- 1 Definition
- 2 Disease Cause
- 3 Occurrence
- 4 Symptoms
- 5 Examinations
- 6 Treatment
- 7 Various febrile syndromes/autoimmune diseases
- 7.1 A20 haploinsufficiency (HA20), TNFAIP3 mutation
- 7.2 Behcet's syndrome
- 7.3 Blau syndrome (juvenile sarcoidosis)
- 7.4 CANDLE, Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated temperature
- 7.5 CAPS
- 7.6 CINCA: Chronic Infantile Neurological Cutaneous and Articular Syndrome / Neonatal-Onset Multisystem Inflammatory Disease (NOMID)
- 7.7 CRMO (chronic multifocal osteomyelitis)
- 7.8 DADA-2, Autoinflammation with immunodeficiency
- 7.9 DIRA (deficiency of the IL-1R antagonist)
- 7.10 DITRA (Deficiency of interleukin-36 receptor antagonist)
- 7.11 Early onset enterocolitis (mutations in IL-10R)
- 7.12 Familial cold autoinflammatory syndrome (FCAS)
- 7.13 Familiar Mediterranean Fever (FMF)
- 7.14 HIDS (Hyper IgD syndrome) (mevalonate kinase deficiency disease, MKD.
- 7.15 JMP Joint contractures – muscle atrophy – microcytic anemia – panniculitis-induced lipodystrophy
- 7.16 MKM (Mevalonate Kinase Deficiency)
- 7.17 Cryopyrin Associated Periodic Syndromes (CAPS) / Cryopyrin Associated Periodic Fever Syndromes
- 7.18 Nakajo-Nishimura disease (NNS)
- 7.19 Neonatal-Onset Multisystem Inflammatory Disease (NOMID) = Chronic Infantile Neurological Cutaneous Articular Syndrome (CINCA)
- 7.20 NLRP12-associated syndrome (nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain)
- 7.21 NLRC4 inflammatory mutation
- 7.22 PAPA syndrome (Acne, sterile arthritis or abscess, pyoderma gangrenosum)
- 7.23 PFAPA (Periodic fever, aphthous stomatitis, pharyngitis of adenopathy syndrome)
- 7.24 SAVI (STING-associated vasculopathy with childhood onset).
- 7.25 Cyclic neutropenia (in children)
- 7.26 TRAPS (Tumor-necrosis factor receptor-associated periodic syndrome)
- 8 Literature
Periodic fever syndromes are also called autoinflammatory diseases. These are rare conditions, but are suspected in children and young people with repeated episodes of fever over months-years, without infection being detected. Many people have fever episodes, for example monthly, with fairly equally long fever-free periods in between. In addition, pain in the throat, ulcers in the mouth, stomach area, joints and muscles, headaches, rashes and swollen lymph nodes, as well as unusual fatigue are also common. Elevated inflammatory tests (CRP, SR) during attacks are typical. Age of onset, duration of fever and other symptoms, as well as genetic analyzes distinguish the individual conditions (see below). The febrile syndromes are different from autoimmune connective tissue disorders og vasculitides, but common is that immune system attacks his own tissue with rheumatic inflammation (inflammation) as a result. There is effective treatment for several of the conditions.
A significant difference from many other rheumatic diseases is that autoinflammatory fever diseases are most often caused by a mutation (lasting change) in a single gene (genetic material). Exceptions are PFAPA (and Still's disease/ systemic JIA) where several genes are involved. Nevertheless, much information about the disease mechanisms is unknown. Due to the mutation, it is missing congenital (innate) immune system braking mechanisms. The reactions occur even if the body has never been in contact with foreign bacteria, viruses, medicines or other substances. The diseases are also separated primary immune immunodeficiency may be raised which causes fever in connection with frequent infections from childhood.
Autoinflammatory diseases usually begin in young children, but some are only diagnosed in adolescence or adulthood. All the periodic fever syndromes / autoinflammatory diseases are defined as rare diseases. Familial Mediterranean fever (FMF, see below) is worldwide the most common monogenic autoinflammatory disease, but less than 1% is of Western European descent (reference: Mortensen SB, 2020). In earlier childhood, "periodic fever, aphthous stomatitis, pharyngitis of adenopathy syndrome" (PFAPA, see below) is considered the most common periodic fever syndrome (reference: Rigante D, 2009).
Autoinflammatory febrile diseases are characterized by onset in early childhood, although familial Mediterranean fever (FMF) and TRAPS may have a later onset. Symptoms typically begin suddenly:
- Episodes of fever and severe rheumatic inflammation: high fever that comes and goes, fatigue, neck pain, rash and joint swelling / Arthritis.
There are many different autoinflammatory diseases that have their own genetic causes (mutations) and characteristics (see more below). What they have in common is that they can occur most commonly among young children or young people. The most common age at onset is under five years. Despite the genetic cause, they are not particularly hereditary.
- Familial Mediterranean fever (FMF) has the shortest fever duration (2-3 days) with irregularly long periods in between.
- TRAPS longest-lasting febrile attack (almost three weeks in severe form, 5-9 days in mild form)
- HIDS Hyper Ig-D associated syndrome (Mevalonate kinase disease) Very regular fever, but rapidly rising temperature
- PFAPA has fairly regular bouts of fever (every 2-4 weeks) with a duration of 4-6 days and becomes less troublesome (lower fever, fewer symptoms) later in childhood.
- Blood tests
- Decrease response (SR) and CRP increase in fever, mild leukocytosis (increased white blood cell count)
- No infection
- Arthritis (joint inflammation): PAPA, Blau syndrome
- Artritt + Interstitial pulmonary disease, often lung hemorrhage: COPA (genetic vasculitis among children)
- Behcet's disease-like (mucous ulcer): A20 protein haplo insufficiency (Reference Zhou Q, 2015)
- MAS (macrophage activation syndrome): Monogenic (hereditary) cases, NLRC4 inflammasome mutation mediated
- Panniculitis (adipose tissue with necrosis): CANDLE
- pustular Psoriasis: DIRA, DITRA
- Urticarial vasculitis: FCAS, Muckle-Wells, CINCA
- Vasculitis and pulmonary disease: SAVI (STING-associated childhood-onset vasculopathy) (Wang Y, 2021)
The examination is often carried out by paediatricians in collaboration with a pediatric rheumatologist, ophthalmologist, dermatologist, geneticist and others if necessary.
Medical history maps age at symptom onset and course. The degree of measured fever, interval duration and frequency are of interest. Also symptoms from the throat, mouth ulcers, eyes, hearing, skin and subcutaneous tissue, joints, skeleton, muscles, nervous system, abdominal pain and diarrhea may be of interest. A triggering cause is rarely detectable, but some cases (CAPS/ Familial cold autoinflammatory syndrome, FCAS) start after exposure to cold.
Clinical a general examination of the eyes, hearing, mouth, throat, skin, joints, nervous system and internal organs is carried out. Signs of infection are ruled out as much as possible (ears, sinuses, pharynx, lungs, gastrointestinal tract, urinary tract, skin, joints)
Blood tests usually shows elevated inflammatory tests (CRP and lowering reaction, SR) during febrile attacks. A transient increase in the number of white blood cells may occur. Genetic testing (not possible for all types). Current tests are conducted here (Genetikportalen.no).
Imaging may show signs of inflammation with symptoms in the stomach area (peritonitis) or whose lungs (pleurisy) and the heart (pericarditis) is attacked. X-ray of the lungs, ultrasound of the abdominal area and CT of the sinuses if sinusitis is suspected.
Bone marrow examined to rule out other disease if the diagnosis is uncertain.
The choice of treatment depends on the type of periodic fever syndromes / autoinflammatory diseases present. Prednisolone (cortisone) og Biological drugs such as anakinra, canakinumab (IL-1 inhibitors) or TNF inhibitors may be appropriate.
Various febrile syndromes/autoimmune diseases
A20 haploinsufficiency (HA20), TNFAIP3 mutation
Definition: A20 Haploinsufficiency is an autoinflammatory disease, first described in 2016. Behcet-like symptoms in children (reference: Zhou Q, 2016). Disease Cause: Heterozygous inherited mutation in TNFAIP3 encoding NF-κΒ regulatory protein A20. Age of debut: Usually children before the age of 10, but can start from infancy to young adults. Symptoms: Recurrent painful oral ulcers most common, but corresponding ulcers further down the throat and gastrointestinal tract are also common. Abdominal pain, joint inflammation (arthritis) and skin symptoms may include pustules, folliculitis, acne and ulcers. Inflammation of the eyes in the form of uveitis/iridocyclitis and retinal vasculitis. Laboratory tests: High inflammatory tests such as CRP and SR. In some, ANA and anti-DNA are elevated. Genetics: All have a mutation in the TNFAIP3 gene. Diagnosis: In the case of typical anamnesis and clinical findings, genetic examination is essential. Differential diagnosis: Behcet's disease, juvenile lupus (JSLE), JIA, PFAPA (see below), inflammatory bowel disease (IBD). Treatment: Biological drugs in the form of IL-1 inhibitors (anakinra, canakinumab) or TNF inhibitors are effective in most people. Literature: Zhou Q, 2016; Aeschlimann AF, 2018.
Some believe that Behcet's syndrome belongs to the autoinflammatory diseases (reference: Leccese P, 2019). This applies in particular to the familial form A20 Haploinsufficiency (HA20) which occurs in children (see if the disease is most often classified among Systemic vasculitis.
Blau syndrome (juvenile sarcoidosis)
Familial cases are called Blau syndrome, while sporadic cases are called neonatal sarcoidosis or pediatric granulomatous arthritis. Disease Cause: The disease is caused by mutations in the "caspase recruitment domain" (CARD 15) which is also called the NOD2 gene. Age of debut: 2-4 years is most common. Symptoms: Triad of eye inflammation in the form of granulomatous uveitis (often in both eyes), joint inflammation (arthritis) and rash (brownish plaques). Joint pain, possibly joint cysts which can damage the joints in the long term. Rashes and small yellow-brown nodules that can peel (lichenoid) on the surface. Tissue sample shows granulomas with giant cells. Joint inflammation can include wrists, MCP, PIP, MTP1, ankles and elbows in both arms. Typically, reduced movement (contractures) develops in the early phase of the disease (reference: Wouters CH, 2014). Tendons can swell significantly, especially over the back of the hand and wrist (reference: Pac Kisaarslan PA, 2020). Imaging; Visible joint damage is uncommon, but fusions in wrist bones do occur. Tissue sample: Blau syndrome is the only autoinflammatory disease that forms granulomas (One demonstrates epithelioid non-necrotizing granulomas with multinucleated giant cells as in sarcoidosis, "early-onset sarcoidosis"). Genetics: Everyone has mutations in the NOD2 gene, but different penetrance means that some are asymptomatic. Treated with IL-1 inhibitors, TNFα blockers, less often with thalidomide. Literature: Punzi L 2009; Wouters CL, 2014.
CANDLE, Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated temperature
Chronic atypical neutrophilic dermatosis with elevated temperature. Disease Cause: The disease is caused by mutation of the PMSMB8 gene (proteasome sub-unit beta type-8). Proteasomes are large protein complexes in the cytoplasm and the cell nucleus. Their functions are to degrade unnecessary or damaged proteins. Proteasomes destroy proteins that are tagged with a small protein called ubiquitin. Age of debut: Starts in the child's first year of life, often the first 2-4 weeks of life. Symptoms: Initially, attacks of daily or next daily fever are seen. Rash (erythematous, annular) lasting a few days or weeks. Later, redness and swelling around the eyes develop (differential diagnosis: juvenile dermatomyositis), swelling in the fingers and toes, enlarged liver, impaired well-being and development, loss of fat tissue (lipodystrophy) and swollen lymph nodes. Rarer manifestations are swelling around the mouth and in the salivary glands (parotitis), eye inflammation (conjunctivitis/episcleritis), blackening of the skin (acanthosis nigricans), increased hair growth, joint pain, inflammation of fatty tissue (panniculitis) and patchy hair loss (alopecia areata). Tissue sample from the skin shows dense interstitial infiltrates of mononuclear cells. Genetics. Variable combinations mutations. Most often, the patients are homozygous or partially heterozygous for PSMB8 mutations, but others also occur. Treatment: Unfortunately, no particularly effective specific therapy has been found. In terms of treatment, cortisone drugs and methotrexate can be tried. If the effect is unsatisfactory, some respond to IL-1 receptor antagonists, TNFα blockers and IL-6 blockers (reference; Liu Y, 2011). Literature: Torrelo A, 2017.
- Please see CINCA below.
CINCA: Chronic infantile neurological cutaneous and articular syndrome / Neonatal Onset Multisystem Inflammatory Disease (NOMID)
CINCA / NOMID is a subgroup of cryopyrin associated fever syndrome (CAPS) with a severe course, please see above. Muckle Wells syndrome (see below) is a milder variant of CAPS. Disease Cause: NLRP3 mutation. Autosomal dominant genetic disease. The gene encodes key components for regulating the activation and secretion of pro-inflammatory interleukin (IL)-1β. However, 30-40% lack this mutation. Other forms include mutations in NLRP12 gene (please see NLRP12 associated febrile syndrome below). Occurrence (prevalence): 12-/million. Age of debut: Most make their debut in the first days after birth with a chronic hives/allergic rash, low-grade fever and persistently elevated inflammatory parameters. Symptoms: Fever, joint and muscle pain, rash, eye inflammation (uveitis), chronic meningitis (meningitis), delayed development. Characteristic face shape with prominent forehead occurs. Genetics: Detection of NLRP3 mutations. Treatment: IL-1 inhibitor: Anakinra, canakinumab. Literature: Finetti M, 2016.
CRMO (chronic multifocal osteomyelitis)
CRMO/Chronic recurrent multifocal osteomyelitis (CNO, chronic non-bacterial osteomyelitis) is often misinterpreted as infection. In adults, the condition is more often classified as a subgroup of the SAPHO syndrome.
Age of debut: Children after 2 years of age. Most are between 8 and 13 years old. The median age at diagnosis is 10 years. Occurrence: Rare disease, but increasing attention and better diagnostics (MRI) means that more cases have been diagnosed in recent times. Symptoms: Bone or joint pain with or without associated swelling. Most symptoms at night or in the morning can reduce sleep at night. Some make their debut with an unexpected broken leg. Skin changes with pimples/acne are rare in children. Joint inflammation (arthritis) in approx. 30%. Laboratory tests: Normal or slightly increased inflammatory tests such as CRP and SR. Other samples that are checked are cell counts (white blood cells, platelets and blood percentage/hemoglobin/erythrocytes). Imaging: With a regular X-ray or CT, skeletal changes can be recognized in the form of areas of clarification (osteolytic or cystic lesions). The most common localizations are close to the joints (metaphyses) in long tubular bones, the pelvis and vertebrae. Jawbones can also be attacked, while the skull is almost never attacked. However, MRI examination is more sensitive because signs of inflammation with swelling are also shown. In order to reveal the extent of the spread of the disease, whole-body MRI is appropriate. If one wants to investigate localized symptoms, on the other hand, MRI of the relevant area provides the best images and the most information. Genetics: In some cases, heterozygous mutation in the filamin-binding domain is onFBLIM1 the gene has been detected. The mutation causes increased amounts of pro-inflammatory cytokines such as IL-1β, IL-6 and TNFα. Differential diagnosis: CRMO is a diagnosis of exclusion. In unclear cases, biopsy from skeletal manifestations is appropriate to rule out chronic infection, cancer or other systemic disease. Important differential diagnoses are Leukemia, Lymphoma, primary and secondary skeletal tumors such as Ewing sarcoma, Rhabdomyosarcoma, Neuroblastoma and metastases. Benign tumors are eosinophilic granuloma and osteoid osteoma. Infections include bacterial infection of the skeleton (osteomyelitis) inclusive tuberculosis (tbc). Langerhans histiocytosis, PAPA, DIRA (see below) and Majeed syndrome (mutation in the LIPIN2 gene) are rare conditions that also resemble CRMO. Also circulatory disorders in the skeleton with osteonecrosis as by Add-Calve Perthes disease is ruled out. Increased calcification in the skeleton (osteosclerosis) wood histiocytosis, sickle cell disease og osteopetrosis may resemble the repair process at CRMO.
Treatment. Initially, NSAIDs are used, which are often sufficient. In some, corticosteroids, DMARDs (methotrexate or sulfasalazine), TNF inhibitors or bisphosphonates are also used. Course: The long-term prognosis is good, although most people experience several relapses. The remission rate is 40% within 1-5 years, but relapse after up to 15 years has been observed. Complications during the course are seen in one in three and include vertebral fractures, skeletal deformities and chronic pain. Literature: Johnson A, 2015; Hofmann SR, 2017; Koryllou A, 2021.
DADA-2, Autoinflammation with immunodeficiency
Stroke, recurrent fever, marbled skin, mild immunodeficiency. Please read about DADA2 on its own page.
DIRA (deficiency of the IL-1R antagonist)
Sterile (no bacteria or other infection) multifocal osteomyelitis with shin bone og pustulosis. Disease Cause: Mutation in IL1RN the gene that codes for interleukin-1 (IL-1) receptor antagonist (IL-1Ra). IL-1Ra deficiency results in high inflammatory activity via IL-1 and IL-1 receptor (IL-1R1). Occurrence: Onset between the first days after birth and within a few weeks. Symptoms: Eczema and multifocal osteolytic lesions (similar to septic osteomyelitis), periostitis, pustulosis, possible heterotrophic bone formation in the proximal femur, thrombosis and rarely vasculitis. Persistently elevated inflammation parameters. Chronic lung disease and thrombosis reported (reference: Jesus AA, 2011). Genetics. The diagnosis is ensured by detection of mutations in IL1RN the gene. Treatment: IL-1 inhibitor (anakinra, canakinumab) is often effective and important. In case of intolerance, hyposensitization to the drug may be relevant. Literature: Mendonca University of Applied Sciences, 2017.
DITRA (Deficiency of interleukin-36 receptor antagonist)
Disease Cause: Mutations in IL36RN the gene causes a lack of IL-36 receptor antagonist. Age at onset: Median 7 months. Symptoms: Fever and generalized pustular palmoplantaris. Boys are most often attacked. Treatment: corticosteroids, DMARDs, biological drugs: TNF inhibitors and IL-1 inhibitors have been used. Literature: Hospach C, 2019.
Early onset enterocolitis (mutations in IL-10R)
Disease Cause. Mutations in the genes IL10RA and IL10RB. The mutations lead to increased secretion of TNF-α and other inflammatory cytokines. Symptoms og age of debut: Serious, enterocolitis which begins in childhood. Bloody diarrhoea, colon abscesses, perianal fistulas, oral ulcers. Treatment: In case of lack of effect of immunosuppressive drugs, allogeneic stem cell transplantation is a possibility. Literature: Glocker EO, 2009.
Familial cold autoinflammatory syndrome (FCAS)
- See cryopyrin associated disease (CPAS) below
Familiar Mediterranean Fever (FMF)
Recurrent fever and rheumatic inflammation (not infection) in the joints, abdominal area (peritonitis), lung or heart sac (pleuritis, pericarditis). Disease Cause: Autosomal recessive inheritance. Mutation in the MEFV gene on chromosome 16. Genetic variations are common. Age of debut: Four out of 5 are under 20 years old, two out of three under five years old at the first symptom. Onset after the age of 30 is unusual. Occurrence: The most common monogenic autoinflammatory disease worldwide, but rare among ethnic Norwegians. More than 100,000 have been attacked globally. FMF primarily affects Non-Ashkenazi Jews, Armenians, Turks, Arabs and Italians. A study from Denmark showed an overall prevalence of 1/11.680 people (0,009%), approximately equally distributed between women and men. Most (41,8%) were of Turkish descent, followed by Lebanese (15,8%), and Syrians (6,5%). The others were from Asia and North Africa. Only 0,8% were of Western European descent (reference: Mortensen SB, 2020). Symptoms: Typical triad is recurrent episodes of fever, abdominal pain and inflammation in large joints. The duration is 1-4 days at irregular intervals, often 2-4 weeks. Before an attack, many feel exhaustion, nausea, loss of appetite, joint pain, chest pain, discomfort when breathing and coughing. Some people get a rash (reference: Babaoglu H, 2020). Milder cases with only fever occur. Between attacks, symptoms are absent. Diagnosis: Symptoms and examination findings. Classification criteria are used in research (reference: Gattorno M, 2019). Similar conditions / differential diagnoses: acute infection, childhood arthritis (most often systemic JIA), other type of periodic fever syndrome / autoinflammatory disease, SLE, Vasculitis, bleeding ulcer (Ulcer ventriculi) or severe abdominal pain (Acute abdomen) for another reason, hereditary angioedema, acute porphyria, recurrent pancreatitis (pancreatitis), high blood fat (hyper-triglyceridemia), abdominal epilepsy, abdominal migraines. Treatment: Colchicine (Adults 1,2-1,8 mg. Seizures: 0,6 mg/hour for 4 hours, then every two hours on the first day. Children < 5 years: Starting dose max. 1,0 mg. > 10 years: Starting dose max. 1,5 mg). About. 90% have an effect. Some experience side effects including diarrhoea, abdominal pain, rash, leukopenia, thrombocytopenia, neuropathy, myopathy and liver enzyme elevation. IL-1 inhibitors (anakinra, canakinumab) can be tried in destructive arthritis, non-response or intolerance. Alternatives are TNF-alpha inhibitor or IL-6 inhibitor (tocilizumab). Prognosis: The treatment must be continued for many years. AA-Amyloidosis (AA amyloidosis) is a dreaded complication after several years of illness. Symptoms are increasing nerve pain, numbness, proteins in urine samples and kidney failure over time. Consistent treatment of FMF prevents the development of amyloidosis. Literature: Kucuk A, 2014.
HIDS (Hyper IgD syndrome) (mevalonate kinase deficiency disease, MKD.
Disease Cause: Autosomal recessive. Mutation in the MVK gene (mevalonate kinase). Severe enzyme deficiency causes mevalonic aciduria. Occurrence: Frequent in Northern Europe, especially among the French and Dutch. Seizures over 4-5 days at irregular intervals of 4-8 weeks. The attacks can be triggered by vaccinations or infections. Age of debut: toddlers, most often in the first year of life. Symptoms: Sick child during seizures. Fever, rash, arthralgia, arthritis (70% non-erosive and in several joints on both sides of the body and transient), abdominal pain (often pronounced with vomiting and diarrhoea), swollen lymph nodes in the neck, headache, enlarged spleen, ulcers in the mouth and abdomen. Severe forms also with neurological symptoms, vision loss and hearing loss. Laboratory tests: Increased IgD in 78%, possibly also IgA. High SR and CRP, as well as leukocytosis. Seizures often subside in adulthood. Amyloidosis in 3%. Diagnosis: Symptoms and examination findings. In research, classification criteria are used: Eurofever/PRINO 2019 (reference: Gattorno M, 2019). Similar conditions / differential diagnoses: IgD increased in blood is elevated by: Hodgkin lymphoma, Sarcoidosis, Tuberculosis, Aspergillosis, ataxia-telangiectasia, HIV / AIDS. Treatment: NSAIDs, steroids, possibly a TNF inhibitor (etanercept) or an IL-1 inhibitor (anakinra, canakinumab) can be tried. Literature: Steichen et al. J Rheumatol 2009, van der Hilst & Frenkel. J Clin Rheum 2010. Mulders-Manders CM, 2015.
JMP Joint contractures – muscle atrophy – microcytic anemia – panniculitis-induced lipodystrophy
Disease Cause: Probably the same mutation as in CANDLE syndrome (see "small children" above), but JMP debuts in adulthood. Proteosome mutation. Symptoms: Joint contractures, muscle wasting, low blood percentage / anaemia, inflammation of fatty tissue (panniculitis). Literature: Agarwal AK, 2010.
MKM (Mevalonate Kinase Deficiency)
- Please see HIDS above
Cryopyrin Associated Periodic Syndromes (CAPS) / Cryopyrin associated with periodic fever syndromes
This is three diseases with similar clinical features are the interleukin-1-associated autoinflammatory diseases:
Onset first year of life. Symptoms: Cold from air conditioning or cold climates regularly leads to a systemic inflammatory reaction with fever and joint pain.
Start approx. 7 hours after cold exposure). Conjunctival redness (of the eye). Significant joint pain. Increased number of white blood cells (leukocytosis) up to 30.000 (after approx. 10 hours). The episodes gradually pass after 24 hours.
3. Muckle-Wells syndrome (MWS)
Disease Cause: Dominant autosomal. Muckle Wells syndrome is a subset of cryopyrin-associated periodic syndrome (CAPS) of which CINCA is a more severe form (please see above). Occurrence (prevalence): 1-10/million, most common among Caucasians. Age of debut: young children, median age under one year. Symptoms: Episodes of acute hives/urticaria/allergy, red eyes (conjunctivitis), recurrent fever, joint pain and fatigue are the most common symptoms. Arthritis, swollen fingertips (clubbing), hearing loss (70%), abdominal pain, alternating cellulitis, muscle inflammation (myositis), muscle fasciitis (fasciitis) and amyloidosis (25%) are also seen. Fever attacks last 12-48 hours. Genetics: Mutation in the CIA51 gene. Treatment: IL-1 inhibits anakinra, canakinumab. Start as early in the course of the disease as possible. See also CINCA above. Literature: Tran TA, 2017.
Nakajo-Nishimura disease (NNS)
Disease Cause: Mutation in PSMB4 (proteasome). Autosomal recessive inheritance, but approx. 50% do not have similar cases in the family. Age of debut: Most often around 2 years of age, but some first at 6–12 years of age. Symptoms: Periodic fever, eczema, fatty tissue recedes (lipodystrophy) especially in the upper part of the body, joint contractures and long fingers with swelling of the fingertips (clubbing). Some have eczema over the eyes (heliotropic eczema, differential diagnosis: Juvenile dermatomyositis). A clinical overlap with CANDLE syndrome (see above) and partial genetic overlap with JMP syndrome (joint contractures, muscular atrophy, microcytic anemia, and panniculitis-associated lipodystrophy) occur (described below). Laboratory: In blood tests, CRP and SR are always elevated. CK elevated in some. Hypergammaglobulin and elevated ANA test (with DNA and SSA antibody), also MPO-ANCA occurs. Genetics: Mutation in PSMB4 (proteasome). Treatment: Corticosteroids, DMARDs, biological drugs. Literature: Ohmura K, 2019.
Neonatal-Onset Multisystem Inflammatory Disease (NOMID) = Chronic Infantile Neurological Cutaneous Articular Syndrome (CINCA)
- Please see CINCA above
NLRP12-associated syndrome (nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain)
Disease Cause. The syndrome is related to CAPS (see above), but the mutation is i NLRP12 the gene, not NLRP3. Dominant inheritance, but variable how strongly one is attacked (different expressiveness and penetrance). Occurrence: Early childhood years. Symptoms: Similar to CAPS (see above): High fever, attacks every 3-4 week, lasts 2-10 days, often triggered by cold. Joint pain, muscle pain, stomach pain and vomiting, possibly mouth ulcers and swollen lymph nodes. Hearing loss. Symptoms can also be cold-induced. Genetically: molecular screening of NLRP12 gene is used diagnostically. Literature: Borghini S, 2011
NLRC4 inflammatory mutation
- Recurrent fever from early childhood. Joint pain, intestinal inflammation. Risk of developing macrophage activation syndrome as a serious complication. Literature Canna SW, 2014).
PAPA syndrome (Acne, sterile arthritis or abscess, pyoderma gangrenosum)
Disease Cause/genetics: Due to mutations in PSTPIP1 (or CD2 binding protein). Other autoinflammatory syndromes that are caused by mutations in the PSTPIP1 gene or have overlapping clinical manifestations with the PAPA syndrome can be included in the disease group PAPA-like diseases. These include PASH (Pyoderma Gangrenosum [PG], acne and hidradenitis suppurativa), PAPASH (PASH associated with pyogenic sterile arthritis), PsAPASH (PASH combined with psoriatic arthritis, PASS (PG, acne, ankylosing spondylitis, with or without HS), PAC (PG, acne and ulcerative colitis) and the PAMI syndrome (PSTPIP1-associated myeloid-related-proteinaemia inflammatory syndrome). Age of debut: Skin manifestations begin among children and young adults, arthritis during 10-30 years of age. Symptoms: -Skin can display the patergy phenomenon, which means that pustules and ulcerations develop after small injuries. Pyoderma gangrenosum and pronounced acne most often begin in early adolescence and persist into adulthood. Pyoderma gangrenosum can develop into the most severe manifestation. - Joints: Painful, recurring arthritis, most often in the elbow, knee or ankle. The symptoms from joints are difficult to distinguish from infection (septic arthritis) before synovial fluid analyzes have been completed. Treatment: Ciclosporin A can have a good effect on pyoderma gangrenosum in this condition (reference: Kanameichi S, 2016). IL-1 blockers can be tried against arthritis, possibly TNF inhibitors (etanercept). Joint puncture and corticosteroid injections are appropriate for arthritis. Literature: Genovese G, 2020.
PFAPA (Periodic fever, aphthous stomatitis, pharyngitis or adenopathy syndromee)
PFAPA is the most common periodic fever syndrome in children in Norway (FMF, which more often debuts somewhat later, is most common worldwide) (reference: Rigante D, 2009). The cause of the disease is unclear, but familial cases suggest a genetic cause. One assumes that several genes are involved (polygenetic etiology) as opposed to monogenetic in most other autoinflammatory diseases (references: Esposito S, 2014; Stojanov S, 2011). Age of debut: Onset of the disease is before 5 years of age. The symptoms usually regress completely by adulthood. Symptoms: The triad of episodic mouth ulcers (aphthous stomatitis), swollen lymph nodes on the neck (cervical adenitis) and sore throat (pharyngitis) is typical. Periodic fever occurs regularly every 2-6 weeks. The episodes last 3-6 days. Headache and abdominal pain. Growth is not affected. Blood tests shows an increased number of white blood cells, increased CRP, SR and fibrinogen during seizures. Some have elevated immunoglobulin IgD. Genetics: Several genes are thought to be involved. No genetic test available. Treatment: There is no particularly effective treatment. Corticosteroids for short periods may be appropriate, but the risk of side effects limits their use. Colchicine has an effect in some people (reference: Quintana-Ortega C, 2020). H2-blockers in the form of cimetidine should be effective in approx. 30% of patients (reference: Feder H, 1992). A biological drug in the form of an Il-1 inhibitor (anakinra) can be tested. Removal of the tonsils (tonsillectomy) can also be considered. The disease episodes decrease in intensity and number beyond adolescence, but some have symptoms also in adulthood. Literature: Vanoni F, 2016.
SAVI (STING-associated vasculopathy with childhood onset).
- Serious illness from infancy with fever, lung disease, severe vasculitis-inflammation of the skin, especially on the fingers, toes, veins and nose. (ref. : Wang Y, 2021)
Cyclic neutropenia (In children)
Cyclic neutropenia is a blood disease with periodic fever and an autosomal dominant inheritance. Occurrence. New cases (incidence) are 1-2/million/year and incidence (prevalence) 1-9/1. Onset of the disease before the age of two is typical, but an adult form also occurs. Disease cause/genetics. Mutations in the elastase gene (ELA2=ELANE) on chromosome 19p13.3 have been detected. Blood tests: Low neutrophil count. Symptoms and diagnosis. Cyclical fever every 21 days (14-35 days). Duration 5-7 days. Ulcers in the mouth (stomatitis). Gingivitis and sore throat. Complications with bacterial Sepsis and rare infections. Often clostridium septicum. Diagnosis: neutrophils less than 200/microL at least three to five consecutive days per cycle for at least three regular periods. Test for ELANE gene mutation. Prognosis: The disease may return at the age of 30. Similar conditions, differential diagnoses: Idiopathic (autoimmune) neutropenia: Not uncommon with periodic neutrophilia in the 500 – 1000/microL range, but with a chronic benign course. Usually do not have the other symptoms or chronic gingival infection, other autoimmune diseases (TRAPS, Hyper-IgD, FMF), Shwachman syndrome, "Lymphoproliferative disorders of large granular lymphocytes" (LDGL), primary immune immunodeficiency may be raised considered when cyclic neutropenia and hepatosplenomegaly occur. Treatment: Granulocyte colony stimulating factor (G-CSF), Infection treatment. Literature: Newburger PE, 2013 (Neutropenia); Donadieu J, 2011.
TRAPS (Tumor-necrosis factor receptor-associated periodic syndrome)
The condition was previously called Familial Hebernian Fever and is caused by a mutation in the TNFR1 gene (chromosome 12). The condition causes increased levels of inflammatory proteins (proinflammatory cytokines) including IL-1β, TNFα and IL-6. Disease Cause: Autosomal dominant inherited disease that affects children. Occurrence: 1 per million (prevalence). Age of debut: Onset of the disease in early childhood is most common, with a median age of onset of 4,3 years. However, diagnosed approx. 10% of cases in people over 30 years of age, then usually with milder variants of the disease. Symptoms: TRAPS causes recurrent long-term episodes of fever, varying red rash (erythema migrans), abdominal pain (peritonitis), diarrhea or hard stools (constipation), inflammation of large joints), eye inflammation (conjunctivitis, uveitis), swelling around the eyes, muscle pain, leg pain (fasciitis ) chest pain and headache. The episodes come every 4-6 weeks and last 4-21 days. Genetics. The diagnosis can be confirmed by genetic testing of TNFRSF1A genotype. Diagnosis is based on symptoms and examination findings. In research, classification criteria are used Classification criteria Eurofever/PRINO 2019 (reference: Gattorno M, 2019). Treatment: Biological drugs are relevant. TNF inhibitors (etanercept), IL-1 inhibitors (anakinra, canakinumab) or IL-6 inhibitors (tocilizumab) often have an effect so that the disease activity falls, the risk of amyloidosis and progressive organ damage decreases (reference: Cudrici C, 2020).
- Lidar M, 2017
- Ter Haar NM, 2019
- De Jesus AA, 2013
- Grans Compendium in Rheumatology
- The Health Library/Pediatrics supervisor
- You can search for rare diseases via Orphanet (which also has one Norwegian information page)
- More about auto-inflammatory diseases are also found NOMID Alliance (in English)