<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Miliary tuberculosis and explain in detail? [/INST] Miliary tuberculosis is a form of tuberculosis that is characterized by a wide dissemination into the human body and by the tiny size of the lesions (1–5 mm). Its name comes from a distinctive pattern seen on a chest radiograph of many tiny spots distributed throughout the lung fields with the appearance similar to millet seeds—thus the term "miliary" tuberculosis.  Miliary TB may infect any number of organs, including the lungs, liver, and spleen. Miliary tuberculosis is present in about 2% of all reported cases of tuberculosis and accounts for up to 20% of all extra-pulmonary tuberculosis cases.

Signs and symptoms
Patients with miliary tuberculosis often experience non-specific signs, such as coughing and enlarged lymph nodes. Miliary tuberculosis can also present with enlarged liver (40% of cases), enlarged spleen (15%), inflammation of the pancreas (<5%), and multiple organ dysfunction with adrenal insufficiency (adrenal glands do not produce enough steroid hormones to regulate organ function). Stool may also be diarrheal in nature and appearance.Other symptoms include fever, hypercalcemia, choroidal tubercles, and cutaneous lesions.
Firstly, many patients can experience a fever lasting several weeks with daily spikes in morning temperatures.Secondly,  hypercalcemia prevails in 16 to 51% of tuberculosis cases. It is thought that hypercalcemia occurs as a response to increased macrophage activity in the body. Such that, 1,25 dihydroxycholecalciferol (also referred to as calcitriol) improves the ability of macrophages to kill bacteria; however,  higher levels of calcitriol lead to higher calcium levels, and thus hypercalcemia in some cases. Thus, hypercalcemia proves to be an important symptom of miliary tuberculosis.Thirdly, chorodial tubercules, pale lesions on the optic nerve, typically indicate miliary tuberculosis in children. These lesions may occur in one eye or both; the number of lesions varies between patients. Chorodial tubercules may serve as important symptoms of miliary tuberculosis, since their presence can often confirm suspected diagnosis.Lastly, between 10 and 30% of adults, and 20–40% of children with miliary tuberculosis have tuberculosis meningitis. This relationship results from mycobacteria from miliary tuberculosis spreading to the brain and the subarachnoid space; as a result, leading to tuberculosis meningitis.The risk factors for contracting miliary tuberculosis are being in direct contact with a person who has it, living in unsanitary conditions, and poor nutrition. In the U.S., risk factors for contracting the disease include homelessness and HIV/AIDS.

Cause
Miliary tuberculosis is a form of tuberculosis that is the result of Mycobacterium tuberculosis travelling to extrapulmonary organs, such as the liver, spleen and kidneys. Although it is well understood that the bacteria spread from the pulmonary system to the lymphatic system and eventually the blood stream, the mechanism by which this occurs is not well understood.One proposed mechanism is that tuberculous infection in the lungs results in erosion of the epithelial layer of alveolar cells and the spread of infection into a pulmonary vein. Once the bacteria reach the left side of the heart and enter the systemic circulation, they may multiply and infect extrapulmonary organs. Once infected, the cell-mediated immune response is activated. The infected sites become surrounded by macrophages, which form granuloma, giving the typical appearance of miliary tuberculosis.Alternatively, the bacteria may attack the cells lining the alveoli and enter the lymph node(s). The bacteria then drain into a systemic vein and eventually reach the right side of the heart. From the right side of the heart, the bacteria may seed—or re-seed as the case may be—the lungs, causing the eponymous "miliary" appearance.

Diagnosis
Testing for miliary tuberculosis is conducted in a similar manner as for other forms of tuberculosis, although a number of tests must be conducted on a patient to confirm diagnosis. Tests include chest x-ray, sputum culture, bronchoscopy, open lung biopsy, head CT/MRI, blood cultures, fundoscopy, and electrocardiography. The tuberculosis (TB) blood test, also called an Interferon Gamma Release Assay or IGRA, is a way to diagnose latent TB.
A variety of neurological complications have been noted in miliary tuberculosis patients—tuberculous meningitis and cerebral tuberculomas being the most frequent. However, a majority of patients improve following antituberculous treatment. Rarely lymphangitic spread of lung cancer could mimic miliary pattern of tuberculosis on regular chest X-ray.
The tuberculin skin test, commonly used for detection of other forms of tuberculosis, is not useful in the detection of miliary tuberculosis. The tuberculin skin test fails due to the high numbers of false negatives. These false negatives may occur because of higher rates of tuberculin anergy compared to other forms of tuberculosis.A case of miliary tuberculosis in an 82-year-old woman:

Treatment
The standard treatment recommended by the WHO is with isoniazid and rifampicin for six months, as well as ethambutol and pyrazinamide for the first two months.  If there is evidence of meningitis, then treatment is extended to twelve months.  The U.S. guidelines recommend nine months treatment. "Common medication side effects a patient may have such as inflammation of the liver if a patient is taking pyrazinamide, rifampin, and isoniazid. A patient may also have drug resistance to medication, relapse, respiratory failure, and acute respiratory distress syndrome."

Prognosis
If left untreated, miliary tuberculosis is almost always fatal. Although most cases of miliary tuberculosis are treatable, the mortality rate among children with miliary tuberculosis remains 15 to 20% and for adults 25 to 30%. One of the main causes for these high mortality rates includes late detection of disease caused by non-specific symptoms. Non-specific symptoms include: coughing, weight loss, or organ dysfunction. These symptoms may be implicated in numerous disorders, thus delaying diagnosis. Misdiagnosis with tuberculosis meningitis is also a common occurrence when patients are tested for tuberculosis, since the two forms of tuberculosis have high rates of co-occurrence.

History
John Jacob Manget described a form of disseminated tuberculosis in 1700 and expressed its resemblance to numerous millet seeds in size and appearance and coined the term from Latin word miliarius, meaning related to millet seed.

See also
Lupus vulgaris
Metastatic tuberculous abscess or ulceration
Thomas Wolfe
List of cutaneous conditions

References
Further reading
Sharma, SK; Mohan, A; Sharma, A (2012). "Challenges in the diagnosis & treatment of miliary tuberculosis" (PDF). The Indian Journal of Medical Research. 135 (5): 703–30. PMC 3401706. PMID 22771605.
Reichman, Lee B., M.D., M.P.H. & Tanne, Janice H. (2002). "Timebomb: The Global Epidemic of Multi-Drug-Resistant Tuberculosis. Mcgraw-Hill. ISBN 0-07-135924-9
Albino, Juan A.; Reichman, Lee B. (1 January 1998). "The Treatment of Tuberculosis". Respiration </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Gray matter heterotopia and explain in detail? [/INST] Gray matter heterotopias are neurological disorders caused by clumps of gray matter (nodules of neurons) located in the wrong part of the brain. A grey matter heterotopia is characterized as a type of focal cortical dysplasia.  The neurons in heterotopia appear to be normal, except for their mislocation; nuclear studies have shown glucose metabolism equal to that of normally positioned gray matter. The condition causes a variety of symptoms, but usually includes some degree of epilepsy or recurring seizures, and often affects the brains ability to function on higher levels.  Symptoms range from nonexistent to profound; the condition is occasionally discovered as an incidentaloma when brain imaging performed for an unrelated problem and has no apparent ill effect on the patient.  At the other extreme, heterotopia can result in severe seizure disorder, loss of motor skills, and mental retardation.  Fatalities are practically unknown, other than the death of unborn male fetuses with a specific genetic defect.

Preliminary Material: Neurological Development of the Human Fetus
The development of the brain in the human fetus is extraordinarily complex and is still not fully understood.  Neural matter originates in the outer, ectodermic layer of the gastrula;  thus, it originates from the cell layer primarily responsible for skin, hair, nails, etc., rather than from the layers that develop into other internal organs.  The nervous system originates as a tiny, simple open tube called the neural tube;  the front of this tube develops into the brain (and retinas of the eye), while the spinal cord develops from the very back end.
Neurons begin to form early, but most of them become structural rather than active nerve cells.  The brain generally forms from the inside-out, especially in the case of the neocortex.  The difficulties arising from this are readily apparent, as each successive layer of cells must travel through the previous layer to reach its destination.  Therefore, nervous tissue develops ladders made of radial glial cells that neurons climb, through the previous layers, to reach their proper destination. Some destinations, such as the cerebral cortex, even have "placeholder" neurons that travel up the ladder to form a structure;  when the final neurons germinate, they find a correct placeholder and then the placeholder cell dies.

Heterotopia
The complexity of neural development makes it fraught with opportunities for error.  Grey matter heterotopia is such an example.  It is believed that gray matter heterotopia are caused by arrested migration of neurons to the cerebral cortex; that is, when neurons that are supposed to form part of the cerebral cortex. fail to climb to the end of their ladder correctly and are permanently situated in the wrong location.
Gray matter heterotopia are common malformations of cortical development classed as neuronal migration disorders. Heterotopias are classed in two groups: nodular and diffuse. Nodular types are subependymal and subcortical; diffuse types are termed band heterotopias. Affected patients are generally divided into three groups, depending on the location of the formation: subependymal, subcortical, and band heterotopia. In addition, especially with heterotopia that are genetically linked, there are gender differences. Men seem to develop more severe symptoms than women with similar formations.
In general, band heterotopia, also known as double cortex syndrome, are seen exclusively in women; men with a mutation of the related gene (called XLIS or DCX) usually die in utero or have a much more severe brain anomaly. Symptoms in affected women vary from normal to severe developmental delay or intellectual disability; the severity of the syndrome is related to the thickness of the band of arrested neurons. Nearly all affected patients that come to medical attention have epilepsy, with partial complex and atypical absence epilepsy being the most common syndromes. Some of the more severely affected patients develop drop attacks.

Periventricular or subependymal
Periventricular means beside the ventricle, while subependymal (also spelled subepydymal) means beneath the ependyma; because the ependyma is the thin epithelial sheet lining the ventricles of the brain, these two terms are used to define heterotopia occurring directly next to a ventricle.  This is by far the most common location for heterotopia. Patients with isolated subependymal heterotopia usually present with a seizure disorder in the second decade of life.
Subependymal heterotopia present in a wide array of variations.  They can be a small single node or a large number of nodes, can exist on either or both sides of the brain at any point along the higher ventricle margins, can be small or large, single or multiple, and can form a small node or a large wavy or curved mass.
Symptomatic women with subependymal heterotopia typically present with partial epilepsy during the second decade of life; development and neurologic examinations up to that point are typically normal. Symptoms in men with subependymal heterotopia vary, depending on whether their disease is linked to their X-chromosome. Men with the X-linked form more commonly have associated anomalies, which can be neurological or more widespread, and they usually suffer from developmental problems. Otherwise (i.e., in non-X-linked cases) the symptomology is similar in both sexes.

Focal subcortical
Subcortical heterotopia form as distinct nodes in the white matter, "focal" indicating specific area.  In general, patients present fixed neurologic deficits and develop partial epilepsy between the ages of 6 and 10.  The more extensive the subcortical heterotopia, the greater the deficit; bilateral heterotopia are almost invariably associated with severe developmental delay or intellectual disability. The cortex itself often has an absence of gray matter and may be unusually thin or lack deep sulci.  Subependymal heterotopia are frequently accompanied by other structural abnormalities, including an overall decrease in cortical mass. Patients with focal subcortical heterotopia have a variable motor and intellectual disturbance depending on the size and site of the heterotopion.

Band form
Like focal subcortical heterotopia, "band" heterotopia form in the white matter beneath the cortex, but the gray matter is more diffuse and is symmetric between the hemispheres.  On imaging, band heterotopia appears as bands of gray matter situated between the lateral ventricle and cerebral cortex and separated from both by a layer of normal appearing white matter. Band heterotopia may be complete, surrounded by simple white matter, or partial. The frontal lobes seem to be more frequently involved when it is partial.  Patients with band heterotopia may present at any age with variable developmental delay and seizure disorder, which vary widely in severity.
Subcortical band heterotopia, also known as "double cortex" syndrome, refers to a band of subcortical heterotopia neurons, located midway between the ventricles and the cerebral cortex. The disorder is seen primarily in females and typically causes varying degrees of intellectual disability and almost all of them have epilepsy.  Approximately two thirds of patients with epilepsy ultimately develop intractable seizures. MRI of the brain in subcortical band heterotopia demonstrates two parallel layers of gray matter: a thin outer ribbon and a thick inner band, separated by a very thin layer of white matter between them. The severity of epilepsy and developmental delay is directly correlated with the degree of migration arrest, as indicated by the thickness of the subcortical band heterotopia.
Subcortical band heterotopia is caused by mutations in the microtubule-associated DCX gene. The DCX protein is thought to direct neuronal migration by regulating the organization and stability of microtubules, necessary for neuronal motility. The malformation is seen only in females, as the gene is found on the X-chromosome. Since there are two X chromosomes in females, after X-inactivation, only some neurons lose doublecortin function. These neurons with the mutant DCX gene fail to migrate into the cortex and thus form the underlying heterotopic band, while neurons which express the normal gene successfully migrate out to the cortical plate. Males with DCX mutations develop classical lissencephaly.

Diagnosis
Detection of heterotopia generally occurs when a patient receives brain imaging—usually an MRI or CT scan—to diagnose seizures that are resistant to medication.  Correct diagnosis requires a high degree of radiological skill, due to the heterotopias resemblance to other masses in the brain.

Treatment
When seizures are present in any forms of cortical dysplasia, they are resistant to medication </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Susacs syndrome and explain in detail? [/INST] Susacs syndrome (retinocochleocerebral vasculopathy) is a very rare form of microangiopathy characterized by encephalopathy, branch retinal artery occlusions and hearing loss.  The cause is unknown but it is theorized that antibodies are produced against endothelial cells in tiny arteries which leads to damage and the symptoms related to the illness.  Despite this being an extremely rare disease, there are 4 registries collecting data on the illness; two are the United States, one in Germany, and one in Portugal.

Presentation
Susacs syndrome is named for Dr. John Susac (1940–2012), of Winter Haven, Florida, who first described it in 1979. Susacs syndrome is a very rare disease, of unknown cause, and many persons who experience it do not display the bizarre symptoms named here. Their speech can be affected, such as the case of a female of late teens who suffered speech issues and hearing problems, and many experience unrelenting and intense headaches and migraines, some form of hearing loss, and impaired vision. The problem usually corrects itself, but this can take up to five years. In some cases, subjects can become confused. The syndrome usually affects women around the age of 18 years, with female to male ratio of cases of 2:1.
William F. Hoyt was the first to call the syndrome "Susac syndrome" and later Robert Daroff asked Dr. Susac to write an editorial in Neurology about the disorder and to use the eponym of Susac syndrome in the title, forever linking this disease with him.

Pathogenesis
In the March 1979 report in Neurology, Drs. Susac, Hardman and Selhorst reported two patients with the triad of encephalopathy, hearing loss and microangiopathy of the retina. The first patient underwent brain biopsy, which revealed sclerosis of the media and adventitia of small pial and cortical vessels, suggestive of a healed angiitis. Both patients underwent fluorescein retinal angiography that demonstrated multifocal retinal artery occlusions without evidence of embolic disease. Though the exact pathogenesis of this disorder is unknown, the retinal and brain biopsy findings suggest a small vessel vasculopathy leading to arteriolar occlusion and microinfarction of cerebral, retinal and cochlear tissue. Demyelination is not a typical feature of Susacs syndrome. Muscle biopsies from such patients are usually normal, but some have also shown nonspecific signs of inflammation such as dense hyaline material surrounding endomysial capillaries. This suggests a possible systemic component of this disease, despite the predominance of central nervous system features.  The latest thinking is that an antibody directed against endothelial cells is the pathogenic mechanism in this disease which causes the microscopic strokes in the brain, retina, and inner ear.

Diagnosis
Patients typically present with low frequency hearing loss detectable via an audiogram.  Headaches are frequently present in addition to roaring tinnitus and often some degree of paranoia.  Partial vision loss is often present and caused by branch retinal artery occlusions.  The presence of refractile or non-refractile yellow Gass plaques in the retinal arterioles is near pathognomonic for the disease.  Fluorescein angiography may demonstrate leakage in areas remote from the retinal infarctions.

Radiographic appearance
In a recent analysis (Susac et al., 2003), MRI images from 27 patients fulfilling the diagnostic criteria of Susacs syndrome were reviewed. Multifocal supratentorial lesions were present in all patients. Most lesions were small (3 to 7 mm), though some were larger than 7 mm. All 27 patients had corpus callosum lesions. These all had a punched-out appearance on follow up MRI. Though most commonly involving white matter, many patients also had lesions in deep grey matter structures, as well as leptomeningeal enhancement. Multiple sclerosis (MS) and acute disseminated encephalomyelitis (ADEM) can mimic the MRI changes seen in patients with Susacs syndrome. However, the callosal lesions in Susacs syndrome are centrally located. In comparison, patients with MS and ADEM typically have lesions involving the undersurface of the corpus callosum. Deep gray matter involvement commonly occurs in ADEM but is very rare in MS. Leptomeningeal involvement is not typical of either MS or ADEM.  What this means is that if 10 lesions are found in the brain of an MS patient, a lesion may be found in the corpus callosum.  If you have 10 lesions in a Susac patient, more than half will be in the corpus callosum.
A concern about this illness is that it mimics multiple sclerosis when looking at the vision loss and brain lesions.  If close attention is not paid to the retina of a patient with vision loss and brain lesions, their symptoms may be mistaken for MS instead of Susacs syndrome.  This may account for the low prevalence of the illness. There is also a pathological similarity between the endotheliopathy in Susacs syndrome with that seen in juvenile dermatomyositis.

Treatment
Early and aggressive treatment is important to prevent irreversible neurological damage, hearing loss, or vision loss. Medications used include immunosuppressive agents and corticosteroids such a prednisone, or intravenous immunoglobulins (IVIG). Other drugs that have been used are mycophenolate mofetil (Cellcept), azathioprine (Imuran), cyclophosphamide, rituximab, and anti-TNF therapies.Hearing aids or cochlear implants may be necessary in the event of hearing loss.

References

Egan RA, Nguyen TH, Gass JDM, Rizzo JF, Tivnan J, Susac JO.  Retinal Artery Wall Plaques in Susac Syndrome.  American Journal of Ophthalmology  135: 483-6; 2003
Susac JO, Murtagh FR, Egan RA, Berger JR, Fox RJ, Galetta S, Costello F, Lee AG, Bakshi R, Lincoff N, Clark J, Daroff R.  MRI Findings in Susac Syndrome </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Syndactyly and explain in detail? [/INST] Syndactyly is a condition wherein two or more digits are fused together. It occurs normally in some mammals, such as the siamang and diprotodontia, but is an unusual condition in humans. The term is from Greek σύν, syn together and δάκτυλος, daktulos finger.

Classification
Syndactyly can be simple or complex.
In simple syndactyly, adjacent fingers or toes are joined by soft tissue.
In complex syndactyly, the bones of adjacent digits are fused.  The kangaroo exhibits complex syndactyly.Syndactyly can be complete or incomplete.

In complete syndactyly, the skin is joined all the way to the tip of the involved digits.
In incomplete syndactyly, the skin is only joined part of the distance to the tip of the involved digits.Complex syndactyly occurs as part of a syndrome (such as Apert syndrome) and typically involves more digits than simple syndactyly.
Fenestrated syndactyly, also known as acrosyndactyly or terminal syndactyly, means the skin is joined for most of the digit but in a proximal area there are gaps in the syndactyly with normal skin.  This type of syndactyly is found in amniotic band syndrome.
Simple syndactyly can be full or partial, and is present at birth (congenital). In early human fetal development, webbing (syndactyly) of the toes and fingers is normal. At about 6 weeks of gestation, apoptosis takes place due to a protein named sonic hedgehog, also known as SHH, which dissolves the tissue between the fingers and toes, and the webbing disappears. In some fetuses, this process does not occur completely between all fingers or toes and some residual webbing remains.

Genetics
Five types of syndactyly have been identified in humans. The corresponding loci associated with these types and their common phenotypical expression are as follows:

type I:  2q34-q36; webbing occurs between middle and ring fingers and/or second and third toes.
type II:  2q31; also involves long and ring fingers, but has a sixth finger merged in between.
type III:  6q21-q23; small finger is merged into the ring finger.
type IV:  7q36; involves all fingers and/or toes.
type V:  2q31-q32; similar to type I, but the metacarpals and metatarsals may also be fused.

Management
Syndactyly of the border digits (thumb/index finger or ring/small fingers) is treated at early age to prevent the larger digit from curving towards the smaller digit with growth.  Typically, syndactyly of these digits is treated at six months of age.  The treatment of syndactyly of the other digits is elective and is more commonly performed when the digits have grown, at 18–24 months of age.

Techniques
Because the circumference of the conjoined fingers is smaller than the circumference of the two separated fingers, there is not enough skin to cover both digits once they are separated at the time of surgery.  Therefore, the surgeon must bring new skin into the area at the time of surgery </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is PES and explain in detail? [/INST]  </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Waardenburg syndrome and explain in detail? [/INST] Waardenburg syndrome is a group of rare genetic conditions characterised by at least some degree of congenital hearing loss and pigmentation deficiencies, which can include bright blue eyes (or one blue eye and one brown eye), a white forelock or patches of light skin. These basic features constitute type 2 of the condition; in type 1, there is also a wider gap between the inner corners of the eyes called telecanthus, or dystopia canthorum. In type 3, which is rare, the arms and hands are also malformed, with permanent finger contractures or fused fingers, while in type 4, the person also has Hirschsprungs disease. There also exist at least two types (2E and PCWH) that can result in central nervous system (CNS) symptoms such as developmental delay and muscle tone abnormalities.The syndrome is caused by mutations in any of several genes that affect the division and migration of neural crest cells during embryonic development (though some of the genes involved also affect the neural tube). Neural crest cells are stem cells left over after the closing of the neural tube that go on to form diverse non-CNS cells in different parts of the body, including melanocytes, various bones and cartilage of the face and inner ear and the peripheral nerves of the intestines. Type 1 is caused by a mutation in the PAX3 gene, while the gene that most often causes type 2 when mutated is MITF. Type 3 is a more severe presentation of type 1 and is caused by a mutation in the same gene, while type 4 is most often caused by a mutation in SOX10. Mutations in other genes can also cause the different types, and some of these have been given their own lettered subtypes. Most types are autosomal dominant.
The estimated prevalence of Waardenburg syndrome is 1 in 42,000. Types 1 and 2 are the most common, comprising approximately half and a third of cases, respectively, while type 4 comprises a fifth and type 3 less than 2% of cases. An estimated 2–5% of congenitally deaf people have Waardenburg syndrome. Descriptions of the syndrome date back to at least the first half of the 20th century, however it is named after Dutch ophthalmologist and geneticist Petrus Johannes Waardenburg, who described it in 1951. Its subtypes were progressively discovered in the following decades and had genes attributed to them mostly in the 1990s and 2000s.

Signs and symptoms
Waardenburg syndrome has multiple different types with some variations in symptoms, and symptoms can vary among those with the same type. The two features consistent across all types of Waardenburg syndrome are some degree of congenital sensorineural hearing loss and some degree of pigmentation deficiencies, most consistently in the eyes.

Type 1
Type 1 is characterised by congenital sensorineural hearing loss, pigmentary deficiencies of the hair such as a white lock of hair (poliosis) in the front-centre of the head or premature greying, pigmentary deficiencies of the eyes such as different-coloured eyes (complete heterochromia iridum), multiple colours in an eye (sectoral heterochromia iridum) or brilliant blue eyes, patches of skin depigmentation, and a wider gap between the inner corners of the eyes called telecanthus or dystopia canthorum. Other facial features associated with type 1 can include a high nasal bridge, a flat nose tip, a unibrow (synophrys), smaller edges of the nostrils (alae) or a smooth philtrum.

Type 2
The difference that defines type 2 from type 1 is that patients do not have the wider gap between the inner corners of the eyes (telecanthus/dystopia canthorum). Sensorineural hearing loss tends to be more common and more severe in this type. By far the most common gene to cause this type when mutated is MITF (classified as type 2A). If two individuals with a mutation in this gene have a child carrying both mutations (homozygous), for which there is 25% chance, additional symptoms are present in the child, such as a hole in the iris (coloboma), small eyes (microphthalmia), hardened bones (osteopetrosis), macrocephaly, albinism and deafness.There have been two known patients identified with mutations in both copies of SNAI2 (classified as type 2D); these individuals presented with Waardenburg syndrome type 2 but did not have hair pigmentation deficiencies.When Waardenburg syndrome type 2 is caused by a mutation in SOX10 (classified as type 2E), it can on some occasions present with multiple neurological symptoms. These can include developmental delay, early childhood nystagmus, increased muscle tone, white matter anomalies or hypomyelination in the brain, autistic-like behaviour and the underdevelopment or complete absence of many inner-ear structures such as the vestibular system or cochlea. Lack of a sense of smell (anosmia) due to a missing olfactory bulb in the brain may also be present.

Type 3
Also known as Klein–Waardenburg syndrome, or Waardenburg–Klein syndrome, type 3 has the same symptoms as type 1 (and is caused by mutations in the same gene) but has additional symptoms that affect the arms and hands. These can include joint contractures of the fingers (camptodactyly), due to underdeveloped muscles, as well as fused digits (syndactyly) or winged scapulae. Microcephaly and developmental delay are also possible.

Type 4
Also known as Shah–Waardenburg syndrome, or Waardenburg–Shah syndrome, type 4 has most of the same features as type 2 (i.e. no telecanthus, or apparent wider eye gap), but with the addition of Hirschsprungs disease, which is a congenital lack of nerves in the intestines leading to bowel dysfunction. Additionally, hearing loss is not as common as in type 2. Rarely, cleft lip has been reported in this form of Waardenburg syndrome.Type 4 can also be caused by a mutation in SOX10 (the same gene as in type 2E), in which it is known as type 4C; hearing loss is very common and severe in this type.

PCWH
A mutation in SOX10, the gene involved in type 2E and type 4C, can sometimes result in the symptoms of both types (neurological symptoms, as sometimes seen in type 2E, and Hirschsprungs disease, as seen in type 4). When this happens, it is called peripheral demyelinating neuropathy–central dysmyelinating leukodystrophy–Waardenburg syndrome–Hirschsprung disease (PCWH).

Cause
Waardenburg syndrome is caused by mutations in any of several genes that affect the operation of neural crest cells in embryonic development. Most types of Waardenburg syndrome are caused by autosomal dominant mutations. The few that are autosomal recessive are rare. In most cases, an affected person has inherited it from one parent with one of the dominant forms of the condition. A small percentage of cases result from spontaneous new mutations in the gene, where no family history of the condition exists.The neural crest is a group of temporary migratory cells that are left over after the neural tube has closed (neurulation), around the fourth week of embryonic development. They are responsible for differentiating into a diverse group of cells that reach different areas of the body. The neural tube and neural crest are derived from the ectoderm; the neural tube goes on to form the brain and spinal cord, while the neural crest cells eventually go on to form various bones and cartilage of the skull and face by migrating through the pharyngeal arches. They also differentiate into the stria vascularis of the cochlea, the nerves and glia of the intestines (myenteric plexus), Schwann cells, which myelinate the peripheral nervous system to allow sufficient conductivity, odontoblasts, which produce dentin deep in the teeth, some neuroendocrine cells, connective tissue around the salivary, lacrimal, pituitary, thymus and thyroid glands, connective tissue of the eye, such as the stroma of the iris and cornea and the trabecular meshwork, and melanocytes, including those in the stroma of the iris that give rise to brown eye colour through melanin. Neural crest cells also have a role in muscle formation, including the wall muscle of certain cardiac arteries.

Causes of subtypes
Type 1 is caused by an autosomal dominant mutation in the gene PAX3. PAX3, or paired box 3, is a transcription factor that has a role in maintaining an open window of time for certain neural crest cells (such as those of the head and eyes) to divide and migrate before their terminal differentiation (i.e. to maintain them in the stem-cell state). Mutations in this gene therefore prematurely arrest their division and migration, resulting in a minor lack of development of certain face cartilage and bones, as well as underdeveloped inner-ear structures and a lack of melanocytes in the iris stroma. Some evidence shows that PAX3 also regulates cells from before the neural crest forms, i.e. the neural tube, since mice with loss-of-function mutations in one of the copies of PAX3 have neural tube defects such as spina bifida or exencephaly.
Type 2 is caused by a mutation in any of a range of genes, the most common being MITF, when it is classed as type 2A.
Type 2A is caused by an autosomal dominant mutation in the gene MITF. MITF, or microphthalmia-associated transcription factor, has a more specialised role in the neural crest and is more strictly involved after the neural crest forms (PAX3 and SOX10 have been found to activate MITF). It is known to allow melanocytes, osteoclasts, mast cells and retinal pigment epithelial cells to divide and migrate. The involvement in osteoclasts explains why mutations in both copies of MITF can lead to bone hardening (osteopetrosis), as the osteoclasts are responsible for breaking down bone. MITF also activates transcription of tyrosinase, the enzyme that performs the first step in the creation of melanin (oxidising tyrosine). A mutation in a copy of MITF can also lead to Tietz syndrome, which is distinguished from Waardenburg syndrome by uniform albinism instead of patchy depigmentation.
Type 2B is caused by an autosomal dominant mutation in an unknown gene on chromosome 1 in the locus range of 1p21–1p13.3. The gene has been provisionally termed WS2B.
Type 2C is caused by an autosomal dominant mutation in an unknown gene on chromosome 8 in the locus of 8p23. The gene has been provisionally termed WS2C.
Type 2D is caused by an autosomal recessive mutation in both copies of the gene SNAI2. The study that discovered this association found that SNAI2 is activated by MITF as part of neural crest development, and this explained why mutations in MITF cause Waardenburg syndrome, as it results in a lack of activation of SNAI2. Mutations in a single copy of SNAI2 have also been found to cause patches of hair depigmentation (piebaldism) without any other symptoms.
Type 2E is caused by an autosomal dominant mutation in the gene SOX10.
Rarely, a mutation in a gene other than those currently known may be responsible for a Waardenburg syndrome with features of type 2. This is usually initially classified as simply type 2 but may be given its own subtype once a gene or locus is identified and established.
Type 3 is caused by a mutation in the gene PAX3, the same gene as in type 1. It can be inherited in an autosomal dominant or autosomal recessive manner; it is possible for two parents with Waardenburg syndrome type 1 to have a child carrying both mutated copies of the PAX3 gene (25% chance) and present with Waardenburg syndrome type 3. A missense mutation has been documented to have this effect. However, it is also possible for Waardenburg syndrome type 3 to present spontaneously with just one mutated copy of PAX3. A deletion of the paired domain region of the gene has been documented to have this effect. However, no major correlation has been found between type of mutation and disease severity. Severity tends to be dictated by mutations in other genes (epistasis), as evidenced by distinct familial patterns in severity not tied to Waardenburg mutation type. Mutations in both copies of PAX3 have sometimes led to death before or shortly after birth, and mice with loss-of-function mutations in both copies of the gene do not survive.
Type 4 is caused by a mutation in any of a range of genes, the most common being SOX10, when it is classed as type 4C.
Type 4A is caused by an autosomal dominant or autosomal-recessive mutation in the gene EDNRB.
Type 4B is caused by an autosomal dominant or autosomal-recessive mutation in the gene EDN3.
Type 4C is caused by an autosomal dominant or autosomal-recessive mutation in the gene SOX10, the same gene as in type 2E.A study was done on a rare case of a double heterozygous child with each parent having only single mutations in MITF or PAX3. The effect of double heterozygous mutations in the genes MITF and PAX3 in WS1 and WS2 can increase the pigment-affected symptoms. It leads to the conclusion that the double mutation of MITF is associated with the extremity of Waardenburg syndrome and may affect the phenotypes or symptoms of the syndrome.

Classification table
Treatment
There is currently no treatment or cure for Waardenburg syndrome. The symptom most likely to be of practical importance is deafness, and this is treated as any other irreversible deafness would be. In marked cases, there may be cosmetic issues. Other abnormalities (neurological, structural, Hirschsprungs disease) associated with the syndrome are treated symptomatically.

Epidemiology
The prevalence of all types of Waardenburg syndrome is estimated at around 1 in 42,000. Types 1 and 2 are by far the most common, with type 1 appearing to be slightly more common. In a 2015 review looking at 417 patients, type 1 was found to be the most common type, encompassing around half of all cases (47%), while type 2 was the second-most common type, encompassing around a third (33%). The vast majority (around 85%) of type 2 cases are type 2A. The prevalence of type 2B is unknown, as it was only reported in one 1996 study. Type 2C has so far only been found in one Italian family, and type 2D had only been found in 2 unrelated patients as of 2018. The number of known cases of type 2E that involved neurological abnormalities was reported to be 23 as of 2017, while the number of the rest is unknown. Type 3 is rarer than types 1, 2 and 4, comprising less than 2% of cases. Type 4 appears to encompass around a fifth of cases (19%). Of its subtypes, type 4C is by far the most common (about 71% of type 4), followed by type 4A (19%) and type 4B (10%).It is estimated that Waardenburg syndrome is present in 2–5% of congenitally deaf people. Congenital deafness comprises around half of deafness as a whole. About 1 in 30 students in schools for the deaf have Waardenburg syndrome. The variable presentation of the syndrome makes it difficult to arrive at precise figures for its prevalence.

History
Early descriptions
In 1916, Dutch ophthalmologist Jan van der Hoeve (1878–1952) described a pair of twin girls with deafness and a particular type of blepharophimosis, believed to be the dystopia canthorum found in Waardenburg syndrome types 1 and 3. Blepharophimosis describes eyelids which are underdeveloped such that they permanently cover part of the eyes.
In 1926, German physician Irmgard Mende described a family of four generations in which five children had symptoms of depigmentation of hair, skin and eyes, deafness and a "mongoloid" appearance. (Waardenburg later attributed this description to the dystopia canthorum.) This later led to the synonym Mende syndrome being recorded in some databases.In 1929, Dutch physician K. T. A. Halbertsma described a familial pattern to dystopia canthorum, and in 1930, Italian physician Vincenzo Gualdi (1891–1976) also confirmed a hereditary pattern to dystopia canthorum. This later led to the synonym Van der Hoeve–Halbertsma–Waardenburg–Gualdi syndrome being recorded in some databases.In 1947, Swiss ophthamologist David Klein (1908–1993) first reported a patient with bilateral deafness, pigmentation deficiencies, characteristic facial features and malformation of the arms. Although this was the first full description of a patient with Waardenburg syndrome type 3, contemporary clinicians did not consider the syndrome he described to be the same as that described by Waardenburg four years later, in part due to how severe the arm malformations were in his patient.The syndrome was first fully formalised and described by Dutch ophthalmologist and geneticist Petrus Johannes Waardenburg (1886–1979) in 1951. The condition he described is now categorised as Waardenburg syndrome type 1.

Descriptions of subtypes
Type 2 was first established in 1971 when a study noticed that some Waardenburg syndrome patients did not have dystopia canthorum. A 1977 study confirmed a familial pattern to this other presentation. Two 1994 studies first confirmed a link between this type of Waardenburg syndrome and mutations in the MITF gene (now classed as type 2A), located on chromosome 3 at locus 3p14.1–p12.3.Type 2B was first established in 1994 when the same study which found mutations in MITF in patients with Waardenburg syndrome type 2 also found that some patients did not have any mutations in this region. A second 1994 study found a link to chromosome 1 in the locus 1p21–p13.3. This became known as type 2B of the condition (with the gene designated WS2B), however it has not been documented since, and the gene responsible remains unknown.Type 2C was established in 2001 when a study of an Italian family with Waardenburg syndrome type 2 features found that they were due to an unknown gene on chromosome 8 at locus 8q23 that had been broken by a chromosomal translocation. The study established a provisional name for the gene, WS2C. However, mutations in this region in Waardenburg syndrome patients have not been found since.Type 2D was established in 2002 when a study looking to find mutations in the human version of the SNAI2 gene, known to cause depigmentation in mice, found deletions of both copies of this gene in two unrelated individuals with Waardenburg syndrome type 2. Mutations in both copies of this gene have not been found in those with Waardenburg syndrome type 2 since.Type 2E was first established in 1996 when a study identified a girl with symptoms of Waardenburg syndrome type 2 but with additional underdevelopment of the front of the eye, leading to blindness. In 1999, it was found that she had a mutation in her SOX10 gene, and later studies confirmed the association between mutations in this gene and this phenotype, as well as neurological symptoms such as developmental delay.Type 3 was first given its name by Goodman et al. in 1981, in collaboration with Klein, in which they established the association with arm abnormalities first reported by Klein in 1947. Mutations in PAX3 were first linked to this phenotype in 1992.The comorbidity with Hirschsprungs disease, which would later constitute type 4, was first noticed in various studies in the 1970s. Indian paediatrician Krishnakumar Shah and his associates first outlined the syndrome as a possible variant of Waardenburg syndrome in 1981. The variant was first attributed to a mutation in EDNRB in 1994 (now classed as type 4A). Type 4B was established in 1996 when mutations in EDN3 were found to lead to this type of Waardenburg syndrome, and type 4C was first established in 1998 when mutations in SOX10 were also found to lead to this type.

Society and culture
Popular culture
The 2001 novel Shock by Robin Cook mentions a character with the disorder.
Enzo MacLeod, protagonist of Peter Mays 2006–2017 book series The Enzo Files, has Waardenburg syndrome. His eyes are different colors, and he has a white streak in his hair.
In the 2011 season 6 episode of Bones "The Signs in the Silence", the team must solve a case in which the suspected killer has Waardenburg syndrome.
The 2013 book Reconstructing Amelia by Kimberly McCreight features several characters with Waardenburg symptoms.
The 2014 book Closer Than You Think by Karen Rose features three characters, siblings, with Waardenburg syndrome.
The 2017 book Murder at the Mayan Temple by M.J. Mandrake features several characters with Waardenburg syndrome.
The 2019 novel The Whisper Network by Chandler Baker uses the syndrome as a plot point.

Notable people
Canadian YouTube vlogger Stef Sanjati has Waardenburg syndrome type 1.

Other animals
Waardenburg syndrome type 2A (with a mutation in MITF) has been found in dogs, Fleckvieh cattle, minks, mice and a golden hamster </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Vasculitis and explain in detail? [/INST] Vasculitis is a group of disorders that destroy blood vessels by inflammation. Both arteries and veins are affected. Lymphangitis (inflammation of lymphatic vessels) is sometimes considered a type of vasculitis. Vasculitis is primarily caused by leukocyte migration and resultant damage. Although both occur in vasculitis, inflammation of veins (phlebitis) or arteries (arteritis) on their own are separate entities.

Signs and symptoms
Possible signs and symptoms include:
General symptoms: Fever, unintentional weight loss
Skin: Palpable purpura, livedo reticularis
Muscles and joints: Muscle pain or inflammation, joint pain or joint swelling
Nervous system: Mononeuritis multiplex, headache, stroke, tinnitus, reduced visual acuity, acute visual loss
Heart and arteries: Heart attack, high blood pressure, gangrene
Respiratory tract: Nosebleeds, bloody cough, lung infiltrates
GI tract: Abdominal pain, bloody stool, perforations (hole in the GI tract)
Kidneys: Inflammation of the kidneys filtration units (glomeruli)

Cause
Classification
Vasculitis can be classified by the cause, the location, the type of vessel or the size of vessel.

Underlying cause. For example, the cause of syphilitic aortitis is infectious (aortitis simply refers to inflammation of the aorta, which is an artery.) However, the causes of many forms of vasculitis are poorly understood. There is usually an immune component, but the trigger is often not identified. In these cases, the antibody found is sometimes used in classification, as in ANCA-associated vasculitides. Clinical studies with immunosuppressive drugs targeting specific cytokines and cells can also be used to understand the heterogeneous immunopathogenic mechanisms of vasculitis and support a mechanistic immunological classification.
Location of the affected vessels. For example, ICD-10 classifies "vasculitis limited to skin" with skin conditions (under "L"), and "necrotizing vasculopathies" (corresponding to systemic vasculitis) with musculoskeletal system and connective tissue conditions (under "M"). Arteritis/phlebitis on their own are classified with circulatory conditions (under "I").
Type or size of the blood vessels that they predominantly affect. Apart from the arteritis/phlebitis distinction mentioned above, vasculitis is often classified by the caliber of the vessel affected. However, there can be some variation in the size of the vessels affected.A small number have been shown to have a genetic basis. These include adenosine deaminase 2 deficiency and haploinsufficiency of A20.
According to the size of the vessel affected, vasculitis can be classified into:
Large vessel: Takayasus arteritis, Temporal arteritis
Medium vessel: Buergers disease, Kawasaki disease, Polyarteritis nodosa
Small vessel: Behçets syndrome, Eosinophilic granulomatosis with polyangiitis, Cutaneous vasculitis, granulomatosis with polyangiitis, Henoch–Schönlein purpura, and microscopic polyangiitis. Condition of some disorders have vasculitis as their main feature. The major types are given in the table below:Takayasus arteritis, polyarteritis nodosa and giant cell arteritis mainly involve arteries and are thus sometimes classed specifically under arteritis.
There are also many conditions that have vasculitis as an accompanying or atypical feature, including:

Rheumatic diseases, such as rheumatoid arthritis, systemic lupus erythematosus, and dermatomyositis
Cancer, such as lymphomas
Infections, such as hepatitis C
Primary Immunodeficiencies, such as DADA2, GATA2, and RAG deficiency
Exposure to chemicals and drugs, such as amphetamines, cocaine, and anthrax vaccines which contain the Anthrax Protective Antigen as the primary ingredient. Sympathomimetics such as phenylpropanolamine, methylphenidate, and others are also implicated.In pediatric patients varicella inflammation may be followed by vasculitis of intracranial vessels. This condition is called post varicella angiopathy and this may be responsible for arterial ischaemic strokes in children.Several of these vasculitides are associated with antineutrophil cytoplasmic antibodies. These are:

Granulomatosis with polyangiitis
Eosinophilic granulomatosis with polyangiitis
Microscopic polyangiitis

Diagnosis
Laboratory tests of blood or body fluids are performed for patients with active vasculitis. Their results will generally show signs of inflammation in the body, such as increased erythrocyte sedimentation rate (ESR), elevated C-reactive protein (CRP), anemia, increased white blood cell count and eosinophilia. Other possible findings are elevated antineutrophil cytoplasmic antibody (ANCA) levels and hematuria.
Other organ functional tests may be abnormal. Specific abnormalities depend on the degree of various organs involvement </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Polydactyly and explain in detail? [/INST] Polydactyly or polydactylism (from Greek  πολύς (polys) many, and  δάκτυλος (daktylos) finger), also known as hyperdactyly, is an anomaly in humans and animals resulting in supernumerary fingers and/or toes. Polydactyly is the opposite of oligodactyly (fewer fingers or toes).

Signs and symptoms
In humans/animals this condition can present itself on one or both hands. The extra digit is usually a small piece of soft tissue that can be removed. Occasionally it contains bone without joints; rarely it may be a complete functioning digit. The extra digit is most common on the ulnar (little finger) side of the hand, less common on the radial (thumb) side, and very rarely within the middle three digits. These are respectively known as postaxial (little finger), preaxial (thumb), and central (ring, middle, index fingers) polydactyly. The extra digit is most commonly an abnormal fork in an existing digit, or it may rarely originate at the wrist as a normal digit does.The incidence of congenital deformities in newborns is approximately 2%, and 10% of these deformities involve the upper extremity. Congenital anomalies of the limb can be classified in seven categories, proposed by Frantz and O’Rahilly and modified by Swanson, based on the embryonic failure causing the clinical presentation. These categories are failure of formation of parts, failure of differentiation, duplication, overgrowth, undergrowth, congenital constriction band syndrome, and generalized skeletal abnormalities. Polydactyly belongs to the category of duplication.
Because there is an association between polydactyly and several syndromes, children with a congenital upper extremity deformity should be examined by a geneticist for other congenital anomalies. This should also be done if a syndrome is suspected, or if more than two or three generations of the family are affected.
Research has shown that the majority of congenital anomalies occur during the 4-week embryologic period of rapid limb development. Polydactyly has been associated with 39 genetic mutations. More specific loci and genetic mechanisms responsible for disorders of duplications will be defined with time, as molecular research continues.
Polydactyly can be divided into three major types, which are discussed below.

Ulnar or postaxial polydactyly
This is the most common situation, in which the extra digit is on the ulnar side of the hand, thus the side of the little finger. This can also be called postaxial polydactyly. It can manifest itself very subtly, for instance only as a nubbin on the ulnar side of the little finger, or very distinctly, as a fully developed finger. Most commonly, the extra finger is rudimentary, consisting of an end phalanx with a nail, and connected to the hand with a small skin pedicle. Mostly one neurovascular bundle can be identified, with no tendons present in the extra digit. In case of a fully developed extra finger, the duplication usually presents itself at the level of the metacarpophalangeal joint. A triplication of the little finger is very rare. Ulnar polydactyly occurs ten times more often in African populations. The incidence in Caucasians is reported as 1 in 1,339 live births, compared with 1 in 143 live births in Africans and African Americans. Ulnar polydactyly is also often part of a syndrome. In patients with African ancestry ulnar polydactyly mostly occurs isolated, whereas the presentation in Caucasians is often associated with a syndrome, though in a retrospective review, only 4 of 37 cases of ulnar polydactyly in Caucasians were syndromic.

Radial or preaxial polydactyly
This is a less common situation, in which the affectation is on the side of the hand towards the thumb. Radial polydactyly refers to the presence of an extra digit (or extra digits) on the radial side of the hand. It is most frequent in Indian populations and it is the second most common congenital hand disorder. The incidence of radial polydactyly is reported as 1 in every 3,000 live births. The clinical features of radial polydactyly will depend upon the extent of duplication.
Radial polydactyly varies from a barely visible radial skin tag to complete duplication. Thumb polydactyly varies from barely visible broadening of the distal phalanx to full duplication of the thumb including the first metacarpal.
Radial polydactyly is frequently associated with several syndromes.

Central polydactyly
This is a very rare situation, in which the extra digit is on the ring, middle or index finger. Of these fingers, the index finger is most often affected, whereas the ring finger is rarely affected.
This type of polydactyly can be associated with syndactyly, cleft hand and several syndromes.
Polysyndactyly presents various degrees of syndactyly affecting fingers three and four.

Causes
Polydactyly is associated with different mutations, either mutations in a gene itself or in a cis-regulatory element responsible for the expression of a specific gene. Mutations in Hoxa- or Hoxd clusters are reported leading to polydactyly. Interactions of Hoxd13 and GLI3 induce synpolydactyly, a combination of extra and consolidated digits. Other signal transduction pathways in this context are the Wnt signaling pathway or Notch.In the specific case of preaxial polydactyly (Hemingway mutant), a cis-acting mutation approximately 1Mb upstream of SHH gene has been implicated. Normally SHH is expressed in an organiser region, called the zone of polarizing activity (ZPA) on the posterior limb side. From there it diffuses anteriorly, laterally to the growth direction of the limb. In the mutant, smaller ectopic expression in a new organiser region is seen on the anterior side of the limb. This ectopic expression causes cell proliferation delivering the raw material for one or more new digits.In addition to the study of genetic causes of polydactyly, limb patterning models are used to simulate the congenital disorder at the limb, being able to explain the development paths of polydactyly.Polydactyly can occur by itself, or more commonly, as one feature of a syndrome of congenital anomalies. When it occurs by itself, it is associated with autosomal dominant mutations in single genes, i.e. it is not a multifactorial trait. But mutation in a variety of genes can give rise to polydactyly. Typically the mutated gene is involved in developmental patterning, and a syndrome of congenital anomalies results, of which polydactyly is one feature or two.Polydactyly has been linked to the prenatal environment, however, with a recent study showing a relationship to maternal pollution exposure in China.Types include:

97 genetic syndromes have been associated with different kinds of polydactyly.

Ulnar polydactyly
Ulnar polydactyly is often bilateral and associated with syndactyly and polydactyly of the feet. This can be a simple or complex polydactyly. Ulnar polydactyly occurs as an isolated congenital condition, but can also be part of a syndrome. The syndromes which occur with ulnar polydactyly are: Trisomy 13, Greig cephalopolysyndactyly syndrome, Meckel syndrome, Ellis–van Creveld syndrome, McKusick–Kaufman syndrome, Down syndrome, Bardet–Biedl syndrome, Smith–Lemli–Opitz syndrome

Radial polydactyly
Type VII of radial polydactyly is associated with several syndromes:
Holt–Oram syndrome, Fanconi anemia (aplastic anemia by the age of 6), Townes–Brocks syndrome, and Greig cephalopolysyndactyly (also known to occur with ulnar polydactyly).

Central polydactyly
The syndromes associated with central polydactyly are:
Bardet–Biedl syndrome, Meckel syndrome, Pallister–Hall syndrome, Legius syndrome, Holt–Oram syndrome. Also, central polydactyly can be associated with syndactyly and cleft hand. Other syndromes including polydactyly include acrocallosal syndrome, basal cell nevus syndrome, Biemond syndrome, ectrodactyly-ectodermal dysplasias-cleft lip/palate syndrome, mirror hand deformity, Mohr syndrome, oral-facial-digital syndrome, Rubinstein-Taybi syndrome, short rib polydactyly, and VATER association.
It can also occur with a triphalangeal thumb.

Diagnosis
Classification is performed by using x-ray imaging to see the bone structures.

Ulnar polydactyly
The classification of ulnar polydactyly exists of either two or three types. The two-stage classification, according to Temtamy and McKusick, involves type A and B. In type A there is an extra little finger at the metacarpophalangeal joint, or more proximal including the carpometacarpal joint. The little finger can be hypoplastic or fully developed. Type B varies from a nubbin to an extra, non-functional little finger part on a pedicle. According to the three-type classification, type I includes nubbins or floating little fingers, type II includes duplications at the MCPJ, and type III includes duplications of the entire ray.

Radial polydactyly
The Wassel classification is the most widely used classification of radial polydactyly, based upon the most proximal level of skeletal duplication. The most common type is Wassel 4 (about 50% of such duplications) followed by Wassel 2 (20%) and Wassel 6 (12%).

Central polydactyly
The classification of central polydactyly is based on the extent of duplication and involves the following three types:
Type I is a central duplication, not attached to the adjacent finger by osseous or ligamentous attachments; it frequently does not include bones, joints, cartilage, or tendons.
Type IIA is a nonsyndactylous duplication of a digit or part of a digit with normal components, and articulates with a broad or bifid metacarpal or phalanx.
Type IIB is a syndactylous duplication of a digit or part of a digit with normal components, and articulates with a broad or bifid metacarpal or phalanx.
Type III is a complete digital duplication, which has a well-formed duplicated metacarpal.

Treatment
Ulnar polydactyly
Ulnar polydactyly usually does not interfere with hand function, but for social reasons it can be treated operatively.

Type A ulnar polydactyly
The treatment of Type A ulnar polydactyly is complex as its goal is to remove the accessory digit while maintaining a stable, functional small finger. When the duplicated proximal phalanx articulates with a common, broad metacarpal head, the ulnar collateral ligament must be considered. In those cases with a common articulation or with a sixth metacarpal the muscle executing the abduction of the little finger (abductor digiti minimi) must be preserved.
In patients with a common metacarpal articulation an elliptical incision at the base of the post-axial digit is made. This incision may be extended proximally in order to adequately expose the abductor digiti minimi. The ulnar collateral ligament and the insertions of the abductor digiti minimi are then elevated with a periosteal sleeve. The duplicated extensor and flexor tendons to the ulnar digit are transected and after that the digit is amputated at its articulation with the metacarpal. If the articular surface is wide the metacarpal may be shaved. At last the collateral ligament and abductor digiti minimi are reinserted at the base of the preserved proximal phalanx and a wire is then placed across the reconstructed joint.
In patients with a duplicated metacarpal, the accessory digit is amputated in a standard ray fashion with transfer of the abductor digiti minimi to the retained small finger.

Type B ulnar polydactyly
In this situation there is an absence of osseous and ligamentous structures. The surgical technique is analogous to radial polydactyly, in which the level of duplication and anatomical components should guide operative treatment.
The pedicled ulnar extra digit can be removed by  suture ligation to devise the skin bridge of the newborn child. This might be easier than an excision of the extra digit when the child is 6 to 12 months old. Ligation occludes the vascular supply to the duplicated digit, resulting in dry gangrene and subsequent autoamputation. This must be done with consideration of the presence of a neurovascular bundle, even in very small skin bridges. When the ligation is done inappropriately it can give a residual nubbin. Also, a neuroma can develop in the area of the scar. An excision can prevent the development of a residual nubbin and the sensitivity due to a neuroma.
For infants with ulnar type B polydactyly the recommended treatment is ligation in the neonatal nursery. Studies have shown that excision of the extra digit in the neonatal nursery is a safe and simple procedure with a good clinical and cosmetic outcome.

Radial polydactyly
Because neither of the two thumb components is normal, a decision should be taken on combining which elements to create the best possible composite digit. Instead of amputating the most hypoplastic thumb, preservation of skin, nail, collateral ligaments and tendons is needed to augment the residual thumb. Surgery is recommended in the first year of life, generally between 9 and 15 months of age.
Surgical options depend on type of polydactyly.

Bilhaut-Cloquet procedure
This type of procedure is recommended for Wassel types 1 and 2 (in which both thumbs are severely hypoplastic) by some congenital hand surgeons. The technique contains a composite wedge resection of the central bone and soft-tissue. This will be achieved with approach of the lateral tissue of each thumb. The goal is to achieve a normal thumb, what concerns the size, which is possible. If the width of the nail bed is greater than 70% of the contralateral thumb, it may be split.

Ablation with collateral ligament reconstruction
This type of procedure is used for all Wassel types of polydactyly and is the most commonly used technique. It is recommended in all cases of thumb duplication with a hypoplastic, less-functional thumb. Otherwise, one could consider the Bilhaut-Cloquet. The ulnar thumb is preferably preserved as it is the more developed one in most cases.By detaching the radial collateral ligament from distal to proximal, a periosteal sleeve can be preserved.
In this way, the radial collateral band of the radial digit, will function as the absent radial collateral ligament of the preserved ulnar thumb.
Elevation of the APB and FPB is performed in Wassel type 4 duplication; this can be accomplished via the periosteum or separately. As the tendons insert proximally, the elevation is performed proximally too to potentially rebalance the ulnar thumb. After the radial thumb is amputated, the ulnar elements are centralized and fixed with a Kirschner wire. In most cases, a longitudinal and sagittal osteotomy is needed to centralize the bony parts of the ulnar thumb. While the soft-tissue of the radial thumb was preserved, it is now attached to the radial side of the ulnar thumb together with the periosteal sleeve. The APB and FPB of the ablated radial thumb are attached to the distal phalanx for more stability. If necessary, the extensor pollicis longus and the flexor pollicis longus are reattached to centralize their course.In Wassel type 5 and 6 the opponens pollicis muscle must be transferred to the ulnar metacarpal. Soft tissue with collateral ligament reconstruction is used to avoid any angular deformity in the preserved thumb. Tendon centralization is also often used for correction. Still, cases with osseous deformities may happen. To provide alignment, osteotomies are necessary to be done. This operation may need bone grafting, which is obtained from the amputated thumb.

On top plasty procedure
This type is indicated when one thumb is larger proximally and the other thumb has a larger distal component. (The procedure is initially described as a way to lengthen amputated digits.) The goal is to create a functional thumb by combining less-hypoplastic components. On top plasty procedure is rarely employed in the treatment of congenital thumb duplication. It might be necessary for Wassel types 4, 5, 6.At the level of the mid-proximal phalanx or mid-metacarpal, the distal component is transferred to the proximal component. The tendons of the distal component are preserved as the rest of the distal component is amputated. The neurovascular bundle which supplies the distal component is reserved and transferred proximally.

Central polydactyly
Early osteotomy and ligament reconstructions should be done to prevent deformities, such as angular growth deformities.The surgical treatment of central polydactyly is highly variable. After the surgery the hand must be functional and stable, but also aesthetically pleasing. This requires intraoperative creativity and flexibility. The surgeon must also consider whether retention of a fully functional supranumerary digit is preferable to surgical intervention. In contrast, a functional, four-fingered hand achieved via ray amputation may be preferable to a five-fingered hand with a deformed or stiff reconstructed finger.Cases of polysyndactyly are approached through a standard opposing zig-zag incision. The incision is favored toward the accessory digit, preserving extra skin for subsequent closure. Depending on the level and extent of duplication, the flexor and extensor tendons may require centralization or rebalancing. Also, the collateral ligaments must be preserved or reconstructed. Wide articular surfaces should be narrowed and phalangeal wedge osteotomies may be required to provide an axial alignment. Attention must also be given to reconstruct the intermetacarpal ligament. Furthermore, one should take in mind the provision for adequate web-space soft tissue.

Prognosis
Ulnar polydactyly
Type A ulnar polydactyly
There are no substantive outcome studies regarding the function of these hands following surgical intervention. This is mainly caused by the fact that there is a generally normal function of these patients’ hands following ablation with collateral ligament reconstruction. In a study on 27 patients undergoing surgical excision for Type A ulnar polydactyly, only one complication was noted in the form of an infection
However, no investigators have objectively reviewed functional range of motion or articular stability.

Type B ulnar polydactyly
In a study on 21 patients with Type B ulnar polydactyly treated with suture ligation it was found that the duplicated digit was typically amputated at an average of 10 days and no complications of infection or bleeding were reported.
In a large study on 105 patients treated with suture ligation an overall complication rate of 23.5% was reported, citing a residual tender or unacceptable bump in 16%, infection in 6%, and bleeding in 1% of patients.
In general, suture ligation is safe and effective when applied to appropriate cases of Type B polydactyly in which no substantial ligamentous or osseous structures are present within the pedicle. Parents should be educated as to the progression of necrosis, and that revision of residual tissue or scar may be necessary when the child is six months of age or older.

Radial polydactyly
Bilhaut procedure
Advantages:
By combining two hypoplastic thumbs a sufficient thumb size is acquired. Furthermore, the IP and MCP joints are very stable as the collateral ligaments are not violated during reconstruction.
Disadvantages:
Violation during reconstruction can lead to growth arrest or asymmetric growth. Nail deformity could also occur after reconstruction. Although the joints are stable, restriction of flexion may be possible.
The average IP flexion in a reconstructed thumb is 55 degrees less than the contralateral thumb. MCP flexion averaged 55 degrees in reconstructed thumbs, compared to 75 degrees in the contralateral thumb.

Ablation with collateral ligament reconstruction
Advantages:
The reconstructed joints tend to remain flexible. Also, it preserves the nail bed and physis, this increases the prevention of nail deformities over time.
Disadvantages:
Although surgeons try to obtain a stable thumb of appropriate size, instability of the IP and MCP joint may occur, as well as a size mismatch. Thumbs are defined as unacceptable if IP joint deviation exceeds 15 degrees, MCP joint deviation exceeds 30 degrees, and thumb size is inappropriate based on the examiners assessment. Also, thumb size one-third greater or less than the contralateral thumb is defined as unacceptable.

On-top plasty procedure
No surgical outcomes studies exist for evaluating the function of the thumbs after an on-top plasty reconstruction.

Central polydactyly
Few clinical outcome studies exist regarding the treatment of central polydactyly. Tada and colleagues note that satisfactory surgical correction of central polydactyly is difficult to achieve and that outcomes are generally poor. In Tadas study, 12 patients were reviewed. All patients required secondary surgical procedures to address flexion contractures and angular deviation at the IP joint level.
However, several primary factors contribute to the complexity of central polydactyly reconstruction. Hypoplastic joints and soft tissues that predispose the reconstructed finger to joint contracture, and angular deformities as well as complex tendon anomalies, are often difficult to address. Therefore, treatment is wholly dependent on the anatomic components present, the degree of syndactyly, and the function of the duplicated finger.

Epidemiology
The condition has an estimated occurrence of 0.3–3.6 per 1000 live births. Postaxial hand polydactyly is most frequent in the United States in Black males. Preaxial polydactyly occurs in 0.08 to 1.4 in 1,000 live births. In the United States, it is more common in White people and also relatively frequent in Native American and Asian people. A 1994 study by Finley et al. combined data from Jefferson County, Alabama, United States, and Uppsala County, Sweden. This study found incidence of all types of polydactyly at rates of 2.3 per 1000 live births of White males, 0.6 per 1000 live births of White females, 13.5 per 1000 live births of Black males, and 11.1 per 1000 live births of Black females.

Society and culture
People with polydactyly
Antonio Alfonseca, retired MLB professional baseball pitcher known as "El Pulpo" – Spanish for "the Octopus" with regard to his extra digit on each extremity.
Endre Ady, Hungarian poet born with six fingers, but one was removed as a child. The poet later interpreted it as a sign of his selection (according to the ancient Hungarian belief, the táltos are born with more bones, such as six fingers).
Brites de Almeida, a legendary Portuguese woman who killed seven hiding Castilian soldiers in her oven after the Battle of Aljubarrota, had six fingers on each hand.
The actress Gemma Arterton was born with six fingers on each hand, the additional fingers being removed after birth.
Anne Boleyn, former Queen of England, was rumoured to have six fingers on one hand. However, considering that this rumour first emerged in the 1580s from a Catholic dissenter, it is generally deemed false.
Robert Chambers, purported author of Vestiges of the Natural History of Creation, and his brother William had six digits on each limb.
Lucille Clifton, an African-American poet and civil rights advocate.
Zerah Colburn, American prodigious math calculating savant.
Calvin Choy, a Hong Konger singer and actor nicknamed "Sir One One" (Sir11) as he has six digits on his right hand.
Several members of a Da Silva family in São Paulo, Brazil, have two thumbs on each hand.
Vicente Fox, former President of Mexico, has six toes on each foot.
Danny Garcia, boxing champion, has six toes on his right foot.
Yoandri Hernández Garrido, nicknamed "Veinticuatro" ("twenty four" in Spanish), has six fully formed fingers on both hands and six perfect toes on each foot.
Hampton Hawes, jazz pianist, was born with six fingers on each hand (the extra fingers were surgically removed shortly after birth).
Henry II the Pious, High Duke of Poland 1238–1241, had six toes on his left foot.
A boy named Hong Hong born in Pingjiang County, Hunan province, China, has 31 fingers and toes.
Kamani Hubbard, a boy in California was born in 2009 with a rare case of polydactyly, with 12 fingers and 12 toes, all fully functional.
Johann Jacob Freiherr von Moscon (1621–1661), Lower Styrian baron, is depicted with six fingers at his left hand on a portrait from Brežice, Slovenia.
Jiang Qing, Mao Zedongs fourth wife, reportedly had six toes on her right foot.
Hrithik Roshan, a Bollywood actor born with a supernumerary thumb on his right hand.
Nayanthara, an Indian actress who is a polydactyl, with a rudimentary finger on her left hand.
Akshat Saxena from Uttar Pradesh, India is the world record holder for highest number of digits. He was born in 2010 with seven digits on each hand and 10 digits on each foot, for a total of 34 digits.
Garfield Sobers, West Indian cricketer, had an extra finger on each hand which he removed himself during childhood "with the aid of catgut and a sharp knife".
Theodore Roosevelt "Hound Dog" Taylor, American Chicago-based blues guitarist, was born with polydactyly on both hands, although around age 41, he removed the extra finger on his right hand.
Varalakshmi V, a girl from Bangalore with eight fingers on each hand and about four to five extra toes on each foot.
Volcacius Sedigitus, a Roman poet of the 1st century, probably received his epithet, signifying "Sixfinger", because he was born with six fingers on each hand, according to Pliny,
Zhu Yunming, a Chinese calligrapher, had six fingers on his right hand.
Reggy B, a drag queen and contestant on the second season of Drag Race Holland, revealed on the show that she was born with an extra thumb on her left hand, three extra toes on one foot, and two extra toes on her other foot. Her extra fingers and toes were surgically removed at a young age.
Ish Madon (איש מדון), a biblical Philistean figure who fought against King Davids army. The Bible mentions he was a relative to Goliath.

Fictional people
In The Silence of the Lambs, Hannibal Lecter is described as having mid-ray duplication polydactyly (a duplicated middle finger) on his left hand, which he later removes in Hannibal as part of his cosmetic surgery to disguise himself.
In the cartoon series Gravity Falls, Stanford Pines ("Grunkle Ford") has six fingers on both of his hands, a trait which also identifies him in the shows mythology.
Tyrone Rugen, a Count in The Princess Bride, is described many times as the "six-fingered man."
Void, an antagonist of the manga series Berserk, has six fingers on each hand.
Billy, a character from Adventure Time had six fingers on each hand.

Other animals
Polydactyly occurs in numerous types of animals. The condition is sporadically seen in livestock, where it affects cattle, sheep, pigs, and occasionally horses. Conversely, it is a common trait in several heritage chicken breeds. Chickens normally have 4 toes on each foot. The chicken breeds known for being polydactyl are the Dorking, Faverolle, Houdan, Lincolnshire Buff, Meusienne, Sultan, and non-bearded Silkie Bantams. The breed standard of these varieties of chickens calls for five toes on each foot, although sometimes more than five toes will occur. The extra digit in these breeds presents as an extra "thumb" that does not touch the ground. Mixed-breed chickens may also have extra digits if the aforementioned breeds are part of their genetic makeup.Polydactyly also occurs in dogs, cats, and small mammals such as guinea pigs and mice </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Right ventricular hypertrophy and explain in detail? [/INST] Right ventricular  (RVH) is a condition defined by an abnormal enlargement of the cardiac muscle surrounding the right ventricle. The right ventricle is one of the four chambers of the heart. It is located towards the lower-end of the heart and it receives blood from the right atrium and pumps blood into the lungs.
Since RVH is an enlargement of muscle it arises when the muscle is required to work harder. Therefore, the main causes of RVH are pathologies of systems related to the right ventricle such as the pulmonary artery, the tricuspid valve or the airways.
RVH can be benign and have little impact on day-to-day life or it can lead to conditions such as heart failure, which has a poor prognosis.

Signs and symptoms
Symptoms
Although presentations vary, individuals with right ventricular hypertrophy can experience symptoms that are associated with pulmonary hypertension, heart failure and/or a reduced cardiac output. These include:
Difficulty breathing on exertion
Chest pain (angina) on exertion
Fainting (syncope) on exertion
General fatigue/lethargy
Dizziness
Feeling of fullness in the upper abdominal area
Discomfort or pain in the right upper abdomen
Reduced appetite
Swelling (oedema) of the legs, ankles or feet
Racing heart beat (palpitations)People may rarely present with the symptoms of Ortners syndrome, which include cough, haemoptysis and hoarseness.

Signs
On physical examination, the most prominent features are due to the development of right-sided heart failure. These can include a raised jugular venous pressure, ascites, left parasternal heave and a tender, enlarged liver on palpation.
On inspection, patients may be chronically ill, cyanotic, cachectic and occasionally jaundiced.On auscultation, an accentuated second pulmonary sound (S2), a third heart sound termed a ‘right ventricular gallop’, as well as a systolic murmur over the tricuspid area accentuated by inspiration may be present. On occasion, the systolic murmur can be transmitted and auscultated over the liver. Less typically, diastolic murmur may also be heard as a result of pulmonary insufficiency.

Causes
RVH usually occurs due to chronic lung disease or structural defects in the heart. One of the most common causes of RVH is pulmonary hypertension (PH), defined as increased blood pressure in the vessels supplying blood to the lungs. PH leads to increased pulmonary artery pressure. The right ventricle tries to compensate for this increased pressure by changing its shape and size. Hypertrophy of individual myocytes results in an increase in right ventricular wall thickness. The worldwide incidence of PH is 4 per million people. RVH occurs in approximately 30% of these cases.PH is broadly split into five categories by the World Health Organization, based on the underlying cause. The incidence of RVH varies between the groups. Common causes of PH include chronic obstructive pulmonary disease (COPD), pulmonary embolism, and other restrictive lung diseases. RVH often occurs as a result of these disorders. RVH is seen in 76% of patients with advanced COPD and 50% of patients with restrictive lung disease.RVH also occurs in response to structural defects in the heart. One common cause is tricuspid insufficiency. This is a disorder where the tricuspid valve fails to close properly, allowing backward flow of blood. Other structural defects which lead to RVH include tetralogy of Fallot, ventricular septal defects, pulmonary valve stenosis, and atrial septal defects. RVH is also associated with abdominal obesity, elevated fasting blood glucose, high systolic blood pressure, and fractional shortening of the left ventricular mid-wall.Other risk factors for RVH include smoking, sleep apnea, and strenuous activity. These increase the risk of heart and lung disease and hence RVH.

Pathophysiology
Right ventricular hypertrophy can be both a physiological and pathophysiological process. It becomes pathophysiological (damaging) when there is excessive hypertrophy. The pathophysiological process mainly occurs through aberrant signalling of the neuroendocrine hormones; angiotensin II, endothelin-1 and the catecholamines (e.g. noradrenaline).

Angiotensin-II and endothelin-1
Angiotensin-II and endothelin-1 are hormones that bind to the angiotensin (AT) and endothelin (ET) receptors. These are G-protein coupled receptors that act via internal signalling pathways. Through several intermediates, these pathways directly or indirectly increase reactive oxygen species (ROS) production causing accumulation in myocardial cells. This can subsequently induce necrotic cell death, fibrosis, and mitochondrial dysfunction.This has been demonstrated in animal studies. Protein Kinase C (PKC) is an intermediate molecule in the signalling pathway and mice lacking PKC shown resistance to heart failure compared to mice overexpressing PKC which shown heart dysfunction.Targeting the renin–angiotensin (RAAS) system (using angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers) are a well-recognized clinical approach for reversing maladaptive cardiac hypertrophy independently of blood pressure.

Catecholamines
Catecholamines levels increase due to increased sympathetic nervous system activity. Catecholamines can act on the alpha-adrenergic receptors and beta-adrenergic receptors which are G-protein coupled receptors. This binding initiates the same intracellular signalling pathways as angiotensin and endothelin. There is also activation of cAMP and an increase in intracellular Ca2+ which leads to contractile dysfunction and fibrosis.

Others
Hormones are not the only cause of RVH. Hypertrophy can also be caused by mechanical forces, mTOR pathways, nitric oxide and immune cells. Immune cells can cause hypertrophy by inducing inflammation.

Diagnosis
The two main diagnostic tests used to confirm right ventricular hypertrophy are electrocardiography and echocardiography.

Electrocardiography
The use of electrocardiogram (ECG) to measure cardiac chamber hypertrophy is well established but since the left ventricular activity is dominant on the ECG a large degree of RVH is often required for any detectable changes. Nonetheless, the ECG is used to assist with the diagnosis of RVH. A post mortem study on 51 adult male patients concluded that anatomical RVH may be diagnosed using one or more of the following ECG criteria:
Right axis deviation of more than (or equal to) 110° (see hexaxial reference figure)
R-wave dominant over S-wave in V1 or V2
S-wave dominant over R-wave in V6However, the American Heart Association recommended the use of additional diagnostic tests to diagnose RVH because no single criteria or set of criteria were considered sufficiently reliable.

Echocardiography
Echocardiography can be used to directly visualise right ventricular wall thickness. The preferred technique is the trans-oesophageal approach giving a view of 4 chambers. The normal thickness of a right ventricular free wall ranges from 2-5 millimetres, with a value above 5 mm considered to be hypertrophic.

Treatment
It is important to understand that right ventricular hypertrophy in itself is not the main issue, but what right ventricular hypertrophy represents is. Right ventricular hypertrophy is the intermediate stage between increased right ventricular pressure (in the early stages) and right ventricle failure (in the later stages). As such, management of right ventricular hypertrophy is about either preventing the development of right ventricular hypertrophy in the first place, or preventing the progression towards right ventricle failure. Right ventricular hypertrophy in itself has no (pharmacological) treatment.

Treating the cause
Since the main causes of right ventricular hypertrophy is tricuspid regurgitation or pulmonary hypertension (discussed above), management involves treatment of these conditions.
Tricuspid regurgitation is typically treated conservatively by aiming to treat the underlying cause and following up the patient regularly </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Galactosemia and explain in detail? [/INST] Galactosemia (British galactosaemia, from Greek γαλακτόζη + αίμα, meaning galactose + blood, accumulation of galactose in blood) is a rare genetic metabolic disorder that affects an individuals ability to metabolize the sugar galactose properly. Galactosemia follows an autosomal recessive mode of inheritance that confers a deficiency in an enzyme responsible for adequate galactose degradation.
Friedrich Goppert (1870–1927), a German physician,  first described the disease in 1917, with its cause as a defect in galactose metabolism being identified by a group led by Herman Kalckar in 1956. Galactosemia was the second disorder found to be detectable through newborn screening methods by Robert Guthrie.Its incidence is about 1 per 60,000 births for people of European ancestry.  In other populations the incidence rate differs. Galactosaemia is about one hundred times more common (1:480 births) in the Irish Traveller population.

Symptoms
Adults
Infants
Infants may appear asymptomatic at birth, however, upon ingestion of galactose a few days later (via breast and/or formula feeding), children start to experience life-threatening symptoms, which include:
poor feeding, and weight gain
vomiting and diarrhea
hepatocellular damage
lethargy, and hypotoniaProgression of this acute neonatal toxicity syndrome may include the development of sepsis, cataracts, and even pseudotumor cerebri (which may cause a bulging of fontanelle).

Cause
Lactose in food (such as dairy products) is broken down by the enzyme lactase into glucose and galactose. In individuals with galactosemia, the enzymes needed for further metabolism of galactose (Galactokinase and galactose-1-phosphate uridyltransferase) are severely diminished or missing entirely, leading to toxic levels of galactose or galactose 1-phosphate (depending on which enzyme is missing) in various tissues as in the case of classic galactosemia, resulting in hepatomegaly (an enlarged liver), cirrhosis, kidney failure, cataracts, vomiting, seizure, low blood sugar (hypoglycemia), lethargy, brain damage, and ovarian failure. Without treatment, mortality in infants with galactosemia is about 75%.Galactosemia is inherited in an autosomal recessive manner, meaning a child must inherit one defective gene from each parent to show the disease. Heterozygotes are carriers, because they inherit one normal gene and one defective gene. Carriers show no symptoms of galactosemia.

Accumulation of galactose
Reduction to galactitol
In galactosemic patients, the accumulation of galactose becomes the substrate for enzymes that catalyze the polyol pathway of carbohydrate metabolism. The first reaction of this pathway is the reduction of aldoses, types of sugars including galactose, to sugar alcohols. Recent data suggests that aldose reductase is the enzyme responsible for the primary stage of this pathway. Therefore, aldose reductase reduces galactose to its sugar alcohol form, galactitol. Galactitol, however, is not a suitable substrate for the next enzyme in the polyol pathway, polyol dehydrogenase. Thus, galactitol accumulates in body tissues and is excreted in the urine of galactosemic patients. Accumulation of galactitol has been attributed to many of the negative effects of galactosemia, and high concentrations of galactitol have been found in people with classic galactosemia (GALT deficiency or Galactose-1-phosphate uridylyltransferase deficiency), galactokinase deficiency, and epimerase deficiency with glucose.

Oxidation to galactonate
Accumulated galactose can also undergo an alternative reaction: Oxidation to galactonate. The mechanism of galactonate formation is still unclear. However, recent studies suggest that galactose dehydrogenase is responsible for converting galactose to galactonolactone, which then spontaneously or enzymatically converts to galactonate. Once formed, galactonate may enter the pentose phosphate pathway. Thus, Oxidation to galactonate serves as an alternate pathway for metabolizing galactose. This oxidative pathway renders accumulated galactonate less harmful than accumulated galactitol.

Diagnosis
In many states throughout the world, infants routinely undergo newborn screening (NBS) for galactosemia. This allows a diagnosis to be made while the person is still an infant. Infants affected by galactosemia typically present with symptoms of lethargy, vomiting, diarrhea, failure to thrive, and jaundice. None of these symptoms are specific to galactosemia, often leading to diagnostic delays. If the family of the baby has a history of galactosemia, doctors can test prior to birth by taking a sample of fluid from around the fetus (amniocentesis) or from the placenta (chorionic villus sampling or CVS). Galactosemia is normally first detected through newborn screening which if available, is able to diagnose the majority of affected infants.
A galactosemia test is a blood test (from the heel of the infant) or urine test that checks for three enzymes that are needed to change galactose sugar that is found in milk and milk products into glucose, a sugar that the human body uses for energy. A person with galactosemia doesnt have one of these enzymes. This causes high levels of galactose in the blood or urine.Affected children can have serious, irreversible effects or even die within days from birth.  It is important that newborns be screened for metabolic disorders without delay.  Galactosemia can even be detected through NBS before any ingestion of galactose-containing formula or breast milk.
Detection of the disorder through NBS does not depend on protein or lactose ingestion, and, therefore, it should be identified on the first specimen unless the infant has been transfused. A specimen should be taken prior to transfusion.  The enzyme is prone to damage if analysis of the sample is delayed or exposed to high temperatures.  The routine NBS is accurate for detection of galactosemia.  Two screening tests are used to screen infants affected with galactosemia—the Beutlers test and the Hill test </s>