<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 Mycetoma and can you explain it in depth? [/INST] Mycetoma is a chronic infection in the skin caused by either bacteria (actinomycetoma) or fungi (eumycetoma), typically resulting in a triad of painless firm skin lumps, the formation of weeping sinuses, and a discharge that contains grains. 80% occur in feet.Most eumycetoma is caused by M. mycetomatis, whereas most actinomycetoma is caused by N. brasiliensis, S. somaliensis, A. madurae and Actinomadura pelletieri. People who develop mycetoma likely have a weakened immune system. It can take between 3 months to 50 years from time of infection to first seeking healthcare advice.Diagnosis requires ultrasound and fine needle aspiration.While most cases of mycetoma occur in Sudan, Venezuela, Mexico, and India, its true prevalence and incidence are not well-known. It appears most frequently in people living in rural areas, particularly in farmers and shepherds, who are often men between 20 and 40 years earning the primary incomes for their families. It has been reported since 1840. Noteworthy, the diagnosis of Mycetoma in non-endemic or low endemic areas as Europe and North Africa is challenging. Physicians in these areas are usually unfamiliar with the disease-specific manifestations and need to exercise extra vigilance regarding those patients who are at high risk of contracting Mycetoma infections. Recent evidence suggests that Egypt which borders Sub-Saharan Africa, is a low-endemic country. Additionally, recent evidence suggests that Pakistan which borders India, is a moderate-endemic country. Unlike bacterial acute hematogenous osteomyelitis and septic arthritis, misdiagnosed or delayed diagnosis of Mycetoma osteomyelitis can result in amputation or radical resection. The disease is listed by the World Health Organization (WHO) as a neglected tropical disease.

Risk
Frequent exposure to penetrating wounds by thorns or splinters is a risk factor. This risk can be reduced by disinfecting wounds and wearing shoes.

Pathogenesis
Mycetoma is caused by common saprotrophs found in the soil and on thorny shrubs in semi-desert climates. Some common causative agents are:
Madurella mycetomatis (fungus)
Nocardia brasiliensis (bacteria)
Actinomadure madura (bacteria)
Streptomyces somaliensis (bacteria)
Actinomadura pelletieri (bacteria)Infection is caused as a result of localized skin trauma, such as stepping on a needle or wood splinter, or through a pre-existing wound.The first visible symptom of mycetoma is a typically painless swelling beneath the skin; over several years, this will grow to a nodule (lump). Affected people will experience massive swelling and hardening of the area, in addition to skin rupture and the formation of sinus tracts that discharge pus and grains filled with organisms. In many instances, the underlying bone is affected. Some people with mycetoma will not experience pain or discomfort, while others will report itching and/or pain.

Diagnosis
There are currently no rapid diagnostic tools for mycetoma. Mycetoma is diagnosed through microscopic examination of the grains in the nodule and by analysis of cultures. Since the bacterial form and the fungal form of mycetoma infection of the foot share similar clinical and radiological features, diagnosis can be a challenge. Magnetic resonance imaging is a very valuable diagnostic tool. However, its results should be closely correlated with the clinical, laboratory and pathological findings.

Treatment
While treatment will vary depending on the cause of the condition, it may include antibiotics or antifungal medication </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 Evans syndrome and can you explain it in depth? [/INST] Evans syndrome is an autoimmune disease in which an individuals immune system attacks their own red blood cells and platelets, the syndrome can include immune neutropenia. These immune cytopenias may occur simultaneously or sequentially.Its overall phenotype resembles a combination of autoimmune hemolytic anemia and immune thrombocytopenic purpura.
Autoimmune hemolytic anemia is a condition in which the red blood cells that normally carry oxygen are destroyed by an autoimmune process. Immune thrombocytopenic purpura is a condition in which platelets are destroyed by an autoimmune process. Platelets are a component of blood that contribute to the formation of blood clots in the body to prevent bleeding.
The syndrome was first described in 1951 by R. S. Evans and colleagues.

Signs and symptoms
The symptoms of Evans syndrome vary between patients depending on which blood cells are affected. If red blood cells are attacked, symptoms may include weakness and fatigue, paleness or jaundice, shortness of breath, lightheadedness, and/or a fast heartbeat. If platelets are attacked, symptoms may include increased bruising, prolonged nosebleeds, increased bleeding from minor cuts, and/or Petechiae. In the less common instance that white blood cells are attacked, symptoms may include increased proneness to infection, fevers, and/or mouth sores.It has been variously reported that between 7.8% and 23% of patients who have autoimmune hemolytic anemia, will also have thrombocytopenia and thus Evans syndrome. The two cytopenias may occur together or sequentially.

Causes
Although Evans syndrome seems to be a disorder of immune regulation, the exact pathophysiology is unknown, but a gradual loss of self-tolerance is postulated. Autoantibodies targeted at different antigenic determinants on red cells and platelets are assumed to cause isolated episodes of hemolytic anemia and thrombocytopenia, respectively.

Diagnosis
Diagnosis of Evans syndrome is separated into primary and secondary presentation. There is no single test to confirm a diagnosis of either form of Evans syndrome.  It is instead a diagnosis made after a thorough clinical history, documentation of common symptoms, clinical evaluation, and exclusion of all other possible conditions.The diagnosis of primary Evans syndrome is made upon blood tests to confirm not only hemolytic anemia and immune thrombocytopenic purpura, but also a positive direct antiglobulin test (DAT) and an absence of any known underlying cause. Additional tests used to eliminate the possibility of other conditions include a computed tomography (CT) scan and a biopsy of bone marrow.A diagnosis of secondary Evans syndrome is indicative of occurrence after another autoimmune disease is already present. In 27% to 50% of cases there is an associated malignancy or a predisposing autoimmune disease </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 Body-focused repetitive behavior 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 Monomelic amyotrophy and can you explain it in depth? [/INST] Monomelic amyotrophy (MMA) is a rare motor neuron disease first described in 1959 in Japan.  Its symptoms usually appear about two years after adolescent growth spurt and is significantly more common in males, with an average age of onset between 15 and 25 years.  MMA is reported most frequently in Asia but has a global distribution.  It is typically marked by insidious onset of muscle atrophy of an upper limb, which plateaus after two to five years from which it neither improves nor worsens. There is no pain or sensory loss associated with MMA.  MMA is not believed to be hereditary.Both the names for the disorder and its possible causes have been evolving since first reported in 1959. It is most commonly believed the condition occurs by asymmetrical compression of the cervical spinal column by the cervical dural sac, especially when the neck is flexed.  However, the disease is uncommon and diagnosis is confused by several atypical reports.

Symptoms
In terms of the signs and symptoms that are consistent for an individual who has monomelic amyotrophy are the following (although this does not reflect a complete list):

Initially most people notice weakness in one hand; they may feel contracture of middle and ring finger and notice a thinning of the subdigital palm of the affected fingers. Progress of the condition varies, and weakness in the arm ranges from minimal to significant. Fasciculations are uncommon (>20%); increased weakness under cold conditions is commonly reported (cold paresis).

Cause
The disability originates with impaired functioning of the anterior horn cells of the lower cervical cord (lower neck), but the cause of the decline is not fully understood and is still considered unknown. Researchers, including Hirayama, believe that "forward displacement of the cervical dural sac and compressive flattening of the lower cervical cord during neck flexion" is the contributing factor.  Studies consistently note a loss of normal neck curvature (the cervical lordosis) and compression of the cervical chord by the dural sac in forward flexion.
"There is a debate about whether this condition represents a focal form of primary LMN degeneration (ie, a focal form of spinal muscular atrophy) or a local consequence of chronic compression from a dural expansion in the cervical spine."A familial link has been found in a minor percentage of cases, including parent-child and sibling-sibling. Because of the unusual distribution of the disease, some researchers speculate that there could be an ethnic link.

Diagnosis
The condition presents almost exclusively in 15- to 25-year-old adults experiencing weakness in hand and arm. A patient history and a neurological exam narrows down the possible diagnosis; this preliminary exam typically includes strength and reflex tests. Cold paresis (increased weakness in cold weather) is reported by most patients (> 80%). Fasciculations are reported as uncommon (< 20%) to common; larger tremors  are more consistently cited. Males are far more likely to be diagnosed with the condition.The disease is rare and several cited cases deviate from the expected norm, making diagnosis more difficult. Proposed diagnostic criteria:

Distal predominant muscle weakness and atrophy in forearm and hand
Involvement of the unilateral upper extremity almost always all the time
Onset between the ages of 10 to early 20s
Insidious onset with gradual progression for the first several years, followed by stabilization
No lower extremity involvement
No sensory disturbance and tendon reflex abnormalities
Exclusion of other diseases (e.g., motor neuron disease, multifocal motor neuropathy, brachial plexopathy, spinal cord tumors, syringomyelia, cervical vertebral abnormalities, anterior interosseous, or deep ulnar neuropathy)
A neurological exam can suggest different motor neuron diseases (such as MMA), but to more confidently distinguish MMA from the diseases it mimics, advanced diagnostic tools are called for. These include exam tools such as magnetic resonance imaging (MRI), and electromyography (EMG) and nerve conduction velocity (NCV) tests. An MRI examination of the neck would typically reveal—for a positive MMA diagnosis—some constriction of the cervical cord and an abnormal forward extension of the neck, ("loss of cervical lordosis"); pressure by the dura on the nerve cord apparently causes the flattening / narrowing. An EMG test reveals loss of the nerve supply, or denervation, in the affected limb without a conduction block (a nerve blockage restricted to a small segment of the nerve).In early stages of the disease MMA may be confused for amyotrophic lateral sclerosis (ALS), cervical spondylotic amyotrophy (CSA), and other challenging neurological diseases, as well as conditions that are minor but that call for very different treatments, such as advanced carpal tunnel syndrome (CTS). Symptoms somewhat differ.  Pain and tingling in the hand is typically present in CTS and absent from MMA; loss of function presents differently; with careful electrophysiological study and neurological exams the two are distinguished.  In early stages, ALS, SCA, and MMA, presentation may be similar.  Both CSA and ALS ultimately have more extensive symptoms. MMA is more prevalent in young people while ALS and CSA are more common in older populations.  With ALS, hand symptoms usually more commonly both proximal and distal vs in MMA mostly distal only, and with ALS fasciculations (twitching) are often present in upper extremities, but rarely in MMA. MMA is usually eliminated from consideration if disability expresses itself in more than one extremity or in lower extremities (legs), but symptomatic absence may not rule out ALS for three to five years after initial onset. Electrophysiological texts and reflex tests tend to yield different results, but interpretation is at times subjective.

Treatment
At present there is no cure for MMA. The impact on the affected individual ranges from minimal to significant depending on the extent of the weakness. Physical and occupational therapies include muscle strengthening exercises and training in hand coordination. Early use of a cervical collar is increasingly encouraged as therapeutic for arresting further compression of the cervical spinal cord. Spinal surgery on patients with more advanced symptoms has met with reported success, but is still regarded as experimental.

Prognosis
The symptoms of MMA usually progress slowly for two to five years and then remain stable for many years. The weakness can progress to the opposite limb, although whether this progression is typical or rare is under discussion. Cases of patient improvement and deterioration have both been described, but are atypical. Initially MMA can be confused for slowly progressing case of other neurological diseases such as amyotrophic lateral sclerosis (ALS); initial symptoms can be similar, but their causes are apparently different, and their outcomes markedly so.  Diagnostic tools have improved since first described, and a few therapies are being introduced.  But sometimes several years of observation are needed before a definitive diagnosis can be made.Use of a cervical collar may afford relief, and some researchers advocate its therapeutic use </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 Milk fever and can you explain it in depth? [/INST] Milk fever, postparturient hypocalcemia, or parturient paresis is a disease, primarily in dairy cattle but also seen in beef cattle and non-bovine domesticated animals, characterized by reduced blood calcium levels (hypocalcemia).  It occurs following parturition, at onset of lactation, when demand for calcium for colostrum and milk production exceeds the bodys ability to mobilize calcium.  "Fever" is a misnomer, as body temperature during the disease is generally not elevated.  Milk fever is more commonly seen in older animals (which have reduced ability to mobilize calcium from bone) and in certain breeds (such as Channel Island breeds).

Clinical signs
The clinical signs of milk fever can be divided into three distinct stages:

Stage 1
Cows are mobile but show signs of hypersensitivity and excitability such as restlessness, tremors, ear twitching, head bobbing, and mild ataxia. If not treated, symptoms usually progress to stage 2.

Stage 2
Cows can no longer stand and present in sternal recumbency. Tachycardia, weakened heart contraction and peripheral pulses.  Cows appear dull, have dry muzzles, cold extremities and a lower than normal body temperature. Smooth muscle paralysis can cause bloat, and the inability to urinate or defecate. Cows often tuck their heads into their flanks.

Stage 3
Lateral recumbency, muscle flaccidity, unresponsiveness to stimuli, and loss of consciousness progressing to coma. Heart rate can approach 120 bpm, with peripheral pulses  becoming undetectable. If untreated, progression will continue to death.

Cause
During the dry period (late gestation, non-lactating), dairy cattle have relatively low calcium requirements, with a need to replace approximately 30 g of calcium per day due to utilization for fetal growth and fecal and urinary losses. At parturition, the requirement for calcium is greatly increased due to initiation of lactation, when mammary drainage of calcium may exceed 50g per day. Due to this large increase in demand for calcium, most cows will experience some degree of hypocalcemia for a short period following parturition as the metabolism adjusts to the increased demand. When the mammary drain of plasma calcium causes hypocalcemia severe enough to compromise neuromuscular function, the cow is considered to have clinical milk fever.

Mechanism
In normal calcium regulation, a decrease in plasma calcium levels causes the parathyroid glands to secrete parathyroid hormone (PTH), which regulates the activation of Vitamin D3 in the kidney. These two compounds act to increase blood calcium levels by increasing absorption of dietary calcium from the intestine, increasing renal tubular reabsorption of calcium in the kidney, and increasing resorption of calcium from bones.It has been found that tissue is less responsive to parathyroid hormone prepartum, compared to postpartum. It is believed that hypocalcemia causing milk fever is due to a lower level of responsiveness of the cows tissues to circulating parathyroid hormone.The resultant decreased plasma calcium causes hyperexcitability of the nervous system and weakened muscle contractions, which result in both tetany and paresis.

Prevention
Diet
Proper dietary management will prevent most cases of milk fever. This generally involves close attention to mineral and fiber levels in the diet prior to calving, as well as improving cow comfort to eliminate other problems that may interfere with appetite (and so trigger hypocalcemia). General advice is to restrict calcium intake before calving, as this leads to the parathyroid gland stimulating the release of calcium from bones.

Calcium Salts
A synthetic analogue of 25-hydroxycholecalciferol can be given by injection in the days leading up to calving, although the timing of this prophylaxis makes it difficult to use.Oral administration of a dose of a calcium salt in a gel has been advised by some veterinarians. An orally administered bolus containing a much higher concentration of calcium than the injectable solutions can also be given so long as the cow is standing or sitting up. If the cow is lying flat out then immediate intravenous therapy is required to avoid death.

Treatment
Treatment generally involves calcium injection by intravenous, intramuscular or subcutaneous routes. Before calcium injection was employed, treatment comprised inflation of the udder using a pneumatic pump. Inflation of the udder worked because the increased pressure created in the udder pushed the calcium in the udder back into the bloodstream of the cow.Intravenous calcium, though indicated in many cases, is potentially fatal through "heart blockade", or transient high calcium levels stopping the heart, so should be administered with care. Cows are to be fed jaggery along with the lime water mixture. In unclear cases of downer cows, intravenous calcium injection can lead to diagnosis. The typical reaction will be a generalized tremor of the skeletal muscles, and sometimes cardiac arrhythmia. Defecation, urination and eructation are frequent during the treatment, due to pharmacological effect of calcium on the smooth muscles.

Prognosis
The prognosis is generally good, even in advanced cases. However, some cows can relapse the following day, and even a third time the day after. Without treatment, between 60% and 80% of cows usually die, although death rates as high as 90% have been recorded.

History
It is thought that milk fever has existed for a very long time in dairy cattle. The first reports in veterinary literature can be traced to around 1793.

Early Theories
Early treatments involved venesection, but this proved ineffective.

Potassium Iodide
In the late 1800s, Jurgens Schmidt proposed the use of an infused solution of potassium iodide for treatment </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 Facioscapulohumeral muscular dystrophy and can you explain it in depth? [/INST] Facioscapulohumeral muscular dystrophy (FSHD) is a type of muscular dystrophy, a group of heritable diseases that cause degeneration of muscle and progressive weakness. Per the name, FSHD tends to sequentially weaken the muscles of the face, those that position the scapula, and those overlying the humerus bone of the upper arm. These areas can be spared, and muscles of other areas usually are affected, especially those of the chest, spine, abdomen, and shin. Almost any skeletal muscle can be affected in severe disease. Abnormally positioned, or winged, scapulas are common, as is the inability to lift the foot, known as foot drop. The two sides of the body are often affected unequally. Weakness typically manifests at ages 15 – 30 years. FSHD can also cause hearing loss and blood vessel abnormalities in the back of the eye.
FSHD is caused by a genetic mutation leading to deregulation of the DUX4 gene. Normally, DUX4 is expressed (i.e., turned on) in cells of the ovary and in very early human development, becoming repressed (i.e., turned off) by the time an embryo is several days old. In FSHD, DUX4 is inadequately repressed, allowing sporadic expression throughout life. Deletion of DNA in the region surrounding DUX4 is the causative mutation in 95% of cases, termed "D4Z4 contraction" and defining FSHD type 1 (FSHD1). FSHD caused by other mutations is FSHD type 2 (FSHD2). For disease to develop, also required is a 4qA allele, which is a common variation in the DNA next to DUX4. The chances of a D4Z4 contraction with a 4qA allele being passed on to a child is 50% (autosomal dominant); in 30% of cases, the mutation arose spontaneously. Mutations of FSHD cause inadequate DUX4 repression by unpacking the DNA around DUX4, making it accessible to be copied into messenger RNA (mRNA). The 4qA allele stabilizes this DUX4 mRNA, allowing it to be used for production of DUX4 protein. DUX4 protein is a modulator of hundreds of other genes, many of which are involved in muscle function. How this genetic modulation causes muscle damage remains unclear.Signs, symptoms, family history, and diagnostic tests can suggest FSHD; genetic testing can provide definitive diagnosis. No intervention has proven effective for slowing progression of weakness. Screening allows for early detection and intervention for various disease complications. Symptoms can be addressed with physical therapy, bracing, and reconstructive surgery such as surgical fixation of the scapula to the thorax. FSHD affects up to 1 in 8,333 people, putting it in the three most common muscular dystrophies with myotonic dystrophy and Duchenne muscular dystrophy. Prognosis is variable. Many are not significantly limited in daily activity, whereas a wheel chair or scooter is required in 20% of cases. Life expectancy is not affected, although death can rarely be attributed to respiratory insufficiency due to FSHD.FSHD was first distinguished as a disease in the 1870s and 1880s when French physicians Louis Théophile Joseph Landouzy and Joseph Jules Dejerine followed a family affected by it, thus the initial name Landouzy–Dejerine muscular dystrophy. Their work is predated by descriptions of probable individual FSHD cases. The significance of D4Z4 contraction on chromosome 4 was established in the 1990s. The DUX4 gene was discovered in 1999, found to be expressed and toxic in 2007, and in 2010 the genetic mechanism causing its expression was elucidated. In 2012, the gene most frequently mutated in FSHD2 was identified. In 2019, the first drug designed to counteract DUX4 expression entered clinical trials.

Signs and symptoms
Classically, weakness develops in the face, then the shoulder girdle, then the upper arm. These muscles can be spared and other muscles usually are affected. The order of muscle involvement can cause the appearance of weakness "descending" from the face to the legs. Distribution and degree of muscle weakness is extremely variable, even between identical twins. Musculoskeletal pain is very common, most often described in the neck, shoulders, lower back, and the back of the knee. Fatigue is also common. Muscle weakness usually becomes noticeable on one side of the body before the other, a hallmark of the disease. The right shoulder and arm muscles are more often affected than the left upper extremity muscles, independent of handedness.: 139  Otherwise, neither side of the body has been found to be at more risk. Classically, symptoms appear in those 15 – 30 years of age, although infantile onset, adult onset, and absence of symptoms despite having the causal genetics also occur. FSHD1 with a very large D4Z4 deletion (EcoRI 10-11 kb) is more strongly associated with infantile onset and severe weakness. On average, FSHD2 presents 10 year later than FSHD1. Otherwise, FSHD1 and FSHD2 are indistinguishable on the basis of weakness. Disease progression is slow, and long static phases, in which no progression is apparent, is not uncommon. Less commonly, individual muscles rapidly deteriorate over several months.

Face
Weakness of the muscles of the face is the most distinguishing sign of FSHD. It is typically the earliest sign, although it is rarely the initial complaint. At least mild facial weakness can be found in 90% or more with FSHD. One of the most common deficits is inability to close the eyelids, which can result in sleeping with the eyelids open and dry eyes. The implicated muscle is the orbicularis oculi muscle. Another common deficit is inability to purse the lips, causing inability to pucker, whistle, or blow up a balloon. The implicated muscle is the orbicularis oris muscle. A third common deficit is inability raise the corners of the mouth, causing a "horizontal smile," which looks more like a grin. Responsible is the zygomaticus major muscle.Weakness of various facial muscles contributes to difficulty pronouncing the letters M, B, and P. Facial expressions can appear diminished, arrogant, grumpy, or fatigued. Muscles used for chewing and moving the eyes are not affected. Difficulty swallowing is not typical, although can occur in advanced cases. FSHD is generally progressive, but it is not established whether facial weakness is progressive or stable throughout life.

Shoulder, chest, and arm
After the facial weakness, weakness usually develops in the muscles of the chest and those that span from scapula to thorax. Symptoms involving the shoulder, such as difficulty working with the arms overhead, are the initial complaint in 80% of cases. Predominantly, the serratus anterior and middle and lower trapezii muscles are affected; the upper trapezius is often spared. Trapezius weakness causes the scapulas to become downwardly rotated and protracted, resulting in winged scapulas, horizontal clavicles, and sloping shoulders; arm abduction is impaired. Serratus anterior weaknesss impairs arm flexion, and worsening of winging can be demonstrated when pushing against a wall. Muscles spanning from the scapula to the arm are generally spared, which include deltoid and the rotator cuff muscles. The deltoid can be affected later on, especially the upper portion.Severe muscle wasting can make bones and spared shoulder muscles very visible, a characteristic example being the "poly-hill" sign elicited by arm elevation. The first "hill" or bump is the upper corner of scapula appearing to "herniate" up and over the rib cage. The second hill is the AC joint, seen between a wasted upper trapezius and wasted upper deltoid. The third hill is the lower deltoid, distinguishable between the wasted upper deltoid and wasted humeral muscles. Shoulder weakness and pain can in turn lead to shoulder instability, such as recurrent dislocation, subluxation, or downward translation of the humeral head.Also affected is the chest, particularly the parts of the pectoralis major muscle that connect to the sternum and ribs. The part that connects to the clavicle is less often affected. This muscle wasting pattern can contribute to a prominent horizontal anterior axillary fold. Beyond this point the disease does not progress further in 30% of familial cases. After upper torso weakness, weakness can "descend" to the upper arms (biceps muscle and, particularly, the triceps muscle). The forearms are usually spared, resulting in an appearance some compare to the fictional character Popeye, although when the forearms are affected in advanced disease, the wrist extensors are more often affected.

Lower body and trunk
After the upper body, weakness can next appear in either the pelvis, or it "skips" the pelvis and involves the tibialis anterior (shin muscle), causing foot drop. One author considers the pelvic and thigh muscles to be the last group affected. Pelvic muscle weakness can manifest as pelvic tilt, causing the hips to be held in slight flexion. Pelvic weakness can also cause a Trendelenburgs sign. Weakness of the back of the thigh (hamstrings) is more common than weakness of the front of the thigh (quadriceps).Weakness can also occur in the abdominal muscles and paraspinal muscles, which can manifest as a protuberant abdomen and lumbar hyperlordosis. Abdominal weakness can cause inability to do a sit-up or the inability to turn from one side to the other while lying on ones back. Of the rectus abdominis muscle, the lower portion is preferentially affected, manifesting as a positive Beevors sign. In advanced cases, neck extensor weakness can cause the head to lean towards the chest, termed head drop.

Non-muscular
The most common non-musculoskeletal manifestation of FSHD is abnormalities in the small arteries (arterioles) in the retina. Tortuosity of the arterioles is seen in approximately 50% of those with FSHD. Less common arteriole abnormalities include telangiectasias and microaneurysms. These abnormalities of arterioles usually do not affect vision or health, although a severe form of it mimics Coats disease, a condition found in about 1% of FSHD cases and more frequently associated with large 4q35 deletions. High-frequency hearing loss can occur in those with large 4q35 deletions, but otherwise is no more common compared to the general population. Large 4q35 deletion can lead to various other rare manifestations.Scoliosis can occur, thought to result from weakness of abdominal, hip extensor, and spinal muscles. Conversely, scoliosis can be viewed as a compensatory mechanism to weakness. Breathing can be affected, associated with kyphoscoliosis and wheelchair use; it is seen in one-third of wheelchair-using patients. However, ventilator support (nocturnal or diurnal) is needed in only 1% of cases. Although there are reports of increased risk of cardiac arrhythmias, general consensus is that the heart is not affected.

Genetics
The genetics of FSHD is complex. FSHD and the myotonic dystrophies have unique genetic mechanisms that differ substantially from the rest of genetic myopathies. The DUX4 gene is the focal point of FSHD genetics. Normally, DUX4 is expressed during embryogenesis and later repressed in all tissues except the testes. In FSHD, there is failure of DUX4 repression and continued production of DUX4 protein, which is toxic to muscles. The mechanism of failed DUX4 repression is hypomethylation of DUX4 and its surrounding DNA on the tip of chromosome 4 (4q35), allowing transcription of DUX4 into messenger RNA (mRNA). Several mutations can result in disease, upon which FSHD is sub-classified into FSHD type 1 (FSHD1) and FSHD type 2 (FSHD2). Disease can only result when a mutation is present in combination with select, commonly found variations of 4q35, termed haplotype polymorphisms. There are at least 17 4q35 haplotype polymorphisms, roughly dividable into the groups 4qA and 4qB. A 4qA haplotype polymorphism, often referred to as a 4qA allele, is necessary for disease, as it contains a polyadenylation sequence that allows DUX4 mRNA to resist degradation long enough to be translated into DUX4 protein.

DUX4 and the D4Z4 repeat array
DUX4 resides within the D4Z4 macrosatellite repeat array, a series of tandemly repeated DNA segments in the subtelomeric region (4q35) of chromosome 4. Each D4Z4 repeat is 3.3 kilobase pairs (kb) long and is the site of epigenetic regulation, containing both heterochromatin and euchromatin structures. In FSHD, the heterochromatin structure is lost, becoming euchromatin.The subtelomeric region of chromosome 10q contains a tandem repeat structure highly homologous (99% identical) to 4q35, containing "D4Z4-like" repeats with protein-coding regions identical to DUX4 (D10Z10 repeats and DUX4L10, respectively). Because 10q usually lacks a polyadenylation sequence, it is usually not implicated in disease. However, chromosomal rearrangements can occur between 4q and 10q repeat arrays, and involvement in disease is possible if a 4q D4Z4 repeat and polyadenylation signal are transferred onto 10q, or if rearrangement causes FSHD1.
DUX4 consists of three exons. Exons 1 and 2 are in each repeat. Exon 3 is in the pLAM region telomeric to the last partial repeat. Multiple RNA transcripts are produced from the D4Z4 repeat array, both sense and antisense. Some transcripts might be degraded in areas to produce si-like small RNAs. Some transcripts that originate centromeric to the D4Z4 repeat array at the non-deleted element (NDE), termed D4Z4 regulatory element transcripts (DBE-T), could play a role in DUX4 derepression. One proposed mechanism is that DBE-T leads to the recruitment of the trithorax-group protein Ash1L, an increase in H3K36me2-methylation, and ultimately de-repression of 4q35 genes.

FSHD1
FSHD involving deletion of D4Z4 repeats (termed D4Z4 contraction) on 4q is classified as FSHD1, which accounts for 95% of FSHD cases. Typically, chromosome 4 includes between 11 and 150 D4Z4 repeats. In FSHD1, there are 1–10 D4Z4 repeats. The number of repeats is roughly inversely related to disease severity. Namely, those with 8 - 10 repeats tend to have the mildest presentations, sometimes with no symptoms; those with 4 - 7 repeats have moderate disease that is highly variable; and those with 1 - 3 repeats are more likely to have severe, atypical, and early-onset disease. Deletion of the entire D4Z4 repeat array does not result in FSHD because then there are no complete copies of DUX4 to be expressed, although other birth defects result. One contracted D4Z4 repeat array with an adjoining 4qA allele is sufficient to cause disease, so inheritance is autosomal dominant. De novo (new) mutations are implicated in 10 - 30% of cases, 50% of which exhibit somatic mosaicism.It has been proposed that FSHD1 undergoes anticipation, a trend primarily associated with trinucleotide repeat disorders in which disease manifestation worsens with each subsequent generation. As of 2019, more detailed studies are needed to definitively show whether or not anticipation plays a role. If anticipation does occur in FSHD, the mechanism is different than that of trinucleotide repeat disorders, since D4Z4 repeats are much larger than trinucleotide repeats, an underabundance of repeats (rather than overabundance) causes disease, and the repeat array size in FSHD is stable across generations.

FSHD2
FSHD without D4Z4 contraction is classified as FSHD2, which constitutes 5% of FSHD cases. Various mutations cause FSHD2, all resulting in D4Z4 hypomethylation, at which the genetic mechanism converges with FSHD1. Approximately 80% of FSHD2 cases are due to deactivating mutations in the gene SMCHD1 (structural maintenance of chromosomes flexible hinge domain containing 1) on chromosome 18. SMCHD1 is responsible for DNA methylation, and its deactivation results in hypomethylation of the D4Z4 repeat array. Another cause of FSHD2 is mutation in DNMT3B (DNA methyltransferase 3B), which also plays a role in DNA methylation. As of 2020, early evidence indicates that a third cause of FSHD2 is mutation in both copies of the LRIF1 gene, which encodes the protein ligand-dependent nuclear receptor-interacting factor 1 (LRIF1). LRIF1 is known to interact with the SMCHD1 protein. As of 2019, there are presumably additional mutations at other unidentified genetic locations that can cause FSHD2.Mutation of a single allele of SMCHD1 or DNMT3B can cause disease. Mutation of both copies LRIF1 has been tentatively shown to cause disease in a single person as of 2020. As in FSHD1, a 4qA allele must be present for disease to result. However, unlike the D4Z4 array, the genes implicated in FSHD2 are not in proximity with the 4qA allele, and so they are inherited independently from the 4qA allele, resulting in a digenic inheritance pattern. For example, one parent without FSHD can pass on an SMCHD1 mutation, and the other parent, also without FSHD, can pass on a 4qA allele, bearing a child with FSHD2.

Two ends of a disease spectrum
Initially, FSHD1 and FSHD2 were described as two separate genetic causes of the same disease. However, they can also be viewed not as distinct causes, but rather as risk factors. Not rarely do both contribute to disease in the same individual.In those with FSHD2, although they have do not have a 4qA allele with D4Z4 repeat number less than 11, they still often have one less than 17 (relatively short compared to the general population), suggesting that a large number of D4Z4 repeats can prevent the effects of an SMCHD1 mutation. Further studies need to be done to determine the upper limit of D4Z4 repeats in which FSHD2 can occur.In those with a 4qA allele and 10 or fewer repeats, an additional SMCHD1 mutation has shown to worsen disease, classifying them as both FSHD1 and FSHD2. In these FSHD1/FSHD2 individuals, the methylation pattern of the D4Z4 repeat array resembles that seen in FSHD2. This combined FSHD1/FSHD2 presentation is most common in those with 9 - 10 repeats, and is seldom found in those with 8 or less repeats. The relative abundance of SMCHD1 mutations in the 9 - 10 repeat group is likely because a sizable portion of the general population has 9 - 10 repeats with no disease, yet with the additive effect of an SMCHD1 mutation, symptoms develop and a diagnosis is made. In those with 8 or fewer repeats, symptoms are more likely than in those with 9 - 10 repeats, leading to diagnosis regardless of an additional SMCHD1 mutation.The apparent frequency of FSHD1/FSHD2 cases in the 9 - 10 repeat range, combined with the FSHD2-like methylation pattern, suggest the 9 - 10 repeat size to be an overlap zone between FSHD1 and FSDH2.

Pathophysiology
Molecular
As of 2020, there seems to be a consensus that aberrant expression of DUX4 in muscle is the cause of FSHD. DUX4 is expressed in extremely small amounts, detectable in 1 out of every 1000 immature muscle cells (myoblast), which appears to increase after myoblast maturation, in part because the cells fuse as they mature, and a single nucleus expressing DUX4 can provide DUX4 protein to neighboring nuclei from fused cells.It remains an area of active research how DUX4 protein causes muscle damage. DUX4 protein is a transcription factor that regulates many other genes. Some of these genes are involved in apoptosis, such as p53, p21, MYC, and β-catenin, and indeed it seems that DUX4 protein makes muscle cells more prone to apoptosis. Other DUX4 protein-regulated genes are involved in oxidative stress, and indeed it seems that DUX4 expression lowers muscle cell tolerance of oxidative stress. Variation in the ability of individual muscles to handle oxidative stress could partially explain the muscle involvement patterns of FSHD. DUX4 protein downregulates many genes involved in muscle development, including MyoD, myogenin, desmin, and PAX7, and indeed DUX4 expression has shown to reduce muscle cell proliferation, differentiation, and fusion. DUX4 protein regulates a few genes that are involved in RNA quality control, and indeed DUX4 expression has been shown to cause accumulation of RNA with subsequent apoptosis. Estrogen seems to play a role in modifying DUX4 protein effects on muscle differentiation, which could explain why females are lesser affected than males.
The cellular hypoxia response has been reported in a single study to be the main driver of DUX4 protein-induced muscle cell death. The hypoxia-inducible factors (HIFs) are upregulated by DUX4 protein, possibly causing pathologic signaling leading to cell death.Another study found that DUX4 expression in muscle cells led to the recruitment and alteration of fibrous/fat progenitor cells, which helps explain why muscles become replaced by fat and fibrous tissue.A single study implicated RIPK3 in DUX4-mediated cell death.

Muscle histology
Unlike other muscular dystrophies, early muscle biopsies show only mild degrees of fibrosis, muscle fiber hypertrophy, and displacement of nuclei from myofiber peripheries (central nucleation). More often found is inflammation. There can be endomysial inflammation, primarily composed of CD8+ T-cells, although these cells do not seem to directly cause muscle fiber death. Endomysial blood vessels can be surrounded by inflammation, which is relatively unique to FSHD, and this inflammation contains CD4+ T-cells. Inflammation is succeeded by deposition of fat (fatty infiltration), then fibrosis. Individual muscle fibers can appear whorled, moth-eaten, and, especially, lobulated.

Muscle involvement pattern
Why certain muscles are preferentially affected in FSHD remains unknown. There are multiple trends of involvement seen in FSHD, possibly hinting at underlying pathophysiology. Individual muscles can weaken while adjacent muscles remain healthy. The right shoulder and arm muscles are more often affected than the left upper extremity muscles, a pattern also seen in Poland syndrome and hereditary neuralgic amyotrophy; this could reflect a genetic, developmental/anatomic, or functional-related mechanism. The deltoid is often spared, which is not seen in any other condition that affects the muscles around the scapula.Medical imaging (CT and MRI) have shown muscle involvement not readily apparent otherwise
A single MRI study shows the teres major muscle to be commonly affected.
The semimembranosus muscle, part of the hamstrings, is commonly affected,  deemed by one author to be "the most frequently and severely affected muscle."
Of the quadriceps muscles, the rectus femoris is preferentially affected
Of the  gastrocnemius, the medial section is preferentially affected;
The iliopsoas, a hip flexor muscle, is very often spared.

Retinopathy
Tortuosity of the retinal arterioles, and less often microaneurysms and telangiectasia, are commonly found in FSHD. Abnormalities of the capillaries and venules are not observed. One theory for why the arterioles are selectively affected is that they contain smooth muscle. The degree of D4Z4 contraction correlates to the severity of tortuosity of arterioles. It has been hypothesized that retinopathy is due to DUX4-protein-induced modulation of the CXCR4–SDF1 axis, which has a role in endothelial tip cell morphology and vascular branching.

Diagnosis
FSHD can be presumptively diagnosed in many cases based on signs, symptoms, and/or non-genetic medical tests. Genetic testing can provide definitive diagnosis. In the absence of an established family history of FSHD, diagnosis can be difficult due to the variability in how FSHD manifests.

Genetic testing
Genetic testing is the gold standard for FSHD diagnosis, as it is the most sensitive and specific test available. Commonly, FSHD1 is tested for first. A shortened D4Z4 array length (EcoRI length of 10 kb to 38 kb) with an adjacent 4qA allele supports FSHD1. If FSHD1 is not present, commonly FSHD2 is tested for next by assessing methylation at 4q35. Low methylation (less than 20%) in the context of a 4qA allele is sufficient for diagnosis. The specific mutation, usually one of various SMCHD1 mutations, can be identified with next-generation sequencing (NGS).

Assessing D4Z4 length
Measuring D4Z4 length is technically challenging due to the D4Z4 repeat array consisting of long, repetitive elements. For example, NGS is not useful for assessing D4Z4 length, because it breaks DNA into fragments before reading them, and it is unclear from which D4Z4 repeat each sequenced fragment came. In 2020, optical mapping became available for measuring D4Z4 array length, which is more precise and less labor-intensive than southern blot.Molecular combing is also available for assessing D4Z4 array length. These methods, which physical measure the size of the D4Z4 repeat array, require specially prepared high quality and high molecular weight genomic DNA (gDNA) from serum, increasing cost and reducing accessibility to testing.

Restriction fragment length polymorphism (RFLP) analysis was the first genetic test developed and is still used as of 2020, although it is being phased out by newer methods. It involves dicing the DNA with restriction enzymes and sorting the resulting restriction fragments by size using southern blot. The restriction enzymes EcoRI and BlnI are commonly used. EcoRI isolates the 4q and 10q repeat arrays, and BlnI dices the 10q sequence into small pieces, allowing 4q to be distinguished. The EcoRI restriction fragment is composed of three parts: 1) 5.7 kb proximal part, 2) the central, variable size D4Z4 repeat array, and 3) the distal part, usually 1.25 kb. The proximal portion has a sequence of DNA stainable by the probe p13E-11, which is commonly used to visualize the EcoRI fragment during southern blot. The name "p13E-11" reflects that it is a subclone of a DNA sequence designated as cosmid 13E during the human genome project. Considering that each D4Z4 repeat is 3.3 kb, and the EcoRI fragment contains 6.9 kb of DNA that is not part of the D4Z4 repeat array, the number of D4Z4 units can be calculated.

D4Z4 repeats = (EcoRI length - 6.9) / 3.3Sometimes 4q or 10q will have a combination of D4Z4 and D4Z4-like repeats due to DNA exchange between 4q and 10q, which can yield erroneous results, requiring more detailed workup. Sometimes D4Z4 repeat array deletions can include the p13E-11 binding site, warranting use of alternate probes.

Assessing methylation status
Methylation status of 4q35 is traditionally assessed after FSHD1 testing is negative. Methylation sensitive restriction enzyme (MSRE) digestion showing hypomethylation has long been considered diagnostic of FSHD2. Other methylation assays have been proposed or used in research settings, including methylated DNA immunoprecipitation and bisulfite sequencing, but are not routinely used in clinical practice. Bisulfite sequencing, if validated, would be valuable due to it being able to use lower quality DNA sources, such as those found in saliva.

Auxiliary testing
Other tests can support the diagnosis of FSHD, although they are all less sensitive and less specific than genetic testing. Nonetheless, they can rule out similar-appearing conditions.
Creatine kinase (CK) blood level is often ordered when muscle damage is suspected. CK is an enzyme found in muscle, leaking into the blood when muscles become damaged. In FSHD, CK level is normal to mildly elevated, never exceeding five times the upper limit of normal.
Electromyogram (EMG) measures the electrical activity in the muscle. EMG can show nonspecific signs of muscle damage or irritability.
Nerve conduction velocity (NCV) measures the how fast signals travel along a nerve. The nerve signals are measured with surface electrodes (similar to those used for an electrocardiogram) or needle electrodes.
Muscle biopsy is the surgical removal and examination of a small piece of muscle, usually from the arm or leg. Microscopy and a variety of biochemical tests are used for examination. Findings in FSHD are nonspecific, such as presence of white blood cells or variation in muscle fiber size. This test is rarely indicated.
Muscle MRI is sensitive for detecting muscle damage, even in mild cases. Because of the particular muscle involvement patterns of FSHD, MRI can help differentiate FSHD from other muscle diseases, directing genetic testing.

Differential diagnosis
Included in the differential diagnosis of FSHD are limb-girdle muscular dystrophy (especially calpainopathy), scapuloperoneal myopathy, mitochondrial myopathy, Pompe disease, and polymyositis. Calpainopathy and scapuloperoneal myopathy, like FSHD, present with scapular winging. Features that suggest FSHD are facial weakness, asymmetric weakness, and lack of benefit from immunosuppression medications. Features the suggest an alternative diagnosis are contractures, respiratory insufficiency, weakness of muscles controlling eye movement, and weakness of the tongue or throat.

Management
No intervention has proven to significantly slow progression of weakness or improve strength.

Screening and monitoring of complications
The American Academy of Neurology (AAN) recommends several medical tests to detect complications of FSHD. A dilated eye exam to look for retinal abnormalities is recommended in those newly diagnosed with FSHD; for those with large D4Z4 deletions, an evaluation by a retinal specialist is recommended yearly. A hearing test is recommended for individuals with early-onset FSHD prior to starting school, or for any other FSHD-affected individual with symptoms of hearing loss. Pulmonary function testing (PFT) is recommended in those newly diagnosed to establish baseline pulmonary function, and recurrently for those with pulmonary insufficiency symptoms or risks. Routine screening for heart conditions, such as through an electrocardiogram (EKG) or echocardiogram (echo), is considered unnecessary in those without symptoms of heart disease.

Physical and occupational therapy
Aerobic exercise has been shown to reduce chronic fatigue and decelerate fatty infiltration of muscle in FSHD. The ANN recommends that people with FSHD engage in low-intensity aerobic exercise to promote energy levels, muscle health, and bone health. Moderate-intensity strength training appears to do no harm, although it has not been shown to be beneficial. Physical therapy can address specific symptoms; there is no standardized protocol for FSHD. Anecdotal reports suggest that appropriately applied kinesiology tape can reduce pain. Occupational therapy can be used for training in activities of daily living (ADLs) and to help adapt to new assistive devices. Cognitive behavioral therapy (CBT) has been shown to reduce chronic fatigue in FSHD, and it also decelerates fatty infiltration of muscle when directed towards increasing daily activity.Braces are often used to address muscle weakness. Scapular bracing can improve scapular positioning, which improves shoulder function, although it is often deemed as ineffective or impractical. Ankle-foot orthoses can improve walking, balance, and quality of life.

Pharmacologic management
No pharmaceuticals have definitively proven effective for altering the disease course. Although a few pharmaceuticals have shown improved muscle mass in limited respects, they did not improve quality of life, and the AAN recommends against their use for FSHD.

Reconstructive surgery
Scapular winging is amenable to surgical correction, namely operative scapular fixation. Scapular fixation is restriction and stabilization of the position of the scapula, putting it in closer apposition to the rib cage and reducing winging. Absolute restriction of scapular motion by fixation of the scapula to the ribs is most commonly reported. This procedure often involves inducing bony fusion, called arthrodesis, between the scapula and ribs. Names for this include scapulothoracic fusion, scapular fusion, and scapulodesis. This procedure increases arm active range of motion, improves arm function, decreases pain, and improves cosmetic appearance. Active range of motion of the arm increases most in the setting of severe scapular winging with an unaffected deltoid muscle; however, passive range of motion decreases. In other words, the patient gains the ability to slowly raise their arms to 90+ degrees, but they lose the ability to "throw" their arm up to a full 180 degrees. The AAN states that scapular fixation can be offered cautiously to select patients after balancing these benefits against the adverse consequences of surgery and prolonged immobilization.Another form of operative scapular fixation is scapulopexy. "Scapulo-" refers to the scapula bone, and "-pexy" is derived from the Greek root "to bind." Some versions of scapulopexy accomplish essentially the same result as scapulothoracic fusion, but instead of inducing bony fusion, the scapula is secured to the ribs with only wire, tendon grafts, or other material. Some versions of scapulopexy do not completely restrict scapular motion, examples including tethering the scapula to the ribs, vertebrae, or other scapula. Scapulopexy is considered to be more conservative than scapulothoracic fusion, with reduced recovery time and less effect on breathing. However, they also seem more susceptible to long-term failure. Another form of scapular fixation, although not commonly done in FSHD, is tendon transfer, which involves surgically rearranging the attachments of muscles to bone. Examples include pectoralis major transfer and the Eden-Lange procedure.
Various other surgical reconstructions have been described. Upper eyelid gold implants have been used for those unable to close their eyes. Drooping lower lip has been addressed with plastic surgery. Select cases of foot drop can be surgically corrected with tendon transfer, in which the tibialis posterior muscle is repurposed as a tibialis anterior muscle, a version of this being called the Bridle procedure. Severe scoliosis caused by FSHD can be corrected with spinal fusion; however, since scoliosis is a compensatory change in response to muscle weakness, correction of spinal alignment can result in further impaired muscle function.

Scapular winging management

Prognosis
Genetics partially predicts prognosis. Those with large D4Z4 repeat deletions (with a remaining D4Z4 repeat array size of 10-20 kbp, or 1-4 repeats) are more likely to have severe and early disease, as well as non-muscular symptoms. Those who have the genetic mutations of both FSHD1 and FSHD2 are more likely to have severe disease. It has also been observed that disease manifestation is milder when a prominent family history is present, as opposed to a new mutation. In some large families, 30% of those with the mutation do not show symptoms, and 30% of those with symptoms do not progress beyond facial and shoulder weakness. Women are less likely to be symptomatic, and if symptomatic have less severe manifestations.Remaining variations in disease course are attributed to unknown environmental factors. A single study found that disease course is not worsened by tobacco smoking or alcohol consumption, common risk factors for other diseases.

Pregnancy
Pregnancy outcomes are overall good in mothers with FSHD; there is no difference in rate of preterm labor, rate of miscarriage, and infant outcomes. However, weakness can increase the need for assisted delivery.A single review found that weakness worsens, without recovery, in 12% of mothers with FSHD during pregnancy, although this might be due to weight gain or deconditioning.

Epidemiology
The prevalence of FSHD ranges from 1 in 8,333 to 1 in 15,000. The Netherlands reports a prevalence of 1 in 8,333, after accounting for the undiagnosed. The prevalence in the United States is commonly quoted as 1 in 15,000.After genetic testing became possible in 1992, average prevalence was found to be around 1 in 20,000, a large increase compared to before 1992. However, 1 in 20,000 is likely an underestimation, since many with FSHD have mild symptoms and are never diagnosed, or they are siblings of affected individuals and never seek definitive diagnosis.Race and ethnicity have not been shown to affect FSHD incidence or severity.Although the inheritance of FSHD shows no predilection for biological sex, the disease manifests less often in women, and even when it manifests in women, they on average are less severely affected than affected males. Estrogen has been suspected to be a protective factor that accounts for this discrepancy. One study found that estrogen reduced DUX4 activity. However, another study found no association between disease severity and lifetime estrogen exposure in females. The same study found that disease progression was not different through periods of hormonal changes, such as menarche, pregnancy, and menopause.

History
The first description of a person with FSHD in medical literature appears in an autopsy report by Jean Cruveilhier in 1852. In 1868, Duchenne published his seminal work on Duchenne muscular dystrophy, and as part of its differential was a description of FSHD. First in 1874, then with a more commonly cited publication in 1884, and again with pictures in 1885, the French physicians Louis Landouzy and Joseph Dejerine published details of the disease, recognizing it as a distinct clinical entity, and thus FSHD is sometimes referred to as Landouzy Dejerine disease. In their paper of 1886, Landouzy and Dejerine drew attention to the familial nature of the disorder and mentioned that four generations were affected in the kindred that they had investigated. Formal definition of FSHDs clinical features did not occur until 1952 when a large Utah family with FSHD was studied. Beginning about 1980 an increasing interest in FSHD led to increased understanding of the great variability in the disease and a growing understanding of the genetic and pathophysiological complexities. By the late 1990s, researchers were finally beginning to understand the regions of chromosome 4 associated with FSHD.Since the publication of the unifying theory in 2010, researchers continued to refine their understanding of DUX4.  With increasing confidence in this work, researchers proposed the first a consensus view in 2014 of the pathophysiology of the disease and potential approaches to therapeutic intervention based on that model.Alternate and historical names for FSHD include the following:

facioscapulohumeral disease
faciohumeroscapular
Landouzy-Dejerine disease (or syndrome or type of muscular dystrophy)
Erb-Landouzy-Dejerine syndrome

Chronology of important FSHD-related genetic research
Past pharmaceutical development
Early drug trials, before the pathogenesis involving DUX4 was discovered, were untargeted and largely unsuccessful. Compounds were trialed with goals of increasing muscle mass, decreasing inflammation, or addressing provisional theories of disease mechanism. The following drugs failed to show efficacy:

Prednisone, a steroid, based on its antiinflammatory properties and therapeutic effect in Duchenne muscular dystrophy.
Oral albuterol, a β2 agonist, on the basis of its anabolic properties. Although it improved muscle mass and certain measures of strength in those with FSHD, it did not improve global strength or function. Interestingly, β2 agonists were later shown to reduce DUX4 expression.
Diltiazem, a calcium channel blocker, on the bases of anecdotal reports of benefit and the theory that calcium dysregulation played a part in muscle cell death.
MYO-029 (Stamulumab), an antibody that inhibits myostatin, was developed to promote muscle growth. Myostatin is a protein that inhibits the growth of muscle tissue.
ACE-083, a TGF-β inhibitor, was developed to promote muscle growth.

Society and culture
Media
In the Amazon Video series The Man in the High Castle, Obergruppenführer John Smiths son, Thomas, is diagnosed with Landouzy-Dejerine syndrome.
In the biography Stuart: A Life Backwards, the protagonist was affected by muscular dystrophy, presumably FSHD.

Patient and research organizations
The FSHD Society (named "FSH Society" until 2019) was founded in 1991 on the East Coast by two individuals with FSHD, Daniel Perez and Stephen Jacobsen. The FSHD Society claims to have advocated for the standardization of the disease name facioscapulohumeral muscular dystrophy and its abbreviation FSHD. The FSHD Society claims to have raised funding for seed grants for FSHD research and co-wrote the MD-CARE Act of 2001, which provided federal funding for all muscular dystrophies. The FSHD Society has grown into the worlds largest grassroots organization advocating for patient education and scientific and medical research for FSHD. One notable spokesperson for FSHD Society has been Max Adler, an actor on the TV series Glee.
Friends of FSH Research is a research-oriented nonprofit organization founded in 2004 by Terry and Rick Colella from Kirkland, Washington after their son was diagnosed with FSHD.
The FSHD Global Research Foundation was founded in 2007 by Bill Moss in Australia, a former Macquarie Bank executive affected by FSHD. It is currently directed by Mosss daughter. It was named Australian charity of the year for 2017. It is the largest funder of FSHD medical research outside of the United States as of 2018.
FSHD EUROPE was founded in 2010. Spanning multiple countries in Europe, it has launched the European Trial Network.

Notable cases
Chip Wilson is a Canadian billionaire and founder of Lululemon. He has pledged 100 million Candian dollars to research through the venture Solve FSHD.
Chris Carrino is the radio voice of the Brooklyn Nets. He founded the Chris Carrino Foundation for FSHD, oriented towards research funding.
Morgan Hoffman is an American professional golfer. He started the Morgan Hoffman Foundation, oriented towards research funding.

Research directions
Pharmaceutical development
After achieving consensus on FSHD pathophysiology in 2014, researchers proposed four approaches for therapeutic intervention:
enhance the epigenetic repression of the D4Z4
target the DUX4 mRNA, including altering splicing or polyadenylation;
block the activity of the DUX4 protein
inhibit the DUX4-induced process, or processes, that leads to pathology.Small molecule drugs
Most drugs used in medicine are "small molecule drugs," as opposed to biologic medical products that include proteins, vaccines, and nucleic acids. Small molecule drugs can typically be taken by ingestion, rather than injection.

Losmapimod, a selective inhibitor of p38α/β mitogen-activated protein kinases, was identified by Fulcrum Therapeutics as a potent suppressor of DUX4 in vitro. Results of a phase IIb clinical trial, revealed in June 2021, showed statistically significant slowing of muscle function deterioration </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 Pyruvate carboxylase deficiency and can you explain it in depth? [/INST] Pyruvate carboxylase deficiency is an inherited disorder that causes lactic acid to accumulate in the blood. High levels of these substances can damage the bodys organs and tissues, particularly in the nervous system. Pyruvate carboxylase deficiency is a rare condition, with an estimated incidence of 1 in 250,000 births worldwide. Type A of the disease appears to be much more common in some Algonkian Indian tribes in eastern Canada, while the type B disease is more present in European populations.

Signs and symptoms
Pyruvate carboxylase deficiency causes lactic acidosis and hyperammonaemia. Lactic acidosis may then lead to liver failure, hepatomegaly, reduced ketone body synthesis, and demyelination of neurons.

Genetics
Pyruvate carboxylase deficiency is caused by mutations in the PC gene. The PC gene provides instructions for making an enzyme called pyruvate carboxylase.
This condition is inherited in an autosomal recessive pattern, which means two copies of the gene must be inherited for the disorder to be present. The parents of an individual with an autosomal recessive disorder are carriers of one copy of the altered gene, but do not show signs and symptoms of the disorder.

Mechanism
Pyruvate carboxylase is active in mitochondria in cells. It is involved in the generation of glucose through gluconeogenesis. By generating oxaloacetate, it catalyses an important anaplerotic reaction that maintains the citric acid cycle to generate energy by aerobic respiration. Pyruvate carboxylase also plays a role in the formation of the myelin sheath that surrounds certain nerve cells, and the production of neurotransmitters for communication between neurons.
Mutations in the PC gene reduce the amount of pyruvate carboxylase in cells or disrupt the enzymes activity. The missing or altered enzyme cannot carry out its essential role in generating glucose, which impairs the bodys ability to make energy in mitochondria. Additionally, a loss of pyruvate carboxylase allows potentially toxic compounds, such as lactic acid and ammonia, to build up and damage organs and tissues </s>


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<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 Achondrogenesis and can you explain it in depth? [/INST] Achondrogenesis is a number of disorders that are the most severe form of congenital chondrodysplasia (malformation of bones and cartilage). These conditions are characterized by a small body, short limbs, and other skeletal abnormalities. As a result of their serious health problems, infants with achondrogenesis are usually born prematurely, are stillborn, or die shortly after birth from respiratory failure </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 Lupus vasculitis 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 Lichen spinulosus 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 Ring chromosome 20 syndrome and can you explain it in depth? [/INST] Ring chromosome 20, ring-shaped chromosome 20 or r(20) syndrome is a rare human chromosome abnormality where the two arms of chromosome 20 fuse to form a ring chromosome. The syndrome is associated with epileptic seizures, behaviour disorders and intellectual disability.When not all cells contain a ring chromosome 20, the individual has ring 20 chromosomal mosaicism. Ring Chromosome 20 syndrome is thought to be an underdiagnosed condition. Since chromosomal analysis or karyotype testing is not a routine investigation for patients with epilepsy, the diagnosis of ring chromosome 20 syndrome is typically delayed or unrecognized.

Presentation
Recurrent seizures are the most recognizable feature of this syndrome and are most often the first sign of this syndrome.  These syndromes are often ongoing and poorly responsive to anti-seizure medications.  Most patients develop seizures the first few years of life, but the age of onset ranges from ages 1 to 17.  Different types of seizure have been reported in this syndrome. The most common seizure type appears to be brief focal onset epileptic seizures with impairment of consciousness and awareness, known as complex partial seizures. Other features you may see in these complex partial seizures include staring, oral automatisms, unspecified automatic behavior, involuntary motor movements and/or head turning.
Furthermore, many patients have subtle nighttime behavioral changes, such as stretching, rubbing, and turning resembling a nighttime awakening. However, electroencephalography (EEG) studies during these events show abnormal electrical seizure activity, indicating that nocturnal behavioral events are actually subtle nocturnal seizures or non-convulsive status epilepticus. Many of these patients experience their seizures only during sleep.  They can have seemingly bizarre features as they originate from the frontal lobe of the brain. Often, individuals with ring chromosome 20 syndrome are initially found to have complex partial seizures of frontal lobe origin, though imaging studies do not show a corresponding structural brain abnormality. In certain patients, these seizures may secondarily generalized.
Individuals from the ages of 0–17 years should be considered for ring 20 chromosome analysis if they have: predominantly complex partial seizures, medically refractory cryptogenic epilepsy, Lennox-Gastaut-like features with no cause identified, frequent subtle nocturnal seizures, an EEG showing prolonged high voltage frontally dominant slowing intermixed with spikes or sharp waves, an EEG showing overlapping features of continuous slow spike and wave discharges in sleep (CSWS) and electrical status epilepticus in sleep (ESES), and/or subsequent cognitive impairment/learning difficulties/mild retardation.These patients will typically have a normal childhood development until onset of epilepsy and lack evidence of dysmorphism or other congenital malformations.

Genetics
Rather than the typical linear pattern of a chromosome, deletion of the endings of a chromosome can lead to ring formation. A chromosome has two arms, one long and one short.  Deletion of the short arm of chromosome 20 does not appear to result in epilepsy; however, terminal deletion of the long arm is associated with epilepsy. Therefore, some gene loss from the terminal segment could be responsible for the manifestation of epilepsy in ring chromosome 20 syndrome.  The most common breakpoint in patients is in the q13.33 region of chromosome 20.
As chromosomes occur in pairs, the affected individual usually has one normal chromosome and the other replaced by a ring chromosome.  However, this is not usually the case for every cell in the patient.  In most individuals with ring chromosome 20 syndrome, a certain percentage have two normal chromosome 20s and the remainder have one normal and one ring 20 chromosome. This mixture is called mosaicism.  A higher degree (percentage) of mosaicism appears to be associated with earlier age of seizure onset and presence of malformations. Yet, the degree of mosaicism does not determine response to drug treatment. Since the range in age of onset of seizures and IQ for a given mosaic ratio is relatively wide, prediction of phenotype based on the mosaicism ratio is somewhat limited.
Occasionally, there is a variation, where the ring chromosome 20 syndrome is characterized by an extra ring chromosome in addition to the two normal ones and hence gives rise to a partial trisomy or supernumerary ring 20. This supernumerary ring 20 can cause multiple anomalies but no epilepsy, and this resulting syndrome should be differentiated from ring chromosome 20 syndrome. This confusion has persisted even in the literature.
The genes in the q13.33 region of chromosome 20 have yet to be fully delineated.  However, this telomeric region includes two genes that are related to other distinct epilepsy syndromes, autosomal dominant nocturnal frontal lobe epilepsy and benign familial neonatal convulsions. The genes identified in these two syndromes are the nicotinic acetylcholine receptor alpha-4 subunit and potassium voltage-gated channel subfamily KQT member 2 respectively. Mutations in these genes lead to the clinical manifestations found in these disorders.  It is theorized that deletions in these regions from the ringed chromosome may lead to epilepsy in affected patient. A similar association between a ring chromosome and an autosomal-dominant disease has been reported for ring 17 chromosome and Miller-Dieker syndrome.
The recurrence risk for ring chromosome 20 syndrome is very low.  The ring formation is typically not identified in parents, and occurs de novo during pre-natal development.

Diagnosis
The ring 20 abnormality may be limited to as few as 5% of cells, so a screen for chromosomal mosaicism is critical. Newer array technology will not detect the ring chromosome and the standard metaphase chromosome analysis has been recommended. A karyotype analysis examining at least 50 cells should be requested to properly detect mosaicism.

Treatment
Successful management of seizures plays a key role in improving quality of life. Antiepileptic medications are the main therapies for seizures; however, it appears that seizures in this syndrome do not respond well to drugs. In the cases reported in literature, numerous new and old antiepileptic drugs have been tried, but no one drug appears to be more efficacious than others. Therefore, no recommendations can be made regarding the selection of the most appropriate antiepileptic drug.   As not all cases of ring chromosome 20 syndrome are the same, different individuals may respond to treatment in different ways.Alternates to antiepileptic drug treatment include the ketogenic diet and vagus nerve stimulation but not epilepsy surgery.

Ketogenic Diet
The ketogenic diet is a high fat, low carbohydrate diet reserved for intractable childhood epilepsies. There are no published reports on the use of the ketogenic diet in patients with ring chromosome 20 syndrome. However, its efficacy and safety are well established in other difficult to control epilepsy syndromes.

Epilepsy Surgery
Epilepsy surgery investigations are performed to identify a discrete seizure focus. Extensive investigations in ring chromosome 20 syndrome  patients fails to identify a discrete seizure focus and published data supports that that epilepsy in ring chromosome 20 syndrome  is not amenable to resective surgery. The Cost ranges between £50,000 - £200,000.

VNS Therapy
The vagal nerve stimulator is a battery-powered device similar to a pacemaker that is implanted under the skin.  It delivers a mild electrical stimulation to the brain via the vagus nerve and has proven to be effective for the treatment of complex partial seizures. There are only a few published reports on the success of this therapy in ring chromosome 20 epilepsy syndrome, making it unclear if this is the optimal therapy.

Prognosis
Limited data is available for the long-term prognosis of ring chromosome 20 syndrome since only over 60 patients with this syndrome have been reported in published literature. Optimal control of seizures appears to be the determining factor, but early diagnosis and a comprehensive management plan with multidisciplinary support is also thought be to be important.

Research
Two international research studies are currently underway </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 Situs inversus and can you explain it in depth? [/INST] Situs inversus (also called situs transversus or oppositus) is a congenital condition in which the major visceral organs are reversed or mirrored from their normal positions. The normal arrangement of internal organs is known as situs solitus. Although cardiac problems are more common, many people with situs inversus have no medical symptoms or complications resulting from the condition, and until the advent of modern medicine, it was usually undiagnosed.
Situs inversus is found in about 0.01% of the population, or about 1 person in 10,000. In the most common situation, situs inversus totalis, it involves complete transposition (right to left reversal) of all of the viscera. The heart is not in its usual position in the left chest, but is on the right, a condition known as dextrocardia (literally, "right-hearted"). Because the relationship between the organs is not changed, most people with situs inversus have no associated medical symptoms or complications.An uncommon form of situs inversus is isolated levocardia, in which the position of the heart is not mirrored alongside the other organs. Isolated levocardia carries a risk of heart defects, and so patients with the condition may require surgery to correct them.
In rarer cases such as situs ambiguus or heterotaxy, situs cannot be determined. In these patients, the liver may be midline, the spleen absent or multiple, and the bowel malrotated. Often, structures are duplicated or absent altogether. This is more likely to cause medical problems than situs inversus totalis.

Signs and symptoms
In the absence of congenital heart defects, individuals with situs inversus are homeostatically normal, and can live standard healthy lives, without any complications related to their medical condition. There is a 5–10% prevalence of congenital heart disease in individuals with situs inversus totalis, most commonly transposition of the great vessels. The incidence of congenital heart disease is 95% in situs inversus with levocardia.Many people with situs inversus totalis are unaware of their unusual anatomy until they seek medical attention for an unrelated condition, such as a rib fracture or a bout of appendicitis. The condition may also be discovered during the administration of certain medicines or during tests such as a barium meal or enema. The reversal of the organs may then lead to some confusion, as many signs and symptoms will be on the atypical side. For example, if an individual with situs inversus develops appendicitis, they will present to the physician with lower left abdominal pain, since that is where their appendix lies. Thus, in the event of a medical problem, the knowledge that the individual has situs inversus can expedite diagnosis. People with this rare condition should inform their doctors before an examination, so the doctor can redirect their search for heart sounds and other signs.  Wearing a medical identification tag can help inform health care providers in the event the person is unable to communicate.Situs inversus also complicates organ transplantation operations as donor organs will more likely come from situs solitus (normal) donors. As hearts and livers are chiral, geometric problems arise placing an organ into a cavity shaped in the mirror image. For example, a person with situs inversus who requires a heart transplant needs all their great vessels reattached to the donor heart. However, the orientation of these vessels in a person with situs inversus is reversed, necessitating steps so that the blood vessels join properly.

Cause
Situs inversus is generally an autosomal recessive genetic condition, although it can be X-linked or found in identical "mirror image" twins.About 25% of individuals with situs inversus have an underlying condition known as primary ciliary dyskinesia (PCD). PCD is a dysfunction of the cilia that occurs during early embryonic development. Normally functioning cilia determine the position of the internal organs during early development, and so embryos with PCD have a 50% chance of developing situs inversus. If they do, they are said to have Kartagener syndrome, characterized by the triad of situs inversus, chronic sinusitis, and bronchiectasis. Cilia are also responsible for clearing mucus from the lung, and the dysfunction causes increased susceptibility to lung infections. Kartagener syndrome can also manifest with male infertility as functional cilia are required for proper sperm flagella function.

Effect on anatomy
The condition affects all major structures within the thorax and abdomen. Generally, the organs are simply transposed through the sagittal plane. The heart is located on the right side of the thorax, the stomach and spleen on the right side of the abdomen and the liver and gall bladder on the left side. The hearts normal right atrium occurs on the left, and the left atrium is on the right. The lung anatomy is reversed and the left lung has three lobes while the right lung has two lobes. The intestines and other internal structures are also reversed from the normal, and the blood vessels, nerves, and lymphatics are also transposed.
If the heart is swapped to the right side of the thorax, it is known as "situs inversus with dextrocardia" or "situs inversus totalis". If the heart remains on the normal left side of the thorax, a much rarer condition (1 in 2,000,000 of the general population), it is known as "situs inversus with levocardia" or "situs inversus incompletus".
Situs inversus of the optic disc may occur unilaterally or bilaterally, associated with reduced binocularity and stereoacuity resembling monofixation syndrome </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 Odontogenic keratocyst and can you explain it in depth? [/INST] An odontogenic keratocyst is a rare and benign but locally aggressive developmental cyst. It most often affects the posterior mandible and most commonly presents in the third decade of life. Odontogenic keratocysts make up around 19% of jaw cysts.In the WHO/IARC classification of head and neck pathology, this clinical entity had been known for years as the odontogenic keratocyst; it was reclassified as keratocystic odontogenic tumour (KCOT) from 2005 to 2017. In 2017 it reverted to the earlier name, as the new WHO/IARC classification reclassified OKC back into the cystic category. Under The WHO/IARC classification, Odontogenic Keratocyst underwent the reclassification as it is no longer considered a neoplasm due to a lack of quality evidence regarding this hypothesis, especially with respect to clonality. Within the Head and Neck pathology community there is still controversy surrounding the reclassification, with some pathologists still considering Odontogenic Keratocyst as a neoplasm in line with the previous classification.

Signs and symptoms
Odontogenic keratocysts can occur at any age, however they are more common in the third to sixth decades. The male to female ratio is approximately 2:1. The majority are found in the mandible, with half occurring at the angle of the mandible.

Early odontogenic keratocysts usually do not display symptoms. Typically, clinical signs and symptoms present with bony expansion, or infection. However, bony expansion is uncommon as odontogenic keratocysts grow due to increased epithelial turnover rather than osmotic pressure. When symptoms are present they usually take the form of pain, swelling and discharge due to secondary infection. Odontogenic keratocysts are usually noted as incidental radiographic findings. Radiographically they can be seen as unilocular or multilocular radiolucencies. They can be mistaken for other cysts such as residual cysts or a dentigerous cyst if they occur over an unerupted tooth.

Pathogenesis
Odontogenic keratocysts originate from the odontogenic epithelium (dental lamina) in the alveolus left from tooth development stages. They are mainly thought to arise from rests of Serres.

Genetics
Sporadic (non-syndromic) and syndromic OKCs are associated with mutations in the gene PTCH found on chromosome 9q, which is part of the Hedgehog signaling pathway. PTCH is a tumour suppressor gene. Loss of PTCH activity leads to a brake in the cell cycle. A third of OKCs show mutations in PTCH, resulting in the cyst epithelium undergoing highly proliferative activity. This leads to growth of the cyst wall and when removed favours recurrence if following incomplete removal of the epithelium.

Nevoid basal-cell carcinoma syndrome
Multiple odontogenic keratocysts are a feature, and major diagnostic criteria, of nevoid basal cell carcinoma syndrome (NBCCS, also known as Gorlin-Goltz Syndrome). Almost all individuals with NBCCS have odontogenic keratocysts which require numerous treatments. Consideration of the syndrome needs to be taken into account if found in children or if multiple OKCs are present; diagnosis of multiple OKCs in a child necessitates referral for genetic evaluation. Histologically, the cysts are indistinguishable to non-syndromic cysts and over 80% will have PTCH mutations.

Diagnosis
Diagnosis is usually radiological. However, definitive diagnosis is through biopsy. Aspirational biopsy of odontogenic keratocysts contains a greasy fluid which is pale in colour and contains keratotic squames. Protein content of cyst fluid below 4g% is diagnostic of odontogenic keratocysts. Smaller and unilocular lesions resembling other types of cysts may require a biopsy to confirm the diagnosis. On a CT scan, the radiodensity of a keratocystic odontogenic tumour is about 30 Hounsfield units, which is about the same as ameloblastomas. However, ameloblastomas show more bone expansion and seldom show high density areas.Radiographs of odontogenic keratocysts show well-defined radiolucent areas with rounded or scalloped margins which are well demarcated. These areas can be multilocular or unilocular. The growth pattern of the lesion is very characteristic from which a diagnosis can be made as there is growth and spread both forward and backward along the medullary cavity with little expansion. No resorption of teeth or inferior dental canal and minimal displacement of teeth is seen. Due to lack of expansion of the odontogenic keratocyst, the lesion can be very large when radiographically discovered.

Differential diagnosis
Radiologically

Odontogenic myxoma
Ameloblastoma
Central giant-cell granuloma
Adenomatoid odontogenic tumor
Dentigerous cyst (follicular cyst)Histologically

Orthokeratocyst
Radicular cyst (particularly if the OKC is very inflamed)
Ameloblastoma

Histology
Odontogenic keratocysts have a diagnostic histological appearance. Under the microscope, OKCs vaguely resemble keratinized squamous epithelium; however, they lack rete ridges and often have an artifactual separation from their basement membrane.The fibrous wall of the cyst is usually thin and uninflamed. The epithelial lining is thin with even thickness and parakeratinised with columnar cells in the basal layer which have focal reverse polarisation (nuclei are on the opposite pole of the cell). The basal cells are an indication of the odontogenic origin as they resemble pre-ameloblasts. The epithelium can separate from the wall, resulting in islands of epithelium. These can go on to form satellite or daughter cysts, leading to an overall multilocular cyst. Presence of daughter cysts is particularly seen in those with NBCCS. Inflamed cysts show hyperplastic epithelium which is no longer characteristic of OKCs and can have resemblance to radicular cysts instead. Due to areas of focal inflammation, a larger biopsy is required for correct diagnosis of odontogenic keratocysts.

Treatment
As the condition is quite rare, opinions among experts about how to treat OKCs differ. A 2015 Cochrane review found that there is currently no high quality evidence to suggest the effectiveness of specific treatments for the treatment of odontogenic keratocysts. Treatment depends on extent of multilocularity and cyst. Small multilocular and unilocular cysts can be treated more conservatively through enucleation and curretage. Treatment options for KTOC may vary according to its size, extent, site, and adjacent structures.
Treatment options:
Surgical enucleation: surgical removal of the entire epithelial lining of the cyst.
Marsupialisation followed by enucleation: this method is carried out by surgeons for larger cysts.
Curettage involving simple excision and scraping-out of cavity.
Carnoys solution fixative (ethanol, chloroform and acetic acid) which is usually used in conjunction with excision and curretage. Cavity wall can be treated with the fixative either before enucleation to kill the lining of the wall or added after curretage to bony walls, killing any residual epithelial cells to a depth of 1-2mm. Used with care near mandibular canal and the neurovascular bundle within.
Marsupialization which involves the surgical opening of the cyst cavity and a creation of a marsupial-like pouch. This allows the cavity to be in contact with the outside of the cyst for an extended period of time. Marsupialisation results in slow shrinkage of the cyst allowing later enucleation. However, resolution can take up to 20 months and patients are required to clean the open cavity and irrigate it.
Peripheral ostectomy after curettage and/or enucleation. Extensive cysts may require a bone graft after bone resection and reconstruction of the area.
Simple excision
Enucleation and cryotherapy. Decompression followed by enucleation has been shown to be most successful with lowest recurrence rates.
Topical application of 5FU after enucleation
Ostectomy or En – bloc resection: in addition to the above treatments, these may be required due to the issue of recurrence. Ostectomy is removal of peripheral bone. En – block resection is removal of the cyst with the surrounding tissue. Extensive cysts may require a bone graft after bone resection and reconstruction of the area.

Follow-up
Annual radiographic review has been recommended. Long-term clinical follow-up is also recommended due to recurrences occurring many years after treatment.

Recurrence and neoplastic nature
Malignant transformation to squamous cell carcinoma may occur, but is unusual.Recurrence is likely when treated by simple enucleation. Contributing causes include thin and fragile epithelium leading to incomplete removal, cyst extensions extending into cancellous bone, satellite cysts found in the wall, experience of the surgeon, formation of further new cysts from other remnants of the dental epithelium </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 Rud syndrome and can you explain it in depth? [/INST]  </s>