Leyens et al. Orphanet J Rare Dis (2021) 16:326 https://doi.org/10.1186/s13023-021-01945-8

RESEARCH Open Access The combined prevalence of classifed rare rheumatic diseases is almost double that of ankylosing spondylitis Judith Leyens1,2, Tim Th. A. Bender1,3, Martin Mücke1, Christiane Stieber4, Dmitrij Kravchenko1,5, Christian Dernbach6 and Matthias F. Seidel7*

Abstract Background: Rare diseases (RDs) afect less than 5/10,000 people in Europe and fewer than 200,000 individuals in the United States. In rheumatology, RDs are heterogeneous and lack systemic classifcation. Clinical courses involve a variety of diverse symptoms, and patients may be misdiagnosed and not receive appropriate treatment. The objec- tive of this study was to identify and classify some of the most important RDs in rheumatology. We also attempted to determine their combined prevalence to more precisely defne this area of rheumatology and increase awareness of RDs in healthcare systems. We conducted a comprehensive literature search and analyzed each disease for the speci- fed criteria, such as clinical symptoms, treatment regimens, prognoses, and point prevalences. If no epidemiological data were available, we estimated the prevalence as 1/1,000,000. The total point prevalence for all RDs in rheumatol- ogy was estimated as the sum of the individually determined prevalences. Results: A total of 76 syndromes and diseases were identifed, including vasculitis/vasculopathy (n 15), arthritis/ arthropathy (n 11), autoinfammatory syndromes (n 11), myositis (n 9), bone disorders (n 11),= connective tissue diseases =(n 8), overgrowth syndromes (n 3), =and others (n 8).= Out of the 76 diseases,= 61 (80%) are clas- sifed as chronic, with= a remitting-relapsing course= in 27 cases (35%)= upon adequate treatment. Another 34 (45%) diseases were predominantly progressive and difcult to control. Corticosteroids are a therapeutic option in 49 (64%) syndromes. Mortality is variable and could not be determined precisely. Epidemiological studies and prevalence data were available for 33 syndromes and diseases. For an additional eight diseases, only incidence data were accessible. The summed prevalence of all RDs was 28.8/10,000. Conclusions: RDs in rheumatology are frequently chronic, progressive, and present variable symptoms. Treatment options are often restricted to corticosteroids, presumably because of the scarcity of randomized controlled trials. The estimated combined prevalence is signifcant and almost double that of ankylosing spondylitis (18/10,000). Thus, healthcare systems should assign RDs similar importance as any other common disease in rheumatology. Keywords: Rheumatology, Rare diseases, Epidemiology, Vasculitis, Arthritis, Myositis, Fever

Background Rare diseases (RDs) are a complex problem in medicine, and the defnition of a RD varies around the world. Te

*Correspondence: [email protected] European Union (EU) defnes a disease as rare when it 7 Department of Rheumatology, Spitalzentrum-Centre hospitalier, afects less than 5 people in 10,000 living in the EU, which Biel‑Bienne, Switzerland translates to approximately 370,500 individuals being Full list of author information is available at the end of the article afected. In the United States, the Rare Diseases Act of

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2002 defned a disease as rare when it afects less than (FCU), Muckle-Wells syndrome (MWS), and neonatal- 200,000 people. Patients frequently remain undiagnosed onset multisystem infammatory disease (NOMID or for many years, and treatment is often inefcacious. chronic infantile neurologic cutaneous articular syn- Data on prevalence, disease burden, treatment regimens, drome [CINCA]) were originally thought to be three access to healthcare systems, and mortality are, to a great similar but distinct diseases. Further evidence has shown extent, unknown. Tus, RDs remain an unresolved chal- that all three syndromes are the result of mutations in lenge in modern medicine. the same gene, CIAS1. Tey are now referred to as dif- Te classifcation, overall prevalence, and treatment ferent phenotypes of the same disorder, namely cryop- options of rare rheumatic diseases are poorly defned. orin-associated periodic syndrome (CAPS) [11, 12]. Te Disorders may afect the musculoskeletal apparatus with MEFV gene, best known for causing familial Mediterra- arthritis and myalgia but also involve other tissues in the nean fever (FMF) equally demonstrates the importance form of myositis, vasculitis, autoimmune organ involve- of genetics in RDs [13, 14]. Heterozygous mutations in ment, or bone diseases. Patients are often diagnosed MEFV are also found in many children with periodic as having a psychosomatic disorder due to missing or fever, stomatitis, pharyngitis, adenitis (PFAPA) [15, 16]. unrecognized somatic and/or objective fndings. Patients Findings suggest that exon variants in MEFV may also be not only have to cope with their disease burden, but are associated with AOSD [17]. also at risk of developing additional psychiatric comor- With respect to pathogenesis, infectious agents may bidities. For example, patients with undiagnosed diseases also play a role in RDs. As some diseases follow a distinct in Germany have a prevalence of depressive symptoms seasonal pattern, infectious pathogenesis has been sug- three times higher than the average population (22% vs. gested for Kawasaki disease [18, 19], and IgA-vasculitis 8.1%) [1, 2]. On the other hand, a verifed diagnosis may (formerly Henoch-Schönlein purpura) [20, 21]. aid the patient in accepting their diagnosis and coping Furthermore, some diseases are probably modulated with the ensuing symptoms and challenges. However, due by hormonal alterations, such as pachydermoperiostosis to the scarcity of randomized controlled trials, treatment [22]. Although a disease-causing genetic mutation has options for RDs are often limited and remain empirical. been detected [23], males are seemingly more commonly In addition, the defnitions of key symptoms often vary in and severely afected [24]. RDs in rheumatology involve a clinical studies, hampering uniform analyses. variety of tissues and organ systems. For example, joints RDs in rheumatology may be analyzed systematically are afected by pigmented villonodular synovitis [25], by prevalence, genetic background and pathogenesis, the skeletal system by Camurati-Engelmann disease [26], clinical involvement, treatment options, and prognosis. and internal organs by AOSD [27]. Te skin is involved in Prevalence data vary according to age, as well as global pyogenic arthritis, pyoderma gangrenosum, acne (PAPA) and ethnic background. For example, seronegative sym- syndrome [28], blood vessels in granulomatosis with pol- metrical synovitis with pitting edema (RS3PE) has a high yangiitis (GPA) [29], connective tissue in systemic scle- prevalence among the elderly, with 0.09% of all individu- rosis [30], and muscles in inclusion body myositis (IBM) als over the age of 50 years being afected in Japan [3], but [31]. seems to be a quite rare disorder among younger individ- Treatment options often, but not exclusively, include uals. Similarly, the prevalence of adult onset Still’s disease corticosteroids, such as in RS3PE [32] and eosinophilic- (AOSD) varies globally: 3.4–6.9/100,000 in Norway [4], myalgia syndrome [33]. Although research on RDs is 6.77/100,000 in Turkey [5], and 3.9/100,000 in Japan [6]. often limited to retrospective, single center trials or case With respect to ethnic background, the estimated world- reports only, randomized controlled trials (RCTs) have wide prevalence of Gaucher’s disease is 1–2/100,000, been increasingly available in recent years for some con- but in Ashkenazi-Jews the prevalence may be as high as ditions, such as granulomatosis with polyangiitis [34], 1/850 [7]. PFAPA syndrome [35], and FMF [36]. Te pathogenesis and genetic backgrounds of some Te disease course may be classifed as self-limited RDs in rheumatology have been studied increasingly (e.g., Kawasaki disease), chronic with a variable remit- in recent years, and in some cases well elucidated. Blau ting-relapsing course during treatment (e.g., Takayasu syndrome was described in 2001 and is characterized by arteritis), and chronic with a predominantly progressive mutations in the CARD15/NOD2 gene [8] and overex- and difcult to control course (e.g., systemic sclerosis). pression of autoinfammatory cytokines [9]. Interestingly, Te prognosis for RD varies and may be afected by the mutations in CARD15/NOD2 are also associated with primary disease, complications, and treatment, especially other diseases with infammatory involvement, such as long-term immunosuppression. Crohn´s disease and arthritis [10]. Familial cold urticaria Leyens et al. Orphanet J Rare Dis (2021) 16:326 Page 3 of 43

Te objective of this study was to analyze the com- such as commonly reported symptoms, diferent treat- plexity of RDs in rheumatology. Based on data from the ment regimens, and outcomes. However, such studies literature, we identifed some of the most important may involve reporting bias and, thus, are difcult to com- sets of rheumatic diseases and calculated their com- pare. For example, multicentric histiocytosis is a disease bined prevalence. Our data may give better insight into primarily reported in Caucasian women. However, this this area of rheumatology, aid specialized centers for may be due to increased awareness in Western countries. RDs, and raise overall awareness in the healthcare feld. Furthermore, women may consult a doctor more often and simulate a female Caucasian predominance [37]. Most studies scrutinizing RDs are designed as sin- Results gle center, retrospective studies due to a lack of patient Te diseases extracted from the databases are summa- numbers or networks. Larger registries would provide an rized in Table 2 of Appendix. Te 76 syndromes and opportunity to conduct retrospective or prospective and diseases were classifed as follows: vasculitis/vascu- multicenter studies with a greater number of participat- lopathy (n = 15), arthritis/arthropathy (n = 11), autoin- ing patients. Terefore, further development of interna- fammatory syndromes (n = 11), myositis (n = 9), bone tional expert centers and registries is in great demand. In disorders (n = 11), connective tissue diseases (n = 8), recent years, advances have been made due to the estab- which include infammatory as well as non-infamma- lishment of international expert/reference centers. For tory conditions, overgrowth syndromes (n = 3), and example, the Eurofever project for autoinfammatory dis- others (n = 8). A defnitive genetic cause was identifed eases provided classifcation criteria and evaluated treat- in 26 diseases (34%). Out of the 76 conditions, 34 dis- ment options for multiple disorders [38, 39]. eases (44%) were classifed as chronic, primarily pro- In addition, genetic testing has become increasingly gressive, and difcult to control. Twenty-seven diseases available and, thus, more important in recent years. For (35%) were classifed as chronic with a variable remit- example, whole exome sequencing in patients with simi- ting-relapsing course. Six diseases (7%) were classifed lar symptoms without previous knowledge of candidate as self-limited. Acute phase reactants may be elevated genes led to the identifcation of WISP 3 and SLCO2A1 in 49 diseases (64%). Corticosteroids are used as a as the pathogenic mutations in progressive pseudorheu- therapeutic option in 49 diseases (64%). Te mortality matoid dysplasia [40] and primary hypertrophic osteoar- was variable and could not be determined precisely, but thropathy [23]. nine diseases (11%) were considered severe and poten- In this study, we aimed to identify and classify RDs in tially lethal if left untreated. rheumatology. We were able to show that the most com- Prevalence data were available for 28 syndromes and mon symptoms in rare rheumatic diseases are arthri- diseases. For an additional fve diseases, estimated prev- tis (31.0%, 89.3/100,000), followed by vasculitis (26.6%, alence data were already available. For another eight 76.8/100,000), and connective tissue involvement (16.0%, diseases, only incidence data were available. Te preva- 46.1/100,000), which in this study includes infammatory lence of 38 diseases was estimated at 1/1,000,000, for 4 as well as non-infammatory conditions. Importantly, diseases at 1/100,000, and for 1 disease at 1/10,000. Te the total prevalence of a symptom was commonly domi- combined prevalence per 10,000 is given in Table 1 (see nated by only a few comparatively prevalent diseases. For also Figs. 1 and 2). Te summed prevalence of all avail- example, systemic sclerosis (prevalence: 22.5/100,000) able and estimated RDs was 28.8/10,000. makes up 48.8% of all rare rheumatic diseases with con- nective tissue involvement. Discussion Our study has several limitations. First, the nomen- RDs are challenging for patients, healthcare profession- clature for diseases and syndromes is often used inter- als, and societies. Signs and symptoms often remain changeably, and the same disease or a variation in the unrecognized and patients are excluded from specifc same group of diseases is sometimes named diferently. treatment. Patients are frequently diagnosed with a psy- For example, CAPS is formerly known as Muckle-Wells, chosomatic disorder. Conversely, some patients with true CINCA/NOMID, or familial cold autoinfammatory syn- extrasomatic diagnoses insist on the presence of a RD drome [12]. Tis may lead to incomplete search results and cause signifcant expenses to healthcare systems. To and impede the comparability of available studies. Sec- overcome this bias, the importance of RDs should be rec- ond, most prevalence data are almost exclusively based ognized in public healthcare. on retrospective analyses of hospital information or Te knowledge of RDs is mostly available from case questionnaires. Prevalence data also vary according to reports or case studies. On one hand, these studies are ethnic background, geography, and age, which makes important in order to document essential information, the use of overall prevalence data quite uncertain. For Leyens et al. Orphanet J Rare Dis (2021) 16:326 Page 4 of 43

Total prevalence/100.000 per classification 112.5 Vasculitis Arthritis Autoinflammatory Bone disorders Myositis Connective tissue disease 0 90 Others Overgrowth syndromes 89.3

67.5 76.8 alence/100.00

prev 45 46.1

22.5 30,9 Combined 21.11 19.5 4,2 0.3 0 s s s s e ti thri Others matory sorder Ar Myositi di Vasculitis am fl toin Bone Au Overgrowth syndrome Connective tissue diseas Classification Fig. 1 Overview of the total number of diseases in each classifcation

example, FMF or Behçet´s are more common in Mediter- [44]), but rare among all other studied populations [45]. ranean and Middle Eastern populations [41, 42] and rare Tis may be due to a unique HLA haplotype, but other in other regions, demonstrating the difculty in using a environmental factors may also play a role. Furthermore, local geographic prevalence. Similarly, although cur- our estimates of prevalence data may be somewhat inac- rently considered a RD by the European defnition, an curate. We probably underestimated the prevalence by Italian study found an unexpectedly high overall preva- choosing 1 in 1,000,000 rather than 1 in 100,000, and the lence of 8.5/10,000 for cryoglobulinemic vasculitis, which total prevalence of rare rheumatic diseases is likely to be would no longer be defned as a RD. Although this study even higher than our estimate of 29.6/10,000. had some limitations, including the implementation of Prevalence data may also difer depending on age. For a questionnaire leading to a higher participation rate in example, giant cell arteritis is probably extremely rare the elderly population than the younger age groups, we in younger patients but quite frequent in patients older decided to exclude cryoglobulinemic vasculitis from than 55 years of age (UK 250/100,000 [46]), with age- our list of rare rheumatological diseases. Our reasoning independent prevalence data being difcult to obtain. for this was the methodically more accurate estimation Because the overall estimated prevalence may be even of prevalence by this study [43]. A well-known, veri- higher than 1/10,000, we also excluded giant cell arteritis fed RD, systemic sclerosis is quite common in Choctaw from our list of RDs in rheumatology. Native Americans (prevalence 66/100,000 in Oklahoma Similarly, we also excluded systemic lupus erythe- Choctaws and 469/100,000 in full-blooded Choctaws matodes, one of the better known “rare” diseases in Leyens et al. Orphanet J Rare Dis (2021) 16:326 Page 5 of 43

Classification in %/all rheumatic RD 40 Vasculitis Arthritis Autoinflammatory Bone disorders Myositis Connective tissue disease Others Overgrowth syndromes 30 30.9 26,6 20

16,0 %/all rheumatic RD 10 10,7 7,3 6,8 1,4 0.1 0 s s s s e riti th Others matory sorder Ar Myositis di Vasculiti am fl toin Bone Au Overgrowth syndrome Connective tissue diseas Classification Fig. 2 Flow chart of syndrome inclusion in the analysis. After conducting the literature search and analysis with regard to prevalence, four diseases were excluded due to high prevalence, and seven diseases were merged into three, resulting in a total of 76 syndromes included in further analysis

rheumatology from our study, as recent epidemiological etiology in common. However, overlaps between studies suggest that it is probably not a rare disease by the included conditions may have occurred because of the above mentioned European defnition [47]. Furthermore, complex nature of some RDs. we also excluded rhupus syndrome, because it is sus- Another pitfall is that diagnostic and/or classifcation pected to be an overlap of systemic lupus erythematodes criteria may difer in varying defnitions of the diseases and rheumatoid arthritis and thus its prevalence may be (e.g., familial Mediterranean fever), are not well estab- difcult to obtain and distinguish [48]. lished, and have been suggested based on radiographic or Te classifcation system we used also has its limita- histological fndings. In most cases, no validation studies tions. Conditions can be classifed by their etiology or are available to confrm specifcity and sensitivity. by their clinical appearance. As the etiology of many rare We observed that RCTs are available only for some diseases remains unknown, we decided to classify dis- RDs, such as Behcet´s disease [49] or ANCA-associated eases according to their main organ system involved in vasculitis [34]. Furthermore, most follow-ups of patients the clinical appearance of the disease. Exceptions include with RDs are rarely published. Larger patient cohorts the category of autoinfammatory and overgrowth syn- would be necessary to obtain reliable data on outcome, dromes, where multiple organ systems may be involved, disease progression, morbidity, and mortality. Treatment and the conditions in one group have a basic (suspected) complications in most, if not all, RDs may be due to the Leyens et al. Orphanet J Rare Dis (2021) 16:326 Page 6 of 43

Literature search: 88 syndromes identified

Excluded: N = 5 - Reactive arthritis Literature analysis/ - Polymyositis/scler prevalence oderma overlap - Systemic lupus erythematodes - Cryoglobulinemic vasculitis - Giant cell arteritis Merged: N = 7 —> 3 - CAPS (CINCA, Muckle-Wells, familial cold urticaria) - CREST/systemic sclerosis - Dermatomyositis/ polymyositis Total syndromes included in analysis: 76

Fig. 3 Overview of the combined prevalence per 100,000 per classifcation

disease itself or adverse events to immunosuppressive disease) [50]. Tis trend may be due to a true increase treatment. Tese data merit in-depth analyses, as they in incidence, increased diagnosis of previously undiag- may shed more light on the disease and its pathophysiol- nosed patients due to an upsurge in physician or patient ogy or potential treatment options. awareness (internet, patient support groups, RD asso- Incidence and prevalence data have become available ciations, etc.), or simply due to better national reporting for increasingly more RDs and, in some cases, the preva- systems and databases. In addition, an increased overall lence has even increased in recent years (e.g., Kawasaki life expectancy in the general population has led to an Leyens et al. Orphanet J Rare Dis (2021) 16:326 Page 7 of 43

increased incidence and prevalence of conditions that infammation, joint pain, muscle pain, myalgia, and predominantly afect the elderly (e.g., GCA). Continu- swollen joint. Identifed syndromes were then classifed ously better treatment options may also lead to prolonged according to their main appearance under the following overall survival with an increase in prevalence rates. terms: arthritis/arthropathy, bone disorders, autoinfam- In this study, we found that the cumulative prevalence matory syndromes, connective tissue diseases, myositis/ of RDs in rheumatology is at least 28.8/10,000, which is myopathy, overgrowth syndromes, vasculitis/vasculopa- almost double that of ankylosing spondylitis (18/10,000) thy, and others. Furthermore, we conducted a search [51], a rather common disease seen in practice. Tis of the literature and analyzed each disease according to observation suggests that symptoms should be carefully the following criteria: prevalence, genetics/pathogen- acknowledged in all patients, especially when an overt esis, diagnostic criteria, symptoms, laboratory fndings, psychopathology is present, as many patients with a yet therapy, and prognosis. Diseases and syndromes were undiagnosed disorder show signs of depression or other assessed for their overall prevalence and excluded if they psychosomatic disorders [1], which can obscure the dif- did not meet the European defnition of a RD (< 5/10,000) ferentiation between primary disease and secondary (see Fig. 3). complication even more for the treating physician. Our If more than one prevalence was available, the preva- study may aid physicians as a simple tool for diagnosing lence data were averaged accordingly. patients with an undiagnosed rheumatic disease by com- For statistical reasons, we estimated the prevalence for paring the symptoms, prevalence, and likeliness of one diseases for which no epidemiological data were available disorder to another. as one of three possible values: < 1/1,000,000, 1/100,000 or 1/10,000. Te overall total prevalence for all RDs in Conclusion rheumatology was estimated by summing up the avail- Our study shows that RDs in rheumatology are not as able or estimated individual prevalence of each disease. rare as previously thought, afecting at least 28.8/10,000 people. Terefore, for every patient diagnosed with anky- losing spondylitis, 1.6 patients may sufer from a rare Appendix rheumatic disease. Although research and case reports See Table 1, 2. of RDs are important, international expert centers are necessary to initiate and perpetuate patient cohorts and registries, establish classifcation/diagnostic criteria, and Table 1 Results from the literature analyses conduct clinical trials. Standard questionnaires and labo- Classifcation N Combined %/All RD ratory analyses may aid in obtaining better insight into = prevalence/100.000 (prevalence) the pathophysiology of RDs. Vasculitis 15 76.8 26.55 Methods and materials Arthritis 11 89.3 30.9 Autoinfammatory 11 21.105 7.32 Te abstract archives of the European League Against Bone disorders 11 4.15 1.44 Rheumatism, the American College of Rheumatology, Myositis 9 19.5 6.76 Orpha.net, and the PubMed database were searched for Connective tissue disease 8 46.1 15.99 the following terms: “rare” in combination with arthri- Others 8 30.89 10.72 tis, arteritis, connective tissue disease, rheumatic, and Overgrowth syndromes 3 0.3 0.1 vasculitis. Furthermore, terms were used in various Total 76 288.15 100 combinations including arthralgia, autoimmune, fever, Leyens et al. Orphanet J Rare Dis (2021) 16:326 Page 8 of 43 lopathy lopathy lopathy Classifcation Vasculitis/ vascu - Vasculitis/ Vasculitis/ vascu - Vasculitis/ Vasculitis/ vascu - Vasculitis/ relapsing, life life relapsing, expectancy usually normal, but morbidity (e.g., increased amputations) remitting- main relapsing, complication with increased mortality is - cardiomyopa but overall thy mortality low systemic variant,systemic variantsystemic 50% has over mortality within 2–3 years bowel to (due perforation and peritonitis) Prognosis/ Prognosis/ Complications Remitting- Chronic or Chronic Limited and Limited - tion, prosta glandin analogs, blood maximize reduce supply, risk of vasocon - striction (avoid etc.) coldness. - immunosuppres rituximab sants, treprostinil, treprostinil, eculizumab Therapy Smoking cessa - Corticosteroids, Corticosteroids, Anticoagulants, Anticoagulants, - - - ers usually normal positive (mainly positive but MPO, 3 also proteinase possible), eosino philia; depending involve on organ ment, elevated enzymesrenal possible; elevated IgG4 can be found some patients Laboratory fndings Infammatory mark 30 – 40% ANCA- Coagulopathy in Coagulopathy - - - - - middle-aged, pre dominantly males; ischemic pain in numb extremities, skinness, ulcera - thrombo tions, Raynaud´s phlebitis, phenomenon dle-aged males and asthma, females; loss, weight mononeuritis multi - plex, non-erosive sinusitis/polyposis, skin lung lesions, pleural infltrates, - efusion, cardiomy glomerulo opathy, nephritis years, papu - 20–50 years, lar skin lesions with central atrophy and peripheral rim,telangiectatic sudden onset involve systemic ment possible with high morbidity and mortality (bowel perforation,- throm hemorrhage)bosis, Clinical features Clinical Disease onset in Disease onset in mid - Onset usually at age diagnostic diagnostic by criteria (e.g., and Shionoya Olin) Chapel Hill nomenclature defnition histopathological histopathological diagnosis Diagnostic Diagnostic criteria Many diferent diferent Many ACR criteria, ACR Clinical and - - - mediated vas - mediated possibly culitis, with associated agent; infectious associa - strong tion with smok ing; segmental ing; segmental infam - occlusive matory vasculitis (mainly small arteriesvessels, and veins) multiple diferent multiple diferent HLA genotypes, possibly IgG4- disorder; related cells and Th-2 eosinophils seem a major play to in pathogen - role esis; small vessel necrotizing vasculitis somal dominant inheritance discussed; thrombo-obliter vasculopa - ative thy Genetics/ pathogenesis Probably immune- Probably Association with Association Unknown; auto Middle and Far East, Middle and Far prevalence: estimated 5/100,000 (Japan) 0.65/100,000 (Taiwan) → 2.8/100,000 (estimated, Japan) (estimated, 10.7/1,000,000 (France) 14/1,000,000 (Sweden) → 1.4/100,000 cases reported, esti - cases reported, < 1/1,000,000 mate Prevalence Most common in 17.8/1,000,000 Unknown, less than 200 - Overview rheumatic diseases of rare - (thromboangii tis obliterans) [ 52 – 56 ] granulomatosis granulomatosis with polyangiitis Churg- (EGPA, Strauss syn - [ 57 – 63 ] drome) (malignant (malignant papulo atrophic sis) [ 64 – 67 ] 2 Table Disease Buerger’s disease Buerger’s Eosinophilic Eosinophilic Degos disease Leyens et al. Orphanet J Rare Dis (2021) 16:326 Page 9 of 43 lopathy lopathy lopathy Classifcation Vasculitis/ vascu - Vasculitis/ Vasculitis/ vascu - Vasculitis/ Vasculitis/ vascu - Vasculitis/ - massive hemop massive tysis and aneu - rysmal rupture main causes are of death depending on organ systemic involvement (pulmonary, cardiac), renal, mortality low prognosis if prognosis but treated, coronary artery abnormalities occur in 25% if left untreated, leading cause of acquired heart disease in - in devel children oped countries Prognosis/ Prognosis/ Complications Poor prognosis, prognosis, Poor Chronic, prognosis prognosis Chronic, Self-limited, good Self-limited, - - pressants, pressants, anticoagulant/ thrombolytic surgeryagents, immunosup pressants immunosup immunoglobu - high dose lins, aspirin Therapy Corticosteroids, Corticosteroids, Corticosteroids, Corticosteroids, Intravenous - mia, elevated ESR mia, elevated and CRP levels, anti-C1q-levels, antibodies leukocytosis, thrombocytosis Laboratory fndings Leukocytosis, ane Leukocytosis, Low complement Low Elevated CRP, ESR, CRP, Elevated - - males afected, males afected, multiple lung aneurysms cause cough, dyspnea, chest pain, fever, hemoptysis middle-aged chronic females, urticarial exan - - thema, angi oedema, arthralgia/ arthritis, ocular infammation, glo merulonephritis, abdominal pain, angioedema, obstructive pulmo nary disease children until the children age of 4 years with male afected predominance; conjunctivitis, exanthema, GI fever, symptoms, oropharynx involvement, lymphadenopa - cracked lips, thy, erythema of hand coronaryand feet, aneurysm Clinical features Clinical Predominantly young young Predominantly Predominantly in Predominantly Predominantly young young Predominantly radiographic radiographic diagnosis by Schwartzby et al. Association Association guidelines, (AHA) but primarily clinical diagnosis, as incomplete is presentation common Diagnostic Diagnostic criteria Clinical and Proposed criteria Proposed American Heart - - angiodysplasia angiodysplasia and infections discussed, variantmaybe of Behcet´s disease; absence of oral/ genital ulcers important for distinction described, SE1L3 described, possible asso ciation with SLE; infammation of dermal capillaries and postcapillary possibly venules; IgG4-related disease but genetic predisposition suspected (much common more probably in Asia), triggerinfectious (seasonal peaks) causing small and medium vasculitis vessel Genetics/ pathogenesis Unknown; Mutations in DNA Unknown, years years described, esti - described, < 1/1,000,000 mate < 1/1,000,000 mate incidence ranges from incidence ranges from 3.7/100,000 (Australia) 243/100,000 (Japan)to for < 5 children in and increased esti - years, previous < 1/100,000 mate Prevalence Unknown, ~ 40 cases Unknown, esti - Prevalence unknown, Prevalence - - (continued) syndrome syndrome (incomplete/ cardiovascular Behcet´s disease) [ 68 , 69 ] mentemic urtimentemic - carial vasculitis (McDufe syn - [ 70 – 74 ] drome) (mucocutane ous lymph node [ 18 , syndrome) 75 – 77 ] 2 Table Disease Hughes-Stovin Hughes-Stovin Hypocomple Kawasaki disease Leyens et al. Orphanet J Rare Dis (2021) 16:326 Page 10 of 43 lopathy lopathy lopathy Classifcation Vasculitis/ vascu - Vasculitis/ Vasculitis/ vascu - Vasculitis/ Vasculitis/ vascu - Vasculitis/ monly remitting- with relapsing treatment, survivaloverall good relapsing with relapsing treatment, poor prognosis without therapy, complica - tions include end-stage disease, renal cardiovascular involvement, and malignancy, infections with remitting- course, relapsing increased mortality in case of arterial and neurological involvement, possible cause of blindness Prognosis/ Prognosis/ Complications Variable, com - Variable, Remitting- Chronic disease Chronic - pressants immunosup - immunosuppres sants (rituximab, cyclophospha - mide) colchicine, colchicine, - immunosuppres biologicals, sants, small molecules, anticoagulants Therapy Corticosteroids, Corticosteroids, Corticosteroids, Corticosteroids, Corticosteroids, Corticosteroids, - - sis, elevated renal renal elevated sis, enzymes scopic hematuria enon, leukocytosis Laboratory fndings Anemia, leukocyto MPO-ANCA, micro - Pathergy-phenom - years). years). ≥ 60 ous variant with palpable purpura and lesions (often extrem - on lower ity), or systemic involvement organ possible (most commonly renal) commonly afected commonly afected onset than females, primarily in elderly (age Dyspnea, cough, hemoptysis, rapidly progressive glomerulonephritis, palpable purpura, GI symptoms, - peripheralneuropa thy in third decade in third age (any of life possible), recurrent infammation eye (iridocyclitis/uvei - tis), oral and genital skin- ulcers, manifes tations (erythema nodosum, etc.), arthralgia,- throm neurological bosis, cardiac symptoms, involvement Clinical features Clinical Limited cutane Limited Males slightly more Males slightly more Peak of disease onset Peak - (histopathologi cal) - (histopathologi cal) criteria exist (e.g., criteria exist (e.g., New Interna - tional Criteria of Disease) Behçet’s Diagnostic Diagnostic criteria Chapel Hill criteria Chapel Hill criteria Many diferent diferent Many - than 50% idi - other opathic, possible causes include malig - - autoim nancy, mune diseases, drugs (antibiot ics, NSAIDs); ics, neutrophilic infammation in postcapillary venules related to MHC II to related - genes; environ mental (silica) - and autoim mune infuence discussed; small - necrotiz vessel, ing vasculitis or no with few immune depos - primarilyits, kidneysafecting and lungs HLA-B51; most common along the ancient silk infectious road; or environmental triggers; systemic vasculi - occlusive tis discussed Genetics/ pathogenesis Unknown; more Unknown; possibly Association with Association incidence 4.5/1,000,000 < 1/1,000,000 estimate 94/1,000,000 (Sweden) 94/1,000,000 (Sweden) → 6/100,000 Scandinavia: 2/100,000 Scandinavia: 188/100,000 (80–370/100,000), 5/10,000 estimate Prevalence Prevalence unknown, Prevalence 25.1/1,000,000 (France) 25.1/1,000,000 (France) Estimated prevalence in prevalence Estimated 10.5/100,000 Europe: Mediterranean: Others: 15.7/100,000 Turkey in Not rare (continued) cutaneous small - vessel/hypersen sitivity vasculitis [ 78 – 80 ] polyangiitis polyangiitis (microscopic polyarteritis) [ 58 , 59 , 81 82 ] [ 41 , 83 – 85 ] 2 Table Disease Leukocytoclastic/ Microscopic Behçet’s disease Behçet’s Leyens et al. Orphanet J Rare Dis (2021) 16:326 Page 11 of 43 lopathy lopathy Classifcation Vasculitis/ vascu - Vasculitis/ Vasculitis/ vascu - Vasculitis/ - are common are acute, remitting- acute, relapsing (10–20%) course - possible; poten tially life-threat remission ening, can be achieved cases, in many good survival if treated rate early Prognosis/ Prognosis/ Complications Chronic, relapses relapses Chronic, Variable; chronic, chronic, Variable; - pressants underlying potassium cause, NSAIDs, iodide, corticosteroids, immunosup - immunosuppres sant, biologicals (TNFi), antivirals, NSAIDs Therapy Treatment of Treatment Corticosteroids, Corticosteroids, - underlying cause elevated, leuko elevated, cytosis, anemia, occasionally hypereosinophilia, hepatitis serology, enzymes,liver ANCA negative Laboratory fndings Depending on ESR and CRP - nance, recurrent recurrent nance, usually nodules, on posterior lower with focal legs, ulceration and heal drainage, with scarring and post-infammatory hyperpigmentation malaise, weight weight malaise, arthral- fever, loss, livedo ulcers, gia, racemosa, myalgia, mononeuritis multi - plex, purpura, GI kidneysymptoms, orchitis, infarctions, hearing loss; no pulmonary involve ment! Clinical features Clinical - predomi Female Male predominance, Male predominance, - (histopathologi cal) Diagnostic Diagnostic criteria Chapel Hill criteria - - - - sensitivity reac tion suspected; with associated - drugs (propylthi - ouracil), infec tious (tuberculo or type IV hyper hepatitis) or sis, non-infectious diseases (leuke mia, RA); difuse panniculitis with neutrophilic vasculitis yarteritis nodosa; mutations in CECR1 , leading defciencyto in adenosine deaminase 2 other (DADA2); idiopathic, forms: cutaneous, and infection- (HBV);associated medium vessel, necrotizing vasculitis with segmental, infamma - mixed tory at infltrates branching points - and microaneu rysms in (often renal, hepatic, and mesenteric arteries), that the lung spares Genetics/ pathogenesis Unknown; type III Early-onset pol - < 1/1,000,000 mate 31/1,000,000 (Sweden) 31/1,000,000 (Sweden) → 3.1/100,000 Prevalence Unknown, esti - 30.7/1,000,000 (France) 30.7/1,000,000 (France) 87 ] (continued) ratum (Bazin nodular disease, vasculitis) [ 86 , tis nodosa (Kussmaul-Maier disease) [ 58 , 59 88 , 89 ] 2 Table Disease Erythema indu - Polyarteri - Leyens et al. Orphanet J Rare Dis (2021) 16:326 Page 12 of 43 lopathy lopathy lopathy Classifcation Vasculitis/ vascu - Vasculitis/ Vasculitis/ vascu - Vasculitis/ Vasculitis/ vascu - Vasculitis/ lable with medi - cation, relapses common, fatal in the past, current mortality ~ 15% but remitting- course relapsing poor possible, in prognosis case of renal involvement, prognosis worse in adults overall survival,overall cardiovascular disease is most common cause - of death (infarc tion, thrombosis, etc.) Prognosis/ Prognosis/ Complications - control Chronic, Usually self-limited, Usually self-limited, Chronic, good Chronic, - - + immu - oids nosuppressants nosuppressants cyclophos - (e.g., phamide) pressants teroids, immu - teroids, noglobulins, immunosup - immunosuppres biologicals sants, (TNFi, IL-6i) Therapy Corticoster NSAIDs, corticosNSAIDs, - Corticosteroids, Corticosteroids, - systemic disease, disease, systemic infammatory markers in blood but normal, are cerebrospinal fuid should be investigated leukocytosis, ane mia, proteinuria MMP-3 levels, levels, MMP-3 PTX-3 Laboratory fndings Because of lack Increased ESR, CRP, Increased ESR, CRP, Elevated CRP, ESR CRP, Elevated years, years, ≥ 50 mon in white males mon in white age depending on localization dif - symptoms ferent occur: headache, dementia, stroke, menin - chronic personality gitis, changes children afected, afected, children purpuric rash, abdominal pain, joint pain, edema, involvement renal nance, fever, fever, nance, weight fatigue, headache, loss, in blood diferences of extremi - pressure “pulseless ties, disease” Clinical features Clinical Disease most com - Predominantly male Predominantly - predomi Female - by Calabrese and Calabrese by Mallek, histo criteria by logical et al. Alrawi by Michet by et al., EULAR pediatric criteria Diagnostic Diagnostic criteria Proposed criteria Proposed ACR criteria, criteriaACR ACR criteria ACR - agents sug - as triggested - segmental gers, infammation of CNS vessels reports describe to relationship HLA diferent genes and MEFV gene muta - tions; infectious agent suggested in children (seasonal peak in fall and winter), in adults linked cancer;to small- leukocytovessel clastic vasculitis genes: HLA FCGR2A/ variants, , IL12B ; FCGR3A frequent more aorticin Asia; vessel and large vasculitis Genetics/ pathogenesis Diferent infectious infectious Diferent Unknown; several Diferent candidate candidate Diferent incidence: 2.4/1,000,000 3–26.7/100,000 in chil - 0.8–1.8/100,000 dren, estimate in adults, 1/100,000 → 1.7/100,000 Prevalence Prevalence unknown, Prevalence < 1/1,000,000 estimate Incidence 2.82/100,000 (Korea) 4.7/1,000,000 (UK) 22/1,000,000 (Norway) 12.8/1,000,000 (Turkey) (continued) tral nervous vasculitis system (PACNS/primary of the angiitis CNS) [ 90 – 93 ] purpura (IgA vasculitis) [ 21 , 94 , 95 ] [ 96 – 100 ] 2 Table Disease Primary cen - Henoch-Schonlein Takayasu arteritis Takayasu Leyens et al. Orphanet J Rare Dis (2021) 16:326 Page 13 of 43 lopathy thy Classifcation Vasculitis/ vascu - Vasculitis/ Arthritis/ arthropa - are veryare com - mon, infections main cause are of death self-limiting, 1/3 self-limiting, 1/3 relapsing, overall chronic; survival good, complications include MAS Prognosis/ Prognosis/ Complications Chronic, relapses relapses Chronic, Variable; 1/3 Variable; - - immunosuppres sants (rituximab, cyclophospha - azathio mide, prine) teroids, DMARDs, DMARDs, teroids, - immunosuppres biologicals sants, IL-6i) (IL-1i, Therapy Corticosteroids, Corticosteroids, NSAIDs, corticosNSAIDs, - - - matory markers, ANCA positive 3 (proteinase in 80%), urine analysis - mia, hypoalbu minemia, elevated enzymes,liver ESR and elevated ANA, ACPA CRP; and RF usually elevated negative, mild pro ferritin, teinuria, increased IgE or elevated β2-microglobulin Laboratory fndings Elevated infam - Elevated Leukocytosis, ane Leukocytosis, - arthralgia, anorexia, fever, loss, weight ear/ oral ulcers, nose/throat manifestations typical: mani - eye (scleritis/ festations nasal etc.), uveitis, epistaxis, discharge, upper airway obstructive disease afected, disease afected, onset often at age fever, 17–35 years, maculopapular rash, arthralgia/ arthritis (most com - monly big joints), lymphadenopathy, hepatospleno pleuritis, megaly, pericarditis, eye pneumonitis, involvement, abdominal pain, alopecia, myalgia, weight throat, sore cranial nerveloss, palsy Clinical features Clinical Malaise, myalgia, myalgia, Malaise, Females slightly more slightly more Females - - Chapel Hill crite ria (histopatho logical) Fautrel criteria Fautrel Diagnostic Diagnostic criteria ACR criteria, ACR Yamaguchi criteria, Yamaguchi - - ; infectious, PINA1 ; infectious, environmental (decreasing north–south and gradient), drug-induced triggers sus - pected; ANCA- small associated, vasculitis vessel suspected: HLA SER variants, ent triggers - suspected (infec - malignan tions, medications, cies, vaccinations) related to MIF , to related HLA antigens, MEFV ; difer Genetics/ pathogenesis Diferent genes Diferent Unknown; possibly 23.7/1,000,000 (France) 23.7/1,000,000 (France) → 9.2/100,000 (Norway) 6.77/100,000 (Turkey) 3.9/100,000 (Japan) → 5.3/100,000 Prevalence 160/1,000,000 (Sweden) 160/1,000,000 (Sweden) 3.4 – 6.9/100,000 (continued) with polyangiitis with polyangiitis formerly (GPA, - granu Wegener [ 29 , lomatosis) 58 , 59 101 ] Still’s disease Still’s Wissler’s (AOSD, [ 4 – 6 , syndrome) 102 , 103 ] 2 Table Disease Granulomatosis Granulomatosis Adult-onset Leyens et al. Orphanet J Rare Dis (2021) 16:326 Page 14 of 43 thy thy thy Classifcation Arthritis/ arthropa - Arthritis/ arthropa- Arthritis/ arthropa- - - prognosis prognosis good because organ systemic is involvement absent not life-threat ening, but high ening, morbidity ting-relapsing, ting-relapsing, locally aggressive and frequent relapses Prognosis/ Prognosis/ Complications Chronic, overall overall Chronic, Chronic, usually Chronic, Chronic or remit Chronic - - NSAIDs Corticosteroids, Corticosteroids, colchicine, NSAIDs therapy tomy, radiother tomy, immuno apy, Therapy Symptomatic: Symptomatic: Symptomatic: Symptomatic: - synovec Surgical infammation markers be may elevated CRP possible Laboratory fndings No signs of systemic of systemic No signs Infammatory Elevated ESR and Elevated in childhood (age - progres 3–8 years), joint stifness, sive - swell contractures, ing of fnger joints, slow osteopenia, shortlinear growth, osteopenia, stature, arthritis, difculty in walking, genu valgum, hip pain, adult height 3rd usually below normal percentile, intelligence childhood with calcium crystal joint deposition; arthritis/arthralgia, most commonly in knee and other big joints years, age 20–40 years, of pain/swelling joints (mainly knee - tem rarely or hip, poromandibular joint) with “locking phenomenon”, fatigue Clinical features Clinical Disease onset usually Disease onset in early Peak of disease onset Peak - - graphic diagno graphic sis with genetic confrmation radiographic radiographic diagnosis histopathological histopathological diagnosis Diagnostic Diagnostic criteria Clinical and radio Clinical and Radiographic or sive; diferent diferent sive; mutations in WISP3 ; possible efect founder in Turkey; WISP cell mediates and growth in diferentiation chondrocytes autosomal autosomal dominant with variable pen - etrance; CCAL2: mutations in ANKH ; CCAL1: chromosome 8 suspected, but gene not identi - yet fed; increased extracellular pyrophosphate - and forma levels tion of CPPD association with trauma/surgery, lipometabolism; infammatory or process tumor- benign, like process suggested Genetics/ pathogenesis - reces Autosomal Most cases Unknown; possible misdiagnosed as JIA; misdiagnosed - preva estimated lence < 1/1,000,000 < 1/1,000,000 mate (USA), esti - < 1/1,000,000 mate Prevalence Maybe not rare, but Maybe not rare, Unknown, esti - Incidence: 1.8/1,000,000 - (continued) dorheumatoid arthropathy of childhood PPD/ (PPAC/ PPRD/ SEDT-PA) [ 104 – 109 ] - chondrocal cinosis (CPPD deposition disease/CCAL1 and CCAL2) [ 110 – 114 ] nodular synovitis nodular synovitis [ 25 , 115 – 118 ] 2 Table Disease Progressive pseu - Progressive Familial articular Familial Pigmented villo Pigmented Leyens et al. Orphanet J Rare Dis (2021) 16:326 Page 15 of 43 thy thy thy Classifcation Arthritis/ arthropa - Arthritis/ arthropa - Arthritis/ arthropa- - mortality due to infections can usually be with achieved corticosteroid poor use only, if prognosis malignancy- associated gress rapidly into rapidly into gress arthritis mutilans, but most patients achieve spon - remission taneously within 10 years Prognosis/ Prognosis/ Complications Chronic, increased increased Chronic, Good, remission remission Good, Variable, may pro may Variable, - - DMARDs, bio DMARDs, logicals, G-CSF, G-CSF, logicals, splenectomy response to to response corticosteroids, rarely DMARDs treatment used, of underlying malignancy if present teroids, DMARDs, DMARDs, teroids, biologicals, bisphospho nates, treatment treatment nates, of underlying malignancy if present Therapy Corticosteroids, Corticosteroids, Usually excellent Usually excellent NSAIDs, corticosNSAIDs, - - penia, infections, penia, infections, ANA, RF phase reactants, phase reactants, usually RF and autoantibodies negative - anemia, hyperlipi demia, diferent autoantibodies be positive may Laboratory fndings Anemia, neutro Elevated acute acute Elevated Elevated ESR, CRP, ESR, CRP, Elevated - - - females, chronic chronic females, symmetric arthritis joint with severe destruction (often knee, wrist ankle, PIP), hepato MCP, splenomegaly, lymphadenopathy, pleuritis, episcleritis, weight vasculitis, loss afected, sym - afected, metrical of synovitis hands and ankles, sudden onset polyarthritis, pitting edema (especially hands or feet) females (3:1) with females peak of onset in 4th symmetric decade, polyarthritiserosive or spondylitis with axial involvement (most afected joints: distal inter phalangeal joints) with typical papulo nodular skin lesions, involvement organ possible (heart, lung), arthritis skinoften precedes by involvement years Clinical features Clinical More common in More Usually older males Mainly Caucasian nostic criteria Karmacharyaby et al. diagnosis Diagnostic Diagnostic criteria Clinical diagnosis Proposed diag - Proposed Histopathological - - ciation (78%), autoantibodies against neutro phil extracellular traps chromatin anti-GCSF (NETs), antibodies ated with other ated rheumatic condi - infections, tions, and neoplasms (associated malignancy rate and 7% in Asia 31% in Western countries); VEGF in a role play may pathogenesis ferent triggers ferent suspected (malignancies, dis - autoimmune infections/ eases, tuberculosis); crucial workup neoplasms for necessary; macrophages, cytokines, and osteoclastic activity seem in a role play to pathogenesis Genetics/ pathogenesis HLA-DR4 asso Unknown; associ - Unknown; dif - = 1/1,111) years years (not estimated = estimated prevalence 1/10,000 prevalence in Japan 0.09% (90/100,000 > 50 for among elderly), rare 1/100,000 estimate in literature, esti - in literature, < 1/1,000,000 mate Prevalence 1% of RA Unknown, prevalence Unknown, ~ 300 cases (continued) (splenomegaly- neutropenia- rheumatoid arthritis syndrome) [ 119 – 122 ] seronegative seronegative symmetrical with synovitis pitting edema) [ 3 , 32 123 124 ] lohistiocytosis [ 37 , 125 – 127 ] 2 Table Disease Felty syndrome syndrome Felty RS3PE (remitting RS3PE (remitting - Multicentric reticu Leyens et al. Orphanet J Rare Dis (2021) 16:326 Page 16 of 43 thy thy thy Classifcation Arthritis/ arthropa - Arthritis/ arthropa- Arthritis/ arthropa- complications or disease-associ - death rare ated self-limiting or remitting- ~ 50% relapsing, - recov complete riskery, of MAS if untreated, if untreated, increased mortality in case of neurological involvement or occurrence of immune reconstitution infammatory syndrome (IRIS; ~ 10%) Prognosis/ Prognosis/ Complications Chronic disease, disease, Chronic Variable, chronic, chronic, Variable, Chronic, lethal Chronic, - - - costeroids, costeroids, bisphospho nates, antimicro nates, bial treatment, bial treatment, DMARDs, biologicals teroids, DMARDs, DMARDs, teroids, (IL-1, biologicals IL-6) corticosteroids, corticosteroids, bio DMARDs, logicals (IL-1) logicals Therapy NSAIDs, cortiNSAIDs, - NSAIDs, corticosNSAIDs, - Antibiotics, Antibiotics, - - ESR (sometimes), non-spe diferent - cifc autoantibod sometimes P.ies, acnes ferritin, markedferritin, polymorphonu - clear leukocytosis, thrombocytosis, ESR/CRP elevated anemia, thrombo cytosis, reduced IgM and IgA, leukocytosis, RF, may anti-CCP-AB be present Laboratory fndings Elevated CRP and Elevated High of serum levels Elevated ESR, CRP, ESR, CRP, Elevated - - - - °C, skin dominance, onset dominance, often in children or middle-aged adults; infam - painful, matory, sterile (sometimes acnes -positive) P. in (often osteitis anterior chest wall or axial skeleton) with variety of dif - skin diseases ferent (most commonly palmoplantar pustulosis), onset years can be many or after before bone and articular (often involvement or sterno sacroiliac joints) clavicular mation (spiking > 39 fever rash, hepatospleno lymphad - megaly, serositis, enopathy, arthritis afected, intermit afected, polyarthritistent and gastrointestinal any symptoms, can be other organ - (neurol afected cardiovascular, ogy, skin), eyes, lungs, loss, weight fever, abdominal pain, malabsorption, diarrheaheadaches, Clinical features Clinical Slight female pre Slight female Systemic infam - Systemic Predominantly males Predominantly exclusion criteria exclusion Benhamou by Kahnet al., et al. criteria for JIA criteria for diagnosis or PCR diagnosis Diagnostic Diagnostic criteria Inclusion and ILAR classifcation Histopathological - - - - ciation with HLA- B27, possibly other to related genes connected - autoinfam to matory disorders; autoimmune - or infec process tion/molecular ) acnes mimicry ( P. suspected MEFV and MIF- 173 polymor and phism; IL-6 a major play IL-1 role ment discussed; with infection Tropheryma whipplei , pre dominantly male patients and patients with immune modu - latory conditions abuse, (alcohol, disease) chronic afected Genetics/ pathogenesis No clear asso Association with Association HLA-B27 involve 40/100,000 10.5/100,000 can be found whipplei can be found in ~ 10% (Europe)/20% samples of fecal (Africa) population, in healthy < 1/1,000,000 estimate Prevalence Estimated prevalence prevalence Estimated Estimated prevalence prevalence Estimated Tropheryma Unknown, Tropheryma (continued) - terial osteomy elitis (CNO)/ CRMO/SAPHO [ 128 – 132 ] juvenile idi - juvenile opathic arthritis (Still`s disease) [ 133 – 141 ] [ 142 – 149 ] 2 Table Disease Chronic non-bac - Chronic Systemic-onset Whipple’s disease Whipple’s Leyens et al. Orphanet J Rare Dis (2021) 16:326 Page 17 of 43 thy syndrome syndrome Classifcation Arthritis/ arthropa - Autoinfammatory Autoinfammatory - depends on stability of lesion and patient age depends on systemic involvement, ocular severe and articular morbidity signifcantly signifcantly since improved availability of anti-IL-1-treat ment (65–85% complete with remission Anakinra) Prognosis/ Prognosis/ Complications Chronic, prognosis prognosis Chronic, Chronic, prognosis prognosis Chronic, Chronic, prognosis prognosis Chronic, - NSAIDs, surgeryNSAIDs, teroids, immu - teroids, nosuppressants, biologicals, hyper systemic usually tension to responds ACE-inhibitors Therapy Supportive: NSAIDs, corticosNSAIDs, - Biologicals (IL-1) Biologicals matory markers normal thrombocytosis, thrombocytosis, ESR, elevated acute-phase CRP, ACE reactants, normal phase reactants, phase reactants, leukocytosis, anemia; chronic SAA biomarker for of development AA-amyloidosis Laboratory fndings Usually infam - Leukocytosis, Leukocytosis, Elevation of acute Elevation of acute physically active physically or male children Pain adolescents. with (worsening swelling, exercise), joint locking, most often in the knee, joint can be but any afected of life, later boggy later of life, polyarthritis, uveitis, non-caseating epi - thelioid and giant cell granulomas; lymphad - fever, - neuropa enopathy, renal/hepatic/ thy, lung/cardiovascular involvement urticarial rash, infamma - chronic tion, typical facies in CINCA (frontal saddle bossing, back nose), CNS manifestations, polyarthrichronic - conjunctivitis, tis, papilledema Clinical features Clinical Predominantly in Predominantly Skin rash in frst year Intermittent fever, Intermittent fever, diagnosis genetic testing, genetic testing, skin biopsy diagnostic/ clas - diagnostic/ sifcation Diagnostic Diagnostic criteria Radiographic Clinical diagnosis, Clinical diagnosis, Eurofever clinical Eurofever osteonecrosis osteonecrosis of subchondral bone; vascular disruption, multi - ple microtrauma, and genetic predisposition suggested nant, sporadic gonosomal form, mosaicism in NOD2/CARD15 ; NF-κB activation and excessive infammatory cytokine- produc tion nant, gain of function muta - tion in NLRP3/ leads to CIAS1 caspase-1 and infammasome activation with IL-1β increased mosai - secretion; cism possible, usually de novo Genetics/ pathogenesis Unknown; Autosomal domi - Autosomal Autosomal domi - Autosomal → 22/100,000 0.29/100,000 (Denmark), esti - < 1/1,000,000 mate and 1–2/360,000 ( = 4.6/1,000,000) in → estimated France 3.05/1,000,000 Prevalence Incidence 6.09/100,000 15–29/100,000 Estimated Unknown, incidence: 1–2/1,000,000 in US (continued) tis dissecans [ 150 – 152 ] (familial)/early onset sarcoidosis (sporadic)/ pedi - - atric granuloma arthritistous [ 9 , 153 – 158 ] - autoinfamma tory syndrome/ familial cold urticaria, Muckle- syndrome, Wells CINCA syn - drome/NOMID/ IOMID) [ 38 , 39 159 – 161 ] 2 Table Disease Osteochondri - Blau syndrome Blau syndrome CAPS (familial cold Leyens et al. Orphanet J Rare Dis (2021) 16:326 Page 18 of 43 syndrome syndrome Classifcation Autoinfammatory Autoinfammatory - sion and fewer sion and fewer can relapses be achieved therapy, by complications - include amyloi dosis (strongest seems predictor be countryto of and residence) MAS tions include infections, amyloidosis, peritonitis with abdominal adhe and MAS, sions, joint contrac - tures Prognosis/ Prognosis/ Complications - remis Chronic, Chronic, complica - Chronic, IL-1 tase inhibitors, tase inhibitors, corticosteroids, - immunosuppres biologicals sants, (Il-1) Therapy Colchicine, anti- Colchicine, - HMG-CoA-reduc 100 IU/ml), IgA phase reactants leukocytosis, IgD elevated (> elevated in blood, mevalonic acid in urine Laboratory fndings Elevated acute acute Elevated Elevated ESR, CRP, ESR, CRP, Elevated - - - ally in childhood, ally in childhood, age of 90% before recurrent 20 years, and serositis, fever arthralgia, myalgia, abdominal pain, chest vomiting, pain, rash, prodro mal phase with unspecifc symp (restlessness, toms irritability),anxiety, rapid onset of lasting symptoms at least 12 h for episodes starting in infancy (most common before end of 1st year lasts fever of life), and can 4–6 days by be provoked and psy - physical stress; chological lymphadenopathy, splenomegaly, arthralgia, GI symp skintoms, rash, sometimes oral and aphthous vaginal neurological ulcers, symptoms Clinical features Clinical Disease onset usu - Recurrent fever Recurrent fever Eurofever clinical Eurofever - diagnostic/clas sifcation criteria, Tel-Hashomer, Yalcinkaya-Ozen and Livneh- criteria - diagnostic/classi fcation criteria Diagnostic Diagnostic criteria Multiple criteria: Eurofever clinical Eurofever - sive, mutation sive, in MEFV leading abnormalto function of infammasome; environmental factors also seem as a role, play to the patients from eastern Mediter ranean often a milder have phenotype sive, muta - sive, tions in MVK (homozygosity most often, or, compound heterozygosity); MVK essential for syn - cholesterol thesis; increased production of possible IL-1β; in efect founder the Netherlands Genetics/ pathogenesis - reces Autosomal - reces Autosomal geographically; in eastern Mediterranean Turkey 1/500 – 1/1000, - 1/150 – 1/10,000, Ash kenazi Jews 1/73,000 1/10,000 Estimate dence in Germany: 0.39/1,000,000 Prevalence Prevalence highly difers highly difers Prevalence Unknown, inci - < 1/1,000,000 estimate - (continued) nean fever (famil - nean fever ial paroxysmal [ 38 , polyserositis) 162 – 166 ] defciency (hyperimmuno globulinemia D with periodic HIDS) [ 38 , fever, 167 – 170 ] 2 Table Disease Familial Mediterra- Familial Mevalonate kinase Leyens et al. Orphanet J Rare Dis (2021) 16:326 Page 19 of 43 syndrome syndrome Classifcation Autoinfammatory Autoinfammatory - lethal, most lethal, patients die of - or res cardiac piratory failure ting-relapsing Prognosis/ Prognosis/ Complications Chronic and often Chronic Chronic or remit Chronic - kallikrein, dap sone biologicals (IL-1 (IL-1 biologicals β) Therapy Corticosteroids, Corticosteroids, Corticosteroids, Corticosteroids, - - gammaglobuline IgG mia, elevated and IgE, positive ANA described ESR, CRP, chronic chronic ESR, CRP, anemia, hyper IL-1β Laboratory fndings Constantly elevated elevated Constantly Elevated ESR, CRP, ESR, CRP, Elevated - ally at age of 2 months—8 years with pernio-like rash, rash often appears in frst win - after birthter and everyreappears Symptoms year. with cold worsen stimuli; periodic skin rash, fever, high hepato myositis, splenomegaly, partial lipomuscu - joint lar atrophy, (mainly contracture in upper body), shorthyperhidrosis, IQ, low stature, lymphadenopa - described, thy characteristic thin facial appearance, clubbed elongated fngers arthritis, fever, pus - arthritis, fever, abdominal tulosis, pain, hidradenitis, pyoderma acne, gangrenosum, ulcerations Clinical features Clinical Onset usu - Recurrent sterile - diagnostic crite diagnostic NNS ria for with genetic confrmation Diagnostic Diagnostic criteria Distinctive clinical Clinical diagnosis Clinical diagnosis - ably common founder; reduced proteasome activity and accumulation of ubiquitinated and oxidized leading proteins, increased to cytokine levels sive, mutation sive, in PSMB8 ; prob nant, missense mutation in PSTPIP1/ CD2BP1 , which causes - hyperphos phorylation of PSTPIP1 protein and induction of infammasome Genetics/ pathogenesis - reces Autosomal Autosomal domi - Autosomal cases in Japan until 2010 (19 males, esti - 9 females), < 1/1,000,000 mate fve families world- fve wide reported (34 until 2006), esti - < 1/1,000,000 mate Prevalence Unknown, 28 reported Only few patients from patients from Only few (continued) syndrome (NNS) syndrome [ 171 – 173 ] (pyogenic arthri(pyogenic - tis-pyoderma gangrenosum acne syndrome) [ 28 , 39 174 – 177 ] 2 Table Disease Nakajo-Nishimura PAPA syndrome syndrome PAPA Leyens et al. Orphanet J Rare Dis (2021) 16:326 Page 20 of 43 syndrome syndrome syndrome Classifcation Autoinfammatory Autoinfammatory Autoinfammatory - - self-limited self-limited within 4–5 years, normal develop ment ous remission ous remission and relapses common, complications - include amyloi dosis and overt - lymphoprolifera tion retrospective retrospective study 8% (higher mortality in adults) Prognosis/ Prognosis/ Complications Good prognosis, Good prognosis, Chronic, spontane Chronic, Mortality in one - - surgery- (tonsil cime lectomy), anakinra,tidine, colchicine rapidly controls rapidly controls - (diag symptoms nosis should be reconsidered if inefective), canakinumab, colchicine, - pefoxa NSAIDs, cin, hydroxychlo roquine Cyclosporine, Cyclosporine, Biologicals, receptor IL-1 blockade Therapy Corticosteroids, Corticosteroids, Anakinra (IL-1) Anakinra (IL-1) Corticosteroids, Corticosteroids, ferritine, + ferritine, elevated ESR in elevated episodes (rarely IgG) (rarely gammopathy, ESR, elevated κ -light chain, leukocytosis elevated transami - elevated nases low NK cell activlow - sIL2-R elevates ity, Laboratory fndings Leukocytosis and Monoclonal IgM cytopenia, - - - - - usually in early slight male infancy, predominance, episodes last 5 days everyand recur prodro 28 days; mal: aphthous malaise, stomatitis, irritability, fatigue, headache; then sudden onset of phar high fever, lymphad - yngitis, chills, enopathy, cough, headache, abdominal pain, nausea, diarrhea, rash; patients are remarkably healthy between episodes dominance (1.6:1), disease onset in adulthood (mean age 51 years), urticarialrecurrent rash (most constant fever, symptom), muscle/bone/joint pain, lymphad - enopathy megaly, cytopenias, megaly, liver coagulopathy, dysfunction, neuro symptoms, logical lymphadenopathy, skin rash, jaundice, edema Clinical features Clinical Disease onset Slight female pre Slight female Fever, hepatospleno Fever, - by Marshall/by Cantar Thomas; ini et al. nostic criteria diagnostic diagnostic guidelines/2016 MAS criteria for complicating JIA systemic Diagnostic Diagnostic criteria Diagnostic criteria Diagnostic Strasbourg diag - Strasbourg HLH-2004 - patients have patients have heterozygous MEFV mutation, familial occur poly - rence; genetic cause suspected; IL-1 and vitamin D in a role play may pathogenesis involvement of involvement and IL-6 IL-1β suspected Activation of T-lymphocytes and mac - - Pos rophages. sible association NK with impaired - cell cytotoxic ity PRF1 due to mutation Genetics/ pathogenesis Unknown; many Unknown; Excessive Excessive 2.3/10,000 in children 2.3/10,000 in children (Norway), 5 years up to not so rare, probably < 1/10,000 estimate patients, mainly from mainly from patients, esti - Europe, western < 1/1,000,000 mate patients with systemic patients with systemic onset JIA. Prevalence unknown, esti - < 1/1,000,000 mate Prevalence Unknown, incidence Unknown, ~ 250 reported Seen in about 10% of - (continued) (periodic fever, (periodic fever, aphthous phar stomatitis, cervicalyngitis, adenitis; Marshall with syndrome periodic fever) [ 178 – 182 ] drome (chronic (chronic drome urticaria with gammopathy) [ 183 – 186 ] vation syndrome vation syndrome [ 187 – 192 ] 2 Table Disease PFAPA syndrome syndrome PFAPA Schnitzler syn - Macrophage actiMacrophage - Leyens et al. Orphanet J Rare Dis (2021) 16:326 Page 21 of 43 syndrome syndrome Classifcation Autoinfammatory Autoinfammatory Myositis/myopathy - elitis probably elitis probably anemia life-long, in is prominent childhood relapsing, but relapsing, course chronic possible; compli - cations include and amyloidosis MAS prognosis in prognosis case of treat able underly - but ing cause, in most chronic cases Prognosis/ Prognosis/ Complications - osteomy Chronic, Often remitting- Variable, good Variable, - sions, NSAIDs, NSAIDs, sions, corticosteroids, biologicals (IL1 β) ticosteroids, ticosteroids, (most biologicals is promising anti-IL-1) corticosteroids, corticosteroids, DMARDs Therapy Blood transfu - NSAIDS, cor Statin withdrawal, Statin withdrawal, - - anemia with microcytosis, ESR elevated gammaglobuline mia; SAA levels with correlate disease activity leukocytosis, thrombocytosis, anemia, hyper ies present in ies present 16%, anti-HMGCR antibodies seem be specifc and to present in ~ 60% - of patients previ ously exposed to statins; CRP and CK elevated Laboratory fndings Dyserythropoietic Elevated ESR, CRP, ESR, CRP, Elevated Anti-SRP antibod - - - bone and skin, in growth resulting disturbances and joint contractures; high recurrent pain; severe fevers, associ - frequently with cutane ated ous infammatory (e.g., syndromes Sweet psoriasis, syndrome) ally in infancy or attacks childhood, 11 days, last around 70 on average symptomatic with a year days limb high fever, pain, abdominal pain, rash, cervical lymphadenopathy, periorbital edema nance (73%), dysphagia, myalgia, fatigue, loss, weight arthralgia, ILD, Raynaud´s phe nomenon Clinical features Clinical Infammation of Disease onset usu - - predomi Female genetic testing diagnostic/ clas - diagnostic/ sifcation criteria diagnosis Diagnostic Diagnostic criteria Clinical diagnosis, Clinical diagnosis, Eurofever clinical Eurofever Histopathological - - - sive, mutation sive, in LPIN2 , which in fat a role plays metabolism and, mitosis possibly, nant with vari - able penetrance, mutations in TNFRSF1A , difer ent hypotheses ent hypotheses - on pathophysiol including ogy, intracellular trafcking, recep tor shedding, shedding, tor or induction of lead - apoptosis, increase ing to in cytokines; triggers include menstrual stress, cycle, fatigue, exer infections, cise, vaccinations cise, immune-medi - muscle fber ated without necrosis infammation statin due to other drugs, use, or malignancies, connective tissue diseases Genetics/ pathogenesis - reces Autosomal Autosomal domi - Autosomal Unknown; families/14 patients with Middle Eastern esti - reported, origin < 1/1,000,000 mate 1/1,785,714 for chil - 1/1,785,714 for < 16 dren (Germany); most patients are Caucasian, European 1/1,000,000 estimate < 1/1,000,000 mate Prevalence Unknown, only 4 Unknown, incidence Unknown, esti - - - (continued) (chronic recur (chronic multifocal rent osteomyelitis) [ 193 – 195 ] necrosis factor necrosis 1 asso receptor periodicciated famil - syndrome; ial Hibernian [ 38 , 39 fever) 196 – 198 ] autoimmune autoimmune myopathy (anti-HMG-CoA [ 199 , myopathy) 200 ] 2 Table Disease Majeed syndrome Majeed syndrome TRAPS (tumor Necrotizing Necrotizing Leyens et al. Orphanet J Rare Dis (2021) 16:326 Page 22 of 43 Classifcation Myositis/myopathy Myositis/myopathy Myositis/myopathy survival good but decreased in case of lung involvement good prognosis; good prognosis; rhabdomyolysis renal can lead to failure patients improve patients improve time with over - prog treatment, nosis depends on associated diseases (malig - nancies) Prognosis/ Prognosis/ Complications Chronic, overall overall Chronic, Chronic, but Chronic, Variable, most Variable, - - immunosuppres sants (rituximab), DMARDs triggers (fasting, triggers (fasting, prolonged low exercise), fat and high carbohydrate diet, carnitine pressants immunosup Therapy Corticosteroids, Corticosteroids, Avoidance of Avoidance Corticosteroids, Corticosteroids, PL12, many other PL12, many antibodies pos - sibly positive myoglobinuria, myoglobinuria, hepatic steatosis tis-specifc autoantibodies can be found: NXP2/ anti-Jo-1, anti- MJ antibody, 155/140 antibod - anti-MDA5, ies, MI-2-antibodies Laboratory fndings Anti-Jo-1, anti-Pl7/ Anti-Jo-1, Elevated CK,Elevated BUN, - myosi Diferent - more often afected often afected more - at pres than males, entation often only RA-like arthritis, then infammatory inter myopathy, stitial lung disease, Raynaud´s, fever, papules, Gottron´s mechanic´s hands adolescence or males adulthood, commonly more severely and more myalgia, afected; rhabdomyolysis, muscle weakness, pain, lipid accumu - lation in muscle females, myalgia, myalgia, females, arthritis, dyspnea, muscle dysphagia, weakness, rash (not myocarditis, in PM), papules Gottron´s Clinical features Clinical Females 2–3 times Females Disease onset in Predominantly Predominantly - - + antibody sis fndings ment, genetic testing diagnosis Diagnostic Diagnostic criteria Clinical diagno Enzyme measure Histopathological - T-cells) + T-cells) in bodies against anti-threonyl- tRNA-synthetase; to relationship to exposure airborne particles discussed sive, mutation sive, ; CPT is in CPTII in the involved transportation of long chain fatty acids in mitochondria; energy impaired metabolism; triggers frequent physical are and expo stress sure to cold to sure humoral-medi - infam - ated mation in DM, cell-mediated (CD8 often associ - PM; with other ated autoimmune diseases and malignancies Genetics/ pathogenesis Unknown; anti - - reces Autosomal Unknown; of patients diag - nosed with PM/DM; of PM/DM prevalence 15/100,000 → approx. 3.4/100,000 300 published cases, 300 published cases, one of the most common disorders fatty of oxidative acid metabolism, probably prevalence higher than suspected; < 1/100,000 estimate 8.7/100,000 (Norway) 7–10/100,000 (Brazil) → 9.6/100,000 Prevalence Unknown, 20–25% Unknown, than more 10–13/100,000 (Japan) (continued) syndrome syndrome [ 201 – 204 ] of carnitine - palmitoyltrans II) II (CPT ferase defciency [ 205 , 206 ] Polymyositis Polymyositis [ 207 – 210 ] 2 Table Disease Antisynthetase Myopathic form Myopathic form Dermatomyositis/ Leyens et al. Orphanet J Rare Dis (2021) 16:326 Page 23 of 43 Classifcation Myositis/myopathy Myositis/ myopathy Myositis/myopathy Myositis/myopathy - progressing, progressing, most patients wheelchair- within reliant 10 years with systemic with systemic involve organ ment not uncommon within few weeks weeks within few or months, possible relapses but uncommon able in severity; complications include renal and failure cardiovascular diseases Prognosis/ Prognosis/ Complications Chronic and slowly and slowly Chronic Chronic course Chronic Usually self-limited Usually self-limited Chronic, but vari - Chronic, - - immune therapy, immune therapy, - can be used ten in case of tatively other to relation autoimmune diseases ment, corticos - in acute teroids be phase may used tentatively corticoster oids in case of infammation or complications moderately moderately active lifestyle and inges - tion of simple carbohydrates exercise before recommended Therapy Refractory to Supportive treat No treatment, No treatment, No treatment; No treatment; - or normal phils, WBC phils, acute phase acute CK may reactants, but be elevated usually normal CK,- myoglobinu ria,- rhabdomy olysis Laboratory fndings CK may be elevated be elevated CK may Elevation of eosino Usually no elevated Usually no elevated Elevated baseline Elevated - - - (2:1) and elderly, (2:1) and elderly, progressive slowly muscle weakness - begin (often ning in wrists or quadriceps muscle), dysphagia myalgia, cough, myalgia, joint fatigue, fever, pain, edema; long- term symptoms include eosino alo philic fasciitis, pecia, CNS involve ment, myocarditis, GI arrhythmias, involvement in a single muscle, in a single muscle, most commonly in usually limbs, lower painless variability, rapid variability, myalgia fatigue, and cramping with and fast exercise with recovering (“second-wind rest phenomenon”) Clinical features Clinical Predominantly males Predominantly Rapid onset of severe Rapid onset of severe Rapidly growing mass Rapidly growing High clinical - - diagnosis graphic, and graphic, histopathological diagnosis - ment, histopa genetic thology, testing Diagnostic Diagnostic criteria Histopathological Clinical diagnosis Clinical, radio Clinical, Enzyme measure - - , leading somal recessive somal recessive with onset form adults, in young mutations in GNE (very sporadic rare); in elderly, form with associated HLA-DR3 and MHC variants; - environ genetic, aging, mental, and immune- factors mediated related probably pathogenesis to phan associated phan associated with disease onset; increased and IL-4 TGF-β - be responsi may fbrosis ble for consumption of manufactured or L-tryptophan 5-hydroxytrypto factors poorly (e.g., understood trauma) physical sive, mutations sive, in PGYM glycogen to phosphorylase defciency Genetics/ pathogenesis Hereditary auto Unknown; Unknown; trigger - reces Autosomal 10.7 – 71 /1,000,000 (USA) → 3.7/100,000 people afected, people afected, females predominantly in the US (epidemic in 1989), esti - < 1/1,000,000 mate < 1/1,000,000 mate – 1:140,000 (Spain) → 1.4/100,000 Prevalence 33/1,000,000 (Norway) Unknown, 5000–10,000 Unknown, esti - Estimated 1:50,000 (US) Estimated (continued) myositis [ 31 , 211 myositis 212 ] gia syndrome syndrome gia [ 213 ] 215 ] (glycogenosis (glycogenosis type 5) [ 216 – 219 ] 2 Table Disease Inclusion body - Eosinophilia-myal Focal myositis [ 214 , myositis Focal McArdle’s disease McArdle’s Leyens et al. Orphanet J Rare Dis (2021) 16:326 Page 24 of 43 Classifcation Myositis/myopathy Bone disorder Bone disorder Bone disorder tions include and cardiac renal involvement may become may wheelchair- reliant sive, and lethal sive, - within approxi 40 years, mately most patients - wheelchair-reli ant at the end of second decade of life prognosis, prognosis, normal life expectancy Prognosis/ Prognosis/ Complications Chronic, complica - Chronic, Chronic, patients Chronic, - progres Chronic, Benign and good Benign - - - avoid extensive extensive avoid exercise NSAIDs, bispho NSAIDs, sphonates, all sphonates, with vari - able outcomes; experimental: (e.g., anti-TGFβ losartan) muscle relax NSAIDs, ants, Cox-2-inhibitors, corticosteroids, bisphospho nates; opera - nates; tions should be (triggers avoided ups new fare and bone growth) Therapy No treatment; No treatment; Corticosteroids, Corticosteroids, Short-term Symptomatic hemolytic anemia, hyperuricemia, hyperCKemia, reticulocytosis TGF-β1 although ESR be and AP may elevated Laboratory fndings Myoglobinuria, Increased of levels Usually normal, Usually normal, Usually normal - myalgia, cramps, cramps, myalgia, cardiomyopathy bones and skull, bones and skull, limb pain, severe muscle atrophy, wide-based waddling gait, joint progressive hear contractures, absence of ing loss, subcutaneous fat tion, tumor-like and swellings short, malformed (early toes great cervicalsign), spine - osteochon fusions, hearing loss droma, diagnosis usually diagnosis dif - in adolescence, fuse back pain Clinical features Clinical Exercise intolerance, intolerance, Exercise Hyperostosis of long Hyperostosis Heterotopic ossifca - Heterotopic Disease onset and - - - - + radio logical diagnosis, diagnosis, logical genetic testing graphic images graphic clinical fnd - ings graphic, histo graphic, pathological diagnosis diagnosis Diagnostic Diagnostic criteria Histopatho Genetic testing, Genetic testing, Clinical, radio Clinical, Radiographic - sive, mutations sive, in PFKM , leading muscle phos - to phofructokinase defciency nant, mutations , result in TGFB1 ing in increased factor growth signaling dominant (most cases de novo), mutation in , leading to ACVR1 enhanced BMP with signaling - fbroprolifera - tion, angiogen enchondral esis, ossifcation; risk seems to be increased with older age of mother and fathers father, often exposed to chemicals dominant, gene unknown Genetics/ pathogenesis - reces Autosomal Autosomal domi - Autosomal Autosomal Autosomal Autosomal Autosomal 100 cases described, 100 cases described, in Common esti - Ashkenazi-Jews, < 1/1,000,000 mate < 1/1,000,000 mate 1.36/1,000,000 (France) 1.36/1,000,000 (France) worldwide estimated - (litera prevalence 1/2,000,000 → ture): 0.74/1,000,000 - predomi reported, France, nantly from < 1/1,000,000 estimate Prevalence Unknown, than more Unknown, esti - 0.36/1,000,000 (Spain) Unknown, < 50 cases - (continued) (GSD7) [ 220 , 221 ] (GSD7) mann disease (progressive diaphyseal dysplasia) [ 26 , 222 , 223 ] - fcans progres siva (Munch - disease) meyer’s [ 224 , 225 ] sis [ 226 ] 2 Table Disease Tarui disease Tarui - Camurati-Engel Fibrodysplasia ossi - Fibrodysplasia Osteomesopykno Leyens et al. Orphanet J Rare Dis (2021) 16:326 Page 25 of 43 Classifcation Bone disorder Bone disorder Bone disorder Bone disorder expectancy with increased but limited ERT, cardiovascular by func - and renal tion progressive. progressive. Death due to respiratory insuf - fciency caused pulmonaryby granulomas life expec - life tancy due to neurological and involvement malignancies and morbidity varies with onset Prognosis/ Prognosis/ Complications Chronic. Life Life Chronic. Chronic and Chronic Chronic, reduced reduced Chronic, Chronic, mortalityChronic, - - - ment therapy ment therapy in ment therapy Stem progress; cell transplanta - tion replacement or replacement - reduc substrate tion therapy ment therapy for for ment therapy pediatric onset - hypophosphata sia Therapy Enzyme replace Enzyme replace Lifelong enzymeLifelong Enzyme replace - - - be impaired penia, anemia, monoclonal gam - vitamin mopathy, D defciency; biomarkers: chito 18, CCL triosidase, glucosylsphingo ferritine sine, hypercalcemia Laboratory fndings renal function may renal Thrombocyto low serum AP, serum AP, low - hypohidrosis, hypohidrosis, gastrointestinal kidneysymptoms, - cardiovascu failure, lar disease ules, joint disease, joint disease, ules, hoarseness of infammatoryvoice, granuloma disease course variable; fatigue, - retarda growth tion, delayed puberty, bone pain, necrosis avascular gallstones, of bone, hepatospleno Parkinson´s megaly, - malignan disease, cies (predominantly hematological) disease course very variable; perina - tal death, bone stress deformities, loss of fractures, dentition, muscu - loskeletal pain and weakness Clinical features Clinical Neuropathic pain, Neuropathic Subcutaneous nod - Age of onset and Age Age of onset and Age - + radio enzyme activity, genetic testing enzyme activity; histopathology of granuloma; ceramide accumulation in granuloma enzyme activity, genetic testing values features, logic confrmed by genetic testing Diagnostic Diagnostic criteria Measurement of Measurement Measurement of Measurement Measurement of Measurement Laboratory - - dase A defciency mutation due to in GLA -gene on X-chromosome (X-linked disor der) recessive, recessive, -gene;ASAH1 acid ceramidase defciency sive, mutations in sive, GBA1 ; defciency in lysosomal glucocerebro sidase leads to accumulation of glucocerebroside recessive or recessive autosomal-dom - inant; mutations in TNSALP lead to accumulation of pyrophosphate, of an inhibitor mineralization Genetics/ pathogenesis alpha-galactosi - Autosomal- - reces Autosomal Autosomal- < 1/1,000,000 mate worldwide, 1/850 in worldwide, → Ashkenazi-Jews 1.5/100,000 1/6370 for moderate moderate 1/6370 for 1/100,000 HP Estimate Prevalence Australia 0,85/100,000 Australia Unknown, esti - Estimated 1–2/100,000 Estimated 1/300.000 for severe HP, HP, severe 1/300.000 for (continued) [ 227 – 229 ] [ 230 , 231 ] (type 1 in 90% of cases) [ 232 – 235 ] (HP) [ 236 – 238 ] 2 Table Disease Fabry disease Fabry Farber disease Farber Gaucher’s disease Gaucher’s Hypophosphatasia Leyens et al. Orphanet J Rare Dis (2021) 16:326 Page 26 of 43 Classifcation Bone disorder Bone disorder - - chair-reliance chair-reliance in beginning adolescence, mor increased tality cer due to vical instability and pulmonary compromise progressive, progressive, morbidity mostly pain, due to and stifness, range of reduced motion Prognosis/ Prognosis/ Complications Chronic, wheel - Chronic, Chronic and Chronic - - - ment therapy, ment therapy, pain manage ment, supportive surgery therapy, bisphospho nates, surgerynates, com - (relapses mon) Therapy Enzyme replace Pain management, Pain metabolism usually normal etc.) AP, (calcium, Laboratory fndings GAGs in urine GAGs Markers of bone - - - childhood; pro skeletal gressive dysplasia, short trunk dwarfsm, - spondyloepiphy seal dysplasia with ligamentous joint pain, laxity, preserved- intel odon - ligence, hypoplasia toid cardiac, pulmonary, ophthalmologic, dental, audiologic, abdominal and involve neurologic ment possible childhood or adolescence; limb deformity, joint contractures, and bone pain, leg length discrepancy, - hyperos stifness, (usually long tosis bones in lower extremity) usually but in one limb, be bilateral, may soft tissue involve ment (hypertri - fbrosis, chosis, erythema) above bone afected Clinical features Clinical Disease onset in Disease onset in enzyme activity, genetic testing nostic criteria (Freyschmidt) Diagnostic Diagnostic criteria Measurement of Measurement Radiographic diag - sive, mutations in sive, GALNS , resulting in N-acetylgalac - tosamine-6-sul - sulfatase-fate defciency somatic LEMD3 mutations suspected as a possible cause; disturbance in bone formation and mod - eling; possible association with and scleroderma Buschke-Ollen - dorf syndrome Genetics/ pathogenesis - reces Autosomal Usually sporadic; 1/599,000 (UK) 1/1,872,000 (Malaysia) 1/926,000 (Australia) → 1.6/1,000,000 estimate 1/1,000,000 estimate Prevalence 1/323,000 (Denmark) ~ 400 cases reported, (continued) (mucopolysac - charidosis type [ 239 – 241 ] IVa) (Leri´s disease) (Leri´s [ 105 , 242 – 244 ] 2 Table Disease Morquio disease Morquio Melorheostosis Leyens et al. Orphanet J Rare Dis (2021) 16:326 Page 27 of 43 disease Classifcation Bone disorder Bone disorder Connective tissue Connective - gressive for for gressive 5–20 years lethal within 20—30 years (cardiovascular involvement patients limiting), - with attenu may form ated normal life have expectancy self-limiting in early child - chronic hood, or remitting- course relapsing possible Prognosis/ Prognosis/ Complications Chronic, pro Chronic, Chronic, often Chronic, Good, usually Good, - costeroids, costeroids, bis - colchicine, phosphonates, plastic retinoids, surgery ment therapy, ment therapy, supportive pain treatment, management NSAIDs Therapy NSAIDs, cortiNSAIDs, - Enzyme replace Symptomatic: Symptomatic: thrombocytosis, thrombocytosis, anemia, increased immunoglobulin Laboratory fndings Unspecifc GAGs in urine GAGs Elevated ESR, AP, ESR, AP, Elevated - - - nantly in males (7:1), disease onset often in puberty, for progression - pachy 5–20 years; club dermia, digital periostosis, bing, cranioosteoar congeni - thropathy, tal heart diseases patent (especially ductus arteriosus), hyperhidrosis, rash, myelofbrosis, gastrointestinal involvement childhood; peau cognitive d´orange, impairment, joint con - stifness, cardiac tractures, and respiratory shortinvolvement, carpal stature, tunnel syndrome, - hepatosplenomeg glaucoma aly, tissues, hyperosto tissues, corticalsis of outer surface in frst 5 months of life, unusual irritability Clinical features Clinical - Occurs predomi Disease onset in Fever, swelling of soft swelling Fever, - - enzyme activity, genetic testing graphic diagno graphic sis with genetic confrmation Diagnostic Diagnostic criteria Clinical diagnosis Measurement of Measurement Clinical and radio - - moting prolifera tion suspected dominant with pen - incomplete etrance proven, - reces autosomal and X-linked sive inheritance also muta - suggested, , tions in SLCOA21 HPGD , possibly to also related HLA-B12 or BMP pathway; of involvement pro testosterone mutation in IDS ; lysosomal disorder:storage iduronate-2-sul - fatase enzyme defciency nant, heterozy - gous mutation with in COL1A1 incomplete penetrance Genetics/ pathogenesis Autosomal Autosomal X-linked recessive, recessive, X-linked Autosomal domi - Autosomal - < 1/1,000,000 mate 0.44/1,000,000 (Nor 0.91/1,000,000 way) (Denmark) → 0.67/1,000,000 < 1/1,000,000 mate Prevalence Unknown, esti - 0.65/1,000,000 (Sweden) 0.65/1,000,000 (Sweden) Unknown, esti - (continued) ostosis (primaryostosis hypertrophic osteoarthropa - thy; Touraine- Solente-Golé [ 23 , syndrome) 24 , 245 – 247 ] charidosis type 2 (Hunter syndrome) [ 248 – 250 ] (infantile cortical hyperostosis, Cafey-Silverman Smyth syndrome, syndrome) [ 251 – 253 ] 2 Table Disease - Pachydermoperi Mucopolysac - Cafey disease Cafey Leyens et al. Orphanet J Rare Dis (2021) 16:326 Page 28 of 43 disease disease disease disease Classifcation Connective tissue Connective Connective tissue Connective Connective tissue Connective Connective tissue Connective prognosis in prognosis vascular subtype, obstetrical complications common chronic and chronic progressive, potentially lethal because dis - of invading/ placing growth relapsing. Usually relapsing. mild symptoms, only slowly progressing depends on cardiovascular involvement, expectancylife normal with follow-up regular and treatment Prognosis/ Prognosis/ Complications Chronic, worst worst Chronic, Variable, often Variable, Chronic, remitting- Chronic, Chronic, mortalityChronic, - and supportive treatment local therapies, local therapies, surgery and/or orthope dic surgery Therapy Only symptomatic Only symptomatic Corticosteroids, Corticosteroids, Corticosteroids β–blockers, cardiac cardiac β–blockers, status despite status despite easy bruising elevated Laboratory fndings Normal coagulation Usually normal Serum IgG4 may be Serum IgG4 may Usually normal - - - - type: joint hyperlax ity and luxation, easy bruising, arthralgia, vascular aneurysm, muscle hypotonia people afected; people afected; cough, hemoptysis, dyspnea, other depend symptoms of on grade obstruction of sur structures rounding afected; any organ organ any afected; pos - involvement most often sible, gastrointestinal or salivaryorgans leading glands, and fbrosis to subsequent organ dysfunction hypermobility, hypermobility, arachnodactyly, aortic aneurysm, pro mitral valve ectopia lentis, lapse, dural scoliosis, ectasia Clinical features Clinical Depending on sub Often younger Elderly men primarily Tall stature, joint stature, Tall sifcation diagnosis sifcation Criteria criteria Diagnostic Diagnostic criteria Villefranche clas - Villefranche Radiographic ACR/EULAR Clas - ACR/EULAR Revised Ghent dominant or - reces autosomal mutations in sive, COL5A1/COL5A2/ COL5A3/COL3A1 and other, depending on subtype opathic, or due opathic, infections to (histoplasma, or aspergillus) sarcoidosis; of proliferation tissue, fbrous possibly IgG4- related multiple possible risk factors nant, mutation in in FBN1 , resulting disturbed fbrillin 1 function and TGF β altered large regulation, phenotypic vari - ability Genetics/ pathogenesis Autosomal Autosomal Most cases idi - Immune mediated, Immune mediated, Autosomal domi - Autosomal = 7/100,000 1/25,000 < 1/1,000,000 mate proven patients in proven Denmark) Prevalence 1/10,000 – Unknown, esti - 6/100.000 (Japan) 6.5/100,000 (genetically (continued) drome [ 254 – 256 ] drome nitis [ 257 – 259 ] ease [ 260 – 263 ] [ 264 – 266 ] 2 Table Disease Ehlers-Danlos syn - Fibrosing mediasti - Fibrosing IgG4-related Dis - IgG4-related Marfan syndrome Leyens et al. Orphanet J Rare Dis (2021) 16:326 Page 29 of 43 disease disease disease Classifcation Connective tissue Connective Connective tissue Connective Connective tissue Connective usually occurs spontaneously or with therapy progressive, may may progressive, other into evolve connectivetissue mortalitydisease, with increased cardiovascular involvement progressive, progressive, - prog worst nosis among all connective tissue diseases, mean survival after 11–12 years diagnosis Prognosis/ Prognosis/ Complications Variable, remission remission Variable, Chronic and Chronic Chronic and Chronic - - MTX; not all patients require treatment teroids, immuno teroids, suppressants and supportive of treatment Raynaud´s phe nomenon, digital nomenon, digital skin, lung, ulcer, and GI disease Therapy Corticosteroids, Corticosteroids, NSAIDs, corticosNSAIDs, - Symptomatic Symptomatic - - hypergamma globulinemia, ESR, elevated possibly TIMP-1 marker disease for activity tein antibodies tein (anti-U1RNP) - anti-topoi AB, somerase-I-AB (Scl70), anti-RNA- polymerase III Laboratory fndings Blood eosinophilia, Anti-ribonucleopro Anti-centromere- - - - - age (mean 4th-5th decade); abrupt onset of painful and thick swelling ening of skin and other soft tissues, joint contractures, most often extremi - ties symmetrical involved nance (3.3:1), Raynaud´s phe nomenon, pufy arthritis,hands, - pericardi pleuritis, inter myositis, tis, stitial lung disease, esophageal PAH, dysp dysmotility, nea, cardiovascular involvement nance (3:1), peak incidence at age 45 – 64 years; skin thicken - Raynaud´s ing, phenomenon, pulmonary fbrosis, ulcers, digital PAH, esophageal hypomobility, arthralgia, myalgia, variable organ involvement Clinical features Clinical Disease onset at any Disease onset at any - predomi Female - predomi Female nostic criteria by Pinal-Fernandez et al. nostic criteria exist (Sharp´s, Alarcón-Segovia and Villareal, Kasukawa) Diagnostic Diagnostic criteria Proposed diag - Proposed Diferent diag - Diferent ACR criteria ACR - with HLA-A2 many described, theories diferent on pathogen - esis and possible triggers (e.g., exercise) physical exist may play a role in a role play may pathogenesis association difer suspected, - ent pathophysi factors ological suspected (vasculopathy, - autoantibod fbroblast ies, dysfunction, immune system alteration, silica dust, toxins, infections) Genetics/ pathogenesis Association Association Unknown, B cells Unknown, HLA- → 15–30/100,000 < 1/1,000,000 mate Europe than Asia, less than Asia, Europe common in northern highest ever countries, reported in prevalence population of Choctaw Indians in Oklahoma (469/100,000), world - wide ( = 22.5) Prevalence Unknown, esti - 3.8/100,000 More common in More (continued) (eosinophilic (eosinophilic fasciitis) [ 267 , 268 ] (mixed connec - (mixed tissue dis - tive ease) [ 269 – 271 ] [ 30 , 44 45 272 – 275 ] 2 Table Disease Shulman disease Sharp syndrome Sharp syndrome Systemic sclerosis sclerosis Systemic Leyens et al. Orphanet J Rare Dis (2021) 16:326 Page 30 of 43 drome drome Classifcation Overgrowth syn - Overgrowth Overgrowth syn - Overgrowth - - depends on somatic mosaic, recur frequent of lipo rence masses, matous risk increased of tumors (e.g., tumor) Wilms cause of death, higher mortality in Parkes-Weber syndrome because of AV compli - fstulas, cations include coagulopathy - thromboem and bolic events Prognosis/ Prognosis/ Complications Chronic, severity Chronic, Chronic, but rarely but rarely Chronic, - mTOR kinase- mTOR and inhibitors selective PIK3CA- laser, inhibitors; or sclerosing, treat surgical ment compression compression stockings, laser surgery, of treatment infections, thromboembolic events Therapy Clinical trials with Symptomatic: Symptomatic: Laboratory fndings Normal Normal - + AV tions, thoracic tions, hyper lipomatous plasia, asymmetric visceral growth, and neurological linear disorders, epidermal nevus, of hand gigantism - macrodac and feet, sandal gap toe, tyly, anomalies renal malformations malformations (portwine stain), varicous veins, of hypertrophy bone and soft tis - resulting sue (often limb in diferent lengths), usually one to isolated extremity (most commonly leg), pain, edema, pruri - tus; in Parkes-Weber syndrome: fstulas Clinical features Clinical - malforma Vascular Cutaneous capillaryCutaneous tic criteria for tic criteria for PIK3CA-related overgrowth spectrum (Keppler-Noreuil genetic et al.), testing radiographic radiographic diagnosis Diagnostic Diagnostic criteria - Clinical diagnos Clinical and - - - - ing, postzygoticing, mutation in PIK3CA , causing tissue over growth diferent inherit diferent ance modes suspected; cur candidate rent genes: VG5Q , , PIK3CA , AGGF1 ; ING5 , HDAC9 congenital in spinal defects and vessels, cord, mesodermal tis - sues suspected Genetics/ pathogenesis Mosaic activat Unknown, multiple cases reported, esti - cases reported, < 1/1,000,000 mate reported cases in estimated literature, incidence 1/100,000 Prevalence Unknown, only a few Unknown, ~ 1000 < 1/1,000,000 estimate - - - = Klip (continued) = Parkes- (congenital (congenital over lipomatous vascular growth, malformations, epidermal nevi syndrome) [ 276 – 279 ] Weber syndrome syndrome Weber complex (angio-osteo hypertrophic syndrome pel-Trenaunay, pel-Trenaunay, special form with AV fstulas Weber syndrome) [ 280 – 283 ] 2 Table Disease CLOVES syndrome syndrome CLOVES Klippel-Trénaunay- Leyens et al. Orphanet J Rare Dis (2021) 16:326 Page 31 of 43 drome Classifcation Overgrowth syn - Overgrowth Other ture death in ture 20% due to respiratory or neurological involvement lethal, 5-year 5-year lethal, survival < 70% Prognosis/ Prognosis/ Complications - prema Chronic, Chronic and often Chronic antithrombotic antithrombotic prophylaxis, orthopedic surgeries, psychological support corticosteroids, corticosteroids, - immunosuppres biologicals sants, (TNFi, IL-1i), BRAF-inhibitors Therapy Supportive: Interferon, DVT possible CRP, signs of pitui - signs CRP, tary insufciency Laboratory fndings Coagulopathy and Coagulopathy Elevated ESR, AP, or ESR, AP, Elevated - - - monly afected monly afected (2:1); than females of overgrowth tissues: diferent con - cerebriform nective tissue vascular nevus, malformations, - throm deep vein dysregulated boses, adipose tissue (lipomas), pulmo nary abnormalities, asymmetric and disproportion - overgrowth, ate facial tumors, - phenotype, intel lectual impairment, seizures males in 5th-7th bone decade of life; nearly involvement present, always CNS involvement insipidus, (diabetes visual distur pyramidal/ bances, extra-pyramidal other syndromes), involvement organ possible (cardiac/ lung/retroperito neal/cutaneous, etc.) Clinical features Clinical Males more com - Males more Predominantly Predominantly - criteria (Turner Cohen), et al., genetic testing tissue of afected histopatho diagnosis, logical genetic testing Diagnostic Diagnostic criteria Revised diagnostic Radiographic and activating AKT1 mutation, growth increased cells in afected -mutations, BRAF -mutations, non-Langerhans cell-histiocytosis with hyperactiva - tion of cytokines Genetics/ pathogenesis Somatic mosaic In than 50% more over-/misdiagnosed over-/misdiagnosed because of similarities other overgrowth to spectrum disorders, incidence estimated 1/1,000,000 esti - < 1/1,000,000 mate reported cases, esti - reported cases, < 1/1,000,000 mate Prevalence Unknown, possibly Unknown, ~ 600 (continued) [ 284 – 286 ] disease [ 287 – 290 ] 2 Table Disease Proteus syndrome syndrome Proteus Erdheim-Chester Erdheim-Chester Leyens et al. Orphanet J Rare Dis (2021) 16:326 Page 32 of 43 Classifcation Other Other Other course, but often course, lethal within of frst 2 years (infantile life oldest form), known patient is old 58 years therapy-induced therapy-induced remission, more relapses common in malignancy- SS associated rate variable, but variable, rate studies recent report good survival rates Prognosis/ Prognosis/ Complications Chronic, variable Chronic, Spontaneous or Chronic, survivalChronic, - surgery, surgery, D-penicillamine, physiotherapy, nutri- NSAIDs, tional therapy suppressants in suppressants cases, relapsing of treatment underlying cause if found potassium colchi - iodide, immuno cine, teroids, dapsone, dapsone, teroids, colchicine, - immunosuppres biologicals sants, Therapy Symptomatic: Symptomatic: Corticosteroids, Corticosteroids, NSAIDs, corticosNSAIDs, - depending on complications diarrhea) (e.g., elevated ESR, CRP elevated may be positive may Laboratory fndings No specifc fndings Leukocytosis, Leukocytosis, Elevated CRP, ANCA CRP, Elevated nodules, gingival gingival nodules, joint hypertrophy, contractures, deposition, hyaline - infec osteopenia. protein-losing tions, - enteropathy; cogni development tive normal predominance, predominance, abrupt onset of peripheral fever, tender neutrophilia, erythematous skin difuse lesions, dermal neutrophilic arthralgia,infltrate, headaches, malaise, myalgia middle-aged adults; infam - recurrent mation of cartilage, especially ears, respiratorynose, tract; vasculitis of all aortic vessels, sized or mitral valve eyes joints, disease, and skin possible Clinical features Clinical Subcutaneous skin Slight female Slight female Typically onset in Typically - hyaline deposi - hyaline tion in dermis, genetic testing nostic criteria Su and Liu by van (modifed by den Driesch); drug-induced SS: diagnostic criteria Walker by and Cohen McAdams´ crite McAdams´ ria, Damiani and criteria Levine Diagnostic Diagnostic criteria Demonstration of Classic SS: diag - Michet´s criteria, - - sive, mutations in sive, CMG2/ANTXR2 - CMG2 is a gene, transmembrane that protein in a role plays capillary mor phogenesis (also binds anthrax higher toxins); carrier frequency in Middle Eastern populations suspected cially females cially females with Crohn´s disease) SS (idiopathic), malignancy- and associated, drug-induced histiocytoid SS; commonly infam - to related matory bowel diseases (espe HLA-DR4, 30% of all patients associated have or autoimmune hematological disease (MDS); vasculitis of all vessels sized occurs Genetics/ pathogenesis - reces Autosomal Unknown; classic Association with Association - reported (pre dominantly from Middle East), esti - < 1/1,000,000 mate < 1/1,000,000 mate mated prevalence in prevalence mated 4.5/1,000,000 literature: → 1.2/100,000 Prevalence Unknown, ~ 150 cases Unknown, esti - 2/100,000 (Hungary) esti - (continued) tous syndrome syndrome tous (infantile sys - hyalinosis/ temic hyaline juvenile fbromatosis) [ 291 – 294 ] (SS, acute febrile febrile (SS, acute neutrophilic dermatosis) [ 295 – 300 ] polychondritis polychondritis [ 301 – 306 ] 2 Table Disease Hyaline- fbroma Sweet syndrome syndrome Sweet Relapsing Leyens et al. Orphanet J Rare Dis (2021) 16:326 Page 33 of 43 Classifcation Other Other Other - - ting-relapsing, ting-relapsing, complications include persis - hearingtent loss - and cardiovascu lar involvement with increased mortality variable, poor in variable, case of systemic involve organ ment progression, progression, into evolve may leukemia Prognosis/ Prognosis/ Complications Chronic or remit Chronic Chronic, prognosis prognosis Chronic, Chronic, variable Chronic, - DMARDs, immu - DMARDs, nosuppressants, - ves biologicals; tibulo-auditory often symptoms to unresponsive treatment - immunosuppres biologicals sants, matic treatment, matic treatment, interferon-α, corticosteroids, 2-chlorodeoxy - adenosine Therapy Corticosteroids, Corticosteroids, Corticosteroids, Corticosteroids, Imatinib, sympto Imatinib, - - - - sis, thrombocyto sis, ESR elevated sis, or CRP possible mia, leukocytosis or leucopenia, hypocomple mentemia bocytopenia, leukocytosis, eosinophilia, tryptase,elevated LDH, uric acid, bilirubin, ferritin, hypoalbuminemia Laboratory fndings Anemia, leukocyto Elevated ESR, ane Elevated - Anemia, throm - interstitial keratitisinterstitial other ocular (or then symptoms, called atypical vestibulo-Cogan), auditory symptoms, loss, weight fever, arthromyalgia, headache dle-aged females recurrent afected, subcutaneous infammatory pain - fever, ful nodules, arthralgia,malaise, hepatospleno anorexia, megaly, ocular loss, weight infammation, lung systemic nodules, involvement organ possible tion and accumula - tion of mast cells cause urticaria pigmentosa, urticaria,fushing, GI symptoms, musculoskeletal pain, headaches, weight anaphylaxis, osteoporosis loss, Clinical features Clinical Non-syphilitic Predominantly mid - Predominantly - Abnormal prolifera criteria for typicalcriteria for and atypical syndrome Cogan diagnosis criteria Diagnostic Diagnostic criteria Clinical diagnostic Clinical diagnostic Histopathological WHO diagnostic WHO diagnostic - mune process mune process suggested (additional autoimmune disease diag - nosed in ~ 10% of patients), association with smok cigarette ing suspected infammation of and necrosis subcutaneous adipose tissue, mechanism probably unclear, autoimmune of function mutation in KIT , KIT is a tyrosine kinase receptor essential for correct mast cell development and function Genetics/ pathogenesis Unknown,- autoim Unknown, Somatic gain cases reported, esti - cases reported, < 1/1,000,000 mate cases reported, esti - cases reported, < 1/1,000,000 mate including all systemic including all systemic subtypes) Prevalence Unknown, 250 over Unknown, only a few 9.59/100,000 (Denmark, - (continued) [ 307 – 309 ] panniculitis (relapsing nodular febrile nonsuppurative panniculitis; idi - opathic lobular panniculitis) [ 310 – 313 ] cytosis (mast cell disease) [ 314 – 318 ] 2 Table Disease Cogan syndrome syndrome Cogan Weber-Christian Weber-Christian Systemic masto Systemic Leyens et al. Orphanet J Rare Dis (2021) 16:326 Page 34 of 43 Classifcation Other limiting within 24 months, increased mortality with organ systemic involvement Prognosis/ Prognosis/ Complications Variable, often self- Variable, - immunosuppres biologicals sants, Therapy Corticosteroids, Corticosteroids, phase reactants, phase reactants, s-IL2R ACE, Laboratory fndings Elevated acute acute Elevated and more severely severely and more peak onset afected, in second decade, patients are many or asymptomatic unspecifc have such symptoms, fatigue, as fever, loss; most weight commonly afected lung organ: Clinical features Clinical Females more often more Females histopathological histopathological diagnosis Diagnostic Diagnostic criteria Clinical and diferent HLA diferent subtypes and , inhaled BTNL-2 antigens are a considered possible trigger Genetics/ pathogenesis Associated with Associated Ireland) 28.13/100,000 (Ireland) → 19.6/100,000 Prevalence 11.16/100,000 (Northern (continued) (Boeck’s sarcoid) sarcoid) (Boeck’s [ 319 – 321 ] 2 Table Disease Sarcoidosis Sarcoidosis Leyens et al. Orphanet J Rare Dis (2021) 16:326 Page 35 of 43

Abbreviations Competing interests AKT: Serine/threonine kinase 1; ANA: Antinuclear antibody; ANCA: Anti-neu- The authors declare that they have no competing interests. trophil cytoplasmic antibody; ANKH: ANKH inorganic pyrophosphate transport regulator; ANTRX2: Anthrax toxin receptor 2; AP: Alkaline phosphatase; BMP: Author details Bone morphogenetic protein; BUN: Blood urea nitrogen; CAPS: Cryoporin- 1 Center for Rare Diseases Bonn (ZSEB), University Hospital, Bonn, Germany. associated periodic syndrome; CCL18: CC-chemokine ligand 18; CECR1: Cat 2 Department of Neonatology and Pediatric Care, Children’s University Hospital, eye syndrome chromosome region; CIAS1: Cold-induced autoinfammatory Bonn, Germany. 3 Institute of Human Genetics, University Hospital, Bonn, Ger- syndrome 1; CINCA: Chronic infantile neurological, cutaneous, and articular many. 4 Institute of General Practice and Family Medicine, University Hospital, syndrome; CMG2: Capillary morphogenesis gene 2; COL1A1: Collagen type 1 Venusberg‑Campus 1, 53127 Bonn, Germany. 5 Department of Radiology, Uni- alpha 1; CPTII: Carnitine palmitoyltransferase 2; CPPD: Calcium pyrophosphate versity Hospital, Bonn, Germany. 6 Division of Medical Psychology and Depart- dehydrate; DM: Dermatomyositis; DMARD: Disease-modifying anti-rheumatic ment of Psychiatry, University Hospital, Bonn, Germany. 7 Department of Rheu- drug; DNASE1L3: Deoxyribonuclease 1 like 3; DVT: Deep vein thrombosis; matology, Spitalzentrum-Centre hospitalier, Biel‑Bienne, Switzerland. FBN1: Fibrillin 1; FCGR2A/3A: Fc fragment of IgG receptor 2A/3A; GAG:​ Glycosa- minoglycan; GALNS: Galactosamine (N-acetyl)-6-sulfatase; GBA1: Glucocer- Received: 13 April 2021 Accepted: 2 July 2021 ebrosidase beta; GCSF: Granulocyte colony-stimulating factor; GI: Gastrointes- tinal; GNE: Glucosamine (UDP-N-acetyl)-2-epimerase/N-acetylmannosamine kinase; HDAC9: Histone deacetylase 9; HLA: Human leukocyte antigene; HMG- CoA: 3-Hydroxy-3-methylglutaryl-coenzyme A; HPGD: Hydroxyprostaglandin dehydrogenase; IDS: Iduronate 2-sulfatase; IL: Interleukin; ILAR: International References League of Associations for Rheumatology; ILD: Interstitial lung disease; ING5: 1. Windheuser IC, Mücke M, Klawonn F, Stieber C. Patients without Inhibitor of growth family member 5; IOMID: Infantile-onset multisystem diagnosis: A profle. (Poster Presentation 2nd World Congress on Rare infammatory disease; JIA: Juvenile idiopathic arthritis; KIT: KIT proto-oncogene Diseases and Orphan Drugs. London 2017) receptor tyrosine kinase; MIF: Macrophage migration inhibitory factor; HLA: 2. Busch MA, Maske UE, Ryl L, Schlack R, Hapke U. Prävalenz von depres- Human leukocyte antigene; MAS: Macrophage activation syndrome; MDS: siver Symptomatik und diagnostizierter Depression bei Erwachsenen Myelodysplastic syndrome; MEFV: Mediterranean fever; MIF: Macrophage in Deutschland: Ergebnisse der Studie zur Gesundheit Erwachsener in migration inhibitory factor; MMP3: Matrix metalloproteinase-3; MPO: Myelop- Deutschland (DEGS1). Bundesgesundheitsblatt - Gesundheitsforschung eroxidase; MVK: Mevalonate kinase; NF-κB: Nuclear factor kappa-light-chain- - Gesundheitsschutz. 2013;56:733–9. enhancer of activated B-cells; NOD2: Nucleotide binding oligomerization 3. Okumura T, Tanno S, Ohhira M, Nozu T. The rate of polymyalgia rheu- domain containing 2; NOMID: Neonatal onset multisystem infammatory matica (PMR) and remitting seronegative symmetrical synovitis with disease; NSAID: Nonsteroidal anti-infammatory drug; PAH: Pulmonary arterial pitting edema (RS3PE) syndrome in a clinic where primary care physi- hypertension; PFKM: Muscle phosphofructokinase; PGYM: Muscle glycogen cians are working in Japan. Rheumatol Int. 2012;32:1695–9. phosphorylase; PIK3CA: Phosphatidylinositol-4,5-bisphosphate 3-kinase 4. Evensen KJ, Nossent HC. Epidemiology and outcome of adult-onset catalytic subunit Α; PM: Polymyositis; PPD/PPRD: Progressive pseudorheu- Still’s disease in Northern Norway. Scand J Rheumatol. 2006;35:48–51. matoid dysplasia; PSMB8: Proteasome subunit beta 8; PSTPIP1: Proline- 5. Balci MA, Pamuk ON, Pamuk GE, Uzundere FK, Donmez S. AB1142 epi- serine-threonine phosphatase interacting protein 1; PTX3: Pentraxine 3; RF: demiology and outcome of adult-onset still9s disease in northwestern Rheumatoid factor; RA: Rheumatoid arthritis; SAA: Serum amyloid A; SAPHO: thrace region in Turkey. Ann Rheum Dis. 2015;74:1284–1284. Synovitis-acne-pustulosis-hyperostosis-osteitis-syndrome; SEDT-PA: Spondy- 6. Asanuma YF, Mimura T, Tsuboi H, Noma H, Miyoshi F, Yamamoto K, et al. loepiphyseal dysplasia tarda with progressive arthropathy; SLE: Systemic lupus Nationwide epidemiological survey of 169 patients with adult Still’s erythematosus; TGFB1: Transforming growth factor; TIMP1: Tissue inhibitor of disease in Japan. Mod Rheumatol. 2015;25:393–400. metalloproteinase; TNFi: Tumor necrosis factor inhibitor; TNFRSF: Tumor necro- 7. Mistry PK, Cappellini MD, Lukina E, Özsan H, Pascual SM, Rosenbaum H, sis factor receptor superfamily; VEGF: Vascular endothelial growth factor; WBC: et al. Consensus conference: a reappraisal of Gaucher disease—diagno- White blood cell; WISP3: WNT1 inducible signaling pathway protein. sis and disease management algorithms. Am J Hematol. 2011;86:110–5. 8. Miceli-Richard C, Lesage S, Rybojad M, Prieur A-M, Manouvrier-Hanu Acknowledgements S, Häfner R, et al. CARD15 mutations in Blau syndrome. Nat Genet. San Francisco edit for editing and proofreading the manuscript. 2001;29:19–20. 9. Wouters CH, Maes A, Foley KP, Bertin J, Rose CD. Blau Syndrome, the Authors’ contributions prototypic auto-infammatory granulomatous disease. Pediatr Rheuma- MM, CS and MS conceptualized the work and substantively revised it. JL, TB, tol Online J. 2014;12:33. and CD acquired and analyzed the data. JL, DK and MS analyzed and inter- 10. Zhong Y, Kinio A, Saleh M. Functions of NOD-like receptors in human preted the data, and wrote the manuscript. All authors read and approved the diseases. Front Immunol [Internet]. 2013 [cited 2018 Aug 29];4. Avail- fnal manuscript. able from: https://​www.​ncbi.​nlm.​nih.​gov/​pmc/​artic​les/​PMC37​97414/ 11. Levy R, Gérard L, Kuemmerle-Deschner J, Lachmann HJ, Koné-Paut Funding I, Cantarini L, et al. Phenotypic and genotypic characteristics of Open Access funding enabled and organized by Projekt DEAL. This research cryopyrin-associated periodic syndrome: a series of 136 patients did not receive any specifc grant from funding agencies in the public, com- from the Eurofever Registry. Ann Rheum Dis. 2015;74:2043–9. mercial, or not-for-proft sectors. 12. Hofman HM, Mueller JL, Broide DH, Wanderer AA, Kolodner RD. Mutation of a new gene encoding a putative pyrin-like protein Availability of data and materials causes familial cold autoinfammatory syndrome and Muckle–Wells All data generated or analysed during this study are included in this published syndrome. Nat Genet. 2001;29:301–5. article. Data citations are included in the reference list. 13. Consortium TFF, Bernot A, Clepet C, Dasilva C, Devaud C, Petit J-L, et al. A candidate gene for familial Mediterranean fever. Nat Genet. 1997;17:25–31. Declarations 14. The International FMF Consortium. Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Ethics approval and consent to participate mediterranean fever. Cell. 1997;90:797–807. Not applicable. 15. Celiksoy MH, Ogur G, Yaman E, Abur U, Fazla S, Sancak R, et al. Could familial Mediterranean fever gene mutations be related to PFAPA Consent for publication syndrome? Pediatr Allergy Immunol. 2016;27:78–82. Not applicable. 16. Taniuchi S, Nishikomori R, Iharada A, Tuji S, Heike T, Kaneko K. MEFV variants in patients with PFAPA syndrome in Japan. Open Rheumatol J. 2013;7:22–5. Leyens et al. Orphanet J Rare Dis (2021) 16:326 Page 36 of 43

17. Nonaka F, Migita K, Jiuchi Y, Shimizu T, Umeda M, Iwamoto N, et al. 39. ter Haar N, Lachmann H, Özen S, Woo P, Uziel Y, Modesto C, et al. Treat- Increased prevalence of MEFV exon 10 variants in Japanese patients ment of autoinfammatory diseases: results from the Eurofever Registry with adult-onset Still’s disease. Clin Exp Immunol. 2015;179:392–7. and a literature review. Ann Rheum Dis. 2013;72:678–85. 18. Yim D, Curtis N, Cheung M, Burgner D. Update on Kawasaki disease: 40. Rai E, Mahajan A, Kumar P, Angural A, Dhar MK, Razdan S, et al. Whole epidemiology, aetiology and pathogenesis. J Paediatr Child Health. Exome Screening Identifes Novel and Recurrent WISP3 Mutations 2013;49:704–8. Causing Progressive Pseudorheumatoid Dysplasia in Jammu and 19. Rodó X, Ballester J, Cayan D, Melish ME, Nakamura Y, Uehara R, et al. Kashmir-India. Sci Rep [Internet]. 2016 [cited 2017 Jun 23];6. Available Association of Kawasaki disease with tropospheric wind patterns. Sci from: http://​www.​ncbi.​nlm.​nih.​gov/​pmc/​artic​les/​PMC49​04372/ Rep [Internet]. 2011 [cited 2018 Aug 30];1. Available from: https://​ 41. Adeeb F, Stack AG, Fraser AD. Knitting the Threads of Silk through Time: www.​ncbi.​nlm.​nih.​gov/​pmc/​artic​les/​PMC32​40972/ Behçet’s Disease—Past, Present, and Future. Int J Rheumatol [Internet]. 20. Yan M, Wang Z, Niu N, Zhao J, Peng J. Relationship between chronic 2017 [cited 2017 Nov 30];2017. Available from: https://​www.​ncbi.​nlm.​ tonsillitis and Henoch–Schonlein purpura. Int J Clin Exp Med. nih.​gov/​pmc/​artic​les/​PMC56​10876/ 2015;8:14060–4. 42. Ben-Chetrit E, Touitou I. Familial mediterranean fever in the world. 21. Piram M, Mahr A. Epidemiology of immunoglobulin A vasculitis Arthritis Rheum. 2009;61:1447–53. (Henoch–Schönlein): current state of knowledge. Curr Opin Rheuma- 43. Monti G, Saccardo F, Castelnovo L, Novati P, Sollima S, Riva A, et al. tol. 2013;25:171–8. Prevalence of mixed cryoglobulinaemia syndrome and circulating cryo- 22. Bianchi L, Lubrano C, Carrozzo AM, Iraci S, Tomassoli M, Spera G, et al. globulins in a population-based survey: the Origgio study. Autoimmun Pachydermoperiostosis: study of epidermal growth factor and steroid Rev. 2014;13:609–14. receptors. Br J Dermatol. 1995;132:128–33. 44. Arnett FC, Howard RF, Tan F, Moulds JM, Bias WB, Durban E, et al. 23. Zhang Z, Xia W, He J, Zhang Z, Ke Y, Yue H, et al. Exome sequencing Increased prevalence of systemic sclerosis in a native american tribe identifes SLCO2A1 mutations as a cause of primary hypertrophic in Oklahoma. Association with an Amerindian HLA haplotype. Arthritis osteoarthropathy. Am J Hum Genet. 2012;90:125–32. Rheum. 1996;39:1362–70. 24. Castori M, Sinibaldi L, Mingarelli R, Lachman R, Rimoin D, Dallapiccola 45. Barnes J, Mayes MD. Epidemiology of systemic sclerosis: incidence, B. Pachydermoperiostosis: an update. Clin Genet. 2005;68:477–86. prevalence, survival, risk factors, malignancy, and environmental trig- 25. Xie G, Jiang N, Liang C, Zeng J, Chen Z, Xu Q, et al. Pigmented Vil- gers. Curr Opin Rheumatol. 2012;24:165–70. lonodular Synovitis: A Retrospective Multicenter Study of 237 Cases. 46. Yates M, Graham K, Watts RA, MacGregor AJ. The prevalence of giant PLoS One [Internet]. 2015 [cited 2017 Sep 8];10. Available from: cell arteritis and polymyalgia rheumatica in a UK primary care popula- http://​www.​ncbi.​nlm.​nih.​gov/​pmc/​artic​les/​PMC43​70558/ tion. BMC Musculoskelet Disord [Internet]. 2016 [cited 2017 Dec 4];17. 26. Janssens K, Vanhoenacker F, Bonduelle M, Verbruggen L, Van Available from: https://​www.​ncbi.​nlm.​nih.​gov/​pmc/​artic​les/​PMC49​ Maldergem L, Ralston S, et al. Camurati-Engelmann disease: review 46178/ of the clinical, radiological, and molecular data of 24 families and 47. Stojan G, Petri M. Epidemiology of systemic lupus erythematosus: an implications for diagnosis and treatment. J Med Genet. 2006;43:1–11. update. Curr Opin Rheumatol. 2018;30:144–50. 27. Kadavath S, Efthimiou P. Adult-onset Still’s disease—pathogenesis, 48. Tani C, D’Aniello D, Sedie AD, Carli L, Cagnoni M, Possemato N, et al. clinical manifestations, and new treatment options. Ann Med. Rhupus syndrome: Assessment of its prevalence and its clinical and 2015;47:6–14. instrumental characteristics in a prospective cohort of 103 SLE patients. 28. Smith EJ, Allantaz F, Bennett L, Zhang D, Gao X, Wood G, et al. Clinical, Autoimmun Rev. 2013;12:537–41. molecular, and genetic characteristics of PAPA syndrome: a review. 49. Vallet H, Riviere S, Sanna A, Deroux A, Moulis G, Addimanda O, et al. Curr Genom. 2010;11:519–27. Efcacy of anti-TNF alpha in severe and/or refractory Behçet’s disease: 29. Comarmond C, Cacoub P. Granulomatosis with polyangiitis multicenter study of 124 patients. J Autoimmun. 2015;62:67–74. (Wegener): clinical aspects and treatment. Autoimmun Rev. 50. Descriptive Epidemiology of Kawasaki Disease in Japan. 2011–2012: 2014;13:1121–5. from the results of the 22nd Nationwide Survey. J Epidemiol. 30. Kowal-Bielecka O, Fransen J, Avouac J, Becker M, Kulak A, Allanore Y, 2015;25:239–45. et al. Update of EULAR recommendations for the treatment of systemic 51. Exarchou S, Lindström U, Askling J, Eriksson JK, Forsblad-d’Elia H, sclerosis. Ann Rheum Dis. 2017;76:1327–39. Neovius M, et al. The prevalence of clinically diagnosed ankylosing 31. Needham M, Mastaglia FL. Inclusion body myositis: current pathoge- spondylitis and its clinical manifestations: a nationwide register study. netic concepts and diagnostic and therapeutic approaches. Lancet Arthritis Res Ther [Internet]. 2015 [cited 2018 Sep 25];17. Available from: Neurol. 2007;6:620–31. https://​www.​ncbi.​nlm.​nih.​gov/​pmc/​artic​les/​PMC44​24886/ 32. Karmacharya P, Donato AA, Aryal MR, Ghimire S, Pathak R, Shah K, et al. 52. Arkkila PE. Thromboangiitis obliterans (Buerger’s disease). Orphanet J RS3PE revisited: a systematic review and meta-analysis of 331 cases. Rare Dis. 2006;1:14. Clin Exp Rheumatol. 2016;34:404–15. 53. Zheng J-F, Chen Y-M, Chen D-Y, Lin C-H, Chen H-H. The incidence and 33. Hertzman PA. The eosinophilia-myalgia syndrome: status of 205 prevalence of thromboangiitis obliterans in Taiwan: a nationwide, patients and results of treatment 2 years after onset. Ann Intern Med. population-based analysis of data collected from 2002 to 2011. Clinics 1995;122:851. (Sao Paulo). 2016;71:399–403. 34. Stone JH, Merkel PA, Spiera R, Seo P, Langford CA, Hofman GS, et al. 54. Puéchal X, Fiessinger J-N. Thromboangiitis obliterans or Buerger’s Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N disease: challenges for the rheumatologist. Rheumatology (Oxford). E J Med. 2010;363:221–32. 2007;46:192–9. 35. Renko M, Salo E, Putto-Laurila A, Saxen H, Mattila PS, Luotonen J, 55. Shionoya S. Diagnostic criteria of Buerger’s disease. Int J Cardiol. et al. A randomized, controlled trial of tonsillectomy in periodic fever, 1998;66:S243–5. aphthous stomatitis, pharyngitis, and adenitis syndrome. J Pediatr. 56. Olin JW. Thromboangiitis Obliterans (Buerger’s Disease). N E J Med. 2007;151:289–92. 2000;343:864–9. 36. Ben-Zvi I, Kukuy O, Giat E, Pras E, Feld O, Kivity S, et al. Anakinra for 57. Sada K-E, Amano K, Uehara R, Yamamura M, Arimura Y, Nakamura Y, colchicine-resistant familial mediterranean fever: a randomized, dou- et al. A nationwide survey on the epidemiology and clinical features of ble-blind, placebo-controlled trial. Arthritis Rheumatol. 2017;69:854–62. eosinophilic granulomatosis with polyangiitis (Churg–Strauss) in Japan. 37. Tariq S, Hugenberg ST, Hirano-Ali SA, Tariq H. Multicentric reticulohis- Mod Rheumatol. 2014;24:640–4. tiocytosis (MRH): case report with review of literature between 1991 58. Mahr A, Guillevin L, Poissonnet M, Aymé S. Prevalences of polyarteritis and 2014 with in depth analysis of various treatment regimens and nodosa, microscopic polyangiitis, Wegener’s granulomatosis, and outcomes. Springerplus [Internet]. 2016 [cited 2017 Sep 13];5. Available Churg–Strauss syndrome in a French urban multiethnic population in from: http://​www.​ncbi.​nlm.​nih.​gov/​pmc/​artic​les/​PMC47​66148/ 2000: A capture–recapture estimate. Arthritis Rheum. 2004;51:92–9. 38. Federici S, Sormani MP, Ozen S, Lachmann HJ, Amaryan G, Woo P, et al. 59. Mohammad AJ, Jacobsson LTH, Mahr AD, Sturfelt G, Segelmark M. Evidence-based provisional clinical classifcation criteria for autoinfam- Prevalence of Wegener’s granulomatosis, microscopic polyangiitis, matory periodic fevers. Ann Rheum Dis. 2015;74:799–805. Leyens et al. Orphanet J Rare Dis (2021) 16:326 Page 37 of 43

polyarteritis nodosa and Churg–Strauss syndrome within a defned 81. Kallenberg CGM. The diagnosis and classifcation of microscopic poly- population in southern Sweden. Rheumatology (Oxford). angiitis. J Autoimmun. 2014;48–49:90–3. 2007;46:1329–37. 82. Greco A, De Virgilio A, Rizzo MI, Gallo A, Magliulo G, Fusconi M, et al. 60. Comarmond C, Pagnoux C, Khellaf M, Cordier J-F, Hamidou M, Viallard Microscopic polyangiitis: advances in diagnostic and therapeutic J-F, et al. Eosinophilic granulomatosis with polyangiitis (Churg–Strauss): approaches. Autoimmun Rev. 2015;14:837–44. Clinical characteristics and long-term followup of the 383 patients 83. Mahr A, Belarbi L, Wechsler B, Jeanneret D, Dhote R, Fain O, et al. enrolled in the French Vasculitis Study Group cohort. Arthritis Rheum. Population-based prevalence study of Behçet’s disease: diferences by 2013;65:270–81. ethnic origin and low variation by age at immigration. Arthritis Rheum. 61. Mahr A, Moosig F, Neumann T, Szczeklik W, Taillé C, Vaglio A, et al. 2008;58:3951–9. Eosinophilic granulomatosis with polyangiitis (churg–strauss): evolu- 84. Saadoun D, Wechsler B. Behçet’s disease. Orphanet J Rare Dis. 2012;7:20. tions in classifcation, etiopathogenesis, assessment and management. 85. Hatemi G, Silman A, Bang D, Bodaghi B, Chamberlain AM, Gul A, et al. Curr Opin Rheumatol. 2014;26:16–23. EULAR recommendations for the management of Behçet disease. Ann 62. Greco A, Rizzo MI, De Virgilio A, Gallo A, Fusconi M, Ruoppolo G, et al. Rheum Dis. 2008;67:1656–62. Churg–Strauss syndrome. Autoimmun Rev. 2015;14:341–8. 86. Gilchrist H, Patterson JW. Erythema nodosum and erythema induratum 63. Masi AT, Hunder GG, Lie JT, Michel BA, Bloch DA, Arend WP, et al. The (nodular vasculitis): diagnosis and management. Dermatol Ther. American College of Rheumatology 1990 criteria for the classifcation of 2010;23:320–7. churg-strauss syndrome (allergic granulomatosis and angiitis). Arthritis 87. Mascaró JM, Baselga E. Erythema induratum of Bazin. Dermatol Clin. Rheum. 1990;33:1094–100. 2008;26:439–45. 64. Theodoridis A, Konstantinidou A, Makrantonaki E, Zouboulis C. Malig- 88. Caorsi R, Penco F, Grossi A, Insalaco A, Omenetti A, Alessio M, et al. nant and benign forms of atrophic papulosis (Köhlmeier–Degos dis- ADA2 defciency (DADA2) as an unrecognised cause of early onset pol- ease): systemic involvement determines the prognosis. Br J Dermatol. yarteritis nodosa and stroke: a multicentre national study. Ann Rheum 2014;170:110–5. Dis. 2017;76:1648–56. 65. Theodoridis A, Makrantonaki E, Zouboulis CC. Malignant atrophic 89. De Virgilio A, Greco A, Magliulo G, Gallo A, Ruoppolo G, Conte M, papulosis (Köhlmeier–Degos disease)—a review. Orphanet J Rare Dis. et al. Polyarteritis nodosa: a contemporary overview. Autoimmun Rev. 2013;8:10. 2016;15:564–70. 66. Magro CM, Wang X, Garrett-Bakelman F, Laurence J, Shapiro LS, DeSan- 90. Hajj-Ali RA, Calabrese LH. Diagnosis and classifcation of central nervous cho MT. The efects of Eculizumab on the pathology of malignant system vasculitis. J Autoimmun. 2014;48–49:149–52. atrophic papulosis. Orphanet J Rare Dis. 2013;8:185. 91. Salvarani C, Brown RD, Christianson T, Miller DV, Giannini C, Huston J, 67. Shapiro LS, Toledo-Garcia AE, Farrell JF. Efective treatment of malignant et al. An Update of the Mayo Clinic Cohort of Patients With Adult Pri- atrophic papulosis (Köhlmeier–Degos disease) with treprostinil—early mary Central Nervous System Vasculitis. Medicine (Baltimore) [Internet]. experience. Orphanet J Rare Dis. 2013;8:52. 2015 [cited 2017 Dec 4];94. Available from: https://​www.​ncbi.​nlm.​nih.​ 68. Khalid U, Saleem T. Hughes-Stovin Syndrome. Orphanet J Rare Dis. gov/​pmc/​artic​les/​PMC46​16419/ 2011;6:15. 92. Salvarani C, Brown RD, Christianson TJH, Huston J, Giannini C, Miller DV, 69. Erkan D, Yazici Y, Sanders A, Trost D, Yazici H. Is Hughes–Stovin syndrome et al. Adult primary central nervous system vasculitis treatment and Behçet’s disease? Clin Exp Rheumatol. 2004;22:S64-68. course: analysis of one hundred sixty-three patients. Arthritis Rheuma- 70. Jachiet M, Flageul B, Deroux A, Le Quellec A, Maurier F, Cordoliani F, tol. 2015;67:1637–45. et al. The clinical spectrum and therapeutic management of hypocom- 93. Calabrese LH, Mallek JA. Primary angiitis of the central nervous system. plementemic urticarial vasculitis: data from a French Nationwide study Report of 8 new cases, review of the literature, and proposal for diag- of ffty-seven patients. Arthritis Rheumatol. 2015;67:527–34. nostic criteria. Medicine (Baltimore). 1988;67:20–39. 71. Özçakar ZB, Foster J, Diaz-Horta O, Kasapcopur O, Fan Y-S, Yalçınkaya F, 94. Trapani S, Micheli A, Grisolia F, Resti M, Chiappini E, Falcini F, et al. et al. DNASE1L3 mutations in hypocomplementemic urticarial vasculitis Henoch Schonlein Purpura in childhood: epidemiological and clinical syndrome. Arthritis Rheum. 2013;65:2183–9. analysis of 150 cases over a 5-year period and review of literature. 72. Wakamatsu R, Watanabe H, Suzuki K, Suga N, Kitagawa W, Miura N, et al. Semin Arthritis Rheum. 2005;35:143–53. Hypocomplementemic urticarial vasculitis syndrome is associated with 95. Ozen S, Pistorio A, Iusan SM, Bakkaloglu A, Herlin T, Brik R, et al. EULAR, high levels of serum IgG4: a clinical manifestation that mimics IgG4- PRINTO, PRES criteria for Henoch–Schönlein purpura, childhood pol- related disease. Intern Med. 2011;50:1109–12. yarteritis nodosa, childhood Wegener granulomatosis and childhood 73. Schwartz HR, McDufe FC, Black LF, Schroeter AL, Conn DL. Hypocom- Takayasu arteritis: Ankara 2008. Part II: Final classifcation criteria. Ann plementemic urticarial vasculitis: association with chronic obstructive Rheum Dis. 2008;2010(69):798–806. pulmonary disease. Mayo Clin Proc. 1982;57:231–8. 96. Park SJ, Kim HJ, Park H, Hann HJ, Kim KH, Han S, et al. Incidence, preva- 74. Buck A, Christensen J, McCarty M. Hypocomplementemic urticarial lence, mortality and causes of death in Takayasu Arteritis in Korea—a vasculitis syndrome. J Clin Aesthet Dermatol. 2012;5:36–46. nationwide, population-based study. Int J Cardiol. 2017;235:100–4. 75. Uehara R, Belay ED. Epidemiology of Kawasaki Disease in Asia, Europe, 97. Watts R, Al-Taiar A, Mooney J, Scott D, MacGregor A. The epide- and the United States. J Epidemiol. 2012;22:79–85. miology of Takayasu arteritis in the UK. Rheumatology (Oxford). 76. Singh S, Vignesh P, Burgner D. The epidemiology of Kawasaki disease: a 2009;48:1008–11. global update. Arch Dis Child. 2015;100:1084–8. 98. Gudbrandsson B, Molberg Ø, Garen T, Palm Ø. Prevalence, incidence, 77. Takahashi K, Oharaseki T, Yokouchi Y. Update on etio and immu- and disease characteristics of takayasu arteritis by ethnic background: nopathogenesis of Kawasaki disease. Curr Opin Rheumatol. data from a large, population-based cohort resident in southern Nor- 2014;26:31–6. way. Arthritis Care Res. 2017;69:278–85. 78. Arora A, Wetter DA, Gonzalez-Santiago TM, Davis MDP, Lohse CM. 99. Birlik M, Kücükyavas Y, Aksu K, Solmaz D, Can G, Taylan A, et al. Incidence of leukocytoclastic vasculitis, 1996–2010: a population-based Epidemiology of Takayasu’s arteritis in Turkey. Clin Exp Rheumatol. study in Olmsted County, Minnesota. Mayo Clin Proc. 2014;89:1515–24. 2016;34:S33-39. 79. Bouiller K, Audia S, Devilliers H, Collet E, Aubriot MH, Leguy-Seguin V, 100. Saruhan-Direskeneli G, Hughes T, Aksu K, Keser G, Coit P, Aydin SZ, et al. et al. Etiologies and prognostic factors of leukocytoclastic vasculitis Identifcation of multiple genetic susceptibility loci in Takayasu Arteritis. with skin involvement. Medicine (Baltimore) [Internet]. 2016 [cited 2017 Am J Hum Genet. 2013;93:298–305. Nov 30];95. Available from: https://​www.​ncbi.​nlm.​nih.​gov/​pmc/​artic​les/​ 101. Lutalo PMK, D’Cruz DP. Diagnosis and classifcation of granulomato- PMC49​56825/ sis with polyangiitis (aka Wegener’s granulomatosis). J Autoimmun. 80. Johnson E, Wetter D, Lehman J, Hand J, Davis D, Tollefson M. Leukocy- 2014;48–49:94–8. toclastic vasculitis in children: clinical characteristics, subtypes, causes 102. Yamaguchi M, Ohta A, Tsunematsu T, Kasukawa R, Mizushima Y, Kashi- and direct immunofuorescence fndings of 56 biopsy-confrmed cases. wagi H, et al. Preliminary criteria for classifcation of adult Still’s disease. J J Eur Acad Dermatol Venereol. 2017;31:544–9. Rheumatol. 1992;19:424–30. Leyens et al. Orphanet J Rare Dis (2021) 16:326 Page 38 of 43

103. Fautrel B, Zing E, Golmard J, Le Moel G, Bissery A, Rioux C, et al. Proposal of felty’s syndrome: a systematic review. Semin Arthritis Rheum. for a new set of classifcation criteria for adult-onset still disease. Medi- 2012;41:658–68. cine. 2002;81:194–200. 123. Li H, Altman RD, Yao Q. RS3PE: clinical and research development. Curr 104. Wynne-Davies R, Hall C, Ansell BM. Spondylo-epiphysial dysplasia tarda Rheumatol Rep. 2015;17:49. with progressive arthropathy. A “new” disorder of autosomal recessive 124. Origuchi T, Arima K, Umeda M, Kawashiri S, Tamai M, Nakamura H, et al. inheritance. Bone Joint J. 1982;64-B:442–5. Clinical outcomes in the frst year of remitting seronegative symmetri- 105. Wynne-Davies R, Gormley J. The prevalence of skeletal dysplasias. An cal synovitis with pitting edema (RS3PE) syndrome. Mod Rheumatol. estimate of their minimum frequency and the number of patients 2017;27:150–4. requiring orthopaedic care. Bone Joint J. 1985;67:133–7. 125. Selmi C, Greenspan A, Huntley A, Gershwin ME. Multicentric Reticu- 106. Delague V, Chouery E, Corbani S, Ghanem I, Aamar S, Fischer J, et al. lohistiocytosis: a Critical Review. Current Rheumatology Reports Molecular study of WISP3 in nine families originating from the Middle- [Internet]. 2015 [cited 2017 Sep 13];17. https://​doi.​org/​10.​1007/​ East and presenting with progressive pseudorheumatoid dysplasia: s11926-​015-​0511-6 identifcation of two novel mutations, and description of a founder 126. Islam AD, Naguwa SM, Cheema GS, Hunter JC, Gershwin ME. Multicen- efect. Am J Med Genet A. 2005;138A:118–26. tric reticulohistiocytosis: a rare yet challenging disease. Clin Rev Allergy 107. Cassa CA, Smith SE, Docken W, Hofman E, McLaughlin H, Chun S, et al. Immunol. 2013;45:281–9. An argument for early genomic sequencing in atypical cases: a WISP3 127. Brackenridge A, Bashir T, Wheatley T. Multicentric reticulohistiocytosis variant leads to diagnosis of progressive pseudorheumatoid arthropa- and pregnancy. BJOG Int J Obst Gynaecol. 2005;112:672–3. thy of childhood. Rheumatology (Oxford). 2016;55:586–9. 128. Hayem G, Bouchaud-Chabot A, Benali K, Roux S, Palazzo E, Silbermann- 108. Nakamura Y, Weidinger G, Liang JO, Aquilina-Beck A, Tamai K, Moon RT, Hofman O, et al. SAPHO syndrome: a long-term follow-up study of 120 et al. The CCN family member Wisp3, mutant in progressive pseu- cases. Semin Arthritis Rheum. 1999;29:159–71. dorheumatoid dysplasia, modulates BMP and Wnt signaling. J Clin 129. Witt M, Meier J, Hammitzsch A, Proft F, Schulze-Koops H, Grunke M. Invest. 2007;117:3075–86. Disease burden, disease manifestations and current treatment regimen 109. Garcia Segarra N, Mittaz L, Campos-Xavier AB, Bartels CF, Tuysuz B, of the SAPHO syndrome in Germany: results from a nationwide patient Alanay Y, et al. The diagnostic challenge of progressive pseudorheuma- survey. Semin Arthritis Rheum. 2014;43:745–50. toid dysplasia (PPRD): a review of clinical features, radiographic features, 130. Nguyen MT, Borchers A, Selmi C, Naguwa SM, Cheema G, Gershwin ME. and WISP3 mutations in 63 afected individuals. Am J Med Genet. The SAPHO syndrome. Semin Arthritis Rheum. 2012;42:254–65. 2012;160C:217–29. 131. Zimmermann P, Curtis N. Synovitis, acne, pustulosis, hyperostosis, and 110. Williams CJ, Zhang Y, Timms A, Bonavita G, Caeiro F, Broxholme J, et al. osteitis (SAPHO) syndrome—a challenging diagnosis not to be missed. Autosomal dominant familial calcium pyrophosphate dihydrate deposi- J Infect. 2016;72:S106–14. tion disease is caused by mutation in the transmembrane protein 132. Rukavina I. SAPHO syndrome: a review. J Child Orthop. 2015;9:19–27. ANKH. Am J Hum Genet. 2002;71:985–91. 133. Prakken B, Albani S, Martini A. Juvenile idiopathic arthritis. The Lancet. 111. Andrew LJ, Brancolini V, de la Pena LS, Devoto M, Caeiro F, Marchegiani 2011;377:2138–49. R, et al. Refnement of the chromosome 5p locus for familial calcium 134. Vastert SJ, Kuis W, Grom AA. Systemic JIA: new developments in the pyrophosphate dihydrate deposition disease. Am J Hum Genet. understanding of the pathophysiology and therapy. Best Pract Res Clin 1999;64:136–45. Rheumatol. 2009;23:655–64. 112. Netter P, Bardin T, Bianchi A, Richette P, Loeuille D. The ANKH gene and 135. Woo P. Systemic juvenile idiopathic arthritis: diagnosis, management, familial calcium pyrophosphate dihydrate deposition disease. Joint and outcome. Nat Clin Pract Rheumatol. 2006;2:28–34. Bone Spine. 2004;71:365–8. 136. Petty RE, Southwood TR, Manners P, Baum J, Glass DN, Goldenberg J, 113. Pendleton A, Johnson MD, Hughes A, Gurley KA, Ho AM, Doherty M, et al. International League of Associations for Rheumatology classifca- et al. Mutations in ANKH cause chondrocalcinosis. Am J Hum Genet. tion of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J 2002;71:933–40. Rheumatol. 2004;31:390–2. 114. Rosales-Alexander JL, Balsalobre Aznar J, Magro-Checa C. Calcium 137. Ombrello MJ, Arthur VL, Remmers EF, Hinks A, Tachmazidou I, Grom AA, pyrophosphate crystal deposition disease: diagnosis and treatment. et al. Genetic architecture distinguishes systemic juvenile idiopathic Open Access Rheumatol. 2014;6:39–47. arthritis from other forms of juvenile idiopathic arthritis: clinical and 115. Verspoor FGM, Zee AAG, Hannink G, van der Geest IC, Veth RPH, et al. therapeutic implications. Ann Rheum Dis. 2017;76:906–13. Long-term follow-up results of primary and recurrent pigmented vil- 138. Ayaz NA, Özen S, Bilginer Y, Ergüven M, Taşkıran E, Yılmaz E, et al. MEFV lonodular synovitis. Rheumatology (Oxford). 2014;53:2063–70. mutations in systemic onset juvenile idiopathic arthritis. Rheumatology 116. Myers BW, Masi AT. Pigmented villonodular synovitis and tenosynovitis: (Oxford). 2009;48:23–5. a clinical epidemiologic study of 166 cases and literature review. Medi- 139. De Benedetti F, Meazza C, Vivarelli M, Rossi F, Pistorio A, Lamb R, et al. cine (Baltimore). 1980;59:223–38. Functional and prognostic relevance of the 173 polymorphism of 117. Fiocco U, Sfriso P, Lunardi F, Pagnin E, Oliviero F, Scagliori E, et al. the macrophage migration inhibitory factor− gene in systemic-onset Molecular pathways involved in synovial cell infammation and tumoral juvenile idiopathic arthritis. Arthritis Rheum. 2003;48:1398–407. proliferation in difuse pigmented villonodular synovitis. Autoimmun 140. Quartier P, Allantaz F, Cimaz R, Pillet P, Messiaen C, Bardin C, et al. Rev. 2010;9:780–4. A multicentre, randomised, double-blind, placebo-controlled trial 118. Cassier PA, Italiano A, Gomez-Roca CA, Le Tourneau C, Toulmonde M, with the interleukin-1 receptor antagonist anakinra in patients with Cannarile MA, et al. CSF1R inhibition with emactuzumab in locally systemic-onset juvenile idiopathic arthritis (ANAJIS trial). Ann Rheum advanced difuse-type tenosynovial giant cell tumours of the soft Dis. 2010;70:747–54. tissue: a dose-escalation and dose-expansion phase 1 study. Lancet 141. van Dijkhuizen EHP, Wulfraat NM. Early predictors of prognosis in Oncol. 2015;16:949–56. juvenile idiopathic arthritis: a systematic literature review. Ann Rheum 119. Dwivedi N, Upadhyay J, Neeli I, Khan S, Pattanaik D, Myers L, et al. Felty’s Dis. 2015;74:1996–2005. syndrome autoantibodies bind to deiminated histones and neutrophil 142. Edouard S, Fenollar F, Raoult D. The rise of Tropheryma whipplei: a extracellular chromatin traps. Arthritis Rheum. 2012;64:982–92. 12-year retrospective study of PCR diagnoses in our reference center. J 120. Hellmich B, Csernok E, Schatz H, Gross WL, Schnabel A. Autoantibod- Clin Microbiol. 2012;50:3917–20. ies against granulocyte colony-stimulating factor in Felty’s syndrome 143. Ramharter M, Harrison N, Bühler T, Herold B, Lagler H, Lötsch F, et al. and neutropenic systemic lupus erythematosus. Arthritis Rheum. Prevalence and risk factor assessment of Tropheryma whipplei in a rural 2002;46:2384–91. community in Gabon: a community-based cross-sectional study. Clin 121. Balint GP, Balint PV. Felty’s syndrome. Best Pract Res Clin Rheumatol. Microbiol Infect. 2014;20:1189–94. 2004;18:631–45. 144. Fenollar F, Trani M, Davoust B, Salle B, Birg M, Rolain J, et al. Prevalence 122. Narváez J, Domingo-Domenech E, Gómez-Vaquero C, López-Vives of asymptomatic Tropheryma whipplei carriage among humans and L, Estrada P, Aparicio M, et al. Biological agents in the management nonhuman primates. J Infect Dis. 2008;197:880–7. Leyens et al. Orphanet J Rare Dis (2021) 16:326 Page 39 of 43

145. Feurle GE, Junga NS, Marth T. Efcacy of ceftriaxone or merope- 165. Yalçınkaya F, Özen S, Özçakar ZB, Aktay N, Çakar N, Düzova A, et al. A nem as initial Therapies in Whipple’s disease. Gastroenterology. new set of criteria for the diagnosis of familial Mediterranean fever in 2010;138:478–86. childhood. Rheumatology (Oxford). 2009;48:395–8. 146. Feurle GE, Moos V, Bläker H, Loddenkemper C, Moter A, Stroux A, 166. Livneh A, Langevitz P, Zemer D, Zaks N, Kees S, Lidar T, et al. Criteria et al. Intravenous ceftriaxone, followed by 12 or three months of oral for the diagnosis of familial mediterranean fever. Arthritis Rheum. treatment with trimethoprim-sulfamethoxazole in Whipple’s disease. J 1997;40:1879–85. Infect. 2013;66:263–70. 167. Haas D, Hofmann GF. Mevalonate kinase defciencies: from mevalonic 147. Feurle GE, Moos V, Schinnerling K, Geelhaar A, Allers K, Biagi F, et al. The aciduria to hyperimmunoglobulinemia D syndrome. Orphanet J Rare immune reconstitution infammatory syndrome in whipple disease: a Dis. 2006;1:13. cohort study. Ann Intern Med. 2010;153:710–7. 168. Lainka E, Neudorf U, Lohse P, Timmann C, Bielak M, Stojanov S, et al. 148. Lagier J-C, Fenollar F, Lepidi H, Giorgi R, Million M, Raoult D. Treatment Incidence and clinical features of hyperimmunoglobulinemia D and of classic Whipple’s disease: from in vitro results to clinical outcome. J periodic fever syndrome (HIDS) and spectrum of mevalonate kinase Antimicrob Chemother. 2014;69:219–27. (MVK) mutations in German children. Rheumatol Int. 2012;32:3253–60. 149. Moos V, Schneider T. Tropheryma whipplei: Erreger verschiedener Infek- 169. Ozen S, Kuemmerle-Deschner JB, Cimaz R, Livneh A, Quartier P, Kone- tionen und Pathogen des Morbus Whipple. Dtsch med Wochenschr. Paut I, et al. International retrospective chart review of treatment 2015;140:428–32. patterns in severe familial mediterranean fever, tumor necrosis factor 150. Pareek A, Sanders TL, Wu IT, Larson DR, Saris DBF, Krych AJ. Incidence receptor-associated periodic syndrome, and mevalonate kinase def- of symptomatic osteochondritis dissecans lesions of the knee: ciency/hyperimmunoglobulinemia d syndrome: real-world experience a population-based study in Olmsted County. Osteoarthr Cartil. in three periodic fever syndromes. Arthritis Care Res. 2017;69:578–86. 2017;25:1663–71. 170. van der Hilst JCH, Bodar EJ, Barron KS, Frenkel J, Drenth JPH, van der 151. Chambers HG, Shea KG, Carey JL. AAOS Clinical Practice Guideline: diag- Meer JWM, et al. Long-term follow-up, clinical features, and quality nosis and treatment of osteochondritis dissecans. J Am Acad Orthop of life in a series of 103 patients with hyperimmunoglobulinemia D Surg. 2011;19:307–9. syndrome. Medicine. 2008;87:301–10. 152. Kocher MS, Tucker R, Ganley TJ, Flynn JM. Management of Osteochon- 171. Arima K, Kinoshita A, Mishima H, Kanazawa N, Kaneko T, Miz- dritis Dissecans of the Knee: Current Concepts Review. Am J Sports ushima T, et al. Proteasome assembly defect due to a proteasome Med. 2006;34:1181–91. subunit beta type 8 (PSMB8) mutation causes the autoinfamma- 153. Aróstegui JI, Arnal C, Merino R, Modesto C, Antonia Carballo M, Moreno tory disorder, Nakajo–Nishimura syndrome. Proc Natl Acad Sci USA. P, et al. NOD2 gene-associated pediatric granulomatous arthritis: clini- 2011;108:14914–9. cal diversity, novel and recurrent mutations, and evidence of clinical 172. McDermott A, Jacks J, Kessler M, Emanuel PD, Gao L. Proteasome- improvement with interleukin-1 blockade in a Spanish cohort. Arthritis associated autoinfammatory syndromes: advances in pathogeneses, Rheum. 2007;56:3805–13. clinical presentations, diagnosis, and management. Int J Dermatol. 154. Rosé CD, Aróstegui JI, Martin TM, Espada G, Scalzi L, Yagüe J, et al. 2015;54:121–9. NOD2-associated pediatric granulomatous arthritis, an expanding 173. Kanazawa N. Nakajo-Nishimura syndrome: an autoinfammatory disor- phenotype: study of an international registry and a national cohort in der showing pernio-like rashes and progressive partial lipodystrophy. Spain. Arthritis Rheum. 2009;60:1797–803. Allergol Int. 2012;61:197–206. 155. Caso F, Galozzi P, Costa L, Sfriso P, Cantarini L, Punzi L. Autoinfamma- 174. Schellevis MA, Stofels M, Hoppenreijs EPAH, Bodar E, Simon A, van der tory granulomatous diseases: from Blau syndrome and early-onset Meer JWM. Variable expression and treatment of PAPA syndrome. Ann sarcoidosis to NOD2-mediated disease and Crohn’s disease. RMD Open Rheum Dis. 2011;70:1168–70. [Internet]. 2015 [cited 2017 Jun 27];1. Available from: http://​www.​ncbi.​ 175. Wise CA, Gillum JD, Seidman CE, Lindor NM, Veile R, Bashiardes S, et al. nlm.​nih.​gov/​pmc/​artic​les/​PMC46​12691/ Mutations in CD2BP1 disrupt binding to PTP PEST and are responsible 156. Rosé CD, Pans S, Casteels I, Anton J, Bader-Meunier B, Brissaud P, et al. for PAPA syndrome, an autoinfammatory disorder. Hum Mol Genet. Blau syndrome: cross-sectional data from a multicentre study of clini- 2002;11:961–9. cal, radiological and functional outcomes. Rheumatology (Oxford). 176. Lindor NM, Arsenault TM, Solomon H, Seidman CE, McEvoy MT. 2015;54:1008–16. A new autosomal dominant disorder of pyogenic sterile arthritis, 157. Hofmann AL, Milman N, Byg KE. Childhood sarcoidosis in Denmark pyoderma gangrenosum, and acne: PAPA syndrome. Mayo Clin Proc. 1979–1994: incidence, clinical features and laboratory results at presen- 1997;72:611–5. tation in 48 children. Acta Paediatr. 2004;93:30–6. 177. Yeon HB, Lindor NM, Seidman JG, Seidman CE. Pyogenic arthritis, pyo- 158. Mensa-Vilaro A, Cham WT, Tang SP, Lim SC, González-Roca E, Ruiz-Ortiz derma gangrenosum, and acne syndrome maps to chromosome 15q. E, et al. Brief Report: First Identifcation of Intrafamilial Recurrence of Am J Hum Genet. 2000;66:1443–8. Blau Syndrome due to Gonosomal NOD2 Mosaicism. Arthritis Rheuma- 178. Førsvoll J, Kristofersen EK, Øymar K. Incidence, clinical characteristics tol (Hoboken, NJ). 2016;68:1039–44. and outcome in Norwegian children with periodic fever, aphthous sto- 159. Finetti M, Omenetti A, Federici S, Caorsi R, Gattorno M. Chronic Infantile matitis, pharyngitis and cervical adenitis syndrome; a population-based Neurological Cutaneous and Articular (CINCA) syndrome: a review. study. Acta Paediatr. 2013;102:187–92. Orphanet J Rare Dis [Internet]. 2016 [cited 2017 Sep 21];11. Available 179. Thomas KT, Feder HM, Lawton AR, Edwards KM. Periodic fever syn- from: http://​www.​ncbi.​nlm.​nih.​gov/​pmc/​artic​les/​PMC51​42346/ drome in children. J Pediatr. 1999;135:15–21. 160. Cuisset L, Jeru I, Dumont B, Fabre A, Cochet E, Le Bozec J, et al. Muta- 180. Vanoni F, Theodoropoulou K, Hofer M. PFAPA syndrome: a review on tions in the autoinfammatory cryopyrin-associated periodic syndrome treatment and outcome. Pediatr Rheumatol Online J [Internet]. 2016 gene: epidemiological study and lessons from eight years of genetic [cited 2017 Oct 12];14. Available from: https://​www.​ncbi.​nlm.​nih.​gov/​ analysis in France. Ann Rheum Dis. 2011;70:495–9. pmc/​artic​les/​PMC49​24332/ 161. Kuemmerle-Deschner JB. CAPS—pathogenesis, presentation and 181. Marshall GS, Edwards KM, Butler J, Lawton AR. Syndrome of periodic treatment of an autoinfammatory disease. Semin Immunopathol. fever, pharyngitis, and aphthous stomatitis. J Pediatr. 1987;110:43–6. 2015;37:377–85. 182. Cantarini L, Vitale A, Sicignano LL, Emmi G, Verrecchia E, Patisso I, et al. 162. Koné-Paut I, Hentgen V, Touitou I. Current data on familial Mediterra- Diagnostic Criteria for Adult-Onset Periodic Fever, Aphthous Stomatitis, nean fever. Joint Bone Spine. 2011;78:111–4. Pharyngitis, and Cervical Adenitis (PFAPA) Syndrome. Front Immunol 163. Ozen S, Demirkaya E, Amaryan G, Koné-Paut I, Polat A, Woo P, et al. [Internet]. 2017 [cited 2018 Sep 5];8. Available from: https://​www.​ncbi.​ Results from a multicentre international registry of familial Mediter- nlm.​nih.​gov/​pmc/​artic​les/​PMC56​09591/ ranean fever: impact of environment on the expression of a monogenic 183. Simon A, Asli B, Braun-Falco M, De Koning H, Fermand J-P, Grattan disease in children. Ann Rheum Dis. 2014;73:662–7. C, et al. Schnitzler’s syndrome: diagnosis, treatment, and follow-up. 164. Sari I, Birlik M, Kasifoglu T. Familial Mediterranean fever: an updated Allergy. 2013;68:562–8. review. Eur J Rheumatol. 2014;1:21–33. 184. Krause K, Tsianakas A, Wagner N, Fischer J, Weller K, Metz M, et al. Ef- cacy and safety of canakinumab in Schnitzler syndrome: a multicenter Leyens et al. Orphanet J Rare Dis (2021) 16:326 Page 40 of 43

randomized placebo-controlled study. J Allergy Clin Immunol. 204. Cavagna L, Nuño L, Scirè CA, Govoni M, Longo FJL, Franceschini F, et al. 2017;139:1311–20. Serum Jo-1 autoantibody and isolated arthritis in the antisynthetase 185. Tinazzi E, Puccetti A, Patuzzo G, Sorleto M, Barbieri A, Lunardi C. syndrome: review of the literature and report of the experience of Schnitzler syndrome, an autoimmune–autoinfammatory syndrome: AENEAS Collaborative Group. Clinic Rev Allerg Immunol. 2017;52:71–80. Report of two new cases and review of the literature. Autoimmun Rev. 205. Lehmann D, Motlagh L, Robaa D, Zierz S. Muscle Carnitine Palmitoyl- 2011;10:404–9. transferase II Defciency: A Review of Enzymatic Controversy and 186. Gusdorf L, Asli B, Barbarot S, Néel A, Masseau A, Puéchal X, et al. Clinical Features. Int J Mol Sci [Internet]. 2017 [cited 2017 Nov 18];18. Schnitzler syndrome: validation and applicability of diagnostic criteria Available from: https://​www.​ncbi.​nlm.​nih.​gov/​pmc/​artic​les/​PMC52​ in real-life patients. Allergy. 2017;72:177–82. 97716/ 187. Vastert SJ, van Wijk R, D’Urbano LE, de Vooght KMK, de Jager W, Ravelli 206. Sigauke E, Rakheja D, Kitson K, Bennett MJ. Carnitine palmitoyltrans- A, et al. Mutations in the perforin gene can be linked to macrophage ferase II defciency: a clinical, biochemical, and molecular review. Lab activation syndrome in patients with systemic onset juvenile idiopathic Invest. 2003;83:1543–54. arthritis. Rheumatology (Oxford). 2010;49:441–9. 207. Ohta A, Nagai M, Nishina M, Tomimitsu H, Kohsaka H. Prevalence and 188. Davì S, Minoia F, Pistorio A, Horne A, Consolaro A, Rosina S, et al. Perfor- incidence of polymyositis and dermatomyositis in Japan. Mod Rheuma- mance of current guidelines for diagnosis of macrophage activation tol. 2014;24:477–80. syndrome complicating systemic juvenile idiopathic arthritis. Arthritis 208. Dobloug C, Garen T, Bitter H, Stjärne J, Stenseth G, Grøvle L, et al. Preva- Rheumatol. 2014;66:2871–80. lence and clinical characteristics of adult polymyositis and dermatomy- 189. Ravelli A, Minoia F, Davì S, Horne A, Bovis F, Pistorio A, et al. Classif- ositis; data from a large and unselected Norwegian cohort. Ann Rheum cation criteria for macrophage activation syndrome complicating Dis. 2015;74:1551–6. systemic juvenile idiopathic arthritis. Ann Rheum Dis Ann Rheum Dis. 209. Rosa J, Garrot LF, Navarta DA, Saucedo C, Scolnik M, Bedran Z, et al. 2016;75:481–9. Incidence and Prevalence of Polymyositis and Dermatomyositis in a 190. Henter J-I, Horne A, Aricó M, Egeler RM, Filipovich AH, Imashuku S, et al. Health Management Organization in Buenos Aires. J Clin Rheumatol. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic 2013;19:303–7. lymphohistiocytosis. Pediatr Blood Cancer. 2007;48:124–31. 210. Malik A, Hayat G, Kalia JS, Guzman MA. Idiopathic Infammatory Myopa- 191. Minoia F, Davì S, Horne A, Demirkaya E, Bovis F, Li C, et al. Clinical thies: Clinical Approach and Management. Front Neurol [Internet]. 2016 features, treatment, and outcome of macrophage activation syndrome [cited 2017 Nov 19];7. Available from: https://​www.​ncbi.​nlm.​nih.​gov/​ complicating systemic juvenile idiopathic arthritis: a multinational, pmc/​artic​les/​PMC48​73503/ multicenter study of 362 patients. Arthritis Rheumatol. 2014;66:3160–9. 211. Dobloug GC, Antal EA, Sveberg L, Garen T, Bitter H, Stjärne J, et al. High 192. Ruscitti P, Cipriani P, Ciccia F, Masedu F, Liakouli V, Carubbi F, et al. prevalence of inclusion body myositis in Norway; a population-based Prognostic factors of macrophage activation syndrome, at the time of clinical epidemiology study. Eur J Neurol. 2015;22:672-e41. diagnosis, in adult patients afected by autoimmune disease: analysis 212. Paltiel AD, Ingvarsson E, Lee DKK, Lef RL, Nowak RJ, Petschke KD, et al. of 41 cases collected in 2 rheumatologic centers. Autoimmun Rev. Demographic and clinical features of inclusion body myositis in North 2017;16:16–21. America. Muscle Nerve. 2015;52:527–33. 193. Ferguson P, Chen S, Tayeh M, Ochoa L, Leal S, Pelet A, et al. Homozy- 213. Allen JA, Peterson A, Suft R, Hinchclif ME, Mahoney JM, Wood TA, gous mutations in LPIN2 are responsible for the syndrome of chronic et al. Post-epidemic eosinophilia myalgia syndrome associated with recurrent multifocal osteomyelitis and congenital dyserythropoietic L-Tryptophan. Arthritis Rheum [Internet]. 2011 [cited 2017 Nov 9];63. anaemia (Majeed syndrome). J Med Genet. 2005;42:551–7. Available from: https://​www.​ncbi.​nlm.​nih.​gov/​pmc/​artic​les/​PMC38​ 194. El-Shanti H, Ferguson P. Majeed Syndrome. In: Adam MP, Ardinger HH, 48710/ Pagon RA, Wallace SE, Bean LJ, Meford HC, et al., editors. GeneR- 214. Devic P, Gallay L, Streichenberger N, Petiot P. Focal myositis: a review. eviews(®) [Internet]. Seattle (WA): University of Washington, Seattle; Neuromuscul Disord. 2016;26:725–33. 1993 [cited 2017 Nov 23]. Available from: http://​www.​ncbi.​nlm.​nih.​gov/​ 215. Auerbach A, Fanburg-smith JC, Wang G, Rushing EJ. Focal myositis: a books/​NBK19​74/ clinicopathologic study of 115 cases of an intramuscular mass-like reac- 195. Herlin T, Fiirgaard B, Bjerre M, Kerndrup G, Hasle H, Bing X, et al. tive process. Am J Surg Pathol. 2009;33:1016–24. Efcacy of anti-IL-1 treatment in Majeed syndrome. Ann Rheum Dis. 216. De Castro M, Johnston J, Biesecker L. Determining the prevalence of 2013;72:410–3. McArdle disease from gene frequency by analysis of next generation 196. Lachmann HJ, Papa R, Gerhold K, Obici L, Touitou I, Cantarini L, et al. The sequencing data. Genet Med. 2015;17:1002–6. phenotype of TNF receptor-associated autoinfammatory syndrome 217. Santalla A, Nogales-Gadea G, Encinar AB, Vieitez I, González-Quintana (TRAPS) at presentation: a series of 158 cases from the Eurofever/EURO- A, Serrano-Lorenzo P, et al. Genotypic and phenotypic features of all TRAPS international registry. Ann Rheum Dis. 2014;73:2160–7. Spanish patients with McArdle disease: a 2016 update. BMC Genomics. 197. Lainka E, Neudorf U, Lohse P, Timmann C, Stojanov S, Huss K, et al. 2017;18:819. Incidence of TNFRSF1A mutations in German children: epidemiological, 218. Nogales-Gadea G, Santalla A, Brull A, de Luna N, Lucia A, Pinós T. The clinical and genetic characteristics. Rheumatology. 2009;48:987–91. pathogenomics of McArdle disease—genes, enzymes, models, and 198. Bachetti T, Chiesa S, Castagnola P, Bani D, Zanni ED, Omenetti A, et al. therapeutic implications. J Inherit Metab Dis. 2015;38:221–30. Autophagy contributes to infammation in patients with TNFR-associ- 219. Nogales-Gadea G, Pinós T, Andreu AL, Martín MA, Arenas J, Lucia A. ated periodic syndrome (TRAPS). Ann Rheum Dis. 2013;72:1044–52. Next-generation sequencing to estimate the prevalence of a great 199. Allenbach Y, Drouot L, Rigolet A, Charuel JL, Jouen F, Romero NB, et al. unknown: McArdle disease. Genetics in Medicine. 2015;17:gim201576. Anti-HMGCR Autoantibodies in European Patients With Autoimmune 220. Musumeci O, Bruno C, Mongini T, Rodolico C, Aguennouz M, Barca Necrotizing Myopathies. Medicine (Baltimore) [Internet]. 2014 [cited E, et al. Clinical features and new molecular fndings in muscle 2017 Nov 18];93. Available from: https://​www.​ncbi.​nlm.​nih.​gov/​pmc/​ phosphofructokinase defciency (GSD type VII). Neuromuscul Disord. artic​les/​PMC46​32910/ 2012;22:325–30. 200. Carroll MB, Newkirk MR, Sumner NS. Necrotizing autoimmune myo- 221. Toscano A, Musumeci O. Tarui disease and distal glycogenoses: clinical pathy: a unique subset of idiopathic infammatory myopathy. J Clin and genetic update. Acta Myol. 2007;26:105–7. Rheumatol. 2016;22:376–80. 222. Kinoshita A, Saito T, Tomita H, Makita Y, Yoshida K, Ghadami M, et al. 201. Targof IN. Autoantibodies and their signifcance in myositis. Curr Rheu- Domain-specifc mutations in TGFB1 result in Camurati–Engelmann matol Rep. 2008;10:333–40. disease. Nat Genet. 2000;26:ng900_19. 202. Manole C, Inimioara Mihaela C, Bogdan C. New insights into antisyn- 223. Simsek-Kiper PO, Dikoglu E, Campos-Xavier B, Utine GE, Bonafe L, Unger thetase syndrome. Maedica (Buchar). 2016;11:130–5. S, et al. Positive efects of an angiotensin II type 1 receptor antagonist 203. Lega J-C, Fabien N, Reynaud Q, Durieu I, Durupt S, Dutertre M, et al. The in Camurati–Engelmann disease: a single case observation. Am J Med clinical phenotype associated with myositis-specifc and associated Genet. 2014;164:2667–71. autoantibodies: a meta-analysis revisiting the so-called antisynthetase 224. Morales-Piga A, Bachiller-Corral J, Trujillo-Tiebas MJ, Villaverde-Hueso syndrome. Autoimmun Rev. 2014;13:883–91. A, Gamir-Gamir ML, Alonso-Ferreira V, et al. Fibrodysplasia ossifcans Leyens et al. Orphanet J Rare Dis (2021) 16:326 Page 41 of 43

progressiva in Spain: epidemiological, clinical, and genetic aspects. 245. Busch J, Frank V, Bachmann N, Otsuka A, Oji V, Metze D, et al. Muta- Bone. 2012;51:748–55. tions in the prostaglandin transporter SLCO2A1 cause primary hyper- 225. Baujat G, Choquet R, Bouée S, Jeanbat V, Courouve L, Ruel A, et al. trophic osteoarthropathy with digital clubbing. J Investig Dermatol. Prevalence of fbrodysplasia ossifcans progressiva (FOP) in France: 2012;132:2473–6. an estimate based on a record linkage of two national databases. 246. Lee S, Park SY, Kwon HJ, Lee C-H, Kim O-H, Rhee Y. Identifcation of Orphanet J Rare Dis [Internet]. 2017 [cited 2017 Nov 17];12. Available the mutations in the prostaglandin transporter gene, SLCO2A1 and from: https://​www.​ncbi.​nlm.​nih.​gov/​pmc/​artic​les/​PMC54​93013/ clinical characterization in korean patients with pachydermoperios- 226. Heursen E-M, Partida M del CG, Expósito JP, Díaz FN. Osteomesopyk- tosis. J Korean Med Sci. 2016;31:735–42. nosis—a benign axial hyperostosis that can mimic metastatic disease. 247. Uppal S, Diggle CP, Carr IM, Fishwick CWG, Ahmed M, Ibrahim GH, Skeletal Radiol. 2016;45:141–6. et al. Mutations in 15-hydroxyprostaglandin dehydrogenase cause 227. Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomal primary hypertrophic osteoarthropathy. Nat Genet. 2008;40:789–93. storage disorders. JAMA. 1999;281:249–54. 248. Jurecka A, Ługowska A, Golda A, Czartoryska B, Tylki-Szymańska A. 228. Biegstraaten M, Arngrímsson R, Barbey F, Boks L, Cecchi F, Deegan PB, Prevalence rates of mucopolysaccharidoses in Poland. J Appl Genet. et al. Recommendations for initiation and cessation of enzyme replace- 2015;56:205–10. ment therapy in patients with Fabry disease: the European Fabry Work- 249. Malm G, Lund AM, Månsson J-E, Heiberg A. Mucopolysaccharidoses ing Group consensus document. Orphanet J Rare Dis. 2015;10:36. in the Scandinavian countries: incidence and prevalence. Acta Pædi- 229. Elliott PM, Germain DP, Hilz MJ, Spada M, Wanner C, Falissard B. Why sys- atrica. 2008;97:1577–81. tematic literature reviews in Fabry disease should include all published 250. Gufon N, Heron B, Chabrol B, Feillet F, Montauban V, Valayanno- evidence. European Journal of Medical Genetics. 2019;62:103702. poulos V. Diagnosis, quality of life, and treatment of patients with 230. Ehlert K, Frosch M, Fehse N, Zander A, Roth J, Vormoor J. Farber disease: Hunter syndrome in the French healthcare system: a retrospective clinical presentation, pathogenesis and a new approach to treatment. observational study. Orphanet J Rare Dis [Internet]. 2015 [cited 2017 Pediatr Rheumatol. 2007;5:15. Nov 24];10. Available from: https://​www.​ncbi.​nlm.​nih.​gov/​pmc/​artic​ 231. Alves MQ, Le Trionnaire E, Ribeiro I, Carpentier S, Harzer K, Levade T, les/​PMC44​07793/ et al. Molecular basis of acid ceramidase defciency in a neonatal form 251. Kitaoka T, Miyoshi Y, Namba N, Miura K, Kubota T, Ohata Y, et al. Two of Farber disease: Identifcation of the frst large deletion in ASAH1 Japanese familial cases of Cafey disease with and without the com- gene. Mol Genet Metab. 2013;109:276–81. mon COL1A1 mutation and normal bone density, and review of the 232. Orenstein M, Barbouth D, Bodamer OA, Weinreb NJ. Patients with type literature. Eur J Pediatr. 2014;173:799–804. 1 Gaucher disease in South Florida, USA: demographics, genotypes, dis- 252. Gensure RC, Mäkitie O, Barclay C, Chan C, DePalma SR, Bastepe M, et al. ease severity and treatment outcomes. Orphanet J Rare Dis. 2014;9:45. A novel COL1A1 mutation in infantile cortical hyperostosis (Cafey dis- 233. Stirnemann J, Vigan M, Hamroun D, Heraoui D, Rossi-Semerano L, ease) expands the spectrum of collagen-related disorders. J Clin Invest. Berger MG, et al. The French Gaucher’s disease registry: clinical charac- 2005;115:1250–7. teristics, complications and treatment of 562 patients. Orphanet J Rare 253. Guerin A, Dupuis L, Mendoza-Londono R. Cafey Disease. In: Adam MP, Dis. 2012;7:77. Ardinger HH, Pagon RA, Wallace SE, Bean LJ, Meford HC, et al., editors. 234. Stirnemann J, Belmatoug N, Camou F, Serratrice C, Froissart R, Cail- GeneReviews® [Internet]. Seattle (WA): University of Washington, Seat- laud C, et al. A Review of Gaucher Disease Pathophysiology, Clinical tle; 1993 [cited 2017 Dec 5]. Available from: http://​www.​ncbi.​nlm.​nih.​ Presentation and Treatments. Int J Mol Sci [Internet]. 2017 [cited 2017 gov/​books/​NBK99​168/ Nov 24];18. Available from: https://​www.​ncbi.​nlm.​nih.​gov/​pmc/​artic​les/​ 254. Germain DP. Ehlers-Danlos syndrome type IV. Orphanet J Rare Dis. PMC53​43975/ 2007;2:32. 235. Nalysnyk L, Rotella P, Simeone JC, Hamed A, Weinreb N. Gaucher dis- 255. De Paepe A, Malfait F. The Ehlers–Danlos syndrome, a disorder with ease epidemiology and natural history: a comprehensive review of the many faces. Clin Genet. 2012;82:1–11. literature. Hematology. 2017;22:65–73. 256. Malfait F, Francomano C, Byers P, Belmont J, Berglund B, Black J, et al. 236. Gurevich E, Hershkovitz E, Yarza S, Landau D. High prevalence of The 2017 international classifcation of the Ehlers–Danlos syndromes. hypophosphatasia in Southern Israel. Acta Paediatr. 2020;109:851–2. Am J Med Genet. 2017;175:8–26. 237. Högler W, Langman C, Gomes da Silva H, Fang S, Linglart A, Ozono K, 257. Gorospe L, Ayala-Carbonero AM, Fernández-Méndez MÁ, Arrieta P, et al. Diagnostic delay is common among patients with hypophos- Muñoz-Molina GM, Cabañero-Sánchez A, et al. Idiopathic fbrosing phatasia: initial fndings from a longitudinal, prospective, global registry. mediastinitis: spectrum of imaging fndings with emphasis on its asso- BMC Musculoskelet Disord [Internet]. 2019 [cited 2020 Sep 7];20. Avail- ciation with IgG4-related disease. Clin Imaging. 2015;39:993–9. able from: https://​www.​ncbi.​nlm.​nih.​gov/​pmc/​artic​les/​PMC63​76686/ 258. Rossi SE, McAdams HP, Rosado-de-Christenson ML, Franks TJ, Galvin JR. 238. Mornet E, Yvard A, Taillandier A, Fauvert D, Simon-Bouy B. A Molecular- Fibrosing mediastinitis. Radiographics. 2001;21:737–57. Based Estimation of the Prevalence of Hypophosphatasia in the 259. Wu Z, Jarvis H, Howard LS, Wright C, Kon OM. Post-tuberculous European Population. Ann Hum Genet. 2011;75:439–45. fbrosing mediastinitis: a review of the literature. BMJ Open Respir Res 239. Montaño AM, Tomatsu S, Gottesman GS, Smith M, Orii T. International [Internet]. 2017 [cited 2017 Dec 8];4. Available from: https://​www.​ncbi.​ Morquio A Registry: clinical manifestation and natural course of nlm.​nih.​gov/​pmc/​artic​les/​PMC55​01238/ Morquio A disease. J Inherit Metab Dis. 2007;30:165–74. 260. Uchida K, Masamune A, Shimosegawa T, Okazaki K. Prevalence of 240. Leadley RM, Lang S, Misso K, Bekkering T, Ross J, Akiyama T, et al. IgG4-Related Disease in Japan Based on Nationwide Survey in 2009. Int A systematic review of the prevalence of Morquio A syndrome: J Rheumatol [Internet]. 2012 [cited 2020 Sep 7];2012. Available from: challenges for study reporting in rare diseases. Orphanet J Rare Dis https://​www.​ncbi.​nlm.​nih.​gov/​pmc/​artic​les/​PMC34​15093/ [Internet]. 2014 [cited 2017 Nov 24];9. Available from: https://​www.​ 261. Umehara H, Okazaki K, Masaki Y, Kawano M, Yamamoto M, Saeki T, et al. ncbi.​nlm.​nih.​gov/​pmc/​artic​les/​PMC42​51694/ A novel clinical entity, IgG4-related disease (IgG4RD): general concept 241. Hendriksz CJ, Berger KI, Giugliani R, Harmatz P, Kampmann C, and details. Mod Rheumatol. 2012;22:1–14. Mackenzie WG, et al. International guidelines for the manage- 262. Wallace ZS, Zhang Y, Perugino CA, Naden R, Choi HK, Stone JH. Clinical ment and treatment of morquio a syndrome. Am J Med Genet A. phenotypes of IgG4-related disease: an analysis of two international 2015;167:11–25. cross-sectional cohorts. Ann Rheum Dis. 2019;78:406–12. 242. Kotwal A, Clarke BL. Melorheostosis: a rare sclerosing bone dysplasia. 263. Wallace ZS, Naden RP, Chari S, Choi H, Della-Torre E, Dicaire J-F, et al. The Curr Osteoporos Rep. 2017;15:335–42. 2019 American College of Rheumatology/European League Against 243. Smith GC, Pingree MJ, Freeman LA, Matsumoto JM, Howe BM, Kan- Rheumatism Classifcation Criteria for IgG4-Related Disease. Arthritis nas SN, et al. Melorheostosis: a retrospective clinical analysis of 24 Rheumatol (Hoboken, NJ). 2020;72:7–19. patients at the Mayo Clinic. PM&R. 2017;9:283–8. 264. Groth KA, Hove H, Kyhl K, Folkestad L, Gaustadnes M, Vejlstrup N, et al. 244. Freyschmidt J. Melorheostosis: a review of 23 cases. Eur Radiol. Prevalence, incidence, and age at diagnosis in Marfan Syndrome. 2001;11:474–9. Orphanet J Rare Dis [Internet]. 2015 [cited 2017 Nov 23];10. Available from: https://​www.​ncbi.​nlm.​nih.​gov/​pmc/​artic​les/​PMC46​68669/ Leyens et al. Orphanet J Rare Dis (2021) 16:326 Page 42 of 43

265. Loeys BL, Dietz HC, Braverman AC, Callewaert BL, Backer JD, Devereux 287. Cives M, Simone V, Rizzo FM, Dicuonzo F, Cristallo Lacalamita M, Ingrav- RB, et al. The revised Ghent nosology for the Marfan syndrome. J Med allo G, et al. Erdheim–Chester disease: a systematic review. Crit Rev Genet. 2010;47:476–85. Oncol Hematol. 2015;95:1–11. 266. Judge DP, Dietz HC. Marfan’s syndrome. Lancet. 2005;366:1965–76. 288. Diamond EL, Dagna L, Hyman DM, Cavalli G, Janku F, Estrada-Veras J, 267. Pinal-Fernandez I, Selva-O’Callaghan A, Grau JM. Diagnosis and clas- et al. Consensus guidelines for the diagnosis and clinical management sifcation of eosinophilic fasciitis. Autoimmun Rev. 2014;13:379–82. of Erdheim–Chester disease. Blood. 2014;124:483–92. 268. Mazori DR, Femia AN, Vleugels RA. Eosinophilic fasciitis: an updated 289. Cavalli G, Guglielmi B, Berti A, Campochiaro C, Sabbadini MG, Dagna L. review on diagnosis and treatment. Curr Rheumatol Rep. 2017;19:74. The multifaceted clinical presentations and manifestations of Erdheim– 269. Gunnarsson R, Molberg Ø, Gilboe I-M, Gran JT, Group PS. The Chester disease: comprehensive review of the literature and of 10 new prevalence and incidence of mixed connective tissue disease: a cases. Ann Rheum Dis. 2013;72:1691–5. national multicentre survey of Norwegian patients. Ann Rheum Dis. 290. Mazor RD, Manevich-Mazor M, Shoenfeld Y. Erdheim–Chester disease: a 2011;70:1047–51. comprehensive review of the literature. Orphanet J Rare Dis. 2013;8:137. 270. Tani C, Carli L, Vagnani S, Talarico R, Baldini C, Mosca M, et al. The diag- 291. Hanks S, Adams S, Douglas J, Arbour L, Atherton DJ, Balci S, et al. Muta- nosis and classifcation of mixed connective tissue disease. J Autoim- tions in the gene encoding capillary morphogenesis protein 2 cause mun. 2014;48–49:46–9. juvenile hyaline fbromatosis and infantile systemic hyalinosis. Am J 271. Amigues JM, Cantagrel A, Abbal M, Mazieres B. Comparative study of Hum Genet. 2003;73:791–800. 4 diagnosis criteria sets for mixed connective tissue disease in patients 292. Haidar Z, Temanni R, Chouery E, Jitesh P, Liu W, Al-Ali R, et al. Diagnosis with anti-RNP antibodies. Autoimmunity Group of the Hospitals of implications of the whole genome sequencing in a large Lebanese Toulouse. J Rheumatol. 1996;23:2055–62. family with hyaline fbromatosis syndrome. BMC Genet [Internet]. 2017 272. Valter I, Saretok S, Maricq HR. Prevalence of scleroderma spectrum [cited 2017 Nov 21];18. Available from: https://​www.​ncbi.​nlm.​nih.​gov/​ disorders in the general population of Estonia. Scand J Rheumatol. pmc/​artic​les/​PMC52​44738/ 1997;26:419–25. 293. Shieh JTC, Swidler P, Martignetti JA, Ramirez MCM, Balboni I, Kaplan J, 273. Ferri C, Valentini G, Cozzi F, Sebastiani M, Michelassi C, La Montagna G, et al. Systemic hyalinosis: a distinctive early childhood-onset disorder et al. Systemic sclerosis: demographic, clinical, and serologic features characterized by mutations in the anthrax toxin receptor 2 gene and survival in 1,012 Italian Patients. Medicine. 2002;81:139. (ANTRX2). Pediatrics. 2006;118:e1485-92. 274. van den Hoogen F, Khanna D, Fransen J, Johnson SR, Baron M, Tyndall 294. Lindvall LE, Kormeili T, Chen E, Ramirez MCM, Grum-Tokars V, Glucksman A, et al. 2013 classifcation criteria for systemic sclerosis: an American MJ, et al. Infantile systemic hyalinosis: case report and review of the college of rheumatology/European league against rheumatism col- literature. J Am Acad Dermatol. 2008;58:303–7. laborative initiative. Ann Rheum Dis. 2013;72:1747–55. 295. Marzano AV, Ishak RS, Saibeni S, Crosti C, Meroni PL, Cugno M. Autoin- 275. Mayes MD, Lacey JV, Beebe-Dimmer J, Gillespie BW, Cooper B, Laing fammatory skin disorders in infammatory bowel diseases, pyoderma TJ, et al. Prevalence, incidence, survival, and disease characteris- gangrenosum and sweet’s syndrome: a comprehensive review and dis- tics of systemic sclerosis in a large US population. Arthritis Rheum. ease classifcation criteria. Clinic Rev Allerg Immunol. 2013;45:202–10. 2003;48:2246–55. 296. Ghouf L, Ortonne N, Ingen-Housz-Oro S, Barhoumi W, Begon E, Haioun 276. Martinez-Lopez A, Blasco-Morente G, Perez-Lopez I, Herrera-Garcia C, et al. Histiocytoid Sweet Syndrome Is More Frequently Associated J, Luque-Valenzuela M, Sanchez-Cano D, et al. CLOVES syndrome: With Myelodysplastic Syndromes Than the Classical Neutrophilic Vari- review of a PIK3CA-related overgrowth spectrum (PROS). Clin Genet. ant. Medicine (Baltimore) [Internet]. 2016 [cited 2017 Oct 18];95. Avail- 2017;91:14–21. able from: https://​www.​ncbi.​nlm.​nih.​gov/​pmc/​artic​les/​PMC48​39791/ 277. Keppler-Noreuil KM, Rios JJ, Parker VER, Semple RK, Lindhurst MJ, Sapp 297. Cohen PR. Sweet’s syndrome—a comprehensive review of an acute JC, et al. PIK3CA-related overgrowth spectrum (PROS): diagnostic and febrile neutrophilic dermatosis. Orphanet J Rare Dis. 2007;2:34. testing eligibility criteria diferential diagnosis and evaluation. Am J 298. Su WP, Liu HN. Diagnostic criteria for Sweet’s syndrome. Cutis. Med Genet A. 2015;1:287–95. 1986;37:167–74. 278. Kurek KC, Luks VL, Ayturk UM, Alomari AI, Fishman SJ, Spencer SA, 299. Walker DC, Cohen PR. Trimethoprim-sulfamethoxazole-associated et al. Somatic mosaic activating mutations in PIK3CA cause CLOVES acute febrile neutrophilic dermatosis: Case report and review of drug- syndrome. Am J Hum Genet. 2012;90:1108–15. induced Sweet’s syndrome. J Am Acad Dermatol. 1996;34:918–23. 279. Keppler-Noreuil KM, Sapp JC, Lindhurst MJ, Parker VE, Blumhorst C, 300. von den Driesch P. Sweet’s syndrome (acute febrile neutrophilic derma- Darling T, et al. Clinical delineation and natural history of the PIK3CA- tosis). J Am Acad Dermatol. 1994;31:535–56. related overgrowth spectrum. Am J Med Genet A. 2014;164:1713–33. 301. Horváth A, Páll N, Molnár K, Kováts T, Surján G, Vicsek T, et al. A 280. Kihiczak GG, Meine JG, Schwartz RA, Janniger CK. Klippel-Trenaunay nationwide study of the epidemiology of relapsing polychondritis. Clin syndrome: a multisystem disorder possibly resulting from a patho- Epidemiol. 2016;8:211–30. genic gene for vascular and tissue overgrowth. Int J Dermatol. 302. Dion J, Costedoat-Chalumeau N, Sène D, Cohen-Bittan J, Leroux G, Dion 2006;45:883–90. C, et al. Relapsing polychondritis can be characterized by three diferent 281. Wang SK, Drucker NA, Gupta AK, Marshalleck FE, Dalsing MC. Diagnosis clinical phenotypes: analysis of a recent series of 142 patients. Arthritis and management of the venous malformations of Klippel–Trénaunay Rheumatol. 2016;68:2992–3001. syndrome. J Vasc Surg Venous Lymphat Disord. 2017;5:587–95. 303. Mathew SD, Battafarano DF, Morris MJ. Relapsing polychondritis in the 282. Dimopoulos A, Sicko RJ, Kay DM, Rigler SL, Fan R, Romitti PA, et al. Copy department of defense population and review of the literature. Semin number variants in a population-based investigation of Klippel–Trenau- Arthritis Rheum. 2012;42:70–83. nay syndrome. Am J Med Genet. 2017;173:352–9. 304. Michet CJ. Relapsing polychondritis: survival and predictive role of early 283. Zhang T, Yao Y, Wang J, Li Y, He P, Pasupuleti V, et al. Haploinsufciency disease manifestations. Ann Intern Med. 1986;104:74. of Klippel–Trenaunay syndrome gene Aggf1 inhibits developmental 305. McAdam LP, O’Hanlan MA, Bluestone R, Pearson CM. Relapsing and pathological angiogenesis by inactivating PI3K and AKT and polychondritis: prospective study of 23 patients and a review of the disrupts vascular integrity by activating VE-cadherin. Hum Mol Genet. literature. Medicine (Baltimore). 1976;55:193–215. 2016;25:5094–110. 306. Damiani JM, Levine HL. Relapsing polychondritis–report of ten cases. 284. Lindhurst MJ, Sapp JC, Teer JK, Johnston JJ, Finn EM, Peters K, et al. Laryngoscope. 1979;89:929–46. A mosaic activating mutation in AKT1 associated with the proteus 307. Durtette C, Hachulla E, Resche-Rigon M, Papo T, Zénone T, Lioger B, syndrome. N Engl J Med. 2011;365:611–9. et al. Cogan syndrome: characteristics, outcome and treatment in a 285. Cohen MM. Proteus syndrome review: molecular, clinical, and patho- French nationwide retrospective study and literature review. Autoim- logic features. Clin Genet. 2014;85:111–9. mun Rev. 2017;16:1219–23. 286. Turner JT, Cohen MM, Biesecker LG. Reassessment of the proteus syn- 308. Gluth MB, Baratz KH, Matteson EL, Driscoll CLW. Cogan syndrome: a drome literature: application of diagnostic criteria to published cases. retrospective review of 60 patients throughout a half century. Mayo Am J Med Genet. 2004;130A:111–22. Clinic Proc. 2006;81:483–8. Leyens et al. Orphanet J Rare Dis (2021) 16:326 Page 43 of 43

309. Tayer-Shifman OE, Ilan O, Tovi H, Tal Y. Cogan’s syndrome—clinical 316. Pardanani A. Systemic mastocytosis in adults: 2017 update on diagno- guidelines and novel therapeutic approaches. Clinic Rev Allerg Immu- sis, risk stratifcation and management. Am J Hematol. 2016;91:1146–59. nol. 2014;47:65–72. 317. Pieri L, Bonadonna P, Elena C, Papayannidis C, Grifoni FI, Rondoni 310. Wang Y, Zhao J, Ji L lan, Zhang S, Zhang Z. Weber–Christian disease M, et al. Clinical presentation and management practice of sys- present with lung nodules dramatically improved with corticoster- temic mastocytosis. A survey on 460 Italian patients. Am J Hematol. oid therapy: one case report and literature review. Int J Rheum Dis. 2016;91:692–9. 2015;n/a-n/a. 318. Valent P, Akin C, Metcalfe DD. Mastocytosis: 2016 updated WHO 311. Verrilli S, Ciarnella A, Laganà B, Calafore S, Guglielmelli F, Basile L, et al. classifcation and novel emerging treatment concepts. Blood. Ocular infammation: can it be a sign of activity of Weber–Christian 2017;129:1420–7. disease? A case report and review of literature. Ocul Immunol Infamm. 319. Dubrey S, Shah S, Hardman T, Sharma R. Sarcoidosis: the links between 2016;24:223–6. epidemiology and aetiology. Postgrad Med J. 2014;90:582–9. 312. White JW, Winkelmann RK. Weber–Christian panniculitis: a review of 30 320. Nicholson TT, Plant BJ, Henry MT. Sarcoidosis in Ireland: regional difer- cases with this diagnosis. J Am Acad Dermatol. 1998;39:56–62. ences in prevalence and mortality from 1996–2005. Sarcoidosis Vasc 313. Mavrikakis I, Georgiadis T, Fragiadaki K, Sfkakis PP. Orbital lobular pan- Difuse Lung Dis. 2010;27:111–20. niculitis in Weber–Christian disease: sustained response to anti-TNF 321. Wessendorf TE, Bonella F, Costabel U. Diagnosis of sarcoidosis. Clinic treatment and review of the literature. Surv Ophthalmol. 2010;55:584–9. Rev Allerg Immunol. 2015;49:54–62. 314. Cohen SS, Skovbo S, Vestergaard H, Kristensen T, Møller M, Bindslev- Jensen C, et al. Epidemiology of systemic mastocytosis in Denmark. Br J Haematol. 2014;166:521–8. Publisher’s Note 315. Lim K-H, Teferi A, Lasho TL, Finke C, Patnaik M, Butterfeld JH, et al. Springer Nature remains neutral with regard to jurisdictional claims in pub- Systemic mastocytosis in 342 consecutive adults: survival studies and lished maps and institutional afliations. prognostic factors. Blood. 2009;113:5727–36.

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