毛发-鼻-指(趾)综合征2型

Trichorhinophalangeal syndrome type II (TRPS2), also known as Langer-Giedion syndrome, is an extremely rare inherited multisystem disorder. TRPS2 is characterized by fine, thin hair; unusual facial features; progressive growth retardation resulting in short stature (dwarfism); abnormally short fingers and toes (brachydactyly); cone-shaped formation of the growing ends of certain bones (epiphyseal coning); and/or development of multiple bony growths (exostoses) projecting outward from the surfaces of various bones of the body. In addition, affected individuals may exhibit unusually flexible (hyperextensible) joints, diminished muscle tone (hypotonia), excess folds of skin (redundant skin), and/or discolored elevated spots on the skin (maculopapular nevi). Affected individuals may also exhibit mild to severe mental retardation, hearing loss (sensorineural deafness), and/or delayed speech development. The range and severity of symptoms varies greatly from case to case. TRPS2 is due to the absence of genetic material (chromosomal deletions) on chromosome 8. The size of the deletion varies from case to case.

The range and severity of symptoms varies among individuals with trichorhinophalangeal syndrome type II. Affected individuals will not have all of the symptoms listed below.  The most common symptoms include fine, thin hair; unusual facial features; short stature; abnormalities of the hands and feet; and/or development of multiple bony growths (exostoses) projecting outward from the surfaces of various bones of the body. Additional characteristic abnormalities may include mental retardation, diminished muscle tone (hypotonia), and/or skin abnormalities.

With few exceptions, most cases of trichorhinophalangeal syndrome type II are the result of the absence of genetic material (chromosome deletions). Rarely, those with the syndrome have children. Two documented cases show that the deletion is inherited in an autosomal dominant manner.

Trichorhinophalangeal syndrome type II is an extremely rare disorder that appears to affect males approximately three times as frequently as females. More than 60 cases have been reported in the medical literature.

Symptoms of the following disorders can be similar to those of Trichorhinophalangeal Syndrome Type II.  Comparisons may be useful for a differential diagnosis:

The diagnosis of trichorhinophalangeal syndrome type II may be suspected at birth in some cases by a thorough clinical evaluation and identification of characteristic features. Abnormalities that are usually present at birth include unusual facial features including a large, rounded (bulbous) nose, thin, sparse hair and/or excess skin. Molecular genetic testing can confirm a diagnosis of TRPS2 by identifying mutations of the TRPS1 or EXT1 genes.


Trichorhinophalangeal Syndrome Type III

毛发鼻指(趾)综合征1型和3型

Trichorhinophalangeal syndrome type III (TRPS3), also known as Sugio-Kajii syndrome, is an extremely rare inherited multisystem disorder. TRPS3 is characterized by fine, thin light-colored hair; unusual facial features; abnormalities of the fingers and/or toes; and multiple abnormalities of the growing ends (epiphyses) of the bones (skeletal dysplasia), especially in the hands and feet. Characteristic facial features may include a pear-shaped or rounded (bulbous) nose; an abnormally long prominent groove (philtrum) in the upper lip; and/or abnormalities such as delayed eruption of teeth. In addition, affected individuals also exhibit severe shortening of the fingers and toes (brachydactyly) due to improper development of bones in the hands and feet (metacarpophalangeal shortening). Additional features often include short stature (dwarfism) and/or additional skeletal abnormalities. The range and severity of symptoms may vary from case to case. TRPS3 is thought to have autosomal dominant inheritance.

The symptoms of trichorhinophalangeal syndrome type III may vary in range and severity from case to case.  Common symptoms include fine, thin light-colored hair; unusual facial features; multiple abnormalities affecting the growing ends (epiphyses) of the certain bones, particularly those in the hands and feet; severe shortening of the fingers and toes (brachydactyly); and/or additional skeletal abnormalities.

Trichorhinophalangeal syndrome type III is inherited in an autosomal dominant trait. Genetic diseases are determined by two genes, one received from the father and one from the mother.

Trichorhinophalangeal syndrome type III is an extremely rare disorder that, in theory, affects males and females in equal numbers. However, of the reported cases, most affected individuals have been female. Approximately 15 cases have been reported in the medical literature.

Symptoms of the following disorders can be similar to those of Trichorhinophalangeal Syndrome Type III (TRPS3).  Comparisons may be useful for a differential diagnosis:

Trichorhinophalangeal Syndrome Type I (TRPS1) is an extremely rare inherited multisystem disorder characterized with symptoms and physical features similar to those associated with TRPS3.  These may include fine, thin hair; a rounded (bulbous) pear-shaped nose; dental anomalies; multiple abnormalities of the growing ends (epiphyses) of bones, particularly in the hands and feet; abnormally short (brachydactyly) and curved fingers and toes; and/or short stature (dwarfism).  In most cases, the shortening of the fingers and toes in individuals with TRPS1 is typically much less severe than in individuals with TRPS3.  Trichorhinophalangeal Syndrome Type I has autosomal dominant inheritance.   (For more information on this disorder, choose Trichorhinophalangeal Syndrome Type I as your search term in the Rare Disease Database.)


Trichothiodystrophy

TTD is a genetically heterogenous condition. This means that mutations in several different genes may be responsible for the syndrome. Many patients with TTD have abnormalities in genes involved in the nucleotide excision repair pathway which is responsible for repairing DNA damage caused by ultraviolet radiation. The inability to repair DNA damage can lead to excessive sunburn in some patients and skin cancer in a few rare patients. These DNA repair genes also play a role in gene transcription, which is the first step in the process of creating proteins that tell the body how to function.

TTD presents at birth. Males and females are affected in equal numbers. The estimated incidence is about 1 in 1,000,000 newborns in the United States and Europe. Over 100 patients have been reported worldwide. TTD has been reported in all ethnic groups.

Symptoms of the following disorders may resemble those of trichothiodystrophy. Comparisons may be useful for a differential diagnosis.

An initial evaluation for TTD involves a diagnostic work-up, including obtaining a detailed history of the patient’s prenatal and neonatal history. A thorough physical exam is performed to assess clinical features such as hair abnormalities, short stature, small chin, ichthyosis, intellectual impairment or developmental delay, cataracts, cryptorchidism (in males) and bone and teeth anomalies. Evaluation by a developmental pediatrician or neurologist may determine whether there is any developmental delay or intellectual disability. MRI imaging of the brain to identify abnormal patterns of myelination is often performed. Laboratory testing for immune function, blood count, low red blood cell MCV, elevated hemoglobin A2 level and iron levels can also be performed. TTD is often diagnosed by polarized light microscopy of hair shafts, revealing a tiger-tail pattern. The classical tiger-tail pattern alone usually is enough to diagnose TTD. However, there are other conditions with similar hair shaft abnormalities and often genetic testing is needed to confirm the diagnosis. Some patients with features of TTD will not have mutations in the known genes. They may have mutations in yet to be identified TTD associated genes.


Trigeminal Neuralgia

The most significant symptom of trigeminal neuralgia is recurring episodes of intense, short-lived spasms of pain of the lower portion of the face and the jaw. The nose is not infrequently affected. Much less often, the eyes and forehead are affected. In most cases, pain is limited to one side of the face (unilateral). The pain has been compared to a series of electrical shocks followed by a steady dull ache. The pain often starts and stops rapidly. Intense pain usually lessens rapidly (usually within several seconds), but the following dull aching pain may persist for as much as one to two minutes. For many individuals, pain is completely gone in between episodes. However, for some individuals, even some individuals with TN1, some degree of pain may persist.

The exact cause of trigeminal neuralgia is not fully understood. In most cases, the disorder results from a blood vessel pressing against the trigeminal nerve near the base of the brain. This compression may damage the nerve and cause excess bursts of neurological activity. The reason a blood vessel ends up pressing against the trigeminal nerve is not fully understood.

Trigeminal neuralgia affects females slightly more often than males. Although the exact incidence is unknown, approximately 10,000-15,000 new cases occur each year in the United States. The disorder most frequently affects individuals more than 50 years of age. However, cases can occur in younger adults as well. In younger individuals, the cause is often idiopathic, but when compared to older adult cases are more likely to be caused by damage to the central nervous system as in individuals with multiple sclerosis. Although extremely rare, TN can occur in children.

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

A diagnosis of trigeminal neuralgia is based upon identification of characteristic symptoms, a detailed patient history, and a thorough clinical evaluation. TN should be suspected in individuals with facial pain affecting one side of the face. Because there is no specific diagnostic test for TN, physicians rely on individual’s personal history and description of symptoms when considering a diagnosis of TN.


Trigeminal trophic syndrome

The following symptoms may develop in the areas of the face affected by TTS:

TTS occurs after injury or damage to the trigeminal nerve. Symptoms can appear weeks to years after injury.

Trigeminal trophic syndrome is an extremely rare diagnosis. Females are more often affected than males. TSS is more common in middle to late adulthood, but younger people are also diagnosed with this syndrome. The average age of diagnosis is 57 years. Until 2019, there were about 200 patients reported in the medical literature.

There are several disorders that have symptoms similar to TTS. These include:


Trimethylaminuria

Trimethylaminuria is a rare disorder in which the body is not able to metabolize the chemical trimethylamine, and this causes body odor. Trimethylamine is the chemical that gives rotten fish a bad smell. When the normal metabolic process fails, trimethylamine accumulates in the body, and its odor is detected in the person’s sweat, urine and breath. The foul odor can be socially and psychologically damaging in adolescents and adults.

The fish-odor smell is the obvious symptom; otherwise affected individuals appear normal and healthy.

Primary trimethylaminuria is a rare metabolic disorder caused by changes (variants) in the FMO3 gene. Humans have several FMO genes, but only variants in FMO3 cause trimethylaminuria. For reasons that are unclear, many different variants of the FMO3 gene exist.

Trimethylaminuria is a rare metabolic disorder. Several hundred cases have been reported in the medical literature. Some clinicians believe that the disorder is under-diagnosed since many people with mild symptoms do not seek help. However, some physicians do not recognize the symptoms of trimethylaminuria when a person with body odor seeks a diagnosis.

The presence of the rotten-fish odor is indicative, especially in severe cases. However, diagnosis based on smell is unreliable because the odor is often episodic and not everyone can detect the smell of trimethylamine. In addition, based on smell, trimethylaminuria can be difficult to distinguish from other conditions that cause an unpleasant body odor. Diagnosis is based on urinary analysis of trimethylamine and trimethylamine N-oxide, which can distinguish between severe and mild cases. Urine analysis after the administration of large doses of trimethylamine can distinguish carriers of the condition from unaffected individuals. Genetic testing is available to distinguish between primary genetic trimethylaminuria, which will result in severe symptoms, and secondary, non-genetic forms of the disorder.


Triosephosphate Isomerase Deficiency

Triosephosphate isomerase (TPI) deficiency is a rare genetic multisystem disorder. It is characterized by lack or reduced activity of the enzyme triosephosphate isomerase, an enzyme necessary for the breakdown (metabolism) of certain sugars in the body. Affected individuals experience low levels of circulating red blood cells due to premature destruction of red blood cells (hemolytic anemia) and severe, progressive neurological symptoms. Specific symptoms vary from case to case. Intellectual disability is a variable finding. Additional symptoms may develop including disease of the heart muscle (cardiomyopathy) and a susceptibility to developing chronic infections. Affected individuals usually develop life-threatening complications early during childhood. TPI deficiency is inherited as an autosomal recessive trait.

The symptoms of TPI deficiency vary from case to case. The disorder is characterized by hemolytic anemia and progressive neurological findings. Hemolytic anemia occurs before birth (neonatally) in approximately half of the cases.

TPI deficiency is inherited as an autosomal recessive trait. Genetic diseases are determined by two genes, one received from the father and one from the mother.

TPI deficiency affects males and females in equal numbers. Approximately 30 to 50 cases have been reported in the medical literature since the disorder initial description in 1965.

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

A diagnosis of TPI deficiency is suspected based upon a thorough clinical evaluation, a detailed patient history, and identification of characteristic findings. A diagnosis may be confirmed by molecular genetic testing that identifies the characteristic genetic mutation associated with TPI deficiency.


Triploidy

Most fetuses (unborn babies) affected with triploidy are spontaneously miscarried early in the pregnancy. If the pregnancy continues to term, the baby dies within the first days of life. Infants affected with complete triploidy have the following signs and symptoms:

Triploidy is the presence of a complete additional set of chromosomes. The triplication of the chromosomes is caused by the fertilization of an egg by two sperms, or the fertilization of an egg by a sperm that has an extra set of chromosomes or by the fertilization of an egg that has an extra set of chromosomes by a normal sperm. This disorder does not run in families and is not associated with maternal or paternal age.

Triploidy occurs in about 1-3% of all pregnancies. About 2/3 of triploid pregnancies are male.

Symptoms of the following disorders are caused by duplication, triplication or deletion of chromosomes:

The presence of multiple major malformations, low amniotic fluid and/or growth restriction on fetal ultrasound during pregnancy raises the suspicion of triploidy. The diagnosis can be made during pregnancy by chromosome analysis (karyotyping) of cells obtained by amniocentesis or chorionic villus sampling (CVS). The diagnosis can be confirmed after birth by chromosome analysis of tissue (skin) obtained from the affected infant. Triploidy cannot be diagnosed by chromosome microarray testing. The accuracy of non-invasive prenatal testing using cell-free fetal (cff) DNA in the diagnosis of triploidy is still being studied. Abnormal levels of specific maternal blood proteins such as alpha-fetoprotein, human chorionic gonadotropin, estriol and pregnancy-assisted plasma protein-A have been associated with an increased risk for triploidy.


Trismus-pseudocamptodactyly syndrome

牙关紧闭-假性先天性指屈曲综合征

TPS is a rare genetic disorder of muscle development and function. It is characterized by the inability to fully open the mouth (trismus), often resulting in problems with chewing. Although this is one of the most significant findings, it may not be as severe in some affected individuals. In those whom this abnormality is severe, limited and/or impaired chewing may cause difficulties with eating and proper digestion.

TPS is an autosomal dominant disorder caused by changes in the MYH8 gene. All cases of TPS studied to date were found to have the same change in the MYH8 gene. This gene is involved in making the instructions for the development of the limb skeletal muscles and the muscles in the face.

TPS affects females and males equally. However, twice as many affected females have been reported. The current prevalence rate of TPS is unknown. Approximately 11 families and over 300 individual cases have been reported since the disorder was first described in 1969. Of those cases, some have been traced to a Dutch female who came to the United States and settled in Tennessee during the eighteenth century. In addition, other reported cases have included five affected individuals in three generations of one Japanese family, six affected members of a German family. Affected individuals of families from the Netherlands, Canada, United Kingdom, Belgium, and Taiwan have also been reported.

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

Freeman-Sheldon syndrome, is a rare, autosomal dominant disorder genetic condition that is apparent at birth (congenital). It is characterized by abnormal skeletal development and an unusual expressionless face with full cheeks and a small mouth, giving a typical whistling facial appearance. Symptoms may include permanent fixation of the fingers in a flexed position (camptodactyly), unusual outward positioning of the fingers (ulnar deviation of the fingers), and/or abnormal inward bending of the foot (clubfoot). In addition, affected individuals may have deep set and widely-spaced eyes, small nose and nostrils, small mouth, vertical folds in the jaw skin, and/or other facial features. In some cases, sideways curvature of the spine (scoliosis) may be present. Other skeletal malformations may become clear during X-ray or other imaging procedures. Individuals with Freeman-Sheldon syndrome are of normal height. (For more information on this disorder, search Freeman Sheldon syndrome in the Rare Disease Database.)


Trisomy 13 Syndrome

Trisomy 13 Syndrome is a rare chromosomal disorder in which all or a portion of chromosome 13 appears three times (trisomy) rather than twice in cells of the body. In some affected individuals, only a percentage of cells may contain the extra 13th chromosome (mosaicism), whereas other cells contain the normal chromosomal pair.

Associated symptoms and findings may vary in range and severity from case to case.  However, Trisomy 13 Syndrome is often characterized by craniofacial, neurologic, heart (cardiac), and/or other defects.

In individuals with Trisomy 13 Syndrome, all or a relatively large region of chromosome 13 is present three times (trisomy) rather than twice in cells.  In about five percent of cases, only a percentage of cells contains the extra 13th chromosome (mosaicism).

Trisomy 13 Syndrome is sometimes called Patau Syndrome, after one of the researchers (Patau K) who identified the syndrome’s trisomic origin in 1960.  The syndrome appears to affect females slightly more frequently than males and occurs in about one in 5,000 to 12,000 live births.

Symptoms of the following disorders may be similar to those of Trisomy 13 Syndrome. Comparisons may be useful for a differential diagnosis:

Pseudo-trisomy 13 Syndrome is a rare disorder characterized by holoprosencephaly; associated midline facial abnormalities; extra fingers and/or toes (polydactyly); and/or heart defects, such as atrial or ventricular septal defects.  In some cases, additional abnormalities may also be present, including genital defects; absence of the band of nerve fibers joining the two hemispheres of the brain (agenesis of corpus callosum); hydrocephalus; and/or other features. Although symptoms and findings are similar to those potentially associated with Trisomy 13 Syndrome, infants with this disorder do not have an extra chromosome 13 and their chromosomal studies appear normal.  Evidence suggests that this disorder may be inherited as an autosomal recessive trait.


Trisomy 18

Trisomy 18 is a rare chromosomal disorder in which all or a critical region of chromosome 18 appears three times (trisomy) rather than twice in cells of the body. In some children, trisomy 18 may be present in only a percentage of cells, whereas other cells contain the typical chromosomal pair (mosaicism). Trisomy 18 is usually not inherited but occurs by chance.

The symptoms associated with trisomy 18 are extremely variable. Severity can be dependent upon the percentage of cells that contain the third copy of the chromosome (mosaicism), but this percentage can change as a child grows as well as what type of sample was obtained (saliva versus blood for example). In many patients, there is decreased movement in utero. This may be due to polyhydramnios (excess amniotic fluid) during the mother’s pregnancy.

Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as p and a long arm identified by the letter q. Chromosomes are further subdivided into bands that are numbered.

Trisomy 18 affects females more frequently than males by a ratio of three or four to one. Large population surveys indicate that it occurs in about one in 5,000 to 7,000 livebirths. The frequency of trisomy 18 appears to increase with advancing maternal age. Reports indicate the mean maternal age is 32.5 years. There are also reports of mothers in their late teens and early 20’s.

Symptoms of the following disorder may be similar to those of trisomy 18. Comparisons may be useful for a differential diagnosis:

Trisomy 13 is a chromosomal disorder in which all or a portion of chromosome 13 is present three times rather than twice in all or some cells of the body. Associated symptoms and findings may vary in range and severity. These infants have some similar characteristics to trisomy 18 infants, but in general the signs and symptoms are different. Affected infants typically are small for gestational age, have feeding difficulties and have various craniofacial malformations. These may include an abnormally small head (microcephaly) and a sloping forehead; wideness of the soft spots (fontanelles) at the front and back of the skull; incomplete closure of the lip and/or roof of the mouth (palate); a small jaw; scalp ulceration at the top of the head; low-set ears; small eyes (microphthalmia); and/or other eye defects such as colobomas. The disorder may also be associated with extra fingers and toes (polydactyly); failure of the forebrain to divide properly during embryonic development (holoprosencephaly); additional defects of the central nervous system; renal malformations; and/or heart defects. In most cases, trisomy 13 is due to errors during the division of reproductive cells in one of the parents. (For further information, choose trisomy 13 as your search term in the Rare Disease Database.)


Tropical Sprue

Tropical Sprue is a rare digestive disease in which the small intestine’s ability to absorb nutrients is impaired (malabsorption). Consequently, nutritional deficiencies and abnormalities in the mucous lining of the small intestine may be present. The exact cause of this disorder is not known, however it may be related to environmental and nutritional conditions in the tropical regions where it is most prevalent.

The symptoms of Tropical Sprue may include fatigue and diarrhea with stools that are abundant, pale and foul-smelling.  People with this disorder may also experience a profound loss of appetite (anorexia), a sore tongue, night blindness, weight loss, a loss of strength and energy (asthenia) and general weakness.

The exact cause of Tropical Sprue is not known.  It is an acquired disorder that may be related to environmental and nutritional factors, or Tropical Sprue may be related to an infectious organism (either viral or bacterial), dietary toxin, parasitic infestation, or a nutritional deficiency such as folic acid.  Tropical Sprue causes damage to the mucosal lining of the intestine resulting the impaired absorption of food, minerals, and water.

Tropical Sprue is a rare disorder in temperate regions.  It occurs mainly in the tropical regions of the Caribbean, India, South Africa, and Southeast Asia.  Transients, tourists and visitors to these areas can be affected.

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

Malabsorption syndromes refer to a group of digestive disorders which are characterized by the impairment of absorption of nutrients and the excessive loss of nonabsorbed substances in the stool. There are many underlying diseases that are associated with these syndromes.  Symptoms vary directly with the severity of the disease.  Diarrhea and large volumes of fatty stools are consistent symptoms in people with malabsorption syndromes.

Treatment for Tropical Sprue includes the use of folic acid, cobalamin, and antibiotics such as tetracycline, oxytetracycline, or ampicillin. The dosage of these medications depends on the severity of the disorder as well as how the patient responds to the therapy. Combined therapy with folic acid and tetracycline seems to rapidly reduce the severity of the symptoms and also heal unhealthy tissue in the small intestine. Other nutrients may be given as needed (i.e., iron, vitamin B12). Diarrhea associated with this disorder may be controlled with anti-diarrhea agents.


Common arterial trunk

Truncus arteriosus is a rare type of heart disease that is present at birth. Affected individuals have one main blood vessel, rather than two, carrying blood away from the heart. Instead of having a separate pulmonary artery to carry blood to the lungs, and an aorta to carry blood to the rest of the body, a baby with truncus arteriosus has just one blood vessel leaving the heart which then branches into other blood vessels. Blood from both pumping chambers (ventricles) of the heart is mixed, resulting in a situation in which some oxygen-rich blood travels needlessly back to the lungs and some oxygen-poor blood travels to the rest of the body. The most common symptoms include a bluish tint to the skin (cyanosis) and rapid breathing (tachypnea). Standard treatment involves corrective open-heart surgery in the newborn period.

At birth, infants may have symptoms including a bluish tint to the skin (cyanosis), rapid breathing (tachypnea) and poor feeding (sweating with feeds, needing to stop and take breaks and difficulty gaining weight). Most infants have a heart murmur – a sound heard when the heart is listened to with a stethoscope. Some infants may develop an accumulation of fluid in the face, arms and/or legs.

A single cause of truncus arteriosus has not been identified. Like many congenital heart defects, it has been suggested that the interaction of multiple genetic and environmental factors lead to this disease. The malformation of the heart that characterizes truncus arteriosus occurs during embryonic development. Medical literature suggests that variants of transmembrane protein 260 (TMEM260), a protein coding gene, may be associated with the development of type I truncus arteriosus.

Males and females are affected equally by this disease. This disorder occurs in approximately 1 in 15,000 births in the United States.

Similar congenital heart defects that are present in infancy with excessive blood flow to the lungs and congenital heart failure include ventricular septal defects (VSD), atrioventricular septal defects (AVSD) and patent ductus arteriosus (PDA). In patients with VSD, the wall (septum) separating the two ventricles is incompletely formed before birth and a hole between the pumping chambers (ventricles) persists. Patients with AVSD have a hole in the wall (septum) between the two upper chambers of the heart (atria). Patients with PDA have a persistent opening between the pulmonary artery (which carries blood to the lungs) and aorta (which carries blood to the rest of the body). This duct is a normal fetal connection that functionally closes within 24 hours of birth. Failure of this duct to close results in the excess blood flow to the lungs that characterizes PDA.

Truncus arteriosus can often be detected before the baby is born by prenatal ultrasound evaluation that a mother receives as part of her prenatal care. If it is not detected prenatally, the signs and symptoms described above (rapid breathing, cyanosis, heart murmur etc.) often lead to an evaluation of the baby after birth by a pediatric cardiologist and an echocardiogram (ultrasound of the heart) is performed which confirms the diagnosis. A recording of the heart’s electrical activity (electrocardiogram), a CT scan and/or cardiac catheterization may also be used to further evaluate the heart. Cardiac catheterization is a procedure that measures pressures and oxygen levels within the heart and surrounding blood vessels. Angiography is often performed during cardiac catheterization and involves injection of dye to visualize the flow of blood as it moves through the heart structures.

Open heart surgery is necessary for the infant to thrive and for long-term survival. This corrective surgery will separate the arteries, close the hole in the ventricular septum (VSD) and reattach the pulmonary artery to the ventricle wall via a valve-containing tube (conduit). Without surgery, about 85% of patients will not survive past one year of age. Patients will require regular follow-up evaluation with a cardiologist.


Tuberculosis

Tuberculosis (TB) is an acute or chronic bacterial infection found most commonly in the lungs. The infection is spread like a cold, mainly through airborne droplets breathed into the air by a person infected with TB. The bacteria causes formation of small tissue masses called tubercles.  In the lungs these tubercles produce breathing impairment, coughing and release of sputum. TB may recur after long periods of inactivity (latency) if not treated adequately. Many variations of TB exist and are distinguished by the area of the body affected, degree of severity and affected population. This disease today is considered curable and preventable. It is very rare in the United States but is on an upsurge.

Tuberculosis most commonly affects the lungs, producing breathing difficulties.  It may also affect the kidneys, bones, lymph nodes, and membranes surrounding the brain.  In some cases, it can spread throughout the body.  In the initial stages patients may experience fever, loss of appetite, weight loss, weakness, and sometimes a dry cough.

Tuberculosis is a bacterial infection usually caused by either Mycobacterium tuberculosis or Mycobacterium bovis.  The Mycobacterium tuberculosis is the most common source of infection and is spread by airborne droplets breathed or coughed into the air by a person infected with active TB.  In the past the disorder was caused in most cases by Mycobacterium bovis, a bacteria which was passed to humans through dairy products.  Today, dairy and cattle are carefully inspected and tested for this type of TB, and infected products are not sold to the public in the United States.  However, in less developed countries the TB infection is still passed to humans through dairy products.

In 1944, the Public Health Service launched a TB control program when the yearly number of cases in the United States averaged 126,000.  In 1985, the number of cases had dropped to 22,201.  However, health officials warn that TB is still a serious health problem, due in part to the rise of AIDS cases and the lowered resistance of AIDS patients to the TB infection.  There are still approximately 2,000 deaths annually from TB in the United States, which is more than from all other infectious diseases excluding pneumonia and influenza.

AIDS (Acquired Immune Deficiency Syndrome) involves progressive deterioration of the body’s ability to ward off infection.  Organisms which in a healthy person would either fail to cause disease, cause mild disease, or at least provoke immunity, can completely overwhelm the AIDS patient.  Patients with AIDS can contract various life-threatening infections such as pneumocystis carinii pneumonia and Tuberculosis (TB).  Additionally, they may develop a rare type of cancer called Kaposi’s Sarcoma.

The continued testing of dairy herds as preventive therapy remains essential to the control of tuberculosis. Since some individuals with tuberculosis do not develop respiratory symptoms (latent tuberculosis), they often go undiagnosed and can potentially spread the disease. A tuberculin skin test, required for school age children in the United States, is also extremely useful in identifying unsuspected cases of TB. Researchers have developed blood tests that can identify latent cases of tuberculosis. These blood tests can be used alone or in combination with the tuberculin skin test.


Tuberous sclerosis complex

Tuberous sclerosis is a rare genetic multisystem disorder that is typically apparent shortly after birth. The disorder can cause a wide range of potential signs and symptoms and is associated with the formation of benign (non-cancerous) tumors in various organ systems of the body. The skin, brain, eyes, heart, kidneys and lungs are frequently affected. These tumors are often referred to as hamartomas. Hamartoma is a general term for a tumor or tumor-like growth that is made up of cells normally found in the area of the body where the hamartoma forms. Hamartomas are not malignant; they do not typically metastasize and spread to other areas of the body. However, these abnormal growths can grow larger and can damage the affected organ system. The number, size, and specific location of these abnormal growths in individuals with tuberous sclerosis can vary widely and consequently the severity of the disorder can vary widely as well. Tuberous sclerosis results from alterations (mutations) in a gene or genes that may occur spontaneously (sporadically) for unknown reasons or be inherited as an autosomal dominant trait. Most cases represent new (sporadic or de novo) gene mutations, with no family history of the disease. Mutations within at least two different genes are known to cause tuberous sclerosis, the TSC1 gene or the TSC2 gene.

Tuberous sclerosis is a highly variable disorder. The signs, symptoms, and severity of the disorder can vary dramatically from one person to another, even among members of the same family. This is due, in part, to the specific organ systems that are involved. Any organ system of the body can be affected. Tuberous sclerosis can cause mild disease in which individuals go undiagnosed into adulthood or it can cause significant complications that can impact quality of life or the disorder can cause potentially severe, life-threatening complications.

Tuberous sclerosis is caused by an alteration (mutation) in one of two different genes, the TSC1 gene or the TSC2 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, including the brain. Generally, alterations in the TSC2 gene result in a more severe disease expression.

Tuberous sclerosis is a rare genetic disorder that affects 1 in 6,000 newborns in the United States. Approximately 40,000 to 80,000 people in the United States have tuberous sclerosis. The prevalence in Europe is estimated to be approximately 1 in 25,000 to 1 in 11,300. As many as 2 million people worldwide are believed to have the disorder. Males and females are affected in equal numbers and the disorder occurs in all races and ethnic groups.

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

The various symptoms of tuberous sclerosis are nonspecific and many can occur as isolated findings or as part of another syndrome or disorder. Examples of such disorders include hypomelanosis of Ito, Sturge-Weber syndrome, epidermal nevus syndromes, Birt-Hogg-Dube syndrome, multiple endocrine neoplasia, and various seizures disorders. Isolated brain tumors and cardiac myxoma as well as other tumors may need to be differentiated from tuberous sclerosis. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)


Tularemia

Tularemia, is caused by infection with the bacterium Francisella tularensis, which is found in small mammals such as rodents and rabbits, and arthropods, such as ticks. The bacterium that causes tularemia is most often transmitted to humans by tick or biting fly bite, handling of an infected animal, or inhalation or ingestion of the bacterium. People have not been known to transmit the infection to others. The severity of tularemia varies greatly. Some cases are mild and self-limiting, others may have serious complications, and a small percentage (less than 2 percent) of cases in the United States is fatal.

The symptoms of tularemia vary greatly among affected individuals. Some individuals may have no apparent symptoms (asymptomatic); others can develop serious complications affecting several organ systems with potentially life-threatening complications. After infection, the period of time it takes symptoms to appear (incubation period) is usually three to five days, but may take as long as two weeks.

Tularemia is caused by the bacterium Francisella tularensis. Most cases occur from being bitten by flies or ticks carrying the bacterium or from exposure to tissue from an animal infected with the bacteria.

Tularemia affects males and females, although the majority of cases are males, probably because of greater outdoor exposure opportunities. The disease is rare in the United States with approximately 100-200 new cases reported each year. Some researchers believe that many cases of tularemia often go unreported or misdiagnosed, making it difficult to determine the true frequency of this disease in the general population.

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

Tularemia must be differentiated from other, more common causes of fever, chronic fatigue, weakness, and other nonspecific flu-like symptoms, and should be highly suspected in individuals in endemic regions who may have been exposed to infected animals or recently received a tick or biting fly bite.


肿瘤坏死因子受体1相关周期性发热综合征

Tumor Necrosis Factor Receptor-Associated Periodic Syndrome

autosomal dominant periodic fever with amyloidosis

Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is a rare multisystem genetic disorder characterized by unexplained periodic episodes of fever associated with additional symptoms including muscle pain (myalgia), abdominal pain, headaches and skin rashes. The specific symptoms can vary greatly from one person to another. The duration of the characteristic episodes can also vary, lasting anywhere from a couple days to one week to more than one month. Onset is usually during infancy or childhood. TRAPS is caused by changes (variants or mutations) of the tumor necrosis factor receptor-1 (TNFRSF1A) gene that encodes the 55-kDa receptor for tumor necrosis factor (TNF) cytokine. Since its description in 1999, about 200 cases have been reported in the literature.

The specific symptoms associated with TRAPS vary from one person to another. Nearly all affected individuals will develop recurrent episodes of high-grade fever, pain and inflammation. However, some individuals may only develop fever or only fever and abdominal pain. The duration of the episodes varies, but they usually last more than one week. Some individuals may experience constant inflammation.

TRAPS can occur randomly due to a spontaneous genetic change (i.e., new variant) or it may be inherited in an autosomal dominant pattern (a variant that is received either from the father or the mother).

TRAPS was first described in the medical literature in 1982 in a large Irish family and initially termed familial Hibernian fever. The name was later changed when numerous individuals from other ethnic groups were identified to have variants in the same gene, namely TNFRSF1A. TRAPS has been reported in individuals of many different ethnic groups. TRAPS is a rare disease that often goes undiagnosed or misdiagnosed 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 TRAPS. Comparisons may be useful for a differential diagnosis.

A diagnosis of TRAPS is made based upon a thorough clinical evaluation, identification of characteristic symptoms (e.g., long lasting fever episodes) and blood tests for inflammatory markers. A diagnosis of TRAPS is usually confirmed by molecular genetic testing, which can identify either de novo or dominantly inherited variants in the TNFRSF1A gene. All TRAPS pathogenic variants are clustered in exons 2-4, which encodes the extracellular domain of the protein. Most are missense nucleotide changes that affect the folding of the extracellular domain. Pathogenic variants in other protein domains may be associated with different symptoms. There is also evidence for gonadal mosaicism (gene variants occur after conception) in TRAPS, which can be found in patients with late- onset symptoms.


Turcot Syndrome

Turcot综合征息肉病型

Turcot syndrome is a rare inherited disorder characterized by the association of benign growths (adenomatous polyps) in the mucous lining of the gastrointestinal tract with tumors of the central nervous system. Symptoms associated with polyp formation may include diarrhea, bleeding from the end portion of the large intestine (rectum), fatigue, abdominal pain, and weight loss. Affected individuals may also experience neurological symptoms, depending upon the type, size and location of the associated brain tumor. Some researchers believe that Turcot syndrome is a variant of familial adenomatous polyposis. Others believe that it is a separate disorder. The exact cause of Turcot syndrome is not known.

Turcot syndrome is characterized by the formation of multiple benign growths (polyps) in the colon that occur in association with a primary brain tumor. These growths are associated with bleeding from the rectum, diarrhea, constipation, abdominal pain, and/or weight loss. The number and size of these polyps may vary greatly from case to case, ranging from fewer than 10 to more than 100.

Recent research indicates that one type of Turcot syndrome is inherited as an autosomal recessive trait and the other as an autosomal dominant trait.

Turcot syndrome affects males and females in equal numbers. Approximately 150 cases have been reported in the medical literature.

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

A diagnosis of Turcot syndrome is made based upon a detailed patient history, a thorough clinical evaluation, and a variety of specialized tests. Because children of an affected parent have a genetic risk of developing Turcot syndrome, regular screening via sigmoidoscopy is required until approximately age 35 to 40 to help ensure early detection and prompt, appropriate treatment. During sigmoidoscopy, a viewing instrument is used to examine the rectum and the last part of the large intestine (sigmoid colon). In addition, in some cases, DNA testing may be available to help detect family members who have inherited certain changes (mutations) of the APC gene or DNA mismatch repair genes, potentially diagnosing the disorder before polyp development. In addition, x-rays of the large intestine may reveal the presence of polyps. X-rays of the brain may reveal the presence of a central nervous system tumor.


Turner syndrome

The symptoms and severity of Turner syndrome can be quite variable from one person to another. Many features of the disorder are nonspecific, and others may develop slowly over time or can be subtle. It is important to note that affected individuals may not have all the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.

Turner syndrome is caused by a partial or complete loss (monosomy) of an X chromosome. Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual and they come in pairs. We receive one copy from each parent. Chromosomes are numbered from 1 through 22. The 23rd pair normally consists of one X and one Y chromosome for males and two X chromosomes for females. Thus, females with a normal chromosome make-up (karyotype) have 46 chromosomes, including two X chromosomes (46, XX karyotype). Each chromosome has a short arm designated p and a long arm designated q. Chromosomes are further sub-divided into many bands that are numbered.

Turner syndrome affects approximately 1 in 2,000-2,500 live female births. It is estimated that more than 70,000 females in the United States have Turner syndrome. There are no known racial or ethnic factors that influence frequency of the disorder. In some people, the disorder is diagnosed before birth or shortly after birth. However, mild cases can remain undiagnosed until later in life and even during adulthood.

Noonan syndrome is a common genetic disorder that is typically evident at birth (congenital). The disorder is characterized by a wide spectrum of symptoms and physical features that vary greatly in range and severity. In many affected individuals, associated abnormalities include a distinctive facial appearance; a broad or webbed neck; a low posterior hairline; a typical chest deformity and short stature. Characteristic abnormalities of the head and facial (craniofacial) area may include widely set eyes (ocular hypertelorism); skin folds that may cover the eyes’ inner corners (epicanthal folds); drooping of the upper eyelids (ptosis); a small jaw (micrognathia); a depressed nasal root; a short nose with broad base; and low-set, posteriorly rotated ears (pinnae). Distinctive skeletal malformations are also typically present, such as abnormalities of the breastbone (sternum), curvature of the spine (kyphosis and/or scoliosis), and outward deviation of the elbows (cubitus valgus). Many infants with Noonan syndrome also have heart (cardiac) defects, such as obstruction of proper blood flow from the lower right chamber of the heart to the lungs (pulmonary valvular stenosis). Additional abnormalities may include malformations of certain blood and lymph vessels, blood clotting and platelet deficiencies, learning difficulties or mild intellectual disability, failure of the testes to descend into the scrotum (cryptorchidism) by the first year of life in affected males, and/or other symptoms and findings. Noonan syndrome is an autosomal dominant genetic disorder caused by abnormalities (mutations or pathogenic variants) in multiple single genes that make up the rasopathy pathway. Some symptoms associated with Noonan syndrome may superficially resemble those with Turner syndrome (due to certain findings that may be associated with both disorders, such as short stature, webbed neck, etc.). Consequently, in the past, Noonan syndrome has been referred to as male Turner syndrome, female pseudo-Turner syndrome, or Turner phenotype with normal chromosomes karyotype. However, there are many important differences between the two disorders. Noonan syndrome affects both males and females, and there is a normal chromosomal makeup (karyotype). Only females are affected by Turner syndrome, which is characterized by abnormalities affecting the X chromosome. (For more information on this disorder, choose Noonan as your search term in the Rare Disease Database.)

A detailed patient history, a thorough clinical evaluation, and a variety of specialized tests. Turner syndrome should be suspected in girls with growth deficiency or short stature of unknown cause.


Twin anemia-polycythemia sequence

Twin anemia polycythemia sequence (TAPS) is a rare but severe complication in identical twin pregnancies that share a single placenta (monochorionic). TAPS is caused by an imbalance in red blood cells exchanged between the twins through tiny placental blood circulations (anastomoses). This leads to too few red blood cells (anemia) in the donor twin and too many red blood cells (polycythemia) in the recipient twin. TAPS was first described in 2006,1 and being a relatively new disease; it is sometimes confused with the better-known twin-to-twin transfusion syndrome (TTTS).

Before birth, TAPS may go undetected due to lack of symptoms and the lack of excess amniotic fluid  (polyhydramnios) like in TTTS. TAPS can be detected using Doppler ultrasound examination, focusing specifically on the blood flow (peak systolic velocity, PSV) in the middle cerebral artery (MCA). In the donor, the MCA-PSV is increased as a sign of fetal anemia. In the recipient, the MCA-PSV is decreased as a sign of polycythemia.

Tiny blood vessels in the shared placenta that connects the babies’ umbilical cords and blood circulations (anastomoses) cause TAPS. These connections are present in all monochorionic twin pregnancies. In most cases, the blood flow stays relatively balanced through these connecting blood vessels. However, in TAPS, the blood between the two babies is not balanced. One baby, the donor, gives more blood to the other, the recipient, leading to the donor becoming anemic and the recipient polycythemic.

TAPS is a rare disorder affecting a small number of monochorionic twin pregnancies. Many cases go undiagnosed and unrecorded; the actual frequency is unknown.

Symptoms of the following disorders can be similar to those of twin anemia polycythemia sequence. Comparisons may be helpful to show the differences.

TAPS can be detected during pregnancy  by Doppler ultrasonography. Ultrasound findings in TAPS include twins of the same gender; a single, shared placenta (monochorionic), a thin membrane dividing the babies’ amniotic sacs; no differences in amniotic fluid (TTTS); and the presence of discordant MCA-PSV Dopplers.


Twin to twin transfusion syndrome

Twin-twin transfusion syndrome (TTTS) is a rare disorder that sometimes occurs when women are pregnant with identical (monozygotic) twins. It is a rare disease of the placenta, the organ that joins the mother to her offspring and provides nourishment to the developing fetuses. During the development of identical twins, there are always blood vessels in the fetuses’ shared placenta that connect their blood circulations (placental anastomoses). In most cases, the blood flows properly through these vessels. However, in twin-twin transfusion syndrome, the blood begins to flow unevenly, with one fetal twin receiving too much blood (recipient) and one receiving too little (donor). The recipient twin may experience heart failure due to continual strain on its heart and blood vessels (cardiovascular system). The donor twin, on the other hand, may experience life-threatening anemia, insufficient nutrition and oxygen due to its inadequate supply of blood. Such an imbalance in blood flow (i.e., twin-twin transfusion) can occur at any time during the pregnancy, including during delivery.

Twin-twin transfusion syndrome (TTTS) is a rare disorder that sometimes occurs when women are pregnant with identical (monozygotic) twins. TTTS is a disease of the placenta, the organ that develops in the uterus during pregnancy, links the mother’s blood supply to the fetuses’, and provides nourishment to her offspring. The developing fetal twins are typically normal until abnormalities in blood flow within the placenta cause the TTTS disease process to occur.

The exact cause of TTTS is not fully understood. However, it is known that abnormalities during division of the mother’s egg after it has been fertilized lead to the placental abnormalities that can ultimately result in twin-twin transfusion syndrome.

TTTS is a rare disorder that sometimes occurs when a mother is pregnant with identical (monozygotic) twins. There have been a few reported cases in which TTTS also affected identical triplets. Twin-twin transfusion syndrome affects approximately 5 to 15 percent of identical twin pregnancies, meaning that approximately 6,000 babies may be affected each year. However, it is difficult to determine the true frequency of TTTS in the general population since many cases are never diagnosed and many go unrecorded.

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

TTTS can be detected during mid-pregnancy (second trimester) by ultrasonography, an instrument that creates a fetal image by measuring the reflection of sound waves. Ultrasound findings that may indicate twin-twin transfusion syndrome include the presence of same-sex twins; a single, shared placenta (monochorionic), a thin membrane dividing the fetuses' amniotic sacs; differences in the amount of amniotic fluid with polyhydramnios (defined as a largest vertical pocket of fluid greater than 8 cm in the larger twin) and oligohydramnios (defined as a largest vertical pocket of less than 2cm in the smaller twin), and a size difference of greater than 20%. Present staging or classification of the severity of the disease currently follows that proposed by Quintero in 1999. This staging system has been a useful tool to allow physicians to compare treatment results and for choosing between different management strategies as it incorporates the worsening severity of the disease process in each of the increasing stages. It does, however, create the impression that the natural history of TTTS follows an orderly progression over time. Unfortunately, clinical experience has shown that this is not the case and progression of the disease processes are highly variable and somewhat unpredictable. This staging system also does not include elements describing the fundamental cardiovascular changes that are key to understanding the disease and are present in subtle forms even at the earliest stages of the disease process.


Typhoid

Typhoid fever is a bacterial infection that is rare in the United States. However, it is not rare in many other countries. Major symptoms may include unusually high fever, headache, loss of appetite, fatigue, abdominal pain and diarrhea.

Typhoid is an intestinal infection caused by the bacterium Salmonella typhi. Antibodies to the bacteria can be detected in the blood (Widal’s test). Salmonella typhi can be cultured from the patient’s blood, urine and feces as well.  The infection incubates for one or two weeks.  A gradual development of headache, loss of appetite, fatigue and constipation occurs.   During the following weeks there is a gradual rise in temperature to about 104 F, abdominal pain, a slowed pulse rate, nosebleeds, rose-colored spots on the chest and diarrhea.  Intestinal ulceration and bleeding can lead to anemia and peritonitis.  These conditions may be fatal if the patient is left untreated.  Heart failure may also occur.

Typhoid is caused by the bacterium Salmonella Typhi.  It is the most serious of the Salmonella infections.  Contaminated food or water is most often the source of a Typhoid outbreak.  Contact with a carrier of the bacterium, polluted water, infected food or milk, shellfish harvested from polluted water, or fresh vegetables grown in contaminated soil are all sources of the Salmonella Typhi bacterium.  People who have had Typhoid are carriers until the bacteria is completely gone from their body.  If they touch food served to other people when their hands are not properly washed, they can spread Typhoid to those who eat the food.

Typhoid affects males and females in equal numbers.  In the United States there are only about 500 cases of typhoid diagnosed each year, and over 62% of these are contracted in other countries.  The major sources of cases in the United States between the years 1975-1984 were Mexico (39%) and India (14%).  In Mexico, Latin America, Asia, Africa and the Middle East where the fatality rate is as high as 10% each year, typhoid is still a serious health problem.  In the U.S., outbreaks are usually traced to a typhoid carrier in the food handling business (e.g. restaurants, hotels, etc.).

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

Salmonella poisoning is a form of gastroenteritis. It is the most common cause of outbreaks of foodborne disease in the United States.  This bacteria may infect meat, dairy and vegetable products.  Outbreaks are most common in warm weather and in children under the age of seven.  Nausea, vomiting, and chills are the most common initial symptoms.  These are followed by abdominal pain, diarrhea and fever which may last from five days to several weeks.  The CDC estimates that there are approximately 2 to 4 million Salmonellosis cases in the United States each year.

Typhoid is treated with the antibiotic drugs chloramphenicol, ampicillin, cefoperazone, pefloxacin, co-trimoxazole or trimethoprim-sulfamethoxazole. Precautions to take, especially when visiting countries with unsanitary conditions, includes the practice of good personal hygiene and careful washing of hands. Avoid drinking untreated water, drinks served with ice, unpeeled fruits and vegetables, and other food that is cooked and not served hot. In food preparation; wash and sanitize utensils in hot water; carefully clean cutting boards, work areas and equipment; keep hot foods at 165 F and cold foods at 40 F or colder to avoid the possible growth of bacteria in food. Typhoid vaccination and food precautions are necessary before traveling to developing countries where this kind of disease is prevalent.


常染色体隐性遗传多巴反应性肌张力障碍

Autosomal recessive dopa-responsive dystonia

autosomal recessive dopa-responsive dystonia

Tyrosine hydroxylase deficiency (THD) is a rare genetic disorder characterized by a wide spectrum of symptoms. These symptoms can vary widely in people who are affected, and even among members of the same family. Common symptoms include an uncoordinated manner of walking (abnormal gait) and dystonia. Dystonia is a general term describing involuntary muscle contractions that force the body into abnormal, sometimes painful, movements and positions (postures). In THD, dystonia usually affects the legs, but can include other parts of the body (generalized dystonia). Additional symptoms may include a tendency to walk on tiptoes, difficulty walking, tremors, eye abnormalities, muscle weakness (hypotonia) and intellectual disability. However, there are fewer than 100 case reports of individuals with THD in the medical literature, so it is difficult to predict all the features of the disorder.

THD represents a spectrum of disease, and the symptoms can vary greatly from one person to another. In the severe form, symptoms may be obvious early in infancy. In more moderate or mild cases, symptoms may arise later during infancy or even during early childhood.

THD is caused by mutations of the tyrosine hydroxylase (TH) gene and is inherited in an autosomal recessive pattern.

The exact incidence of THD in the general population is unknown. Approximately 100 cases have been reported in the medical literature. Researchers believe that the disorder is often misdiagnosed or goes undiagnosed, making it difficult to determine its true frequency in the general population.

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

A diagnosis of THD is made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic findings and a variety of specialized tests. These tests include examination of cerebrospinal fluid (CSF) to detect certain substances (metabolites) that are byproducts of metabolism. Identification of certain metabolites at specific levels can help to distinguish THD from other related neurotransmitter disorders. A sample of CSF is obtained through a procedure called a spinal tap (lumbar puncture) in which a needle is inserted into the spinal canal in the lower back.


Tyrosinemia type 1

Tyrosinemia type I is a rare autosomal recessive genetic metabolic disorder characterized by lack of the enzyme fumarylacetoacetate hydrolase (FAH), which is needed for the final break down of the amino acid tyrosine. Failure to properly break down tyrosine leads to abnormal accumulation of tyrosine and its metabolites in the liver, potentially resulting in severe liver disease. Tyrosine may also accumulate in the kidneys and central nervous system.

Symptoms associated with tyrosinemia type I often vary greatly from person to person. Infants with tyrosinemia type I typically present with either the acute or chronic form of the disorder.

Tyrosinemia is caused by mutations in the fumarylacetoacetate hydrolase (FAH) gene that is responsible for the production of the FAH enzyme. Deficiency of this enzyme leads to an accumulation of fumarylacetoacetate and accumulation of tyrosine and its metabolites in the liver, kidney, and central nervous system eventually causing tyrosinemia type I.

Tyrosinemia type I affects males and females in equal numbers. The prevalence has been estimated to be 1 in 100,000 to 120,000 births worldwide. In Quebec, Canada, the birth prevalence is estimated to be 1/16,000. The estimated prevalence in the Saguenay-Lac Saint-Jean region of Quebec is one in 1,850 births. In Norway, the birth prevalence is estimated to be 1 in 60,000 births.

Signs and symptoms of the following disorders can be similar to those of tyrosinemia type I. Comparisons may be useful for a differential diagnosis:

Acute intermittent porphyria (AIP) is one of a group of inherited metabolic disorders known as the porphyrias. AIP is characterized by the deficiency of the enzyme porphobilinogen deaminase (PBG-D), also known as uroporphyrinogen I-synthase. Symptoms may include severe abdominal pain, nausea, vomiting, and constipation. Neurological symptoms similar to tyrosinemia type I may also be present including pain in arms and legs, muscle weakness, rapid heart rate, and increased blood pressure. Affected individuals may also experience hallucinations and seizures. AIP is inherited as an autosomal recessive genetic condition (For more information on this disorder, choose acute intermittent porphyria as your search term in the Rare Disease Database.)


Ulcerative Colitis

欧洲非罕见：溃疡性结肠炎

Ulcerative colitis is an inflammatory bowel disease (IBD) of unknown cause. It is characterized by chronic inflammation and ulceration of the lining of the major portion of the large intestine (colon). In most affected individuals, the lowest region of the large intestine, known as the rectum, is initially affected. As the disease progresses, some or all, of the colon may become involved. Although associated symptoms and findings usually become apparent during adolescence or young adulthood, some individuals may experience an initial episode between ages 50 to 70. In other cases, symptom onset may occur as early as the first year of life.

In most cases, the symptoms associated with ulcerative colitis develop gradually; however, in some individuals, symptom onset may be rapid and severe (fulminant). Although the disorder is usually characterized by repeated recurrences and periods of remission, some affected individuals may have infrequent episodes and others may have severe symptoms that are ongoing.

The exact cause of ulcerative colitis is not known. However, researchers indicate that genetic, immunologic, infectious, and/or other factors may play some contributing role. Because the disorder more commonly occurs in particular populations, such as in people of Jewish descent, and within certain families (kindreds), researchers suggest that genetic predisposition may be a factor in development of the disease. Some indicate that a genetic predisposition may lead to an abnormal intestinal immune response to particular infectious or other environmental agents. However, despite much research in this area, a specific bacterial, viral, fungal, or other infectious cause has not been identified. In addition, no causative immunologic abnormalities specific to ulcerative colitis have been determined.

Ulcerative colitis affects males and females in equal numbers. In the United States and Western Europe, the frequency (i.e., prevalence) of the disease is approximately 70 to 150 cases per 100,000 in the general population. Although symptoms associated with the disorder typically begin between the ages of approximately 15 to 35 years, some people may experience an initial episode between ages 50 to 70. In other cases, symptom onset may occur as early as the first year of life.

Symptoms of the following disorders may be similar to those of ulcerative colitis. Comparisons may be useful for a differential diagnosis:

Crohn’s disease is an inflammatory bowel disease (IBD) characterized by chronic inflammation that typically affects the entire thickness of the intestinal wall. (As mentioned above, ulcerative colitis is usually limited to the lining of the colon [except in cases of toxic megacolon and perforation].) Diseased regions may be separated by apparently normal areas (skip lesions). Although Crohn’s cisease most commonly affects the lowest region of the small intestine (ileum) or the colon, it may involve any region of the gastrointestinal tract. In those with the disorder, chronic inflammation typically leads to thickening, scarring, and ulceration of the intestinal wall.


Urofacial syndrome

As the term urofacial suggests, the disorder is characterized by urinary and facial problems. The initial finding that may be apparent in affected infants is an unusual inverted facial expression. When affected infants attempt to laugh or smile, their facial musculature inverts so that they appear to be grimacing or crying. The symptoms and severity of urofacial syndrome can vary greatly, even among affected members of the same family.

Urofacial syndrome is caused by changes (mutations or pathogenic variants) in one of two different genes, the HPSE2 gene or the LRIG2 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 protein, this can affect many organ systems of the body.

Urofacial syndrome affects males and females in equal numbers. More than 150 cases have been reported in the medical literature. According to the literature, most families are from Columbia although affected families have also been reported in Turkey, the United States, the United Kingdom, Kuwait, Denmark, Germany, Netherlands, Australia and Spain.

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

Hinman syndrome, also known as Hinman-Allen syndrome or non-neurogenic neurogenic bladder, is a rare voiding disorder that is believed to be neuropsychological in origin as no neurologic deficit is present. Affected individuals exhibit extremely similar clinical features to those seen in individuals with urofacial syndrome, except for abnormalities in facial expression, which does not occur.


Upper tract urothelial carcinoma

Urothelial carcinoma of the renal pelvis and ureter

Transitional cell carcinoma of the renal pelvis and ureter

Urothelial cell (UC) cancers of the renal pelvis and ureter are relatively rare (approximately 2 per 100,000 people) and make up approximately 5% of transitional cell cancers in the urinary tract. Of these 2 locations – the renal pelvis (located in the kidney) and the ureters (which connect the kidney to the bladder) – UC occurs twice as often in the renal pelvis. The most common initial symptom for these types of cancer is blood in the urine (hematuria). Risk factors for UC include smoking, genetics, painkiller abuse, excessive coffee drinking, and cyclophosphamide (a drug used in chemotherapy). Surgery is the most common treatment for these cancers, however higher stage cancers may also require chemotherapy or radiation. These cancers may most commonly spread down towards the bladder and can spread (metastasize) to other organs. The prognosis after surgery varies and highly depends on the cancer stage and a patients’ risk factors.

Painless blood in the urine (hematuria) is the most common symptom in patients with transitional cancers of the upper urinary tract. Other less common symptoms include lower back pain, pain with urination, or unexplained weight loss.

Urothelial cell cancer is thought to be caused by a mutation leading to the loss of a tumor suppressor gene. Losing a tumor suppressor gene is like taking the brakes off a car, allowing cells to replicate uncontrollably, resulting in cancer. Cancers may be classified as low-grade or high-grade.  Low-grade cancers are associated with mutations leading to a loss of functioning tumor suppressor genes such as p53, p19 and p16. High-grade cancers have additional mutations such as the loss of the RB1 tumor suppressor gene. More aggressive cancers tend to spread initially towards the bladder and may metastasize (spread) to other organs. Notably, loss of certain tumor suppressor genes (such as those listed above) does not reflect the patient prognosis (predicted outcome) and scientists are still studying how the loss of certain genes can affect prognosis in patients with different mutations. Due to family genetics, some people may be predisposed to loss of these tumor suppressor genes compared to others. Patients with Lynch syndrome are at an increased risk for transitional cell cancers.

The average age of patients who develop upper urinary tract urothelial tumors is 65 years, and one’s risk of this cancer increases to a peak in their 70’s-80’s. Urothelial tumors are 3 times more common in men than women and twice as common in people of European descent compared to people of African descent. Patients with a smoking history are at highest risk for these cancers. A family history of transitional cell cancer, especially when a family member was diagnosed at a young age (<45 years old) without a history of smoking and/or Lynch syndrome may increase the risk for transitional cell cancers as well.

Doctors will usually start by running urine and blood tests to check kidney function, liver function, bladder function, and assess for infection. They will also usually obtain some imaging such as a CT scan, which may show an irregular mass blocking the ureter or kidney suggestive of cancer. Doctors may get additional imaging tests such as a CT using contrast, known as a CT urogram. If the cancerous mass is small and is not obstructing the renal pelvis or ureters, it may not be initially detected by these imaging tests. A urologist, which is a doctor specializing in the urinary tract, may perform a procedure called a uroscopy, which is the use of a flexible scope inserted through the urethra (opening in the penis or above the vagina through which urine leaves the body) to directly visualize the cancerous mass in the ureter or renal pelvis and may remove small bits of tissue for further testing. Once a diagnosis is confirmed, doctors will stage the cancer by performing more imaging scans to see if it has spread to other parts of the body such as the lungs or lymph nodes. To help with staging, doctors may also perform genetic tests, urine cell tests, and biopsies.

The standard of therapy for transitional cell cancer of the renal pelvis and ureter is surgery. The most common surgery is known as a radical nephroureterectomy in which the kidney, ureter, adrenal gland, and nearby lymph nodes are removed. The surgery may be done laparoscopically via a camera with small incisions or robotically to minimize the complications and decrease hospitalization length, but larger or more aggressive tumors may require an open surgery. Most people fully recover from a nephroureterectomy within 6 weeks. Lower grade tumors may instead undergo an ablation of the tumor using a laser or a ureterectomy in which only a part of the ureter is removed to preserve the kidney function. The major risks associated with these surgeries include injury to major blood vessels or nerves, infection, side effects of anesthesia such as nausea and vomiting, and blood loss. Following radical nephroureterectomies, recurrence of the original cancer is not common but UC may arise in other parts of the urinary system such as the bladder. Patients should follow up with their doctor routinely to check for bladder cancer using a cystoscopy and selective urine cytology. The frequency of follow-up may depend on the stage of the original cancer as well as the likelihood for a recurrence. Most patients should follow-up every 3 months after their surgery during the first year and every six months after that.


Usher syndrome

Usher syndrome is characterized by deafness due to an impaired ability of the inner ear and auditory nerves to transmit sensory (sound) input to the brain (sensorineural hearing loss) as well as abnormal accumulation of colored (pigmented) material on the nerve-rich membrane (the retina) lining the eyes (retinitis pigmentosa or RP). RP eventually causes retinal degeneration leading to progressive loss of vision and legal blindness. Sensorineural hearing loss may be profound or mild and may be progressive. The vision loss caused by RP may begin during childhood or later during life, and often first presents with difficulty seeing at night or in low light (night blindness). Studies show that clear central vision may be maintained for many years even while side (peripheral) vision decreases. These narrowed visual fields are also referred to as tunnel vision. Issues with balance are seen mainly in individuals with Usher syndrome types 1 and 3, although balance difficulties in Usher syndrome type 2 have been reported.

Usher syndrome is caused by changes (variants or mutations) in specific genes. So far, Usher syndrome has been associated with variants in at least nine genes:

Usher syndrome is the most common genetic disorder involving both hearing and vision abnormalities and affects approximately three to ten in 100,000 people worldwide. Higher than average numbers of people with Usher syndrome have been found among Jewish people in Israel and Germany; French Canadians of Louisiana; Argentineans of Spanish descent and Nigerian Africans. USH3, the rarest form in most populations, comprises about 40% of Usher patients in Finland. Usher syndrome types 1 and 2 account for approximately 10 percent of all cases of bilateral (both ears) moderate to profound deafness in children.

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

Alström syndrome is an inherited disorder characterized by retinal degeneration with nystagmus and loss of central vision. This disorder is associated with obesity in childhood. Sensorineural deafness and diabetes mellitus tend to develop after the age of ten years. (For more information on this condition, choose Alström as your search term in the Rare Disease Database.)


Hao-Fountain syndrome due to 16p13.2 microdeletion

The symptoms and severity of USP7-related diseases can vary from one person to another. Many features of the disorder are nonspecific and others may develop slowly over time or can be subtle. It is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis. Often this requires input from a clinical geneticist or genetic counselor to supply the most recent and accurate information about the disorder and discuss genetic testing options or treatment plans.

USP7-related diseases are extremely rare disorders that have been described in only 25 families worldwide. The incidence and prevalence of the disorder is unknown. It is likely that people with these disorders go undiagnosed or misdiagnosed, making it difficult to determine the true frequency in the general population.

Prader-Willi syndrome (PWS) and Schaaf-Yang syndrome (SYS) are two other genetic multisystem disorders characterized by intellectual disability, hypotonia, and hypogonadism. USP7-related diseases and SYS also share an increased prevalence of autism; however, the prevalence of joint contractures is higher in SYS than in USP7¬-related diseases. In addition, though some families have described hyperphagia and lack of satiety in their children with USP7-related diseases, the prevalence is not known and these features are not as pronounced as what is seen in classic PWS. Furthermore, individuals with USP7-related diseases do not seem to manifest the corresponding morbid obesity typically present in PWS individuals.

USP7 mutations are diagnosed through either whole exome sequencing, USP7 sequencing, or chromosome microarray analysis.


Uterine Leiomyosarcoma

A uterine leiomyosarcoma is a rare malignant (cancerous) tumor that arises from the smooth muscle lining the walls of the uterus (myometrium). There are essentially two types of muscles in the body: voluntary and involuntary. Smooth muscles are involuntary muscles; the brain has no conscious control over them. Smooth muscles react involuntarily in response to various stimuli. For example, the myometrium stretches during pregnancy to help accommodate the fetus and contracts during labor to help push out a baby during childbirth. Leiomyosarcoma is a form of cancer. The term cancer refers to a group of diseases characterized by abnormal, uncontrolled cellular growth that invades surrounding tissues and may spread (metastasize) to distant bodily tissues or organs via the bloodstream, the lymphatic system, or other means. Different forms of cancer, including leiomyosarcomas, may be classified based upon the cell type involved, the specific nature of the malignancy, and the disease’s clinical course. Leiomyosarcoma is classified as a soft tissue sarcoma. Sarcomas are malignant tumors that arise from the connective tissue, which connects, supports and surrounds various structures and organs in the body. Soft tissue includes fat, muscle, never, tendons, tissue surrounding the joints (synovial tissue), and blood and lymph vessels. The exact cause of leiomyosarcoma, including uterine leiomyosarcoma, is unknown.

Symptoms of uterine leiomyosarcoma may vary from case to case depending upon the exact location, size and progression of the tumor. Many women will not have any apparent symptoms (asymptomatic). The most common symptom is abnormal bleeding from the vagina and the uterus. Postmenopausal bleeding is an important factor that may indicate a uterine leiomyosarcoma.

The exact cause of uterine leiomyosarcoma is unknown. They often occur spontaneously, for no apparent reason. In extremely rare cases, some researchers believe they may signify a malignant change (transformation) of a benign (noncancerous) fibroid. However, other researchers argue that malignant transformation of fibroids is unproven. Fibroids are the most common tumors affecting women and often appear during childbearing years. Fibroids may also be known as leiomyomas or myomas. Most fibroids do not cause any symptoms or complications.

Uterine leiomyosarcoma is an extremely rare form of cancer, estimated to occur in 6 out of every 1,000,000 women in the United States each year. The average age at diagnosis is 51. Uterine leiomyosarcomas account for 1-2 percent of all malignant tumors of the uterus.

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

The diagnosis of a uterine leiomyosarcoma is most commonly made incidentally when affected individuals are operated on for benign smooth muscle tumors of the uterus (leiomyomas or fibroids). The pathologic review of the fibroid surgery specimens may reveal certain characteristics under the microscope that are more characteristic of a leiomyosarcoma than a benign myoma. Thus, pathologic review is key diagnostic aspect is distinguishing malignant leiomyosarcoma from its benign counterpart, the leiomyoma.


VACTERL/VATER association

VACTERL association is a nonrandom association of birth defects that affects multiple anatomical structures. The term VACTERL is an acronym with each letter representing the first letter of one of the more common findings seen in affected children:

VACTERL association involves multiple anatomical defects. These defects are congenital and may be obvious at birth (e.g., anal atresia, tracheoesophageal fistula and esophageal atresia, radial defects) or not become recognized until later (e.g., cardiac, vertebral, and renal malformations). The combination of malformations may vary greatly from one child to another and an affected child will typically not have all of the malformations listed below.

The exact cause of VACTERL association is unknown. Clearly, the factors that lead to the widespread malformations must influence the very early stages of embryonic development. One or more VACTERL defects have occurred with greater frequency to women with diabetes than in the general population. Rarely, VACTERL association has been associated with gene alterations including duplications or deletions (copy number variation), and mitochondrial dysfunction (the mitochondria is a cellular structure responsible for energy production in the cell).

Estimates place the birth prevalence of VACTERL association at about 1 per 10,000 to 40,000 live births. The true frequency may be difficult to determine because different diagnostic criteria are used in different studies. In addition, VACTERL association is likely to be underdiagnosed, especially in children with fewer problems. Some studies have shown that males might be slightly more commonly affected than females, but no association with a specific geographic region or ethnic group has been determined. VACTERL association is generally not a heritable disease, and the risk of recurrence in another child from the same parents is low.

The malformations that occur in VACTERL association can be seen in a number of other disorders. To avoid misdiagnosis, a complete evaluation is required to consider other possible causes of congenital malformations. Some of the disorders that can mimic VACTERL association are heritable and some occur sporadically. Examples of such conditions are described below.

VACTERL association is a diagnosis made when other possible causes of birth defects have been ruled out (diagnosis of exclusion). No clearly-established set or validated diagnostic criteria has been published to date, and no laboratory test exists that can diagnose or rule out VACTERL association. At the moment, the most stringent approach defines a secure designation of VACTERL association in presence of at least one anomaly in all three involved body parts (i.e. limbs, thorax and pelvis/lower abdomen), and probable in presence of two or more anomalies in two body parts. The diagnosis is a clinical diagnosis based on the defects present and therefore starts with a complete physical examination. Other tests performed will depend on the suspected birth defects. For example, X-ray imaging might be used to detect vertebral and limb anomalies and ultrasound imaging might identify cardiac or renal defects. Laboratory and genetic tests can be useful to rule out alternative diagnoses. Some malformations seen in VACTERL association might be identified before birth with imaging techniques such as prenatal ultrasound. Importantly, the presence of a single umbilical artery should prompt evaluation for VACTERL association and other birth defects.


VACTERL with hydrocephalus

VACTERL with hydrocephalus (VACTERL-H) is a rare disorder in which the non-random congenital malformations of VACTERL association co-occur with hydrocephalus. The term VACTERL is an acronym with each letter representing the first letter of the associated malformation:

VACTERL with hydrocephalus (VACTERL-H) is a rare disorder that affects multiple anatomical systems. Affected children typically present with a variety of congenital anomalies at birth, however, in some children core features of the disorder are not noted until later in life. The combination of congenital anomalies and the related symptoms may vary considerably in different affected individuals.

VACTERL-H is generally considered to be a sporadic disorder, not passed down through families, and a consequence of defective differentiation of specific tissue types during early fetal development. However, in a subset of patients there is evidence for a familial or inherited component with some patients reporting multiple affected family members. In patients with a family history of VACTERL-H, the disorder is thought to show autosomal recessive or X-linked inheritance.

VACTERL with hydrocephalus is an extremely rare disorder that affects males and females in equal numbers. The exact prevalence of the disorder in the general population is unknown.

The congenital malformations described in VACTERL-H can occur as isolated defects or as a component of other complex disorders. To avoid misdiagnosis, a complete evaluation including detailed clinical examinations and laboratory studies are often required to rule out other more common associated disorders. Some of the conditions often considered in the differential diagnosis of VACTERL-H are discussed below.

The diagnosis of VACTERL-H is made clinically. Presence of at least three of the core features or the disorder, including presence of hydrocephalus, is usually typically considered sufficient for diagnosis. Other more common disorders should be ruled out with clinical and/or laboratory studies. Clinical diagnosis is based on the features seen and therefore starts with a complete physical examination. The diagnosis of VACTERL-H is usually made after birth, however, findings seen on prenatal imaging such as a single umbilical artery or radial aplasia may be suggestive of this diagnosis and prompt evaluation for other anomalies. Imaging studies, while not required are typically used to aid in diagnosis as milder anomalies may be difficult to diagnose on clinical examination alone.


Variegate porphyria

The symptoms and severity of variegate porphyria can vary greatly from one person to another. Symptoms are rarely apparent before puberty. Affected individuals often develop skin (cutaneous) or neurological abnormalities or both. It is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals should talk to their physicians about their specific clinical situations, associated symptoms and overall prognosis.

Variegate porphyria is caused by mutations of the PPOX gene.  A PPOX mutation is inherited as an autosomal dominant trait within a family. Dominant genetic disorders occur when only a single copy of an altered 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 (gene change) in the affected individual. The risk of passing the altered gene from an affected parent to an offspring is 50% for each pregnancy.  The risk is the same for males and females.

Some reports suggest that variegate porphyria affects more women than men. The incidence is estimated to occur in 1 in 100,000 individuals in the general population in European populations. The disorder occurs with the greatest frequency in South Africa in individuals of Dutch ancestry 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 genetic trait. Most individuals with variegate porphyria in South Africa carry the same PPOX mutation and are descendants of a Dutch settler from the late 1600s. The incidence of variegate porphyria in South Africa among Caucasians is estimated to be 1 to 3 in 1,000 individuals.

Acute attacks of variegate porphyria are identical to those that occur in three other porphyrias. Therefore, these are often classified as acute porphyrias based on these symptoms.

A diagnosis of variegate porphyria is suspected based upon symptoms and examination of the skin. None of the symptoms are specific, so the diagnosis must be confirmed by biochemical testing. In the evaluation of neurological symptoms, the other acute porphyrias need to be considered. For initial screening, a spot urine sample should be obtained for measurement of PBG, ALA and total porphyrins. If none of these is elevated, acute porphyrias can be excluded as a cause of recent or concurrent symptoms. PBG measurement is most important and specific for acute porphyrias. However PBG and ALA may be less elevated and return to normal more quickly after an attack of variegate porphyria (or hereditary coproporphyria) than in acute intermittent porphyria. Therefore, measurement of total urine porphyrins is important, keeping in mind that an elevation of urine porphyrins can occur in many other medical conditions.


Vascular Malformations of the Brain

As the name suggests, vascular malformations of the brain is an umbrella term for at least six conditions in which blood vessels of the brain are affected. Such malformations are classified into several types in which the symptoms, severity, and causes vary. These types of VMB are: (1) arteriovenous malformations (AVM), abnormal arteries and veins; (2) cavernous malformations (CM), enlarged blood-filled spaces; (3) venous angiomas (VA), abnormal veins; (4) telangiectasias (TA), enlarged capillary-sized vessels; (5) vein of Galen malformations (VGM); and (6) mixed malformations (MM).

Vascular malformations of the brain may cause headaches, seizures, strokes, or bleeding in the brain (cerebral hemorrhage).  Some researchers believe that the type of malformation determines the symptoms and progression of the disease.  Other researchers believe that only the severity rather than the type of malformation is important.

Three types or forms of VMB have a genetic component.  The evidence for a genetic cause is strong in the case of cavernous hemangiomas and telangiectasias.  The case is much weaker for arteriovenous malformation of the brain (AVM).  In each of these cases, the condition is transmitted as an autosomal dominant trait.  The malfunctioning gene in the case of cavernous malformations has been tracked to gene map locus 7q11.2-q21, and in the case of telangiectasia to gene map locus 9q34.1.

Vascular malformations of the brain affect males and females in equal numbers.  A hereditary form of cavernous malformations tends to occur more frequently in Mexican-Americans.  Arteriovenous malformations occur more frequently in males.

Symptoms of the following disorders can be similar to those of vascular malformations of the brain.  Comparisons may be useful for a differential diagnosis:


Vasculitis

Vasculitis is inflammation of blood vessels. In individuals with vasculitis, inflammation damages the lining of affected blood vessels, causing narrowing, the formation of blood clots (thrombosis), and/or blockage. As a result, there may be restriction of oxygenated blood supply to certain tissues (ischemia), potentially resulting in pain, tissue damage, and, in some cases, malfunction of certain affected organs. Vasculitis may affect veins and arteries of any type or size; may involve a single organ or many organs and tissues of the body; and may be a primary disease process or occur due to or in association with a number of different underlying disorders. Therefore, the range and severity of symptoms and findings associated with vasculitis may vary greatly. The specific underlying cause of vasculitis is not fully understood. However, in most cases, it is thought to be due to disturbances of the body’s immune system.

Vasculitis is a general term that means inflammation of blood vessels. This inflammation causes a narrowing of the inside of the vessel and can obstruct the flow of blood to the tissues (ischemia). The lack of blood may result in damage to nearby tissues (necrosis), formation of blood clots (thrombosis), and, in rare cases, a weakening or ballooning that may rupture of the vessel wall (aneurysm).

The specific underlying cause of vasculitis is not fully understood. However, in most cases, vasculitis is thought to be due to disturbances of the body’s immune system. Some forms of vasculitis may be due to allergic reactions or hypersensitivity to certain medications such as sulfur drugs, penicillin, propylthiouracil, other drugs, toxins, or other inhaled environmental irritants. Other forms may occur due to fungal, parasitic, or viral infections. In some instances, it is thought that vasculitis may be an autoimmune disorder. 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.

Vasculitis usually affects males and females in equal numbers. It is most commonly seen in the elderly.

The following are diseases that are associated with vasculitis:

Because of the wide range of symptoms and body systems involved, an extensive history and physical exam is needed before a clear diagnosis of the type of vasculitis can be made. In some cases, an x-ray of the blood vessels using dye (angiogram), or a biopsy of the affected organ may be recommended to give an accurate diagnosis and to insure proper treatment.


Ventricular Septal Defects

Ventricular septal defects are heart defects that are present at birth (congenital). The normal heart has four chambers. The two upper chambers, known as atria, are separated from each other by a fibrous partition known as the atrial septum. The two lower chambers are known as ventricles and are separated from each other by the ventricular septum. Valves connect the atria (left and right) to their respective ventricles. The aorta, the main vessel of arterial circulation, carries blood from the left ventricle and away from the heart.

Infants with small ventricular septal defects may have no symptoms unless they experience infection that spreads to the lining of the heart and the valves (infective endocarditis).  This form of the disease is known as Roger’s disease.

The exact cause of VSDs is not known. These defects probably occur as the result of errors in the development of an embryo. During the early part of fetal development there is no wall (septum) to separate the left and right ventricles. As the fetus grows, so does a muscular wall that splits the lower chamber into two ventricles.  If the muscle does not form a solid wall, a hole remains and is what is called the ventricular septal defect. The why and how of these developmental errors is not fully understood. However, research suggests that they may occur as the result of the complex interaction of many factors, both genetic and environmental (multifactorial).

Ventricular septal defects are rare congenital malformations of the heart that occur more frequently in males than females.  Approximately 1 percent of newborns have a congenital heart defect.  About 25 to 30 percent of these infants are diagnosed with ventricular septal defects.  Of the babies born with VSDs, 80 to 90 percent present with a small hole and mild symptoms.

Symptoms of the following disorders may be similar to those of ventricular septal defects.  Comparisons may be useful for a differential diagnosis:

Atrial septal defects are common congenital heart defects characterized by the presence of a small opening between the two atria of the heart.  These defects lead to an increase in the workload on the right side of the heart as well as excessive blood flow to the lungs.  The symptoms, which may become apparent during infancy, childhood, or adulthood, depend on the severity of the defect and can vary greatly.  The symptoms tend to be mild at first and may include difficulty breathing (dyspnea), increased susceptibility to respiratory infections, and/or abnormal bluish discoloration of the skin and mucous membranes (cyanosis).  Some people with atrial septal defects may be at increased risk for the formation of blood clots that can travel to the major arteries (embolism) and block blood circulation.  (For more information on this disorder, choose atrial septal defect as your search term in the Rare Disease Database.)

The diagnosis of ventricular septal defects is confirmed by a thorough clinical evaluation and specialized tests that allow physicians to evaluate the structure and function of the heart as well as the exact nature of the defect. X-ray studies and electrocardiogram (EKG) results may help to confirm the diagnosis. In one procedure, ultrasonic waves are directed toward the heart (Doppler echocardiogram), enabling physicians to study the motion and function of the heart and the surrounding vessels. During cardiac catheterization, a small hollow tube (catheter) is inserted into a large vein and threaded through the blood vessels that lead to the heart. This procedure allows physicians to determine the rate of blood flow through the heart, measure pressure within the heart, and thoroughly identify anatomical abnormalities.