Susac syndrome

The specific symptoms, severity, and outcome of Susac syndrome vary from one person to another. Commonly, the three main features (encephalopathy, branch retinal arterial occlusions and hearing loss) are not all present at disease onset, and all three do not necessarily develop in all patients. When patients are first evaluated by a physician, any one of the three main features may be the only feature present, with one or both of the other features appearing only later. The skin may also be involved, and the symptoms may include livedo reticularis and a diffuse micropapular rash.

Susac syndrome is an autoimmune endotheliopathy, a disorder in which the body’s immune system mistakenly attacks the inside lining (endothelium) of the walls of the very tiny blood vessels that supply blood to the brain, retina and inner ear. The exact, underlying reason why this occurs is unknown. Why the microvasculature in the brain, retina, and inner ear are primarily affected is also unclear. The skin may also be involved.

Susac syndrome primarily affects young women between the ages of 20-40 but has occurred in individuals ranging in age from 9 to 72. Women are affected three times more often than men. Although considered a rare disorder, Susac syndrome is being recognized more often worldwide and may be more common than originally thought. However, because the disorder often goes unrecognized or misdiagnosed, determination of the true frequency of Susac syndrome in the general population has been difficult.

The encephalopathic form of Susac syndrome is frequently misdiagnosed as multiple sclerosis (MS) or acute disseminated encephalomyelitis (ADEM). When Susac syndrome presents primarily with hearing loss, tinnitus, and vertigo, it is frequently misdiagnosed as Meniere disease.

The possibility of Susac syndrome is raised when a patient presents with one or more components of the clinical triad (encephalopathy, BRAO, hearing loss). A diagnosis of definite or probable Susac syndrome is based on the presence of at least two components of the triad and documentation of typical snowball lesions in the corpus callosum upon brain MRI. The process of making a diagnosis includes a detailed patient history, a thorough evaluation of all plausible explanations for the illness and a variety of specialized tests including magnetic resonance imaging (MRI), fluorescein angiography and an audiogram.


Sweet syndrome

Sweet syndrome is a rare disorder characterized by fever and the sudden onset of a rash, which consists of multiple tender, red or bluish-red bumps or lesions. These lesions usually occur on the arms, legs, trunk, face or neck. In some cases, additional systems of the body can become involved including the musculoskeletal system such as inflammation of the joints (arthritis), the eyes such as inflammation of the conjunctiva or the membrane that lines the eyes (conjunctivitis), and the internal organs. In the majority of affected individuals, the disorder occurs by itself for no known reason (idiopathic Sweet syndrome); this is also known as classical Sweet syndrome. Less often, the disorder can be associated with an underlying cancer (malignancy), usually a blood (hematologic) cancer such as certain types of leukemia; this is known as malignancy-associated Sweet syndrome. The disorder can also result as a reaction to taking certain drugs, especially a drug known as granulocyte-colony stimulating factor; this is known as drug-induced Sweet syndrome. Sweet syndrome is treated with corticosteroids.

The major symptom of Sweet syndrome is the sudden onset of tender or painful bumps (nodules or papules) on the arms, legs, face or neck. They may also occur on the thighs and trunk. Papules are solid, raises lesions; nodules are slightly larger and may extend deeper into the skin. These initial lesions are usually several millimeters to centimeters in diameter, but sometimes up to an inch in diameter, flat or slightly elevated, irregularly-shaped, and inflamed. They tend to grow slowly, eventually joining together (coalescing) to form larger, irregular plaques. Small pus-filled blisters (pustules) may develop.

The exact cause of Sweet syndrome is not fully understood. Most likely, the disorder results from multiple, complex factors including immunological, and environmental factors. Some researchers speculate that Sweet syndrome occurs as an allergic reaction (reactive process) to an unknown agent. In such instances, there is an oversensitive, or hypersensitivity, reaction by the immune system to a specific agent such as a bacterial or viral infection, cancer or certain type of drug.

Classical Sweet syndrome in adults affects women more often than men by as much as 15:1 by some estimates. This female preponderance has not been seen in malignancy-associated or drug-induced Sweet syndrome. Classical Sweet syndrome usually affects women between the ages of 30-50, but can be seen in individuals of any age including children. There is no gender predominance seen in children. Several hundred individuals of Sweet syndrome have been reported in the medical literature. Only approximately 80 children have been reported in the medical literature.

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

Pyoderma gangrenosum is a rare skin disorder of unknown origin. Major symptoms include small pustules that develop into large ulcers at various sites on the body. Skin abnormalities associated with pyoderma gangrenosum are slowly growing, purple-colored lesions with an undermined border and an irregular base of pus and decaying tissue. The ulcers most frequently develop on the legs but they may appear on the trunk, head and neck, scrotum and in the mucous membranes (mucosa). (For more information on this disorder, choose pyoderma gangrenosum as your search term in the Rare Disease Database.)


46,XY complete gonadal dysgenesis

46，XY完全性腺发育不全

Most individuals with Swyer syndrome do not experience any outward symptoms until their early teens when they fail to begin having a period (primary amenorrhea). At this point, it is usually discovered that these girls lack ovaries and, therefore, do not have sex hormones (estrogen or progesterone) that are required to undergo puberty. When hormone replacement therapy is started, these girls will develop enlarged breasts, underarm and pubic hair, regular menstrual cycles and other aspects of normal development during puberty.

In most cases of Swyer syndrome, the exact cause of the disorder is unknown. Researchers believe that disruptions or changes (mutations) of a gene or genes that are involved in normal sex differentiation of a fetus with an XY chromosomal makeup cause Swyer syndrome.

Swyer syndrome affects girls who have an XY chromosomal makeup, no ovaries, but functional female organs including the uterus, fallopian tubes and vagina. The exact incidence is unknown. One estimate placed the incidence at 1 in 80,000 births. Another estimate placed the incidence of Swyer syndrome (complete gonadal dysgenesis) and partial gonadal dysgenesis combined at 1 in 20,000 births. Genital anomalies in general occur in approximately 1 in 4,500 births.

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

A diagnosis of Swyer syndrome is made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic findings (e.g., no periods, streak gonads) and a variety of tests including chromosomal analysis. For example, a specific technique called fluorescent in situ hybridization (FISH) can be used to determine a person’s karyotype. A karyotype is a visual representation of a person’s chromosomal makeup, (i.e., the 46 chromosomes in a cell). These 46 chromosomes are broken down into 22 matched pairs (each pair has one chromosome received from the father and one receive from the mother). The sex chromosomes are seen as a separate pair, either XX or XY. A diagnosis of Swyer syndrome is usually made when young adults are tested for delayed puberty.


Sydenham Chorea

The severity of chorea and the presence of non-chorea symptoms of Sydenham chorea may vary greatly from one person to another. Most cases follow an identifiable streptococcal infection. Streptococcus is a group of bacteria that can cause several different infections, most commonly strep throat – often presenting with a sore throat (pharyngitis) or fever. Symptoms of Sydenham chorea may appear anywhere from 1 week to 6 months following streptococcal infection.

Sydenham chorea is believed to be an autoimmune disorder. Most cases develop following a streptococcal infection or more severe rheumatic fever. An autoimmune disorder occurs when the body’s immune system mistakenly reacts against healthy tissue. In Sydenham chorea, streptococcal infection induces the body’s immune system to produce antibodies to combat the infection. For unknown reasons, these antibodies persist and subsequently target certain cells in the joints, kidneys, heart, and, in the brain, specifically cells of the basal ganglia (a key part of the brain for controlling motor movements). Researchers believe this ultimately leads to the characteristic symptoms of Sydenham chorea.

According to most studies, Sydenham chorea affects girls more often than boys. It usually develops in children between the ages of 5-15. Rarely, the disorder has been reported in children under age 5 years or in adults. Sydenham chorea affects individuals of all races and ethnicities.

Symptoms of some other disorders can be similar to those of Sydenham chorea. While Sydenham chorea should be suspected as the most likely cause of acute chorea in children, there are other conditions doctors should consider as well.

A diagnosis of Sydenham chorea is made based upon identification of new onset choreic movements, a detailed patient history, and a thorough clinical evaluation. In the presence of new onset chorea, which is uncommon in childhood, the documentation of a prior streptococcal infection through throat swabs and/or the current presence of high blood titers of streptococcal antibodies (ASO, anti DNAseB) is useful, as are identification of co-occurring arthritis or cardiac valve abnormalities. In some cases, certain imaging techniques such as magnetic resonance imaging (MRI) may be recommended to exclude other causes. Usually, brain imaging is normal in Sydenham chorea. Of note, because the onset of Sydenham chorea usually occurs weeks after the infection, the characteristic signs of rheumatic fever or streptococcal infection are usually no longer present.


Neurodevelopmental delay-intellectual disability-skeletal defects syndrome

SYNCRIP-related neurodevelopmental disorder (SYNCRIP-RNDD) is a rare disorder characterized by developmental delay/intellectual disability, autism spectrum disorder, motor speech delay and low muscle tone (hypotonia). This condition is caused by changes (variants) in the SYNCRIP gene which is also known as the HNRNPQ gene.

SYNCRIP-RNDD is characterized by developmental delay/intellectual disability, motor and speech delay, hypotonia and behavioral differences. Cognitive disabilities are typically in the mild to borderline intellectual disability range. Autism spectrum disorder is common. Some structural brain anomalies have been observed but are not consistent. Some affected individuals have had seizures and physical differences have been reported in some patients.

SYNCRIP-RNDD is caused by pathogenic or likely pathogenic variants in the SYNCRIP (also known as HNRNPQ) gene. Most variants are loss-of-function and result in a nonfunctional protein product that leads to half of the necessary amount of SYNCRIP/hnRNPQ protein for normal cellular function (haploinsufficiency). Missense and insertion/deletion (indel) variants are rarer but have been reported more frequently with increased genomic testing. To date, all variants reported in the medical literature are de novo, which means that they occurred for the first time in the affected person and were not inherited from a parent.

SYNCRIP-RNDD has been described all over the world and is not population specific.

SYNCRIP-RNDD is in the group of conditions called HNRNP-related neurodevelopmental disorders (HNRNP-RNDDs). These include HNRNPC-RNDD, HNRNPG (RBMX)-RNDD (also referred to as Gustavson syndrome and Shashi-type intellectual disability), HNRNPH1-RNDD, HNRNPH2-RNDD, Au-Kline syndrome (due to variants in HNRNPK), HNRNPR-RNDD and HNRNPU-RNDD). Several other HNRNP genes are being studied.

SYNCRIP-RNDD may be suspected based on the signs and symptoms associated with the disorder. The diagnosis is confirmed with genomic testing that shows a pathogenic or likely pathogenic variant in the SYNCRIP gene.

Standard therapies have not been described for SYNCRIP-RNDD. Multidisciplinary care is recommended and includes management of multiple subspecialty appointments, equipment, medications and supplies. Ongoing assessment for palliative care involvement and/or home nursing is needed.


Syringomyelia

The specific symptoms and severity of syringomyelia can vary greatly from one person to another. Some individuals may not have any noticeable symptoms (asymptomatic); others may have a variety of symptoms that can progress to cause significant disability. It is important to note the highly variable nature of syringomyelia and to realize that affected individuals can have different sets of symptoms and a different rate of progression (or no progression of the disease at all).

The exact, underlying reason for the formation of a syrinx is unknown. Most theories implicate the obstruction or disruption of the flow of cerebrospinal fluid (CSF) as the most common cause. CSF is a clear fluid that surrounds and is within the brain and surrounds the spinal cord. CSF has several functions including protecting and cushioning the brain and giving the brain buoyancy. CSF is also found in the central canal, a small canal that runs through the center of the spinal cord in infants. The central canal eventually collapses over time.

Syringomyelia most commonly presents in young adults between 20 and 40 years of age, but can also develop in young children or older adults. Some reports suggest that syringomyelia is slightly more common in males than females. One estimate places the incidence at 8.4 individuals per 100,000 in the general population in the United States.

Chiari malformations are commonly associated with syringomyelia. They are a group of complex brain abnormalities that affect the area in lower back of the skull where the brain and spinal cord connect. Chiari malformations are thought to be present at birth (congenital), although in many cases, the symptoms that they cause may not become apparent until adulthood. In extremely rare cases, a Chiari malformation may be acquired during life. The exact cause of Chiari malformations is not known, but often the cavity near the base of the skull (posterior cranial fossa) is abnormally small in relation to the size of the cerebellum, which this portion of the skull encloses. Researchers believe that in some cases, the small posterior cranial fossa may cause the developing brain, specifically the cerebellum and the brainstem, to be pushed downward. Part of the cerebellum (known as the cerebellar tonsils) may protrude (herniate) through the foramen magnum, which is the normal opening found in the occipital bone at the base of the skull. The tonsils thus interfere with the flow of cerebrospinal fluid (CSF) from the skull into the spinal canal. A Chiari malformation can also cause hydrocephalus (pressure due to excessive cerebrospinal fluid accumulation in the brain), potentially causing a wide variety of symptoms. The severity of Chiari malformations can vary dramatically as well. Some affected individuals may not develop any symptoms (asymptomatic); in others, severe, potentially debilitating or life-threatening symptoms can develop. Traditionally, Chiari malformations have been defined and classified by how much of the cerebellum and other parts of the posterior cranial fossa protrude through the foramen magnum. A diagnosis of a Chiari type I malformation usually signifies that the cerebellar tonsils protrude below the foramen magnum (often cited as at least 5 millimeters). Researchers have determined that the length of tonsil descent in a Chiari malformation does not always correspond to the severity of symptoms or to the response to treatment. In fact, some individuals are classified as having Chiari malformation type 0. These individuals make up a very small percent of the Chiari population and are defined as having minimal or no descent of the cerebellar tonsils and syringomyelia that improves after surgical treatment at the base of the skull. Chiari type II malformations are seen only in patients with spina bifida. There is also herniation of the cerebellum through the foramen magnum but instead of the cerebellar tonsils, the cerebellar vermis is herniated. Syringomyelia is also very common in patients with the Chiari II malformation. Research is ongoing to understand the complex, underlying mechanisms that cause Chiari malformations. (For more information on this disorder, choose Chiari as your search term in the Rare Disease Database.)

A diagnosis of syringomyelia is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. In some cases, syringomyelia is discovered incidentally when a person is being evaluated for another reason.


Systemic capillary leak syndrome

系统性毛细血管渗漏综合征

Symptoms of SCLS usually involve a brief warning, which can include nasal congestion and cough that might be associated with a viral upper respiratory infection. Patients may develop malaise, nausea, lightheadedness, a faint feeling, abdominal pain, headache and swelling of extremities. Fever, chills, rash, or signs of infection may be absent.  Patients may also exhibit elevated white blood cell count (leukocytosis) which may produce a false diagnosis when blood is tested. Spontaneous resolution of symptoms is uncommon without treatment.

The cause of SCLS is not yet known, but there appears to be no hereditary predisposition for the condition. Most patients have a monoclonal or M protein detected in the blood, and these patients are designated as having monoclonal gammopathy associated systemic capillary leak syndrome (MG-CLS) or Clarkson disease. The level of M protein is usually low. The M protein is produced by plasma cells in the marrow. The role of the M protein in acute attacks is unknown. Many possible explanations for the production of M protein in SCLS patients have been suggested including an autoimmune mechanism in which the immune system mistakenly attacks the body. Recently it has been suggested that capillary lining cells may be damaged by a factor in the blood which is produced during the acute attack.

There are less than 500 patients with MG-CLS reported in the world literature since its first description in 1960 by Clarkson. Although most clinical studies were performed in Caucasians, MG-CLS has been recognized in a range of racial backgrounds and nationalities. MG-CLS occurs equally in males and females. Most diagnoses are made at the median age of 48 years of age. The disease may be more frequent than the literature suggests because the diagnosis is often missed or delayed.

Symptoms of the following disorders may be similar to those of systemic capillary leak syndrome. Comparisons may be useful for a differential diagnosis:

MG-CLS may be mistaken for a severe infection such as septic shock or toxic shock syndrome. Some features such as swelling may lead to a suspected diagnosis of heart failure or kidney disease. C-1 esterase inhibitor deficiency syndrome may present with a type of recurring edema called angioedema and is often thought of in patients presenting with MG-CLS. In some patients, the hemoconcentration and resulting high hematocrit and hemoglobin level have been mistaken for polycythemia.


Systemic primary carnitine deficiency

CDSP can present in three ways. Infants with the infantile metabolic (hepatic) type present in the first two years of life with episodes of irritability, tiredness and abnormal enlargement of the liver (hepatomegaly). Laboratory results show hypoglycemia with little to no ketones in urine (hypoketotic hypoglycemia), high levels of ammonia in the blood hyperammonemia), and elevated liver transaminases. Some children with the infantile presentation may also have symptoms of muscle disease.

CDSP is caused by mutations in the CLC22A5 gene, resulting in absent or dysfunctional OCTN2 protein. Normally, this protein functions to reabsorb carnitine in kidneys and transport carnitine inside cells.  If the protein is absent or abnormal, there is a shortage of carnitine in cells. Carnitine functions to carry fatty acids obtained through diet to the energy centers in muscle cells (mitochondria). A deficiency of carnitine results in an inability to utilize fat leading to hypoglycemia and the accumulation of fats in the liver, muscle, and heart.

CDSP is a rare disorder that affects males and females in equal numbers. Based on newborn screening and reports in medical literature, the prevalence in the US is estimated to be 1:50,000.

Symptoms of the following disorders can be similar to those of systemic primary carnitine deficiency. Comparisons may be useful for a differential diagnosis:

Carnitine deficiency can occur as a result of other metabolic disorders (secondary carnitine deficiency) such as organic acidemias and fatty acid oxidation defects.

The main treatment for CDSP is L-carnitine supplementation, which is very effective if started before organ damage occurs. Hypoglycemic episodes associated with carnitine deficiency are treated with intravenous dextrose infusion or proper feeding and diet. Maintaining normal carnitine levels through supplementation and preventing hypoglycemia through frequent feeding and diet can prevent the metabolic, hepatic, cardiac, and muscular complications of CDSP.


Systemic sclerosis

Systemic scleroderma is a disease characterized by rapid growth of fibrous (connective) tissue that leads to scarring of skin and internal organs. Approximately one in 10,000 individuals is affected. It is more common in women and most often develops around age 30 to 50. Systemic scleroderma can affect almost any organ in the body, and there is a large variability of symptoms among affected individuals. One of the most common and earliest manifestations of the disease is Raynaud phenomenon, which involves blood vessel spasms (vasospasms) induced by cold temperature or stress. This can lead to temporary finger discoloration, numbness and pain and is also associated with the development of finger ulcers. Of note, Raynaud phenomenon also commonly occurs in healthy individuals. Other manifestations of systemic scleroderma include muscle and joint pain, skin tightening, and dilated blood vessels that can be seen through the skin (telangiectasias). Scarring of internal organs can also lead to gastrointestinal, pulmonary, cardiac, and renal disease. Although systemic scleroderma cannot be cured, many of the symptoms can be treated. A timely diagnosis is important to ensure appropriate management of the disease and associated complications.

Systemic scleroderma can affect multiple organ systems and therefore lead to numerous symptoms and complications. The symptoms present, their severity, the rate of progression of the disease, the response to treatment, and overall survival vary widely depending on the affected individual. In most cases, people start to develop symptoms between age 30 and 50. Symptoms related to the different organs involved are described below.

Although the exact cause and disease mechanism of systemic scleroderma are not known, it is thought to occur in genetically predisposed individuals following a trigger, possibly exposure to virus or toxins. Systemic scleroderma is an autoimmune disease, which means that it involves a dysregulated immune system that attacks the affected individual’s own body. The first event to occur is possibly injury to small blood vessels (microvascular injury). In healthy individuals, response to injury leads to recruitment of inflammatory mediators that facilitate repair. In individuals with systemic scleroderma, microvascular injury leads to disproportionate inflammatory mediator recruitment and excessive fibrous tissue deposition. This fibrous tissue can replace healthy tissue and lead to symptoms of systemic scleroderma such as skin thickening, internal organ scarring and associated complications.

Systemic scleroderma affects between 38 and 341 individuals per million throughout the world (prevalence) and develops in 8 to 56 individuals per million each year (incidence). It is more common in populations from southern Europe, North America and Australia, and less common in populations from northern Europe and Japan. The disease most often starts to manifest in the fifth decade of life (age of onset). Although it most commonly occurs in women, men tend to have more severe disease. African American individuals tend to have a lower age of onset, higher rates of the diffuse cutaneous subtype, and overall more severe disease.

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

Localized scleroderma (also known as morphea) is characterized by skin symptoms similar to those seen in systemic scleroderma but without internal organ involvement. It is considered a disease distinct from systemic scleroderma.


Tako-Tsubo cardiomyopathy

Takotsubo cardiomyopathy can occur in adults of any age, but most often develops in elderly women. The most common symptoms are the abrupt (acute) onset of crushing chest pain and difficulty breathing (dyspnea). Anxiety, sweating (diaphoresis), nausea, vomiting, palpitations, and transient loss of consciousness (syncope) can also occur.

The mechanism by which takotsubo cardiomyopathy develops in not entirely understood. In about 2/3 of cases, the disease is preceded by intense emotional stress (such as divorce, death of a loved one, or bankruptcy) or physical stress (such as a stroke, fracture, or infection). A hypothesis is that these stressors lead to the release of large amounts of adrenaline (epinephrine) and other stress-related hormones collectively known as catecholamines. This surge of hormones might lead to spasms of the blood vessels and disruption of the ventricles of the heart, which would be responsible for the ventricular dysfunction and ballooning seen in takotsubo cardiomyopathy.

Takotsubo cardiomyopathy can develop in men and women of any age and ethnic background. However, about 90% of affected individuals are women, and 80% are women over the age of 50. The exact frequency of the disease is not known and might be underestimated, but is thought to comprise approximately 2% of all individuals (and up to 5% of women) with suspected ST-segment elevation myocardial infarction, which is the most severe type of heart attack. This represents more than 4000 individuals in the United States.

Angina is a condition caused by limitation of blood flow to the heart. It is usually caused by partial obstruction of the arteries that feed the heart (coronary arteries) by a fatty plaque (atheroma), but can also rarely be caused by spasms of the arteries (vasospastic angina). Angina is usually triggered by exercise or stress and is relieved by rest, except in the case of vasospastic angina, which occurs at rest. The main symptom of angina is chest pain, which patients usually describe as a squeezing, pressure, or tightness. It is often accompanied by difficulty breathing (dyspnea), sweating (diaphoresis), nausea, and anxiety. Angina that occurs at rest, lasts longer than before, becomes more frequent, or becomes more intense is known as unstable angina.

Typically, individuals with takotsubo cardiomyopathy present with symptoms undistinguishable from a myocardial infarction and will therefore be considered to have a heart attack until proven otherwise. The two most common and useful initial tests for an individual with symptoms suggesting an acute MI is an electrocardiogram (ECG), which measures electrical activity of the heart and blood troponin levels, which is a marker of damage to the heart. In takotsubo cardiomyopathy, the ECG shows changes that are typically seen in a ST-segment elevation myocardial infarction (the most severe type of heart attack), and troponin levels are elevated, as they also are in an MI. However, when coronary angiography (a medical imagining technique in which a dye is injected into the coronary arteries to visualize them with radiographs) is performed in individuals with takotsubo cardiomyopathy, no significant coronary artery occlusion is seen. Ventricular dysfunction and ballooning can be identified with ventriculography (which uses the same principles as coronary angiography but allows visualization of the ventricles), or echocardiography (which uses ultrasound waves to make visualization of the heart possible). Cardiac magnetic resonance imaging (MRI) is a specialized imaging technique that can occasionally be used to diagnose takotsubo cardiomyopathy and assess the extent of ventricular dysfunction and ballooning.


Tangier disease

Tangier disease is a rare inherited disorder characterized by significantly reduced levels of high-density lipoproteins (HDL) in the blood. HDL-cholesterol (HDL-C) is often referred to as the good cholesterol as it can facilitate the removal of cholesterol out of the walls of arteries, particularly the coronary (heart) arteries. Classic features of Tangier disease include fatty accumulations that present as enlarged and yellow- or orange-colored tonsils, or enlarged liver (hepatomegaly), spleen (splenomegaly), or lymph nodes. Tangier disease may also be associated with an increased risk of cardiovascular disease, moderate elevation in triglycerides (hypertriglyceridemia), nerve disturbances (neuropathy), and rarely an opaqueness in the covering of the eye (corneal clouding). This disorder was originally named after the location in which it was first discovered – Tangier Island in the Chesapeake Bay. Later, the disease was further characterized as more individuals were found to have the disease in other areas of the United States and around the globe.

Symptoms of Tangier disease are variable and depend on which organs are involved and the severity of those manifestations. Tangier disease is most often characterized by enlarged orange- or yellow-colored tonsils. This discoloration is due to fatty deposits accumulating in the tonsils. Fatty deposits can also form in other organs causing enlargement of the throat, liver, spleen, or lymph nodes. Fat accumulations in nerves can cause disturbances and loss-of-sensation called peripheral neuropathy. Discoloration may also occur in the digestive system, particularly the rectum and large intestine. Cardiovascular disease has been reported in adults with Tangier disease. In rare cases, a clouding of the cornea of the eye can occur, but is generally mild and does not cause vision impairment.

Tangier disease is an autosomal recessive genetic disorder. Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for Tangier disease, the individual will be a carrier for the disease but will not show the classic characteristics. However, carriers of Tangier disease often are found to have relatively low levels of HDL-C.

Tangier disease is a rare disorder with only approximately 100 cases diagnosed worldwide. Tangier disease is thought to be present at birth, but the age of diagnosis can be highly variable (from infancy through 7th decade) due to the nature of symptoms.

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


TANGO2 Deficiency Disorder

复发性代谢性脑脊髓病-横纹肌溶解症-心脏心律不齐-智力障碍综合征

TANGO2-related metabolic encephalopathy and arrhythmias

TANGO2 deficiency disorder is a rare genetic disorder caused by disease causing changes in the TANGO2 gene. Affected individuals experience episodes of acute illness called metabolic crises. These episodes can be triggered, often by a preceding infection or from decreased oral intake or fasting for an extended period of time. Irregularities in the rhythm of the heart (arrhythmias), the breakdown of muscle tissue (rhabdomyolysis) and other complications can occur during an episode. The term encephalopathy is a general term for brain disease. Neurological problems including intellectual disability and delays in reaching developmental milestones can occur. Additional signs and symptoms can occur both within and outside of metabolic crisis. TANGO2 deficiency can affect people very differently. There is no cure for the disorder, but research is underway to better understand and treat this disease. Current treatment is aimed at the specific symptoms present in each individual.

Although researchers have been able to establish a clear syndrome with characteristic or core symptoms, much about the basis of these symptoms remains unclear. Parents should talk to their children’s physician and medical team about their specific case, associated symptoms and overall prognosis.

TANGO2 deficiency is caused by variations in the TANGO) gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When alteration of a gene occurs, the protein product may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the protein, this can affect many organ systems of the body, including the brain. Researchers are not sure what the protein produced (encoded) by the TANGO2 gene does. It may have a role in secretory protein loading within the endoplasmic reticulum, which is an extensive membrane network found within certain cells where proteins are processed. Studies also indicate that it may play a role in synthesis of lipids, important for cell functions.

TANGO2 deficiency is a rare disorder that was first reported in the medical literature in 2016. According to the TANGO2 Research Foundation, as of January 2023, over 100 individuals have been identified with the disorder worldwide. Based on the known carrier frequency of TANGO2 changes in different populations, it is likely that over 8,000 individuals are affected with TANGO2 deficiency in the world. Rare diseases often go undiagnosed or misdiagnosed, making it difficult to determine the true frequency in the general population.

Symptoms of the following disorders can be similar to those of TANGO2-deficiency. Comparisons may be useful for a differential diagnosis.

A diagnosis of TANGO2 deficiency is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Diagnostic criteria for this disorder have not yet been established.


Tarsal Carpal Coalition Syndrome

The most common initial signs and symptoms of tarsal carpal coalition syndrome are worsening joint stiffness, joint pain and joint deformity. Common complaints include pain with walking and abnormal walking pattern (gait).

Tarsal carpal coalition syndrome is caused by changes (pathogenic variants) in the NOG gene. These variants result in a loss of the noggin protein which normally forms a receptor that decreases the concentration of proteins associated with bone and cartilage growth. This excess of bone-forming and cartilage-forming proteins or cells (osteoblasts) leads to oversized growth plates and excess cartilage and bone formation. This causes failure of joint formation and fusion of adjacent bones. Multiple pathogenic variants have been identified that lead to various presentations of TCC with overlapping symptoms. These variants cause abnormal cartilage formation but do not affect the overall shape or length of limbs. Most cases run in families, but some have been isolated (sporadic, non-familial). Different families with similar/identical pathogenic variants may have different symptoms, different severity, or even different NOG gene-related disorders due to differences in gene expression. Though there is variation in presentation, it appears that everyone with a pathogenic variant in the NOG gene has some form of disease with similar findings in males and females.

Tarsal carpal coalition syndrome is a rare condition with a prevalence of 1/1,000,000 in the general population.

Tarsal carpal coalition syndrome is one of several NOG-related symphalangism spectrum disorders (NOG-SSD) that share similarities in their pattern of joint involvement but can vary in other features such as stature, hearing loss, fusion of the humerus and radius (upper and lower arm bones) and presence of short fingers or toes. For example, patients with multiple synostoses syndrome-1 and proximal symphalangism have conductive hearing loss unlike TCC. Also, multiple synostoses syndrome-1 can be differentiated from proximal symphalangism because it consistently involves the hips and cervical spine (neck level).

Diagnosis of tarsal carpal coalition syndrome begins with recognizing the symptoms of joint stiffness, pain and deformity which are highly suspicious for this condition. Often these suspicions are confirmed by imaging such as CT or MRI which show the characteristic joint fusion, shortening of fingers/toes, deformity of bones and joint deformity. It should be noted that on plain imaging such as x-rays, children under 8 years old may not have enough bone formation to show bone fusion, and instead the cartilage fusion is still causing them to have symptoms. A definitive diagnosis can be made through genetic testing showing characteristic pathogenic variants in the NOG gene.


Tatton Brown Rahman Syndrome

身材高大-智力障碍-面部畸形综合征

The severity and symptoms of TBRS vary from person to person. Patients and parents should consult with their physician to determine risks for specific symptoms and a plan for medical management.

TBRS is caused by pathogenic variants in the DNMT3A (DNA methyltransferase 3 alpha) gene, which produces the DNMT3A enzyme. The function of DNMT3A is not completely understood, but it is believed that this enzyme is responsible for methylating DNA. Methylation is a process involving the addition of methyl groups to DNA: methylation results in transcriptional repression. Patients with TBRS have pathogenic variants in the DNMT3A gene that prevent the DNMT3A enzyme from functioning properly, causing a suspected decreased methylation (hypomethylation).

The incidence and prevalence of TBRS are unknown. Since 2014, the TBRS Community is aware of more than 300 individuals with TBRS. Individuals have been diagnosed at different ages. This syndrome seems to affect males and females equally.

Clinical features that may lead to suspicion of TBRS include:

Current therapies for TBRS involve management of symptoms. Genetic counseling may help to inform affected individuals and caregivers of the implications of TBRS, the risks associated with the syndrome and medical actions that may be needed. Creation of a treatment plan may aid in this process.


Tay Sachs Disease

Tay-Sachs disease is a rare, neurodegenerative disorder in which deficiency of an enzyme (hexosaminidase A) results in excessive accumulation of certain fats (lipids) known as gangliosides in the brain and nerve cells. This abnormal accumulation of gangliosides leads to progressive dysfunction of the central nervous system. Tay-Sachs disease is categorized as a lysosomal storage disease. Lysosomes are the major digestive units in cells. Enzymes within lysosomes break down or digest nutrients, including certain complex carbohydrates and fats (like glycosphingolipids). When one of these lysosomal enzymes (such as hexosaminidase A) is missing or ineffective, glycosphingolipids start to build up in the lysosome. If there is too much accumulation of these materials in the lysosome, the cells in the nervous system degenerate and die, triggering an inflammatory response that amplifies damage in surrounding tissue.

Tay-Sachs disease is caused by a change (mutation) in the hexosaminidase subunit alpha (HEXA) gene. Genes provide the instructions for the basic structure of proteins, all of which that play a critical role in many functions and structure of the body. When a mutation occurs in a gene, 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, including the brain.

Tay-Sachs disease affects males and females in equal numbers. Tay-Sachs disease used to be considered a prototypical disease of Jewish people of Ashkenazi descent.  Community counselling and carrier screening efforts in these communities have succeeded in reducing disease prevalence to figures roughly equivalent to those of non-Jewish populations.  Increased prevalence of Tay Sachs disease is also reported in other ethnic groups including those living in the Cajun community of Louisiana and southeastern Quebec. In the general population, the carrier rate for Tay-Sacks disease is approximately 1 in 250-300 people.

Symptoms of the following disorders can share similarities to those of Tay-Sachs disease. Comparisons may be useful for a differential diagnosis:

Sandhoff disease is closely related and shares many clinical and biochemical features to Tay-Sachs. Like Tay-Sachs disease, Sandhoff disease affects the function of the enzyme Hexosaminidase A. It does so by disruption of the beta subunit (HEXB subunit) of hexosaminidase A encoded by the gene HEXB.  Like Tay-Sachs, Sandhoff disease is inherited in an autosomal recessive pattern. (For more information on this disorder, choose Sandhoff as your search term in the Rare Disease Database.)


Tenosynovial Giant Cell Tumor

giant cell tumor of the tendon sheath (GCTTS)

The signs and symptoms of tenosynovial giant cell tumors (TGCTs) can vary depending upon the exact location involved and the subtype present. Symptoms tend to be non-specific, and most patients report pain and swelling as a symptom of the disease. Other symptoms include limitation in range of motion, tenderness to the touch, warmth coming from the joint, clicking or popping of the joint and stiffness.

A minority of the cells that make up a TGCT (2-16%) carry a specific chromosomal translocation. Chromosomes, which are present in the nucleus of all human cells, carry genetic information for each individual, like the blueprint of the body. Each human body cell normally has 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. 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. For example, chromosome 11p13 refers to band 13 on the short arm of chromosome 11. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

Tenosynovial giant cell tumors mainly affect individuals between 25-50 years of age, with a median age of diagnosis of 40. However, these tumors can affect the elderly and younger children as well. Slightly more females than males are affected with localized TGCT. For diffuse TGCT, males and females are equally affected. Based on a 2017 Dutch study, the global incidence has been estimated to be 43 cases of TGCT per 1 million people in the general population. For localized TGCT, 39 cases per 1 million are estimated, whereas for diffuse TGCT, 4 cases per 1 million are estimated. Incidence refers to the number of new cases in a population in a specific time period. A Dutch study reported that the prevalence of TGCT is 11 per 100,000 people for diffuse TGCT and 44 per 100,000 people for localized TGCT. Prevalence refers to all cases diagnosed, regardless of when they were diagnosed. More people live with TGCT long-term than are newly diagnosed, thus, the prevalence of the disease is higher than the incidence.

Symptoms of the following disorders can be similar to those of tenosynovial giant cell tumors (TGCTs). Comparisons may be useful for a differential diagnosis.

A diagnosis of TGCT is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. The initial symptoms of these tumors are often vague and may go unrecognized. Consequently, there is usually a significant delay, 3-4 years on average, from the onset of symptoms until a diagnosis is made.


Tethered Cord Syndrome

Tethered cord syndrome is a stretch-induced functional disorder associated with the fixation (tethering) effect of inelastic tissue on the caudal spinal cord, limiting its movement. This abnormal attachment is associated with progressive stretching and increased tension of the spinal cord as a child ages, potentially resulting in a variety of neurological and other symptoms. Due to the variation of the growth rate of the spinal cord and the spinal column, the progression of neurological signs and symptoms is highly variable. Some individuals present with tethered cord syndrome at birth (so-called congenital), while others develop the symptomatology in infancy or early childhood. Other individuals may not develop any noticeable symptoms until adulthood. Although some authors call these cases acquired, the majority of these cases are mostly developmental, corresponding to the progressive development of excess fibrous connective tissue (fibrosis) in the filum terminale. The filum terminale is a strand of tissue that bridges the spinal cord tip and the tailbone (sacrum). The inelastic structures in children originated from defective closure of the neural tube (the precursor of the spinal cord) during embryonic development, eventually forming a condition known as spina bifida. Because of its functional (physiological) nature, tethered cord syndrome can be reversible if surgically treated in its early stage.

The specific symptoms, severity and progression of tethered cord syndrome vary from one individual to another. In most cases, individuals experience symptoms during childhood. In some cases, symptoms are stabilized in childhood, but become apparent only in adulthood.

Tethered cord syndrome can be of a congenital (primary) origin or acquired (secondary or developmental).

Tethered cord syndrome affects males and females in equal numbers. The exact incidence of the disorder in the general population is unknown. In the past, the diagnosis of tethered cord syndrome has been controversial and the disorder often still remains unrecognized and underdiagnosed. After many years of skepticism, tethered cord syndrome is now considered a distinct clinical entity. In order to help clarify the situation, a proposed definition for true tethered cord syndrome limits that this disorder to individuals who exhibit neurological signs and symptoms due to inelastic structures anchoring the caudal end of the spinal cord. There are cases in which individuals have the symptoms and signs similar to true tethered cord syndrome, but have associated defects that cause compression and impaired blood flow of the spinal cord, or congenital neuronal dysgenesis (failure of neuronal development). For example, in myelomeningoceles and lipomyelomeningoceles that are directly connected to the entire dorsal surface of lumbosacral spinal cord, their neurological deficits are unrelated to spinal cord stretching (tethered cord syndrome). Symptomatically, patients with these anomalies present with complete or nearly complete paralsysis of lower limbs and total loss of bladder and rectal control.

Symptoms of the following disorders may present with sign and symptoms similar to those of tethered cord syndrome. Comparisons may be useful for a differential diagnosis. They are extradural lesions, intradural-extramedullary lesions, intramedullary lesions extraspinal lesions, and peripheral neuropathy or myelpathy.

A diagnosis of tethered cord syndrome is made based upon identification of characteristic signs and symptoms (see the symptom section) that can neurologically locate the lesion to be above the attachment of the anomalies to the spinal cord. For this purpose, a detailed patient history and a thorough clinical evaluation and detailed MRI studies must be carried out. In children, typical imaging features such as a low lying spinal cord and a thickened filum terminale is confirmed by special imaging techniques such as magnetic resonance imaging (MRI) or computed tomography (CT) scan and ultrasound studies.


Tetrahydrobiopterin Deficiency

四氢生物蝶呤缺乏性高苯丙氨酸血症

Although researchers have been able to establish distinct syndromes with characteristic or core symptoms, much about these disorders is not fully understood. Several factors including the small number of identified cases, the lack of large clinical studies and the possibility of other genes influencing the development and progression of these disorders prevent physicians from developing a complete picture of associated symptoms and prognosis.

Tetrahydrobiopterin deficiencies are caused by variants (mutations) in specific genes. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a variant of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the protein, this can affect many organ systems of the body, including the brain.

Tetrahydrobiopterin deficiencies affect males and females in equal numbers and have been diagnosed in a diversity of ethnic groups worldwide. In the United States, these disorders are estimated to affect 1% to 3% of infants diagnosed with high levels of phenylalanine (hyperphenylalaninemia) by newborn screening. Tetrahydrobiopterin deficiencies are estimated to affect approximately 1-2 in 1,000,000 individuals in the general population. Some cases, particularly mild or transient cases, may go undiagnosed or misdiagnosed, making it difficult to determine the true frequency of these disorders in the general population.

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

A diagnosis is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Disorders of tetrahydrobiopterin deficiency are often found by newborn screening that detects elevated levels of phenylalanine. Further testing is required to distinguish these disorders from other causes of hyperphenylalaninemia such as phenylketonuria, and to determine the specific type of tetrahydrobiopterin deficiency present. Additionally, phenylalanine levels may be normal when a newborn screening is done and can be formal during early infancy, therefore an evaluation for tetrahydrobiopterin deficiencies should be considered in any infant with unexplained neurological symptoms, particularly in parents who are related by blood.


Tetralogy of Fallo

The symptoms of tetralogy of Fallot vary widely from person to person. The severity of the symptoms, which may range from mild to severe, is related to the degree of blood flow obstruction from the right ventricle.

The exact cause of tetralogy of Fallot is not known. However, some studies suggest that the disorder may be due to the interaction of several genetic and/or environmental factors (multifactorial). Therefore, researchers suspect that something may affect the genes in the developing fetus, causing this birth defect, but the exact nature of this trigger is not known.

Tetralogy of Fallot is a rare congenital malformation of the heart that occurs more frequently in males than females. Approximately 1 percent of newborns have congenital heart defects. About 10 percent of these infants are diagnosed with tetralogy of Fallot. This heart defect is usually detected weeks or months after birth. The prevalence of tetralogy of Fallot is estimated to be 1 in 3,000 live births.

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

Atrial septal defects (ASDs) 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 vary greatly, may become apparent during infancy, childhood, or adulthood, depend on the severity of the defect. The symptoms tend to be mild at first and may include difficulty breathing (dyspnea), increased susceptibility to respiratory infections, and abnormal bluish discoloration of the skin and/or mucous membranes (cyanosis). Some people with ASDs may be at increased risk for the formation of blood clots that can travel to the major arteries (embolism), blocking blood circulation. (For more information on this disorder, choose Atrial Septal Defect as your search term in the Rare Disease Database.)


Tetrasomy 9p

Tetrasomy 9p is a very rare chromosomal disorder in which the short arm of the ninth chromosome (9p) appears four times (tetrasomy) rather than twice in all or some cells of the body. Individuals with a normal chromosomal make-up (karyotype) have two number 9 chromosomes, both of which have a short arm (9p) and a long arm (9q). In individuals with tetrasomy 9p, four short arms (9p) are present in cells rather than the normal two.

Tetrasomy 9p is a very rare chromosomal disorder in which the short arm of chromosome 9 (9p) appears four times (tetrasomy) rather than twice in cells of the body. In most patients, this chromosomal abnormality is present in all cells of the body; however, in some affected people, only some cells have tetrasomy 9p and other cells have a normal chromosomal make-up, and this is called mosaicism. Symptoms vary in affected individuals, depending upon whether mosaicism is present and, if so, what percentage of cells contain the tetrasomy 9p abnormality.

Tetrasomy 9p is a very rare chromosomal disorder in which the short arm of chromosome 9 (9p) appears four times (tetrasomy) rather than twice in some or all the cells of the body. When only some cells are affected, this is termed mosaicism.

Tetrasomy 9p is a very rare chromosomal disorder that appears to affect males slightly more often than females. Approximately 70 cases have been reported in the medical literature. About 30% of all known cases are mosaic.

Symptoms of the following disorders may be similar to those of tetrasomy 9p. Comparisons may be useful for a differential diagnosis:

Trisomy 9p is a rare chromosomal disorder in which a portion of chromosome 9 appears three times (trisomy) rather than twice in cells of the body. The trisomy may involve a portion of the short arm (9p), the entire short arm, or the short arm and a segment of the long arm (9q). Many of the symptoms associated with trisomy 9p are similar to those occurring in individuals with tetrasomy 9p. Associated symptoms and findings may include an abnormally small head (microcephaly), a bulbous nose, misshapen ears, crossed and/or widely spaced eyes (strabismus and/or ocular hypertelorism), a large mouth with downturned corners, and/or other craniofacial abnormalities. Additional associated features may include growth delay, delayed bone development, hand and finger malformations, heart (cardiac) defects and intellectual disability. In approximately half of known cases, trisomy 9p is due to a balanced chromosomal rearrangement in one of the parents; in other cases, the disorder appears to result from spontaneous (de novo) errors very early in embryonic development that occur for unknown reasons (sporadically).


Thoracic outlet syndrome

*This condition is no longer considered rare

Neurogenic TOS presents with pain, weakness, numbness and tingling in the hand and arm. Additionally, neck pain and headache in the back of the head are common.

Neurogenic TOS is most often caused by neck trauma, whiplash injuries or repetitive stress injury at work being the most common events that bring on symptoms. The injury results in over-stretching neck muscles which heal by forming scar tissue in the muscle. This in turn puts pressure against the nerves to the arm which causes the symptoms.

Pectoralis minor syndrome (PMS) is a condition causing pain, numbness and tingling in the hand and arm. It often coexists with thoracic outlet syndrome (TOS) but can also occur alone.

Neurogenic TOS is diagnosed by using provocative maneuvers to elicit (or provoke) symptoms. These maneuvers put the neck and arms in certain positions which put stress on the nerves to the arm to bring on the symptoms of pain, numbness and tingling in the hand, arm, and neck. Some of these maneuvers have been shown to be unreliable because positive responses are found in many healthy individuals. These include the Adson test, Roos Test, and Wright Test. Other provocative maneuvers which provide greater reliability and seldom are positive in healthy people include rotating the neck or tilt the head to one side which causes symptoms to appear on the opposite side. Another provocative maneuver is extending one arm to the side, bending the wrist upward, and tilting the head to the opposite side (called the upper limb tension test). When all of these maneuvers elicit the same symptoms a diagnosis of neurogenic TOS is highly likely.


Three M Syndrome

Three M syndrome is an extremely rare inherited disorder characterized by low birth weight, delayed bone age, and short stature; characteristic malformations of the head and facial (craniofacial) area; and/or finger (digital) and/or skeletal malformations.

Three M syndrome is inherited as an autosomal recessive genetic trait. Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother.

Three M syndrome is an extremely rare inherited disorder that appears to affect males and females in equal numbers. Approximately 25 cases have been reported in the medical literature since the disorder was first described in 1972.

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

In some cases, growth retardation and/or other characteristic findings suggestive of Three M syndrome may be detected before birth (prenatally) by ultrasound. In fetal ultrasonography, reflected sound waves are used to create an image of the developing fetus.


Thrombocytopenia Absent Radius Syndrome

血小板减少-桡骨缺失综合征

Thrombocytopenia-absent radius (TAR) syndrome is a rare disorder that is present at birth (congenital). It is characterized by low levels of platelets in the blood (thrombocytopenia) and absence (aplasia) of the long, thin bones of the forearms (radii) but with presence of thumbs. Other abnormalities are often present including additional skeletal defects such as absence or underdevelopment of the other bone of the forearm (ulna), structural malformations of the heart (congenital heart defects) and kidney (renal) defects. Affected individuals may be short for their age (short stature) and have cow’s milk intolerance. TAR syndrome is inherited as an autosomal recessive genetic disorder and caused by deletion and/or variants in the RBM8A gene.

TAR syndrome can potentially affect multiple systems of the body, but it is especially associated with blood (hematological) and bone (skeletal) abnormalities. The two main findings are thrombocytopenia and radial aplasia. A variety of additional symptoms also occur. The specific symptoms vary from patient to patient. Affected individuals will not have all of the symptoms listed below. Some symptoms improve over time and may cause little or no problems in adulthood. Most affected individuals have normal intelligence, are able live independently and many have married and have had their own children.

TAR syndrome is inherited as an autosomal recessive genetic disorder and caused by two different types of changes (variants) in the RBM8A gene.

The prevalence of TAR syndrome is estimated at 1:200,000-1:100,000.

Symptoms of the following disorders may be similar to those of thrombocytopenia-absent radius (TAR) syndrome. Comparisons may be useful for a differential diagnosis:

Fanconi anemia, also known as Fanconi pancytopenia syndrome, is a rare genetic disorder characterized by deficiency of all blood cell types (pancytopenia), including red blood cells, white blood cells and platelets. Such abnormalities may lead to abnormal bleeding and easy bruising, paleness of the skin (pallor), recurrent infection and other findings that typically become apparent from approximately three to 10 years of age. However, in some patients, pancytopenia and associated abnormalities (hematologic findings) may occur as early as infancy or as late as the third decade of life. Individuals with Fanconi anemia may also have abnormal, patchy, brownish discolorations of the skin, short stature and certain congenital defects. These may include underdevelopment or absence of the thumbs and/or the bones on the thumb side of the forearms (radii), congenital hip dislocation, kidney (renal) malformations, cardiac defects and/or other abnormalities. There are several different subtypes (complementation groups) of Fanconi anemia, each of which is thought to result from variants in different disease genes. The disorder is known to be associated with a high frequency of chromosomal breakage, a finding that may be helpful in distinguishing Fanconi anemia from other disorders with similar symptoms and findings. Fanconi anemia is inherited in an autosomal recessive pattern. (For further information on this disorder, choose Fanconi as your search term in the Rare Disease Database.)


Thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenia purpura (TTP) is a rare, serious blood disease. Major symptoms may include a severe decrease in the number of blood platelets (thrombocytopenia), abnormal destruction of red blood cells (hemolytic anemia) and disturbances in the nervous system and other organs occur as a result of small clots that form in the smallest arteries. The exact cause of TTP is unknown.

The thrombocytopenia and hemolytic anemia are a result of these small clots in the blood vessels of many organs, potentially blocking the normal flow of blood through the vessels. Disturbances affecting the nervous system may include headaches, mental changes, confusion, speech abnormalities, slight or partial paralysis (paresis), seizures or coma.

The exact cause of TTP is not known. However, the disease is associated with a deficiency of an enzyme involved in blood clotting called the von Willebrand factor cleaving protease (also called ADAMTS13). The deficiency of this enzyme allows large complexes of the clotting protein known as von Willebrand factor to circulate in the blood, resulting in platelet clotting and the destruction of red blood cells.

The current rate of occurrence for TTP is about 3.7 cases per million people each year. One estimate places the overall incidence rate at four of 100,000 individuals. Two-thirds of individuals with iTTP cases are women. It usually affects people between 20 to 50 years of age but people of any age may be affected.

Childhood-onset or iTTP often occurs concurrently with systemic lupus erythematosus (SLE). A search of the literature by investigators at the University of Toronto demonstrated that approximately half of the cases of childhood-onset TTP met criteria for incipient or definite SLE. The best indicator for the presence or later development of SLE appeared to be excessive serum proteins in the urine (high-grade proteinuria) at the time of diagnosis of TTP. The researchers recommended that physicians rule out concomitant SLE in all children who present with TTP.

Hemolytic uremic syndrome (STEC HUS) is an uncommon disease that occurs in 5 to 15 percent of individuals, especially children, who are infected by the Escherichia coli (E. coli) bacterium. This organism releases toxins into the gut that are absorbed into the bloodstream and may be transported by white blood cells (leukocytes) to the kidneys. This results in acute renal injury. There may also be damage to the brain with seizures and even coma, the pancreas with pancreatitis and occasionally diabetes mellitus, and other organs. STEC HUS mainly affects young children between one and 10 years. The onset of HUS is preceded by an illness characterized by vomiting, abdominal pain, fever, and, usually, bloody diarrhea. (For more information on this disorder, choose STEC HUS as your search term in the Rare Disease Database.)


Thyroid Cancer

Thyroid cancer (carcinoma) is cancer affecting the thyroid gland, a butterfly-shaped structure located at the base of the neck. The thyroid is part of the endocrine system, the network of glands that secrete hormones.  Thyroid hormones regulate the chemical processes (metabolism) that influence the body’s activities as well as regulating the heart rate, body temperature, and blood pressure. Hormones are secreted directly into the bloodstream where they travel to various areas of the body.

The vast majority individuals with thyroid cancer have no symptoms (asymptomatic). In most cases, a small growth or lump (nodule), discovered by the patient, health care provider, or incidentally on an imaging study (e.g., a CT scan, MRI, or carotid artery ultrasound), is the first sign of thyroid cancer. Thyroid nodules or lumps in the thyroid may be caused by a variety of conditions and do not necessarily mean that an individual has cancer. In fact, more than 90 percent of thyroid nodules are not cancerous (benign).

The cause(s) of thyroid cancer are unknown. Researchers speculate that genetic and immunologic abnormalities, environmental factors (e.g., certain chemicals, ionizing radiation), diet, and/or other factors may play contributing roles in causing specific types of cancer. Rarely, thyroid cancer can be hereditary, especially medullary thyroid cancer, as noted above. Investigators are conducting ongoing basic research to learn more about the many factors that may result in cancer.

According to the American Cancer Society, approximately 53,000 new cases of thyroid cancer will be diagnosed in the United States in 2020. Of those cases, more than 41,000 will occur in women. In fact, thyroid cancer is now the 5th most common cancer in women. Thyroid cancer can affect individuals of any age and specific forms occur with greater frequency among different age groups. In general, thyroid nodules in children and adolescents are more likely may be malignant than those that occur in adults. In general, for unclear reasons, the rate of thyroid cancer incidence has been increasing rapidly over the past few decades. Some researchers believe that this increase in frequency is due to the greater use of imaging (e.g., chest CT scans, cervical spine MRI), with the result being an increase in the rate of detection of small thyroid cancers that may not ever have been detected while the individual was alive.  However, there may also be an increase in the frequency of larger thyroid cancers, possibly the result of environmental factors.

Multiple endocrine neoplasia (MEN) type 2 is a rare genetic cancer syndrome in which tumors develop in the endocrine glands (e.g., thyroid, parathyroid, adrenal glands). Two main subtypes exist called MEN 2A and MEN 2B. Familial medullary thyroid carcinoma (FMTC) is considered a third subtype. Nearly all individuals with MEN 2 develop medullary thyroid carcinoma (MTC) at some point. (For more information on these disorders, choose multiple endocrine neoplasia as your search term in the Rare Disease Database.)

The diagnosis of thyroid cancer is based upon a thorough clinical evaluation, including a detailed patient history and physical exam, and a variety of specialized blood tests and imaging tests. Such testing often includes microscopic evaluation of tumor cells obtained by fine needle aspiration biopsy.


Timothy syndrome

Due to the multisystem nature of this disease, its clinical presentation is remarkably complex.

In 2004 Splawski and colleagues [3] discovered that TS is caused by mutations in the CACNA1C gene, which is responsible for regulating the formation of a protein that moves calcium inside the cardiac cells (i.e. the calcium channel). The calcium channel is composed of a long sequence of smaller molecules, called amino acids. In the first cohort described by Splawski in 2004 [3], all patients had an identical mutation (G406R), which caused the substitution of the amino acid glycine (G) in position 406 with the amino acid arginine (R). When this gene is mutated, the closing of the channel is delayed causing too much calcium to enter the cells, which in turn determines the prolongation of the QT interval on the EKG.

TS has been diagnosed in less than 100 children around the world. Because of the multisystem nature of this syndrome, very few children live to adulthood. Thanks to improved recognition of this syndrome and improved medical care, there are a number of TS individuals now in their twenties and early 30s.

There are several genetic forms of long QT syndrome (LQTS) that are more common than TS. All LQTS share an abnormality of cardiac rhythm which can lead to fainting spells, cardiac arrest, and sudden death. LQTS typically presents between the pre-teen age through the twenties, but can occur anywhere from infancy through middle age. (For more information on these conditions, search for long QT syndrome in the Rare Disease Database.) Unlike TS, these LQTS variants are usually non-syndromic, meaning that patients do not exhibit extra-cardiac manifestations. However, other two examples of syndromic LQTS exist: the Andersen-Tawil syndrome (ATS) and the Jervell and Lange Nielsen syndrome (JLNS).

The occurrence of cardiac arrhythmias or the documentation of a prolonged QT interval on the EKG usually permits the establishment of diagnosis in the first days of life. In up to 25% of patients [6], TS may also be suspected before birth due to abnormal heart rate in the womb (fetal bradycardia) but occasionally the diagnosis is made later, during early infancy. Other distinctive features such as cardiac malformations or hypertrophy, syndactyly and typical facial abnormalities are suggestive of TS. Additional symptoms such as recurrent infections, episodes of paroxysmal hypoglycemia, autism spectrum disorders, seizures and intellectual disability may also contribute to the diagnosis. Once clinical suspicion has been raised, diagnosis can be confirmed through genetic testing for mutations in the CACNA1C gene. Once diagnosis is established, evaluations including cardiology, neurology, skeletal and metabolic consultations should be done to evaluate the extent of the disease and to undertake the appropriate therapeutic measures.


Tolosa Hunt Syndrome

Tolosa-Hunt syndrome is a rare disorder characterized by severe periorbital headaches, along with decreased and painful eye movements (ophthalmoplegia). Symptoms usually affect only one eye (unilateral). In most cases, affected individuals experience intense sharp pain and decreased eye movements. Symptoms often will subside without intervention (spontaneous remission) and may recur without a distinct pattern (randomly). Affected individuals may exhibit signs of paralysis (palsy) of certain cranial nerves such as drooping of the upper eyelid (ptosis), double vision (diplopia), large pupil, and facial numbness. The affected eye often abnormally protrudes (proptosis). The exact cause of Tolosa-Hunt syndrome is not known, but the disorder is thought to be associated with inflammation of specific areas behind the eye (cavernous sinus and superior orbital fissure).

Many individuals with Tolosa-Hunt syndrome experience the sudden onset of severe periorbital headache, followed by painful and decreased eye movements (ophthalmoplegia). In some cases of severe ophthalmoplegia, the eye itself is unable to move or look in various directions (frozen globe).

While the exact cause of Tolosa-Hunt syndrome is unknown, one theory is an abnormal autoimmune response linked with an inflammation in a specific area behind the eye (cavernous sinus and superior orbital fissure). In some cases, inflammation may be due to a clumping of a certain type of cell (granulomatous inflammation). 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. Other possible causes may include generalized inflammation and constricted or inflamed cranial blood vessels.

Tolosa-Hunt syndrome is a rare neuro-immunological disorder that occurs in males and females in equal numbers. The average age of onset is 41 years, but there have been cases reported among people younger than age 30. In rare cases, children under the age of 10 have been diagnosed with Tolosa-Hunt syndrome.

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

Orbital cellulitis is characterized by inflammation of the tissues within the cavity which holds the eyeball. Symptoms include extreme pain, impaired eye movement, swelling, fever and a general feeling of discomfort. Possible complications may include impaired vision, vein abnormalities and spread of the inflammation to the entire orbit, brain or the membranes surrounding the brain.


Tongue Cancer

Tongue cancers are oral cancers that are differentiated by their location in the mouth and on the tongue. If the cancer is on the forward portion of the tongue, it is known as a squamous cell cancer of the oral tongue. If the cancer is located towards the rear third of the tongue, it is known as a squamous cell cancer at the base of the tongue.

Generally, the first sign of squamous cell cancer of the oral tongue is a pinkish-red sore at the side of the tongue that persists and seems not to heal over time.  Quite often, the sore bleeds easily if bitten or touched. If this occurs, it is recommended that the person see a physician, especially if the person is older than fifty.

The cause of tongue cancer is unknown.  Inadequate oral hygiene and thickened white patches on the mucous membranes of the oral cavity (leukoplakia) may be a cause.  The disorder is statistically linked with alcoholism, cirrhosis of the liver, excessive smoking, and syphilis.

Tongue cancer is most common in men over age 60.  It is rare in people, particularly women, under age 40.

There are many types of mouth cancer.  All types are relatively rare.

Examination of a sample of tissue from the site of the suspected cancer by a qualified pathologist is the key to diagnosis. MRI and/or CAT scans may be ordered to determine the location and size of the growth. This examination will also determine the stage of the disorder (how advanced it may be), which in turn, will help determine the method and pace of treatment.


Tooth Agenesis

Tooth agenesis is a condition in which teeth are missing. Anodontia is a genetic disorder defined as the absence of all teeth. It usually occurs as part of a syndrome that includes other abnormalities. Also rare but more common than anodontia are hypodontia and oligodontia. Hypodontia is genetic in origin and usually involves the absence of from 1 to 5 teeth. Oligodontia is genetic as well and is the term used to describe a condition in which six or more teeth are missing.

Hypo/oligodontia is characterized by partial and anodontia by complete absence of teeth. Since all primary teeth are usually present by the age of three, their absence is usually noted, and a dentist consulted. Except for wisdom teeth, all permanent teeth are usually present by the ages 12 to 14. When teeth have not appeared by the appropriate age, dental panoramic X-rays are usually taken.

Several different genes have been found to be associated with hypo/oligodontia and anodontia including the EDA, EDAR and EDARADD genes.

The prevalence of anodontia is unknown. This condition affects males and females in equal numbers. The prevalence of hypodontia is 2 to 8% of the general population (excluding third molar) and oligodontia is 0.09%. to 0.3%.

The ectodermal dysplasias are a group of hereditary, non-progressive conditions affecting the development or function of the teeth, hair, nails and sweat glands, salivary glands, mammary glands, nasolacrimal ducts. (For more information, choose Ectodermal Dysplasia as your search term in the Rare Disease Database).

The diagnosis of hypo/oligodontia or anodontia may be confirmed by dental X-rays. Other signs might be associated such as smaller teeth, peg shape lateral incisors, conical teeth, taurodontic molars, and spaced dentition.


Hypodontia-dysplasia of nails syndrome

牙发育不全-指甲发育不良综合征

TNS involves missing and/or the malformation of certain baby teeth (primary teeth) and permanent/adult teeth (secondary teeth). The number affected can range from 6 to 20 teeth. It also involves incorrect development of the nails. Rarely, affected individuals may also have changes affecting scalp hair, like thinning of the hair. Individuals with this condition usually have typical hair and sweat gland function. Symptoms are most obvious around school-age. TNS symptoms are less severe than other types of ectodermal dysplasia. Because of this, some people with TNS may be undiagnosed.

TNS is a genetic condition caused by a harmful change (mutation) in a gene. This leads to lack of a functional protein which ultimately causes the symptoms of TNS. The gene that causes TNS is called MSX1 and was discovered in 2001. This gene makes a protein that is important in tooth formation. Some mutations lead to a non-functioning protein resulting in TNS. Other rare MSX1 gene variants have been found to be associated with cleft lip and/or palate with or without missing teeth. Research has shown that harmful changes in the MSX1 gene affect the quality of a tooth layer called the mesenchyme. The MSX1 protein is involved in only certain stages of tooth development.

TNS affects males and females in equal numbers. Since the condition was originally described in the medical literature in 1965 by C.J. Witkop, over 30 patients have been reported, with many in several families (kindreds). It has been estimated that 1-2 in every 10,000 individuals may be affected by TNS. The condition appears to be more common in Dutch Mennonites of Canada.

Symptoms of the following disorders may be similar to those of TNS. Comparisons may be useful in determining which diagnosis is correct.

TNS may be suspected at birth if one or more toenails and/or fingernails are absent. More commonly, the condition is diagnosed at around four or five years of age, when certain primary (baby) teeth are missing and underdevelopment of nails may be noted. In some people, a diagnosis of TNS may not be confirmed until seven to fifteen years of age. This can be when the missing and/or unusual shape of several permanent, adult teeth and nail dysplasia has been confirmed. A diagnosis of TNS is confirmed based upon a thorough clinical exam noting the typical physical findings. Molecular genetic testing can also confirm a diagnosis. However, the percentage of patients with a clinical diagnosis of TNS and an identifiable mutation in the MSX1 gene is currently unknown.


TORCH Syndrome

TORCH Syndrome refers to infection of a developing fetus or newborn by any of a group of infectious agents. TORCH is an acronym meaning (T)oxoplasmosis, (O)ther Agents, (R)ubella (also known as German Measles), (C)ytomegalovirus, and (H)erpes Simplex. Infection with any of these agents (i.e., Toxoplasma gondii, rubella virus, cytomegalovirus, herpes simplex viruses) may cause a constellation of similar symptoms in affected newborns. These may include fever; difficulties feeding; small areas of bleeding under the skin, causing the appearance of small reddish or purplish spots; enlargement of the liver and spleen (hepatosplenomegaly); yellowish discoloration of the skin, whites of the eyes, and mucous membranes (jaundice); hearing impairment; abnormalities of the eyes; and/or other symptoms and findings. Each infectious agent may also result in additional abnormalities that may be variable, depending upon a number of factors (e.g., stage of fetal development).

TORCH Syndrome refers to any of a group of infections in newborns due to one of the TORCH infectious agents having crossed the placenta during pregnancy.  The acronym TORCH refers to (T)oxoplasmosis, (O)ther Agents, (R)ubella (or German Measles), (C)ytomegalovirus, and (H)erpes Simplex.

TORCH Syndrome results from one of the TORCH agents having crossed the placenta during pregnancy.  These infectious agents include Toxoplasma gondii, the single-celled microorganism (protozoa) responsible for Toxoplasmosis; rubella virus; cytomegalovirus; and herpes simplex viruses.  (Note: According to some reports, the acronym TORCH is sometimes modified to the term STORCH to include syphilis, a disease that may result in symptoms similar to those associated with the other TORCH agents.  Syphilis is caused by infection with the bacterium Treponema pallidum.  In addition, TORCH may encompass other disease-causing agents, such as varicella-zoster virus, which is the virus responsible for chickenpox, and parvovirus.)

TORCH syndrome may affect a developing fetus or newborn, potentially resulting in miscarriage, delayed fetal growth and maturation (intrauterine growth retardation), or early delivery.

Treatment of newborns and infants with TORCH Syndrome is based upon the specific causative agent, the stage of fetal development when infection initially occurred, the severity of the infection and associated symptoms and findings, and/or other factors. For infants with toxoplasmosis, treatment may include administration of the medication pyrimethamine with sulfadiazine. Herpes simplex may be treated with the antiviral agent acyclovir. The treatment of newborns and infants with rubella or cytomegalovirus primarily includes symptomatic and supportive measures.


Townes-Brocks syndrome

deafness, sensorineural, with imperforate anus and hypoplastic thumbs

There are three major symptoms of TBS: A closed anal opening (imperforate anus), small ears that usually have a folded rim of skin and cartilage around the outer ear, and differences in the structures of the thumbs. The thumbs have three bones (triphalangeal) instead of two. People with this syndrome may also have an extra thumb (preaxial polydactyly). Another symptom may be hearing loss present at birth (congenital). The hearing loss can be sensorineural and/or conductive, range from mild to severe and may be progressive. Differences in the feet occur less frequently and include a short third toe, overlapping toes and flat feet. Typical kidney (renal) differences include displaced or rotated kidneys, horseshoe kidney, polycystic kidneys and underdeveloped kidneys. There can also be heart and genital problems present at birth. Intellectual disability occurs in about 10% of affected individuals.

TBS is caused by a harmful genetic change (mutation) in a gene called SALL1. The SALL1 gene has instructions for the body to form certain tissues and organs such as the hands (particularly the thumbs), ears, anus and kidneys. Humans should have two working copies of the SALL1 gene, but people with TBS have one copy of the gene that does not work properly.

It has been estimated that TBS occurs in at least 1 in 250,000 births.

The physical features of TBS are similar to oculo-auriculo-vertebral spectrum disorder, Okihiro syndrome, branchiootorenal syndrome, VACTERL association and STAR syndrome.

The clinical diagnosis of TBS is based on the presence of the three common symptoms (differences of the anus, ear and thumb) and sometimes the minor features. Genetic testing that reveals a harmful variant in the SALL1 gene can confirm the diagnosis.

Treatment includes surgery to correct the differences of the anus and thumbs. Hearing evaluation should be conducted if TBS is suspected. Ultrasound and laboratory tests should be performed to monitor kidney function. A baseline echocardiogram should be performed by a cardiologist.


Toxic Shock Syndrome

Toxic Shock Syndrome is a rare multisystem disease with many widespread symptoms. It is caused by a toxin that is produced and secreted by the bacterium Staphylococcus aureus. The symptoms of Toxic Shock Syndrome may include a sudden high fever, nausea, vomiting, diarrhea, abnormally low blood pressure (hypotension), and a characteristic skin rash that resemble a bad sunburn. Most cases of Toxic Shock Syndrome occur in menstruating females in association with the use of tampons. Other cases may occur in association with postoperative wound infections, nasal packing, or other factors.

The symptoms of Toxic Shock Syndrome begin suddenly and usually include high fever, headache, sore throat (pharyngitis), inflammation of the whites of the eyes (conjunctivitis), muscle aches and pain (myalgia), and/or certain digestive symptoms, such as nausea, vomiting, and profuse watery diarrhea. Involvement of the central nervous system is also common and may be characterized by listlessness, dizziness, confusion, and/or disorientation. A characteristic sunburn-like skin rash typically develops within a few hours of onset, with later scaling and peeling (desquamation) of skin, particularly of the palms and soles.

Toxic Shock Syndrome (TSS) is a rare acute multisystemic disease caused by toxins (such as toxic shock syndrome toxin-1 [TSST-1], enterotoxin B, enterotoxin C) produced by certain strains (particularly phage group I) of the bacterium Staphylococcus aureus (S. aureus). TSS is most common in menstruating women who use highly absorbent tampons. Evidence suggests that the prolonged use of tampons in the presence (i.e., colonization) of toxin-secreting S. aureus strains may promote increased production of the toxin, which may enter the bloodstream through the uterus or tiny cuts within the vaginal lining.

Toxic Shock Syndrome (TSS) was originally described as a disease entity in 1978, when the condition was reported in seven children from age eight to 17 years. In 1980 and 1981, a large number of TSS cases were recognized, primarily in young menstruating women who used tampons. This sudden increase was thought to be due to the introduction and availability of new, highly absorbent tampons.

Symptoms of the following disorders may be similar to those of Toxic Shock Syndrome (TSS). Comparisons may be useful for a differential diagnosis:

Streptococcal Toxic Shock Syndrome may be characterized by TSS-like symptoms and findings, the sudden onset of shock, and impairment of various organ systems due to infection with certain toxin-secreting strains of streptococcus bacteria (group A beta-hemolytic streptococci). The syndrome, which was initially reported in the mid to late 1980s, may occur in adults or children. The skin and soft tissues are usually the primary sites of infection. Factors that appear to increase the risk of infection may include certain surgical procedures, particular viral infections (e.g., varicella, influenza), and exposure to affected individuals in close environments such as hospitals or nursing homes. Associated symptoms and findings may vary from case to case, depending upon the causative bacterial strain and other factors. Reported features have included initial flu-like symptoms, including fever, chills, muscle aches, and vomiting; low blood pressure (hypotension); confusion; an accelerated heart rate (tachycardia), unusually rapid breathing (tachypnea), and other findings; and sudden onset of shock and multiple organ failure, leading to potentially life-threatening complications.


Transverse Myelitis

The spinal cord carries motor nerve fibers to the limbs and trunk and sensory fibers from the body back to the brain. Inflammation within the spinal cord interrupts these pathways and causes the typical presenting symptoms. TM generally presents with rapidly progressing muscle weakness or paralysis, beginning with the legs and potentially moving to the arms with varying degrees of severity. The arm involvement is dependent upon the level of spinal cord affected. Sensation to light touch is diminished below the level of spinal cord lesion in most individuals. Pain (ascertained as appreciation of pinprick by the neurologist) and temperature sensation are generally diminished and appreciation of vibration (as tested by a tuning fork) and joint position sense may also be decreased. Many patients report a tight banding or girdle-like sensation around the trunk and that area may be very sensitive to touch.

The possible causes of TM can be quite varied. TM may occur in isolation or in the setting of another illness. Idiopathic TM is assumed to be a result of abnormal and excessive activation of an immune response against the spinal cord that results in inflammation and tissue damage (for which the exact cause is still undetermined).

TM has a conservatively estimated incidence of between 1 and 8 new cases per million per year, or approximately 1,400 new cases each year. However, this is probably an underestimate. Although this disease affects people of all ages, with a range of six months to 88 years, there are peaks between the ages of 10 to 19 years and 30 to 39 years. In addition, approximately 25% of cases are in children. There is no gender or familial association with TM. In 75-90% of cases TM occurs only once, yet a small percentage of patients have recurrent disease especially if there is a predisposing underlying illness.

As mentioned above, TM may be a relatively uncommon manifestation of several autoimmune diseases, including systemic lupus erythematosus (SLE), Sjogren’s syndrome and sarcoidosis. SLE is an autoimmune disease of unknown cause that affects multiple organs and tissues in the body. SLE may cause TM that may even be recurrent.

Diagnosis of TM is based on clinical and radiological findings. Clinical characteristics of myelopathy are signs and/or symptoms of sensory, motor or autonomic dysfunction attributable to the spinal cord. Evidence of inflammation either on MRI as gadolinium enhancement or on lumbar puncture as elevated CSF white blood cells, or the presence of oligoclonal IgG bands unique to the CSF or elevated IgG index, are frequently observed.


Treacher-Collins syndrome

The symptoms and severity of TCS can vary dramatically from one person to another, even among members of the same family. Some individuals may be so mildly affected that they can go undiagnosed; others may have significant abnormalities and the potential for life-threatening respiratory complications. It is important to note that affected individuals may not have all the symptoms discussed below.

TCS is caused by variants in the TCOF1, POLR1B, POLR1C or POLR1D genes. In the case of TCOF1 the mode of inheritance is autosomal dominant, although very rare cases of autosomal recessive inheritance have been observed. Variants in POLR1B are autosomal dominant, whereas in POLR1C they are autosomal recessive, and for POLR1D, can be autosomal dominant or autosomal recessive.

TCS affects males and females in equal numbers. The prevalence is estimated to be between 1 in 10,000-50,000 individuals in the general population. Some mildly affected individuals may go undiagnosed, making it difficult to determine the disorder’s true frequency in the general population. It is therefore highly recommended that the parents and perhaps siblings of a child affected with TCS in association with a variant in TCOF1, POLR1B, POLR1C or POLR1D, be tested even if they appear unaffected. This is important for future family planning. It should not be assumed that the variant in an affected child occurred spontaneously, just because each parent exhibits no facial differences. However, it should be noted that some individuals (approximately 10-15%) with the features and physical findings of TCS do not have variants in any of the four above mentioned genes, suggesting that variants in additional genes may also cause TCS.

Symptoms of the following disorders can be similar to those of TCS and comparisons may be useful for a differential diagnosis.

A diagnosis of TCS is made based upon a thorough clinical evaluation, a detailed patient history and identification of characteristic physical findings. Many associated characteristics such as malformation or absence of the external ear are present at birth (congenital).


Tricho-dento-osseous syndrome

TDO syndrome is characterized by abnormalities of the hair, teeth, bones and/or nails. In addition, infants and children with TDO syndrome have tight, kinky or curly hair that may also be unusually dry. Hair can straighten in childhood even by four years of age. The hair tends to remain unruly and wavy even after straightening from small tight curls.  Some individuals with the disorder also have unusually long eyelashes and eyebrows.

TDO syndrome is a genetic disorder caused by a change (disease-causing variant) in the DLX3 gene. Several different variants in the DLX3 gene have been reported. This gene is a member of the distal-less homeobox gene family. The disorder occurs because of a deletion in this gene that leads to a DLX3 protein product that is shorter than normal and does not function normally. Research has shown that the DLX3 gene plays a role in the patterning of the part of the embryo that leads to the formation of skin, teeth and ectoderm, as well as the formation of bones. This explains the presentation of the symptoms associated with TDO syndrome.

TDO syndrome is a rare inherited disorder that affects males and females in equal numbers. Approximately 12 affected families (kindreds) have been reported in the medical literature.

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

Amelogenesis imperfecta is a group of genetic conditions in which the tooth enamel is underdeveloped (hypoplastic) or there is a decreased mineral content in the enamel (hypomineralization). Almost 20 different genes are involved in these conditions. Many different forms of the disorder have been classified, based upon varying types of enamel defects. Affected individuals may have abnormally thin, soft, pitted, and/or discolored tooth enamel; heightened susceptibility to disease of the structures surrounding and supporting the teeth (periodontal disease); increased sensitivity of the teeth to hot and cold temperatures; and/or early tooth loss. (For more information on this disorder, choose amelogenesis imperfecta as your search term in the Rare Disease Database.)


Trichorhinophalangeal syndrome type 2

毛发-鼻-指(趾)综合征2型

Trichorhinophalangeal syndrome type I (TRPS1) is an extremely rare inherited multisystem disorder. TRPS1 is characterized by thin, sparse scalp 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 rounded (bulbous) pear-shaped nose, an abnormally small jaw (micrognathia), dental anomalies, and/or unusually large (prominent) ears. In most cases, the fingers and/or toes may be abnormally short (brachydactyly) and curved. In addition, affected individuals may exhibit short stature. The range and severity of symptoms may vary from case to case. In most cases, Trichorhinophalangeal syndrome type I has autosomal dominant inheritance.

The range and severity of symptoms of individuals with trichorhinophalangeal syndrome type I may vary from case to case. Most cases are characterized by thin, sparse scalp hair, unusual facial features, and multiple abnormalities affecting the growing ends (epiphyses) of certain bones, especially those in the hands and feet.

Trichorhinophalangeal syndrome type I is a rare genetic disorder with autosomal dominant inheritance. Genetic diseases are determined by two genes, one received from the father and one from the mother.

Trichorhinophalangeal syndrome type I is an extremely rare inherited disorder that affects males and females in equal numbers. In those individuals with mild symptoms, a diagnosis may be easily missed or go unreported. Therefore, it is difficult to determine the true frequency of this disorder in the general population. Many researchers suspect there may be a higher incidence of TRPS1 than is actually reported in the medical literature.

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

The diagnosis of TRPS1 may be suspected upon identification of characteristic physical features (e.g., rounded [bulbous] nose; thin, sparse hair; etc.). The diagnosis may be confirmed by a thorough clinical evaluation, a detailed patient history, and X-ray studies of the skeleton that reveal distinctive abnormalities of the hands and feet (e.g., epiphyseal coning). Molecular genetic testing can reveal mutations of the TRPS1 gene.