TNF receptor associated periodic syndrome (also known as TRAPS,) is a periodic fever syndrome associated with mutations in a receptor for the molecule tumor necrosis factor (TNF) that is inheritable in an autosomal dominant manner. Individuals with TRAPS have episodic symptoms such as recurrent high fevers, rash, abdominal pain, joint/muscle aches and puffy eyes.

TNF receptor associated periodic syndrome is autosomal dominant, and about 70 mutations of the TNFRSF1A gene have been linked to this condition. Its cytogenetic location is at 12p13.31

It is not known how mevalonate kinase mutations cause the febrile episodes, although it is presumed that other products of the cholesterol biosynthesis pathyway, the prenylation chains (geranylgeraniol and farnesol) might play a role.

Periodic fever syndromes (also known as autoinflammatory diseases or autoinflammatory syndromes) are a set of disorders characterized by recurrent episodes of systemic and organ-specific inflammation. Unlike autoimmune disorders such as systemic lupus erythematosus, in which the disease is caused by abnormalities of the adaptive immune system, patients with autoinflammatory diseases do not produce autoantibodies or antigen-specific T or B cells. Instead, the autoinflammatory diseases are characterized by errors in the innate immune system.

The syndromes are diverse, but tend to cause episodes of fever, joint pains, skin rashes, abdominal pains and may lead to chronic complications such as amyloidosis.

Most autoinflammatory diseases are genetic and present during childhood. The most common genetic autoinflammatory syndrome is familial Mediterranean fever, which causes short episodes of fever, abdominal pain, serositis, lasting less than 72 hours. It is caused by mutations in the MEFV gene, which codes for the protein pyrin.

Pyrin is a protein normally present in the inflammasome. The mutated pyrin protein is thought to cause inappropriate activation of the inflammasome, leading to release of the pro-inflammatory cytokine IL-1β. Most other autoinflammatory diseases also cause disease by inappropriate release of IL-1β. Thus, IL-1β has become a common therapeutic target, and medications such as anakinra, rilonacept, and canakinumab have revolutionized the treatment of autoinflammatory diseases.

However, there are some autoinflammatory diseases that are not known to have a clear genetic cause. This includes PFAPA, which is the most common autoinflammatory disease seen in children, characterized by episodes of fever, aphthous stomatitis, pharyngitis, and cervical adenitis. Other autoinflammatory diseases that do not have clear genetic causes include adult-onset Still's disease, systemic-onset juvenile idiopathic arthritis, Schnitzler syndrome, and chronic recurrent multifocal osteomyelitis. It is likely that these diseases are multifactorial, with genes that make people susceptible to these diseases, but they require an additional environmental factor to trigger the disease.

Another example that shows that autoinflamatory conditions may not be genetic in origin is found in a report published in "Nature" which shows that diet is very important in the development of such diseases. The ingestion levels of highly saturated fats and cholesterol, (high fat diet, HFD) affects the microbiota composition of the gut. Changes in the microbiota induced by a HFD are protective against the susceptibility to develop osteomyelitis (autoimmune disease) as compared with the changes induced by a low-fat diet. The changes in the microbiome of individuals under HFD showed a reduction in "Prevotella" abundance and were accompanied by significantly reduced expression levels of pro-Interleukin-1β in distant neutrophils.

The chronic inflammation present in MWS over time can lead to deafness. In addition, the prolonged inflammation can lead to deposition of proteins in the kidney, a condition known as amyloidosis.

Virtually all people with the syndrome have mutations in the gene for mevalonate kinase, which is part of the HMG-CoA reductase pathway, an important cellular metabolic pathway. Indeed, similar fever attacks (but normal IgD) have been described in patients with mevalonic aciduria – an inborn error of metabolism now seen as a severe form of HIDS.

MWS occurs when a mutation in the "CIAS1" gene, encoding for NLRP3, leads to increased activity of the protein cryopyrin. This protein is partly responsible for the body's response to damage or infection. During these states, a cytokine called interleukin 1β is produced by an innate immune cell known as a macrophage. This cytokine interacts with a receptor on the surface of other immune cells to produce symptoms of inflammation such as fever, arthritis, and malaise. In MWS, the increased activity of cryopyrin leads to an increase in interleukin 1β. This leads to inflammation all throughout the body with the associated symptoms.

Cryopyrin-associated periodic syndrome (CAPS) is a group of rare, heterogeneous autoinflammatory disease characterized by interleukin 1β-mediated systemic inflammation and clinical symptoms involving skin, joints, central nervous system, and eyes. It encompasses a spectrum of three clinically overlapping autoinflammatory syndromes including familial cold autoinflammatory syndrome (FCAS, formerly termed familial cold-induced urticaria), the Muckle–Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID, also called chronic infantile neurologic cutaneous and articular syndrome or CINCA) that were originally thought to be distinct entities, but in fact share a single genetic mutation and pathogenic pathway.

This is a rare condition with an incidence estimated to be less than 1 in a million live births. About 100 cases have been reported worldwide. The bulk of cases are sporadic but familial forms with autosomal dominant transmission have also been described.

Overall, the prognosis for patients with NOMID is not good, though many (80%) live into adulthood, and a few appear to do relatively well. They are at risk for leukemia, infections, and some develop deposits of protein aggregated called amyloid, which can lead to kidney failure and other problems. The neurologic problems are most troubling. The finding that other diseases are related and a better understanding of where the disease comes from may lead to more effective treatments.

The syndromes within CAPS overlap clinically, and patients may have features of more than one disorder. In a retrospective cohort of 136 CAPS patients from 16 countries, the most prevalent clinical features were fever (84% of cases, often with concurrent constitutional symptoms such as fatigue, malaise, mood disorders or failure to thrive), skin rash (either urticarial or maculopapular rash; 97% of cases) especially after cold exposure, and musculoskeletal involvement (myalgia, arthralgia, and/or arthritis, or less commonly joint contracture, patellar overgrowth, bone deformity, bone erosion and/or osteolytic lesion; 86% of cases). Less common features included ophthalmological involvement (conjunctivitis and/or uveitis, or less commonly optic nerve atrophy, cataract, glaucoma or impaired vision; 71% of cases), neurosensory hearing loss (42% of cases), neurological involvement (morning headache, papilloedema, and/or meningitis, or less commonly seizure, hydrocephalus or mental retardation; 40% of cases), and AA amyloidosis (4% of cases). Age of onset is typically in infancy or early childhood. In 57% of cases, CAPS had a chronic phenotype with symptoms present almost daily, whereas the remaining 43% of patients experienced only acute episodes. Up to 56% of patients reported a family history of CAPS. Previous studies confirm these symptoms, although the exact reported rates vary.

Familial dysautonomia is seen almost exclusively in Ashkenazi Jews and is inherited in an autosomal recessive fashion. Both parents must be carriers in order for a child to be affected. The carrier frequency in Jewish individuals of Eastern European (Ashkenazi) ancestry is about 1/30, while the carrier frequency in non-Jewish individuals is unknown. If both parents are carriers, there is a one in four, or 25%, chance with each pregnancy for an affected child. Genetic counseling and genetic testing is recommended for families who may be carriers of familial dysautonomia.

Worldwide, there have been approximately 600 diagnoses recorded since discovery of the disease, with approximately 350 of them still living.

According to present research, PFAPA does not lead to other diseases and spontaneously resolves as the child gets older, with no long term physical effects.

However, PFAPA has been found in adults and may not spontaneously resolve.

FMF affects groups of people originating from around the Mediterranean Sea (hence its name). It is prominently present in the Armenians, Sephardi Jews (and, to a much lesser extent, Ashkenazi Jews), Cypriots and Arabs.

CRMO was once considered strictly a childhood disease, but adults have been diagnosed with it. The affected tends to range from 4 to 14 years old, with 10 as the median age. As stated above, CRMO occurs 1:1,000,000 and primarily in girls with a 5:1 ratio. That means out of six million, there will probably be 5 girls and 1 boy with the condition.

Due to its inflammatory nature, its recurrent outbreaks, and its lack of any known pathogen, CRMO has been reclassified as an autoinflammatory disease. This particular classification encompasses both hereditary types (familial Mediterranean fever, mevalonate kinase deficiency, TNF receptor associated periodic syndrome, cryopyrin-associated periodic syndrome, Blau syndrome, pyogenic sterile arthritis, pyoderma gangrenosum and acne syndrome, CRMO) and multifactorial disorders (Crohn's and Behçet's diseases). CRMO is no longer considered an autoimmune but rather an inherited, autoinflammatory disease.

Periodic fever, aphthous stomatitis, pharyngitis and adenitis or periodic fever aphthous pharyngitis and cervical adenopathy (PFAPA) syndrome is a medical condition, typically starting in young children, in which high fever occurs periodically at intervals of about 3–5 weeks, frequently accompanied by aphthous-like ulcers, pharyngitis and/or cervical adenitis (cervical lymphadenopathy). The syndrome was described in 1987 and named two years later.

Familial Mediterranean fever (FMF) is a hereditary inflammatory disorder. FMF is an autoinflammatory disease caused by mutations in Mediterranean fever gene, which encodes a 781–amino acid protein called pyrin. While all ethnic groups are susceptible to FMF, it "usually occurs in people of Mediterranean origin—including Sephardic Jews, Mizrahi Jews, Armenians, Azerbaijanis, Arabs, Greeks, Turks and Italians".

The disorder has been given various names, including familial paroxysmal polyserositis, periodic peritonitis, recurrent polyserositis, benign paroxysmal peritonitis, periodic disease or periodic fever, Reimann periodic disease or Reimann's syndrome, Siegal-Cattan-Mamou disease, and Wolff periodic disease. Note that "periodic fever" can also refer to any of the periodic fever syndromes.

This disease is more common in women and an association with the gene FLT4 has been described. FLT4 codes for VEGFR-3, which is implicated in development of the lymphatic system.

Milroy's disease is also known as primary or hereditary lymphedema type 1A or early onset lymphedema.

It is a very rare disease with only about 200 cases reported in the medical literature. Milroy's disease is an autosomal dominant condition caused by a mutation in the FLT4 gene which encodes of the vascular endothelial growth factor receptor 3 (VEGFR-3) gene located on the long arm (q) on chromosome 5 (5q35.3).

In contrast to Milroy's disease (early onset lymphedema type 1A,) which typically has its onset of swelling and edema at birth or during early infancy, hereditary lymphedema type II, known as Meige disease, has its onset around the time of puberty. Meige disease is also an autosomal dominant disease. It has been linked to a mutations in the ‘forkhead’ family transcription factor (FOXC2) gene located on the long arm of chromosome 16 (16q24.3). About 2000 cases have been identified. A third type of hereditary lymphedema, that has an onset after the age of 35 is known as lymph-edema tarda.

RHBDF2 may also play a role in ovarian epithelial cancer.

Possible associations with gastric cancer and lung cancer have been suggested. Other possible associations include corneal defects, congenital pulmonary stenosis, total anomalous pulmonary venous connection deafness and optic atrophy.

This condition is inherited as an autosomal dominant syndrome and characterized by palmoplantar keratoderma, oral precursor lesions particularly on the gums (leukoplakia) and a high lifetime risk of esophageal cancer (95% develop esophageal cancer by the age of 65). Relapsing cutaneous horns of the lips has been reported in this condition.

There are several types of this condition have been described – epidermolytic (Vörner type) and non-epidermolytic. Another classification divides these into an early onset type (type B) which occurs in the first year of life and is usually benign and a type A tylosis which occurs between the ages of 5 and 15 years and is strongly associated with esophageal cancer.

Cytoglobin gene expression in oesphageal biopsies is significantly reduced (70% reduction) in this condition. The mechanism of this change is not known.

The prognosis is guarded with an overall mortality of 50%. Poor prognostic factors included HLH associated with malignancy, with half the patients dying by 1.4 months compared to 22.8 months for non-tumour associated HLH patients.

Secondary HLH in some individuals may be self-limited because patients are able to fully recover after having received only supportive medical treatment (i.e., IV immunoglobulin only). However, long-term remission without the use of cytotoxic and immune-suppressive therapies is unlikely in the majority of adults with HLH and in those with involvement of the central nervous system (brain and/or spinal cord).

PAPA syndrome is inherited in an autosomal dominant fashion, which means that if one parent is affected, there is a 100% chance that a child will inherit the disease from a homozygous affected parent and a 50% chance that a

child will inherit the disease from an affected heterozygous parent.

Recently the responsible gene has been identified on Chromosome 15. Two mutations have been found in a protein called CD2 binding protein 1 (CD2BP1).

This protein is part of an inflammatory pathway associated with other autoinflammatory diseases such as familial Mediterranean fever, Hyperimmunoglobulinemia D with recurrent fever, Muckle–Wells syndrome, neonatal onset multisystem inflammatory disease, and familial cold urticaria.

Hereditary gelsolin amyloidosis is a cutaneous condition inherited in an autosomal dominant fashion.

The condition was first described in 1969, by the Finnish ophthalmologist Jouko Meretoja, and is also known as Familial amyloid neuropathy type IV, Meretoja syndrome, Hereditary amyloidosis, Finnish type.

The disorder primarily associated with eye, skin and cranial nerve symptoms. It is a form of amyloidosis, where the amyloid complexes are formed from fragments of the protein gelsolin in the plasma, due to a mutation in the GSN gene (c.654G>A or c.654G>T).

PAPA syndrome is an acronym for pyogenic arthritis, pyoderma gangrenosum and acne. It is a rare genetic disorder characterised by its effects on skin and joints.