Ehlers-Danlos syndrome

EDS can be inherited as a dominant or recessive genetic condition. Human traits are the product of the interaction between two genes. Genes are received in sets of two, one from the father and another from the mother.

Signs and symptoms of EDS may become apparent during childhood. However, depending upon the form and severity, age of diagnosis varies widely. Reported estimates for the incidence of all EDS types range from 1/ 2,500 to 1/5,000 births. hEDS is estimated to affect 1/10,000-1/15,000. cEDS is estimated to affect 1/20,000-1/40,0000. Because those with mild joint and skin manifestations may not seek medical attention they remain undiagnosed and it is difficult to determine the true frequency of EDS mutations in the general population. hEDS, clEDS, and vEDS are most common subtypes. Other subtypes (kEDS, aEDS, and dEDS) are much less common. Only about 60 individuals with kEDS have been identified. Only about 30 patients with aEDS have been reported. Only about 12 patients of dEDS have been described. Some named variants of EDS (e.g. X type or dysfibronectinemic type) have only been identified and reported in single individuals within one affected family.

Several disorders closely mimic EDS in clinical presentation. The following is a non-exhaustive list of conditions that may be considered in the differential diagnosis of a patient’s presentation.

EDS is generally diagnosed based on patient history and clinical findings. Genetic testing can facilitate the diagnosis of some subtypes. Electron microscopic analysis of tissue samples can also sometimes reveal characteristic abnormalities in collagen structure seen in EDS.


Eisenmenger Syndrome

The specific symptoms of Eisenmenger syndrome vary greatly from person to person. Although the heart defect is present at birth, Eisenmenger syndrome with cyanosis often develops around puberty, but may develop earlier or later depending on the location and severity of the congenital heart defect. The symptoms and complications result from a combination of the effects of the heart defect, reduced oxygen in the blood and high pressures in the lungs.

Specific genes that cause Eisenmenger syndrome have not been identified and the condition is not thought to be inherited.

Eisenmenger syndrome appears to affect males and females in relatively equal numbers. Individuals with Down syndrome represent between 25-50% of the adult Eisenmenger population.

Eisenmenger syndrome belongs to a group of conditions called pulmonary arterial hypertension (PAH) and also includes idiopathic PAH, PAH related to connective tissue diseases etc. It is a rare, progressive disorder, characterized by pulmonary vascular disease and high blood pressure (hypertension) in the arteries of the lungs (pulmonary artery), often for no apparent reason (idiopathic). The pulmonary arteries are the blood vessels that carry blood from the right side of the heart through the lungs. Symptoms of PAH include shortness of breath (dyspnea), especially during exercise, fatigue, chest pain, and fainting episodes. The exact cause of PAH is unknown and although it is treatable, there is no known cure for this condition. Idiopathic PAH usually affects women between the ages of 30-60 years. Individuals with PAH may remain undiagnosed for years because their symptoms are initially mild and nonspecific, resembling other conditions such as asthma. It is important to treat PAH as early as possible, to avoid heart failure. The progressive nature of this disease means that an individual may experience only mild symptoms at first, but will eventually require treatment and medical care to maintain a reasonable quality of life. PAH remains life threatening despite treatment.

The diagnosis of Eisenmenger syndrome is not particularly complex but may require cardiac catheterization, an invasive procedure to measure pressures in the heart and lungs. Other tests include pulse oximetry, which checks oxygen levels in the blood, chest x-ray, EKG, pulmonary function test, iron levels and complete blood count (CBC). Echocardiography is fundamental in identifying the heart defect and raising the suspicion of high pressures in the lungs. Other imaging modalities (e.g. cardiac MRI) can provide valuable anatomic information.


Elephantiasis

Elephantiasis is a condition characterized by gross enlargement of an area of the body, especially the limbs. Other areas commonly affected include the external genitals. Elephantiasis is caused by obstruction of the lymphatic system, which results in the accumulation of a fluid called lymph in the affected areas.

The initial symptom of lymphatic dysfunction is a mild edema, which can gradually progress to elephantiasis if not treated.

Elephantiasis is caused by under-treatment of lymphedema, and due to the obstruction of the lymph vessels of the lymphatic system. As lymph moves through the lymphatic system, it is filtered by a network of small structures known as lymph nodes that help to remove microorganisms (e.g., viruses, bacteria, etc.) and other foreign bodies. Groups of lymph nodes are located throughout the body, including in the neck, under the arms (axillae), at the elbows, and in the chest, abdomen, and groin. In addition to the lymph nodes, the lymphatic system includes the spleen, which filters worn-out red blood cells and produces lymphocytes, and the tonsils, which are masses of lymphoid tissue in the throat region that help to fight infection. Lymphatic tissues also include the thymus, a relatively small organ behind the breastbone that is thought to play an important role in the immune system until puberty, as well as the bone marrow, which is the spongy tissue inside the cavities of bones that manufactures blood cells. Lymphatic tissue may also be located in other regions of the body, such as the skin, small intestine, liver, and other organs.

Elephantiasis is present worldwide, but with greater frequency in poor third world regions,  including Southeast Asia, India, Africa and South America, and not only as a manifestation of lymphatic filariasis.

Symptoms of the following disorders can be similar to those of elephantiasis. Comparisons may be useful for a differential diagnosis.

A diagnosis of elephantiasis is made based upon a thorough clinical evaluation, a detailed patient history and identification of characteristic symptoms. A variety of tests may be used to determine the underlying cause of lymphatic damage and subsequent elephantiasis.


Ellis Van Creveld syndrome

Ellis-Van Creveld syndrome is a rare genetic disorder that is mainly characterized by short limb dwarfism, additional fingers and/or toes (polydactyly), abnormal development of fingernails and, in over half of the patients, congenital heart defects. Nearly 50% of patients die by 18 months of age from cardiopulmonary complications. Motor development and intelligence are usually normal. This disorder is caused by variants in several different genes including the EVC1 and EVC2 genes and occasionally the DYNC2LI1, GLI1, WDR35, PRKACA, PRKACB and SMO genes. Inheritance is autosomal recessive. Treatment is symptom-specific and generally requires a team of medical professionals.

Individuals with Ellis-Van Creveld syndrome typically have arms and legs that are abnormally short while the head and trunk are normal. Shortened length between the neck and abdomen and a narrow chest may occur. Extra fingers (polydactyly) are present in all patients with this condition and both hands are usually affected. Abnormal development (dysplasia) of fingernails, toenails, hair, teeth and inner lining of the mouth (oral mucosa) may occur.

Ellis-Van Creveld syndrome is caused by disease-causing variants mainly in two genes called EVC1 and EVC2. These gene variants result in the production of abnormally small EVC1 and EVC2 proteins. While the exact function of these proteins is unclear, they are found on the cilia of the cell and ultimately assist in the proper development of body parts including bones and teeth. Some affected individuals do not have variants in these genes, and it is likely that variants in other genes (DYNC2LI1, GLI1, WDR35, PRKACA, PRKACB and SMO) also cause the condition. The DYNC2LI1 gene encodes a protein that assists in neurotransmitter release and provides architectural support for neurons. The GLI1 gene is a transcriptional regulator involved in the development of different types of cancer. The WDR35, PRKACA, PRKACB, and SMO genes provide instructions for making proteins that are involved in the formation and maintenance of cilia (microscopic, finger-like projections that stick out from the surface of cells).

Ellis-Van Creveld syndrome occurs in many ethnic groups throughout the world and affects males and females equally. This condition has been reported in approximately 150 individuals. It is more common in the Old Order Amish population of Lancaster County, Pennsylvania and in the native population of Western Australia.

Ellis Van-Creveld syndrome is part of a category of rare skeletal disorders called short rib-polydactyly syndromes, belonging to the ciliopathies group.

Ellis-Van-Creveld syndrome is diagnosed by the observation of short stature, slow growth, skeletal abnormalities and dental malformations determined by imaging techniques and sometimes teeth present at birth (natal teeth). Molecular genetic testing for the EVC1, EVC2, GLI1, DYNC2LI1, WDR35, PRKACA, PRKACB, and SMO genes is available on a research basis only. Prenatal diagnosis is possible by ultrasound.


Emery-Dreifuss muscular dystrophy

The age of onset, severity, and progression of EDMD varies greatly from case to case, even among individuals of the same family. Some affected individuals may experience childhood onset with rapid disease progression and severe complications; others may experience adult onset and a slowly progressive course.

In most cases, EDMD is inherited as an X-linked recessive trait. EDMD may also be inherited as an autosomal dominant trait. Autosomal recessive inheritance is extremely rare, but has been reported in at least one family. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.

The overall prevalence of EDMD is unknown. The X-linked form is estimated to affect 1 in 100,000 people in the general population. EDMD is believed to be the third most common form of muscular dystrophy. X-linked EDMD is fully expressed in males only. Approximately 10-20 percent of female carriers for X-linked EDMD will develop heart conduction defects and/or muscle weakness. The autosomal dominant and recessive forms of EDMD affect males and females in equal numbers.

Symptoms of the following disorders can be similar to those of EDMD. Comparisons may be useful for a differential diagnosis.

A diagnosis of X-linked EDMD is based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic symptoms (contractures, myopathy, heart defects, etc.), surgical removal and microscopic study (biopsy) of affected tissue, and specialized tests such as immunodetection and molecular genetic testing.


Emphysema, Congenital Lobar

Congenital lobar emphysema is a rare respiratory disorder in which air can enter the lungs but cannot escape, causing overinflation (hyperinflation) of the lobes of the lung. It is most often detected in newborns or young infants, but some cases do not become apparent until adulthood. This disorder may be severe enough to cause associated heart problems (15% of cases) or so mild as to never become apparent. Some cases of congenital lobar emphysema may be caused by autosomal dominant inheritance while others occur for no apparent reason (sporadic).

Congenital lobar emphysema is characterized by  (1) difficulty in breathing or very rapid respiration (respiratory distress) in infancy, (2) an enlarged chest due to overinflation of at least one lobe of the lung, (3) compressed normal lung tissue in the section of the lung nearest to the diseased lobe, (4) bluish color of the skin due to a lack of oxygen in the blood (cyanosis), and (5) underdevelopment of the cartilage that supports the bronchial tube (bronchial hypoplasia).

Congenital lobar emphysema may result from unknown causes or it may be inherited.  Many cases are sporadic, (unknown causes) but others are transmitted by autosomal dominant genes.

About 50% of cases occur in the first four weeks after birth.  About 75% of cases are found in infants less than six months of age.  This disorder is more common among boys than among girls.

Symptoms of the following disorders can be similar to those of Congenital Lobar Emphysema.  Comparisons may be useful for a differential diagnosis:

Respiratory Distress Syndrome of the Infant, also called Hyaline Membrane Disease of the Newborn, is characterized by respiratory distress seen especially in premature babies.  A clear membrane is found lining the sack like spaces (alveolar) in the lungs and is associated with reduced amounts of lung wetting agents or emulsifier (surfactant).  The surfactant is a lipoprotein that stabilizes alveolar volume.  When this surfactant is missing the affected infant must be placed on some type of ventilator.  Recently new drugs have become available to aid the infant in breathing;  Surfactant TA and Human Surf.  (For more information on this disorder, choose Infant Respiratory Distress Syndrome as your search term in the Rare Disease Database.)


Empty Sella Syndrome

空泡蝶鞍综合征所致垂体缺陷

Empty sella syndrome is a rare disorder characterized by enlargement or malformation of a structure in the skull known as the sella turcica. The sella turcica is a saddle-shaped depression located in the bone at the base of skull (sphenoid bone), in which resides the pituitary gland. In empty sella syndrome, the sella turcica is either partially filled with cerebrospinal fluid and a very small associated pituitary gland lying in the floor of the sella (partially empty sella) or completely filled with cerebrospinal fluid with no visualized pituitary gland (completely empty sella). Most individuals with empty sella syndrome do not have any associated symptoms, but the finding raises concerns about hormone deficiencies. Empty sella syndrome may occur as a primary disorder, for which the cause is unknown (idiopathic), or as a secondary disorder, in which it occurs due to an underlying condition or disorder such as a treated pituitary tumor, head trauma, or a condition known as idiopathic intracranial hypertension (also called pseudotumor cerebri) during which elevated intracranial pressure causes empty sella syndrome.

The symptoms of empty sella syndrome may vary from one person to another and depends on the underlying cause. In most cases, especially in individuals with primary empty sella syndrome, there are no associated symptoms (asymptomatic). Often, empty sella syndrome is discovered incidentally on CT or MRI examination when individuals are being evaluated for other reasons.

The exact, underlying cause of primary empty sella syndrome is unknown (idiopathic).

Primary empty sella syndrome affects approximately 4 times more women than men. Most cases occur in middle-aged women who are obese and have high blood pressure (hypertension). Because most people with empty sella syndrome do not have symptoms and may go undiagnosed, determining the disorder’s true frequency in the general population is difficult. Some researchers have estimated that less than 1 percent of individuals with empty sella syndrome ultimately develop symptoms associated with the disorder, although this may be higher in men compared to women.

A diagnosis of empty sella syndrome is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and specialized imaging techniques. Imaging may include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs, tissues and structures such as the sella turcica.


Encephalitis, Herpes Simple

Herpes simplex encephalitis (HSE) is a rare neurological disorder characterized by inflammation of the brain (encephalitis). Common symptoms include headaches, fevers, drowsiness, hyperactivity, and/or general weakness. The disorder may have some symptoms similar to those associated with meningitis, such as a stiff neck, altered reflexes, confusion, and/or speech abnormalities. Skin lesions usually are not found in association with herpes simplex encephalitis. Herpes simplex encephalitis is caused by a virus known as herpes simplex virus (HSV).

Symptoms associated with herpes simplex encephalitis usually develop over several days, often without warning. Early symptoms include headaches, fevers, and seizures. Additional symptoms include drowsiness with general weakness (stupor), and confusion or disorientation.

Herpes simplex encephalitis is a complication of infection with the herpes simplex virus. In most cases, the disorder results from herpes simplex virus type I (HSV-I). In rare cases, usually in newborns (neonatals), the disorder is caused by herpes simplex virus type II (HSV-II).

Herpes simplex encephalitis usually occurs during early childhood or adulthood. It affects males and females in equal numbers. The disorder is the most common form of acute encephalitis in the United States with approximately 2,000 cases occurring per year. It accounts for 10 percent of all cases of encephalitis in the United States per year.

Symptoms of the following disorders can be similar to those of herpes simplex encephalitis.  Comparisons may be useful for a differential diagnosis:

Encephalitis is an inflammation of the brain. There are several different types of encephalitis that differ in cause, parts of the body affected, severity, and areas of the world where they occur. The symptoms of these disorders may also overlap with or resemble other infectious disorders. Symptoms common to all forms of encephalitis include fever, fatigue, drowsiness, and confusion. Causes of encephalitis include herpes simplex virus, varicella zoster virus, arboviruses, and enteroviruses. Encephalitis may also occur secondary to other disorders.


Encephalitis, Japanese

Japanese Encephalitis is a severe inflammation of the brain caused by the Japanese B Encephalitis Virus that is transmitted by the bite of infected mosquitoes in certain areas of the world, particularly Asia. This disorder most commonly affects children and tends to be more actively spread during the summer. Symptoms include high fever, headaches, weakness, nausea, vomiting, paralysis, personality changes, and coma, possibly leading to neurological damage or death.

Japanese Encephalitis is a rare viral disorder characterized by high fever, headaches, weakness, nausea, vomiting, mental deterioration, personality changes, psychoses, impaired speech, spastic rigidity, and paralysis of the face or extremities.

Japanese Encephalitis is caused by the Japanese B Encephalitis Virus, an arbovirus (mediated via  insect bites), and transmitted through the bite of infected mosquitoes.  Symptoms occur as the virus directly invades the central nervous system causing selective infection, destruction of nerve cells, and weakening of the immune system.

Japanese Encephalitis occurs in approximately 20,000 people each year. The disorder erupts in the form of epidemics usually during the summer months in India, Bangladesh, the eastern part of Russia, China, Korea, Nepal, Burma, Viet Nam, and northern Thailand. In tropical areas of southeast Asia, southern India, southern Thailand, and Sri Lanka, the disease is present year-round and causes sporadic outbreaks. During the tropical rainy season, the illness can be transmitted in epidemic proportions.

Symptoms of the following disorders can be similar to those of Japanese Encephalitis.  Comparisons may be useful for a differential diagnosis:

Murray Valley Encephalitis is also known as Australian X Disease and is characterized by severe brain inflammation.  The virus which causes this disorder is related to the Japanese B virus and is transmitted from mosquitoes to birds to other mosquitoes.  Cases among children tend to be most severe.  The first noticeable symptoms may be headache, fever, a general feeling of discomfort, drowsiness and/or convulsions, and a stiff neck. Extensive brain damage may result.

In Asian nations, vaccinations are available that prevent Japanese Encephalitis. American travelers to areas at risk can obtain the vaccination in the United States. High risk areas include India, Bangladesh, the eastern part of Russia, China, Korea, Nepal, Burma, Viet Nam, northern Thailand, tropical areas of southeast Asia, southern India, southern Thailand, and Sri Lanka.


Encephalocele

Encephaloceles are rare neurological birth defects characterized by sac-like protrusions of brain tissue, the membranes that cover the brain (meninges) and the clear, watery fluid within the tissues that surround the brain (cerebrospinal fluid) through openings in the skull. Encephaloceles are usually congenital (present from birth) and result from the incomplete closing of the neural tube, a structure during fetal development that folds and normally becomes the brain and spinal cord. In some cases, encephaloceles may be acquired from trauma, tumors or injury caused by medical treatment. Surgery is usually necessary to treat encephaloceles.

The signs of an encephalocele depend on the location of the lesion. Some are present as a skin-covered mass near the midline in the head that is filled brain tissue and cerebrospinal fluid. Some encephaloceles protrude into spaces such as the nasal sinuses or the base of the skull and may not have external signs.

The exact underlying cause of encephalocele is unknown but is likely linked to both genetic and environmental factors. Most cases occur sporadically because of neural tube defects. The neural tube typically folds and closes early during pregnancy (third or fourth week) to complete the formation of the brain and spinal cord. A neural tube defect occurs when the neural tube does not close completely, which can occur anywhere along the head, neck or spine. The lack of proper closing of the neural tube can lead to a herniation (movement of brain tissue, blood, and cerebrospinal fluid from its normal position in the brain) process which appears as a pedunculated (having a stalk-like base) or sessile (attached directly to its base without a stalk) cystic lesion protruding through a defect in the cranial vault referred as encephalocele.

The Centers for Disease Control and Prevention (CDC) estimates that approximately 375 babies are born each year in the United States with an encephalocele. That would be approximately 1 in 10,000 babies each year. About 70% of encephaloceles are in females and 90% involve the midline. Additionally, females are more likely to have an encephalocele in the back (occipital area) of the skull, while males are more likely to have one in the front of the skull. In Western populations, encephaloceles are more common in the back of the skull. In Southeast Asia, they are more common in the front of the skull. Anterior encephaloceles are more common in Asia, Africa and Russia, with 1 case in 3,500 to 6,000 births.

Other related disorders include nasal glioma, cranial dermal sinus tract, nasal dermoid cyst, nasal epidermoid, dacryocystitis, dacryocystocele, hemangioma, nasal polyp, Dandy-Walker malformation and Chiari malformation.

Most encephaloceles are diagnosed on a routine prenatal ultrasound or seen right away when a baby is born. In some, small encephaloceles may initially go unnoticed but an individual will present symptoms that lead to diagnosis.


Endocardial fibroelastosis

Endocardial fibroelastosis (EFE) is a rare heart disorder that affects infants and children. It is characterized by a thickening within the muscular lining of the heart chambers due to an increase in the amount of supporting connective tissue (inelastic collagen) and elastic fibers. The normal heart has four chambers. Two chambers, known as atria, are separated from each other by a partition called the atrial septum. The other two chambers, known as ventricles, are also separated by a septum. Valves connect the atria (left and right) to their respective ventricles.

The symptoms of endocardial fibroelastosis begin rapidly, generally between the ages of 4 and 12 months.  Symptoms are due to the overgrowth of fibrous tissue and thickening of the lining of the hearts’ chambers (i.e., endocardium and subendocardium), especially the left ventricle.  In some very rare cases of EFE, the left ventricle is small (hypoplastic) or of normal size and the right ventricle is enlarged.

Some cases of endocardial fibroelastosis occur as a result of random changes (mutations), with no apparent cause (sporadic). These cases are known as endocardial fibroelastosis 1 (EFE1). Others cases are thought to be inherited as an X-linked recessive genetic trait.  These cases are known as endocardial fibroelastosis 2 (EFE2). In EFE1, neither the chromosome nor the precise location of the mutated gene on that chromosome have been determined.  In EFE2, the mutated gene is located on the X chromosome, but its precise location is not known.

Endocardial fibroelastosis is a rare disorder that affects males and females in equal numbers.  Fewer than 1 percent of infants and children with congenital heart disease are diagnosed with this disorder.  A 1964 study suggested an incidence of 1 in 5,000 live births.  However, in the United States there has been a marked reduction in incidence since then for reasons that are not known.  The disorder is extremely rare.

Symptoms of the following disorders can be similar to those of Endocardial Fibroelastosis.  Comparisons may be useful for a differential diagnosis:

Barth Syndrome, also known as Cardioskeletal Myopathy with Neutropenia and Abnormal Mitochondria, is a rare inherited metabolic disorder.  Symptoms may include low levels of certain white blood cells (agranulocytopenia), muscle weakness, and/or abnormal enlargement of the heart (hypertrophic cardiomyopathy) leading to congestive heart failure.  Failure to thrive, growth delays, and/or recurring respiratory infections are common in children with Barth Syndrome.  Some affected infants also have Endocardial Fibroelastosis.  Barth Syndrome is inherited as an X-linked genetic trait.


Tropical endomyocardial fibrosis

Endomyocardial fibrosis (EMF) is a progressive disease of unknown origin (idiopathic) that may seriously affect the heart. Its most obvious feature is a gross change in the makeup of the lining of the heart cavities (the endocardium) of one or both of the lower chambers of the heart (the ventricles) leading to the replacement of normal cells with fibrous tissue (fibrosis). This process is progressive and leads to the narrowing (constriction) of the right or left ventricular cavities. It may involve the valves between the chambers of the heart as well as the tendon-like cords that fix the valves to the ventricles (chordae tendineae).

The main microscopic feature of endomyocardial fibrosis (as well as of Loeffler’s disease) is fibrosis of the inner lining of the heart cavities (the endocardium). This means that the normal endocardium is replaced by a thick, inelastic tissue. The fibrotic lesions may be over 1 cm thick and may extend finger-like projections into the heart muscle (the myocardium).

At this time, clinicians believe that an as yet unknown immunological process is the preferred explanation for the cause of most cases of endomyocardial fibrosis and Loeffler’s disease. In the past, the cause of both conditions was attributed to the presence of the filaria worm in patients or to poor nutrition. Widespread infection with such worms and poor diets are typical in the tropical regions in which these disorders are more common. Eosinophils have been observed in some cases of endomyocardial fibrosis, suggesting a form of hypersensitivity may play a role in select cases. In children, endomyocardial fibrosis has been associated with the mumps virus.

Endomyocardial fibrosis is principally an endemic disease of the equatorial tropics. It is exceedingly rare in Europe and North America. It affects all races, mostly children and young adults. The disease has been described in a few patients over 60 years of age and, rarely, in patients younger than 5 years of age.

Amyloidosis is the term applied to a group of metabolic disorders characterized by the abnormal accumulation of a fibrous protein (amyloid) in various tissues of the body, including the heart. This can lead to impaired function of the affected organs. When amyloidosis affects the gastrointestinal system, symptoms may include ulceration, bleeding, weak stomach activity, protein loss, diarrhea, and/or vomiting. Amyloid accumulation may also cause a lack of movement in the esophagus and intestines. Amyloid accumulation in the heart may lead to heart failure symptoms including shortness of breath, swelling of the legs and ascites. (For more information on this disorder, choose Amyloidosis as your search term in the Rare Disease Database.)

Echocardiography is the primary tool used to diagnose suspected cases of endomyocardial fibrosis or Loeffler’s disease. A heart muscle biopsy is sometimes obtained to confirm the diagnosis.


附着点炎症相关幼年特发性关节炎

Enthesitis-Related Juvenile Idiopathic Arthritis

The symptoms of enthesitis-related juvenile idiopathic arthritis vary from person to person. Initial symptoms often include pain and stiffness in the joints of the lower body, especially knees, hips, ankles and feet. Joint pain, stiffness, and swelling are usually asymmetric (affecting each side of the body differently), and children can have trouble with walking as the joints of the lower body are commonly affected. While joint pain and stiffness may come and go initially, they can last for longer periods over time as the condition progresses. Pain and stiffness are often worse in the morning and can get better with movement. Enthesitis-related JIA is more likely to have pain and stiffness in the hips and midfoot area than other forms of JIA.

The exact cause of enthesitis-related juvenile idiopathic arthritis is not known, but it is thought that both genetic and environmental factors contribute. One gene that is strongly linked with the condition is called HLA-B27. HLA genes make proteins that help the immune system differentiate between its own cells and other harmful organisms. The precise way that HLA-B27 leads to symptoms of arthritis is still being studied, but it may be related to abnormal activation of the immune system towards its own cells. Children with enthesitis-related JIA have an increased number of immune cells in their blood and in the fluid within their joint spaces. These immune cells release more inflammatory proteins which likely contribute to developing the disease. Additionally, abnormal interactions between the immune system and bacteria found in the gut may also contribute to development of the disease.

Enthesitis-related juvenile idiopathic arthritis most commonly affects boys older than six years. It is also the most common type of JIA in children of Asian descent. Children who have relatives with enthesitis-related arthritis or other conditions associated with variants in the HLA-B27 gene, such as ankylosing spondylitis, reactive arthritis, inflammatory bowel disease or acute anterior uveitis, are also at increased risk.

Juvenile idiopathic arthritis (JIA) is defined as pain, swelling and/or limited range of motion of a joint starting before age 16 that lasts for at least six weeks and is not due to an identifiable cause. Enthesitis-related JIA can be differentiated from other types of JIA by unique signs and symptoms. These include asymmetric arthritis in the small joints of the lower body, enthesitis or pain at insertion sites of the ligaments and tendons on bone, acute uveitis (inflammation of the front portion of the eye) and association with HLA-B27 gene variants, which is not seen in other types of JIA.

Enthesitis-related juvenile idiopathic arthritis is often diagnosed via thorough history and physical exam by a pediatric rheumatologist. Common findings in the history include joint pain and/or stiffness persistent for weeks (often worse in the morning) and enthesitis (pain at the insertion points of tendons and ligaments on bone). Physicians may test for enthesitis by physically pressing on the tendon/ligament insertions and checking for tenderness. Imaging studies may also help in diagnosis. Ultrasound and whole-body magnetic resonance imaging (MRI) are occasionally used to identify enthesitis although they are not used commonly in children. For children who are thought to have inflammation of the spine and sacroiliac joint, physicians can test for mobility of the spine during a physical exam. These tests are normal early in the disease course, so imaging of the spine and sacroiliac joint with MRI may be more helpful in showing inflammation.


Eosinophilia-Myalgia Syndrome

色氨酸相关性肌痛-嗜酸性粒细胞增多综合征

The symptoms and severity of eosinophilia-myalgia syndrome can vary greatly from one person to another. In most cases, the onset of the disorder is rapid.

Although almost all cases of eosinophilia-myalgia syndrome in the 1989 epidemic were traced back to ingestion of contaminated L-tryptophan manufactured by a single company, namely Showa Denko K.K. (Tokyo, Japan), a large petrochemical company, the precise contaminant causing the disease is still unknown.

Eosinophilia-myalgia syndrome was identified as an epidemic in 1989 after three people in New Mexico were identified with the disorder. The exact incidence of eosinophilia-myalgia syndrome is unknown. One estimate indicates that anywhere from 5,000-10,000 people developed the disorder during the epidemic. Most reported individuals are females and from the United States. However, eosinophilia-myalgia syndrome has been reported in other countries as well including Germany, Canada and the United Kingdom.

Symptoms of the following disorders can be similar to those of eosinophilia-myalgia syndrome. Comparisons may be useful for a differential diagnosis.

EMS is a syndrome with multiple clinical presentations and variable severity. The first clinical reports showed that most patients developed profound eosinophilia and severe myalgias. Further, other symptoms included joint pains, weakness or fatigue, difficulty breathing or cough, rash, headache, peripheral edema (swelling), fever and abnormal tingling sensations. Most patients also showed an elevation of an enzyme called serum aldolase, which is an indicator of muscle damage. About one-half of the patients had abnormal liver function tests.


Eosinophilic Esophagitis

Eosinophilic esophagitis (EoE) is a chronic disorder of the digestive system in which large numbers of a particular type of white blood cell called eosinophils are present in the esophagus. The esophagus is the tube that carries food from the mouth to the stomach. Eosinophils are part of the immune system and play a role in immune regulation and fighting certain infection, and their accumulation is a hallmark of allergic diseases. This condition is characterized by vomiting, stomach or chest pain, failure to thrive (particularly in children), difficulty swallowing and food getting stuck in the throat.

The symptoms of eosinophilic esophagitis are variable, especially in people of different ages. Common symptoms include difficulty swallowing (dysphagia); food getting stuck in the throat (impaction); nausea; vomiting; poor growth; weight loss; stomach pain; poor appetite; and malnutrition. Because of an overlap of these symptoms with gastroesophageal reflux disease (GERD), many patients are initially thought to have GERD, but EoE patients do not typically have GERD upon diagnostic workup. Recently, it has been appreciated that some patients with pronounced esophageal eosinophilia can have complete responses to proton pump inhibitor (PPI) therapy, typically used for the treatment of GERD, but these patients do not typically have GERD but rather EoE that is responsive to PPIs.  PPI exert this therapeutic effect by direct action rather than blockade of stomach acid alone. For example, PPIs are also ligands (bind to) the aryl hydrocarbon receptor and this elicits an anti-inflammatory and anti-proliferative effect in the esophagus. PPI responsive esophageal eosinophilia has largely overlapping clinical, histological and molecular characteristics with PPI-resistant esophageal eosinophilia, but entities are referred to as EoE and usage of PPIs is now considered a treatment of EoE. Individuals with eosinophilic esophagitis often have allergic diseases such as asthma or eczema.

Eosinophilic esophagitis is associated with the presence of many eosinophils in the esophagus driven by an immune response to a variety of foods. The production and accumulation of eosinophils may be caused by many factors such as immune hypersensitivity responses to particular foods or environmental proteins (allergens) in some affected individuals. Most individuals with this condition have been found to have an unusually high expression of a particular gene called eotaxin-3. This gene codes for a protein that is important in controlling the accumulation of eosinophils. Eosinophilic esophagitis can run in families but the risk for additional family members is <5% unless they are twins with the EoE patient. Several genes have been identified to contribute to EoE including CAPN14 and TSLP. A fundamental step in the development of EoE is loss of esophageal barrier function which is mediated by loss of anti-proteases such as SPINK7 and desmosomal proteins such as desmoglein-1 and dysregulated expression of the CAPN14 gene product (calpain-14). It is now appreciated that esophageal eosinophilia as well as other pathological features of EoE are driven by a strong cellular response of the adaptive immune system, primarily orchestrated by type 2 helper T cells (Th2 cells). These cells, along with esophageal mast cells, produce high levels of the cytokine interleukin (IL)-13, which is essential in eliciting multiple pathological processes in the esophagus.

The overall prevalence rate, standardized to the U.S. population, has been estimated to be about 56.7/100,000, which is about 152,152 cases. EoE is still considered a rare condition in U.S., but the prevalence has increased over the past 2 decades, nearly doubling in both adults and children. It is not considered a rare condition in Europe. This condition has been reported in multiple continents including Europe, Australia and America.

Symptoms of the following disorders are similar to those of eosinophilic esophagitis. Comparisons may be useful for a differential diagnosis:

Gastroesophageal reflux disease (GERD) is a digestive disorder characterized by reflux of the contents of the stomach or small intestines into the esophagus. Symptoms of gastroesophageal reflux may include a sensation of warmth or burning rising up to the neck area (heartburn or pyrosis), swallowing difficulties (dysphagia) and chest pain. This condition is a common problem and may be a symptom of other gastrointestinal disorders.


Eosinophilic fasciitis

Although researchers have been able to establish a clear syndrome with characteristic or core symptoms, much about eosinophilic fasciitis is not fully understood. Several factors including the small number of identified cases, the lack of large clinical studies, and the possibility of other unknown influencing factors prevent physicians from developing an accurate picture of associated symptoms and prognosis. Therefore, it is important to note that affected individuals may not have all of the symptoms discussed below.

The exact cause of eosinophilic fasciitis is unknown (idiopathic). Researchers believe that the disorder results due to a nonspecific triggering event that causes an abnormal immune system response, specifically an abnormal allergic or inflammatory reaction. This abnormal response causes the overproduction and accumulation of eosinophils and other white blood cells in certain tissues of the body. The exact reason for this overproduction and accumulation is not fully understood.

Eosinophilic fasciitis affects both sexes. Some reports suggest that women are affected with greater frequency than men. The disorder can occur at any age (with age at diagnosis ranging from 1-88), but most often occurs in individuals between 30-60 years of age. It occurs with greater frequency in Caucasians. Approximately 300 cases have been reported in the medical literature.

Symptoms of the following disorders can be similar to those of eosinophilic fasciitis. Comparisons may be useful for a differential diagnosis.

A diagnosis of eosinophilic fasciitis is suspected based upon a detailed patient history, a thorough clinical evaluation, and various laboratory studies. Characteristic skin grooves called venous grooving are typically present. The prayer sig. (when someone tries to join hands as in prayer but, cannot press the hands flat so they remain curved with just the fingers touching) is indicative of problems with joint mobility and is associated with eosinophilic fasciitis.


Eosinophilic gastroenteritis

Eosinophilic gastroenteritis is a rare digestive disease characterized by the triad of eosinophilic infiltration of segments of the gastrointestinal tract, abnormalities of gastrointestinal function (varying from dyspepsia and obstruction to diarrhea and ascites) and exclusion of other diseases with peripheral eosinophilia. Eosinophilic esophagitis is increasingly being recognized and is not included in this report.

Eosinophilic gastroenteritis may affect any part of the gastrointestinal tract from the esophagus to the rectum. Symptoms include dysphagia (sometimes presenting as food impaction), heartburn, abdominal pain, nausea, vomiting, diarrhea, weight loss, and bloating (ascites is possible). The eosinophilic infiltration may involve one or more layers of the gastrointestinal wall. The particular symptoms present in each person depend upon the layer and the location of involvement. Most commonly, the stomach wall and the small bowel are involved. Mucosal involvement leads to protein-losing enteropathy and malabsorption. Muscle layer involvement causes abdominal pain, vomiting, dyspeptic symptoms and bowel obstruction. Subserosal involvement predominantly causes ascites with marked eosinophilia. Sometimes eosinophilic pleural effusion is present. Eosinophilic gastroenteritis is a chronic, waxing and waning condition.

The exact cause of eosinophilic gastroenteritis is unknown. Some cases of this disease may be caused by a hypersensitivity to certain foods or other unknown allergens. Often, a family history of allergy is present. Atopy (asthma, hay fever or eczema) is present in a subset of patients. Food allergies are common.

Eosinophilic gastroenteritis is a rare disease (10/100.000) that affects both males and females, but is slightly more common among men. Peak prevalence is in children and adults 20-50 years of age. The reported prevalence has increased markedly, and this is probably due to prior under-diagnosis. People with a history of allergies, eczema, and seasonal asthma are more likely to develop this disease.

Symptoms of the following disorders can be similar to those of eosinophilic gastroenteritis. Comparisons may be useful for a differential diagnosis:

Whipple’s disease is an uncommon digestive disorder of microbial origin that affects the lining of the small intestine and results in malabsorption of nutrients. This disorder may also affect other organs of the body. (For more information on this disorder, choose Whipple as your search term in the Rare Disease Database.)


Eosinophilic granulomatosis with polyangiitis

Eosinophilic Granulomatosis with Polyangiitis

Because multiple organ systems can potentially be affected, the specific symptoms of EGPA vary widely from person to person, including in their severity, duration and onset. Since different organ systems will be affected in different people, all the symptoms discussed below will not occur in every patient. Classically the disorder was separated into three distinct phases – prodromal, eosinophilic and vasculitic; however, these phases may or may not occur sequentially or in all individuals.

The exact cause of EGPA is unknown. Most researchers think that several different factors (e.g., environmental, immunological and genetic) all play a role in the development of the disorder. Researchers also think there may be two different types of EGPA. In one, EGPA is classified as an autoimmune disorder. Autoimmune disorders are caused when the body’s natural defenses against foreign or invading organisms begin to attack healthy tissue for unknown reasons. Researchers do not know what sets off or triggers the abnormal immune system response in individuals with EGPA. An autoantibody called antineutrophil cytoplasmic antibodies (ANCAs) is sometimes present in EGPA. The immune system creates antibodies against granules in neutrophils and these may be found on neutrophils, a type of white blood cell, in the lining of blood vessels suggesting they may be part of the damage that occurs in vasculitis. ANCAs have been identified in other related blood vessel disorders (vasculitides) including granulomatosis with polyangiitis (GPA), or in medication induced vasculitis. The development of ANCAs after exposure to medications or infections suggests that exposures may play a role in the immune response though whether a separate immune process that causes vasculitis and development of ANCAs is not clear. In the autoimmune type of EGPA where ANCAs are present (in 30-50% of individuals with EGPA depending on the study), certain symptoms are more common. For example, the development of kidney involvement or bleeding in the lungs is more common in ANCA-associated EGPA.

EGPA does not have a sex predilection with equal presentation in males and females. The disorder can affect individuals of almost any age, with children and elderly patients being reported. However, it is rarer in children, adolescents and older adults. Most cases occur in individuals between 38 and 54 years of age. The estimated mean prevalence varies globally but ranges from 3-30.7 individuals per million in the USA, among an insured population. Some researchers think that EGPA is underdiagnosed, making it difficult to determine its true frequency in the general population.

Symptoms of the following disorders can be similar to those of EGPA. It is helpful to keep these conditions in mind when diagnosing EGPA.

There are no validated diagnostic criteria for EGPA. Rather, the diagnosis of EGPA may be suspected based on a thorough clinical evaluation, characteristic physical findings and specialized tests particularly in those that present with asthma, sinusitis and blood eosinophilia.  In 2022, the American College of Rheumatology revised their classification criteria for EGPA. Among patients who have been shown to have vasculitis, an individual can be classified as having EGPA rather than another small- or medium-vessel vasculitis) if they have a score of six or more points from the following seven items:


Epidermal Nevus Syndromes

Epidermal nevus syndromes (ENSs) are a group of rare complex disorders characterized by the presence of skin lesions known as epidermal nevi associated with additional extra-cutaneous abnormalities, most often affecting the brain, eye and skeletal systems. Epidermal nevi are overgrowths of structures and tissue of the epidermis, the outermost layer of the skin. The different types of epidermal nevi can vary in size, number, location, distribution and appearance. Neurological abnormalities that can be associated with ENSs can include seizures, cognitive impairment, developmental delays and paralysis of one side of the body (hemiparesis). Skeletal abnormalities can include abnormal curvature of the spine, malformation of the hip and abnormalities of the arms and legs (e.g., underdevelopment or absence or overgrowth of limbs). Ocular abnormalities may include cataracts, clouding (opacity) of the cornea or partial absence of tissue of the iris or retina (colobomas). Endocrine abnormalities such as vitamin D-resistant rickets have been associated with Schimmelpenning syndrome. The specific symptoms and severity of ENSs can vary greatly from one person to another. Most ENSs occur randomly for no apparent reason (sporadically), most likely due to a gene mutation that occurs after fertilization (postzygotic mutation) and is present in only some of the cells of the body (mosaic pattern).

Epidermal nevus syndromes encompass a wide variety of disorders. The specific symptoms present, severity and prognosis can vary greatly depending on the specific type of ENS and the presence and extent of associated extra-cutaneous symptoms. The onset and progression of these disorders varies greatly as well.

Most epidermal nevus syndromes are thought to be caused by a gene mutation that occurs after fertilization of the embryo (postzygotic mutation), at an early stage of embryonic development. Affected individuals have some cells with a normal copy of this gene and some cells with the abnormal gene (mosaic pattern). This may be referred to as having two distinct cell lines in the body. The variability of symptoms associated with ENSs is due in part to the ratio of healthy cells to abnormal cells. When all cells have the abnormal gene, the condition is not compatible with life. Researchers believe that this postzygotic mutation occurs randomly for no apparent reason (sporadically). By  contrast, CHILD syndrome is inherited as an X-linked dominant, male-lethal trait which means that the disorder can be transmitted from a mother to 50% of her daughters. Her sons will not be affected because male embryos can only survive when they have inherited the normal (healthy) X-chromosome from the mother.

Epidermal nevi (including as an isolated finding) have been reported to occur in approximately 1 to 3 per 1,000 live births. The percentage of individuals with epidermal nevi who also have extra-cutaneous malformations is much lower but likewise unknown. The prevalence and incidence of individual ENSs is unknown.

Symptoms of the following disorders can be similar to those of ENS. Comparisons may be useful for a differential diagnosis.

A diagnosis of an epidermal nevus syndrome is made based upon identification of characteristic symptoms, a detailed patient history and a thorough clinical evaluation. In some cases, a small sample of affected skin may be taken for microscopic study (biopsy). Additional tests may be required to detect the presence and extent of associated symptoms. Such tests include a skeletal survey, chest x-rays and specialized imaging techniques to evaluate the brain. Such imaging techniques may include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). Whether a child with an epidermal nevus should undergo such imaging techniques is controversial. Some researchers believe that these tests should be avoided unless there are clinical signs of central nervous involvement. In three of the well-defined ENSs (type 2 segmental Cowden disease, García-Hafner-Happle syndrome, CHILD syndrome), molecular testing is now possible.


Epidermolysis Bullosa

Epidermolysis bullosa (EB) is a genetic skin disorder characterized clinically by blister formation from mechanical trauma. There are four main types with additional sub-types identified. There is a spectrum of severity, and within each type, one may be either mildly or severely affected. EB ranges from being a minor inconvenience requiring modification of some activities, to being completely disabling and, in some cases, fatal.

Epidermolysis bullosa is divided into four subdivisions, and each subdivision has subtypes.

Inherited epidermolysis bullosa is the focus of this report. The inherited forms follow either autosomal dominant or autosomal recessive inheritance. There is also a rare acquired autoimmune disorder called epidermolysis bullosa aquisita. A mutation in any of at least 18 genes encoding the proteins in the epidermis, basement membrane or dermis causes poor integrity of the skin leading to fragility.

Some type of EB occurs in an estimated 1 out of every 50,000 live births. The disorder occurs in every racial and ethnic group throughout the world and affects both sexes equally.

Any blistering disorder in the newborn period may mimic EB. These include herpes simplex virus, epidermolytic ichthyosis, bullous impetigo and incontinentia pigmenti.

Clinical diagnosis of the type of EB based on presentation in the neonatal period should be avoided as all types of EB may look alike in this age group. When EB is suspected, a skin biopsy should be obtained and sent to an appropriate laboratory to confirm the diagnosis with transmission electron microscopy (TEM) and/or immunofluorescent antibody/antigen mapping. Molecular genetic testing for mutations in most of the genes known to be associated with the various types of EB is clinically available.

By definition, inherited EB is a genetically transmitted disorder characterized by marked fragility of the skin. Any trauma, no matter how minimal it may seem, is likely to cause the skin of an EB child or adult to tear or blister. The following are recommended ways to avoid or minimize this problem:


常染色体显性遗传表皮松解性鱼鳞病

Autosomal dominant epidermolytic ichthyosis

bullous congenital ichthyosiform erythroderma (of Brocq)

Epidermolytic ichthyosis (EI) is a genetic skin disorder that is characterized by varying degrees of blistering and scaling of the skin. The symptoms of the disease are often noticed at birth or shortly after, and symptoms change as the patient ages. Symptoms may vary from mild blistering upon friction to severe erosions or widespread warty scaling. Hair and nail abnormalities, reduced sweating and the formation of calluses on the palms or soles (palmoplantar keratoderma) of the feet can also occur. Under a microscope, the skin may show mid-epidermal splitting and skin thickening (hyperkeratosis). Current treatments address the specific symptoms and can include topical treatments, medications and antiseptic washes for skin infections. The cosmetic issues and sometimes unpleasant odor associated with EI can lead to stress and psychological distress.

The symptoms of EI progress with the patient’s age. Infants more commonly show signs of red, blistering skin and will usually develop thickened skin (cornification) and scaling into adulthood. Infants may also show growths on the inner surface of the eyelid (conjunctival hamartoma). Scales tend to form in parallel rows of spines or ridges. Reddened skin (erythroderma), itchiness (pruritus) and abnormal dryness (xerosis) are common symptoms. Skin ulcers and other damage can lead to bacterial infections. Heat intolerance and sensitivity to sunlight may also occur. A palmoplantar keratoderma may be present and can be so severe as to limit movement and hand function. Milder cases usually show minimal blistering in areas subject to friction or have only a palmoplantar keratoderma.

EI is caused by harmful changes (variants) in the KRT1 or KRT10 genes. These variants result in improper expression of keratin 1 and keratin 10, which are structural proteins specifically found in epithelial and epidermal cells. The malfunctioning proteins result in barrier abnormalities that can lead to epidermal inflammation, causing the various symptoms seen with the disease.

EI occurs in approximately 1 in 200,000 individuals, affecting males and females equally.

Epidermolytic ichthyosis can resemble different diseases depending on the stage it is in. Early stages of EI can resemble diseases that involve the extreme onset of blisters and lesions in infants. Specific disorders include toxic epidermal necrolysis (TEN), epidermolysis bullosa (EB) and incontinentia pigmenti (IP). Blister presentation associated with TEN is caused by the first-time exposure to drugs during infancy. EB is a group of diseases, each characterized by the fragility and blistering of skin and mucosae. IP is an X-linked dominant skin disease caused by variants in the IKBKG gene. IP is a multisystem disorder, and the skin is most commonly affected in infants.

EI is diagnosed by clinical signs and symptoms. Histopathology tests and electron microscopy assessments may be used but are not the most definitive. Genetic testing for harmful variants in the KRT1 and KRT10 genes can confirm a diagnosis.

The main goal of treating EI is to ease the presenting symptoms. This can be challenging as it may require a combination of treatments and therapies. The medications that help to remove the excess thickened skin (topical keratolytics or oral retinoids) can leave the very fragile epidermis (underlying living cell layers) exposed. Therefore, application of a barrier repair formula containing ceramides or cholesterol, or topical emollients, may be used in conjunction to relieve and protect the vulnerable skin. Since bacterial infections are a cause of concern, it is recommended that patients wash with antiseptic soap 2-3 times per week. Many patients find baths with salt or sodium bicarbonate, as well as bleach, beneficial as it helps to descale and prevent bacterial overgrowth. If symptoms are seen at birth, the newborn is recommended to be transferred to the neonatal ICU for proper monitoring and care.


Epilepsy with eyelid myoclonia

Eyelid myoclonia with or without absence

Epilepsy with eyelid myoclonia (EEM) is a genetic generalized epilepsy syndrome with an average age of onset between 6-8 years. Patients typically present in childhood with prominent eyelid myoclonia, which is a jerking or flickering up of the eyelids associated with the eyes rolling up. This typically happens many times a day. Patients may be misdiagnosed, as eyelid myoclonia may be mistaken as a tic or a behavioral reaction and these children are often referred to a psychologist or psychiatrist. Eyelid myoclonia may be associated with absence seizures and eye closure sensitivity, and other seizure types may also be present. Intellectual ability and development are typically normal, but school difficulties and attention problems may occur. The underlying cause is thought to be genetic, and studies suggest that many different genes may be involved. Seizures typically persist for life and drug-resistant epilepsy is common.

EEM consists of the following three characteristics: 1) eyelid myoclonia with or without absence seizures, 2) eye closure induced seizures or EEG paroxysms and 3) sensitivity to light (photosensitivity). Eyelid myoclonia is required for the diagnosis, which is defined as a jerking, flickering or fluttering of the eyelids usually associated with upward deviation of the orbit and can be associated with a tendency for the head to go backwards (retropulsion of the head). Eyelid myoclonia is typically prominent and the most difficult to control seizure type. Eyelid myoclonia can be induced by eye closure, especially in sunlight or other bright lights and may be associated with loss of awareness, known as absence seizures.

The underlying cause of EEM is thought to be genetic, which is supported by a positive family history of epilepsy in many patients and cases in twins. Many different genes may be involved and in recent years, changes (variants) in specific genes have been recognized in a minority of patients, including the genes RORB, SYNGAP1, KCNB1, NAA10, COL6A3, NEXMIF and CHD2. An underlying gene variant may influence the severity and prognosis. In many patients, a specific gene variant may not be identified at this time. Further research is needed to clarify the role of genetics in this disorder.

EEM affects about twice as many females than males. Onset is between the ages of 1-15 years with a peak from 6-8 years of age. EEM accounts for only about 1.2-2.7% of patients with epilepsy.

EEM shares similarities with other generalized epilepsy syndromes, which should be considered in the differential diagnosis. The features of EEM, including the eye-closure induced EEG paroxysms, photosensitivity and even the eyelid myoclonia may be seen in other epilepsy syndromes. Childhood absence epilepsy (CAE) is an idiopathic generalized epilepsy with onset around the same age as EEM. Patients typically have multiple absence seizures a day, which can be associated with eye fluttering that is not as pronounced as the eyelid myoclonia seen in EEM. CAE resolves in childhood for most patients, unlike EEM. Rarely, it has been reported that patients with CAE can develop EEM.

EEM is diagnosed based on the presence of three features that include eyelid myoclonia with or without absence seizures, eye closure-induced seizures or EEG paroxysms and photosensitivity. Making the diagnosis requires a thorough clinical history, neurological examination and an EEG. An EEG capturing eyelid myoclonia or other seizures is not required to make the diagnosis if eyelid myoclonia is witnessed on exam by a healthcare provider and other features of the diagnosis are seen on EEG. An MRI of the brain is not required for the diagnosis, but when done is typically normal or shows nonspecific changes unrelated to epilepsy.

Treatment for EEM consists of broad-spectrum antiseizure medications, including valproic acid, levetiracetam, lamotrigine and clobazam. Modern antiseizure medications like lacosamide, brivaracetam and perampanel are also options, but more experience and research are needed to determine the best treatment. The response to different antiseizure medications can vary between patients, and trials of multiple medications may be necessary. In addition, all antiseizure medications have possible side effects that may limit their use and patients should discuss this with their doctors. For patients with significant photosensitivity, sometimes lens therapy can be effective at reducing seizures. Special lenses have been studied but are not readily available worldwide. In addition, these lenses significantly reduce brightness (luminance), and therefore, may not be well tolerated.


Epithelioid Hemangioendothelioma

Epithelioid hemangioendothelioma (EHE) is an ultra-rare vascular sarcoma that has a prevalence of less than one in a million people and affects all age groups, with incidence peaking in the fourth and fifth decade of life and is very rare in children. EHE can arise anywhere in the body and most commonly occurs in the liver, lung and bones with more than 50% of patients presenting with metastatic disease.


Erdheim Chester Disease

Erdheim-Chester disease (ECD) is a rare multisystem disorder of adulthood. It is characterized by excessive production and accumulation of histiocytes within multiple tissues and organs. Histiocytes are large phagocytic cells (macrophages) that normally play a role in responding to infection and injury. (A phagocytic cell is any scavenger cell that engulfs and destroys invading microorganisms or cellular debris.) In people with ECD, sites of involvement may include the long bones, skin, tissues behind the eyeballs, lungs, brain, pituitary gland and/or additional tissues and organs. Associated symptoms and findings and disease course depend on the specific location and extent of such involvement. The underlying cause of ECD is thought to be a malignancy of the myeloid progenitor cells.

ECD characteristically affects certain regions of the long bones of the legs, including the shafts (diaphyses) and the areas (i.e., metaphyses) where the shafts converge with the ends (epiphyses). The ends of the long bones are usually spared or may have mild changes. Infiltration by histiocytes typically leads to widespread or patchy increases in bone density as well as hardening (osteosclerosis) and thickening of bone. In some rare cases, there may also be involvement of other bones, such as the lower jawbone (mandible) or certain bones of the spinal column (vertebrae). In many affected individuals, the initial symptom of the disorder is associated bone pain, usually affecting the knees and legs, that is similar on both sides of the body (symmetrical). In some cases, more generalized symptoms may also develop, including weight loss, fever, muscle and joint aches; and a general feeling of discomfort, weakness, and fatigue (malaise).

ECD is thought to represent an abnormal inflammatory process characterized by excessive proliferation and accumulation of certain cells, with associated scarring or overgrowth of fibrous connective tissue (fibrosis). Somatic mutations in the BRAF-V600 gene and other mutations in the mitogen-activated protein kinase (MAPK) signaling and phosphatidylinositol 3-kinase (PI3K)-ART pathways have established ECD as a malignancy of myeloid progenitor cells. A BRAF V600 gene mutation has been found in about half of patients with ECD. There may be widespread infiltration of affected tissues by histiocytic cells that contain large amounts of fatty (lipid) material (xanthomatous histiocytes); certain lymphocytes; and distinctive, large cells with multiple nuclei (Touton giant cells). (Lymphocytes are an immune system cell type that originates in the bone marrow.) In those with ECD, these fatty, nodular (xanthogranulomatous) cell deposits may infiltrate multiple tissues and organs, leading to impaired organ functioning.

ECD is a rare disorder of adulthood that most frequently becomes apparent in middle age, with an average age of onset in the mid-50s. More than 100 cases have been reported in the medical literature with a slight male preponderance. ECD is named for the two investigators who originally described the disease.

Symptoms of the following disorders may be similar to those of Erdheim-Chester disease. Comparisons may be useful for a differential diagnosis:

Histiocytosis X, also known as Langerhans cell histiocytosis (LCH), is a group of diseases characterized by excessive production and accumulation of histiocytes in various tissues and organs. The lesions may include certain distinctive granule-containing cells (known as Langerhans’ cells) involved in certain immune responses as well as lymphocytes and other immune system cell types (e.g., monocytes, eosinophils). Associated symptoms and findings may vary from case to case, depending on the specific tissues and organs affected and the extent of involvement. Most affected individuals have single or multiple bone lesions characterized by degenerative changes and loss of the calcium of bone (osteolysis). Although the skull is most commonly affected, there may also be involvement of other bones, such as those of the spine (vertebrae) and long bones. Affected individuals may have no apparent symptoms (asymptomatic), experience associated pain and swelling, and/or develop certain complications, such as fractures or secondary compression of the spinal cord. In some cases, other tissues and organs may also be affected, including the skin, lungs, or other regions. In some individuals, LCH may be associated with involvement of the pituitary gland, leading to diabetes insipidus; this form of LCH is known as Hand-Schuller-Christian disease. Certain cellular tissue changes, symptoms, and findings seen in LCH may resemble those associated with ECD, causing some to suggest that the latter may represent a form of LCH. However, evidence suggests that it is a distinct disease entity that differs from LCH regarding age of onset, characteristic bone changes, and other features. LCH most commonly becomes apparent during childhood, while ECD primarily affects middle-aged adults. In addition, the bone changes in LCH are typically characterized by osteolysis and involve the axial skeleton (e.g., the skull and vertebrae); in contrast, as noted earlier, ECD is associated with symmetric hardening (osteosclerosis) and thickening of certain regions of the long bones. (For more information on LCH, choose histiocytosis as your search term in the Rare Disease Database.)


Erythema Multiforme

Dermatostomatitis, Erythema Multiforme Type

Erythema multiforme (EM) is the name applied to a group of hypersensitivity disorders, affecting mostly children and young adults, and characterized by symmetric red, patchy lesions, primarily on the arms and legs. The cause is unknown, but EM frequently occurs in association with herpes simplex virus, suggesting an immunologic process initiated by the virus. In half of the cases, the triggering agents appear to be medications, including anticonvulsants, sulfonamides, nonsteroidal anti-inflammatory drugs, and other antibiotics. In addition, some cases appear to be associated with infectious organisms such as Mycoplasma pneumoniae and many viral agents.

Onset of erythema multiforme is usually sudden in an otherwise healthy individual.  Red spots (macules or papules), or ridges (wheals), and sometimes blisters appear on the tops of the hands and forearms.  Other areas of involvement may include the face, neck, palms, soles of feet, legs, and trunk.  The lesions continue to erupt for two or three days.  Some spots, especially on the hands and forearms, may evolve into concentric circles that resemble a target, with a grayish discoloration in the center.  A crust may develop over the center.  In about half of the cases, lesions may develop on the lips and the mucous membranes in the mouth.  The skin lesions are usually distributed on both sides of the body.  Itching can also occur.

The cause of erythema multiforme is unknown, but it appears to be an allergic reaction that occurs in response to medications, infections, or illness.  As noted above, it often appears in association with herpes simplex virus or with infectious organisms such as Mycoplasma pneumoniae.

Erythema multiforme is a rare disorder that affects slightly more males than females.  It may begin at any age, but is most common in children and young adults.

Symptoms of the following disorders can be similar to those of Erythema Multiforme.  Comparisons may be useful for a differential diagnosis:

Urticaria (hives) is easily recognized by the typical well-defined edematous ridges (wheals).  This type of skin disorder does not include blisters.  (For more information on this disorder, choose Urticaria as your search term in the Rare Disease Database.)


Erythrokeratoderma

The symptoms of PSEK usually develop shortly after birth or during the first year of life. Infants develop reddened plaques of thickened, rough and/or scaly skin, especially on the face, buttocks, arms and legs. Over time, these lesions can cover large areas of the body. The distribution of these lesions is almost perfectly symmetrical, meaning the size, shape and location of the lesions are extremely similar on both sides of the body. These plaques are slowly progressive increasing in number and size throughout early childhood before either stabilizing, regressing or disappearing sometime later during life. Rarely, waxing and waning may occur. In some patients, the chest and abdomen may become involved. Abnormally thickened or calloused skin on the palms and soles (palmoplantar keratoderma; PPK) is not uncommon and can be disabling.

Erythrokeratoderma is typically caused by pathogenic variants (mutations) in any of the known genes or an as of yet unidentified gene. These conditions may occur at random (i.e., spontaneous new mutation) or be inherited in an autosomal dominant or autosomal recessive pattern.

Erythrokeratoderma affects males and females in equal numbers. The prevalence of the disorder in the general population is unknown. The disorder was first described by Darier in 1911. Since then, more than 100 cases have been described in the medical literature. Autosomal recessive inherited forms of erythrokeratoderma have been reported more commonly in Middle Eastern populations with a higher degree of marriage among blood relatives (consanguinity).

Symptoms of the following disorders can be similar to those of erythrokeratoderma. Comparisons may be useful for a differential diagnosis.

A diagnosis of erythrokeratoderma is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and specialized tests including genetic testing or surgical removal (biopsy) and microscopic evaluation of affected tissue.


Autosomal erythropoietic protoporphyria

常染色体遗传红细胞生成性原卟啉病

Erythropoietic Protoporphyria and X-Linked Protoporphyria

The most common symptom of erythropoietic protoporphyria and X-linked protoporphyria is severe pain on sun exposure. Some patients may also be sensitive to some types of artificial light. When the skin is exposed to sun, patients first develop tingling, itching, and/or burning of the skin. These symptoms serve as warning signs as longer exposure can result in severe pain. Affected individuals may also have an abnormal accumulation of body fluid under affected areas (edema) and/or persistent redness or inflammation of the skin (erythema). In rare cases, affected areas of the skin may develop sac-like lesions (blisters) and scar if exposure to sunlight is prolonged. However, scarring and/or discoloring of the skin is uncommon and rarely severe. These affected areas of skin may become abnormally thick. The severity and degree of symptoms is different from case to case. Some patients may only be able to tolerate a few minutes of sun exposure while others may be able to tolerate longer sun exposure without symptoms. The amount of sun tolerated may also be different based on weather conditions. Symptoms are often seen during infancy; however, in some cases, it may not occur until adolescence or rarely in adulthood.

EPP is a rare genetic disorder caused by genetic changes in the FECH gene. The FECH gene is responsible for providing instructions for the body to create an enzyme called ferrochelatase. This enzyme is involved in a long process to make heme, a chemical that functions to transport oxygen around the body. Without enough of the enzyme, ferrochelatase, the body is not able to finish converting a heme precursor called protoporphyrin into heme, causing buildup of protoporphyrins in certain tissues in the body (i.e., the plasma, red blood cells, and the liver). These protoporphyrins also build up in the superficial blood vessels under the skin. These protoporphyrins are highly sensitive to sunlight. When they absorb sunlight, it results in a reaction which causes severe pain and inflammation resulting in symptoms of EPP.

EPP is a very rare inherited disorder that affects males and females in equal numbers. It is estimated that the disorder occurs in about 1 in about 75,000 to 1 in 200,000 individuals in Europe. The number of patients affected by these disorders in the US is unknown. XLP accounts for about 10% of cases in the United States. It is more likely to present in males. Females with XLP may or may not have symptoms.

Symptoms of the following disorders can be similar to those of EPP and XLP. Comparisons may be useful for a differential diagnosis:

There are several other types of porphyrias, all of which involve deficiencies of specific enzymes. Most of the symptoms of these porphyrias are not similar to the symptoms found in erythropoietic protoporphyria. Individuals with porphyria cutanea tarda and congenital erythropoietic porphyria may develop skin lesions; however, these lesions do not resemble the skin lesions found in EPP. It is important to note that individuals with one type of porphyria do not develop any of the other types. In addition, there are skin disorders characterized by hypersensitivity to artificial light and sunlight besides EPP, such as xeroderma pigmentosum and epidermolysis bullosa. The skin lesions in these disorders do not resemble the skin lesions in EPP. (For more information on these disorders, choose porphyria, xeroderma pigmentosum or epidermolysis bullosa as your search terms in the Rare Disease Database.).


ESCO2 Spectrum Disorder

The symptoms associated with Roberts syndrome vary widely from person to person even among members of the same family. Most infants experience growth deficiencies and have abnormalities of the limbs and craniofacial region. Infants with Roberts syndrome often experience life-threatening complications early in infancy.

The ESCO2 spectrum disorders, including Roberts syndrome, are caused by changes (variants or mutations) in the ESCO2 gene.

ESCO2 spectrum disorders affect males and females in equal numbers. Affected children often have parents who are blood relatives. Patients have been reported from all over the world. The two families with Juberg-Hayward syndrome were identified in a tribe in Thailand with the identical ESCO gene mutation.

Symptoms of the following disorders can be similar to those of Roberts syndrome. Comparisons may be useful for a differential diagnosis:

Cornelia de Lange syndrome (CdLS) is a dominantly inherited, multi-system developmental disorder. The asymmetrical upper limb defects are similar but different from those in Roberts syndrome, which is ranging from small hands with single palmar creases and subtle changes in the bones of fingers (phalanges) and the palm (metacarpal bones) to severe forms of lack of fingers (oligodactyly) and truncation of the forearm primarily involving the structures on pinky side (ulnar). The characteristic facial features seen in individuals with CdLS are easy to identify and may be one of the most useful diagnostic signs, which includes one fused heavy eyebrow (synophrys), long eyelashes, depressed nasal bridge, long philtrum, thin upper lip, small widely spaced teeth, disproportionate small and short head (brachycephaly), and low-set ears. Other common clinical presentations are excessive bodily or facial hair (hirsutism), various eye (ophthalmologic) problems, stomach and esophagus (gastroesophageal) dysfunction, heart defects, growth delay, and neurodevelopmental delay. The intellectual disability seen in CdLS is severe; autism and self-destructive tendencies are also seen in many patients. Mildly affected patients may go undiagnosed.About 50% of CdLS patients have a mutation in the NIPBL gene and a small portion of patients have mutations in the SMC1A or SMC3 gene, while the rest have no reported gene mutations. SMC1A and SMC3 proteins are structural subunits of the cohesin complex. Both ESCO2 (the disease-causing gene of RBS) and NIPBL regulate cohesin complex, although through different mechanisms. (For more information on this disorder, choose CdLS as your search term in the Rare Disease Database.)


Esophageal Cancer

掌跖角化病-食管癌综合征

In the early stages esophageal cancer may not be associated with any symptoms (asymptomatic). As the cancer grows, affected individuals may have difficulty swallowing solid foods (dysphagia). This occurs because the tumor has grown enough to partially block the esophageal tube. Initially, this may affect certain foods such as meat, apples or bread, which can stick in the throat. Eventually, affected individuals may have difficulty swallowing liquids. Many individuals may experience pain when attempting to swallow (odynophagia). This most often occurs with dry foods, and can often differentiate cancer from more benign causes of swallowing difficulty.

The exact underlying cause of esophageal cancer is not fully understood. Many cancers are caused by damage to the DNA (deoxyribonucleic acid; genes) in cells which leads to cancer. However, the exact reason normal cells become cancerous is not known. Most likely, multiple factors including genetic and environmental ones play a role in the development of esophageal cancer in certain people. Current research suggests that abnormalities of DNA which is the carrier of the body’s genetic code, are the underlying basis of cellular malignant transformation.

Approximately 17,000 people are diagnosed with esophageal cancer in the United States each year. Squamous cell carcinoma and adenocarcinoma account for about 95% of people with esophageal cancer. The number of people with squamous cell carcinoma is decreasing in the U.S., but the number of people with adenocarcinoma is increasing. The number of people with esophageal cancer varies greatly throughout the world. It is the seventh most common cancer worldwide. Squamous cell carcinoma of the esophagus is more common in East Asia and the Middle East. Adenocarcinoma is more common in Western Europe, North America, and Australia. Adenocarcinoma occurs more often in the lower portion of the esophagus.

Symptoms of the following disorders can be similar to those of esophageal cancer. Comparisons may be useful for a differential diagnosis.

A diagnosis of esophageal cancer is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. A diagnosis is usually confirmed by a biopsy, in which a small piece of tissue is taken and studied under a microscope to identify cancerous cells. The tissue sample is studied by a doctor who specializes in examining tissue and cells and determining what disease is present (pathologist).


Essential Iris Atrophy

ICE syndrome, essential iris atrophy type

Essential iris atrophy is a very rare, progressive disorder of the eye characterized by a pupil that is out of place and/or distorted areas of degeneration on the iris (atrophy), and/or holes in the iris. This disorder most frequently affects only one eye (unilateral) and develops slowly over time. Attachment of portions of the iris to the cornea (peripheral anterior synechiae) and subsequent closure of the drainage angle may lead to secondary glaucoma and vision loss.

Major symptoms of essential iris atrophy may include a displaced and/or distorted pupil, patchy areas of degeneration (atrophy) on the iris, and/or holes in the iris. The edge of the pupil may turn outward (ectropion uveae). The onset of this disorder is gradual, and the changes in the shape and placement of the pupil are usually noticed before any change in vision occurs. Degeneration and holes in the iris may develop over a period of several years.

The cause of essential iris atrophy or any other of the iridocorneal endothelial syndromes is not known. They are thought to be the result of the same mechanism.  The primary defect is believed to be a cellular membrane secreted by the abnormal endothelial cells. This membrane covers the iris and the drainage angle of the eye. The contraction of this membrane leads to pupillary changes and formation of peripheral anterior synechiae with resultant angle closure glaucoma.

Essential iris atrophy is a very rare disorder that predominantly affects females in the middle adult years. The prevalence is not known.

Symptoms of the following disorders can be similar to those of essential iris atrophy. Comparisons may be useful for a differential diagnosis:


Essential thrombocythemia

The greatest health risk in patients with ET is an increased risk of developing blood clots. Blood clots can be in the deep vessels of the legs or lungs; ET patients are also more likely to experience strokes and heart attacks. ET patients can develop clots elsewhere, including within the abdomen, an otherwise rare site for clots to form. The risk of clotting increases with age, and disease-associated risks may be quite different for children than for adults, with children generally being at low risk for clots and other problems related to ET. In addition, (and somewhat counter-intuitively) a subset of ET patients may also be more likely to bleed; this appears to be restricted to a small minority of patients with a very high (over 1.5 million) platelet count. Other symptoms in ET include headaches, fatigue, temporary changes in vision, dizziness, ringing in the ears, vertigo and tingling in the hands.

Over the ensuing decades, Dr. Dameshek’s predictions about a stimulus triggering the proliferation of blood cells were confirmed. The first came in the 1960s, when the genetic basis for another MPN family member known as chronic myelogenous leukemia (CML) was identified as the Philadelphia chromosome, named after the city in which it was discovered. The Philadelphia chromosome is an abnormal chromosome caused by the fusion of two chromosomes in the leukemia cells. This genetic change causes a specific protein, called a kinase, to be overactive. Because kinases are very powerful drivers of cell growth, this genetic change leads to an elevation in blood counts and enlargement of the liver and spleen. Once the genetic basis of CML was identified, drugs that might interfere with kinase activity (kinase inhibitors) were tested and proved to be extraordinarily successful in treating CML. Collectively these studies radically reversed the natural history of the CML by converting what was previously a fatal disease to one with an excellent prognosis. The majority of patients with CML are diagnosed because they have a high white blood cell count, but on occasion patients with CML will only have a high platelet count, therefore every patient with suspected ET is also evaluated for CML, with a test for the Philadelphia chromosome.

Fewer than 1 in 100,000 people are diagnosed with ET in any year (the most recent estimates range from 0.38 to 1.7 per 100,000). Women are more likely to be diagnosed with ET than men, although the reason for this is unknown. The average age of onset is mid-fifties, but the range is wide, and includes women in their childbearing years, which makes up an important subset of ET patients with special therapeutic considerations (discussed below). In children ET is exceedingly rare and typically is an inherited genetic disorder. In adults, the genetic mutations typically identified in ET (described below) are not inherited, and instead are acquired genetic accidents (known as an acquired mutation) that happen during an individual’s lifetime. Genetic accidents happen to all of us as we age, although they do not always result in a disease.

Symptoms of the related myeloproliferative disorders can be similar to those of essential thrombocythemia, although as a general rule the burden of symptoms is milder in ET patients. Comparisons may be useful for a differential diagnosis.

Many, if not most ET patients have no symptoms related to their disease when they are diagnosed, and instead have an abnormally high platelet count identified on routine blood tests. Other ET patients are identified when they have symptoms or a complication – often a blood clot – related to ET. Additional tests may be performed to confirm the elevated platelet count, and to elucidate its possible causes. These may include blood tests that evaluate for iron deficiency and/or inflammatory diseases, and genetic tests for mutations that are seen in ET or related diseases. If no other obvious cause for an elevated platelet count is identified, and/or ET or a related blood disorder is suspected, a hematologist will typically recommend a bone marrow biopsy.


Evans syndrome

The symptoms and severity of Evans syndrome can vary greatly from one person to another as can the onset, course and duration of the disorder. Most individuals exhibit a chronic course with periods of worsening symptoms (exacerbation) and remissions usually induced transiently by treatment. Most symptoms are caused by low levels of specific blood cells in the body. These blood cells perform specific functions. Red blood cells deliver oxygen to the body and remove carbon dioxide, platelets assist in clotting to stop blood loss, and white blood cells help to fight infection.

The exact, underlying cause of Evans syndrome is unknown. Evans syndrome is an autoimmune disorder. It occurs when the immune system produces antibodies that mistakenly attack healthy tissue, specifically red blood cells, platelets and sometimes certain white blood cells.

The incidence and prevalence of Evans syndrome is unknown. The disorder can affect children or adults.

Symptoms of the following disorders can be similar to those of Evans syndrome. Comparisons may be useful for a differential diagnosis.

A diagnosis of Evans syndrome is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation, and a variety of specialized tests. No specific test is conclusive for Evans syndrome and a diagnosis is made after excluding other possible diagnoses. Specifically, a diagnosis of Evans syndrome may be made when autoimmune hemolytic anemia (with a positive direct coombs test) and thrombocytopenia (ITP) occur in the same patient even if not at the same time.


Ewing Sarcoma

Ewing sarcoma is a rare bone tumor that occurs most often in adolescents. It can also arise outside of the bone in soft tissue (extraosseous Ewing sarcoma). Ewing sarcoma is related to another type of tumor known as primitive neuroectodermal tumor (PNET). Researchers have learned that these tumors are associated with the same chromosomal abnormality (balanced reciprocal translocation) and share many physiological characteristics. Consequently, these tumors are sometimes collectively classified as the Ewing family of tumors (EFT). This general term encompasses Ewing sarcoma of bone, extraosseous Ewing sarcoma, primitive neuroectodermal tumor, and Askin’s tumor (a tumor of the chest wall). Ewing sarcoma of bone accounts for approximately 70 percent of the tumors in this family. Generally, the term Ewing sarcoma is preferred because, despite the different names, it is one tumor, molecularly. Ewing sarcoma of bone most often affects the long bone of the legs (femur) and flat bones such as those found in the pelvis and chest well. Ewing sarcoma is an aggressive cancer that may spread (metastasize) to the lungs, other bones, and bone marrow potentially causing life-threatening complications. The exact cause of these tumors is unknown.

Individuals with a tumor in the Ewing family of tumors may exhibit pain, tenderness, and swelling near the affected part of the body. Pain often comes and goes (intermittent) initially, eventually progressing to be more consistent. Weakness and numbness in the affected area can also occur. In some cases, affected individuals may also experience fever, lack of energy, weight loss, low levels of circulating red blood cells (anemia), and increased levels of circulating white blood cells (leukocytosis). A palpable mass is often present.

The exact cause of Ewing sarcoma is unknown and the underlying cell type has not been identified. Most cases are thought to occur randomly, for no specific reason (sporadically).

Ewing sarcoma affects males more often than females. It may affect individuals of any age, but most often occurs in individuals between 10 and 20 years of age. The annual incidence of Ewing sarcoma is 2.93 children per 1,000,000. Approximately 200-250 children and adolescents in the United States are diagnosed with a tumor in the Ewing family of tumors each year. Two-thirds will be long-term survivors (more than five years). The tumor occurs with greater frequency in Caucasians. It is extremely rare in African Americans and Asians.

Symptoms of the following disorders can be similar to those of Ewing sarcoma. Comparisons may be useful for a differential diagnosis:

The diagnosis of a tumor in the Ewing family of tumors is based upon a thorough clinical evaluation, the identification of characteristic symptoms and physical findings, a detailed patient history, and a variety of specialized tests. Such testing includes microscopic evaluation of tumor cells and affected tissue (histopathology) and molecular analysis looking for the EWS-FLI1 translocation.


Fabry disease

Fabry disease is a rare inherited disorder of glycosphingolipid (fat) metabolism resulting from the absent or markedly deficient activity of the lysosomal enzyme, α-galactosidase A (α-Gal A). This disorder belongs to a group of diseases known as lysosomal storage disorders. This enzymatic deficiency is caused by alterations (mutations) in the α-galactosidase A (GLA) gene that instructs cells to make the α-galactosidase A (α-Gal A) enzyme. Lysosomes function as the primary digestive tract of cells. Enzymes within lysosomes break down or digest particular compounds and intracellular structures. α-Gal A functions to break down complex sugar-lipid molecules called glycolipids, specifically, globotriaosylceramide (GL-3 or Gb3), its deacylated form Lyso-GL-3/Gb3 and related glycolipids, by removing the terminal galactose sugar from the end of these glycolipid molecules. The enzyme deficiency causes a continuous build-up of GL-3/Gb3 and related glycolipids in the body’s cells, resulting in the cell abnormalities and organ dysfunction that particularly affect small blood vessels, the heart and kidneys (Desnick 2001, Germain 2010).

Fabry disease is a rare pan-ethnic disorder, meaning that it occurs in all racial and ethnic populations affecting males and females. It is estimated that type 1 classic Fabry disease affects approximately one in 40,000 males. The type 2 later-onset phenotype is more frequent, than the type 1 phenotype by 3-10 fold, and in some populations may occur as frequently as about 1 in 1,500 to 4,000 males (Spada 2006, Hwu 2009, Chien 2012). Data emerging from the newborn screening studies suggests that the incidence of Fabry disease varies in different geographic regions (Spada 2006, Hwu 2009, Burlina 2018, Wasserstein 2019).  Already, newborn screening for Fabry disease has been initiated in several states in the USA.

Symptoms of the following disorders can be similar to those of Fabry disease. Comparisons may be useful for a differential diagnosis:

Schindler disease is a rare inherited metabolic disorder characterized by a deficiency of the lysosomal enzyme alpha-N-acetylgalactosaminidase (alpha-NAGA), which leads to an abnormal accumulation of certain complex compounds (glycosphingolipids and oligosaccharides) in many tissues of the body (Schindler 1989). Schindler disease is inherited as an autosomal recessive disorder. There are three types of Schindler disease. The classic form of the disorder, known as Schindler disease, type I, has an infantile onset. Affected individuals appear to develop normally until approximately one year of age, when they begin to lose previously acquired skills that require the coordination of physical and mental activities (developmental regression). Additional neurological and neuromuscular symptoms may become apparent, including diminished muscle tone (hypotonia) and weakness; involuntary, rapid eye movements (nystagmus); visual impairment; and episodes of uncontrolled electrical activity in the brain (seizures). With continuing disease progression, affected children typically develop restricted movements of certain muscles due to progressively increased muscle rigidity, severe intellectual disability, hearing and visual impairment, and a lack of response to stimuli in the environment. Type II Schindler disease also known as Kanzaki disease, is the adult-onset form with symptoms presenting in the second or third decade of life (Kanzaki 1993). The disorder is characterized by angiokeratoma, a skin lesion and distribution similar to that seen in type 1 classic Fabry disease. Presentation may also include lymphedema, intellectual impairment, and distinct facial features including mildly coarse features, thick lips, a depressed nasal bridge and an enlarged tip of the nose. Type III Schindler disease is an intermediate form the disorder. Symptoms can range from more serious intellectual impairment, neurological dysfunction and seizures to milder neurological and psychiatric issues such as speech and language delays and mild autism-like symptoms. (For more information on this disorder, choose Schindler as your search term in the Rare Disease Database.)