<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Calculus (dental) and can you explain it in depth? [/INST] In dentistry, calculus or tartar is a form of hardened dental plaque. It is caused by precipitation of minerals from saliva and gingival crevicular fluid (GCF) in plaque on the teeth. This process of precipitation kills the bacterial cells within dental plaque, but the rough and hardened surface that is formed provides an ideal surface for further plaque formation. This leads to calculus buildup, which compromises the health of the gingiva (gums). Calculus can form both along the gumline, where it is referred to as supragingival ("above the gum"), and within the narrow sulcus that exists between the teeth and the gingiva, where it is referred to as subgingival ("below the gum").
Calculus formation is associated with a number of clinical manifestations, including bad breath, receding gums and chronically inflamed gingiva. Brushing and flossing can remove plaque from which calculus forms; however, once formed, calculus is too hard (firmly attached) to be removed with a toothbrush. Calculus buildup can be removed with ultrasonic tools or dental hand instruments (such as a periodontal scaler).

Etymology
The word comes from Latin calculus "small stone", from calx "limestone, lime", probably related to Greek χάλιξ chalix "small stone, pebble, rubble", which many trace to a Proto-Indo-European root for "split, break up". Calculus was a term used for various kinds of stones. This spun off many modern words, including "calculate" (use stones for mathematical purposes), and "calculus", which came to be used, in the 18th century, for accidental or incidental mineral buildups in human and animal bodies, like kidney stones and minerals on teeth.Tartar, on the other hand, originates in Greek as well (tartaron), but as the term for the white encrustation inside casks, aka potassium bitartrate commonly known as cream of tartar. This came to be a term used for calcium phosphate on teeth in the early 19th century.

Calculus composition
Calculus is composed of both inorganic (mineral) and organic (cellular and extracellular matrix) components. The mineral proportion of calculus ranges from approximately 40–60%, depending on its location in the dentition, and consists primarily of calcium phosphate crystals organized into four principal mineral phases, listed here in order of decreasing ratio of phosphate to calcium:

whitlockite, Ca9(Mg,Fe)(PO4)6(PO3OH)
hydroxyapatite, Ca5(PO4)3OH
octacalcium phosphate, Ca8H2(PO4)6 · 5 H2O
and brushite, CaHPO4 · 2 H2OThe organic component of calculus is approximately 85% cellular and 15% extracellular matrix. Cell density within dental plaque and calculus is very high, consisting of an estimated 200,000,000 cells per milligram. The cells within calculus are primarily bacterial, but also include at least one species of archaea (Methanobrevibacter oralis) and several species of yeast (e.g., Candida albicans). The organic extracellular matrix in calculus consists primarily of proteins and lipids (fatty acids, triglycerides, glycolipids, and phospholipids), as well as extracellular DNA. Trace amounts of host, dietary, and environmental microdebris are also found within calculus, including salivary proteins, plant DNA, milk proteins, starch granules, textile fibers, and smoke particles.

Calculus formation
The processes of calculus formation from dental plaque are not well understood. Supragingival calculus formation is most abundant on the buccal (cheek) surfaces of the maxillary (upper jaw) molars and on the lingual (tongue) surfaces of the mandibular (lower jaw) incisors. These areas experience high salivary flow because of their proximity to the parotid and sublingual salivary glands. Subgingival calculus forms below the gumline and is typically darkened in color by the presence of black-pigmented bacteria, whose cells are coated in a layer of iron obtained from heme during gingival bleeding. Dental calculus typically forms in incremental layers that are easily visible using both electron microscopy and light microscopy. These layers form during periodic calcification events of the dental plaque, but the timing and triggers of these events are poorly understood. The formation of calculus varies widely among individuals and at different locations within the mouth. Many variables have been identified that influence the formation of dental calculus, including age, gender, ethnic background, diet, location in the oral cavity, oral hygiene, bacterial plaque composition, host genetics, access to professional dental care, physical disabilities, systemic diseases, tobacco use, and drugs and medications.

Clinical significance
Plaque accumulation causes the gingiva to become irritated and inflamed, and this is referred to as gingivitis.  When the gingiva become so irritated that there is a loss of the connective tissue fibers that attach the gums to the teeth and bone that surrounds the tooth, this is known as periodontitis.  Dental plaque is not the sole cause of periodontitis; however it is many times referred to as a primary aetiology.  Plaque that remains in the oral cavity long enough will eventually calcify and become calculus.  Calculus is detrimental to gingival health because it serves as a trap for increased plaque formation and retention; thus, calculus, along with other factors that cause a localized build-up of plaque, is referred to as a secondary aetiology of periodontitis.
When plaque is supragingival, the bacterial content contains a great proportion of aerobic bacteria and yeast, or those bacteria which utilize and can survive in an environment containing oxygen.  Subgingival plaque contains a higher proportion of anaerobic bacteria, or those bacteria which cannot exist in an environment containing oxygen. Several anaerobic plaque bacteria, such as Porphyromonas gingivalis, secrete antigenic proteins that trigger a strong inflammatory response in the periodontium, the specialized tissues that surround and support the teeth. Prolonged inflammation of the periodontium leads to bone loss and weakening of the gingival fibers that attach the teeth to the gums, two major hallmarks of periodontitis.  Supragingival calculus formation is nearly ubiquitous in humans, but to differing degrees. Almost all individuals with periodontitis exhibit considerable subgingival calculus deposits. Dental plaque bacteria have been linked to cardiovascular disease and mothers giving birth to pre-term low weight infants, but there is no conclusive evidence yet that periodontitis is a significant risk factor for either of these two conditions.

Prevention
Toothpaste with pyrophosphates or zinc citrate has been shown to produce a statistically significant reduction in plaque accumulation, but the effect of zinc citrate is so modest that its clinical importance is questionable. Some calculus may form even without plaque deposits, by direct mineralisation of the pellicle.

Calculus in other animals
Calculus formation in other animals is less well studied than in humans, but it is known to form in a wide range of species. Domestic pets, such as dogs and cats, frequently accumulate large calculus deposits. Animals with highly abrasive diets, such as ruminants and equids, rarely form thick deposits and instead tend to form thin calculus deposits that often have a metallic or opalescent sheen. In animals, calculus should not be confused with crown cementum, a layer of calcified dental tissue that encases the tooth root underneath the gingival margin and is gradually lost through periodontal disease.

Archaeological significance
Dental calculus has been shown to contain well preserved microparticles, DNA and protein in archaeological samples. The information these molecules contain can reveal information about the oral microbiome of the host and the presence of pathogens. It is also possible to identify dietary sources as well as study dietary shifts and occasionally evidence of craft activities.

Sub-gingival calculus formation and chemical dissolution
Sub-gingival calculus is composed almost entirely of two components: fossilized anaerobic bacteria whose biological composition has been replaced by calcium phosphate salts, and calcium phosphate salts that have joined the fossilized bacteria in calculus formations.  The initial attachment mechanism and the development of mature calculus formations are based on electrical charge. Unlike calcium phosphate, the primary component of teeth, calcium phosphate salts exist as electrically unstable ions. The following minerals are detectable in calculus by X-ray diffraction: brushite (CaHPO4 · 2 H2O), octacalcium phosphate (Ca8H2(PO4)6 · 5 H2O), magnesium-containing whitlockite (Ca9(Mg,Fe)(PO4)6(PO3OH)), and carbonate-containing hydroxyapatite (approximately Ca5(PO4)3OH but containing some carbonate).The reason fossilized bacteria are initially attracted to one part of the subgingival tooth surface over another is not fully understood; once the first layer is attached, ionized calculus components are naturally attracted to the same places due to electrical charge. The fossilized bacteria pile on top of one another, in a rather haphazard manner. All the while, free-floating ionic components fill in the gaps left by the fossilized bacteria. The resultant hardened structure can be compared to concrete; with the fossilized bacteria playing the role of aggregate, and the smaller calcium phosphate salts being the cement.  The once purely electrical association of fossilized bacteria then becomes mechanical, with the introduction of free-floating calcium phosphate salts.  The "hardened" calculus formations are at the heart of periodontal disease and treatment.

Removal of calculus after formation
The College of Registered Dental Hygienists of Alberta defines a dental hygienist as "a health care professional whose work focuses on the oral health of an individual or community." These dental professionals aim to improve oral health by educating patients on the prevention and management of oral disease. Dental hygienists can be found performing oral health services in various settings, including private dental offices, schools, and other community settings, such as long-term care facilities. As mentioned above in the clinical significance section, plaque and calculus deposits are a major etiological factor in the development and progression of oral disease. An important part of the scope of practice of a dental hygienist is the removal of plaque and calculus deposits. This is achieved through the use of specifically designed instruments for debridement of tooth surfaces. Treatment with these types of instruments is necessary as calculus deposits cannot be removed by brushing or flossing alone. To effectively manage disease or maintain oral health, thorough removal of calculus deposits should be completed at frequent intervals. The recommended frequency of dental hygiene treatment can be made by a registered professional, and is dependent on individual patient needs. Factors that are taken into consideration include an individuals overall health status, tobacco use, amount of calculus present, and adherence to a professionally recommended home care routine.Hand instruments are specially designed tools used by dental professionals to remove plaque and calculus deposits that have formed on the teeth. These tools include scalers, curettes, jaquettes, hoes, files and chisels. Each type of tool is designed to be used in specific areas of the mouth. Some commonly used instruments include sickle scalers which are designed with a pointed tip and are mainly used supragingivally. Curettes are mainly used to remove subgingival calculus, smooth root surfaces and to clean out periodontal pockets. Curettes can be divided into two subgroups: universals and area specific instruments. Universal curettes can be used in multiple areas, while area specific instruments are designed for select tooth surfaces. Gracey curettes are a popular type of area specific curettes. Due to their design, area specific curettes allow for better adaptation to the root surface and can be slightly more effective than universals. Hoes, chisels, and files are less widely used than scalers and curettes. These are beneficial when removing large amounts of calculus or tenacious calculus that cannot be removed with a curette or scaler alone. Chisels and hoes are used to remove bands of calculus, whereas files are used to crush burnished or tenacious calculus.For hand instrumentation to be effective and efficient, it is important for clinicians to ensure that the instruments being used are sharp. It is also important for the clinician to understand the design of the hand instruments to be able to adapt them properly.Ultrasonic scalers, also known as power scalers, are effective in removing calculus, stain, and plaque. These scalers are also useful for root planing, curettage, and surgical debridement. Not only is tenacious calculus and stain removed more effectively with ultrasonic scalers than with hand instrumentation alone, it is evident that the most satisfactory clinical results are when ultrasonics are used in adjunct to hand instrumentation. There are two types of ultrasonic scalers; piezoelectric and magnetostrictive. Oscillating material in both of these handpieces cause the tip of the scaler to vibrate at high speeds, between 18,000 and 50,000 Hz. The tip of each scaler uses a different vibration pattern for removal of calculus. The magnetostrictive power scaler vibration is elliptical, activating all sides of the tip, whereas the piezoelectric vibration is linear and is more active on the two sides of the tip.Special tips for ultrasonic scalers are designed to address different areas of the mouth and varying amounts of calculus buildup. Larger tips are used for heavy subgingival or supragingival calculus deposits, whereas thinner tips are designed more for definitive subgingival debridement. As the high frequency vibrations loosen calculus and plaque, heat is generated at the tip </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Endogenous depression and can you explain it in depth? [/INST] Endogenous depression (melancholia) is an atypical sub-class of major depressive disorder (clinical depression). It could be caused by genetic and biological factors. Endogenous depression occurs due to the presence of an internal (cognitive, biological) stressor instead of an external (social, environmental) stressor. Endogenous depression includes patients with treatment-resistant, non-psychotic, major depressive disorder, characterized by abnormal behavior of the endogenous opioid system but not the monoaminergic system. Symptoms vary in severity, type, and frequency and can be attributed to cognitive, social, biological, or environmental factors that result in persistent feelings of sadness and distress. Since symptoms are due to a biological phenomenon, prevalence rates tend to be higher in older adults. Due to this fact, biological-focused treatment plans are often used in therapy to ensure the best prognosis.Endogenous depression was part of the Kraepelinian dichotomy system.

Signs and symptoms
The forefront indication that a depressive episode is manifesting is the sudden loss of energy or motivation in daily routines. When this occurs, it is not uncommon for individuals to seek medical attention with excessive worrying or anxiety that a more severe, physiological disease may be the underlying issue. However, without an actual disease present, this neurotic thinking often results in severe anxiety, sleep disturbance, and mood swings which may hinder social relationships. Individuals with endogenous depression may experience inconsistencies in symptom severity  which is often the reason for delayed treatment. If left untreated, symptoms may progress to a major depressive episode.

Risk factors
Endogenous depression occurs as the results of an internal stressor—commonly cognitive or biological—and not an external factor. Potential risk factors include these cognitive or biological factors. Patients with endogenous depression often are more likely to have a positive family history of disorders and fewer psychosocial and environmental factors that cause their symptoms. A family history of depression and perceived poor intimate relationships are internal risk factors associated with this type of depression </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Catecholaminergic polymorphic ventricular tachycardia and can you explain it in depth? [/INST] Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited genetic disorder that predisposes those affected to potentially life-threatening abnormal heart rhythms or arrhythmias. The arrhythmias seen in CPVT typically occur during exercise or at times of emotional stress, and classically take the form of bidirectional ventricular tachycardia or ventricular fibrillation. Those affected may be asymptomatic, but they may also experience blackouts or even sudden cardiac death.
CPVT is caused by genetic mutations affecting proteins that regulate the concentrations of calcium within cardiac muscle cells. The most commonly identified gene is RYR2, which encodes a protein included in an ion channel known as the ryanodine receptor; this channel releases calcium from a cells internal calcium store, the sarcoplasmic reticulum, during every heartbeat.
CPVT is often diagnosed from an ECG recorded during an exercise tolerance test, but it may also be diagnosed with a genetic test. The condition is treated with medication including beta-adrenoceptor blockers or flecainide, or with surgical procedures including sympathetic denervation and implantation of a defibrillator. It is thought to affect as many as one in ten thousand people and is estimated to cause 15% of all unexplained sudden cardiac deaths in young people. The condition was first defined in 1978, and the underlying genetics were described in 2001.

Signs and symptoms
Although individuals with CPVT may not experience any symptoms, the most commonly reported symptoms are blackouts or sudden loss of consciousness, referred to as syncope. These blackouts often occur during exercise or as a response to emotional stress—situations in which chemical messengers known as catecholamines, such as adrenaline, are released within the body. Blackouts may be misinterpreted as being caused by simple faints or epilepsy, often leading to delays in reaching the correct diagnosis. In a third of those affected, the first manifestation of the disease may be cardiac arrest, potentially leading to sudden death. This can occur in very young children, presenting as sudden infant death syndrome or cot death. Approximately 30% of those with CPVT will have a family member who has experienced blackouts, seizures, or sudden death in response to exercise or stress.In those with CPVT, catecholamine release can lead to an abnormal heart rhythm or arrhythmia known as ventricular tachycardia. The ventricular tachycardia may take a characteristic form known as bidirectional ventricular tachycardia. This form of ventricular tachycardia occurs relatively infrequently, but if seen is suggestive of an underlying diagnosis of CPVT or the related condition Andersen-Tawil syndrome. These ventricular arrhythmias in some cases terminate by themselves, causing a blackout from which the person then recovers. However, if the abnormal heart rhythm continues, it can degenerate into a more dangerous arrhythmia known as ventricular fibrillation causing a cardiac arrest and, if untreated, sudden death.There are typically very few abnormal signs on clinical examination in persons with CPVT. However, those with CPVT may develop a less serious heart rhythm disturbance called atrial fibrillation, which can be detected on examination as an irregular pulse. Furthermore, approximately 20% of those with CPVT have a slow resting heart rate known as a sinus bradycardia.

Mechanism
Excitation-contraction coupling
The arrhythmias that those with CPVT experience are caused by abnormalities in the way that cardiac muscle cells control their levels of calcium. Calcium interacts with the protein fibres or myofibrils inside the cell that allow the cell to contract, and the concentration of calcium within each cell needs to be tightly regulated. During each heartbeat, the concentration of calcium must rise to allow the muscle to contract and then fall to allow the muscle to relax, a process achieved by using a store within the cell known as the sarcoplasmic reticulum.

At the start of each heartbeat, calcium is released from the sarcoplasmic reticulum through specialised channels known as ryanodine receptors. Ryanodine receptors open when the concentration of calcium near the channel increases. This happens when, in response to an electrical signal from the cell membrane called an action potential, a small amount of calcium flows across the cell membrane into the cell through L-type calcium channels, many of which are located on specialised inpouchings of the membrane called T-tubules designed to bring these surface ion channels close to the sarcoplasmic reticulum.The increase in calcium concentration triggers ryanodine receptors on the sarcoplasmic reticulum to release a puff of calcium known as a calcium spark. Each spark triggers the release of further sparks from neighbouring ryanodine receptors to create an organised rise of calcium throughout the cell known as a calcium transient. At the end of each heartbeat, calcium is pumped back by a protein called SERCA along with its regulatory protein phospholamban. The calcium is then held within the sarcoplasmic reticulum by a protein called calsequestrin.Fine-tuning of this process can be achieved by phosphorylating these proteins. As an example, during exercise catecholamines activate beta-adrenoceptors on the cell surface, which trigger protein kinase A to phosphorylate the L-type calcium channel, increasing the flow of calcium into the cell. Simultaneously, phosphorylation of the regulatory protein phospholamban causes more calcium to be drawn up into the sarcoplasmic reticulum. The overall effect of this is to generate a larger calcium transient with each beat, leading to a more forceful contraction.

Calcium-dependent arrhythmias
Alterations to the proteins involved in excitation-contraction coupling can disrupt this carefully regulated process. In those with CPVT, the normally tight regulation of calcium can become deranged, leading to arrhythmias. While calcium is generally released from the sarcoplasmic reticulum in response to an action potential, calcium sparks can also occur spontaneously. In a healthy heart, a spontaneous calcium spark is generally an isolated event and goes no further, but if ryanodine receptors or the proteins that regulate them are abnormal, these sparks can trigger releases from neighbouring ryanodine receptors which spread throughout the cell as a calcium wave. These calcium waves are much more likely to occur when cardiac muscle cells are stimulated by catecholamines such as adrenaline, which increase the concentration of calcium within the sarcoplasmic reticulum and sensitise the ryanodine receptors. The uncontrolled wave of calcium can be forced out through the cell membrane via the sodium-calcium exchanger, causing an electric current known as a delayed afterdepolarisation. Afterdepolarisations, if large enough, can trigger additional action potentials, premature ventricular contractions, or sustained arrhythmias.

Causes
CPVT can be caused by mutations in several genes, all of which are responsible for regulating the concentrations of calcium within cardiac muscle cells. The most commonly identified genetic mutation in CPVT is a mutation in the RYR2 gene that encodes the cardiac ryanodine receptor, responsible for releasing calcium from the sarcoplasmic reticulum. Mutations associated with CPVT have also been identified in the CASQ2 gene which encodes calsequestrin, a protein that binds calcium within the sarcoplasmic reticulum. Other genes associated with rarer, atypical forms of CPVT include TECRL encoding Trans-2,3-enoyl-CoA reductase-like protein, CALM1, CALM2 and CALM3 all encoding Calmodulin, and TRDN encoding Triadin.

CPVT1: RYR2 mutations
The most commonly identified genetic mutations in those with CPVT occur in the RYR2 gene which encodes the cardiac ryanodine receptor. Mutations in this gene lead to an autosomal dominant form of typical CPVT known as CPVT1. While the precise effect differs between specific mutations in this gene, many RYR2 mutations cause the ryanodine receptor to open in response to lower concentrations of calcium—the threshold for calcium release is lower. As a result, the sarcoplasmic reticulum spontaneously releases calcium through these abnormal ryanodine receptors when the concentration of calcium within the sarcoplasmic reticulum rises, a process known as store-overload induced calcium release. Sarcoplasmic reticulum calcium content increases in response to stimulation from catecholamines, explaining why arrhythmias in those with CPVT occur at times when catecholamine levels are elevated. Some suggest that the increased sensitivity to calcium occurs only when the ryanodine receptor is phosphorylated by protein kinase A, while other suggest that the increased sensitivity also occurs under resting conditions.Two theories have been proposed for the underlying mechanism by which mutations in RYR2 promote store-overload induced calcium release: domain unzipping and FKBP12.6 unbinding. Domain unzipping refers to the separation of two important regions of the ryanodine receptor, the N-terminus and the central domain. Through this mechanism, a mutation might destabilise the ryanodine receptors closed state and increase its sensitivity to calcium. A second potential mechanism involves the regulatory protein FKBP12.6, a protein that binds to and stabilises the ryanodine receptor. The binding of FKBP12.6 to the ryanodine receptor is regulated by phosphorylation. Phosphorylation by protein kinase A leads to the dissociation of FKBP12.6, rendering the ryanodine receptor more sensitive to cytosolic calcium. RYR2 mutations may interfere with the binding of FKB12.6 to the ryanodine receptor and thereby increase sensitivity to calcium. It is likely that FKBP12.6 plays a role in some CPVT mutations but not others.RYR2 mutations responsible for CPVT are mainly found in four major domains of the gene. Mutations affecting domains III and IV of the gene (corresponding to the N-terminal region of the protein and cytosolic linker respectively) occur in 46% of cases. Mutations are seen less frequently affecting domains I and II, both of which encode sections of the N-terminal region of the protein. RYR2 mutations associated with CPVT that occur outside these four domains are very rare, being responsible for as few as 10% of reported cases. RYR2 mutations are most often missense mutations, such as single nucleotide substitutions causing one amino acid to be replaced by another, although in-frame substitutions and duplications have been described. More damaging nonsense mutations have not been reported in association with CPVT, potentially because these variants may lead to different cardiac diseases such as cardiomyopathies.

CPVT2: CASQ2 mutations
Mutations in the CASQ2 gene are associated with an autosomal recessive form of typical CPVT known as CPVT2. This gene encodes calsequestrin, the major calcium-binding protein and calcium buffer within the sarcoplasmic reticulum. Mutations in CASQ2 account for only 3-5% of cases of CPVT. Fourteen mutations in CASQ2 have been identified in association with CPVT. Two of these are nonsense mutations causing the protein to be abnormally short, and two are deletion mutations, while ten are missense mutations that substitute one amino acid for another in the chain forming the protein.Mutations in CASQ2 cause a decrease in sarcoplasmic reticulum calcium-buffering capacity. This means that abrupt changes in sarcoplasmic total calcium will be buffered less and therefore translate to larger shifts in free calcium. The higher peaks in free calcium have greater potential to cause store-overload induced calcium release from the sarcoplasmic reticulum, leading to afterdepolarisations.In addition to its role as a calcium buffer, calsequestrin also regulates the release of calcium from the sarcoplasmic reticulum by directly modulating ryanodine receptors. When the concentration of calcium is low, calsequestrin monomers form a complex with the proteins triadin and junctin, which inhibit ryanodine receptors. However, at high calcium concentrations, calsequestrin forms polymers that dissociate from the ryanodine receptor channel complex, removing the inhibitory response and increasing the sensitivity of the ryanodine receptor to spontaneously releasing calcium.Decreased CASQ2 is also associated with high levels of calreticulin, a protein which among other roles regulates the reuptake of calcium into the sarcoplasmic reticulum by SERCA. In the absence of CASQ2, calreticulin levels increase and provide some compensatory calcium binding within the sarcoplasmic reticulum. It is possible that calreticulin may contribute to the generation of arrhythmias seen in association with CASQ2 mutations.

Diagnosis
CPVT may be challenging to diagnose as the structure of the heart appears normal in those affected by the condition when assessed using an echocardiogram, cardiac MRI scan or cardiac CT scan, while the electrical function of the heart also appears normal at rest when assessed using a standard 12-lead ECG. However, in response to exercise or catecholamines such as adrenaline, abnormal heart rhythms such as bidirectional ventricular tachycardia or frequent polymorphic ventricular ectopic beats may be seen.

12-lead ECG
The resting 12-lead ECG is a useful test to differentiate CPVT from other electrical diseases of the heart that can cause similar abnormal heart rhythms. Unlike conditions such as long QT syndrome and Brugada syndrome, the resting 12-lead ECG in those with CPVT is generally normal. However, approximately 20% of those affected have a slow resting heart rate or sinus bradycardia.

Exercise and other provocative testing
Exercise testing, commonly performed on a treadmill or stationary bicycle, can help to diagnose CPVT. During the test, those with CPVT often experience ectopic beats, which may progress to bidirectional and then polymorphic ventricular tachycardia as the intensity of exercise increases. Some of those suspected of having CPVT, such as young children, may not be able to perform an exercise tolerance test. In these cases, alternative forms of testing include adrenaline provocation testing, during which adrenaline is infused into a vein at gradually increasing doses under close supervision and ECG monitoring. Additionally, long term or Holter ECG monitoring can be performed, although this form of testing is less likely to detect an arrhythmia. Invasive electrophysiological studies do not provide useful information to help diagnose CPVT or to assess the risk of life-threatening arrhythmias.

Genetic testing
CPVT can also be diagnosed by identifying a disease-causing mutation in a gene associated with CPVT using genetic testing. This technique may be the only way to identify the condition in someone suspected of having CPVT who has died, and in this case may be known as a molecular autopsy.

Treatment
Treatments for CPVT aim to prevent lethal abnormal heart rhythms from occurring, and to rapidly restore a normal rhythm if they do occur. As the arrhythmias in CPVT generally occur at times when the heart is exposed to high levels of adrenaline or other similar chemical messengers (catecholamines), many treatments for CPVT aim to lower the levels of catecholamines the heart is exposed to or block their effects on the heart.The first-line treatment for those with CPVT involves lifestyle advice. This includes avoiding competitive sports, very strenuous exercise and highly stressful environments, as high levels of adrenaline can occur in these settings, which can provoke arrhythmias.

Medication
Several medications can be useful for those with CPVT. The mainstays of treatment are beta blockers, which block the effects of adrenaline and other catecholamines on the heart, reducing the chance of abnormal heart rhythms developing. Of all the beta blockers, nadolol has been proven to be the most effective for treating CPVT. This drug lowers the heart rate to a greater extent than other beta blockers and only needs to be taken once daily, reducing the risk of missed doses. Nadolol may be difficult to obtain and is not available in all countries, and an alternative beta blocker suitable for use in CPVT may be propranolol, which however has a more complex dosing regimen. Recently published data suggest that the use of selective beta blockers, such as atenolol, bisoprolol, or metoprolol, is associated with very high treatment failure rates.Flecainide is a class 1c antiarrhythmic drug that is recommended for those with CPVT who experience abnormal heart rhythms despite taking a beta blocker. Flecainide reduces the risk of arrhythmias in those with CPVT, but it remains uncertain how Flecainide achieves this. Some have suggested that Flecainide directly interacts with the cardiac ryanodine receptor, which is frequently abnormal in those with CPVT, while other suggest that the anti-arrhythmic effects of Flecainide rely entirely on its sodium channel blocking effects.Verapamil is a calcium channel antagonist that, when combined with a beta blocker, may reduce the risk of arrhythmias in patients with CPVT. Propafenone is another antiarrhythmic that may reduce the risk of arrhythmias, potentially through direct effects on the ryanodine receptor.

Sympathetic denervation
Some persons with CPVT continue to experience life-threatening arrhythmias despite pharmaceutical therapy. In this case a surgical procedure can be used to affect nerves supplying the heart that communicate using catecholamines. A collection of nerves known as the sympathetic nervous system supply the heart as well as other organs. These nerves, when activated, encourage the heart to beat harder and faster. The sympathetic nervous system uses noradrenaline, a catecholamine, as a chemical messenger or neurotransmitter, which can promote arrhythmias in those with CPVT.To prevent this, a region of the sympathetic nervous system can be intentionally damaged in an operation known as cardiac sympathetic denervation or sympathectomy. While the sympathetic nervous system feeds into the heart from both sides, often only the left sided nerves are targeted during sympathectomy, although destruction of the nerves on both sides may be required. Through this process, sympathectomy is effective at decreasing, but not abolishing, the risk of further life-threatening arrhythmias.

Implantable cardioverter-defibrillator
While medication and sympathectomy aim to prevent abnormal heart rhythms from occurring in the first place, an implantable defibrillator (ICD) may be used to treat arrhythmias that medication has failed to prevent and restore a normal heart rhythm. These devices, usually implanted under the skin at the front of the chest below the shoulder, can continuously monitor the heart for abnormal heart rhythms. If a life-threatening arrhythmia is detected, the device can deliver a small electric shock to terminate the abnormal rhythm and restart the heart.Implantable defibrillators are often recommended for those with CPVT who have experienced blackouts, ventricular arrhythmias or cardiac arrest despite taking appropriate medication. These devices are life-saving, as it has been shown that their use confers a significant survival benefit in patients with CPVT </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Complete androgen insensitivity syndrome and can you explain it in depth? [/INST] Complete androgen insensitivity syndrome (CAIS) is an AIS condition that results in the complete inability of the cell to respond to androgens.  As such, the insensitivity to androgens is only clinically significant when it occurs in individuals who are exposed to significant amounts of testosterone at some point in their lives.  The unresponsiveness of the cell to the presence of androgenic hormones prevents the masculinization of male genitalia in the developing fetus, as well as the development of male secondary sexual characteristics at puberty, but does allow, without significant impairment, female genital and sexual development in those with the condition.
All human fetuses begin fetal development looking similar, with both the Müllerian duct system (female) and the Wolffian duct system (male) developing.  It is at the seventh week of gestation that the bodies of unaffected individuals with the XY karyotype begin their masculinization: i.e., the Wolffian duct system is promoted and the Müllerian duct system is suppressed (the reverse happens with typically developing females). This process is triggered by androgens produced by the gonads, which in individuals with the XX karyotype had earlier become ovaries, but in XY individuals typically had become testicles due to the presence of the Y Chromosome. The cells of unaffected XY individuals then masculinize by, among other things, enlarging the genital tubercle into a penis, which in females becomes the clitoris, while what in females becomes the labia fuses to become the scrotum of males (where the testicles will later descend).
Individuals affected by CAIS develop a normal external female habitus, despite the presence of a Y chromosome, but internally, they will lack a uterus, and the vaginal cavity will be shallow, while the gonads, having been turned into testicles rather than ovaries in the earlier separate process also triggered by their Y chromosome, will remain undescended in the place where the ovaries would have been. This results not only in infertility in individuals with CAIS, but also presents a risk of gonadal cancer later on in life.CAIS is one of the three categories of androgen insensitivity syndrome (AIS) since AIS is differentiated according to the degree of genital masculinization: complete androgen insensitivity syndrome (CAIS) when the external genitalia is that of a typical female, mild androgen insensitivity syndrome (MAIS) when the external genitalia is that of a typical male, and partial androgen insensitivity syndrome (PAIS) when the external genitalia is partially, but not fully masculinized.Androgen insensitivity syndrome is the largest single entity that leads to 46, XY undermasculinization.

Signs and symptoms
Physical
Individuals with complete androgen insensitivity syndrome (grades 6 and 7 on the Quigley scale) are born phenotypically female, without any signs of genital masculinization, despite having a 46,XY karyotype.  Symptoms of CAIS do not appear until puberty, which may be slightly delayed, but is otherwise normal except for absent menses and diminished or absent secondary terminal hair.  Axillary hair (i.e. armpit hair) fails to develop in one third of all cases.  External genitalia is normal, although the labia and clitoris are sometimes underdeveloped.  Vaginal depth varies widely for CAIS women, but is typically shorter than unaffected women; one study of eight women with CAIS measured the average vaginal depth to be 5.9 cm  (vs. 11.1 ± 1.0 cm for unaffected women ).  In some extreme cases, the vagina has been reported to be aplastic (resembling a "dimple"), though the exact incidence of this is unknown.The gonads in these women are not ovaries, but instead, are testes; during the embryonic stage of development, testes form in an androgen-independent process that occurs due to the influence of the SRY gene on the Y chromosome.  They may be located intra-abdominally, at the internal inguinal ring, or may herniate into the labia majora, often leading to the discovery of the condition.  Testes in affected women have been found to be atrophic upon gonadectomy.Testosterone produced by the testes cannot be directly used due to the mutant androgen receptor that characterizes CAIS; instead, it is aromatized into estrogen, which effectively feminizes the body and accounts for the normal female phenotype observed in CAIS. However, up to 5% of individuals with CAIS do not have an AR mutation. The receptor in question is encoded by the AR gene located on the X chromosome at Xq11–12. At least 15 different mutations were known in 2003, and they are all recessive, which makes the disease to follow X-linked recessive inheritance.Immature sperm cells in the testes do not mature past an early stage, as sensitivity to androgens is required in order for spermatogenesis to complete.  Germ cell malignancy risk, once thought to be relatively high, is now thought to be approximately 2%.  Wolffian structures (the epididymides, vasa deferentia, and seminal vesicles) are typically absent, but will develop at least partially in approximately 30% of cases, depending on which mutation is causing the CAIS. The prostate, like the external male genitalia, cannot masculinize in the absence of androgen receptor function, and thus remains in the female form.The Müllerian system (the fallopian tubes, uterus, and upper portion of the vagina) typically regresses due to the presence of anti-Müllerian hormone originating from the Sertoli cells of the testes.  These women are thus born without fallopian tubes, a cervix, or a uterus, and the vagina ends "blindly" in a pouch.  Müllerian regression does not fully complete in approximately one third of all cases, resulting in Müllerian "remnants".  Although rare, a few cases of women with CAIS and fully developed Müllerian structures have been reported.  In one exceptional case, a 22-year-old with CAIS was found to have a normal cervix, uterus, and fallopian tubes.  In an unrelated case, a fully developed uterus was found in a 22-year-old adult with CAIS.Other subtle differences that have been reported include slightly longer limbs and larger hands and feet due to a proportionally greater stature than unaffected women, larger teeth, minimal or no acne, well developed breasts, and a greater incidence of meibomian gland dysfunction (i.e. dry eye syndromes and light sensitivity).

Endocrine
Hormone levels have been reported in gonadally intact CAIS women in a number of studies. Hormone levels are similar to those of males, including high testosterone levels and relatively low estradiol levels. However, luteinizing hormone (LH) levels are elevated while sex hormone-binding globulin (SHBG) levels are more consistent with those of females. Women with CAIS have low levels of progesterone similarly to males. The production rates of testosterone, estradiol, and estrone have been reported to be higher in gonadally intact CAIS women than in men.

Comorbidity
All forms of androgen insensitivity, including CAIS, are associated with infertility, though exceptions have been reported for both the mild and partial forms.CAIS is associated with a decreased bone mineral density.  Some have hypothesized that the decreased bone mineral density observed in women with CAIS is related to the timing of gonadectomy and inadequate estrogen supplementation.  However, recent studies show that bone mineral density is similar whether gonadectomy occurs before or after puberty, and is decreased despite estrogen supplementation, leading some to hypothesize that the deficiency is directly attributable to the role of androgens in bone mineralization.CAIS is also associated with an increased risk for gonadal tumors (e.g. germ cell malignancy) in adulthood if gonadectomy is not performed.  The risk of malignant germ cell tumors in women with CAIS increases with age and has been estimated to be 3.6% at 25 years and 33% at 50 years.  The incidence of gonadal tumors in childhood is thought to be relatively low; a recent review of the medical literature  found that only three cases of malignant germ cell tumors in prepubescent girls have been reported in association with CAIS in the last 100 years.  Some have estimated the incidence of germ cell malignancy to be as low as 0.8% before puberty.Vaginal hypoplasia, a relatively frequent finding in CAIS and some forms of PAIS, is associated with sexual difficulties including vaginal penetration difficulties and dyspareunia.At least one study indicates that individuals with an intersex condition may be more prone to psychological difficulties, due at least in part to parental attitudes and behaviors, and concludes that preventative long-term psychological counseling for parents as well as for affected individuals should be initiated at the time of diagnosis.
Lifespan is not thought to be affected by AIS.Despite the well-developed breasts in CAIS women, and for reasons that are not well-understood, breast cancer has never been reported in CAIS women and does not seem to occur or occurs only rarely. Only a case report of juvenile fibroadenoma exists. A few cases of breast cancer have been reported in individuals with partial androgen insensitivity syndrome however.

Diagnosis
CAIS can only be diagnosed in normal phenotypic females.  It is not usually suspected unless the menses fail to develop at puberty, or an inguinal hernia presents during premenarche.  As many as 1–2% of prepubertal girls that present with an inguinal hernia will also have CAIS.A diagnosis of CAIS or Swyer syndrome can be made in utero by comparing a karyotype obtained by amniocentesis with the external genitalia of the fetus during a prenatal ultrasound.  Many infants with CAIS do not experience the normal, spontaneous neonatal testosterone surge, a fact which can be diagnostically exploited by obtaining baseline luteinizing hormone and testosterone measurements, followed by a human chorionic gonadotropin (hGC) stimulation test.The main differentials for CAIS are complete gonadal dysgenesis (Swyer syndrome) and Müllerian agenesis (Mayer-Rokitansky-Kuster-Hauser syndrome or MRKH).  Both CAIS and Swyer syndrome are associated with a 46,XY karyotype, whereas MRKH is not; MRKH can thus be ruled out by checking for the presence of a Y chromosome, which can be done either by fluorescence in situ hybridization (FISH) analysis or on full karyotype.  Swyer syndrome is distinguished by the presence of a uterus, poor breast development and shorter stature.  The diagnosis of CAIS is confirmed when androgen receptor (AR) gene sequencing reveals a mutation, although up to 5% of individuals with CAIS do not have an AR mutation.Up until the 1990s, a CAIS diagnosis was often hidden from the affected individual, the individuals family, or both.  It is current practice to disclose the genotype at the time of diagnosis, particularly when the affected girl is at least of adolescent age.  If the affected individual is a child or infant, it is generally up to the parents, often in conjunction with a psychologist, to decide when to disclose the diagnosis.

Management
Management of AIS is currently limited to symptomatic management; methods to correct a malfunctioning androgen receptor protein that result from an AR gene mutation are not currently available.  Areas of management include sex assignment, genitoplasty, gonadectomy in relation to tumor risk, hormone replacement therapy, and genetic and psychological counseling. Non-consensual interventions are still often performed, although general awareness on the resulting psychological traumatization is rising.

Sex assignment and sexuality
Most individuals with CAIS are raised as females.  They are born phenotypically female and are usually heterosexual with a female gender identity;  However, at least two case studies have reported male gender identity in individuals with CAIS.

Dilation therapy
Most cases of vaginal hypoplasia associated with CAIS can be corrected using non-surgical pressure dilation methods.  The elastic nature of vaginal tissue, as demonstrated by its ability to accommodate the differences in size between a tampon, a penis, and a babys head, make dilation possible even in cases when the vaginal depth is significantly compromised.  Treatment compliance is thought to be critical to achieve satisfactory results.  Dilation can also be achieved via the Vecchietti procedure, which stretches vaginal tissues into a functional vagina using a traction device that is anchored to the abdominal wall, subperitoneal sutures, and a mold that is placed against the vaginal dimple.  Vaginal stretching occurs by increasing the tension on the sutures, which is performed daily.  The non-operative pressure dilation method is currently recommended as the first choice, since it is non-invasive, and highly successful.  Vaginal dilation should not be performed before puberty.

Gonadectomy
While it is often recommended that women with CAIS eventually undergo gonadectomy to mitigate cancer risk, there are differing opinions regarding the necessity and timing of gonadectomy.  The risk of malignant germ cell tumors in women with CAIS increases with age and has been estimated to be 3.6% at 25 years and 33% at 50 years.  However, only three cases of malignant germ cell tumors in prepubescent girls with CAIS have been reported in the last 100 years.  The youngest of these girls was 14 years old.  If gonadectomy is performed early, then puberty must be artificially induced using gradually increasing doses of estrogen.  If gonadectomy is performed late, then puberty will occur on its own, due to the aromatization of testosterone into estrogen.  At least one organization, the Australasian Paediatric Endocrine Group, classifies the cancer risk associated with CAIS as low enough to recommend against gonadectomy, although it warns that the cancer risk is still elevated above the general population, and that ongoing cancer monitoring is essential.  Some choose to perform gonadectomy if and when inguinal hernia presents.  Estrogen replacement therapy is critical to minimize bone mineral density deficiencies later in life.

Hormone replacement therapy
Some have hypothesized that supraphysiological levels of estrogen may reduce the diminished bone mineral density associated with CAIS.  Data has been published that suggests affected women who were not compliant with estrogen replacement therapy, or who had a lapse in estrogen replacement, experienced a more significant loss of bone mineral density.  Progestin replacement therapy is seldom initiated, due to the absence of a uterus.  Androgen replacement has been reported to increase a sense of well-being in gonadectomized women with CAIS, although the mechanism by which this benefit is achieved is not well understood.

Counseling
It is no longer common practice to hide a diagnosis of CAIS from the affected individual or her family.  Parents of children with CAIS need considerable support in planning and implementing disclosure for their child once the diagnosis has been established.  For parents with young children, information disclosure is an ongoing, collaborative process requiring an individualized approach that evolves in concordance with the childs cognitive and psychological development.  In all cases, the assistance of a psychologist experienced in the subject is recommended.

Neovaginal construction
Many surgical procedures have been developed to create a neovagina, as none of them is ideal.  Surgical intervention should only be considered after non-surgical pressure dilation methods have failed to produce a satisfactory result.  Neovaginoplasty can be performed using skin grafts, a segment of bowel, ileum, peritoneum, an absorbable adhesion barrier (Interceed, made by Johnson & Johnson), buccal mucosa, amnion, dura mater. or with the support of vaginal stents/expanders.  Success of such methods should be determined by sexual function, and not just by vaginal length, as has been done in the past.  Ileal or cecal segments may be problematic because of a shorter mesentery, which may produce tension on the neovagina, leading to stenosis.  The sigmoid neovagina is thought to be self-lubricating, without the excess mucus production associated with segments of small bowel </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Buschke–Ollendorff syndrome and can you explain it in depth? [/INST] Buschke–Ollendorff syndrome (BOS) is a rare genetic disorder associated with LEMD3. It is believed to be inherited in an autosomal dominant manner. It is named for Abraham Buschke and Helene Ollendorff Curth, who described it in a 45-year-old woman. Its frequency is almost 1 case per every 20,000 people, and it is equally found in both males and females.

Signs and symptoms
The signs and symptoms of this condition are consistent with the following (possible complications include aortic stenosis and hearing loss):

Osteopoikilosis
Bone pain
Connective tissue nevi
Metaphysis abnormality

Pathogenesis
Buschke–Ollendorff syndrome is caused by one important factor: mutations in the LEMD3 gene (12q14), located on chromosome 12.Among the important aspects of Buschke–Ollendorff syndrome condition, genetically speaking are:

LEMD3 (protein) referred also as MAN1, is an important protein in inner nuclear membrane.
LEMD3 gene gives instructions for producing protein that controls signaling for transforming growth factor-beta.
LEMD3 gene helps in the bone morphogenic protein pathway
Both of the above pathways help grow new bone cells
BMP and TGF-β pathways controls SMADs proteins, which then bind to DNA
LEMD3 once mutated, causes a reduction of the protein, which in turn causes excess of the above two pathways.

Diagnosis
The diagnosis of this condition can be ascertained via several techniques one such method is genetic testing, as well as:
X-ray
Ultrasound
Histological test

Differential diagnosis
The differential diagnosis for an individual believed to have Buschke–Ollendorff syndrome is the following:
Melorheostosis
Sclerotic bone metastases.

Treatment
In terms of the treatment of Buschke–Ollendorff syndrome, should the complication of aortic stenosis occur then surgery may be required.Treatment for hearing loss may also require surgical intervention.

See also
Osteopoikilosis
List of cutaneous conditions
Melorheostosis

References
Further reading
Pope, V.; Dupuis, L.; Kannu, P.; Mendoza-Londono, R.; Sajic, D.; So, J.; Yoon, G.; Lara-Corrales, I. (2016). "Buschke-Ollendorff syndrome: a novel case series and systematic review" </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Superior oblique myokymia and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Familial hyperaldosteronism and can you explain it in depth? [/INST] Familial hyperaldosteronism is a group of inherited conditions in which the adrenal glands, which are small glands located on top of each kidney, produce too much of the hormone aldosterone. Excess aldosterone causes the kidneys to retain more salt than normal, which in turn increases the bodys fluid levels and causes high blood pressure. People with familial hyperaldosteronism may develop severe high blood pressure, often early in life. Without treatment, hypertension increases the risk of strokes, heart attacks, and kidney failure. There are other forms of hyperaldosteronism that are not inherited.This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.  The various types of familial hyperaldosteronism have different genetic causes.It is unclear how common these diseases are. All together they appear to make up less than 1% of cases of hyperaldosteronism.

Types
Familial hyperaldosteronism is categorized into three types, distinguished by their clinical features and genetic causes.

Type I
In familial hyperaldosteronism type I, hypertension generally appears in childhood to early adulthood and can range from mild to severe. This type can be treated with steroid medications called glucocorticoids, so it is also known as glucocorticoid remediable aldosteronism (GRA).

Type II
In familial hyperaldosteronism type II, hypertension usually appears in early to middle adulthood and does not improve with glucocorticoid treatment.

Type III
In most with familial hyperaldosteronism type III, the adrenal glands are enlarged up to six times their normal size.  These affected have severe hypertension that starts in childhood.  The hypertension is difficult to treat and often results in damage to organs such as the heart and kidneys.  Rarely, individuals with type III have milder symptoms with treatable hypertension and no adrenal gland enlargement.

Cause
This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. The various types of familial hyperaldosteronism have different genetic causes </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Encephalocraniocutaneous lipomatosis and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Osteochondroma and can you explain it in depth? [/INST] Osteochondromas are the most common benign tumors of the bones.
The tumors take the form of cartilage-capped bony projections or outgrowth on the surface of bones exostoses. It is characterized as a type of overgrowth that can occur in any bone where cartilage forms bone. Tumors most commonly affect long bones about the knee and in the forearm. Additionally, flat bones such as the pelvis and scapula (shoulder blade) may be affected. Hereditary multiple exostoses usually present during childhood. Yet, the vast majority of affected individuals become clinically manifest by the time they reach adolescence. Osteochondromas occur in 3% of the general population and represent 35% of all benign tumors and 8% of all bone tumors. The majority of these tumors are solitary non-hereditary lesions and approximately 15% of osteochondromas occur as hereditary multiple exostoses preferably known as hereditary multiple osteochondromas (HMOs). Osteochondromas do not result from injury and the exact cause remains unknown. Recent research has indicated that multiple osteochondromas is an autosomal dominant inherited disease. Germ line mutations in EXT1 and EXT2 genes located on chromosomes 8 and 11 have been associated with the cause of the disease.
The treatment choice for osteochondroma is surgical removal of solitary lesion or partial excision of the outgrowth, when symptoms cause motion limitations or nerve and blood vessel impingements. In hereditary multiple exostoses the indications of surgery are based upon multiple factors that are taken collectively, namely: patients age, tumor location and number, accompanying symptomatology, esthetic concerns, family history and underlying gene mutation. A variety of surgical procedures have been employed to remedy hereditary multiple exostoses such as osteochondroma excision, bone lengthening, corrective osteotomy and hemiepiphysiodesis. Sometimes a combination of the previous procedures is used. The indicators of surgical success in regard to disease and patient characteristics are greatly disputable. Because most studies of hereditary multiple exostoses are retrospective and of limited sample size with missing data, the best evidence for each of the currently practiced surgical procedures is lacking.

Signs and symptoms
Limited normal functions and movements are caused by osteochondromas growing slowly and inwardly. The majority of osteochondromas are symptomless and are found incidentally. Each individual with osteochondroma may experience symptoms differently and most of the time individuals will experience no symptoms at all. Some of the most common symptoms are a hard immobile painless palpable mass, adjacent muscle soreness, and pressure or irritation with heavy exercising.
Major symptoms arise when complications such as fractures, bone deformity or mechanical joint problems occur. If the occurrence of an osteochondroma is near a nerve or a blood vessel, the affected limb can experience numbness, weakness, loss of pulse or color change. Periodic changes in the blood flow can also take place. Approximately 20% of patients experiencing nerve compression commonly acknowledge vascular compression, arterial thrombosis, aneurysm, and pseudoaneurysm. Formation of pseudoaneurysm and venous thrombosis lead to claudication, pain, acute ischemia, and symptoms of phlebitis. If the tumor is found under a tendon, it can cause pain during movement causing restriction of joint motion. Pain can also occur due to bursal inflammation, swelling or fracture at the base of the tumor stalk. Some of the clinical signs and symptoms of malignant osteochondroma are pain, swelling, and mass enlargement.

Mechanism
Osteochondromas are long and slender, pedunculated on a stalk often taking the shape of a cauliflower. The cartilage cap is covered by fibrous perichondrium and continues with the periosteum of the underlying bone. The cartilage cap is less than 2 cm thick and the thickness decreases with age. A cap more than 2 cm thick, indicates malignant transformation of a tumor. The cartilage cap merges with the epiphyseal area of the long bones called spongiosa. In the spongiosa, the chondrocytes are arranged in accordance with the epiphyseal growth plate. The spongiosa of the stalk continues with the underlying cancellous bone. Fractures within the stalk causes fibroblastic proliferation and formation of a new bone. Development of bursa takes place over the osteochondroma, which is attached to the perichondrium of the cap. Inflammation of the bone is indicated by the bursal wall lined by the synovium. As a result, patients may have swelling for years related to the location and site of the lesion indicative of mechanical obstruction, nerve impingement, pseudoaneurysm of the overlying vessel, fracture at the stalk of the lesion, or formation of bursa over the osteochondroma. Heparan sulphate (HS) are glycosaminoglycans which are involved in the formation of proteoglycans. The biosynthesis of HS takes place in the Golgi apparatus and endoplasmic reticulum, where glycosaminoglycans chains are maintained by type II glycosyltransferases encoded by EXOSTOSIN genes EXT1 and EXT2. Decreased levels of HS leads to mutations in EXT1 or EXT2 causing skeletal abnormality. The underlying mechanism for solitary and multiple osteochondromas have been associated with genetic alterations in EXT1 or EXT2 genes located on chromosomes 8 and 11. Approximately 65% of osteochondromas arise in the EXT1 gene loci on chromosome 8 and 35% arise in EXT2 gene loci on chromosome 11. About 70–75% of multiple osteochondromas are caused by point mutations, often involving deletion of single or multiple axons as found in 10% of all hereditary cases. In about 10–15% of all cases no genomic alterations are detected. The mechanism behind the formation of multiple osteochondroma is large genomic deletions of EXT1 and EXT2 genes. The identified mechanism behind solitary osteochondromas is the homozygous deletions of the EXT1 gene. However, the exact cause of osteochondroma is unknown. Additionally, the molecular basis of genetics and clinical variability of multiple osteochondroma as well as the underlying causes for the malignant transformation and the onset of osteochondroma in EXT negative patients is also currently unknown.

Diagnosis
Osteochondromas are often asymptomatic and may not cause any kind of discomfort. They are often found accidentally when an X-ray is done for an unrelated reason.
X-rays are the first tests performed that characterize a lesion. They show a clear picture of dense structures of bones, and will also indicate bone growth pertaining to osteochondroma.
Computed tomography (CT) scan can identify the bony lesion in great details and show the presence of calcification. These tests also provide great details, especially in soft tissues with the aide of cross-sectional images.
Magnetic resonance imaging (MRI) is the most accurate method for detecting bone masses in symptomatic cases to depict precise morphology of a tumor. It is used to verify if the palpable mass is continuous with the cortex of the affected bone and to differentiate an osteochondroma from other lesions on the surface of the bone. MRI can also be used to look for cartilage on the surface of tumor and can depict any vascular complications caused by the tumor. An MRI can identify tumors of the spinal column and is often used to diagnose low grade osteosarcoma.
Ultrasound is done if aneurysms or pseudoaneurysms and venous or arterial thrombosis is suspected. Ultrasound is an accurate method for examining the cartilaginous cap of the osteochondroma. It is also a way of pinpointing bursitis. However, it cannot be used to predict if the growth of tumor is inward in regards to the cap.
Angiography is used to detect vascular lesions caused by osteochondroma due to ossified cartilaginous cap. It is also used to characterize malignant transformation lesions through neovascularity.
Clinical testing such as sequence analysis can be done of the entire coding regions of both EXT1 and EXT2 to detect mutations.
A biopsy of the tissue sample of the tumor can also be taken to check for cancer.Tests for osteochondroma can also identify diseases such as secondary peripheral chondrosarcoma and multiple osteochondromatosis. In large, secondary chondrosarcoma arises at the site of osteochondroma due to increased thickness of the cartilage cap indicating potential malignant transformation. The symptoms of multiple osteochondromatosis are similar to solitary osteochondroma, but they are often more severe. Painless bumps can arise at the site of tumor and pain and other discomforts can also take place if pressure is put on the soft tissues, nerves, or blood vessels. Dysplasia Epiphysealis Hemimelica (DEH) or Trevors disease and metachondromatosis (MC) are considered differential diagnosis of both solitary and hereditary osteochondromas. DEH is described as a type of over growth at one or more epiphyses. Similar to osteochondroma, DEH is diagnosed prior to 15 years of age and the growth of lesions end at puberty, when the growth plates close. Metachondromatosis is a rare disorder that exhibit symptoms of both multiple osteochondromas and enchondromas in children and is also inherited in autosomal dominant mode.A type that contains fat is known as an osteolipochondroma (osteo, bone, lipos, fat, + chondros, cartilage, oma, tumor).

Treatment
Osteochondromas are benign lesions and do not affect life expectancy. Complete excision of osteochondroma is curative and the reoccurrences take place when the removal of tumor is incomplete. Multiple reoccurrences in a well-excised lesion indicate that it may be malignant. The risk of malignant transformation takes place in 1–5% of individuals. If any symptoms of cancerous tumor takes place, then the patient should be evaluated by a bone specialist. No treatment is necessary for Solitary osteochondromas that are asymptomatic. Treatments for solitary osteochondroma are careful observation over time and taking regular x-rays to monitor any changes in the tumor. If the lesion is causing pain with activity, nerve or vessel impingement, or if the bone growth has fully matured and the presence of a large cartilage cap is prominent, then it is advised that the tumor be surgically removed.Osteochondromas have a low rate of malignancy (<1%) and resection of the tumor is suggested if symptoms such as pain, limitation of movement, or impingement on nerves or vessels occur. Resection of the tumor also takes place when the tumor increases in size and progresses towards malignancy. During surgical resection, the entire lesion along with the cartilaginous cap should be removed to minimize any chances of reoccurrences. Surgical treatment becomes the sole treatment of choice if common complications such as fractures, symptoms of peripheral nerves such as paresthesia, paraplegia, peroneal neuropathy, and upper limb neuropathy  take place. A prophylactic resection is suggested if the lesion lies next to a vessel.Depending on the size and location of the tumor, the time it takes to return to normal daily activities varies between individuals. Limitation on some activities is advised if pain or discomfort persists after surgical excision.

Research
Research done using Zebrafish dackel (dak) have shown that in EXT2-/- Zebrafish, chondrocytes fail to undergo terminal differentiation and bone formation fails to progress from pre-osteoblasts stage to osteoblasts. Instead, abnormal lipid deposition and premature adipocyte differentiation takes place. The expression of xbp1, master regulator of osterix gets reduced, suggesting that unfolded proteins responses may play a role in pathogenesis of multiple osteochondroma. The research concludes that heparan sulphates are required for terminal differentiation and formation of scaffold that is needed for bone development. At least one copy of EXT2 gene is needed for proper bone development and to maintain the balance between bone and fat cell lineages. Due to homozygous loss of EXT2 function, leads to imbalance between cartilage, bone, and fat cell lineages. These observations in null zebrafish points toward the musculoskeletal defects observed in patients with multiple osteochondroma. Due to the findings of bone-fat imbalance in Zebra fish model, future studies should address status of lipid composition in patients with multiple osteochondroma.
Research conducted using sequencing methods has identified a novel frame shift mutation at the glycosyltransferase domain (c.1457insG) located at codon 486 of exon 6 of the EXT1 gene, that causes multiple osteochondromas. This study was conducted in two multiple osteochondroma (MO) patients from the Chinese descent (same family) and the results were validated with four other members of the same MO family and 200 unrelated healthy subjects. The results of the mutations were validated using two different sequencing methods (Exome and Sanger). The results of immunohistochemistry and multiple sequence alignment supports the cause of MO being a mutation in EXT1 gene </s>