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Table 2 Overview of rare rheumatic diseases

From: The combined prevalence of classified rare rheumatic diseases is almost double that of ankylosing spondylitis

Disease

Prevalence

Genetics/pathogenesis

Diagnostic criteria

Clinical features

Laboratory findings

Therapy

Prognosis/ Complications

Classification

Buerger's disease (thromboangiitis obliterans) [52,53,54,55,56]

Most common in Middle and Far East, estimated prevalence: 5/100,000 (Japan) 0.65/100,000 (Taiwan) → 2.8/100,000

Probably immune-mediated vasculitis, possibly associated with infectious agent; strong association with smoking; segmental occlusive inflammatory vasculitis (mainly small vessels, arteries and veins)

Many different diagnostic criteria (e.g., by Shionoya and Olin)

Disease onset in middle-aged, predominantly males; ischemic pain in extremities, numbness, skin ulcerations, thrombophlebitis, Raynaud´s phenomenon

Inflammatory markers usually normal

Smoking cessation, prostaglandin analogs, maximize blood supply, reduce risk of vasoconstriction (avoid coldness. etc.)

Remitting-relapsing, life expectancy usually normal, but morbidity increased (e.g., amputations)

Vasculitis/ vasculopathy

Eosinophilic granulomatosis with polyangiitis (EGPA, Churg-Strauss syndrome) [57,58,59,60,61,62,63]

17.8/1,000,000 (estimated, Japan) 10.7/1,000,000 (France) 14/1,000,000 (Sweden) → 1.4/100,000

Association with multiple different HLA genotypes, possibly IgG4-related disorder; Th-2 cells and eosinophils seem to play a major role in pathogenesis; small vessel necrotizing vasculitis

ACR criteria, Chapel Hill nomenclature definition

Disease onset in middle-aged males and females; asthma, weight loss, mononeuritis multiplex, non-erosive sinusitis/polyposis, skin lesions, lung infiltrates, pleural effusion, cardiomyopathy, glomerulonephritis

30 – 40% ANCA-positive (mainly MPO, but proteinase 3 also possible), eosinophilia; depending on organ involvement, elevated renal enzymes possible; elevated IgG4 can be found

Corticosteroids, immunosuppressants, rituximab

Chronic or remitting-relapsing, main complication with increased mortality is cardiomyopathy but overall mortality low

Vasculitis/ vasculopathy

Degos disease (malignant atrophic papulosis) [64,65,66,67]

Unknown, less than 200 cases reported, estimate < 1/1,000,000

Unknown; autosomal dominant inheritance discussed; thrombo-obliterative vasculopathy

Clinical and histopathological diagnosis

Onset usually at age 20–50 years, papular skin lesions with central atrophy and peripheral telangiectatic rim, sudden onset systemic involvement possible with high morbidity and mortality (bowel perforation, thrombosis, hemorrhage)

Coagulopathy in some patients

Anticoagulants, treprostinil, eculizumab

Limited and systemic variant, systemic variant has over 50% mortality within 2–3 years (due to bowel perforation and peritonitis)

Vasculitis/ vasculopathy

Hughes-Stovin syndrome (incomplete/ cardiovascular Behcet´s disease) [68, 69]

Unknown, ~ 40 cases described, estimate < 1/1,000,000

Unknown; angiodysplasia and infections discussed, maybe variant of Behcet´s disease; absence of oral/genital ulcers important for distinction

Clinical and radiographic diagnosis

Predominantly young males affected, multiple lung aneurysms cause cough, dyspnea, fever, chest pain, hemoptysis

Leukocytosis, anemia, elevated ESR and CRP

Corticosteroids, immunosuppressants, anticoagulant/ thrombolytic agents, surgery

Poor prognosis, massive hemoptysis and aneurysmal rupture are main causes of death

Vasculitis/ vasculopathy

Hypocomplementemic urticarial vasculitis (McDuffie syndrome) [70,71,72,73,74]

Unknown, estimate < 1/1,000,000

Mutations in DNASE1L3 described, possible association with SLE; inflammation of dermal capillaries and postcapillary venules; possibly IgG4-related disease

Proposed criteria by Schwartz et al.

Predominantly in middle-aged females, chronic urticarial exanthema, angioedema, arthralgia/arthritis, ocular inflammation, glomerulonephritis, abdominal pain, angioedema, obstructive pulmonary disease

Low complement levels, anti-C1q-antibodies

Corticosteroids, immunosuppressants

Chronic, prognosis depending on systemic organ involvement (pulmonary, renal, cardiac), mortality low

Vasculitis/ vasculopathy

Kawasaki disease (mucocutaneous lymph node syndrome) [18, 75,76,77]

Prevalence unknown, incidence ranges from 3.7/100,000 (Australia) to 243/100,000 (Japan) for children < 5 years and increased in previous years, estimate < 1/100,000

Unknown, but genetic predisposition suspected (much more common in Asia), probably infectious trigger (seasonal peaks) causing small and medium vessel vasculitis

American Heart Association (AHA) guidelines, but primarily clinical diagnosis, as incomplete presentation is common

Predominantly young children until the age of 4 years affected with male predominance; conjunctivitis, exanthema, GI symptoms, fever, oropharynx involvement, lymphadenopathy, cracked lips, erythema of hand and feet, coronary aneurysm

Elevated CRP, ESR, leukocytosis, thrombocytosis

Intravenous immunoglobulins, high dose aspirin

Self-limited, good prognosis if treated, but coronary artery abnormalities occur in 25% if left untreated, leading cause of acquired heart disease in children in developed countries

Vasculitis/ vasculopathy

Leukocytoclastic/cutaneous small vessel/hypersensitivity vasculitis [78,79,80]

Prevalence unknown, incidence 4.5/1,000,000 estimate < 1/1,000,000

Unknown; more than 50% idiopathic, other possible causes include malignancy, autoimmune diseases, drugs (antibiotics, NSAIDs); neutrophilic inflammation in postcapillary venules

Chapel Hill criteria (histopathological)

Limited cutaneous variant with palpable purpura and lesions (often on lower extremity), or systemic organ involvement possible (most commonly renal)

Anemia, leukocytosis, elevated renal enzymes

Corticosteroids, immunosuppressants

Variable, commonly remitting-relapsing with treatment, overall survival good

Vasculitis/ vasculopathy

Microscopic polyangiitis (microscopic polyarteritis) [58, 59, 81, 82]

25.1/1,000,000 (France) 94/1,000,000 (Sweden) → 6/100,000

Unknown; possibly related to MHC II genes; environmental (silica) and autoimmune influence discussed; small vessel, necrotizing vasculitis with few or no immune deposits, primarily affecting kidneys and lungs

Chapel Hill criteria (histopathological)

Males slightly more commonly affected than females, onset primarily in elderly (age ≥ 60 years). Dyspnea, cough, hemoptysis, rapidly progressive glomerulonephritis, palpable purpura, GI symptoms, peripheral neuropathy

MPO-ANCA, microscopic hematuria

Corticosteroids, immunosuppressants (rituximab, cyclophosphamide)

Remitting-relapsing with treatment, poor prognosis without therapy, complications include end-stage renal disease, cardiovascular involvement, malignancy, and infections

Vasculitis/ vasculopathy

Behçet's disease [41, 83,84,85]

Estimated prevalence in Scandinavia: 2/100,000

Europe: 10.5/100,000

Mediterranean: 188/100,000

Others: 15.7/100,000

Not rare in Turkey (80–370/100,000), estimate 5/10,000

Association with HLA-B51; most common along the ancient silk road; infectious or environmental triggers; systemic occlusive vasculitis discussed

Many different criteria exist (e.g., New International Criteria of Behçet’s Disease)

Peak of disease onset in third decade of life (any age possible), recurrent eye inflammation (iridocyclitis/uveitis), oral and genital ulcers, skin manifestations (erythema nodosum, etc.), arthralgia, thrombosis, neurological symptoms, cardiac involvement

Pathergy-phenomenon, leukocytosis

Corticosteroids, colchicine, immunosuppressants, biologicals, small molecules, anticoagulants

Chronic disease with remitting-relapsing course, increased mortality in case of arterial and neurological involvement, possible cause of blindness

Vasculitis/ vasculopathy

Erythema induratum (Bazin disease, nodular vasculitis) [86, 87]

Unknown, estimate < 1/1,000,000

Unknown; type III or type IV hypersensitivity reaction suspected; associated with drugs (propylthiouracil), infectious (tuberculosis, hepatitis) or non-infectious diseases (leukemia, RA); diffuse panniculitis with neutrophilic vasculitis

 

Female predominance, recurrent nodules, usually on posterior lower legs, with focal ulceration and drainage, heal with scarring and post-inflammatory hyperpigmentation

Depending on underlying cause

Treatment of underlying cause, potassium iodide, NSAIDs, corticosteroids, immunosuppressants

Chronic, relapses are common

Vasculitis/ vasculopathy

Polyarteritis nodosa (Kussmaul-Maier disease) [58, 59, 88, 89]

30.7/1,000,000 (France) 31/1,000,000 (Sweden) → 3.1/100,000

Early-onset polyarteritis nodosa; mutations in CECR1, leading to deficiency in adenosine deaminase 2 (DADA2); other forms: idiopathic, cutaneous, and infection-associated (HBV); medium vessel, necrotizing vasculitis with segmental, mixed inflammatory infiltrates at branching points and microaneurysms (often in hepatic, renal, and mesenteric arteries), that spares the lung

Chapel Hill criteria (histopathological)

Male predominance, malaise, weight loss, fever, arthralgia, ulcers, livedo racemosa, myalgia, mononeuritis multiplex, purpura, GI symptoms, kidney infarctions, orchitis, hearing loss; no pulmonary involvement!

ESR and CRP elevated, leukocytosis, anemia, occasionally hypereosinophilia, hepatitis serology, liver enzymes, ANCA negative

Corticosteroids, immunosuppressant, biologicals (TNFi), antivirals, NSAIDs

Variable; chronic, acute, remitting-relapsing (10–20%) course possible; potentially life-threatening, remission can be achieved in many cases, good survival rate if treated early

Vasculitis/ vasculopathy

Primary central nervous system vasculitis (PACNS/primary angiitis of the CNS) [90,91,92,93]

Prevalence unknown, incidence: 2.4/1,000,000

estimate < 1/1,000,000

Different infectious agents suggested as triggers, segmental inflammation of CNS vessels

Proposed criteria by Calabrese and Mallek, histological criteria by Alrawi et al.

Disease most common in white males age ≥ 50 years, depending on localization different symptoms occur: headache, stroke, dementia, chronic meningitis, personality changes

Because of lack of systemic disease, inflammatory markers in blood are normal, but cerebrospinal fluid should be investigated

Corticosteroids + immunosuppressants (e.g., cyclophosphamide)

Chronic, controllable with medication, relapses common, fatal in the past, current mortality ~ 15%

Vasculitis/ vasculopathy

Henoch-Schonlein purpura (IgA vasculitis) [21, 94, 95]

Incidence 3–26.7/100,000 in children, 0.8–1.8/100,000 in adults, estimate 1/100,000

Unknown; several reports describe relationship to different HLA genes and MEFV gene mutations; infectious agent suggested in children (seasonal peak in fall and winter), in adults linked to cancer; small-vessel leukocytoclastic vasculitis

ACR criteria, criteria by Michet et al., EULAR pediatric criteria

Predominantly male children affected, purpuric rash, abdominal pain, joint pain, edema, renal involvement

Increased ESR, CRP, leukocytosis, anemia, proteinuria

NSAIDs, corticosteroids, immunoglobulins, immunosuppressants

Usually self-limited, but remitting-relapsing course possible, poor prognosis in case of renal involvement, worse prognosis in adults

Vasculitis/ vasculopathy

Takayasu arteritis [96,97,98,99,100]

2.82/100,000 (Korea)

4.7/1,000,000 (UK)

22/1,000,000 (Norway)

12.8/1,000,000 (Turkey) → 1.7/100,000

Different candidate genes: HLA variants, FCGR2A/FCGR3A, IL12B; more frequent in Asia; aortic and large vessel vasculitis

ACR criteria

Female predominance, fever, fatigue, weight loss, headache, differences in blood pressure of extremities, “pulseless disease”

Elevated CRP, ESR MMP-3 levels, PTX-3

Corticosteroids, immunosuppressants, biologicals (TNFi, IL-6i)

Chronic, good overall survival, cardiovascular disease is most common cause of death (infarction, thrombosis, etc.)

Vasculitis/ vasculopathy

Granulomatosis with polyangiitis (GPA, formerly Wegener granulomatosis) [29, 58, 59, 101]

160/1,000,000 (Sweden) 23.7/1,000,000 (France) → 9.2/100,000

Different genes suspected: HLA variants, SERPINA1; infectious, environmental (decreasing north–south gradient), and drug-induced triggers suspected; ANCA-associated, small vessel vasculitis

ACR criteria, Chapel Hill criteria (histopathological)

Malaise, myalgia, arthralgia, anorexia, weight loss, fever, oral ulcers, ear/nose/throat manifestations typical: eye manifestations (scleritis/uveitis, etc.), nasal discharge, epistaxis, upper airway obstructive disease

Elevated inflammatory markers, positive ANCA (proteinase 3 in 80%), urine analysis

Corticosteroids, immunosuppressants (rituximab, cyclophosphamide, azathioprine)

Chronic, relapses are very common, infections are main cause of death

Vasculitis/ vasculopathy

Adult-onset Still's disease (AOSD, Wissler's syndrome) [4,5,6, 102, 103]

3.4 – 6.9/100,000 (Norway) 6.77/100,000 (Turkey) 3.9/100,000 (Japan) → 5.3/100,000

Unknown; possibly related to MIF, HLA antigens, MEFV; different triggers suspected (infections, malignancies, medications, vaccinations)

Yamaguchi criteria, Fautrel criteria

Females slightly more affected, disease onset often at age 17–35 years, fever, maculopapular rash, arthralgia/arthritis (most commonly big joints), lymphadenopathy, hepatosplenomegaly, pleuritis, pericarditis, pneumonitis, eye involvement, abdominal pain, myalgia, alopecia, sore throat, weight loss, cranial nerve palsy

Leukocytosis, anemia, hypoalbuminemia, elevated liver enzymes, elevated ESR and CRP; ANA, ACPA and RF usually negative, elevated ferritin, mild proteinuria, increased IgE or elevated β2-microglobulin

NSAIDs, corticosteroids, DMARDs, immunosuppressants, biologicals (IL-1i, IL-6i)

Variable; 1/3 self-limiting, 1/3 relapsing, 1/3 chronic; overall survival good, complications include MAS

Arthritis/ arthropathy

Progressive pseudorheumatoid arthropathy of childhood (PPAC/ PPD/ PPRD/ SEDT-PA) [104,105,106,107,108,109]

Maybe not rare, but misdiagnosed as JIA; estimated prevalence < 1/1,000,000

Autosomal recessive; different mutations in WISP3; possible founder effect in Turkey; WISP mediates cell growth and differentiation in chondrocytes

Clinical and radiographic diagnosis with genetic confirmation

Disease onset usually in childhood (age 3–8 years), progressive joint stiffness, contractures, swelling of finger joints, osteopenia, slow linear growth, short stature, osteopenia, arthritis, difficulty in walking, genu valgum, hip pain, adult height usually below 3rd percentile, normal intelligence

No signs of systemic inflammation

Symptomatic: NSAIDs

Chronic, overall prognosis good because systemic organ involvement is absent

Arthritis/ arthropathy

Familial articular chondrocalcinosis (CPPD deposition disease/CCAL1 and CCAL2) [110,111,112,113,114]

Unknown, estimate < 1/1,000,000

Most cases autosomal dominant with variable penetrance; CCAL2: mutations in ANKH; CCAL1: chromosome 8 suspected, but gene not yet identified; increased extracellular pyrophosphate levels and formation of CPPD

Clinical and radiographic diagnosis

Disease onset in early childhood with calcium crystal joint deposition; arthritis/arthralgia, most commonly in knee and other big joints

Inflammatory markers may be elevated

Symptomatic: Corticosteroids, colchicine, NSAIDs

Chronic, usually not life-threatening, but high morbidity

Arthritis/ arthropathy

Pigmented villonodular synovitis [25, 115,116,117,118]

Incidence: 1.8/1,000,000 (USA), estimate < 1/1,000,000

Unknown; possible association with trauma/surgery, lipometabolism; inflammatory process or benign, tumor-like process suggested

Radiographic or histopathological diagnosis

Peak of disease onset age 20–40 years, pain/swelling of joints (mainly knee or hip, rarely temporomandibular joint) with “locking phenomenon”, fatigue

Elevated ESR and CRP possible

Surgical synovectomy, radiotherapy, immunotherapy

Chronic or remitting-relapsing, locally aggressive and frequent relapses

Arthritis/ arthropathy

Felty syndrome (splenomegaly-neutropenia-rheumatoid arthritis syndrome) [119,120,121,122]

1% of RA = estimated prevalence 1/10,000

HLA-DR4 association (78%), autoantibodies against neutrophil extracellular chromatin traps (NETs), anti-GCSF antibodies

Clinical diagnosis

More common in females, chronic symmetric arthritis with severe joint destruction (often knee, wrist ankle, MCP, PIP), hepatosplenomegaly, lymphadenopathy, episcleritis, pleuritis, vasculitis, weight loss

Anemia, neutropenia, infections, ANA, RF

Corticosteroids, DMARDs, biologicals, G-CSF, splenectomy

Chronic, increased mortality due to infections

Arthritis/ arthropathy

RS3PE (remitting seronegative symmetrical synovitis with pitting edema) [3, 32, 123, 124]

Unknown, prevalence in Japan 0.09% (90/100,000 = 1/1,111) for > 50 years (not rare among elderly), estimate 1/100,000

Unknown; associated with other rheumatic conditions, infections, and neoplasms (associated malignancy rate 7% in Asia and 31% in Western countries); VEGF may play a role in pathogenesis

Proposed diagnostic criteria by Karmacharya et al.

Usually older males affected, symmetrical synovitis of hands and ankles, sudden onset polyarthritis, pitting edema (especially hands or feet)

Elevated acute phase reactants, usually RF and autoantibodies negative

Usually excellent response to corticosteroids, DMARDs rarely used, treatment of underlying malignancy if present

Good, remission can usually be achieved with corticosteroid use only, poor prognosis if malignancy-associated

Arthritis/ arthropathy

Multicentric reticulohistiocytosis [37, 125,126,127]

Unknown, ~ 300 cases in literature, estimate < 1/1,000,000

Unknown; different triggers suspected (malignancies, autoimmune diseases, infections/tuberculosis); crucial workup for neoplasms necessary; macrophages, cytokines, and osteoclastic activity seem to play a role in pathogenesis

Histopathological diagnosis

Mainly Caucasian females (3:1) with peak of onset in 4th decade, symmetric erosive polyarthritis or spondylitis with axial involvement (most affected joints: distal interphalangeal joints) with typical papulonodular skin lesions, organ involvement possible (heart, lung), arthritis often precedes skin involvement by years

Elevated ESR, CRP, anemia, hyperlipidemia, different autoantibodies may be positive

NSAIDs, corticosteroids, DMARDs, biologicals, bisphosphonates, treatment of underlying malignancy if present

Variable, may progress rapidly into arthritis mutilans, but most patients achieve remission spontaneously within 10 years

Arthritis/ arthropathy

Chronic non-bacterial osteomyelitis (CNO)/CRMO/SAPHO [128,129,130,131,132]

Estimated prevalence 40/100,000

No clear association with HLA-B27, possibly related to other genes connected to autoinflammatory disorders; autoimmune process or infection/molecular mimicry (P. acnes) suspected

Inclusion and exclusion criteria by Benhamou et al., Kahn et al.

Slight female predominance, onset often in children or middle-aged adults; inflammatory, painful, sterile (sometimes P. acnes-positive) osteitis (often in anterior chest wall or axial skeleton) with variety of different skin diseases (most commonly palmoplantar pustulosis), onset can be many years before or after bone and articular involvement (often sacroiliac or sternoclavicular joints)

Elevated CRP and ESR (sometimes), different non-specific autoantibodies, sometimes P. acnes

NSAIDs, corticosteroids, bisphosphonates, antimicrobial treatment, DMARDs, biologicals

Chronic disease, complications or disease-associated death rare

Arthritis/ arthropathy

Systemic-onset juvenile idiopathic arthritis (Still`s disease) [133,134,135,136,137,138,139,140,141]

Estimated prevalence 10.5/100,000

Association with MEFV and MIF-173 polymorphism; IL-6 and IL-1 play a major role

ILAR classification criteria for JIA

Systemic inflammation (spiking fever > 39 °C, skin rash, hepatosplenomegaly, lymphadenopathy, serositis, arthritis

High levels of serum ferritin, marked polymorphonuclear leukocytosis, thrombocytosis, elevated ESR/CRP

NSAIDs, corticosteroids, DMARDs, biologicals (IL-1, IL-6)

Variable, chronic, self-limiting or remitting-relapsing, ~ 50% complete recovery, risk of MAS

Arthritis/ arthropathy

Whipple's disease [142,143,144,145,146,147,148,149]

Unknown, Tropheryma whipplei can be found in ~ 10% (Europe)/20% (Africa) of fecal samples in healthy population, estimate < 1/1,000,000

HLA-B27 involvement discussed; infection with Tropheryma whipplei, predominantly male patients and patients with immune modulatory conditions (alcohol, abuse, chronic disease) affected

Histopathological diagnosis or PCR

Predominantly males affected, intermittent polyarthritis and gastrointestinal symptoms, any other organ can be affected (neurology, cardiovascular, lungs, eyes, skin), fever, weight loss, abdominal pain, malabsorption, headaches, diarrhea

Elevated ESR, CRP, anemia, thrombocytosis, reduced IgM and IgA, leukocytosis, RF, anti-CCP-AB may be present

Antibiotics, corticosteroids, DMARDs, biologicals (IL-1)

Chronic, lethal if untreated, increased mortality in case of neurological involvement or occurrence of immune reconstitution inflammatory syndrome (IRIS; ~ 10%)

Arthritis/ arthropathy

Osteochondritis dissecans [150,151,152]

Incidence 6.09/100,000

Estimated 15–29/100,000 → 22/100,000

Unknown; osteonecrosis of subchondral bone; vascular disruption, multiple microtrauma, and genetic predisposition suggested

Radiographic diagnosis

Predominantly in physically active male children or adolescents. Pain (worsening with exercise), swelling, joint locking, most often in the knee, but any joint can be affected

Usually inflammatory markers normal

Supportive: NSAIDs, surgery

Chronic, prognosis depends on stability of lesion and patient age

Arthritis/ arthropathy

Blau syndrome (familial)/early onset sarcoidosis (sporadic)/ pediatric granulomatous arthritis [9, 153,154,155,156,157,158]

Unknown, incidence: 0.29/100,000 (Denmark), estimate < 1/1,000,000

Autosomal dominant, sporadic form, gonosomal mosaicism in NOD2/CARD15; NF-κB activation and excessive inflammatory cytokine production

Clinical diagnosis, genetic testing, skin biopsy

Skin rash in first year of life, later boggy polyarthritis, uveitis, non-caseating epithelioid and giant cell granulomas; fever, lymphadenopathy, neuropathy, renal/hepatic/lung/cardiovascular involvement

Leukocytosis, thrombocytosis, elevated ESR, CRP, acute-phase reactants, ACE normal

NSAIDs, corticosteroids, immunosuppressants, biologicals, systemic hypertension usually responds to ACE-inhibitors

Chronic, prognosis depends on systemic involvement, severe ocular and articular morbidity

Autoinflammatory syndrome

CAPS (familial cold autoinflammatory syndrome/familial cold urticaria, Muckle-Wells syndrome, CINCA syndrome/NOMID/IOMID) [38, 39, 159,160,161]

1–2/1,000,000 in US and 1–2/360,000 (= 4.6/1,000,000) in France estimated → 3.05/1,000,000

Autosomal dominant, gain of function mutation in NLRP3/CIAS1 leads to caspase-1 and inflammasome activation with increased IL-1β secretion; mosaicism possible, usually de novo

Eurofever clinical diagnostic/ classification

Intermittent fever, urticarial rash, chronic inflammation, typical facies in CINCA (frontal bossing, saddle back nose), CNS manifestations, chronic polyarthritis, conjunctivitis, papilledema

Elevation of acute phase reactants, leukocytosis, chronic anemia; SAA biomarker for development of AA-amyloidosis

Biologicals (IL-1)

Chronic, prognosis significantly improved since availability of anti-IL-1-treatment (65–85% complete remission with Anakinra)

Autoinflammatory syndrome

Familial Mediterranean fever (familial paroxysmal polyserositis) [38, 162,163,164,165,166]

Prevalence highly differs geographically; in eastern Mediterranean 1/500 – 1/1000, Turkey 1/150 – 1/10,000, Ashkenazi Jews 1/73,000 Estimate 1/10,000

Autosomal recessive, mutation in MEFV leading to abnormal function of inflammasome; environmental factors also seem to play a role, as patients from the eastern Mediterranean often have a milder phenotype

Multiple criteria: Eurofever clinical diagnostic/classification criteria, Tel-Hashomer, Yalcinkaya-Ozen and Livneh-criteria

Disease onset usually in childhood, 90% before age of 20 years, recurrent fever and serositis, myalgia, arthralgia, abdominal pain, vomiting, chest pain, rash, prodromal phase with unspecific symptoms (restlessness, anxiety, irritability), rapid onset of symptoms lasting for at least 12 h

Elevated acute phase reactants

Colchicine, anti-IL-1

Chronic, remission and fewer relapses can be achieved by therapy, complications include amyloidosis (strongest predictor seems to be country of residence) and MAS

Autoinflammatory syndrome

Mevalonate kinase deficiency (hyperimmunoglobulinemia D with periodic fever, HIDS) [38, 167,168,169,170]

Unknown, incidence in Germany: 0.39/1,000,000

estimate < 1/1,000,000

Autosomal recessive, mutations in MVK (homozygosity or, most often, compound heterozygosity); MVK essential for cholesterol synthesis; increased production of IL-1β; possible founder effect in the Netherlands

Eurofever clinical diagnostic/classification criteria

Recurrent fever episodes starting in infancy (most common before end of 1st year of life), fever lasts 4–6 days and can be provoked by physical and psychological stress; lymphadenopathy, splenomegaly, arthralgia, GI symptoms, skin rash, sometimes oral and vaginal aphthous ulcers, neurological symptoms

Elevated ESR, CRP, leukocytosis, elevated IgD (> 100 IU/ml), IgA in blood, elevated mevalonic acid in urine

HMG-CoA-reductase inhibitors, corticosteroids, immunosuppressants, biologicals (Il-1)

Chronic, complications include infections, amyloidosis, peritonitis with abdominal adhesions, MAS, and joint contractures

Autoinflammatory syndrome

Nakajo-Nishimura syndrome (NNS) [171,172,173]

Unknown, 28 reported cases in Japan until 2010 (19 males, 9 females), estimate < 1/1,000,000

Autosomal recessive, mutation in PSMB8; probably common founder; reduced proteasome activity and accumulation of ubiquitinated and oxidized proteins, leading to increased cytokine levels

Distinctive clinical diagnostic criteria for NNS

Onset usually at age of 2 months—8 years with pernio-like rash, rash often appears in first winter after birth and reappears every year. Symptoms worsen with cold stimuli; periodic high fever, skin rash, myositis, hepatosplenomegaly, partial lipomuscular atrophy, joint contracture (mainly in upper body), hyperhidrosis, short stature, low IQ, lymphadenopathy described, characteristic thin facial appearance, elongated clubbed fingers

Constantly elevated ESR, CRP, chronic anemia, hypergammaglobulinemia, elevated IgG and IgE, positive ANA described

Corticosteroids, kallikrein, dapsone

Chronic and often lethal, most patients die of cardiac or respiratory failure

Autoinflammatory syndrome

PAPA syndrome (pyogenic arthritis-pyoderma gangrenosum acne syndrome) [28, 39, 174,175,176,177]

Only few patients from five families worldwide reported (34 until 2006), estimate < 1/1,000,000

Autosomal dominant, missense mutation in PSTPIP1/ CD2BP1, which causes hyperphosphorylation of PSTPIP1 protein and induction of inflammasome

Clinical diagnosis with genetic confirmation

Recurrent sterile arthritis, fever, pustulosis, abdominal pain, hidradenitis, acne, pyoderma gangrenosum, ulcerations

Elevated ESR, CRP, IL-1β

Corticosteroids, biologicals (IL-1 β)

Chronic or remitting-relapsing

Autoinflammatory syndrome

PFAPA syndrome (periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis; Marshall syndrome with periodic fever) [178,179,180,181,182]

Unknown, incidence 2.3/10,000 in children up to 5 years (Norway), probably not so rare, estimate < 1/10,000

Unknown; many patients have heterozygous MEFV mutation, familial occurrence; polygenetic cause suspected; IL-1 and vitamin D may play a role in pathogenesis

Diagnostic criteria by Marshall/Thomas; Cantarini et al.

Disease onset usually in early infancy, slight male predominance, episodes last 5 days and recur every 28 days; prodromal: aphthous stomatitis, malaise, fatigue, irritability, headache; then sudden onset of high fever, pharyngitis, lymphadenopathy, chills, cough, headache, abdominal pain, nausea, diarrhea, rash; patients are remarkably healthy between episodes

Leukocytosis and elevated ESR in episodes

Corticosteroids, surgery (tonsillectomy), cimetidine, anakinra, colchicine

Good prognosis, self-limited within 4–5 years, normal development

Autoinflammatory syndrome

Schnitzler syndrome (chronic urticaria with gammopathy) [183,184,185,186]

Unknown, ~ 250 reported patients, mainly from western Europe, estimate < 1/1,000,000

Unknown; involvement of IL-1β and IL-6 suspected

Strasbourg diagnostic criteria

Slight female predominance (1.6:1), disease onset in adulthood (mean age 51 years), recurrent urticarial rash (most constant symptom), fever, muscle/bone/joint pain, lymphadenopathy

Monoclonal IgM (rarely IgG) gammopathy, elevated ESR, κ -light chain, leukocytosis

Anakinra (IL-1) rapidly controls symptoms (diagnosis should be reconsidered if ineffective), canakinumab, colchicine, NSAIDs, pefloxacin, hydroxychloroquine

Chronic, spontaneous remission and relapses common, complications include amyloidosis and overt lymphoproliferation

Autoinflammatory syndrome

Macrophage activation syndrome [187,188,189,190,191,192]

Seen in about 10% of patients with systemic onset JIA. Prevalence unknown, estimate < 1/1,000,000

Excessive Activation of T-lymphocytes and macrophages. Possible association with impaired NK cell cytotoxicity due to PRF1 mutation

HLH-2004 diagnostic guidelines/2016 criteria for MAS complicating systemic JIA

Fever, hepatosplenomegaly, cytopenias, coagulopathy, liver dysfunction, neurological symptoms, lymphadenopathy, skin rash, jaundice, edema

cytopenia, elevated transaminases + ferritine, low NK cell activity, elevates sIL2-R

Corticosteroids, Cyclosporine, Biologicals, IL-1 receptor blockade

Mortality in one retrospective study 8% (higher mortality in adults)

Autoinflammatory syndrome

Majeed syndrome (chronic recurrent multifocal osteomyelitis) [193,194,195]

Unknown, only 4 families/14 patients with Middle Eastern origin reported, estimate < 1/1,000,000

Autosomal recessive, mutation in LPIN2, which plays a role in fat metabolism and, possibly, mitosis

Clinical diagnosis, genetic testing

Inflammation of bone and skin, resulting in growth disturbances and joint contractures; recurrent high fevers, severe pain; frequently associated with cutaneous inflammatory syndromes (e.g., psoriasis, Sweet syndrome)

Dyserythropoietic anemia with microcytosis, elevated ESR

Blood transfusions, NSAIDs, corticosteroids, biologicals (IL1 β)

Chronic, osteomyelitis probably life-long, anemia is prominent in childhood

Autoinflammatory syndrome

TRAPS (tumor necrosis factor receptor 1 associated periodic syndrome; familial Hibernian fever) [38, 39, 196,197,198]

Unknown, incidence 1/1,785,714 for children < 16 (Germany); most patients are European Caucasian, estimate 1/1,000,000

Autosomal dominant with variable penetrance, mutations in TNFRSF1A, different hypotheses on pathophysiology, including intracellular trafficking, receptor shedding, or induction of apoptosis, leading to increase in cytokines; triggers include stress, menstrual cycle, fatigue, infections, exercise, vaccinations

Eurofever clinical diagnostic/ classification criteria

Disease onset usually in infancy or childhood, attacks last around 11 days, on average 70 symptomatic days a year with high fever, limb pain, abdominal pain, rash, cervical lymphadenopathy, periorbital edema

Elevated ESR, CRP, leukocytosis, thrombocytosis, anemia, hypergammaglobulinemia; SAA levels correlate with disease activity

NSAIDS, corticosteroids, biologicals (most promising is anti-IL-1)

Often remitting-relapsing, but chronic course possible; complications include amyloidosis and MAS

Autoinflammatory syndrome

Necrotizing autoimmune myopathy (anti-HMG-CoA myopathy) [199, 200]

Unknown, estimate < 1/1,000,000

Unknown; immune-mediated muscle fiber necrosis without inflammation due to statin use, other drugs, malignancies, or connective tissue diseases

Histopathological diagnosis

Female predominance (73%), myalgia, dysphagia, weight loss, fatigue, ILD, arthralgia, Raynaud´s phenomenon

Anti-SRP antibodies present in 16%, anti-HMGCR antibodies seem to be specific and present in ~ 60% of patients previously exposed to statins; CRP and CK elevated

Statin withdrawal, corticosteroids, DMARDs

Variable, good prognosis in case of treatable underlying cause, but chronic in most cases

Myositis/myopathy

Antisynthetase syndrome [201,202,203,204]

Unknown, 20–25% of patients diagnosed with PM/DM; prevalence of PM/DM approx. 15/100,000 → 3.4/100,000

Unknown; antibodies against anti-threonyl-tRNA-synthetase; relationship to exposure to airborne particles discussed

Clinical diagnosis + antibody findings

Females 2–3 times more often affected than males, at presentation often only RA-like arthritis, then inflammatory myopathy, interstitial lung disease, fever, Raynaud´s, Gottron´s papules, mechanic´s hands

Anti-Jo-1, anti-Pl7/PL12, many other antibodies possibly positive

Corticosteroids, immunosuppressants (rituximab), DMARDs

Chronic, overall survival good but decreased in case of lung involvement

Myositis/myopathy

Myopathic form of carnitine palmitoyltransferase II (CPT II) deficiency [205, 206]

Unknown, more than 300 published cases, one of the most common disorders of oxidative fatty acid metabolism, prevalence probably higher than suspected; estimate < 1/100,000

Autosomal recessive, mutation in CPTII; CPT is involved in the transportation of long chain fatty acids in mitochondria; impaired energy metabolism; frequent triggers are physical stress and exposure to cold

Enzyme measurement, genetic testing

Disease onset in adolescence or adulthood, males more commonly and more severely affected; myalgia, rhabdomyolysis, muscle weakness, pain, lipid accumulation in muscle

Elevated CK, BUN, myoglobinuria, hepatic steatosis

Avoidance of triggers (fasting, prolonged exercise), low fat and high carbohydrate diet, carnitine

Chronic, but good prognosis; rhabdomyolysis can lead to renal failure

Myositis/myopathy

Dermatomyositis/Polymyositis [207,208,209,210]

10–13/100,000 (Japan) 8.7/100,000 (Norway) 7–10/100,000 (Brazil) → 9.6/100,000

Unknown; humoral-mediated inflammation in DM, cell-mediated (CD8 + T-cells) in PM; often associated with other autoimmune diseases and malignancies

Histopathological diagnosis

Predominantly females, myalgia, arthritis, dyspnea, dysphagia, muscle weakness, rash (not in PM), myocarditis, Gottron´s papules

Different myositis-specific autoantibodies can be found: anti-Jo-1, NXP2/MJ antibody, anti-155/140 antibodies, anti-MDA5, MI-2-antibodies

Corticosteroids, immunosuppressants

Variable, most patients improve over time with treatment, prognosis depends on associated diseases (malignancies)

Myositis/myopathy

Inclusion body myositis [31, 211, 212]

33/1,000,000 (Norway) 10.7 – 71 /1,000,000 (USA) → 3.7/100,000

Hereditary autosomal recessive form with onset in young adults, mutations in GNE (very rare); sporadic form in elderly, associated with HLA-DR3 and MHC variants; genetic, environmental, aging, and immune-mediated factors probably related to pathogenesis

Histopathological diagnosis

Predominantly males (2:1) and elderly, slowly progressive muscle weakness (often beginning in wrists or quadriceps muscle), dysphagia

CK may be elevated or normal

Refractory to immune therapy, can be used tentatively in case of relation to other autoimmune diseases

Chronic and slowly progressing, most patients wheelchair-reliant within 10 years

Myositis/myopathy

Eosinophilia-myalgia syndrome [213]

Unknown, 5000–10,000 people affected, predominantly females in the US (epidemic in 1989), estimate < 1/1,000,000

Unknown; consumption of manufactured L-tryptophan or 5-hydroxytryptophan associated with disease onset; increased TGF-β and IL-4 may be responsible for fibrosis

Clinical diagnosis

Rapid onset of severe myalgia, cough, fever, fatigue, joint pain, edema; long-term symptoms include eosinophilic fasciitis, alopecia, CNS involvement, myocarditis, arrhythmias, GI involvement

Elevation of eosinophils, WBC

Supportive treatment, corticosteroids in acute phase may be used tentatively

Chronic course with systemic organ involvement not uncommon

Myositis/ myopathy

Focal myositis [214, 215]

Unknown, estimate < 1/1,000,000

Unknown; trigger factors poorly understood (e.g., physical trauma)

Clinical, radiographic, and histopathological diagnosis

Rapidly growing mass in a single muscle, most commonly in lower limbs, usually painless

Usually no elevated acute phase reactants, CK may be elevated but usually normal

No treatment, corticosteroids in case of inflammation or complications

Usually self-limited within few weeks or months, relapses possible but uncommon

Myositis/myopathy

McArdle’s disease (glycogenosis type 5) [216,217,218,219]

Estimated 1:50,000 (US) – 1:140,000 (Spain) → 1.4/100,000

Autosomal recessive, mutations in PGYM, leading to glycogen phosphorylase deficiency

Enzyme measurement, histopathology, genetic testing

High clinical variability, rapid fatigue, myalgia and cramping with exercise and fast recovering with rest (“second-wind phenomenon”)

Elevated baseline CK, myoglobinuria, rhabdomyolysis

No treatment; moderately active lifestyle and ingestion of simple carbohydrates before exercise recommended

Chronic, but variable in severity; complications include renal failure and cardiovascular diseases

Myositis/myopathy

Tarui disease (GSD7) [220, 221]

Unknown, more than 100 cases described, Common in Ashkenazi-Jews, estimate < 1/1,000,000

Autosomal recessive, mutations in PFKM, leading to muscle phosphofructokinase deficiency

Histopathological diagnosis, genetic testing

Exercise intolerance, myalgia, cramps, cardiomyopathy

Myoglobinuria, hemolytic anemia, hyperuricemia, hyperCKemia, reticulocytosis

No treatment; avoid extensive exercise

Chronic, complications include renal and cardiac involvement

Myositis/myopathy

Camurati-Engelmann disease (progressive diaphyseal dysplasia) [26, 222, 223]

Unknown, estimate < 1/1,000,000

Autosomal dominant, mutations in TGFB1, resulting in increased growth factor signaling

Genetic testing, clinical findings + radiographic images

Hyperostosis of long bones and skull, severe limb pain, muscle atrophy, wide-based waddling gait, progressive joint contractures, hearing loss, absence of subcutaneous fat

Increased levels of TGF-β1

Corticosteroids, NSAIDs, bisphosphonates, all with variable outcomes; experimental: anti-TGFβ (e.g., losartan)

Chronic, patients may become wheelchair-reliant

Bone disorder

Fibrodysplasia ossificans progressiva (Munchmeyer's disease) [224, 225]

0.36/1,000,000 (Spain) 1.36/1,000,000 (France) estimated worldwide prevalence (literature): 1/2,000,000 → 0.74/1,000,000

Autosomal dominant (most cases de novo), mutation in ACVR1, leading to enhanced BMP signaling with fibroproliferation, angiogenesis, enchondral ossification; risk seems to be increased with older age of mother and father, fathers often exposed to chemicals

Clinical, radiographic, histopathological diagnosis

Heterotopic ossification, tumor-like swellings and short, malformed great toes (early sign), cervical spine fusions, osteochondroma, hearing loss

Usually normal, although ESR and AP may be elevated

Short-term muscle relaxants, NSAIDs, Cox-2-inhibitors, corticosteroids, bisphosphonates; operations should be avoided (triggers new flare ups and bone growth)

Chronic, progressive, and lethal within approximately 40 years, most patients wheelchair-reliant at the end of second decade of life

Bone disorder

Osteomesopyknosis [226]

Unknown, < 50 cases reported, predominantly from France, estimate < 1/1,000,000

Autosomal dominant, gene unknown

Radiographic diagnosis

Disease onset and diagnosis usually in adolescence, diffuse back pain

Usually normal

Symptomatic

Benign and good prognosis, normal life expectancy

Bone disorder

Fabry disease [227,228,229]

Australia 0,85/100,000

alpha-galactosidase A deficiency due to mutation in GLA-gene on X-chromosome (X-linked disorder)

Measurement of enzyme activity, genetic testing

Neuropathic pain, hypohidrosis, gastrointestinal symptoms, kidney failure, cardiovascular disease

renal function may be impaired

Enzyme replacement therapy

Chronic. Life expectancy increased with ERT, but limited by cardiovascular and renal function

Bone disorder

Farber disease [230, 231]

Unknown, estimate < 1/1,000,000

Autosomal-recessive, ASAH1-gene; acid ceramidase deficiency

Measurement of enzyme activity; histopathology of granuloma; ceramide accumulation in granuloma

Subcutaneous nodules, joint disease, hoarseness of voice, inflammatory granuloma

 

Enzyme replacement therapy in progress; Stem cell transplantation

Chronic and progressive. Death due to respiratory insufficiency caused by pulmonary granulomas

Bone disorder

Gaucher's disease (type 1 in 90% of cases) [232,233,234,235]

Estimated 1–2/100,000 worldwide, 1/850 in Ashkenazi-Jews → 1.5/100,000

Autosomal recessive, mutations in GBA1; deficiency in lysosomal glucocerebrosidase leads to accumulation of glucocerebroside

Measurement of enzyme activity, genetic testing

Age of onset and disease course variable; fatigue, growth retardation, delayed puberty, bone pain, avascular necrosis of bone, gallstones, hepatosplenomegaly, Parkinson´s disease, malignancies (predominantly hematological)

Thrombocytopenia, anemia, monoclonal gammopathy, vitamin D deficiency; biomarkers: chitotriosidase, CCL 18, glucosylsphingosine, ferritine

Lifelong enzyme replacement or substrate reduction therapy

Chronic, reduced life expectancy due to neurological involvement and malignancies

Bone disorder

Hypophosphatasia (HP) [236,237,238]

1/300.000 for severe HP, 1/6370 for moderate HP Estimate 1/100,000

Autosomal-recessive or autosomal-dominant; mutations in TNSALP lead to accumulation of pyrophosphate, an inhibitor of mineralization

Laboratory values + radiologic features, confirmed by genetic testing

Age of onset and disease course very variable; perinatal death, bone deformities, stress fractures, loss of dentition, musculoskeletal pain and weakness

low serum AP, hypercalcemia

Enzyme replacement therapy for pediatric onset hypophosphatasia

Chronic, mortality and morbidity varies with onset

Bone disorder

Morquio disease (mucopolysaccharidosis type IVa) [239,240,241]

1/323,000 (Denmark) 1/599,000 (UK) 1/1,872,000 (Malaysia) 1/926,000 (Australia) → 1.6/1,000,000

Autosomal recessive, mutations in GALNS, resulting in N-acetylgalactosamine-6-sulfate sulfatase-deficiency

Measurement of enzyme activity, genetic testing

Disease onset in childhood; progressive skeletal dysplasia, short trunk dwarfism, spondyloepiphyseal dysplasia with ligamentous laxity, joint pain, preserved intelligence, odontoid hypoplasia pulmonary, cardiac, ophthalmologic, audiologic, dental, abdominal and neurologic involvement possible

GAGs in urine

Enzyme replacement therapy, pain management, supportive therapy, surgery

Chronic, wheelchair-reliance beginning in adolescence, increased mortality due to cervical instability and pulmonary compromise

Bone disorder

Melorheostosis (Leri´s disease) [105, 242,243,244]

 ~ 400 cases reported, estimate 1/1,000,000

Usually sporadic; somatic LEMD3 mutations suspected as a possible cause; disturbance in bone formation and modeling; possible association with scleroderma and Buschke-Ollendorf syndrome

Radiographic diagnostic criteria (Freyschmidt)

Disease onset in childhood or adolescence; limb deformity, contractures, joint and bone pain, leg length discrepancy, stiffness, hyperostosis (usually long bones in lower extremity) usually in one limb, but may be bilateral, soft tissue involvement (hypertrichosis, fibrosis, erythema) above affected bone

Markers of bone metabolism usually normal (calcium, AP, etc.)

Pain management, bisphosphonates, surgery (relapses common)

Chronic and progressive, morbidity mostly due to pain, stiffness, and reduced range of motion

Bone disorder

Pachydermoperiostosis (primary hypertrophic osteoarthropathy; Touraine-Solente-Golé syndrome) [23, 24, 245,246,247]

Unknown, estimate < 1/1,000,000

Autosomal dominant with incomplete penetrance proven, autosomal recessive and X-linked inheritance also suggested, mutations in SLCOA21, HPGD, possibly also related to HLA-B12 or BMP pathway; involvement of testosterone promoting proliferation suspected

Clinical diagnosis

Occurs predominantly in males (7:1), disease onset often in puberty, progression for 5–20 years; pachydermia, digital clubbing, periostosis, cranioosteoarthropathy, congenital heart diseases (especially patent ductus arteriosus), hyperhidrosis, rash, myelofibrosis, gastrointestinal involvement

Unspecific

NSAIDs, corticosteroids, colchicine, bisphosphonates, retinoids, plastic surgery

Chronic, progressive for 5–20 years

Bone disorder

Mucopolysaccharidosis type 2 (Hunter syndrome) [248,249,250]

0.65/1,000,000 (Sweden) 0.44/1,000,000 (Norway) 0.91/1,000,000 (Denmark) → 0.67/1,000,000

X-linked recessive, mutation in IDS; lysosomal storage disorder: iduronate-2-sulfatase enzyme deficiency

Measurement of enzyme activity, genetic testing

Disease onset in childhood; peau d´orange, cognitive impairment, joint stiffness, contractures, cardiac and respiratory involvement, short stature, carpal tunnel syndrome, hepatosplenomegaly, glaucoma

GAGs in urine

Enzyme replacement therapy, supportive treatment, pain management

Chronic, often lethal within 20—30 years (cardiovascular involvement limiting), patients with attenuated form may have normal life expectancy

Bone disorder

Caffey disease (infantile cortical hyperostosis, Caffey-Silverman syndrome, Smyth syndrome) [251,252,253]

Unknown, estimate < 1/1,000,000

Autosomal dominant, heterozygous mutation in COL1A1 with incomplete penetrance

Clinical and radiographic diagnosis with genetic confirmation

Fever, swelling of soft tissues, hyperostosis of outer cortical surface in first 5 months of life, unusual irritability

Elevated ESR, AP, thrombocytosis, anemia, increased immunoglobulin

Symptomatic: NSAIDs

Good, usually self-limiting in early childhood, chronic or remitting-relapsing course possible

Connective tissue disease

Ehlers-Danlos syndrome [254,255,256]

1/10,000 – 1/25,000 = 7/100,000

Autosomal dominant or autosomal recessive, mutations in COL5A1/COL5A2/COL5A3/COL3A1 and other, depending on subtype

Villefranche classification

Depending on subtype: joint hyperlaxity and luxation, easy bruising, arthralgia, vascular aneurysm, muscle hypotonia

Normal coagulation status despite easy bruising

Only symptomatic and supportive treatment

Chronic, worst prognosis in vascular subtype, obstetrical complications common

Connective tissue disease

Fibrosing mediastinitis [257,258,259]

Unknown, estimate < 1/1,000,000

Most cases idiopathic, or due to infections (histoplasma, aspergillus) or sarcoidosis; proliferation of fibrous tissue, possibly IgG4-related

Radiographic diagnosis

Often younger people affected; cough, hemoptysis, dyspnea, other symptoms depend on grade of obstruction of surrounding structures

Usually normal

Corticosteroids, local therapies, surgery

Variable, often chronic and progressive, potentially lethal because of invading/ displacing growth

Connective tissue disease

IgG4-related Disease [260,261,262,263]

6/100.000 (Japan)

Immune mediated, multiple possible risk factors

ACR/EULAR Classification Criteria

Elderly men primarily affected; any organ involvement possible, most often gastrointestinal organs or salivary glands, leading to fibrosis and subsequent organ dysfunction

Serum IgG4 may be elevated

Corticosteroids

Chronic, remitting-relapsing. Usually mild symptoms, only slowly progressing

Connective tissue disease

Marfan syndrome [264,265,266]

6.5/100,000 (genetically proven patients in Denmark)

Autosomal dominant, mutation in FBN1, resulting in disturbed fibrillin 1 function and altered TGF β regulation, large phenotypic variability

Revised Ghent criteria

Tall stature, joint hypermobility, arachnodactyly, aortic aneurysm, mitral valve prolapse, ectopia lentis, scoliosis, dural ectasia

Usually normal

β–blockers, cardiac and/or orthopedic surgery

Chronic, mortality depends on cardiovascular involvement, life expectancy normal with regular follow-up and treatment

Connective tissue disease

Shulman disease (eosinophilic fasciitis) [267, 268]

Unknown, estimate < 1/1,000,000

Association with HLA-A2 described, many different theories on pathogenesis and possible triggers (e.g., physical exercise) exist

Proposed diagnostic criteria by Pinal-Fernandez et al.

Disease onset at any age (mean 4th-5th decade); abrupt onset of painful swelling and thickening of skin and other soft tissues, joint contractures, most often extremities symmetrical involved

Blood eosinophilia, hypergammaglobulinemia, elevated ESR, TIMP-1 possibly marker for disease activity

Corticosteroids, MTX; not all patients require treatment

Variable, remission usually occurs spontaneously or with therapy

Connective tissue disease

Sharp syndrome (mixed connective tissue disease) [269,270,271]

3.8/100,000

Unknown, B cells may play a role in pathogenesis

Different diagnostic criteria exist (Sharp´s, Alarcón-Segovia and Villareal, Kasukawa)

Female predominance (3.3:1), Raynaud´s phenomenon, puffy hands, arthritis, pleuritis, pericarditis, myositis, interstitial lung disease, PAH, esophageal dysmotility, dyspnea, cardiovascular involvement

Anti-ribonucleoprotein antibodies (anti-U1RNP)

NSAIDs, corticosteroids, immunosuppressants

Chronic and progressive, may evolve into other connective tissue disease, mortality increased with cardiovascular involvement

Connective tissue disease

Systemic sclerosis [30, 44, 45, 272,273,274,275]

More common in Europe than Asia, less common in northern countries, highest ever reported prevalence in population of Choctaw Indians in Oklahoma (469/100,000), worldwide → 15–30/100,000 (= 22.5)

Unknown, HLA-association suspected, different pathophysiological factors suspected (vasculopathy, autoantibodies, fibroblast dysfunction, immune system alteration, silica dust, toxins, infections)

ACR criteria

Female predominance (3:1), peak incidence at age 45 – 64 years; skin thickening, Raynaud´s phenomenon, pulmonary fibrosis, PAH, digital ulcers, esophageal hypomobility, arthralgia, myalgia, variable organ involvement

Anti-centromere-AB, anti-topoisomerase-I-AB (Scl70), anti-RNA-polymerase III

Symptomatic and supportive treatment of Raynaud´s phenomenon, digital ulcer, skin, lung, and GI disease

Chronic and progressive, worst prognosis among all connective tissue diseases, mean survival 11–12 years after diagnosis

Connective tissue disease

CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal nevi syndrome) [276,277,278,279]

Unknown, only a few cases reported, estimate < 1/1,000,000

Mosaic activating, postzygotic mutation in PIK3CA, causing tissue overgrowth

Clinical diagnostic criteria for PIK3CA-related overgrowth spectrum (Keppler-Noreuil et al.), genetic testing

Vascular malformations, thoracic lipomatous hyperplasia, asymmetric growth, visceral and neurological disorders, linear epidermal nevus, gigantism of hand and feet, macrodactyly, sandal gap toe, renal anomalies

Normal

Clinical trials with mTOR kinase-inhibitors and selective PIK3CA-inhibitors; laser, sclerosing, or surgical treatment

Chronic, severity depends on somatic mosaic, frequent recurrence of lipomatous masses, increased risk of tumors (e.g., Wilms tumor)

Overgrowth syndrome

Klippel-Trénaunay-Weber syndrome complex (angio-osteohypertrophic syndrome = Klippel-Trenaunay, special form with AV fistulas = Parkes-Weber syndrome) [280,281,282,283]

Unknown, ~ 1000 reported cases in literature, estimated incidence 1/100,000

estimate < 1/1,000,000

Unknown, multiple different inheritance modes suspected; current candidate genes: VG5Q, PIK3CA, AGGF1, ING5, HDAC9; congenital defects in spinal cord, vessels, and mesodermal tissues suspected

Clinical and radiographic diagnosis

Cutaneous capillary malformations (portwine stain), varicous veins, hypertrophy of bone and soft tissue (often resulting in different limb lengths), usually isolated to one extremity (most commonly leg), pain, edema, pruritus; in Parkes-Weber syndrome: + AV fistulas

Normal

Symptomatic: compression stockings, laser surgery, treatment of infections, thromboembolic events

Chronic, but rarely cause of death, higher mortality in Parkes-Weber syndrome because of AV fistulas, complications include coagulopathy and thromboembolic events

Overgrowth syndrome

Proteus syndrome [284,285,286]

Unknown, possibly over-/misdiagnosed because of similarities to other overgrowth spectrum disorders, incidence estimated 1/1,000,000 estimate < 1/1,000,000

Somatic mosaic activating AKT1 mutation, increased growth in affected cells

Revised diagnostic criteria (Turner et al., Cohen), genetic testing of affected tissue

Males more commonly affected than females (2:1); overgrowth of different tissues: cerebriform connective tissue nevus, vascular malformations, deep vein thromboses, dysregulated adipose tissue (lipomas), pulmonary abnormalities, asymmetric and disproportionate overgrowth, tumors, facial phenotype, intellectual impairment, seizures

Coagulopathy and DVT possible

Supportive: antithrombotic prophylaxis, orthopedic surgeries, psychological support

Chronic, premature death in 20% due to respiratory or neurological involvement

Overgrowth syndrome

Erdheim-Chester disease [287,288,289,290]

Unknown, ~ 600 reported cases, estimate < 1/1,000,000

In more than 50% BRAF-mutations, non-Langerhans cell-histiocytosis with hyperactivation of cytokines

Radiographic and histopathological diagnosis, genetic testing

Predominantly males in 5th-7th decade of life; bone involvement nearly always present, CNS involvement (diabetes insipidus, visual disturbances, pyramidal/extra-pyramidal syndromes), other organ involvement possible (cardiac/lung/retroperitoneal/cutaneous, etc.)

Elevated ESR, AP, or CRP, signs of pituitary insufficiency

Interferon, corticosteroids, immunosuppressants, biologicals (TNFi, IL-1i), BRAF-inhibitors

Chronic and often lethal, 5-year survival < 70%

Other

Hyaline fibromatous syndrome (infantile systemic hyalinosis/juvenile hyaline fibromatosis) [291,292,293,294]

Unknown, ~ 150 cases reported (predominantly from Middle East), estimate < 1/1,000,000

Autosomal recessive, mutations in CMG2/ANTXR2-gene, CMG2 is a transmembrane protein that plays a role in capillary morphogenesis (also binds anthrax toxins); higher carrier frequency in Middle Eastern populations suspected

Demonstration of hyaline deposition in dermis, genetic testing

Subcutaneous skin nodules, gingival hypertrophy, joint contractures, hyaline deposition, osteopenia. infections, protein-losing enteropathy; cognitive development normal

No specific findings depending on complications (e.g., diarrhea)

Symptomatic: surgery, D-penicillamine, physiotherapy, NSAIDs, nutritional therapy

Chronic, variable course, but often lethal within first 2 years of life (infantile form), oldest known patient is 58 years old

Other

Sweet syndrome (SS, acute febrile neutrophilic dermatosis) [295,296,297,298,299,300]

Unknown, estimate < 1/1,000,000

Unknown; classic SS (idiopathic), malignancy-associated, and drug-induced histiocytoid SS; commonly related to inflammatory bowel diseases (especially females with Crohn´s disease)

Classic SS: diagnostic criteria by Su and Liu (modified by van den Driesch); drug-induced SS: diagnostic criteria by Walker and Cohen

Slight female predominance, abrupt onset of fever, peripheral neutrophilia, tender erythematous skin lesions, diffuse neutrophilic dermal infiltrate, arthralgia, malaise, headaches, myalgia

Leukocytosis, elevated ESR, CRP

Corticosteroids, potassium iodide, colchicine, immunosuppressants in relapsing cases, treatment of underlying cause if found

Spontaneous or therapy-induced remission, relapses more common in malignancy-associated SS

Other

Relapsing polychondritis [301,302,303,304,305,306]

2/100,000 (Hungary) estimated prevalence in literature: 4.5/1,000,000 → 1.2/100,000

Association with HLA-DR4, 30% of all patients have associated autoimmune or hematological disease (MDS); vasculitis of all sized vessels occurs

Michet´s criteria, McAdams´ criteria, Damiani and Levine criteria

Typically onset in middle-aged adults; recurrent inflammation of cartilage, especially ears, nose, respiratory tract; vasculitis of all sized vessels, aortic or mitral valve disease, joints, eyes and skin possible

Elevated CRP, ANCA may be positive

NSAIDs, corticosteroids, dapsone, colchicine, immunosuppressants, biologicals

Chronic, survival rate variable, but recent studies report good survival rates

Other

Cogan syndrome [307,308,309]

Unknown, over 250 cases reported, estimate < 1/1,000,000

Unknown, autoimmune process suggested (additional autoimmune disease diagnosed in ~ 10% of patients), association with cigarette smoking suspected

Clinical diagnostic criteria for typical and atypical Cogan syndrome

Non-syphilitic interstitial keratitis (or other ocular symptoms, then called atypical Cogan), vestibulo-auditory symptoms, fever, weight loss, arthromyalgia, headache

Anemia, leukocytosis, thrombocytosis, elevated ESR or CRP possible

Corticosteroids, DMARDs, immunosuppressants, biologicals; vestibulo-auditory symptoms often unresponsive to treatment

Chronic or remitting-relapsing, complications include persistent hearing loss and cardiovascular involvement with increased mortality

Other

Weber-Christian panniculitis (relapsing febrile nodular nonsuppurative panniculitis; idiopathic lobular panniculitis) [310,311,312,313]

Unknown, only a few cases reported, estimate < 1/1,000,000

Unknown, inflammation and necrosis of subcutaneous adipose tissue, mechanism unclear, probably autoimmune

Histopathological diagnosis

Predominantly middle-aged females affected, recurrent subcutaneous inflammatory painful nodules, fever, malaise, arthralgia, hepatosplenomegaly, anorexia, weight loss, ocular inflammation, lung nodules, systemic organ involvement possible

Elevated ESR, anemia, leukocytosis or leucopenia, hypocomplementemia

Corticosteroids, immunosuppressants, biologicals

Chronic, prognosis variable, poor in case of systemic organ involvement

Other

Systemic mastocytosis (mast cell disease) [314,315,316,317,318]

9.59/100,000 (Denmark, including all systemic subtypes)

Somatic gain of function mutation in KIT, KIT is a tyrosine kinase receptor essential for correct mast cell development and function

WHO diagnostic criteria

Abnormal proliferation and accumulation of mast cells cause urticaria pigmentosa, flushing, urticaria, GI symptoms, musculoskeletal pain, headaches, anaphylaxis, weight loss, osteoporosis

Anemia, thrombocytopenia, leukocytosis, eosinophilia, elevated tryptase, uric acid, LDH, bilirubin, ferritin, hypoalbuminemia

Imatinib, symptomatic treatment, interferon-α, corticosteroids, 2-chlorodeoxyadenosine

Chronic, variable progression, may evolve into leukemia

Other

Sarcoidosis (Boeck’s sarcoid) [319,320,321]

11.16/100,000 (Northern Ireland) 28.13/100,000 (Ireland) → 19.6/100,000

Associated with different HLA subtypes and BTNL-2, inhaled antigens are considered a possible trigger

Clinical and histopathological diagnosis

Females more often and more severely affected, peak onset in second decade, many patients are asymptomatic or have unspecific symptoms, such as fever, fatigue, weight loss; most commonly affected organ: lung

Elevated acute phase reactants, ACE, s-IL2R

Corticosteroids, immunosuppressants, biologicals

Variable, often self-limiting within 24 months, increased mortality with systemic organ involvement

Other