The most prominent symptoms of erythromelalgia are episodes of erythema, swelling, a painful deep-aching of the soft tissue (usually either radiating or shooting) and tenderness, along with a painful burning sensation primarily in the extremities. These symptoms are often symmetric and affect the lower extremities more frequently than the upper extremities. Symptoms may also affect the ears and face. For secondary erythromelalgia, attacks typically precede and are precipitated by the underlying primary condition. For primary erythromelalgia, attacks can last from an hour to months at a time and occur infrequently to frequently with multiple times daily. Common triggers for these episodes are exertion, heating of the affected extremities, and alcohol or caffeine consumption, and any pressure applied to the limbs. In some patients sugar and even melon consumption have also been known to provoke attacks. Many of those with primary erythromelalgia avoid wearing shoes or socks as the heat this generates is known to produce erythromelalgia attacks. Raynaud's phenomenon often coexists in patients with Erythromelalgia. Symptoms may present gradually and incrementally, sometimes taking years to become intense enough for patients to seek medical care. In other cases symptoms emerge full blown with onset.

The symptoms of Freeman–Sheldon syndrome include drooping of the upper eyelids, strabismus, low-set ears, a long philtrum, gradual hearing loss, scoliosis, and walking difficulties. Gastroesophageal reflux has been noted during infancy, but usually improves with age. The tongue may be small, and the limited movement of the soft palate may cause nasal speech. Often there is an H- or Y-shaped dimpling of the skin over the chin.

Erythromelalgia can be found in several billing codes systems and other systems. Erythromelalgia is generally classified as a disease of the circulatory system, falling under the class of "other peripheral vascular disease", as the following two billing code systems will show:

ICD-9-CM

According to the ICD-9-CM database (International Classification of Diseases, Ninth Revision, Clinical Modification), Erythromelalgia is listed under Diseases of the Circulatory System and is identified by number 443.82.

ICD-9-CM Diagnosis Codes > Diseases of the circulatory system (390-459) > Diseases of arteries, arterioles, and capillaries (440-449) > Other peripheral vascular disease (443) > Other specified peripheral vascular disease (443.8) > Erythromelalgia (443.82).

ICD-10-CM

According to the ICD-10-CM database (International Classification of Diseases, Tenth Revision, Clinical Modification), Erythromelalgia is listed under Diseases of the circulatory system and is identified by I73.81.

ICD-10-CM Diagnosis Codes > Diseases of the circulatory system (I00-I99) > Diseases of arteries, arterioles and capillaries (I70-I79) > Other peripheral vascular diseases (173-9) > Erythromelalgia (I73.81)

Mesh

According to the MESH database (Medical Subject Headings), Erythromelalgia is classified under the unique ID number of D004916.

OMIM

According to the OMIM database (NCBI - Online Mendelian Inheritance in Man), Primary Erythromelalgia is listed under the number: 133020.

Freeman–Sheldon syndrome (FSS), also termed distal arthrogryposis type 2A (DA2A), craniocarpotarsal dysplasia (or dystrophy), Cranio-carpo-tarsal syndrome, Windmill-Vane-Hand syndrome, or Whistling-face syndrome, was originally described by Freeman and Sheldon in 1938. Freeman–Sheldon syndrome is a rare form of multiple congenital contracture (MCC) syndromes (arthrogryposes) and is the most severe form of distal arthrogryposis (DA).

Typically, episodic ataxia presents as bouts of ataxia induced by startle, stress, or exertion. Some patients also have continuous tremors of various motor groups, known as myokymia. Other patients have nystagmus, vertigo, tinnitus, diplopia or seizures.

The familial amyloid neuropathies (or familial amyloidotic neuropathies, neuropathic heredofamilial amyloidosis, familial amyloid polyneuropathy) are a rare group of autosomal dominant diseases wherein the autonomic nervous system and/or other nerves are compromised by protein aggregation and/or amyloid fibril formation.

Polyps are most frequent in the stomach and large intestine, are also found in the small intestine, and are least frequent in the esophagus. A biopsy will reveal them to be hamartomas; the possibility that they progress to cancer is generally considered to be low, although it has been reported multiple times in the past. Chronic diarrhea and protein-losing enteropathy are often observed. Possible collateral features include variable anomalies of ectodermal tissues, such as alopecia, atrophy of the nails, or skin pigmentation

The ICHD classification and diagnosis of migraine distinguish 6 subtypes of hemiplegic migraine. FHM can be loosely divided into two categories: with and without cerebellar signs. Cerebellar signs refer to ataxia, sometimes episodic and other times progressive, that can accompany FHM1 mutations and is caused by degeneration of the cerebellum. These cerebellar signs result in a phenotypic overlap between FHM and both episodic ataxia and spinocerebellar ataxia. This is unsurprising as subtypes of these disorders (FHM1, EA2 and SCA6) are allelic, i.e., they result from mutations in the same gene. The other forms of FHM seem to be distinguishable only on the basis of their genetic cause.

Hemiplegic migraine or Hemiplegic migraine headache is a rare and serious subtype of classical migraine that typically includes weakness of half the body which can last for hours, days or weeks. It can be accompanied by other symptoms, such as ataxia, coma and paralysis.

Episodic ataxia (EA) is an autosomal dominant disorder characterized by sporadic bouts of ataxia (severe discoordination) with or without myokymia (continuous muscle movement). There are seven types recognised but the majority are due to two recognized entities. Ataxia can be provoked by stress, startle, or heavy exertion such as exercise. Symptoms can first appear in infancy. There are at least 6 loci for EA, of which 4 are known genes. Some patients with EA also have migraine or progressive cerebellar degenerative disorders, symptomatic of either familial hemiplegic migraine or spinocerebellar ataxia. Some patients respond to acetazolamide though others do not.

Idiopathic scrotal calcinosis (also known as idiopathic calcified nodules of the scrotum) is a cutaneous condition characterized by calcification of the skin resulting from the deposition of calcium and phosphorus occurring on the scrotum. However, the levels of calcium and phosphate in the blood are normal. Idiopathic scrotal calcinosis typically affects young males, with an onset between adolescence and early adulthood. The scrotal calcinosis appears, without any symptoms, as yellowish nodules that range in size from 1 mm to several centimeters.

PDP has a number of visible symptoms. Most important clinical features are: pachydermia (thickening and wrinkling of the skin), furrowing of the face and scalp, periostosis (swelling of periarticular tissue and shaggy periosteal new bone formation of long bones) and digital clubbing (enlargement of fingertips). Other features include excessive sweating, arthralgia and gastrointestinal abnormalities. An overview of all symptoms is provided in table 2.

Table 2. Overview of symptoms

The cause is not well defined. Originally considered idiopathic condition. Now accepted that majority of cases develop from dystrophic calcification of cyst contents.

The aggregation of one precursor protein leads to peripheral neuropathy and/or autonomic nervous system dysfunction. These proteins include: transthyretin (ATTR, the most commonly implicated protein), apolipoprotein A1, and gelsolin.

Due to the rareness of the other types of familial neuropathies, transthyretin amyloidogenesis-associated polyneuropathy should probably be considered first.

"FAP-I" and "FAP-II" are associated with transthyretin. (Senile systemic amyloidosis [abbreviated "SSA"] is also associated with transthyretin aggregation.)

"FAP-III" is also known as "Iowa-type", and involves apolipoprotein A1.

"FAP-IV" is also known as "Finnish-type", and involves gelsolin.

Fibrinogen, apolipoprotein A1, and lysozyme are associated with a closely related condition, familial visceral amyloidosis.

Acquired generalized lipodystrophy (also known as "Lawrence syndrome," and "Lawrence–Seip syndrome", abbreviation: AGL) is a rare skin condition that appears during childhood or adolescence, characterized by fat loss affecting large areas of the body, particularly the face, arms, and legs. There are 4 types of lipodystrophy based on its onset and areas affected: acquired or inherited (congenital or familial), and generalized or partial. Both acquired or inherited lipodystrophy present as loss of adipose tissues. The near-total loss of subcutaneous adipose tissue is termed generalized lipodystrophy while the selective loss of adipose tissues is denoted as partial lipodystrophy. Thus, as the name suggests, AGL is a near-total deficiency of adipose tissues in the body that is developed later in life. It is an extremely rare disease that only about 100 cases are reported worldwide. There are three main etiologies of AGL suspected: autoimmune, panniculitis-associated, or idiopathic. After its onset, the disease progresses over a few days, weeks, months, or even in years. Clinical presentations of AGL are similar to other lipodystrophies, including metabolic complications and hypoleptinemia. Treatments are also similar and mainly supportive for symptomatic alleviation. Although HIV- or drug-induced lipodystrophy are a type of acquired lipodystrophy, its origin is very specific and distinct hence is usually not discussed with AGL (see HIV-Associated Lipodystrophy).

HP is characterised by attacks of epigastric pain, which are often associated with nausea and vomiting. Symptoms may start shortly after birth but onset varies periodically, with some patients not exhibiting symptoms until adulthood. There is usually progression to chronic pancreatitis with endocrine and exocrine failure and a mortally increased risk of pancreatic cancer. Lifetime risk of cancer has been variously calculated as 35–54% to the age of 75 years and screening for early pancreatic cancer is being offered to HP sufferers on a scientific basis. Some patients may choose to have their pancreas surgically removed to prevent pancreatic cancer from developing in the future.

The epidemiology of HP follows a similar pattern to alcohol-associated chronic pancreatitis, but there are important differences. For example, HP typically has an earlier age of pancreatitis onset; although malabsorption and diabetes mellitus occur at a later stage in the disease progression.

Cronkhite–Canada syndrome is a rare syndrome characterized by multiple polyps of the digestive tract. It is sporadic (i.e. it does not seem to be a hereditary disease), and it is currently considered acquired and idiopathic (i.e. cause remains unknown).

About two-thirds of patients are of Japanese descent and the male to female ratio is 2:1. It was characterized in 1955.

Pachydermoperiostosis (PDP) or primary hypertrophic osteoarthropathy (PHO) is a rare genetic disorder that affects both bones and skin. Other names are idiopathic hypertrophic osteoarthropathy or Touraine-Solente-Golé syndrome. It is mainly characterized by pachydermia (thickening of the skin), periostosis (excessive bone formation) and finger clubbing (swelling of tissue with loss of normal angle between nail and nail bed).

This disease affects relatively more men than women. After onset, the disease stabilizes after about 5–20 years. Life of PDP patients can be severely impaired. Currently, symptomatic treatments are NSAIDs and steroids or surgical procedures.

In 1868, PDP was first described by Friedreich as ‘excessive growth of bone of the entire skeleton’. Touraine, Solente and Golé described PDP as the primary form of bone disease hypertrophic osteoarthropathy in 1935 and distinguished its three known forms.

There is no known cause for this disease; however, three origins of AGL are generally suspected: panniculitis-associated, autoimmune-associated, and idiopathic AGLs. Triggers may include infections that aggravate the panniculitis, or any disease state that can induce autoimmunity. Overlap between panniculitis and autoimmune types also exists. Another theory suggest that AGL is an autoimmune disease itself, as panniculitis can be described as an autoimmune disease, however its triggering factors remains to be unknown. Underlying genetic factor may be associated; however neither confirmed nor rejected.

Benign familial infantile epilepsy (BFIE), also known as benign familial infantile seizures (BFIS) or benign familial infantile convulsions (BFIC) is an epilepsy syndrome. Affected children, who have no other health or developmental problems, develop seizures during infancy. These seizures have focal origin within the brain but may then spread to become generalised seizures. The seizures may occur several times a day, often grouped in clusters over one to three days followed by a gap of one to three months. Treatment with anticonvulsant drugs is not necessary but they are often prescribed and are effective at controlling the seizures. This form of epilepsy resolves after one or two years, and appears to be completely benign. The EEG of these children, between seizures, is normal. The brain appears normal on MRI scan.

A family history of epilepsy in infancy distinguishes this syndrome from the non-familial classification (see benign infantile epilepsy), though the latter may be simply sporadic cases of the same genetic mutations. The condition is inherited with an autosomal dominant transmission. There are several genes responsible for this syndrome, on chromosomes 2, 16 and 19. It is generally described as idiopathic, meaning that no other neurological condition is associated with it or causes it. However, there are some forms that are linked to neurological conditions. One variant known as infantile convulsions and choreoathetosis (ICCA) forms an association between BFIE and paroxysmal kinesigenic choreoathetosis and has been linked to the PRRT2 gene on chromosome 16. An association with some forms of familial hemiplegic migraine (FHM) has also been found. Benign familial infantile epilepsy is not genetically related to benign familial neonatal epilepsy (BFNE), which occurs in neonates. However, a variation with seizure onset between two days and seven months called "benign familial neonatal–infantile seizures" (BFNIS) has been described, which is due to a mutation in the SCN2A gene.

Café au lait spots are usually present at birth, permanent, and may grow in size or increase in number over time.

Cafe au lait spots are themselves benign and do not cause any illness or problems. However, they may be associated with syndromes such as Neurofibromatosis Type 1 and McCune-Albright syndrome.

The size and shape of the spots do not have any meaning or implications with regards to diagnosis of associated syndromes.

Hereditary pancreatitis (HP) is an inflammation of the pancreas, attributed to genetic causes. It was first described in 1952 by Comfort and Steinberg but it was not until 1996 that Whitcomb "et al" isolated the first responsible mutation in the trypsinogen gene ("PRSS1") on the long arm of chromosome seven ("7q35").

The term "hereditary pancreatitis" is used when a genetic biomarker is identified, and "familial pancreatitis" otherwise.

Diagnosis is visual with measurement of spot size. The number of spots can have clinical significance for diagnosis of associated disorders such as Neurofibromatosis type I. Greater than or equal to 6 spots of at least 5mm in diameter in pre-pubertal children and at least 15mm in post-pubertal individuals is one of the major diagnostic criteria for NF1.

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.

In the early stages, it can be difficult to distinguish progressive myoclonic epilepsy from benign idiopathic generalised epilepsies, such as juvenile myoclonic epilepsy. With PME, the initial effectiveness of anticonvulsant treatment diminishes as seizures become more frequent and neurological decline progresses. However, these can also be signs of anticonvulsant intoxication. The myoclonus in PME is usually severe and is the prominent seizure type.