fmf.​igh.​cnrs.​fr/​infever). HIDS is associated with a “severe” and a “mild” mutation (the most common being 1129G>A (V377I)), in contrast with MVA which is associated with two “severe” mutations. The activity of the V377I is temperature-dependent, leading to decreased activity with increasing temperature [106], which might partly explain the recurrent attacks seen in HIDS. The reason why mutations in MVK lead to an autoinflammatory disease is still not clear. There have been discussions as to whether the attacks are caused by an increase of mevalonate or a decrease of compounds further down the pathway (Fig. 7.4). The first hypothesis seems unlikely as an attempt to reduce mevalonate production in a patient with MVA has led to disease exacerbation [104]. Animal and ex vivo studies support the notion that the lack of isoprenoid triggers an IL-1β response, but the relevance of these studies need to be further explored. In any case there seems to be an agreement that IL-1β has a central role in HIDS, which is supported by the clinical experience of treating patients with IL-1 blockade [246]. Another study also suggests that decreased lymphocyte apoptosis in MKD is important for the pathogenesis of MKD [21].

A continuous spectrum of clinical presentations is seen from the more benign HIDS to the severe MVA. The symptoms usually start appearing before the age of 1 year [79] and are characterized by episodes of fever and inflammation that recur every 2–8 weeks and last 3–7 days [62, 247]. Other common symptoms during attacks are skin rash, cervical lymphadenopathy, arthritis/arthralgia, diarrhea and abdominal pain (Fig. 7.5). Sometimes there are headache, and oral or genital ulcers. Retinitis pigmentosa and intermittent neutropenia have been described. The disease typically ameliorates somewhat in early adult life. Attacks in patients with HIDS can be triggered by vaccination and stress. MVA is characterized by the same inflammatory symptoms as HIDS but also by dysmorphic features, neurologic symptoms, mental retardation and failure to thrive [104].

MKD is diagnosed by mutational analysis of the MVK gene. The diagnosis is supported by decreased enzymatic activity of mevalonate kinase or increased urine concentration of mevalonate [119, 246]. In HIDS, mevalonate is slightly elevated during attacks, but not during attack-free periods. It is important that the laboratory is able analyze urine mevalonate at low concentrations. Methods used for detecting aminoaciduria are not always sufficiently sensitive for analyzing the low but significantly raised levels of mevalonate in HIDS during attacks. This problem is not encountered in MVA where mevalonate is continuously very high. Acute phase reactants increase during episodes. IgD and IgA are increased in 80 % of the patients both during and between attacks. The reason for the polyclonal rise in IgD and IgA is not known and does not seem to be disease specific as an increase is seen in many other inflammatory diseases including FMF and PFAPA.

The clinical course in MKD is variable and the treatment often needs to be tailored for the individual patient. A treatment algorithm with a step-wise approach has been proposed as a tool to support clinical decisions [246]. Many patients are treated, on demand or continuously, with NSAID and/or corticosteroids [235]. Several other anti-inflammatory agents (e.g. colchicine, statins and thalidomide) have been tried without significant effect [246]. A number of case series indicate that anakinra is the most effective biological agent in MKD, with complete or partial effect in the majority of patients [235]. A smaller proportion of patients respond to etanercept, and patients that do not respond to anakinra might very well respond to etanercept or vice versa [235, 246]. Recently, a patient was reported to respond to alendronate treatment with normalization of all clinical and laboratory abnormalities related to MKD [33]. A few patients with MVA have been treated successfully with hematopoietic stem cell transplantation (HSCT) [12, 173]. The severity of the disease seems to diminish during adulthood [64].

Tumor necrosis factor receptor-associated periodic syndrome (TRAPS; OMIM*142680) was formerly known as familial Hibernian fever due to the heredity factor and the predominance of Irish ancestry in the first cases described [256]. The disease was renamed TRAPS when it was discovered that it was caused by a mutation in the TNF receptor gene 1 [158]. TRAPS is probably the most frequent autosomal dominant hereditary autoinflammatory disease. However, it is still an unusual disease with an estimated prevalence in Europe of approximately one per million [139].

TRAPS is caused by a mutation in the tumor necrosis factor receptor superfamily 1A (TNFRSF1A) gene (OMIM*191190) that encodes for the TNF receptor 1 (=55 kD TNF receptor). The gene for the disease, located on chromosome 12, was found in 1999 [158]. To date more than 100 different disease-causing mutations have been found in TRAPS (http://​fmf.​igh.​cnrs.​fr/​ISSAID/​infevers/​). Two mutations, c.362G>A (R92Q) and c.224C>T (P46L), are regarded as polymorphisms or associated with a milder phenotype [195] and occur in 2 and 10 % of Caucasians and Africans, respectively. In the initial description of TRAPS it was found that there was a shedding defect of the TNF receptor, which led to decreased concentration of soluble TNF receptor in serum [158]. However, this is only true for some of the TRAPS mutations and this is probably not related to the pathogenesis. A new theory is that there is misfolding of the extracellular domain of the mutant TNF receptor 1 leading to retention in the endoplasmatic reticulum and that TRAPS may result from the consequences of the abnormally retained TRAPS mutant TNF receptor 1 [28, 149] giving rise to intracellular stress and production of reactive oxygen species.

TRAPS is characterized by long episodes (>1 week) of fever accompanied by abdominal pain, arthralgia, myalgia, skin rash, arthritis, pleuritis, conjunctivitis and periorbital edema (Figs. 7.6 and 7.7) [137]. The clinical symptoms and severity are variable. The median age of onset is 4 years but the range is wide (2 weeks to 50 years). The attacks last an average of 10 days but the duration varies from several days to more than a month. The myalgia is often migratory with an overlying rash.

The diagnosis of TRAPS is suspected in patients with recurring long attacks (>1 week), myalgia with an overlying erythematous rash, ocular manifestations and a family history suggesting autosomal dominant inheritance. Acute phase reactants are increased during attacks. Reduced soluble TNF receptor levels are seen in many but not all patients. The symptoms of TRAPS are very variable and the diagnosis is based on DNA analysis. Somatic mosaicism, including gonosomal mosaicism, has recently been reported [206]. It is still not settled how to interpret patients with signs and symptoms of autoinflammatory disorder who have the polymorphisms (or low penetrance mutations) R92Q and P46L.

Steroids are effective in treating TRAPS but unacceptably high doses are often required. IL-1 blockade is the current treatment of choice in patients requiring biologics [235]. Etanercept, a TNF blocking agent, has been used with some success, although not in all cases [40, 235]. Infliximab, a humanized mouse antibody to TNF, seems to be ineffective and paradoxal inflammatory reactions have been observed [63, 115].

Until recently this were regarded as three distinct autosomal diseases: Chronic infantile neurologic cutaneous and articular syndrome (CINCA, OMIM*607115) also known as neonatal-onset multisystem inflammatory disease (NOMID), Muckle-Wells syndrome (MWS, OMIM*191900), and familial cold autoinflammatory syndrome (FCAS, OMIM*120100), They have now been linked to mutations in the same gene, however, and are regarded as a clinical continuum [3]. The name cryopyrin-associated periodic syndrome (CAPS), used for all three conditions, indicates that the same protein, cryopyrin, is affected in these diseases. They are all rare. It appears that MWS is more common in Europe and FCAS in North America [3].

All three diseases are caused by a mutation in the NLR family, pyrin domain containing 3 (NLRP3) gene (OMIM*606416), The gene is located on chromosome 1. The gene for FCAS and MWS was found in 2001 [101] and for CINCA/NOMID in 2002 [5, 71]. In total more than 100 disease-causing mutations are known today (http://​fmf.​igh.​cnrs.​fr/​ISSAID/​infevers/​). Some of the mutations are associated with part of the syndrome but overlaps are common [172]. The gene codes for a protein, cryopyrin, which is mainly expressed in neutrophiles, monocytes and chondrocytes. Cryopyrin forms a complex known as the NLRP3 inflammasome (= cryopyrin inflammasome), together with ASC and cardinal [155, 238]. This cleaves pro-caspase-1 to active caspase-1, which in turn activates IL-1β (Fig. 7.2). The mutations in CAPS give rise to a gain-of-function of the NLRP3 inflammasome. However, the understanding of the role of the mutated cryopyrin is still unclear. There are conflicting data regarding apoptosis and regulation of nuclear factor kappa B (NF-κB) in CAPS. Not all patients with the clinical picture of CAPS (especially in CINCA but also in MWS) have a germline mutation in NLRP3, but somatic mosaicisms have been found in some of these patients [170, 232].

Although these diseases have been classified as three different diseases they often have overlapping symptoms such as fever, urticaria-like rash, arthritis/arthralgia and an acute inflammatory reaction. FCAS and MWS are often associated with an autosomal dominant pattern of family history. The diseases can be regarded as a continuum with FCAS as the mildest form, MWS as the intermediate and CINCA as the most severe. There are overlap forms of CINCA/MWS and MWS/FCAS.

FCAS was first described in 1940 [127]. FCAS is characterized by cold-induced attacks of fever associated with urticaria-like rash, arthralgia and conjunctivitis (Figs. 7.8 and 7.9) [103]. The symptoms usually start before the age of 6 months. The average delay between cold exposure and symptoms is 2–3 h and the episode usually lasts less than 24 h. This is in contrast to the more common cold urticaria where the symptoms develop soon after cold exposure. The risk of developing amyloidosis is lower than MWS.

MWS was first described in 1962 [169]. The syndrome is characterized by episodic attacks with urticaria-like rash, fever, malaise, conjunctivitis, arthralgia and progressive sensorineural hearing loss [48, 60]. The duration of the attacks is longer (24–72 h) than in FCAS. The disease usually manifests itself during childhood but hearing loss usually begins in adolescence. About 25 % of patients will develop AA amyloidosis [1].

CINCA was first described in 1981 [190] and NOMID in 1983 [95]. It later turned out to be the same disease and the terms CINCA/NOMID are used interchangeably. In addition to fever, the clinical spectrum includes the triad of cutaneous, neurological and articular symptoms. The non-pruritic urticaria-like skin rash usually develops in the neonatal period or in early infancy. The neurological symptoms, which vary considerably between patients, can include chronic aseptic meningitis, papilledema with optic-nerve atrophy, uveitis, seizures, cerebral atrophy, mental retardation and sensorineural hearing loss [191]. The articular manifestations differ from juvenile idiopathic arthritis by being a deforming arthropathy with bony overgrowth especially affecting the knees but also ankles, elbows, wrists and hands [191]. There is chronic inflammation with increased ESR, CRP and SAA but flares occur at irregular intervals. About 1/5 of untreated patients will not survive through to adulthood.

The diagnosis is made on the basis of clinical criteria, see Table 7.1. Overlaps between the diseases are common and the phenotype can vary even within a family. A germline mutation in CIAS1 is found, using conventional mutation analysis, in only about half of all cases of CINCA/NOMID [3], but somatic mosaicism seems common in “mutation negative CAPS patients” [170, 232].

For many years, the treatment of CAPS was mainly supportive. Steroids, disease modifying anti-rheumatic drugs (DMARD) and anti-TNF therapy were used with some effect. However, a number of case reports and studies have shown substantial success in treating CAPS with IL-1 blocking agents [89, 96, 102, 136, 235]. Recovery of hearing in a patient with MWS has been reported after treatment with anakinra [166].

Sarcoidosis is a granulomatous multisystem disease that mainly affects patients between 20 and 40 years of age. The symptoms in adults usually involve the triad of lung, lymph node and eye manifestations. In the pediatric population two distinctive forms have been identified [204, 217]. School-aged children and adolescents have clinical manifestations similar to the adults involving lungs and lymph nodes. Young children (<5 years) usually have the triad of arthritis often causing camptodactyly, uveitis and dermatitis resulting in a characteristic tan colored rash. This syndrome is usually referred to early onset sarcoidosis (EOS, OMIM*609464). Blau syndrome (OMIM*186580), a rare autosomal dominant inherited disease with granulomatous inflammation [18, 114], was described in 1985 and the symptoms are almost identical to early onset sarcoidosis [100, 164, 204]. Sporadic early onset sarcoidosis (without a family history of the syndrome) has been shown to be the same disease as Blau syndrome [124, 125, 201]. The name pediatric granulomatous arthritis (PGA) has been proposed for both Blau syndrome and early onset sarcoidosis [203], but it has not been widely accepted. Instead, Blau syndrome is now often used for both the familial and sporadic form.

Blau syndrome is caused by a mutation in the nucleotide-binding oligomerization domain protein 2 (NOD2) (also known as caspase recruitment domain family 15 (CARD15)) gene (OMIM*605956) on chromosome 16 [162]. The two most prevalent mutations are, c.1000C>T (R334W) and c.1001G>A (R334Q) [200, 203, 255]. About 20 disease-causing mutations have up today been reported (infevers, http://​fmf.​igh.​cnrs.​fr/​ISSAID/​infevers). The location of the mutations in Blau syndrome is in the NACTH region in contrast to Crohn’s disease where mutations are found in the LRR region. The mechanism for the disease is not fully known but it is probably involved in regulation of apoptosis and in the innate immune response to bacterial lipopolysaccharide via activation of NF-ĸB [201]. In Blau syndrome, there is a gain-of-function of the mutated protein in contrast to Crohn’s disease where there is a loss-of-function. Studies have shown that the same mutations are found in EOS as in Blau syndrome [124, 125, 200]. These mutations are not found in older children and adults with sarcoidosis.

The dermatitis is a cutaneous eruption of small papules often described as a tan colored rash. The rash has also been described as an ichthyosis-like exanthema. This kind of rash is rarely seen in the adult form of sarcoidosis. The dermatitis can be intermittent in contrast to sarcoidosis in adults. The joint symptoms include synovitis and tenosynovitis, which often are polyarticular. Camptodactyly can develop. The most important morbidity is due to the uveitis. About 1/3 of the patients develop moderate to severe visual impairment. Bilateral panuveitis is common uveitis type and is often complicated by band keratopathy, glaucoma, and cataract formation [200].

The clinical manifestations associated with Blau syndrome are expanding [202]. In addition to the three core symptoms (arthritis, uveitis and dermatitis), fever, subcutaneous nodules, erythema nodosum, large-vessel vasculitis (early onset Takayasu disease), and several other symptoms can appear [200, 202].

The diagnosis is supported by the clinical criteria including the core symptoms (dermatitis, arthritis, uveitis), non-caseating granulomas and onset before 5 years of age. The diagnosis can be confirmed by DNA analysis. Most patients (34/45) which are NOD2 mutation positive have the classical triad [200]. Asymptomatic individuals with NOD2 mutation have been reported [200]. Most, but not all patients, with the classical triad have a disease-causing mutation [125, 200, 255]. These disease-causing mutations can also give rise to atypical forms of Blau syndrome [215]. Somatic mosaicisms have been reported in patients with Blau syndrome [52, 161]

Steroids have been used for treatment but relapses are common after withdrawal. Steroid sparing agents may be required. Case studies has shown variable efficacy with anti-TNF therapy [202]. IL-1 blocking agents seem to be largely ineffective but case reports have shown efficacy [224].

Pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome (OMIM*604416) is an autosomal dominant inherited disease characterized by pyogenic arthritis, pyoderma gangrenosum and acne [144]. The disease is only known in a few families [43, 144, 198, 231].

PAPA was mapped for a disease locus on chromosome 15 in 2000 [257, 264]. The disease was found, 2 years later, to be caused by a mutation in the proline serine threonine phosphatase interacting protein 1, (PSTPIP1) gene (OMIM*606347) on chromosome 15 [258]. Eleven different mutations have been associated with PAPA to date. The mechanism by which these cause inflammation is not known. However, the PSTPIP1 protein binds to pyrin, the protein affected in FMF, and may cause inflammation in the same pathway of the innate immune system as FMF [225].

The first manifestation to appear, between 1 and 16 years of age, is usually oligoarticular pyogenic arthritis [258]. The arthritis, often erosive, can start spontaneously but sometimes after a mild trauma. Usually the joint symptoms will be less pronounced with age. Acne develops later, often at puberty. The acne is often severe and cystic. Pyoderma gangranosum-like ulcerative lesions occur in some patients. Other manifestations include sterile abscesses at injection sites and pancytopenia after administration of sulfa-containing drugs. The penetrance of the disease seems to be variable and some mutation-positive family members are symptom free [56].

The diagnosis is made on clinical criteria. The disorder should be suspected if there is a familial appearance suggesting autosomal dominant inheritance. The diagnosis can be confirmed with DNA analysis.

There is no established treatment for this rare disorder. PAPA is only partly responsive to treatment with oral and intraarticular steroids. Case series have shown variable results on anti-TNF treatment [43, 56, 66, 226] as well as anti-IL-1 treatment [56, 58, 218, 258]. The treatment is usually more effective against the arthritis than the skin manifestations.

NLRP12 associated periodic fever syndrome (NAPS12) or familial cold autoinflammatory syndrome 2 (FACS2; OMIM*611762) is an exceptionally rare autosomal dominant disease first described in 2008 causing episodes of fever with variable associated symptoms with some reports of sensorineural deafness and cold induced symptoms [118].

The nonsense and splice site mutations identified in the NLR family, Pyrin domain-containing 12 (NLRP12) gene (OMIM*609648) appear to reduce the inhibitory effect of the protein on NF-κB signaling [8].

Patients presented in infancy or the neonatal period with a syndrome with some features of cold induction, fever, arthralgia and myalgia, urticaria and sensorineural deafness. The first cases reported were from two unrelated families from the Caribbean and subsequent cases have been reported [23, 118, 252].

The diagnosis is made on clinical criteria. The disorder should be suspected if there is a pattern of autosomal dominant inheritance and NLRP3 is wild type. The diagnosis can be confirmed with DNA analysis.

There is no established treatment for this rare disorder.

The deficiency of ADA2 (DADA2) or monogenetic polyarteritis nodosa (PAN) vasculopathy (OMIM*615688) was described independently in 2014 by two groups [171, 270]. The clinical spectrum is wide and so far not well established. Manifestations include childhood systemic and local polyarteritis nodosa (PAN), recurrent fever, mild immunodeficiency, livedo racemosa and early-onset stroke.

The syndrome is caused by recessive loss-of-function mutations in the cat eye syndrome chromosome region, candidate 1 (CECR1) gene (OMIM*607575), encoding adenosine deaminase 2 (ADA2) [171, 270]. The mutations cause reduced activity of ADA2 in plasma. The ADA2 protein is produced by myeloid cells and is thought to be a growth factor for endothelial cells as well as leucocytes. ADA2 deficiency may induce proinflammatory cells leading to inflammation and vasculopathy.

In contrast, overexpression of ADA2 due to gain-of-function mutation in CECR1, causes Cat Eye Syndrome (CES), a congenital malformation syndrome [45].

The manifestations of DADA2 are heterogeneous and the two initial case-series had different inclusion criteria. In the study by Navon Elkan et al, patients were recruited mainly from familial cases (Georgian Jewish) of PAN [171]. All the Georgian Jewish patients were homozygous for a mutation encoding p.Gly47Arg substitution.

In the study by Zhou et al., patients with recurrent fevers, livedo racemosa, mild immunodeficiency and early-onset stroke were included [270]. Six patients were compound heterozygous for eight different CECR1 mutations. The patients with immunodeficiency had hypogammaglobulinemia/low IgM levels, recurrent bacterial and viral infections, varying degrees of lymphopenia

The three patients with PAN phenotype in this study also had homozygous p.Gly47Arg substitution.

The diagnosis is based on clinical criteria including recurrent fever, early onset stroke, livedo racemosa (Fig. 7.10) and features of PAN. The suspicion should be especially high if there is a pattern of autosomal recessive inheritance. The diagnosis can be made by measurement of ADA2 in serum and it is confirmed with DNA analysis.

Treatment with anti-TNF agents [171] had positive results. A few patients underwent HSCT and they are reported to have normalized their ADA2 activity and to have improved clinically [249, 250]. ADA2 replacement treatment or fresh-frozen serum could also be a possible short-term treatment option.

The acronym SAVI (STING-Associated Vasculopathy with Onset in Infancy) (OMIM*615934) was proposed in 2014 for an autosomal dominant disorder, characterized by early-onset systemic inflammation with elevated inflammatory markers, severe cutaneous vasculopathy and lung disease [145].

The syndrome is caused by a gain-of-function mutation in the transmembrane protein 173 (TMEM173) gene (OMIM*612374) (encoding the stimulator of interferon genes, STING) leading to an induction of type I interferon signaling [145]. SAVI is now included among the type I interferonopathies.

So far only about ten cases have been published [39]. The patients described by Liu et al (n = 6), had onset of symptoms before the age of 2 months [145]. All had rash on cheeks, ears, nose, and digits. The symptoms of these areas worsened with time and included scarring of the ear cartilage, perforation of the nasal septa and severely affected digits. Biopsies of affected areas show vascular inflammation of the capillaries. All had fever (mostly recurrent low-grade), systemic inflammation and failure to thrive. All six had pulmonary manifestations including adenopathy, reduced lung function and interstitial lung disease.

The disease should be considered in a child with very early onset (<2 months of age) of rash at the typical locations, fever, failure to thrive, systemic inflammation and lung involvement. The diagnosis can be confirmed with DNA analysis.

There is no established treatment. Corticosteroids, DMARDS and biologics had no or limited effect. Treatment with JAK inhibitor (blockade of interferon signaling) is a possible option.

Deficiency of the IL-1 receptor antagonist (DIRA) or osteomyelitis, sterile multifocal, with periostitis and pustulosis (OMPP) (OMIM*612852) is an extremely rare autosomal recessive disease characterized by a neonatal onset of a pustular rash, multifocal osteitis and periarticular soft-tissue swelling.

DIRA is a model of the consequences of unregulated activity of IL-1α and β in humans. It is caused by missense or deletion mutations in the interleukin 1 receptor antagonist (IL1RN) gene (OMIM*147679), which encodes the IL-1 receptor antagonist (IL-1Ra). Mutations in both alleles result in either complete absence or dysfunction of IL-1Ra and thus unopposed binding of IL-1α and β to the IL-1 receptors [4, 196].

The disease has been reported in only a handful of families of various ethnicities living in Northern Europe and Central America. The disease presents in the immediate neonatal period with a pustular rash, joint swelling, multifocal osteitis of the ribs and long bones, heterotopic ossification and periarticular soft-tissue swelling [4, 113, 143, 196].

The diagnosis is made on clinical criteria. The disorder should be suspected if there is a pattern of autosomal recessive inheritance. The diagnosis can be confirmed with DNA analysis.

Treatment is replacement of IL-1R antagonist with its recombinant form, anakinra [4].

Majeed Syndrome (OMIM*609628) was first reported in 1989 as an autosomal recessive syndrome, characterized by chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anemia and in some cases neutrophilic dermatosis [151].

The disease was found to be due to mutations in the Lipin2 (LPIN2) gene (OMIM*605519) on chromosome 18 in 2005 [73]. Lipin2 is widely expressed in the liver, the kidneys, the gut, and lymphoid tissues, including the bone marrow. Lipin2 protein is thought to play role in lipid metabolism although its exact function and how mutations may cause an inflammatory phenotype is not established.

The disorder has been described in only a handful of children. Disease onset is usually in the neonatal period and attacks consist of several days of fever, severe pain, and the appearance of periarticular soft tissue swelling. Long-term complications of growth retardation and flexion contractures are well recognized.

The diagnosis is made on clinical criteria. The disorder should be suspected if there is a pattern of autosomal recessive inheritance. The diagnosis can be confirmed with DNA analysis.

There have been reports of modest benefit from NSAIDs and corticosteroids. Recent case reports suggest IL-1 blockade with anakinra (IL-1RA) and canakinumab is more effective although the long-term effect on dyserythropoesis is not yet known [99]

Deficiency of IL-36 receptor antagonist (DITRA) or generalized pustular psoriasis (GPP) (OMIM*614204) is an autosomal recessive disease, characterized by recurrent episodes of a generalized sterile pustular rash accompanied neutrophilia, a marked acute phase response and fever.

The disorder is due to mutations in IL-36 receptor antagonist (IL36RN) (OMIM*605507) on chromosome 2 and was identified in 2011 [152, 176]. To date 14 nonsense or deletion mutations have been described. Loss of the IL-36R antagonist is thought to result in unregulated signaling by IL-36 α, β, and γ via the Il-36 receptor. IL-36R antagonist is expressed in keratinocytes and a mouse model supports a central role of IL-36 signaling in psoriatic disease [20].

This extremely rare disease was initially reported in kindreds from North Africa and Japan with recurrent episodes of a generalized sterile pustular rash accompanied neutrophilia, a marked acute phase response and fever. Age at onset varied from childhood to the sixth decade. Episodes could be precipitated by stress, pregnancy or drugs and they could be life threatening [69, 152, 176].

The diagnosis is made on clinical criteria. The disorder should be suspected if there is a pattern of autosomal recessive inheritance. The diagnosis can be confirmed with DNA analysis.

There is no established treatment for this rare disorder. Acitretin has been used with variable effect. There is one report of benefit from anakinra [205] and treatment with TNF blockade and cyclosporine have improved some patients [183].

The acronym CANDLE (Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated temperature) (OMIM*256040), also known as Autoinflammation Lipodystrophy and Dermatosis Syndrome (ALDO) or Nakajo-Nishimura Syndrome (NNS), was proposed in 2010 for an autosomal recessive disease, characterized by early onset, fevers, delayed physical development, microcytic anemia, recurrent annular lesions, swollen violaceous eyelids, thick lips, progressive lipodystrophy and arthralgia [240]. Therefore it could also be named as Joint contractures, Muscular atrophy, microcytic anemia, and Panniculitis-induced lipodystrophy (JMP) syndrome. The acronym proteasome-associated autoinflammatory syndrome (PRAAS) is also used as an umbrella term.

The syndrome was initially described as due to substitution mutations in proteasome subunit beta type 8 (PSMB8) gene (OMIM*177046) on chromosome 6. Most patients are homozygote but in some cases mutations in other proteasome genes have been found [24]. PSMB8 encodes the inducible β5i subunit of the immune proteasome. Proteasomes are ubiquitously expressed and are involved in proteolysis, generating antigenic peptides for class I MHC presentation and maintenance of cell homeostasis. It is suggested that failure of proteolysis leads to accumulation of damaged proteins, increased cellular stress and increased interferon (IFN) signaling. Cytokine profiling and analysis of the transcriptome was consistent with dysregulation of the IFN pathway in four children [2, 11, 83, 128].

Recent studies have shown that mutations in other proteasome genes (PSMA3, PSMA4, PSMB9 and POMP) may also cause the disease [24]. These genes encode other subunits of the proteasome (PSMA3, PSMA4, PSMB9 and POMP). The inheritance is diallelic, but in the case of mutations in POMP autosomal dominant.

CANDLE was initially described in four patients with early onset, fevers, delayed physical development, microcytic anemia, recurrent annular lesions, swollen violaceous eyelids, thick lips, progressive partial lipodystrophy and arthralgia. Skin biopsies demonstrated a perivascular and interstitial infiltrate comprising mature neutrophils and atypical mononuclear cells of myeloid lineage [240]. Nakajo-Nishimura syndrome (NNS) was first described in Japan in 1939 as secondary hypertrophic osteoperiostosis with pernio and is characterized by partial lipomuscular atrophy, clubbing, a pernio-like, heliotrope-like, or nodular erythema-like rash, periodic fever and joint contractures. More than 20 cases have been reported with evidence for a common founder [11]. Joint contractures, muscle atrophy, microcytic anemia and panniculitis-induced childhood onset lipodystrophy (JMP) syndrome was described in 2010 in three adults from a Portuguese kindred and another from Mexico [83]. It is possible that the muscle involvement and joint contractures may be later onset complications of progressive disease in untreated or partially treated patients who survive beyond childhood.

Treatment attempts, including anti-TNF agents and the interleukin-6 (IL-6) receptor blocker tocilizumab, were only partially effective [146]. There is an ongoing clinical study (ClinicalTrials.gov Identifier: NCT01724580) of Janus Kinase (JAK) inhibitors with the aim of reducing IFN gamma-inducible protein 10 production.

Very early onset of inflammatory bowel disease (VEO-IBD) is very rare and presents with severe enterocolitis and perianal manifestations. Extra-intestinal manifestations include recurrent fever, and often folliculitis and arthritis. The disease is autosomal recessive disease (OMIM*613148 and #612567), caused by mutations in IL10RA (OMIM*146933), IL10RB (OMIM*123889) or IL-10 (OMIM*124092) genes [87, 88]. Recently, haploinsufficiency of NFAT5 (OMIM*604708) has also been reported in a case with autoimmune enterocolopathy and infections [22]. Mutations in ADAM17 gene has also been reported in two siblings of a family with inflammatory skin and bowel disease [19].

There is a defect of the IL-10 axis either by loss-of-function of one of the two receptors (IL10 receptor α-chain, or IL10 receptor β-chain) or less commonly IL10. IL10 is a major anti-inflammatory cytokine that can be induced in response to colonic colonization. Decreased ILl0 signaling causes a dysregulated proinflammatory cytokine response that affects macrophage activation [219].

Children develop severe inflammation in the colon and the perianal region with onset before the age of 3 months. These symptoms can be accompanied by recurrent fever, increased inflammatory markers, infections, folliculitis, arthritis, aphthous lesions. Some develops B-cells lymphoma. The patients are in a hyperinflammatory state.

The disease should be thought of in a child with very early onset (<3 months of age) of severe inflammatory bowel disease with perianal fistules [245, 263]. Signs of autoimmunity are absent.

Early onset inflammatory bowel disease is a severe disease and mainly refractory to standard immunosuppressant treatments. HSCT has been used as a curative treatment in small case series [68].

Autoinflammation and PLCγ2-associated antibody deficiency and immune dysregulation (APLAID; OMIM*614878) is an autosomal dominant extremely rare disease, only described in one family [268]. The disease has the uncommon combination of immunodeficiency and autoinflammation.

The APLAID are caused by gain-of-function mutations in the phospholipase Cγ2 (PLCG2) gene (OMIM*600220). The enzyme phospholipase Cγ2 (PLCγ2) is involved in several immunological pathways and the pathway involved in APLAID is not completely understood. Activation of the NLRP3 inflammasome through Ca2+ signaling may, however, be part of the pathogenesis [36].

In contrast, another disease caused by different mutations (deletions) in the PLCG2 gene is the PLCγ2-associated antibody deficiency and immune dysregulation (PLAID) syndrome [175].

The autoinflammatory signs and symptoms of APLAID include recurrent blistering skin lesions, interstitial pneumonitis with bronchiolitis, ocular inflammation and arthralgia. The immunodeficiency is characterized by recurrent sino-pulmonary infections.