Hemiplegic Migraine

家族性或散发性偏瘫型偏头痛

Hemiplegic migraine is a rare disorder in which affected individuals experience a migraine headache along with weakness on one side of the body (hemiplegia). Affected individuals are described as having a migraine with aura. Aura refers to additional neurological symptoms that occur with or sometimes before, the development of migraine headaches. Hemiplegia is an aura symptom. Additional aura symptoms usually affect vision, but also can affect speech, sensation and mental status. In some affected individuals, hemiplegic migraine occurs because of a change (variant or mutation) in a specific gene. This is called familial hemiplegic migraine. Abnormal variants in four genes, CACNA1A, ATP1A2, SCN1A and PRRT2, have all been shown to cause the familial forms. Some affected individuals are thought to develop the disorder because of a variant in an as-yet-unidentified gene. There is usually a family history of hemiplegic migraines in affected individuals. Some individuals may be the first person in their family with hemiplegic migraine; these individuals are described as having sporadic hemiplegic migraine.

Affected individuals experience hemiplegic migraine attacks. These attacks can range from about one a day to fewer than five in a lifetime. There can often be long episode-free periods during life. Generally, episodes become less frequent as a person ages. Individual episodes can vary in severity and duration. Hemiplegic migraine is a chronic disorder and can be extremely painful and debilitating.

Hemiplegic migraine can be classified as either familial or sporadic.

The number of newly affected individuals within a year (incidence) and prevalence (the overall number of people with a disorder at a given time (prevalence) of hemiplegic migraine is unknown. Studies in a population of Denmark placed the prevalence at 1 in 10,000 individuals in the general population. The prevalence was the same for the familial and sporadic forms. Rare disorders often go misdiagnosed or undiagnosed making it difficult to determine the true frequency of disorders like hemiplegic migraine in the general population.

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

A diagnosis of hemiplegic migraine is based upon identification of characteristic symptoms, a detailed patient history, thorough clinical evaluation and a variety of specialized tests. Two proposed diagnostic criteria have been published (The International Classification of Headache Disorders, 3rd edition and a population-based study of familial hemiplegic migraine suggests revised diagnostic criteria, Thomsen et al. 2002) to help physicians diagnose hemiplegic migraine.

The treatment of hemiplegic migraine is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, physicians who specialize in diagnosing and treating disorders of the brain and central nervous system in children (pediatric neurologists), neurologists, physicians who specialized in treating headaches or migraines, pain specialists, physicians who specialize in diagnosing and treating eye disorders (ophthalmologists), social workers and other healthcare professionals may need to plan treatment systematically and comprehensively. Psychosocial support for the entire family may be beneficial as well.


胎儿母体同种异体免疫所致溶血病

Hemolytic disease due to fetomaternal alloimmunization

Hemolytic Disease of the Fetus and Newborn

Hemolytic disease of the fetus and newborn (HDFN) can occur in an unborn baby or newborn if the mother has red cell antibodies (a diagnosis known as maternal red cell alloimmunization). During pregnancy, these antibodies can cross through the placenta and enter the unborn baby’s blood and destroy the baby’s red blood cells causing anemia (low blood count). The child is at risk for HDFN if their blood type matches the mother’s antibody. Symptoms can be mild or severe. Maternal-fetal incompatibility with ABO, Rhesus factor (Rh) and/or other red blood cell antigens, RhD, Kell, and other non-ABO alloantibodies are the primary cause of moderate to severe HDFN, whereas ABO HDFN is typically mild and occurs after birth.

In the unborn baby (fetus) symptoms may include:

A female can develop red cell alloimmunization after exposure to blood that is not her own through blood transfusion, needle drug use, or pregnancy when mother and baby’s blood may mix due to bleeding, miscarriage, delivery or other procedures. Once she develops antibodies, they remain in her bloodstream forever, though antibody levels can drop to undetectable levels at times. In order for the baby to have HDFN, the mother must have red cell alloimmunization.

In the United States, a nationwide Rh HDFN estimate of 106 per 100,000 births in 1986 was obtained from analysis of the nationwide Birth Defects Monitoring Program.  Since then, alloimmunization rates from 740 to 1200 per 100,000 births and HDFN rates from 3 to 150 per 100,000 births have been estimated from single-center studies of Rh, ABO, or other significant red cell antibodies. Variability in estimated rates may be due to small sample size and differences in HDFN severity reported. A recent study utilized the National Hospital Discharge Survey (NHDS) from 1996 to 2010 to identify newborns with HDN and estimated similar rates.

Other disorders can cause anemia and hyperbilirubinemia in the fetus or newborn. Fetal anemia requiring intrauterine transfusion is most often necessary due to HDFN but can also be needed in cases of parvovirus B19, significant bleeding between the mother and baby (called fetal-maternal hemorrhage) or twin-to-twin transfusion syndrome.

In developed countries, screening for red cell alloimmunization is standard in the first trimester of pregnancy. After a positive antibody screen, the antibody is identified, and the level (titer) should be checked with a blood draw on the mother. If the antibody is known to cause HDFN, it is necessary to find out the baby’s antigen status to understand whether the baby is at risk of HDFN.

Early onset of severe disease, though uncommon, requires close monitoring with serial Doppler ultrasounds and rapid treatment with early IUTs and sometimes other medications such as intravenous immune globulin (IVIG).


Hemophagocytic syndrome

Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening condition caused by an overactive, abnormal response of the immune system. The immune system is the body’s natural defense system against foreign or invading organisms or substances. The immune system is a complex network of cells, tissues, organs, and proteins that work together to keep the body healthy. In hemophagocytic lymphohistiocytosis, the immune system responds to a stimulus or ‘trigger’, often an infection, but the response is ineffective and abnormal. This ineffective, abnormal response, causes a variety of signs and symptoms, which, if not treated, can potentially become life-threatening. Some affected individuals may have a genetic predisposition to developing hemophagocytic lymphohistiocytosis. This is known as the primary or familial form. In other individuals, the disorder occurs sporadically usually when there is an underlying predisposing condition or disorder. This is known as the secondary form. The secondary forms are more common than the familial forms. Hemophagocytic lymphohistiocytosis most often affects infants from birth to 18 months, but can affect individuals of any age. Early diagnosis and prompt treatment is essential.

The onset and severity of hemophagocytic lymphohistiocytosis can vary greatly from one person to another. The specific symptoms that develop can also vary greatly, although the condition often causes multiorgan involvement. Generally, affected individuals develop fevers, a rash, an abnormally large liver (hepatomegaly), and an abnormally large spleen (splenomegaly). Fevers may be prolonged and persistent, often failing to respond to antibiotics. Sometimes, the lymph nodes are also abnormally large (lymphadenopathy). Lymph nodes are part of the lymphatic system, a circulatory network of vessels, ducts, and nodes that filter and distribute certain protein-rich (lymph) and blood cells throughout the body. Lymph nodes are small structures, found in groups throughout the body, that help to filter or drain out harmful substances from the body.

Hemophagocytic lymphohistiocytosis is broadly broken down into primary and secondary (acquired) forms. The condition results from an ineffective, abnormal response of the immune system to a stimulus or ‘trigger’. The underlying mechanisms that cause signs and symptoms to develop are complex. There is overproduction and overactivity of immune system cells called histiocytes and T cells. These are types of white blood cells, which are the primary cell of the immune system and help the body to fight off infection.

Hemophagocytic lymphohistiocytosis most often affects infants or young children, but can affect individuals of any age. It affects boys and girls in equal numbers. In adults, it affects men slightly more often than women. The exact incidence and prevalence is unknown. Rare disorders often go misdiagnosed or undiagnosed making it difficult to determine the true frequency in the general population. About 25% of the people with this disorder, have the familial form.

Symptoms of the following disorders can be similar to those of hemophagocytic lymphohistiocytosis and it may be important to distinguish these disorders from it.

A diagnosis is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Guidelines have been published that detail the criteria necessary for a diagnosis of hemophagocytic lymphohistiocytosis. If five of the following eight symptoms are present, then a clinical diagnosis can be made. These eight symptoms are fever; an abnormally large spleen (splenomegaly); low red cell, white cell, or platelet levels (cytopenias); abnormally high levels of a type of fat called a triglyceride in the blood (hypertriglyceridemia) or low levels of a specific blood clotting protein (hypofibrinogenemia); destruction of blood cells by macrophages (hemophagocytosis) in the bone marrow; low or absent natural killer cell activity; abnormal high levels in the blood of a protein that binds to iron (ferritinemia); and elevated soluble interleukin-2 receptor (sCD25), a specialized protein that builds up in the blood when the immune system is stimulated.


Hemophilia A

The severity and symptoms of hemophilia A can vary greatly from one person to another. Hemophilia A can range from mild to moderate to severe. Factor VIII levels in these categories are 5-40% of normal, 1-5%, and less than 1%, respectively. The age of onset and frequency of bleeding episodes depend upon the amount of factor VIII protein and overall clotting ability of the blood. In most individuals, regardless of severity, bleeding episodes tend to be more frequent in childhood and adolescence than in adulthood.

Hemophilia A is caused by disruptions or changes (variants or mutations) of the F8 gene. The F8 gene contains instructions for creating (encoding) factor VIII. Factor VIII is one of the essential blood proteins and plays a role in aiding the blood to clot in response to injury. Mutations of the F8 gene result in deficient levels of functional factor VIII. The symptoms of hemophilia A occur due to this deficiency.

Hemophilia A is the most common X-linked recessive disorder and the second most common inherited clotting factor deficiency after von Willebrand disease. Hemophilia A mostly affects males but females can also be affected. Approximately 1 in 5,000 newborn males  have hemophilia A. Approximately 60% of individuals with hemophilia A have a severe form of the disorder. All racial and ethnic groups are equally affected by hemophilia.

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

A diagnosis of hemophilia A is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized laboratory tests.


Hemophilia B

The symptoms and severity of hemophilia B vary greatly based upon the level of factor IX present. Hemophilia B can range from mild to moderate to severe. Individuals with mild hemophilia have factor IX levels between 5 and 40% of normal; those with moderate hemophilia have factor levels from 1 to 5% of normal; and individuals with severe hemophilia have factor levels less than 1% of normal. The age an individual becomes aware that they have hemophilia B, known as age of diagnosis, and the frequency of bleeding episodes depends upon the amount of factor IX present in the blood and the family history.

Hemophilia B is caused by a change (variant or mutation) in the F9 gene. The F9 gene is located on the X chromosome and thus is inherited in an X-linked recessive pattern. In about 30% of cases of hemophilia B, the altered gene occurs spontaneously without a previous family history.

Hemophilia B occurs in approximately 1 in 25,000 male births. It is less prevalent than hemophilia A which occurs in approximately 1 in 5,000 male births. Although many hemophilia B carrier females do not have symptoms, an estimated 10-25% will develop mild symptoms and females have also been reported with moderate and severe symptoms. All races and ethnic groups are affected equally. Individuals with severe hemophilia B are usually diagnosed around birth or within the first few years of life; those with moderate hemophilia B, five to six years of age; and individuals with mild hemophilia B may not be diagnosed until later in life and even into adulthood.

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

Diagnosis of hemophilia B is made with attention to the following: the patient’s personal history of bleeding, the patient’s family history of bleeding and inheritance and laboratory testing. Several different specialized tests are necessary to confirm a diagnosis of hemophilia B.


Immunoglobulin A vasculitis

Henoch-Schönlein purpura (HSP) is a rare inflammatory disease of the small blood vessels (capillaries) and is usually a self-limited disease. It is the most common form of childhood vascular inflammation (vasculitis) and results in inflammatory changes in the small blood vessels. The symptoms of HSP usually begin suddenly and may include headache, fever, loss of appetite, cramping, abdominal pain, painful menstruation, hives, bloody diarrhea, and joint pain. Red or purple spots typically appear on the skin (petechiae). Inflammatory changes associated with HSP can also develop in the joints, kidneys, digestive system, and, in rare cases, the brain and spinal cord (central nervous system).

The symptoms of HSP usually begin suddenly. In addition to the characteristic red spotting of the skin (most often on the buttocks and backs of the legs), they may include headache, loss of appetite, and/or fever. The skin typically becomes red (diffuse erythema). Cramping abdominal pain may occur and is usually most severe during the night. Blood may be present in the stool and abnormal bleeding (hemorrhaging) from the gastrointestinal tract can cause bloody diarrhea. Joint pain (arthralgia) may develop in any joint of the body, especially the knees and ankles. Some people with HSP experience vomiting and diarrhea; others may have severe constipation and unusually dark stool (melena).

The exact cause of HSP is not known, although research suggests that this disease may be caused by immune system dysfunction (i.e., increased IgA immune complexes). Autoimmune disorders are caused when the body’s natural defenses against foreign or invading organisms (e.g., antibodies) begin to attack healthy tissue for unknown reasons.

HSP is a rare disorder that affects more males than females. The disease may occur in all age groups, although it most commonly affects children.

Common purpura is the most prevalent type of purpura, occurring most often in women over age 50. When there has been no injury, purpura lesions occur more often than subcutaneous bleeding. However, following surgery or even minor injuries, blood vessel fragility results in excessive bleeding. The bleeding may be reduced by short-term corticosteroid therapy and/or, in postmenopausal women, the administration of estrogen.

The diagnosis of  HSP may be difficult, especially in adults. The disease is frequently confused with other forms of vascular inflammation (see Related Disorders section of this report). Routine laboratory tests are usually not definitive for the disorder. The platelet count is typically normal although white blood cell and sedimentation rates may be elevated.


Hereditary elliptocytosis

遗传性椭圆形红细胞增多症

Hepatic encephalopathy is a brain disorder that develops in some individuals with liver disease. Hepatic encephalopathy is a complex disorder that encompasses a spectrum or continuum of disease that ranges from a subtle condition with no outward signs or symptoms to a severe form that can cause serious, life-threatening complications. Symptoms are related to progressive dysfunction of the brain and may include personality changes, intellectual impairment, impaired memory and loss of consciousness (coma). Hepatic encephalopathy can occur in individuals with acute or chronic liver (hepatic) disease or in individuals whose liver is bypassed by a portosystemic shunt (with no liver disease present). A portosystemic shunt is an abnormal passageway that allows blood from the gastrointestinal tract to bypass the liver. They can be present at birth (congenital) or acquired during life. Hepatic encephalopathy is caused when toxins that are normally cleared from the body by the liver accumulate in the blood, eventually traveling to the brain. Many of the symptoms of hepatic encephalopathy are reversible when promptly detected and treated.

Hepatic encephalopathy encompasses a spectrum or continuum of disease and, consequently, the symptoms and severity of the disorder can vary widely from one person to another. The severity of hepatic encephalopathy can range from mild, barely discernable symptoms to serious, life-threatening complications. Hepatic encephalopathy may develop slowly over time in individuals with chronic liver disease or may occur episodically, worsening and then improving only to recur. An episode of hepatic encephalopathy is often triggered by certain conditions such as infection, gastrointestinal bleeding, constipation, certain drugs, surgery or an alcohol binge. Episodes of hepatic encephalopathy can develop rapidly and without warning, often necessitating hospitalization.

Hepatic encephalopathy occurs in individuals with liver disease when toxins that are normally cleared in the liver accumulate in the blood eventually traveling to and damaging the brain. The exact underlying mechanisms by which hepatic encephalopathy develops in individuals with liver disease are not fully understood.

The exact incidence of hepatic encephalopathy in the general population is unknown. It affects males and females in equal numbers and can occur in individuals of any age who have acute or chronic liver disease. Approximately 24-53 percent of individuals whose liver is bypassed by a portosystemic shunt (with no liver disease present) develop hepatic encephalopathy.

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

A diagnosis of hepatic encephalopathy may be suspected in some individuals with liver disease based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests that are used to rule out other conditions. Such tests may include a complete blood count, liver function tests, tests that evaluate serum ammonia levels, and an electroencephalogram, which is a test that measures the electrical activity of the brain, may be useful in detecting encephalopathy. Specialized imaging techniques such as magnetic resonance imaging (MRI) and computed tomography (CT) scans may be used to rule out other conditions affecting the brain such as tumors.


Hepatitis delta

As previously noted, HDV can present as a co-infection or as a superinfection. Co-infection occurs when a person is simultaneously infected with both HBV and HDV, which is generally less common than superinfection. Superinfection occurs when a person who is already infected with HBV acquires HDV infection.  Age of onset can vary from acquiring infection at birth via mother to child transmission to acquiring as an adult through different routes of infection detailed below.

Hepatitis D is caused by the HDV, which is a unique virus with defective replication processes. Because it cannot replicate like other viruses, it requires co-infection with chronic HBV in order to survive and replicate. HDV is a single-stranded RNA virus and only codes for 2 proteins (HDV large and small antigen). As previously noted, it can present as simultaneous HBV-HDV co-infection or more commonly as a HDV superinfection in patients with underlying chronic HBV. HDV has 8 distinct genetic profiles (genotypes), each with 2-4 subtypes. Genotype 1 is the most prevalent worldwide and is seen predominantly in Europe and North America. Genotype 2 is seen more commonly in Asia and the Middle East. Genotype 3 is mostly seen in the Amazon Basin. Genotype 4 is seen in Taiwan, China, and Japan. Genotypes 5-8 are mostly seen in Africa, although some studies have reported presence of genotypes 5-7 in European regions with newer immigration patterns.

Existing studies vary in their estimates of global prevalence of HDV, estimating from 12 to 74 million, but many believe that the true prevalence is between 15 and 20 million. The variation in prevalence estimates is due to lack of high-quality data, which is further compounded by suboptimal awareness of testing, contributing to significant under-diagnosis of this disease. Existing studies estimate that prevalence of HDV in the US ranges from 100,000 to 150,000 individuals affected. While HDV is found globally, certain regions and countries have observed higher prevalence. For example, some of the highest reported prevalence has been observed in Mongolia, Somalia, the Punjab region of India and the Amazon Basin. HDV is mainly transmitted through activities that involve percutaneous contact (for example, a puncture through the skin) and to a lesser extent through mucosal contact (through the digestive, genital, and urinary tracts) with infectious blood or bodily fluids. Examples of potential routes of infection include: sexual contact with an infected individual; injection drug use that involves sharing needles, syringes or drug preparation equipment; contact with blood or open sores with blood from an infected person; needle sticks or exposures to sharp, contaminated instruments; sharing items such as razors or toothbrushes with an infected person; and mother to child via birth from an infected mother.

HDV only occurs in the setting of HBV infection in humans. However, there are other disorders that may present with signs and symptoms similar to HDV. As previously mentioned, the clinical presentation of HDV can be fairly non-specific and can be seen in patients with other liver diseases. For example, other viral hepatitis infections may present similarly. There are 5 main types of viral hepatitis: A, B, C, D, E. Hepatitis A is usually transmitted via contaminated food and can present similarly to an acute HDV infection. HBV reactivation or flare can also occur in patients with underlying chronic HBV and can mimic the signs and symptoms seen in acute HDV infection. Hepatitis C can be acquired through blood (e.g., blood transfusion, shared needles, etc.) as well as via sexual contact. While it is more common for hepatitis C to progress without symptoms initially then become a chronic infection, acute hepatitis C infection can occur and present very similarly to acute HDV infection. Hepatitis E infection is commonly acquired through contaminated food and water especially among travelers to regions with high prevalence of viral hepatitis. The clinical presentation of hepatitis E can also be very similar to HDV infection.

The detection and diagnosis of HDV is based on laboratory testing of blood samples. Recommendations from the American Association for the Study of Liver Diseases (AASLD) suggest testing for HDV with a total antibody test in patients with chronic HBV who are at high risk. One element of high risk is location, including individuals born in regions with high prevalence of viral hepatitis such as West Africa, the horn of Africa, Central and Northern Asia, Mongolia, Pakistan, Japan, Taiwan, Kiribati, Nauru, the Middle East region, Eastern Mediterranean regions, Turkey, the Amazon Basin and Greenland. Other high-risk individuals are persons who inject drugs, men who have sex with men, persons with HIV or hepatitis C co-infection, individuals at risk for sexually transmitted diseases and patients with elevated liver enzymes despite low HBV DNA levels. The Hepatitis B Foundation recommends testing for HDV in all HBsAg+ patients since risk based testing has been a failure and there are no peer reviewed references that support risk based testing will aid in viral hepatitis elimination.


Hepatocellular carcinoma

Most people do not have any noticeable symptoms associated with hepatocellular carcinoma. They may have symptoms related liver cirrhosis that may become more difficult to control.

The exact reasons why hepatocellular carcinoma develops is not fully understood. It is a multifactorial disorder, which means that there are multiple factors that must occur before the disorder develops.

Hepatocellular carcinoma is one of the most prevalent cancers in the world, but relatively rare in the United States. There are approximately six new cases of HCC per every 100,000 people in the general population of the U.S. The number of people who develop HCC in the U.S. has risen in the last four decades. In certain geographic regions in the world, HCC is much more common most likely due to increased frequency of hepatitis B infection or exposure to aflatoxins. One estimate places HCC as the fifth most common cancer that leads to death in the world.

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

Because hepatocellular carcinoma does not cause symptoms early in the disease, getting a prompt diagnosis is difficult. Since there are more effective treatment options the earlier the disease is identified, early diagnosis is very important.


Hepatoerythropoietic porphyria

The symptoms and severity of HEP can vary from one person to another. Onset is usually within the first two years of life, but mild cases that go undiagnosed until adulthood have been reported. Although HEP is associated with specific, characteristic symptoms, several factors, including the small number of identified cases, make it difficult to establish the full range of associated symptoms of the disorder.

HEP is caused by mutations of both alleles of the UROD gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.

HEP is an extremely rare disorder that affects males and females in equal numbers. Approximately 40 cases have been reported in the medical literature. The exact incidence or prevalence of HEP in the general population is unknown.

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

A diagnosis of HEP is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. HEP may be considered in infants and children with chronic, blistering photosensitivity.


Hermansky-Pudlak syndrome

赫曼斯基-普德拉克综合征

The vast majority of HPS patients (82%) initially present with features of their liver disease, while a minority (18%) present with lung (pulmonary) complaints first. Overall, the most common complaint is an insidiously progressive shortness of breath (dyspnea) at rest or upon exertion, reported in 95% of patients and usually developing after years of liver disease2.  However, given the high prevalence and often multifactorial nature of dyspnea in cirrhotic patients, this complaint is easily overlooked, and HPS patients reportedly have respiratory symptoms for a mean of 4.8 years before diagnosis 7.  In a majority of patients,  dyspnea and hypoxemia progress over time 8.  Furthermore, this progressive decline often occurs despite stable liver function 9.

The cause of HPS remains unclear and it is unknown why some patients with liver disease develop IPVDs while others do not. Hypoxemia in HPS is primarily due to limitations to the movement of oxygen from the lungs into the bloodstream (diffusion limitation), and mismatching between air moving through the lungs and blood moving through the lungs (ventilation-perfusion mismatch), caused by the presence of IPVDs1.

Among cirrhotic subjects awaiting orthotopic liver transplantation (replacing the recipient liver with the donor liver), approximately 70% complain of dyspnea, 34-47% have intrapulmonary vascular dilatations (IPVDs), and 5-32% have HPS 6,18-23.

Portopulmonary hypertension is another vascular complication of liver disease, which is often confused with HPS. However, hepatopulmonary syndrome and portopulmonary hypertension are not the same disease. Although both are abnormalities of the pulmonary vasculature resulting from liver disease, HPS is characterized by vasodilatation and hypoxemia whereas portopulmonary hypertension is characterized by obstruction or narrowing (vasoconstriction) of blood vessels with resulting pulmonary arterial hypertension6.

Because dyspnea is common in liver disease, HPS is often missed or diagnosed late. In the absence of an alternative explanation, a saturation of < 96% is suggestive of HPS.24  Worsening dyspnea in the upright compared to supine position (platypnea) and orthodeoxia (PaO2 drop by more than 5% or 4 mmHg in the upright position) occur in only 25% of patients6 but are highly specific for HPS (thought to be from gravitational re-distribution of blood flow to basilar parts of the lungs, where vascular dilatations are more severe), as are clubbing or cyanosis (in any patient with liver disease).21 Accordingly, clinicians should think of HPS in patients with liver disease and an unexplained oxygen saturation of < 96%, or any of: platypnea, orthodeoxia, clubbing, or cyanosis. After pulmonary evaluation, any patient with a PaO2 < 80 mmHg or alveolar-arterial oxygen gradient (AaDO2) ≥ 15 mmHg that cannot be fully explained by other diagnoses should be referred for a diagnostic workup for possible HPS25.


Hepatorenal Syndrome

Hepatorenal syndrome (HRS) is a form of impaired kidney function that occurs in individuals with advanced liver disease. Individuals with hepatorenal syndrome do not have any identifiable cause of kidney dysfunction and the kidneys themselves are not structural damaged. Therefore, hepatorenal syndrome may be referred as a functional form of kidney impairment. In fact, if the kidney of an individual with hepatorenal syndrome were to be transplanted into an otherwise healthy individual, it would function normally. Hepatorenal syndrome is classified into to two distinct types. Type I is a rapidly progressive condition that leads to renal failure; type II does not have a rapid course and progresses slowly over weeks to months.

Individuals with hepatorenal syndrome will have a variety of nonspecific symptoms including fatigue, abdominal pain, and a general feeling of ill health (malaise). Affected individuals also have symptoms related to advanced liver disease including the accumulation of fluid in the abdomen (ascites), yellowing of the skin and the whites of the eyes (jaundice), an enlarged spleen (splenomegaly) and an enlarged, extremely tender liver (hepatomegaly).

The exact cause of hepatorenal syndrome is unknown. It occurs in individuals with advanced liver disease, especially individuals who have scarring and dysfunction of the liver (cirrhosis). The characteristic finding in individuals with hepatorenal syndrome is narrowing (constriction) of the blood vessels that feed the kidneys (renal vasoconstriction), which results in decreased blood flow to the kidneys, eventually impairing kidney function.

Hepatorenal syndrome affects males and females in equal numbers. The exact incidence of hepatorenal syndrome is unknown. It is estimated to occur in approximately 8-10 percent of individuals with the accumulation of fluid in the abdomen (ascites) and cirrhosis. Although it is most common in individuals with advanced cirrhosis and ascites, hepatorenal syndrome has also occurs in individuals with other forms of liver disease including fulminant hepatic failure.

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

A diagnosis of hepatorenal syndrome is made based upon a thorough clinical evaluation, a detailed patient history, and a variety of specialized tests. The International Ascites Club, an organization dedicated to encouraging scientific research into advanced cirrhosis, has established criteria for a diagnosis of hepatorenal syndrome.


Hereditary angioedema

Hereditary angioedema is a rare inherited disorder characterized by recurrent episodes of the accumulation of fluids outside of the blood vessels, blocking the normal flow of blood or lymphatic fluid and causing rapid swelling of tissues in the hands, feet, limbs, face, intestinal tract, or airway. Usually, this swelling is not accompanied by itching, as it might be with an allergic reaction. Swelling of the gastrointestinal tract leads to cramping. Swelling of the airway may lead to obstruction, a potentially very serious complication. These symptoms develop as the result of deficiency or improper functioning of certain proteins that help to maintain the normal flow of fluids through very small blood vessels (capillaries). In some cases, fluid may accumulate in other internal organs. The severity of the disease varies greatly among affected individuals.

The characteristic symptom of hereditary angioedema is recurrent episodes of swelling of affected areas due to the accumulation of excessive body fluid (edema). The areas of the body most commonly affected include the hands, feet, eyelids, lips, and/or genitals. Edema may also occur in the mucous membranes that line the respiratory and digestive tracts, which is more common in people with hereditary angioedema than in those who have other forms of angioedema (i.e., acquired or traumatic). People with this disorder typically have areas of swelling that are hard and painful, not red and itchy (pruritic). A skin rash (urticaria) rarely is present.

Hereditary angioedema is inherited as an autosomal dominant trait. Genetic diseases are determined by two genes, one received from the father and one from the mother.

Hereditary angioedema is a rare disorder that affects males and females in equal numbers. Symptoms typically begin in early childhood. An estimated one in 50,000 to 150,000 individuals is affected by this disorder worldwide.

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

Acute nonhereditary angioedema affects the skin and mucous membranes. It commonly clears up on its own after 1 or 2 days. Any number of allergens may be responsible including drugs, insect stings, bites, and certain foods (e.g., eggs, shellfish, nuts, and fruits). Some people can have very severe allergic reactions (anaphylaxis) that may result in respiratory angioedema. Acquired angioedema can also occur because of immune disorders (e.g., B-cell lymphoproliferative disease), chronic lymphocytic leukemia, multiple myeloma, lupus (SLE), chronic sinusitis, dental infection, or certain blood disorders (essential cryoglobulinemias). Other acquired edemas may occur because of surgery (i.e., mastectomy), malignancy, and/or autoimmune diseases. Acquired angioedema may occur at any age. (For more information on these disorders, choose Anaphylaxis, Leukemia, Myeloma, Lupus, and Cryoglobulinemia as your search term in the Rare Disease Database.)


遗传性乳腺癌-卵巢癌综合征

Hereditary Breast and Ovarian Cancer Syndrome

Hereditary breast and ovarian cancer (HBOC) syndrome is an inherited cancer-predisposition syndrome. Affected individuals have a significantly greater risk of developing certain cancers, particularly breast cancer, in both men and women, and ovarian cancer in women. Affected individuals tend to develop cancer earlier in life as well, usually before the age of 50. Additionally, to a lesser degree, there is also an increased risk of developing other types of cancer including prostrate cancer, melanoma, and pancreatic cancer. HBOC syndrome is most commonly associated with variations (mutations) in the either the BRCA1 gene or the BRCA2 gene. In HBOC syndrome, there is usually a family history of cancer and the variant gene is inherited. The underlying causes of cancer are not completely understood and while inheriting a variation in the BRCA1 or BRCA2 gene greatly increases a person’s risk of developing certain cancers, it does not mean that the people will definitely develop cancer. Some people with variations in these genes never develop cancer. How these gene variants affect individuals and families will be different. Most likely, there are additional genetic (e.g. variations in other genes) or environmental factors (e.g. smoking) that influence whether and how cancer develops.

HBOC syndrome is a cancer predisposition syndrome in which individuals are at a greater risk of developing certain cancers, particularly breast or ovarian cancer. Signs and symptoms are associated with the development of cancer, and depend upon the type and location of cancer. HBOC syndrome can cause cancer in multiple family members over several generations in one family. It can also be associated with more than one cancer in the same person.

HBOC syndrome is caused by a variation in a single major cancer-causing gene, most often the breast cancer susceptibility gene 1 (BRCA1) or the breast cancer susceptibility gene 2 (BRCA2). Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body.

HBOC syndrome can affect both men and women and occurs in people from all ethnic and racial backgrounds. In fact, HBOC syndrome is the most common cause of hereditary breast and ovarian cancer in all ethnic and racial backgrounds. The prevalence, which is the number of people with a disorder at a given time, is not known, but estimated to be somewhere between 1 in 200 to 1 in 800 people in the general population. In certain populations, the prevalence is higher. In individuals of Ashkenazi Jewish descent, HBOC syndrome affects about 1 in 40 people. Sometimes, this is due to a founder effect. A founder effect is when a small, isolated population of people expands over several generations leading to a high prevalence of a genetic trait.

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

Several different groups have put out guidelines for screening and diagnostic criteria for HBOC. These guidelines help to identify individuals who would most benefit from screening for variations in the BRCA1 or BRCA2 genes. One of the most commonly referenced guidelines was created by the National Comprehensive Cancer Network (NCCN). Information on these guidelines can be found at: https://www.nccn.org/professionals/physician_gls/default.aspx


Hereditary Coproporphyria

The episodes or attacks that characterize HCP usually develop over the course of several hours or a few days. Affected individuals usually recover from an attack within days. However, if an acute attack is not diagnosed and treated promptly recovery can take much longer, even weeks or months. Most affected individuals do not exhibit any symptoms in between episodes. Onset of attacks usually occurs in the 20s or 30s, but may occur at or just after puberty. Onset before puberty is extremely rare. Attacks are more common in women than men.

The CPOX gene mutation that predisposes individuals to developing HCP is inherited as an autosomal dominant trait. 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. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.

HCP is a rare disorder that can potentially affect males and females in equal numbers, although symptoms are more prevalent in females. The exact incidence and prevalence of HCP is unknown.

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

A diagnosis of HCP is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. The observation of reddish brown urine that is free of blood is indicative, but not conclusive, of an acute porphyria. The intolerance of medications such as oral contraceptives is also suggestive of an acute porphyria.


Hereditary hemorrhagic telangiectasia

遗传性出血性毛细血管扩张症

The symptoms associated with HHT vary from person to person. Differences in disease expression (phenotype) partially reflect the specific gene that is mutated in HHT.  Phenotypic penetrance is age dependent with approximately 90% showing signs or symptoms by age 40-45 years. Some individuals may experience symptoms during infancy or early childhood; others may show few signs or symptoms until the thirties, forties or later in life.

HHT is caused by changes (mutations) in five different genes. It is likely that more genes are yet to be discovered.

HHT affects males and females in equal numbers. Symptoms can occur at any age. The disorder is estimated to occur in approximately 1 per 5,000 people. However, because some affected individuals develop few obvious symptoms and findings, the disorder often remains unrecognized. HHT is known to be underdiagnosed. This makes it difficult to determine the true frequency of HHT in the general population.

Symptoms of the following disorders can be similar to those of hereditary hemorrhagic telangiectasia. Comparisons may be useful for a differential diagnosis:

Von Willebrand disease (VWD) is a common inherited bleeding disorder in the general population affecting males and females equally. There are three main types of VWD each with differing degrees of severity and inheritance patterns, though AVM are not seen as part of VWD. Uncommonly, individuals with HHT may also have Von Willebrand disease due to random chance. (For more information on this disorder, choose von Willebrand as your search term in the Rare Disease Database.)


Juvenile Paget disease

chronic congenital idiopathic hyperphosphatasemia

Hereditary hyperphosphatasia is a rare genetic bone disorder (osteopathy) that usually becomes apparent during infancy or early childhood. Affected individuals develop progressive skeletal malformations especially in the long bones of the arms and legs. Skeletal malformations in the legs may cause problems walking and may eventually result in short stature. Additional symptoms include pain, fractures of affected bones and muscle weakness. Because the biochemical and radiographic findings of hereditary hyperphosphatasia are similar to those of Paget’s disease (a focal skeletal disorder of adults characterized by abnormal bone turnover), the disorder is sometimes referred to as juvenile Paget’s disease. However, despite these similarities, the two disorders are distinct. Hereditary hyperphosphatasia is inherited in an autosomal recessive pattern.

The severity of symptoms associated with hereditary hyperphosphatasia varies from patient to patient. Symptoms usually become apparent during infancy or early childhood usually between 2 and 3 years of age. Most individuals develop widening and bowing of the long bones of the legs eventually resulting in problems walking and short stature. Thickening of the upper domelike portion of the skull (calvaria) is another common finding.

About two-thirds of cases of hereditary hyperphosphatasia are caused by changes (mutations or pathogenic variants) of the TNFRSF11B gene

Hereditary hyperphosphatasia affects males and females in equal numbers. Like all recessive disorders it is more common in countries where within-family marriage is practiced. More than 50 cases have been described since the disorder was first reported in the medical literature in 1956.

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

A diagnosis of hereditary hyperphosphatasia is made based upon a thorough clinical evaluation, identification of characteristic symptoms and a variety of x-rays tests that reveal distinct radiographic findings. Affected individuals also have elevated levels of serum alkaline phosphatase and other biochemical markers of bone turnover, detectable through blood and urine tests.


遗传性肌瘤病及肾细胞癌综合征

Hereditary leiomyomatosis and renal cell cancer

Hereditary Leiomyomatosis and Renal Cell Carcinoma

The symptoms and progression of HLRCC can vary widely from one person to another, even among members of the same family. Some individuals who inherit a gene variant for HLRCC will not develop any symptoms. The susceptibility to developing symptoms varies among family members as well. For example, if a parent develops kidney cancer, it does not necessarily mean that an affected child will.

HLRCC is caused by variant in the FH gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a variant in a gene occurs, the protein product may be faulty, inefficient or absent. Depending upon the functions of the protein, this can affect many organ systems of the body.

HLRCC affects males and females in equal numbers. The disorder may be recognized more readily in females because of the development of uterine fibroid and associated symptoms. The exact incidence and prevalence of HLRCC in the general population is not well defined but it is generally considered to be underdiagnosed.

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

A diagnosis of HLRCC is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Various clinical criteria have been suggested for diagnosing HLRCC including multiple cutaneous leiomyomas with at least one histologically confirmed leiomyoma or


Hereditary Multiple Osteochondromas

Hereditary multiple osteochondromas is a rare disorder that affects bone growth. Bony tumors (exostoses or osteochondromas), covered with cartilage, typically appear in the growth zones (metaphyses) of the long bones adjacent to the areas where tendon and muscles attach to the bone. These growths vary in size and number among affected individuals, even within the same family. Some individuals will present with a few large lumps while others will show several small growths. The median age of diagnosis is three years and almost all affected individuals are diagnosed by 12 years of age.

Hereditary multiple osteochondromas is inherited as an autosomal dominant genetic condition. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation in the affected individual. Approximately 10% of cases of HMO are thought to be the result of new mutations. At present two genes, EXT1 and EXT2, are known to show mutations in HMO patients and it is thought that these genes function as tumor suppressors. For some affected individuals no mutation in either gene is detected.  In almost all these cases, the mutation negative patients do not have a familial history for exostoses. Most likely, they have an EXT1 or EXT2 mutation in only part of their body cells and the mutation is absent or undetectable in blood cells, which are usually used for DNA analysis.  Data indicates that individuals with EXT1 mutations may have more severe effects than those with EXT2 mutations. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.

The prevalence of HMO has been estimated to be about 1 of 50,000 live births. A high prevalence of this disorder has been reported in some isolated communities. Hereditary multiple osteochondromas is a disorder that affects males and females in equal numbers but in general males tend to be more severely affected.

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

The diagnosis of HMO is based on clinical features, X-ray findings and family history. Molecular genetic testing of the EXT1 and EXT2 genes is available to confirm the diagnosis.


Hereditary Neuralgic Amyotrophy

The hallmark finding is the abrupt onset of pain in one or both of the shoulders and/or arms. The right side of the body is affected more often than the left, but both shoulders are affected in approximately one-third of patients. When both shoulders are affected, symptoms are usually worse on one side.

Some cases of hereditary neuralgic amyotrophy are caused by mutations or duplications in the SEPT9 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body. Although SEPT9 mutations have been shown to cause HNA, these mutations have only been found in approximately 55% of affected individuals in the North Americas, and in only < 5% of the families from Europe. Therefore, it is likely that additional, as-yet-unidentified genes may also cause or contribute to HNA (genetic heterogeneity).

HNA is a rare disorder that affects males a little more often than females. The exact incidence or prevalence is unknown, but can be extrapolated from the incidence of sporadic, non-familial NA which is about 1 in 1000 per year and the fact that in a large group of 1300+ NA patients approximately 1 in 10 people had a family history for the disorder. This combined suggests that HNA occurs in about 1 in 10.000 people in the population.

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

A diagnosis of HNA is based upon identification of characteristic symptoms, a detailed patient history and a thorough clinical evaluation. A variety of specialized tests can help rule out other diagnoses.


Hereditary orotic aciduria

Hereditary orotic aciduria is an extremely rare genetic disorder. When untreated, affected infants can develop a blood (hematologic) disorder called megaloblastic anemia as well as failure to thrive, susceptibility to infection, and orotic acid crystals in the urine (crystalluria) resulting from excretion of orotic acid in the urine. Impaired neurological development has been observed, but invariably, especially since a treatment has become available.

Some affected infants develop megaloblastic anemia, a condition in which the bone marrow produces unusually large, structurally-abnormal, immature red blood cells (megaloblasts). Megaloblastic anemia usually becomes apparent within the first few months of life.

Hereditary orotic aciduria is caused by variations in the uridine monophosphate synthetase (UMPS) gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain.

Hereditary orotic aciduria is an extremely rare disorder that affects both men and women. Only about 20 individuals with this disorder have been reported in the medical literature. The birth prevalence, which is the number of babies born with a disorder compared to the total number of live births, is estimated to be less than 1 in 1,000,000 live births. Because rare diseases often go misdiagnosed or undiagnosed, determining their true frequency in the general population is extremely difficult.

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

A diagnosis of hereditary orotic aciduria is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and examination of the urine.


遗传性感觉和自主神经病变1型

Hereditary Sensory and Autonomic Neuropathy Type 1E

hereditary sensory autonomic neuropathy with dementia and hearing loss

Hereditary sensory and autonomic neuropathy type 1E (HSAN1E) is a rare genetic disorder. It is considered an adult-onset disorder with symptoms usually starting to occur in the 20-30’s. Although HSAN1E is considered to be a subtype of HSAN, a group of genetic disorders most-ly affecting the sensory and autonomic neurons of the peripheral nervous system, the central nervous system is also severely affected in HSAN1E patients, especially in the later stage of the disease. HSAN1E patients usually have three main symptoms, hearing loss, sensory neu-ropathy, and cognitive decline (dementia), and many have other various symptoms such as sleep disorders and epilepsy. The symptoms are progressive, worsening with age. At this time, there are no available treatments other than management for each specific symptom, (i.e., hearing aids for the hearing loss) and there is currently no cure for HSAN1E. Based on a re-cent study, the average life span of HSAN1E patients is approximately 50 years. HSAN1E is an autosomal dominant genetic disorder caused by a mutation in the DNMT1 gene.

The signs and symptoms of HSAN1E and the age of onset are variable, even within members of the same family. HSAN1E typically runs a 15 to 30 year progressive course.

HSAN1E is caused by a mutation in the DNMT1 gene. Genes provide instructions for creating proteins that play critical roles to allow the body to function normally. When a deleterious mu-tation occurs within a gene, the protein produced will not function normally, and this can af-fect a specific organ or multiple organs of the body. The disease mechanism of the HSAN1E mutations is still being investigated.

HSAN1E affects both genders equally. Due to the complexity of disease and relatively lack of awareness of this disease, HSAN1E is often misdiagnosed or undiagnosed, making it difficult to assess its prevalence and incidence in the population.

DNMT1 gene mutations have also found to cause autosomal dominant cerebellar ataxia with deafness and narcolepsy (ADCA-DN). ADCA-DN patients share the same triad of core symp-toms, hearing loss, sensory neuropathy and cognitive decline, and also have adult onset. Progressive cerebellar ataxia and narcolepsy are other common features.

A diagnosis of HSAN1E may be suspected based on the identification of the three main symptoms, a detailed patient history, and a family history. DNA testing for mutations in the DNMT1 gene is necessary to confirm the diagnosis of HSAN1E.


遗传性感觉和自主神经病2型

Hereditary sensory and autonomic neuropathy type 2

Hereditary Sensory and Autonomic Neuropathy Type II

The symptoms of HSNs are highly variable, even among members of the same family. HSNs of various types may attack a single nerve (mononeuropathy) or many nerves simultaneously (polyneuropathy). The resulting symptoms may involve sensory, motor, reflex or blood vessel (vasomotor) function.

HSAN2 is caused by a change (variant or mutation) in one of four genes. HSAN2A is caused by variants in the WNK1 gene, HSAN2B is caused by variants in the FAM134B gene, lately renamed to RETREG1. HSAN2C is caused by variants in the KIF1A gene, HSAN2D is caused by variants in the SCN9A gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a variant of a gene occurs, the protein product may be altered, faulty, inefficient or absent. Depending upon the functions of the protein, this can affect many organ systems of the body.

HSAN2 affects males and females in equal numbers. The exact incidence and prevalence are unknown. HSAN2 may go misdiagnosed or undiagnosed, making it difficult to determine the disorder’s true frequency in the general population.

Symptoms of the following disorders can be similar to those of HSAN2. Comparisons may be useful for a differential diagnosis.

A diagnosis of HSAN2 is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Early onset of sensory deficits and a family history consistent with autosomal recessive inheritance are indicative of HSAN2.


遗传性感觉和自主神经病4型

Hereditary sensory and autonomic neuropathy type 4

Hereditary Sensory and Autonomic Neuropathy Type IV

congenital insensitivity to pain with anhidrosis (CIPA)

Infants cannot or have a markedly decreased ability to sweat (anhidrosis). Sweating is the body’s way of cooling itself and maintaining proper body temperature. The inability to sweat can cause recurrent episodes of fever including extremely high fevers that result in a significant elevation of body temperature (hyperpyrexia). When someone has a significantly increased body temperature it is known as hyperthermia and this can be the initial sign of the disorder. The inability to sweat can affect the entire body, but the trunk and arms are mostly affected. Seizures are sometimes associated with fever episodes. The skin may become abnormally thickened and callused with an exaggeration of normal skin lines (lichenification). There may be areas of hair loss of the scalp (hypotrichosis) and malformation of the fingernails and toenails.

HSAN IV is caused by mutations in the neurotrophic tyrosine kinase receptor type I (NTRK1) gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.

HSAN IV affects males and females in equal numbers. Several hundred cases have been reported in the medical literature. The exact incidence and prevalence is unknown. Many patients have been reported in Japan and the frequency of the disorder is higher in the Japanese and Israeli-Bedouin populations due to a founder effect. A founder effect is when a small isolated population of settlers (founders) expands over several generations leading to a high prevalence of a particular genetic trait. Regions with a high rate of consanguinity also show a higher prevalence. Onset of the disorder is at birth.

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

A diagnosis is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests, mainly genetic testing. Characterized symptoms proposed as necessary for a diagnosis are insensitivity to pain, anhidrosis and intellectual disability. However, the severity of these symptoms is highly variable.


遗传性感觉和自主神经病变1型

hereditary sensory and autonomic neuropathy (HSAN) type I

The symptoms of the HSNs are highly variable, even among members of the same family. HSNs of various types usually involve many nerves simultaneously (polyneuropathy). The resulting symptoms may involve sensory, motor, reflex or blood vessel (vasomotor) function.

HSN1A is caused by a mutation in the SPTLC1 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.

HSN1 affects males and females in equal numbers. The exact incidence and prevalence is unknown. The prevalence is estimated to be approximately 2 in 1,000,000 people in the general population. HSN1 frequently goes undiagnosed or misdiagnosed, making it difficult to determine the true frequency in the general population.

Symptoms of the following disorders can be similar to those of HSN1. Comparisons may be useful for a differential diagnosis.

A diagnosis of HSN1 is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. Characteristic symptoms along with a family history consistent with autosomal dominant inheritance are suggestive of HSN1.


Hereditary spastic paraplegia

Symptoms describe an individual’s experience of a medical disorder. Signs are the objective evidence of the disorder, documented, for example by physician examination, laboratory studies, or magnetic resonance images (MRI). The primary symptom of HSP is difficulty walking due to weakness and tightness (spasticity) in the legs. Both legs are affected, usually to a relatively similar degree.

As with all inherited disorders, the HSPs are due to gene mutations.  Each genetic type of HSP is due to a mutation in a specific HSP gene.  For example, mutations in SPG3A/atlastin, SPG4/spastin, and SPG7/paraplegin genes cause SPG3A, SPG4, and SPG7 HSP, respectively.

HSP affects males and females of all ethnic groups from around the world.

The primary symptom of HSP, walking disturbance due to leg weakness and spasticity also occurs in many other conditions, including non-inherited (non-genetic) conditions, and as a feature of other inherited neurologic conditions. Some of these disorders have specific treatments (e.g. B12 deficiency, 5-methyltetrahydrofolate reductase deficiency, DOPA-responsive dystonia, cervical spondylosis, multiple sclerosis, HIV, and copper deficiency); and others, though not treatable, have prognoses that differ significantly from HSP (e.g. amyotrophic lateral sclerosis and primary lateral sclerosis).

HSP is diagnosed by the following: 1) typical symptoms (lower extremity spastic weakness that may be non-worsening (early childhood onset) or slowly progressive over many years; 2) findings on neurologic examination (lower extremity hyperreflexia usually accompanied by some degree of spasticity and sometimes a specific pattern of muscle weakness); and 3) by the exclusion of alternate disorders (by history, examination, neuroimaging, and laboratory studies as needed).


Hereditary spherocytosis

HS is divided into mild, moderate, and severe forms of the disease. Classification is based on the amounts of hemoglobin, reticulocytes, and bilirubin and the amount of spectrin in red blood cells. Hemoglobin transports oxygen in the blood. Reticulocytes are immature red blood cells. Bilirubin is formed in the liver when hemoglobin is broken down. Spectrin is a protein that helps keep the shape of a cell. Decreased hemoglobin and spectrin and increased reticulocytes and bilirubin are associated with more severe HS. People with severe HS are usually diagnosed at younger ages than those with moderate or mild disease. Those with mild HS may have compensated hemolysis. This means that red blood cells are created at the same rate as they are destroyed. These individuals may not have noticeable symptoms, and thus be diagnosed later in life.

HS is caused by changes (mutations) in five different genes that code for proteins that are part of the membrane of red blood cells. These genes are ANK1, SLC4A1, SPTA1, SPTB, and EPB42. HS is inherited in an autosomal dominant manner 75% of the time and an autosomal recessive manner 25% of the time.

HS affects 1 in 2,000 people in North America. It also occurs in other regions of the world, although not as well studied. No genetic changes that are more common in certain groups of people (founder mutations) have been reported. HS affects males and females equally. Age at diagnosis of HS is often between 3 – 7 years but can occur in infancy with severe disease or into adulthood with mild disease.

Hereditary nonspherocytic hemolytic anemia (HNSHA) is a term used to describe a group of rare, genetically transmitted blood disorders involving destruction of red blood cells. Anemia happens when the red blood cells are destroyed faster than they are replaced. In these disorders, the outside membrane of the cell is weakened, causing it to have an irregular, non-spherical shape and to burst (hemolyze) easily. These disorders are mainly caused by defects in the chemical processes involved in the breakdown of sugar molecules (glycolysis). Red blood cells depend on this process for energy. If this process is not working, the red blood cell cannot function properly and breaks down. The more common forms of HNSHA involve glucose-6-phosphate dehydrogenase (G6PD) deficiency, pyruvate kinase deficiency and hexokinase deficiency. There may be as many as 16 red blood cell enzyme abnormalities that may cause hereditary nonspherocytic hemolytic anemia. In addition, HNSHA may arise as the result of immune disorders, toxic chemicals and drugs, antiviral agents (eg, ribavirin), physical damage, and infections. (For more information on this disorder, choose hereditary hemolytic nonspherocytic anemia as your search term in the Rare Disease Database.)

HS is first suspected based on the clinical picture. People with HS often present with one or more of the characteristic features; anemia, splenomegaly, or jaundice. Jaundice is the most common feature that develops in young infants. Other common reasons that people with HS see a specialist are anemia with an unknown cause or anemia that is resistant to iron supplementation. The family history is suggestive if there are relatives with a diagnosis of HS, any of the characteristic features, or a history of surgical removal of the spleen (splenectomy) or gallbladder (cholecystectomy).


Hermansky-Pudlak syndrome

赫曼斯基-普德拉克综合征

albinism with hemorrhagic diathesis and pigmented reticuloendothelial cells

Hermansky-Pudlak syndrome (HPS) is a rare, hereditary disorder that consists of decreased pigmentation (albinism) with visual impairment, and blood platelet dysfunction with prolonged bleeding. Some individuals have lung fibrosis, inflammatory bowel disease, immunodeficiency or an abnormal storage of a fatty-like substance (ceroid lipofuscin) in various tissues of the body.

The first symptoms of HPS often include easy bruising, bleeding gums, nose bleeds and excessive bleeding after surgery or accidents. The classic symptoms of Hermansky-Pudlak syndrome include the lack of color (pigmentation) in the skin, hair, and eyes (oculocutaneous

HPS is caused by changes (variants or mutations) in 11 different genes. Variants in the HPS1, AP3B1, HPS3, HPS4, HPS5, HPS6, BLOC1S8, BLOC1S3, BLOC1S6, AP3D1, or BLOC1S5 genes are responsible for HPS types 1 to 11, respectively.  Research suggests that an abnormality of the formation or movement of lysosome-like vesicles in specific cells may be responsible for the development of the disease.

HPS is a rare disorder that affects males and females in equal numbers. The worldwide prevalence of HPS is estimated at 1-9 per 1,000,000. Worldwide, HPS is the third most common form of albinism. HPS occurs in different populations, but it is most prevalent in people from Puerto Rico. In northwest Puerto Rico, HPS affects one of every 1,800 individuals, and one in 21 individuals of northwest Puerto Rican descent are believed to be carriers of a variant (mutation) in the HPS type 1 gene. A variant in the HPS type 3 gene is frequent in central Puerto Rico, where an estimated 1 of every 4,000 individuals are affected with HPS type 3.

Symptoms of other disorders can be similar to those of Hermansky-Pudlak syndrome. Comparisons may be useful for a differential diagnosis.

The presence of a combination of hypopigmentation (light hair and skin color), characteristic eye findings and a history of bleeding episodes (bruising, nosebleeds, gum bleeding, prolonged bleeding after minor wounds or surgical procedure) can lead to consideration of a diagnosis of HPS. A specialized test demonstrating characteristic appearance of the blood platelets under an electron microscope is consistent with the diagnosis. The HPS diagnosis and HPS subtype is ultimately established by identifying mutations in one of the HPS genes (HPS1, AP3B1, HPS3, HPS4, HPS5, HPS6, BLOC1S8, BLOC1S3, BLOC1S6, AP3D1, or BLOC1S5) by molecular genetic testing These tests are available on a clinical basis.

Protection from prolonged sun exposure is critical for individuals with HPS because their skin is sun-sensitive, and they are at risk for sun-induced skin damage (skin cancer, solar keratoses and melanocytic nevi).


Herpes, Neonatal

Neonatal herpes is a rare disorder affecting newborn infants infected with the herpes simplex virus (HSV), also called herpesvirus hominis. In most instances, a parent with oral or genital herpes transfers the disorder to an offspring before, during, or shortly after birth. Symptoms vary from mild to severe depending on which of two types of herpes simplex virus is involved. Type 1 HSV is responsible for the more severe cases of the disorder while patients with Type 2 HSV usually present with milder symptoms.

Disseminated Neonatal Herpes Infection (about 25% of cases)

Neonatal herpes is caused by an infection of the newborn by the herpes simplex virus (HSV).

Neonatal Herpes is a very rare disorder.  It affects about 1 in 5,000 to 7,500 live births.  During their first year of life, these infants usually develop antibodies against the Herpes virus.  Only malnourished infants, those with an impaired immune system, or otherwise weakened infants tend to carry the infection after one year.

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

The diagnosis of neonatal herpes is difficult and requires the physician to maintain a high level of skepticism and wariness. Frequently, neither parent is aware that he or she is carrying the virus. HSV infection must be considered for any neonate presenting with non-specific symptoms such as fever, poor feeding, lethargy and/or seizure. Any rash accompanyied by fluid-filled blisters (vesicles) should be cultured for HSV, and because such tests take days before the results are known, anti-viral treatment should be started.


Hiccups, Chronic

A hiccup is an involuntary spasmodic contraction of the muscle at the base of the lungs (diaphragm) followed by the rapid closure of the vocal cords. Usually, hiccups last for a few hours or, occasionally, a day or two. However, chronic hiccups are ones that continue for an extended period of time. Episodes that last for more than two days and less than a month are sometimes called persistent hiccups. On rare occasions, hiccups persist even longer than a month or recur frequently over an extended period of time. The longest recorded episode of these chronic hiccups lasted 60 years.

Hiccups are unmistakable, and rarely taken for anything else. They often start for no apparent reason, and usually go away on their own in a few minutes. Of concern is the period of time required for an episode to run its course. Hiccups that persist over a period of time may cause exhaustion and weight loss from lack of sleep and the interruption of normal eating patterns.

The cause of hiccups often is not known, but some of the triggers sometimes thought to cause them include the following: spicy foods, hot liquids, any disease or illness that irritates the nerves that control the diaphragm.

Hiccups affect males more often than females. Hiccups occur in practically every human being, but chronic hiccups are very rare.

There are many disorders involving the autonomic nervous system which controls unconscious activities of the body such as breathing, sweating, heartbeat, hiccups, coughing, etc.

The diagnosis of chronic hiccups may be obvious, but blood, imaging, and other laboratory studies may be used to determine the underlying cause.


Hinman syndrome

A common presentation of HS is urinary incontinence without symptoms of urgency or the sudden, uncontrollable need to urinate. This is similar to symptoms in patients with neurogenic bladder. Parents may notice their child not urinating as frequently or urinating too much. When asked, parents may report that the patient does not urinate; however, when they are requested or reminded to urinate, the child may empty their bladder. The patient will often report that they cannot feel the sensation of their bladder being full. Other signs include starting and stopping of the urine stream (intermittent stream), squeezing abdominal muscles to urinate and increased urine left in the bladder (residual volume) despite voiding multiple times. These can lead to increased pressure in the bladder due to increased urine volume and bladder muscle contraction. Recurrent UTIs, involuntary defecation (encopresis) and constipation can also be seen in patients with HS.

There continues to be disagreement in the scientific community about whether the disease is acquired or inherited. In other words, it is not clear whether parents pass this condition on to their children or if the disorder occurs by chance or because of environmental causes. Children under higher psychosocial stress are likely to have an increased risk. Children with behavioral issues or developmental delays will sometimes voluntarily contract the external sphincter (bladder outflow valve) to prevent urination, which can further aggravate this issue. A hallmark of HS is called detrusor-external sphincter dyssynergia which means the muscle that contracts the bladder (detrusor) and the external sphincter become disconnected. The nerve signals that usually trigger the bladder to contract and the sphincter to open for urine to flow out become unsynchronized and lead to urinary dysfunction. Similarly, disordered signals from the gastrointestinal tract can contribute to constipation and lack of control over bowel movements (fecal incontinence) in patients with HS.

The prevalence of HS is not known. The medical literature has described that HS occurs more frequently in males, but it has also been reported that females are more likely to develop complications from the disorder. This condition usually begins during childhood, but rarely, HS can occur during puberty, which is associated with increased severity.

Neurogenic bladder occurs because of a disruption of messages between the nervous system and bladder due to abnormalities in brain, spinal cord or nerves. Causes include tethered cord (anchoring of the spinal cord to nearby tissues), multiple sclerosis, diabetes mellitus, stroke, brain tumor or spinal cord injury. The presence of a sacral dimple is a typical telltale sign in children with tethered cord or lower spinal cord abnormalities. Symptoms include intermittent voiding, urinary retention and incontinence without an associated urge to void.

No formal diagnostic criteria have been established for Hinman syndrome. A diagnosis is suspected based upon identification of characteristic findings, a detailed patient and family history, a thorough clinical evaluation and voiding records. This condition is managed by pediatricians, nephrologists (kidney doctors) and urologists (surgical kidney and bladder doctors).


Hirschsprung disease

Hirschsprung disease (HSCR) is a birth defect. This disorder is characterized by the absence of particular nerve cells (ganglions) in a segment of the bowel in an infant. The absence of ganglion cells causes the muscles in the bowels to lose their ability to move stool through the intestine (peristalsis). Peristalsis is a normal process of the body. Peristalsis creates wave-like contractions from the muscles lining the intestines. These contractions propel stool and other waste material through the digestive system. Ineffective peristalsis leads to stool backing up in the intestines. Affected individuals can develop constipation and partial or total obstruction of the bowels. Pain and discomfort can result. If not treated, a potentially serious bacterial infection may develop. The specific symptoms can vary from one person to another. HSCR can occur as an isolated problem or as part of a broader disorder that affects multiple organ systems.

Symptoms in the newborn period include failure to pass the meconium within a short time after birth. Meconium is the dark sticky substance that is normally present in the intestine at birth and is passed as an infant’s first bowel movement after birth. Failure to pass a first stool for 24-48 hours is suggestive of HSCR.

Hirschsprung disease that occurs as an isolated problem has been associated with mutations in several different genes. Approximately 50% of affected individuals have one of these gene abnormalities. This gene changes cause people to be susceptible or predisposed to developing the disorder. A person who is genetically predisposed to a disorder carries a gene (or genes) for the disease, but it may not be expressed unless it is triggered or activated under certain circumstances, such as due to particular environmental factors (multifactorial inheritance).

Hirschsprung disease affects males 3 to 4 times more often than females, although long-segment HSCR has a gender ratio of 1:1. The disorder occurs in approximately one in 5,000 live births. It is usually apparent shortly after birth, but may present in older children and adults. Hirschsprung disease should be considered in people with a history of severe constipation.

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

Chronic intestinal pseudo-obstruction (CIP) is a rare, potentially disabling gastrointestinal disorder characterized by abnormalities affecting the involuntary, coordinated muscular contractions (a process called peristalsis) of the gastrointestinal (GI) tract. Peristalsis propels food and other material through the digestive system under the control of nerves, pacemaker cells and hormones. CIP usually results from abnormalities affecting the muscles or nerves that are involved in peristalsis. Consequently, peristalsis becomes altered and inefficient. The symptoms of CIP resemble those caused by mechanical obstruction of the small bowel. Mechanical obstruction refers to something (such as a tumor, scar tissue, etc.) physically blocking the passage of food and other material through the GI tract. In individuals with CIP no such physical obstruction is present, hence the term pseudo-obstruction. Common symptoms include nausea, vomiting, abdominal pain, abdominal swelling (distention) and constipation. Ultimately, normal nutritional requirements cannot be met leading to unintended weight loss and malnourishment. CIP can potentially cause severe, even life-threatening complications. (For more information on this disorder, choose Intestinal pseudoobstruction as your search term in the Rare Disease Database.)

In almost all cases, treatment of HSCR requires surgery to remove the part of the colon and/or rectum that lacks the normal nerve development, and to join the two healthy ends together. There are three standard surgical procedures designed to correct this disorder. The choice of procedure is a function of the training and experience of the surgeon. Each procedure removes the affected part and attaches the healthy part of the bowel to the rectum completing what is known as a pull-through procedure. Currently most procedures are performed in a single stage.


Histidinemia

Histidinemia is a rare hereditary metabolic disorder characterized by a deficiency of the enzyme histidase, which is necessary for the metabolism of the amino acid histidine. The concentration of histidine is elevated in the blood. Excessive amounts of histidine, imidazole pyruvic acid, and other imidazole metabolism products are excreted in the urine. The majority of individuals with histidinemia have no obvious symptoms that would indicate that a person has this disorder (asymptomatic). Histidinemia is inherited in an autosomal recessive pattern.

Histidinemia is considered a benign condition. For years, intellectual disability and speech disorders were associated with histidinemia. However, these findings are now considered coincidental and not due to the metabolic defect of histidinemia because reports of follow-up from newborn screening have demonstrated that the majority of infants with histidinemia do not develop clinical symptoms (asymptomatic). Nevertheless, clinical symptoms have been reported in some patients with histidinemia. To reconcile this with the benign findings from newborn screening, it has been suggested that histidinemia might be a risk factor for the development of CNS problems, and that such problems might develop only in an unfavorable circumstance such as an abnormal perinatal event.

Histidinemia is inherited in an autosomal recessive pattern. Genetic diseases are determined by two genes, one received from the father and one from the mother.

Histidinemia is one of the most common inborn errors of metabolism. Based upon newborn screening of more than 20 million infants in several countries, histidinemia is estimated to occur in about one in 11,500 births overall. The disorder appears to be most prevalent among people of French Canadian or Japanese descent. Based upon newborn screening reports, approximately one in 8,600 infants in Quebec and one in 9,500 infants in Japan are affected by the disorder. The abnormality begins at birth and affects males and females in equal numbers. Histidinemia is now thought to be a primarily benign disorder.

In some states in the United States (e.g., New York and Massachusetts) routine screening of newborns for histidinemia was conducted through blood or urine tests. However, newborn screening for histidinemia has been discontinued. A diagnosis of histidinemia may be made based upon increased levels of histidine in the blood or urine.


Hodgkin Disease

Hodgkin’s disease is one of a group of cancers known as a lymphoma. Lymphoma is a general term used to describe cancers that affect the lymphatic system, especially the lymph nodes. Tumors often form in the lymph nodes (places where lymphatic vessels unite) and/or the area around the nodes. Fever, night sweats, and weight loss may occur along with swollen lymph nodes. The exact cause of Hodgkin’s disease is unknown.

Usually, the first sign of Hodgkin’s disease is a swollen lymph node. Two-thirds of the time, a lymph node in the neck is affected. Otherwise, lymph nodes in the armpits, chest, groin, or abdomen are affected.  The disease may spread to other lymph nodes, the area around the nodes, the spleen, liver, lungs, and bone marrow.  Some affected individuals may also have fever, night sweats, weight loss, and, rarely, bone pain. In some cases, abnormal enlargement of the spleen (splenomegaly) or the liver (hepatomegaly) may occur. Additional symptoms may include abnormalities affecting the gastrointestinal system and/or kidneys.

The exact cause of Hodgkin’s disease is not known. Some preliminary research suggests that an infectious agent, such as a virus (e.g., Epstein Barr Virus) may play some role in Hodgkin’s disease. Recent studies indicate that there may be a genetic susceptibility to Hodgkin’s disease in the young adult form of the disorder. It is also felt that environmental factors or immune system deficiencies may play a role in the development of Hodgkin’s disease. Thus, the cause may be multifactorial.

The majority of individuals with the adult form of Hodgkin’s disease are between 15 and 40 years of age at the time of diagnosis. A smaller number of individuals are affected after the age of 50. Hodgkin’s disease may also affect children. Hodgkin’s disease accounts for less than one percent of all cases of cancer in the United States.

Symptoms of the following disorders can be similar to those of Hodgkin’s Disease.  Comparisons may be useful for a differential diagnosis:

Non-Hodgkin’s lymphomas are a group of cancers of the lymphatic system. Swollen lymph nodes in the neck or groin occur and usually spread throughout the body.  Anemia (abnormally low levels of red blood cells), leukemia (abnormally high levels of abnormal white blood cells), weight loss, fever, night sweats, and weakness may also occur.  The cause of non-Hodgkin’s lymphoma is unknown but it may be caused by a virus.  Non-Hodgkin’s Lymphoma may occur at any age.


Holoprosencephaly

Holoprosencephaly (HPE) is the failure of the prosencephalon, or forebrain, to develop normally. The forebrain is a region of the brain in the fetus that develops into parts of the adult brain, including the cerebral cortex. Instead of the normal complete separation of the left and right halves of the forebrain, there is an abnormal continuity between the two sides. There are several different types of holoprosencephaly. In the alobar form, there is no separation between the right and left halves at all. In semilobar HPE, at least some separation of the two halves is present. In the lobar form, most of the brain has separated into right and left sides, though there is incomplete division into the two halves.

Holoprosencephaly is a malformation sequence with a very variable degree of severity for both the brain and facial abnormalities. Intellectual disability is associated with HPE and seizures are often present.

Holoprosencephaly is a birth defect that arises during the first few weeks of the pregnancy. Diabetes in the mother during the pregnancy can increase the risk of holoprosencephaly in the fetus. However, for most children, no known intrauterine exposure is identified that is causally related to holoprosencephaly in that child.

Holoprosencephaly affects males and females in equal numbers before birth and has been reported in many ethnic groups. The incidence of holoprosencephaly has been estimated at 1 in 250 during early embryonic development, and approximately 1 in 16,000 live births.

Holoprosencephaly can also occur in association with malformations in other organ systems that are not directly related to holoprosencephaly.

The diagnosis of holoprosencephaly is usually made by MRI or CT of the brain. Holoprosencephaly can sometimes be detected prenatally through ultrasound or MRI, though mild forms may not be reliably detected prenatally.


Heart-hand syndrome

Holt-Oram syndrome is a disorder that affects approximately 1 in 100,000 individuals. It is characterized by abnormalities in the bones of the upper limb, a family or personal history of a congenital heart malformation, and/or an abnormality in the electrical impulses that coordinate the muscle contractions of the heart (cardiac conduction defect). In some affected individuals, an abnormal wrist (carpal) bone is the only evidence of the disease. Seventy-five percent of those affected have a congenital heart malformation. Holt-Oram syndrome is an autosomal dominant genetic condition that is associated with a change (mutation) in the TBX5 gene. While this mutation can be inherited, most cases result from a new mutation in patients without a family history of the disorder.

The symptoms and physical findings associated with Holt-Oram syndrome vary greatly from person to person, even within the same family. Upper limb malformations range from abnormally long thumbs that look like fingers (triphalangy) to an absent thumb bone or absent thumb. Other types of upper limb malformations may also be present including underdevelopment or absence of the bones in the forearm (radius and ulna), fusion or abnormal development of thumb and wrist bones (thenar and carpal), and abnormal position of the thumb, forearm or shoulders. Affected individuals may be unable to fully extend the arms, rotate the arms inward toward the body with the palms facing down (pronation), or rotate the arms outward with the palms facing upward (supination). More severe cases include a malformation in which the hands are attached to shoulder with absent or shortened arms (phocomelia). In some affected individuals, an abnormal wrist (carpal) bone is the only evidence of the disease.

The only gene known to be associated with Holt-Oram syndrome is the TBX5 gene. A TBX5 gene mutation has been identified in approximately 74% of individuals affected with Holt-Oram syndrome. This is likely to be an underestimate of the true TBX5 mutation frequency, since genetic testing does not always detect all types of mutations. Currently, there are more than 70 known mutations in the TBX5 gene that cause Holt-Oram syndrome. Potential causes for the remainder of affected individuals include incorrect reading and translation of the TBX5 gene during protein production.

Holt-Oram syndrome is a rare genetic disorder that occurs in many racial and ethnic groups; and affects males and females in equal numbers. The estimated prevalence is 1/100,000 livebirths.

Symptoms of the following disorders may be similar to those of Holt-Oram syndrome. Comparisons may be useful for a differential diagnosis:

Okihiro syndrome (Duane-radial ray syndrome) is an autosomal dominant genetic condition associated with an abnormality in the SALL4 gene. SALL4-related disorders are characterized by upper limb, vision, hearing and kidney abnormalities and can also be associated with heart defects.


Homocystinuria due to cystathionine beta-synthase deficiency

Homocystinuria due to Cystathionine Beta-Synthase Deficiency

Cystathionine Beta-Synthase (CBS) deficiency, more commonly referred to as homocystinuria is a rare metabolic condition characterized by an excess of the compound homocysteine in the urine and blood. CBS deficiency is one of the conditions which often result from deficiency of any one of several enzymes involved in the conversion of the essential amino acid methionine to another amino acid (cysteine)–or, less commonly, impaired conversion of the compound homocysteine to methionine. Enzymes are proteins that accelerate the rate of chemical reactions in the body. Certain amino acids, which are the chemical building blocks of proteins, are essential for proper growth and development. In most cases, homocystinuria is caused by reduced activity of an enzyme known as cystathionine beta-synthase and this results in CBS deficiency. Infants who develop homocystinuria due to CBS deficiency (which is also known as classical homocystinuria) may fail to grow, or grow longer too fast, often have difficulty with gain weight at the expected rate (failure to thrive) and have developmental delays.

The symptoms associated with homocystinuria due to CBS deficiency are highly variable. Some affected individuals may have only very mild signs of the disorder; others may have many different symptoms including some potentially life-threatening complications. Individuals can be separated into two distinct groups: those who respond to therapy with pyridoxine (vitamin B6) and those who do not. Generally, individuals who respond to pyridoxine therapy have a milder form of the disorder, most likely because of residual activity of the CBS enzyme, but this does not mean that they will not have life-threatening complications. In addition, the presence and specific location of blood clots also determines the severity of associated symptoms in each individual.

Homocystinuria due to CBS deficiency is caused by changes (mutations) of a gene that regulates the production of the enzyme cystathionine beta-synthase. Mutations of the CBS gene may result in reduced activity of the cystathionine beta-synthase enzyme, which is involved in the conversion of the essential amino acid methionine to another amino acid (cysteine). Deficiency of the enzyme leads to increased levels of methionine and the compound homocysteine in bodily fluids, reduced concentrations of cysteine, and the characteristic symptoms and physical findings seen in those with homocystinuria due to CBS deficiency. More than 160 different mutations of the CBS gene have been identified in individuals with the disorder, with many affecting only one or a small number of affected families (kindreds).

Homocystinuria due to CBS deficiency is a rare disorder that affects males and females in equal numbers. Population studies suggest that the worldwide frequency of homocystinuria in the general population is one in 344,000. In individual countries, the prevalence may be higher. In Ireland the prevalence has been estimated to be 1 in 65,000. In Germany, the prevalence has been estimated at 1 in 17,500. Several studies in four European countries, suggested that the prevalence of homocystinuria due to CBS deficiency is as high as 1 in 6,400 to 1 in 20,000.

Symptoms of the following disorders can be similar to those of homocystinuria due to CBS deficiency. Comparisons may be useful for a differential diagnosis.

A diagnosis of homocystinuria due to CBS deficiency may be suspected based upon identification of characteristic findings. A diagnosis may be confirmed by a thorough clinical evaluation, a detailed patient history and a variety of specialized tests. Tests that can detect elevated levels of homocysteine, methionine, or homocysteine in the plasma or urine may be used to help confirm a diagnosis of homocystinuria. Usually individuals will undergo genetic testing looking for changes in both copies of the CBS gene to confirm their diagnosis.  Historically and occasionally now, tests can be performed to determine the level of enzyme function in certain cells of the body to confirm CBS deficiency.


Horner Syndrome

Horner syndrome is a relatively rare disorder characterized by a constricted pupil (miosis), drooping of the upper eyelid (ptosis), absence of sweating of the face (anhidrosis), and sinking of the eyeball into the bony cavity that protects the eye (enophthalmos). These are the four classic signs of the disorder.

The characteristic physical signs and symptoms associated with Horner syndrome usually affect only one side of the face (unilateral).  These include drooping upper eyelid; contracted pupil; dryness (lack of sweating) on the same side of the face (ipsilateral) as the affected eye; and retraction of the eyeball.

Horner syndrome may result from any one of a variety of factors, including carotid artery dissection; the development of a tumor in neck or chest cavity, particularly a neuroblastoma and a tumor of the upper part of the lung (Pancoast tumor); the development of a lesion in midbrain, brain stem, upper spinal cord, neck, or eye orbit; inflammation or growths affecting the lymph nodes of the neck; and/or surgery or other forms of trauma to the neck or upper spinal cord.

Horner syndrome is a rare disorder that affects males and females in equal numbers and may occur at any age, among any ethnic grouping in any geographic location.

Symptoms of the following disorders can be similar to those of Horner’s Syndrome.  Comparisons may be useful for a differential diagnosis.

The diagnosis of Horner syndrome and the localization of the lesions that cause the disorder can be determined by pharmacological tests combined with imaging techniques such as magnetic resonance imaging and ultrasonography of the carotid artery.