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Therapies of Pars Planitis
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TreatmentIf no external causes of Pars planitis are found, treatment typically consists of corticosteroid drugs to control inflammation. If steroids are used, the patient must be carefully monitored.If an external association of pars planitis is identified, then treatment of the associated disorder may take care of the inflammation.Pars planitis may be accompanied by blood leaking from ruptured small blood vessels in the eye. These are generally not serious and, if necessary, can be treated by laser or cryotherapy (freezing of tissue) to seal blood vessels and arrest leakage.Other treatments are symptomatic and supportive, as well as treatment of the complications (cataracts, glaucoma, cystoid macular edema, etc).
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Therapies of Pars Planitis. TreatmentIf no external causes of Pars planitis are found, treatment typically consists of corticosteroid drugs to control inflammation. If steroids are used, the patient must be carefully monitored.If an external association of pars planitis is identified, then treatment of the associated disorder may take care of the inflammation.Pars planitis may be accompanied by blood leaking from ruptured small blood vessels in the eye. These are generally not serious and, if necessary, can be treated by laser or cryotherapy (freezing of tissue) to seal blood vessels and arrest leakage.Other treatments are symptomatic and supportive, as well as treatment of the complications (cataracts, glaucoma, cystoid macular edema, etc).
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Pars Planitis
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nord_943_0
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Overview of Parsonage Turner Syndrome
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SummaryParsonage-Turner syndrome (PTS) is an uncommon neurological disorder characterized by rapid onset of severe pain in the shoulder and arm. This acute phase may last for a few hours to a few weeks and is followed by wasting and weakness of the muscles (amyotrophy) in the affected areas. PTS involves mainly the brachial plexus, the networks of nerves that extend from the spine through the neck, into each armpit and down the arms. These nerves control movements and sensations in the shoulders, arms, elbows, hands, and wrists. Other nerves in the arm or even the leg can also be involved. The exact cause of PTS is unknown, but it is believed to be caused by an abnormality of the immune system (immune-mediated disorder). The severity of the disorder can vary widely from one individual to another due, in part, to the specific nerves involved. Affected individuals may recover without treatment, meaning that strength returns to the affected muscles and pain goes away. However, individuals may experience recurrent episodes. Some affected individuals may experience residual pain and potentially significant disability.IntroductionThe initial descriptions of this disorder in the medical literature date back to the late 1800s. In 1948, Drs. Parsonage and Turner were the first physicians to describe a large series of patients. They termed the disorder ‘amyotrophic neuralgia’. There is an extremely rare, inherited form known as hereditary neuralgic amyotrophy, on which NORD has a separate report. Sometimes PTS is referred to as idiopathic neuralgic amyotrophy to distinguish it from the genetic form and to denote that the cause is unknown. However, usually PTS is simply referred to as neuralgic amyotrophy. PTS can be broadly classified as a form of peripheral neuropathy or disorder of the peripheral nervous system, which encompasses any disorder that primarily affects the nerves outside the central nervous system (i.e. brain and spinal cord).
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Overview of Parsonage Turner Syndrome. SummaryParsonage-Turner syndrome (PTS) is an uncommon neurological disorder characterized by rapid onset of severe pain in the shoulder and arm. This acute phase may last for a few hours to a few weeks and is followed by wasting and weakness of the muscles (amyotrophy) in the affected areas. PTS involves mainly the brachial plexus, the networks of nerves that extend from the spine through the neck, into each armpit and down the arms. These nerves control movements and sensations in the shoulders, arms, elbows, hands, and wrists. Other nerves in the arm or even the leg can also be involved. The exact cause of PTS is unknown, but it is believed to be caused by an abnormality of the immune system (immune-mediated disorder). The severity of the disorder can vary widely from one individual to another due, in part, to the specific nerves involved. Affected individuals may recover without treatment, meaning that strength returns to the affected muscles and pain goes away. However, individuals may experience recurrent episodes. Some affected individuals may experience residual pain and potentially significant disability.IntroductionThe initial descriptions of this disorder in the medical literature date back to the late 1800s. In 1948, Drs. Parsonage and Turner were the first physicians to describe a large series of patients. They termed the disorder ‘amyotrophic neuralgia’. There is an extremely rare, inherited form known as hereditary neuralgic amyotrophy, on which NORD has a separate report. Sometimes PTS is referred to as idiopathic neuralgic amyotrophy to distinguish it from the genetic form and to denote that the cause is unknown. However, usually PTS is simply referred to as neuralgic amyotrophy. PTS can be broadly classified as a form of peripheral neuropathy or disorder of the peripheral nervous system, which encompasses any disorder that primarily affects the nerves outside the central nervous system (i.e. brain and spinal cord).
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Parsonage Turner Syndrome
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nord_943_1
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Symptoms of Parsonage Turner Syndrome
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The hallmark finding of PTS is the abrupt onset of pain in one of the shoulders (unilateral pain). In rare cases, both shoulders can be affected (bilateral). Onset may be rapid in some cases, while in others pain onset is gradual and subtle (insidious), followed by a rapid increase in both intensity and severity. Pain has been described as sharp, aching, burning or stabbing. Pain may also affect the neck and the arm and hand on the same side as the affected shoulder.Again, it is important to note that PTS is a highly variable disorder and one person’s individual case may not resemble another person’s experience. Some individuals (approximately 75%) will only experience one episode, while others (approximately 25%) will experience recurrent episodes. In addition, recurrent episodes may involve the same peripheral nerves that were originally affected, completely different peripheral nerves, or a mix of the same and different peripheral nerves. The intensity, duration and location of pain can also differ greatly from one person to another.Pain is often continuous, severe, and worse during the evening or at night. Pain can potentially be excruciating and debilitating. This initial period may be known as the acute phase. Eventually, affected individuals enter a period where the continuous pain lessens and there may be no pain when the affected shoulder and/or arm are not being used (i.e. at rest). However, specific movements may aggravate the condition, causing sharp, stabbing intense pain that persists for a few hours before lessening. This occurs because previously damaged nerves remain abnormally sensitive (hypersensitive). Eventually, affected individuals develop a chronic, low grade pain that can persist for a year or longer, sometimes known as the chronic phase.Eventually, anywhere from a few days to a few weeks after the onset of the disorder, pain is replaced by progressive weakness of muscles in the affected shoulder. The severity of muscle weakness can vary greatly, ranging from mild weakness that may be barely noticeable to, in rare cases, almost complete paralysis of the affected muscles. In individuals with PTS, muscle weakness results from damage to the nerves that serve the muscles in the shoulders and arms. The degree of weakness is related to the number of nerves affected. In addition to weakness, the affected muscles may progressively shrink and thin (atrophy) due to lack of use. Muscle weakness may go unnoticed at first, until atrophy and wasting of the affected muscles progresses and is easy to observe.Additional symptoms include absent or reduced reflexes and sensory deficits in the affected areas such as the loss of sensation or numbness (hypoesthesia), a sensation of tickling, prickling, or burning on the skin of the affected areas (paresthesia), or an abnormally unpleasant or painful sensation to a light touch (dysesthesia).Additional complications can develop in some cases. The position of the shoulders, arms, wrists, and hands can shift slightly because of atrophy and weakness of affected muscles. This can leave an affected individual at risk of secondary impingement or subluxation. Secondary impingement is a painful condition that occurs when the shoulder’s tendons are compressed or trapped during shoulder movements. Subluxation refers to partial dislocation of the shoulder joint. Affected individuals may also be at risk of developing contractures, in which abnormal shortening of muscles or tendons leads to deformity or rigidity of an affected joint. Contracture of the shoulder, also known as adhesive capsulitis, can result in pain and limitation of the normal range of movement of the joint.In some cases, nerves outside of the brachial plexus may be involved such as the nerves of the lumbosacral plexus, the phrenic nerve, or the recurrent laryngeal nerve. Involvement of the nerves in the lower portion of the back (lumbosacral plexus) can cause pain, hypoesthesia, and paresthesia in the legs. The phrenic nerve sends signals between the brain and the diaphragm, which is the muscle that separates the lungs from the abdomen. Involvement of the phrenic nerve can result in a significant shortness of breath. Involvement of the recurrent laryngeal nerve can result in weakness and partial paralysis of the vocal cords and, consequently, hoarseness and soft speech (hypophonia). In extremely rare cases, facial or other cranial nerves may be affected.Because nerve damage in PTS can affect blood vessels additional symptoms may develop including affected skin, particularly on the hands, becoming reddened, purplish or spotted. Swelling due to fluid retention (edema) may also occur. The skin, hair and nails may grow more quickly than normal. Certain areas of the body particularly the hands and forearms may no longer be able to respond properly to outside temperature. Excessive sweating may occur or affected individuals may feel abnormally cold in the affected areas.Some individuals may recover full strength and functional levels of the shoulder or affected areas. Numerous reports in the medical literature state that most individuals will regain up to 70-90% of their original strength and functional levels within two years. However, recent studies indicate that this can take more than two years in some people, while other people will experience residual, chronic pain and complications such as impaired movement of the shoulder and/or affected joints. In severe cases, affected individuals can be left with significant disability that can impact their ability to work and perform common tasks.
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Symptoms of Parsonage Turner Syndrome. The hallmark finding of PTS is the abrupt onset of pain in one of the shoulders (unilateral pain). In rare cases, both shoulders can be affected (bilateral). Onset may be rapid in some cases, while in others pain onset is gradual and subtle (insidious), followed by a rapid increase in both intensity and severity. Pain has been described as sharp, aching, burning or stabbing. Pain may also affect the neck and the arm and hand on the same side as the affected shoulder.Again, it is important to note that PTS is a highly variable disorder and one person’s individual case may not resemble another person’s experience. Some individuals (approximately 75%) will only experience one episode, while others (approximately 25%) will experience recurrent episodes. In addition, recurrent episodes may involve the same peripheral nerves that were originally affected, completely different peripheral nerves, or a mix of the same and different peripheral nerves. The intensity, duration and location of pain can also differ greatly from one person to another.Pain is often continuous, severe, and worse during the evening or at night. Pain can potentially be excruciating and debilitating. This initial period may be known as the acute phase. Eventually, affected individuals enter a period where the continuous pain lessens and there may be no pain when the affected shoulder and/or arm are not being used (i.e. at rest). However, specific movements may aggravate the condition, causing sharp, stabbing intense pain that persists for a few hours before lessening. This occurs because previously damaged nerves remain abnormally sensitive (hypersensitive). Eventually, affected individuals develop a chronic, low grade pain that can persist for a year or longer, sometimes known as the chronic phase.Eventually, anywhere from a few days to a few weeks after the onset of the disorder, pain is replaced by progressive weakness of muscles in the affected shoulder. The severity of muscle weakness can vary greatly, ranging from mild weakness that may be barely noticeable to, in rare cases, almost complete paralysis of the affected muscles. In individuals with PTS, muscle weakness results from damage to the nerves that serve the muscles in the shoulders and arms. The degree of weakness is related to the number of nerves affected. In addition to weakness, the affected muscles may progressively shrink and thin (atrophy) due to lack of use. Muscle weakness may go unnoticed at first, until atrophy and wasting of the affected muscles progresses and is easy to observe.Additional symptoms include absent or reduced reflexes and sensory deficits in the affected areas such as the loss of sensation or numbness (hypoesthesia), a sensation of tickling, prickling, or burning on the skin of the affected areas (paresthesia), or an abnormally unpleasant or painful sensation to a light touch (dysesthesia).Additional complications can develop in some cases. The position of the shoulders, arms, wrists, and hands can shift slightly because of atrophy and weakness of affected muscles. This can leave an affected individual at risk of secondary impingement or subluxation. Secondary impingement is a painful condition that occurs when the shoulder’s tendons are compressed or trapped during shoulder movements. Subluxation refers to partial dislocation of the shoulder joint. Affected individuals may also be at risk of developing contractures, in which abnormal shortening of muscles or tendons leads to deformity or rigidity of an affected joint. Contracture of the shoulder, also known as adhesive capsulitis, can result in pain and limitation of the normal range of movement of the joint.In some cases, nerves outside of the brachial plexus may be involved such as the nerves of the lumbosacral plexus, the phrenic nerve, or the recurrent laryngeal nerve. Involvement of the nerves in the lower portion of the back (lumbosacral plexus) can cause pain, hypoesthesia, and paresthesia in the legs. The phrenic nerve sends signals between the brain and the diaphragm, which is the muscle that separates the lungs from the abdomen. Involvement of the phrenic nerve can result in a significant shortness of breath. Involvement of the recurrent laryngeal nerve can result in weakness and partial paralysis of the vocal cords and, consequently, hoarseness and soft speech (hypophonia). In extremely rare cases, facial or other cranial nerves may be affected.Because nerve damage in PTS can affect blood vessels additional symptoms may develop including affected skin, particularly on the hands, becoming reddened, purplish or spotted. Swelling due to fluid retention (edema) may also occur. The skin, hair and nails may grow more quickly than normal. Certain areas of the body particularly the hands and forearms may no longer be able to respond properly to outside temperature. Excessive sweating may occur or affected individuals may feel abnormally cold in the affected areas.Some individuals may recover full strength and functional levels of the shoulder or affected areas. Numerous reports in the medical literature state that most individuals will regain up to 70-90% of their original strength and functional levels within two years. However, recent studies indicate that this can take more than two years in some people, while other people will experience residual, chronic pain and complications such as impaired movement of the shoulder and/or affected joints. In severe cases, affected individuals can be left with significant disability that can impact their ability to work and perform common tasks.
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Parsonage Turner Syndrome
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nord_943_2
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Causes of Parsonage Turner Syndrome
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The exact, underlying cause of PTS is not fully understood. Different factors, including immunologic, environmental, and genetic ones, are thought to play a role in the development of the disorder.Researchers believe that most cases result from an immune-mediated inflammatory response to some infection or environmental trigger that damages the nerves of the brachial plexus. A recent viral illness is the most common ‘triggering’ factor associated with the development of the disorder. Additional triggers that have been linked to PTS are recent immunization, surgery on the brachial plexus, unaccustomed strenuous exercise, minor trauma, bacterial infection, parasitic infection, anesthesia, rheumatologic diseases such as connective tissue disorders, and autoimmune disorders such as lupus, temporal arteritis, or polyarteritis nodosa. In women, childbirth can trigger PTS. In some cases, no triggering event or underlying factor can be identified.Some researchers suspect that certain affected individuals are genetically predisposed to developing PTS (i.e. injury to the brachial plexus) following such exposures described above. A person who is genetically predisposed to a disorder carries a gene (or genes) for the disease, but it may not be expressed unless it is triggered or “activated” under certain circumstances, such as due to particular environmental or immunologic factors.
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Causes of Parsonage Turner Syndrome. The exact, underlying cause of PTS is not fully understood. Different factors, including immunologic, environmental, and genetic ones, are thought to play a role in the development of the disorder.Researchers believe that most cases result from an immune-mediated inflammatory response to some infection or environmental trigger that damages the nerves of the brachial plexus. A recent viral illness is the most common ‘triggering’ factor associated with the development of the disorder. Additional triggers that have been linked to PTS are recent immunization, surgery on the brachial plexus, unaccustomed strenuous exercise, minor trauma, bacterial infection, parasitic infection, anesthesia, rheumatologic diseases such as connective tissue disorders, and autoimmune disorders such as lupus, temporal arteritis, or polyarteritis nodosa. In women, childbirth can trigger PTS. In some cases, no triggering event or underlying factor can be identified.Some researchers suspect that certain affected individuals are genetically predisposed to developing PTS (i.e. injury to the brachial plexus) following such exposures described above. A person who is genetically predisposed to a disorder carries a gene (or genes) for the disease, but it may not be expressed unless it is triggered or “activated” under certain circumstances, such as due to particular environmental or immunologic factors.
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Parsonage Turner Syndrome
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nord_943_3
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Affects of Parsonage Turner Syndrome
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PTS affects males more often than females. The incidence of the disorder is based upon available population studies and is estimated to be approximately 1.64 to 3.00 people per every 100,000 individuals in the general population per year. However, cases of PTS may go undiagnosed or misdiagnosed, making it difficult to determine the true frequency in the general population. The condition develops most often in young to middle-aged adults, but has been reported in young children and the elderly.
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Affects of Parsonage Turner Syndrome. PTS affects males more often than females. The incidence of the disorder is based upon available population studies and is estimated to be approximately 1.64 to 3.00 people per every 100,000 individuals in the general population per year. However, cases of PTS may go undiagnosed or misdiagnosed, making it difficult to determine the true frequency in the general population. The condition develops most often in young to middle-aged adults, but has been reported in young children and the elderly.
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Parsonage Turner Syndrome
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nord_943_4
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Related disorders of Parsonage Turner Syndrome
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Additional conditions or disorders that can cause symptoms similar to those seen in PTS include bursitis, rotator cuff injury or disease, calcific tendonitis, impingement syndromes, Guillain-Barre syndrome, cervical disc disease, cervical radiculopathy, mononeuritis monoplex, amyotrophic lateral sclerosis (Lou Gehrig’s disease), chronic inflammatory demyelinating polyneuropathy, polymyalgica rheumatica, thoracic outlet syndrome, and brachial plexus injury secondary to cancer (neoplastic brachial plexopathy). Adhesive capsulitis, which can develop as a complication of PTS, can develop for other reasons as well. NORD has individual reports on some of these disorders and a general report on peripheral neuropathy. (For more information, choose the specific disorder name as your search term in the Rare Disease Database.)
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Related disorders of Parsonage Turner Syndrome. Additional conditions or disorders that can cause symptoms similar to those seen in PTS include bursitis, rotator cuff injury or disease, calcific tendonitis, impingement syndromes, Guillain-Barre syndrome, cervical disc disease, cervical radiculopathy, mononeuritis monoplex, amyotrophic lateral sclerosis (Lou Gehrig’s disease), chronic inflammatory demyelinating polyneuropathy, polymyalgica rheumatica, thoracic outlet syndrome, and brachial plexus injury secondary to cancer (neoplastic brachial plexopathy). Adhesive capsulitis, which can develop as a complication of PTS, can develop for other reasons as well. NORD has individual reports on some of these disorders and a general report on peripheral neuropathy. (For more information, choose the specific disorder name as your search term in the Rare Disease Database.)
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Parsonage Turner Syndrome
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nord_943_5
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Diagnosis of Parsonage Turner Syndrome
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A diagnosis of PTS is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests.Clinical Testing and Workup
Certain tests such as nerve conduction studies or electromyography can be used to assess the health of muscles and the nerves that control muscles. Nerve conduction studies determine the ability of specific nerves in the peripheral nervous system to relay nerve impulses to the brain. During a nerve conduction study, electrodes are placed over specific nerves such as those of the shoulders and arms. The electrodes stimulate the nerves and record the conduction of the signal. This test can help to pinpoint the site of disease or injury to the nerve.During an electromyography, a tiny needle electrode is inserted through the skin into an affected muscle. The electrode records the electrical activity of the muscle. This record shows how well a muscle responds to nerves and can determine whether muscle weakness is caused by the muscles themselves or by the nerves that control those muscles.A specialized imaging technique known as magnetic resonance imaging (MRI) can help to obtain a diagnosis of PTS. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. An MRI can help to exclude other potential cause of shoulder pain, demonstrate atrophy of affected muscles, and detect signal changes caused by lack of nerve supply (denervation).A traditional x-ray (radiograph) of the shoulder may be ordered to rule out specific conditions that can damage the shoulder.
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Diagnosis of Parsonage Turner Syndrome. A diagnosis of PTS is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests.Clinical Testing and Workup
Certain tests such as nerve conduction studies or electromyography can be used to assess the health of muscles and the nerves that control muscles. Nerve conduction studies determine the ability of specific nerves in the peripheral nervous system to relay nerve impulses to the brain. During a nerve conduction study, electrodes are placed over specific nerves such as those of the shoulders and arms. The electrodes stimulate the nerves and record the conduction of the signal. This test can help to pinpoint the site of disease or injury to the nerve.During an electromyography, a tiny needle electrode is inserted through the skin into an affected muscle. The electrode records the electrical activity of the muscle. This record shows how well a muscle responds to nerves and can determine whether muscle weakness is caused by the muscles themselves or by the nerves that control those muscles.A specialized imaging technique known as magnetic resonance imaging (MRI) can help to obtain a diagnosis of PTS. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. An MRI can help to exclude other potential cause of shoulder pain, demonstrate atrophy of affected muscles, and detect signal changes caused by lack of nerve supply (denervation).A traditional x-ray (radiograph) of the shoulder may be ordered to rule out specific conditions that can damage the shoulder.
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Parsonage Turner Syndrome
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nord_943_6
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Therapies of Parsonage Turner Syndrome
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Treatment
There is no specific treatment for PTS. Treatment is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Orthopedic surgeons, neurologists, neuromuscular disease specialists, pediatricians or general internists, and other healthcare professionals may need to systematically and comprehensively plan an affect individual’s treatment. Early diagnosis and prompt treatment are important to increase the chances of a full recovery.In some cases, PTS may resolve on its own without treatment and only require support measures such as various pain management strategies including pain medications (analgesics). Specific pain medications used to treat PTS include opiates and non-steroidal anti-inflammatory drugs (NSAIDs), which are usually used in combination. Some physicians have recommended using oral corticosteroids such as prednisone in the acute phase, which has led to a decreased duration of pain and accelerated the healing process in some cases. However, corticosteroids have proven ineffective for many individuals and are potentially associated with adverse side effects. Consequently, other physicians do not recommend their use.After the acute phase, different medications known as co-analgesics may be administered. Such medications include gabapentin, carbamazepine, and amitryptiline. These drugs specifically treat nerve pain.Physical and rehabilitation therapy are also used to treat individuals with PTS in order to preserve muscle strength and range of motion of affected joints. Specific techniques include active and passive range of motion exercises to help to prevent muscle atrophy and contractures. In most cases, muscle strengthening exercises cannot be used during the acute phase because they worsen pain.Other techniques used to treat individuals with PTS include the application of heat or cold or transcutaneous electrical nerve stimulation (TENS), a procedure during which electrical impulses are sent through the skin to help to control pain by altering or blocking nerve transmissions.Surgery may be considered in individuals who have not responded favorably to other, less aggressive treatments. Surgical techniques can include nerve grafting or tendon transfers. Nerve grafting involves taking a segment of nerve tissue from one part of the body and using it to repair damaged nerves in another part of the body. This surgery is best done within 12 months of the injury (and even within 6 months). Tendon transfer surgery is indicated when muscle function is lost because of nerve injury. This surgery can be done later when no more nerve recovery is likely (typically after 2 years). During this procedure, a healthy tendon is removed from one part of the body and used to replace damaged or diseased tendon in another part of the body. These surgeries restore movement and function to the shoulder muscles and joint.The prognosis for PTS varies greatly. Some individuals only experience one episode and fully recover their strength and functional level in the shoulder and other affected areas. According to older medical literature, most affected individuals will recover up to 70-90% of their original strength and functional level. However, more recent medical articles suggest that residual complications are more common than previously believed. There is approximately a 5-26% risk that PTS will recur after initially resolving or being effectively treated. In approximately 10-20% of cases, affected individuals may be left with residual persistent pain and decreased endurance or exercise intolerance in the affected shoulder. There have been cases reported in which affected individuals experience significant disability that can impact quality of life by making basic household tasks or work extremely difficult. For example, some individuals may have difficulty reaching or lifting. Other people may have difficulty with repetitive tasks that involve the shoulder or arm. Some individuals may develop a winged scapula, a condition in which the shoulder blade (scapula) protrudes or sticks out abnormally from the back. Individuals who experience repeated episodes are more likely to develop long-term complications.
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Therapies of Parsonage Turner Syndrome. Treatment
There is no specific treatment for PTS. Treatment is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Orthopedic surgeons, neurologists, neuromuscular disease specialists, pediatricians or general internists, and other healthcare professionals may need to systematically and comprehensively plan an affect individual’s treatment. Early diagnosis and prompt treatment are important to increase the chances of a full recovery.In some cases, PTS may resolve on its own without treatment and only require support measures such as various pain management strategies including pain medications (analgesics). Specific pain medications used to treat PTS include opiates and non-steroidal anti-inflammatory drugs (NSAIDs), which are usually used in combination. Some physicians have recommended using oral corticosteroids such as prednisone in the acute phase, which has led to a decreased duration of pain and accelerated the healing process in some cases. However, corticosteroids have proven ineffective for many individuals and are potentially associated with adverse side effects. Consequently, other physicians do not recommend their use.After the acute phase, different medications known as co-analgesics may be administered. Such medications include gabapentin, carbamazepine, and amitryptiline. These drugs specifically treat nerve pain.Physical and rehabilitation therapy are also used to treat individuals with PTS in order to preserve muscle strength and range of motion of affected joints. Specific techniques include active and passive range of motion exercises to help to prevent muscle atrophy and contractures. In most cases, muscle strengthening exercises cannot be used during the acute phase because they worsen pain.Other techniques used to treat individuals with PTS include the application of heat or cold or transcutaneous electrical nerve stimulation (TENS), a procedure during which electrical impulses are sent through the skin to help to control pain by altering or blocking nerve transmissions.Surgery may be considered in individuals who have not responded favorably to other, less aggressive treatments. Surgical techniques can include nerve grafting or tendon transfers. Nerve grafting involves taking a segment of nerve tissue from one part of the body and using it to repair damaged nerves in another part of the body. This surgery is best done within 12 months of the injury (and even within 6 months). Tendon transfer surgery is indicated when muscle function is lost because of nerve injury. This surgery can be done later when no more nerve recovery is likely (typically after 2 years). During this procedure, a healthy tendon is removed from one part of the body and used to replace damaged or diseased tendon in another part of the body. These surgeries restore movement and function to the shoulder muscles and joint.The prognosis for PTS varies greatly. Some individuals only experience one episode and fully recover their strength and functional level in the shoulder and other affected areas. According to older medical literature, most affected individuals will recover up to 70-90% of their original strength and functional level. However, more recent medical articles suggest that residual complications are more common than previously believed. There is approximately a 5-26% risk that PTS will recur after initially resolving or being effectively treated. In approximately 10-20% of cases, affected individuals may be left with residual persistent pain and decreased endurance or exercise intolerance in the affected shoulder. There have been cases reported in which affected individuals experience significant disability that can impact quality of life by making basic household tasks or work extremely difficult. For example, some individuals may have difficulty reaching or lifting. Other people may have difficulty with repetitive tasks that involve the shoulder or arm. Some individuals may develop a winged scapula, a condition in which the shoulder blade (scapula) protrudes or sticks out abnormally from the back. Individuals who experience repeated episodes are more likely to develop long-term complications.
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Parsonage Turner Syndrome
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nord_944_0
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Overview of Partial Androgen Insensitivity Syndrome
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SummaryPartial androgen insensitivity syndrome (PAIS) is genetic condition that affects the sexual development of a male fetus. During pregnancy, male fetuses with PAIS are unable to properly respond to male sex hormones (androgens). As a result, this affects the development of the genitals. The appearance of the genitals may vary from person to person. Some males have an unusually small penis (microphallus), undescended testes, hypospadias (urethra located on the underside of the penis), and/ or bifid scrotum (scrotum split in two). Others may have more female-appearing genitals and physical features, including a large clitoris (clitoromegaly), male breast development (gynecomastia), undescended testes, and/ or fusion of the labia. Individuals with PAIS typically have infertility. PAIS is caused by a change in the AR gene, which is located on the X chromosome. It is inherited through an X-linked recessive pattern and typically affects males. It is recommended that parents and caretakers work with an experienced healthcare team to evaluate a child with PAIS before assigning their sex. If the individual is reared as male, they may be given testosterone therapy to improve fertility and surgeries to repair structures of the penis and to reduce the size of the male breasts. If the individual is reared as female, they may be offered surgery to remove the male reproductive organs after puberty, followed by estrogen (female sex hormone) therapy.IntroductionAndrogen insensitivity occurs when a person's body cannot respond properly to male sex hormones (androgens) during pregnancy. Partial androgen insensitivity syndrome (PAIS) belongs to a group of conditions that involves androgen insensitivity, including complete androgen insensitivity syndrome (CAIS) and mild androgen insensitivity syndrome (MAIS). The androgen insensitivity syndromes have historically been called “testicular feminization,” based on the appearance of the genitals. However, because the group of conditions vary from person to person based on one's response to androgens, it is now referred as “androgen insensitivity.”
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Overview of Partial Androgen Insensitivity Syndrome. SummaryPartial androgen insensitivity syndrome (PAIS) is genetic condition that affects the sexual development of a male fetus. During pregnancy, male fetuses with PAIS are unable to properly respond to male sex hormones (androgens). As a result, this affects the development of the genitals. The appearance of the genitals may vary from person to person. Some males have an unusually small penis (microphallus), undescended testes, hypospadias (urethra located on the underside of the penis), and/ or bifid scrotum (scrotum split in two). Others may have more female-appearing genitals and physical features, including a large clitoris (clitoromegaly), male breast development (gynecomastia), undescended testes, and/ or fusion of the labia. Individuals with PAIS typically have infertility. PAIS is caused by a change in the AR gene, which is located on the X chromosome. It is inherited through an X-linked recessive pattern and typically affects males. It is recommended that parents and caretakers work with an experienced healthcare team to evaluate a child with PAIS before assigning their sex. If the individual is reared as male, they may be given testosterone therapy to improve fertility and surgeries to repair structures of the penis and to reduce the size of the male breasts. If the individual is reared as female, they may be offered surgery to remove the male reproductive organs after puberty, followed by estrogen (female sex hormone) therapy.IntroductionAndrogen insensitivity occurs when a person's body cannot respond properly to male sex hormones (androgens) during pregnancy. Partial androgen insensitivity syndrome (PAIS) belongs to a group of conditions that involves androgen insensitivity, including complete androgen insensitivity syndrome (CAIS) and mild androgen insensitivity syndrome (MAIS). The androgen insensitivity syndromes have historically been called “testicular feminization,” based on the appearance of the genitals. However, because the group of conditions vary from person to person based on one's response to androgens, it is now referred as “androgen insensitivity.”
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Partial Androgen Insensitivity Syndrome
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nord_944_1
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Symptoms of Partial Androgen Insensitivity Syndrome
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Characteristics of partial androgen sensitivity syndrome vary from person. Each person with PAIS is unique and may not have the same features.
Some people with PAIS may have more female-appearing features. For example, some can be born with female-appearing genitals but may have an enlarged clitoris (clitoromegaly) or fusion of certain areas of the labia. In addition, some individuals may be born with openings of a female-appearing urethra (duct where urine is released from the bladder to outside the body) and vagina. However, individuals with PAIS do not have female sex organs such as a uterus and ovaries. Some people with this condition may have undescended testes, in which one or both testicles are not able to descend completely by puberty. Because they do not have ovaries and may have issues with the development of the testes, many people with PAIS are infertile, because they produce no or very little sperm. Also, some individuals with PAIS may develop breasts (gynecomastia) during puberty.Other people with PAIS may have more male-appearing features. For example, some may develop a penis. Some affected males may be born with a small penis, which is usually less than 1 cm, and may look similar to a clitoris. Those who develop a penis may be born with a feature called hypospadias, in which the opening of the penis is on the underside. As a result, boys with hypospadias may have issues urinating in certain directions. During puberty, people with PAIS may also develop a bifid scrotum, in which their scrotum area may separated by a groove into two parts.
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Symptoms of Partial Androgen Insensitivity Syndrome. Characteristics of partial androgen sensitivity syndrome vary from person. Each person with PAIS is unique and may not have the same features.
Some people with PAIS may have more female-appearing features. For example, some can be born with female-appearing genitals but may have an enlarged clitoris (clitoromegaly) or fusion of certain areas of the labia. In addition, some individuals may be born with openings of a female-appearing urethra (duct where urine is released from the bladder to outside the body) and vagina. However, individuals with PAIS do not have female sex organs such as a uterus and ovaries. Some people with this condition may have undescended testes, in which one or both testicles are not able to descend completely by puberty. Because they do not have ovaries and may have issues with the development of the testes, many people with PAIS are infertile, because they produce no or very little sperm. Also, some individuals with PAIS may develop breasts (gynecomastia) during puberty.Other people with PAIS may have more male-appearing features. For example, some may develop a penis. Some affected males may be born with a small penis, which is usually less than 1 cm, and may look similar to a clitoris. Those who develop a penis may be born with a feature called hypospadias, in which the opening of the penis is on the underside. As a result, boys with hypospadias may have issues urinating in certain directions. During puberty, people with PAIS may also develop a bifid scrotum, in which their scrotum area may separated by a groove into two parts.
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Partial Androgen Insensitivity Syndrome
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Causes of Partial Androgen Insensitivity Syndrome
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Partial androgen insensitivity syndrome is a genetic condition that is inherited in an X-linked recessive pattern. The gene related to partial androgen sensitivity syndrome is the AR gene, which is located on the X chromosome. When people have a change in the AR gene, their bodies may have issues producing androgen receptors, which are structures in cells that allow the body to properly respond to androgens (male sex hormones). Because of problems with the androgen receptors, people with changes in the AR gene have the characteristics of partial androgen sensitivity syndrome.Chromosomes are located in the nucleus of human cells and carry the genetic information (DNA) for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes numbered from 1 through 22 are called autosomes and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome and manifest mostly in males. Females that have an altered gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and only one carries the altered gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains an altered gene he will develop the disease.Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son. If a male with an X-linked disorder is able to reproduce, he will pass the altered gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.
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Causes of Partial Androgen Insensitivity Syndrome. Partial androgen insensitivity syndrome is a genetic condition that is inherited in an X-linked recessive pattern. The gene related to partial androgen sensitivity syndrome is the AR gene, which is located on the X chromosome. When people have a change in the AR gene, their bodies may have issues producing androgen receptors, which are structures in cells that allow the body to properly respond to androgens (male sex hormones). Because of problems with the androgen receptors, people with changes in the AR gene have the characteristics of partial androgen sensitivity syndrome.Chromosomes are located in the nucleus of human cells and carry the genetic information (DNA) for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes numbered from 1 through 22 are called autosomes and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome and manifest mostly in males. Females that have an altered gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and only one carries the altered gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains an altered gene he will develop the disease.Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son. If a male with an X-linked disorder is able to reproduce, he will pass the altered gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.
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Partial Androgen Insensitivity Syndrome
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Affects of Partial Androgen Insensitivity Syndrome
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Partial androgen sensitivity syndrome is very rare in the general population. 1 in 99,000 male infants are born with one of the several androgen sensitivity syndrome types, including PAIS. PAIS only affects males, but females can be carriers for this genetic condition.
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Affects of Partial Androgen Insensitivity Syndrome. Partial androgen sensitivity syndrome is very rare in the general population. 1 in 99,000 male infants are born with one of the several androgen sensitivity syndrome types, including PAIS. PAIS only affects males, but females can be carriers for this genetic condition.
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Partial Androgen Insensitivity Syndrome
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Related disorders of Partial Androgen Insensitivity Syndrome
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Symptoms of the following disorders can be similar to those of partial androgen insensitivity syndrome. Comparisons may be useful for a differential diagnosis.Mild androgen insensitivity syndrome (MAIS) is a genetic condition that is also caused by changes in the AR gene. Males with this condition have normal male external genitals. They may have some breast development during puberty and may also have sparse body hair and a small penis.Complete androgen insensitivity syndrome (CAIS) is a genetic condition also caused by changes in the AR gene. However, in comparison to PAIS, fetuses with CAIS do not respond at all to androgens during pregnancy. Males who are born with CAIS appear female and have external genitals that are female, but do not have female internal sex organs, such as a uterus or ovaries.Congenital adrenal hyperplasia (CAH) is a group of rare inherited autosomal recessive disorders characterized by a deficiency of one of the enzymes needed to make specific hormones. Females with this condition may be born with genitals that look neither male nor female. (For more information on this condition, search for CAH in the Rare Disease Database.)Mayer-Rokitansky-Kuster-Hauser syndrome (MRKH) is a rare disorder characterized by abnormal development of the uterus and vagina. Affected females have normal ovarian function and normal external genitals. Females with this disorder develop normal secondary sexual characteristics during puberty (e.g., breast development and pubic hair), but do not have a menstrual cycle. (For more information on this condition, search for MRKH in the Rare Disease Database.)
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Related disorders of Partial Androgen Insensitivity Syndrome. Symptoms of the following disorders can be similar to those of partial androgen insensitivity syndrome. Comparisons may be useful for a differential diagnosis.Mild androgen insensitivity syndrome (MAIS) is a genetic condition that is also caused by changes in the AR gene. Males with this condition have normal male external genitals. They may have some breast development during puberty and may also have sparse body hair and a small penis.Complete androgen insensitivity syndrome (CAIS) is a genetic condition also caused by changes in the AR gene. However, in comparison to PAIS, fetuses with CAIS do not respond at all to androgens during pregnancy. Males who are born with CAIS appear female and have external genitals that are female, but do not have female internal sex organs, such as a uterus or ovaries.Congenital adrenal hyperplasia (CAH) is a group of rare inherited autosomal recessive disorders characterized by a deficiency of one of the enzymes needed to make specific hormones. Females with this condition may be born with genitals that look neither male nor female. (For more information on this condition, search for CAH in the Rare Disease Database.)Mayer-Rokitansky-Kuster-Hauser syndrome (MRKH) is a rare disorder characterized by abnormal development of the uterus and vagina. Affected females have normal ovarian function and normal external genitals. Females with this disorder develop normal secondary sexual characteristics during puberty (e.g., breast development and pubic hair), but do not have a menstrual cycle. (For more information on this condition, search for MRKH in the Rare Disease Database.)
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Partial Androgen Insensitivity Syndrome
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Diagnosis of Partial Androgen Insensitivity Syndrome
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Because features of partial androgen insensitivity syndrome vary from person to person, there are no standard diagnostic procedures for PAIS. PAIS may be suspected based on clinical features such as female-appearing genitals, absence of female sex organs (ovaries and the uterus), and issues with sperm production. Some laboratory results can help with the diagnosis. For example, if the patient has some physical features of PAIS and is confirmed through genetic testing to have XY chromosomes, it would further support the possibility of PAIS. Some other lab results that could help with diagnosis include having normal or high levels of testosterone (produced by testes) and luteinizing hormone (produced by pituitary gland).To further confirm a diagnosis of PAIS, genetic testing can be done to look for changes in the AR gene. Sometimes genetic testing cannot find any changes in the AR gene. If this is the case, an androgen binding assay may be performed to measure androgen receptors. This assay can also confirm a diagnosis of PAIS.Clinical Testing and Work-Up
Once a patient is diagnosed with PAIS, it is important for the patient to be evaluated by medical providers who specialize in disorders of sex development. Some of these specialists may be from fields of urology, gynecology, clinical genetics, psychiatry, psychology, and endocrinology.
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Diagnosis of Partial Androgen Insensitivity Syndrome. Because features of partial androgen insensitivity syndrome vary from person to person, there are no standard diagnostic procedures for PAIS. PAIS may be suspected based on clinical features such as female-appearing genitals, absence of female sex organs (ovaries and the uterus), and issues with sperm production. Some laboratory results can help with the diagnosis. For example, if the patient has some physical features of PAIS and is confirmed through genetic testing to have XY chromosomes, it would further support the possibility of PAIS. Some other lab results that could help with diagnosis include having normal or high levels of testosterone (produced by testes) and luteinizing hormone (produced by pituitary gland).To further confirm a diagnosis of PAIS, genetic testing can be done to look for changes in the AR gene. Sometimes genetic testing cannot find any changes in the AR gene. If this is the case, an androgen binding assay may be performed to measure androgen receptors. This assay can also confirm a diagnosis of PAIS.Clinical Testing and Work-Up
Once a patient is diagnosed with PAIS, it is important for the patient to be evaluated by medical providers who specialize in disorders of sex development. Some of these specialists may be from fields of urology, gynecology, clinical genetics, psychiatry, psychology, and endocrinology.
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Partial Androgen Insensitivity Syndrome
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Therapies of Partial Androgen Insensitivity Syndrome
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Treatment
Sex assignment is one of the major tasks that is performed after diagnosis of PAIS. Parents should work with their healthcare team in order to make an informed decision about sex assignment. If the patient is reared as a female, then she may receive surgery to remove the male sex organs. She may also be given estrogen (female sex hormone) therapy after puberty. If the patient is reared as a male, then he would be given testosterone therapy and surgery to repair the male sex organs and remove the breasts (gynecomastia).Some people with PAIS have sex assignment at birth, while others may have it after puberty. This decision is usually based on the circumstances and input of the family, the patient, and medical providers.Genetic counseling is recommended for patients and their families.
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Therapies of Partial Androgen Insensitivity Syndrome. Treatment
Sex assignment is one of the major tasks that is performed after diagnosis of PAIS. Parents should work with their healthcare team in order to make an informed decision about sex assignment. If the patient is reared as a female, then she may receive surgery to remove the male sex organs. She may also be given estrogen (female sex hormone) therapy after puberty. If the patient is reared as a male, then he would be given testosterone therapy and surgery to repair the male sex organs and remove the breasts (gynecomastia).Some people with PAIS have sex assignment at birth, while others may have it after puberty. This decision is usually based on the circumstances and input of the family, the patient, and medical providers.Genetic counseling is recommended for patients and their families.
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Partial Androgen Insensitivity Syndrome
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Overview of PCSK1 Deficiency
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SummaryPCSK1 deficiency is a very rare inherited disorder that affects the metabolism and appetite. Severe diarrhea, digestive problems and slow growth are the earliest symptoms, followed by extreme hunger and obesity in early childhood. Excessive thirst and frequent urination (polyuria polydipsia syndrome) are common. Other symptoms related to abnormalities of the endocrine glands include growth hormone deficiency, low thyroid hormone and adrenal gland disorders. Other symptoms include delayed puberty and low energy. PCSK1 deficiency is caused by changes (pathogenic variants or mutations) in the PCSK1 gene and is inherited in an autosomal recessive pattern. Diagnosis is based on a clinical examination, symptoms, laboratory testing and genetic testing. Treatment is available for this condition using a drug called setmelanotide.IntroductionPCSK1 deficiency was first described in 1995. This condition is rare, making it difficult to predict exactly how it will affect someone who is newly diagnosed with this condition. It is one of several conditions that include early-onset obesity, and these conditions can be difficult to distinguish from each other without a careful physical examination and genetic testing.
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Overview of PCSK1 Deficiency. SummaryPCSK1 deficiency is a very rare inherited disorder that affects the metabolism and appetite. Severe diarrhea, digestive problems and slow growth are the earliest symptoms, followed by extreme hunger and obesity in early childhood. Excessive thirst and frequent urination (polyuria polydipsia syndrome) are common. Other symptoms related to abnormalities of the endocrine glands include growth hormone deficiency, low thyroid hormone and adrenal gland disorders. Other symptoms include delayed puberty and low energy. PCSK1 deficiency is caused by changes (pathogenic variants or mutations) in the PCSK1 gene and is inherited in an autosomal recessive pattern. Diagnosis is based on a clinical examination, symptoms, laboratory testing and genetic testing. Treatment is available for this condition using a drug called setmelanotide.IntroductionPCSK1 deficiency was first described in 1995. This condition is rare, making it difficult to predict exactly how it will affect someone who is newly diagnosed with this condition. It is one of several conditions that include early-onset obesity, and these conditions can be difficult to distinguish from each other without a careful physical examination and genetic testing.
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PCSK1 Deficiency
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Symptoms of PCSK1 Deficiency
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The symptoms of PCSK1 deficiency are due to abnormalities of the endocrine glands. The endocrine glands make hormones that affect growth, sexual development, blood pressure and the way the body makes and uses energy. Babies with PCSK1 deficiency develop severe diarrhea and digestive problems in the first few months of life. Symptoms may last for several months and lead to poor growth and weight gain. Sometimes, the diarrhea is severe enough to lead to hospitalization. These symptoms eventually get better and other symptoms related to endocrine gland abnormalities develop. These include uncontrollable hunger and early-onset obesity which continues through adulthood. Other symptoms include the inability to absorb salt and water, causing extreme thirst (polydipsia) and frequent urination (polyuria). Other endocrine problems include low levels of sex hormones, thyroid gland insufficiency and growth hormone deficiency. Puberty may be delayed or absent. Adults with PCSK1 deficiency are shorter than average and obese.
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Symptoms of PCSK1 Deficiency. The symptoms of PCSK1 deficiency are due to abnormalities of the endocrine glands. The endocrine glands make hormones that affect growth, sexual development, blood pressure and the way the body makes and uses energy. Babies with PCSK1 deficiency develop severe diarrhea and digestive problems in the first few months of life. Symptoms may last for several months and lead to poor growth and weight gain. Sometimes, the diarrhea is severe enough to lead to hospitalization. These symptoms eventually get better and other symptoms related to endocrine gland abnormalities develop. These include uncontrollable hunger and early-onset obesity which continues through adulthood. Other symptoms include the inability to absorb salt and water, causing extreme thirst (polydipsia) and frequent urination (polyuria). Other endocrine problems include low levels of sex hormones, thyroid gland insufficiency and growth hormone deficiency. Puberty may be delayed or absent. Adults with PCSK1 deficiency are shorter than average and obese.
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PCSK1 Deficiency
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Causes of PCSK1 Deficiency
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PCSK1 deficiency is caused by pathogenic variants (mutations) in the PCSK1 gene. This gene makes a protein that plays an important role in processing many of the endocrine gland hormones involved in energy, metabolism and appetite regulation. When the PCSK1 gene is not working, these hormones don’t work correctly.PCSK1 deficiency is inherited in families in a recessive pattern. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.
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Causes of PCSK1 Deficiency. PCSK1 deficiency is caused by pathogenic variants (mutations) in the PCSK1 gene. This gene makes a protein that plays an important role in processing many of the endocrine gland hormones involved in energy, metabolism and appetite regulation. When the PCSK1 gene is not working, these hormones don’t work correctly.PCSK1 deficiency is inherited in families in a recessive pattern. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.
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PCSK1 Deficiency
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Affects of PCSK1 Deficiency
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PCSK1 deficiency is very rare and has been reported in less than 50 people. Many of the people that have been diagnosed with this condition are from Turkey and the Middle East. It has been diagnosed more often in populations where marriage between relatives is customary.
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Affects of PCSK1 Deficiency. PCSK1 deficiency is very rare and has been reported in less than 50 people. Many of the people that have been diagnosed with this condition are from Turkey and the Middle East. It has been diagnosed more often in populations where marriage between relatives is customary.
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PCSK1 Deficiency
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Related disorders of PCSK1 Deficiency
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PCSK1 deficiency is one of several rare inherited conditions that lead to early-onset obesity. These conditions are due to variants in one of the genes that normally work together to help regulate hunger and energy production. These conditions may be difficult to diagnose based solely on clinical examination. Severe diarrhea in infancy may set PCSK1 deficiency apart from other early-onset obesity conditions, but often genetic testing is the only way to tell the difference between them. Some (but not all) of these conditions include:POMC deficiencyPOMC deficiency affects the way the body stores and uses energy. The main symptoms include constant hunger and excessive feeding, known as hyperphagia. Hyperphagia leads to obesity by one year of age, and without treatment, people with POMC deficiency remain obese throughout life. Other symptoms include low levels of a hormone called adrenocorticotropic hormone (ACTH) and adrenal insufficiency, which can be fatal if not treated early. Many individuals with POMC deficiency also have pale skin and hair. POMC deficiency is caused by variants in the POMC gene and is inherited in an autosomal recessive pattern. Diagnosis is based on a clinical examination, symptoms and genetic testing. Treatment is available for people with POMC deficiency over the age of six using a drug called setmelanotide. This drug reverses the constant hunger and allows people with POMC deficiency to lose weight. This condition is very rare, and it is difficult to predict how this condition will impact someone with a new diagnosis.Congenital leptin deficiencyObesity due to congenital leptin deficiency (CLD) is a rare, inherited condition that affects how the body processes energy, responds to food and stores fat. Infants with CLD are constantly hungry and quickly gain weight and become obese. Children with CLD have extreme hunger (hyperphagia), low energy and abnormal behaviors related to food. Many people with CLD produce little or no sex hormones (hypogonadotropic hypogonadism) resulting in late or absent puberty and infertility. CLD is caused by variants in the LEP gene, which is responsible for making a protein called leptin. Leptin is important for regulating appetite and growth of body fat. This condition is inherited in an autosomal recessive pattern. Diagnosis is based on a clinical examination, symptoms and genetic testing. Diet, behavior modification, exercise programs and bariatric surgery have been used to help manage the symptoms of CLD. Treatment is available for this condition using a drug called metreleptin, a recombinant form of human leptin, which reverses the symptoms of CLD. With treatment, people with CLD develop a normal appetite, lose weight and fat and regain normal sex hormone levels.Leptin receptor deficiency (LEPR) deficiency Individuals with LEPR deficiency have almost the same symptoms as individuals with congenital leptin deficiency. Early symptoms of both conditions include constant hunger and feeding (hyperphagia) and rapid weight gain leading to obesity in the first few months of life. In addition, endocrine gland abnormalities affecting levels of sex hormones are common, and puberty may be absent or delayed. This condition is due to variants in the LEPR gene and is inherited in a recessive pattern. Diagnosis is based on a clinical exam, symptoms and genetic testing. Treatment is available for this condition using setmelanotide, which decreases appetite and increases levels of sex hormones.There are other inherited conditions that include obesity in childhood as one of several features. People with these conditions have other signs and symptoms along with excess weight. These conditions include:Bardet-Biedl syndrome (BBS)BBS impacts multiple body systems and is classically defined by six features. People with BBS gain excessive weight, especially around the abdomen. They often also often have intellectual disabilities. The kidneys, eyes and function of the genitalia may be compromised. People with BBS may also be born with an extra digit on the hands. The severity and symptoms of BBS vary greatly, even among individuals in the same family. For more information on this disorder, choose “Bardet-Biedl syndrome” as your search term in the Rare Disease Database. https://rarediseases.org/rare-diseases/bardet-biedl-syndrome/Alström syndromeAlström syndrome is a rare complex disorder that includes with a wide variety of symptoms affecting multiple organ systems of the body. The disorder is characterized by vision and hearing abnormalities, obesity in childhood, insulin resistance and diabetes mellitus. Other symptoms include heart disease (dilated cardiomyopathy) and slowly progressive kidney dysfunction, potentially leading to kidney failure. Additional symptoms include lung, liver, kidney and endocrine dysfunction. Although some children may experience delays in reaching developmental milestones, intelligence is usually unaffected. Alström syndrome is caused by variants in the ALMS1 gene. The protein made by this gene is involved in ciliary function, cell cycle control and intracellular transport. Alström syndrome is inherited in an autosomal recessive pattern. For more information on this disorder, choose “Alstrom syndrome” as your search term in the Rare Disease Database. https://rarediseases.org/rare-diseases/alstrom-syndrome/Prader-Willi syndromePrader-Willi syndrome (PWS) is a multisystem disorder characterized during infancy by lethargy, diminished muscle tone (hypotonia), a weak suck and feeding difficulties with poor weight gain and growth and other hormone deficiencies. In childhood, features of this disorder include short stature, small genitals and an excessive appetite. Affected individuals do not feel satisfied after completing a meal (satiety). Without intervention, overeating can lead to life-threatening obesity. The food compulsion requires constant supervision. Individuals with severe obesity may have an increased risk of cardiac insufficiency, sleep apnea, diabetes, respiratory problems and other serious conditions that can cause life-threatening complications. All individuals with PWS have some cognitive impairment that ranges from low normal intelligence with learning disabilities to mild to moderate intellectual disability. Behavioral problems are common and can include temper tantrums, obsessive/compulsive behavior and skin picking. Motor milestones and language development are often delayed. PWS occurs due to deletions of specific genes on part of the chromosome 15 inherited from the father. This condition is referred to as a genomic imprinting disorder which depends on which parent passes on the chromosome with the genetic changes to the child. For more information on this disorder, choose “Prader-Willi syndrome” as your search term in the Rare Disease Database. https://rarediseases.org/rare-diseases/prader-willi-syndrome/
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Related disorders of PCSK1 Deficiency. PCSK1 deficiency is one of several rare inherited conditions that lead to early-onset obesity. These conditions are due to variants in one of the genes that normally work together to help regulate hunger and energy production. These conditions may be difficult to diagnose based solely on clinical examination. Severe diarrhea in infancy may set PCSK1 deficiency apart from other early-onset obesity conditions, but often genetic testing is the only way to tell the difference between them. Some (but not all) of these conditions include:POMC deficiencyPOMC deficiency affects the way the body stores and uses energy. The main symptoms include constant hunger and excessive feeding, known as hyperphagia. Hyperphagia leads to obesity by one year of age, and without treatment, people with POMC deficiency remain obese throughout life. Other symptoms include low levels of a hormone called adrenocorticotropic hormone (ACTH) and adrenal insufficiency, which can be fatal if not treated early. Many individuals with POMC deficiency also have pale skin and hair. POMC deficiency is caused by variants in the POMC gene and is inherited in an autosomal recessive pattern. Diagnosis is based on a clinical examination, symptoms and genetic testing. Treatment is available for people with POMC deficiency over the age of six using a drug called setmelanotide. This drug reverses the constant hunger and allows people with POMC deficiency to lose weight. This condition is very rare, and it is difficult to predict how this condition will impact someone with a new diagnosis.Congenital leptin deficiencyObesity due to congenital leptin deficiency (CLD) is a rare, inherited condition that affects how the body processes energy, responds to food and stores fat. Infants with CLD are constantly hungry and quickly gain weight and become obese. Children with CLD have extreme hunger (hyperphagia), low energy and abnormal behaviors related to food. Many people with CLD produce little or no sex hormones (hypogonadotropic hypogonadism) resulting in late or absent puberty and infertility. CLD is caused by variants in the LEP gene, which is responsible for making a protein called leptin. Leptin is important for regulating appetite and growth of body fat. This condition is inherited in an autosomal recessive pattern. Diagnosis is based on a clinical examination, symptoms and genetic testing. Diet, behavior modification, exercise programs and bariatric surgery have been used to help manage the symptoms of CLD. Treatment is available for this condition using a drug called metreleptin, a recombinant form of human leptin, which reverses the symptoms of CLD. With treatment, people with CLD develop a normal appetite, lose weight and fat and regain normal sex hormone levels.Leptin receptor deficiency (LEPR) deficiency Individuals with LEPR deficiency have almost the same symptoms as individuals with congenital leptin deficiency. Early symptoms of both conditions include constant hunger and feeding (hyperphagia) and rapid weight gain leading to obesity in the first few months of life. In addition, endocrine gland abnormalities affecting levels of sex hormones are common, and puberty may be absent or delayed. This condition is due to variants in the LEPR gene and is inherited in a recessive pattern. Diagnosis is based on a clinical exam, symptoms and genetic testing. Treatment is available for this condition using setmelanotide, which decreases appetite and increases levels of sex hormones.There are other inherited conditions that include obesity in childhood as one of several features. People with these conditions have other signs and symptoms along with excess weight. These conditions include:Bardet-Biedl syndrome (BBS)BBS impacts multiple body systems and is classically defined by six features. People with BBS gain excessive weight, especially around the abdomen. They often also often have intellectual disabilities. The kidneys, eyes and function of the genitalia may be compromised. People with BBS may also be born with an extra digit on the hands. The severity and symptoms of BBS vary greatly, even among individuals in the same family. For more information on this disorder, choose “Bardet-Biedl syndrome” as your search term in the Rare Disease Database. https://rarediseases.org/rare-diseases/bardet-biedl-syndrome/Alström syndromeAlström syndrome is a rare complex disorder that includes with a wide variety of symptoms affecting multiple organ systems of the body. The disorder is characterized by vision and hearing abnormalities, obesity in childhood, insulin resistance and diabetes mellitus. Other symptoms include heart disease (dilated cardiomyopathy) and slowly progressive kidney dysfunction, potentially leading to kidney failure. Additional symptoms include lung, liver, kidney and endocrine dysfunction. Although some children may experience delays in reaching developmental milestones, intelligence is usually unaffected. Alström syndrome is caused by variants in the ALMS1 gene. The protein made by this gene is involved in ciliary function, cell cycle control and intracellular transport. Alström syndrome is inherited in an autosomal recessive pattern. For more information on this disorder, choose “Alstrom syndrome” as your search term in the Rare Disease Database. https://rarediseases.org/rare-diseases/alstrom-syndrome/Prader-Willi syndromePrader-Willi syndrome (PWS) is a multisystem disorder characterized during infancy by lethargy, diminished muscle tone (hypotonia), a weak suck and feeding difficulties with poor weight gain and growth and other hormone deficiencies. In childhood, features of this disorder include short stature, small genitals and an excessive appetite. Affected individuals do not feel satisfied after completing a meal (satiety). Without intervention, overeating can lead to life-threatening obesity. The food compulsion requires constant supervision. Individuals with severe obesity may have an increased risk of cardiac insufficiency, sleep apnea, diabetes, respiratory problems and other serious conditions that can cause life-threatening complications. All individuals with PWS have some cognitive impairment that ranges from low normal intelligence with learning disabilities to mild to moderate intellectual disability. Behavioral problems are common and can include temper tantrums, obsessive/compulsive behavior and skin picking. Motor milestones and language development are often delayed. PWS occurs due to deletions of specific genes on part of the chromosome 15 inherited from the father. This condition is referred to as a genomic imprinting disorder which depends on which parent passes on the chromosome with the genetic changes to the child. For more information on this disorder, choose “Prader-Willi syndrome” as your search term in the Rare Disease Database. https://rarediseases.org/rare-diseases/prader-willi-syndrome/
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PCSK1 Deficiency
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nord_945_5
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Diagnosis of PCSK1 Deficiency
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PCSK1 deficiency is diagnosed based on a clinical examination, symptoms and the results of blood and genetic testing. Severe malabsorptive diarrhea is one of the first symptoms of PCSK1 deficiency, but has many other, more common causes. Because of that, PCSK1 deficiency is often not diagnosed until the other symptoms, especially early-onset obesity become apparent.Because there are several inherited conditions that include excessive hunger and early onset obesity, genetic testing may be used to help make a specific diagnosis. This testing often involves using a gene panel, allowing the lab to look for genetic variants in several different genes at the same time. Genetic testing is usually done with a blood or saliva sample. It is helpful to speak to a genetics professional prior to having genetic testing to learn more about the risk, benefits and limitations.
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Diagnosis of PCSK1 Deficiency. PCSK1 deficiency is diagnosed based on a clinical examination, symptoms and the results of blood and genetic testing. Severe malabsorptive diarrhea is one of the first symptoms of PCSK1 deficiency, but has many other, more common causes. Because of that, PCSK1 deficiency is often not diagnosed until the other symptoms, especially early-onset obesity become apparent.Because there are several inherited conditions that include excessive hunger and early onset obesity, genetic testing may be used to help make a specific diagnosis. This testing often involves using a gene panel, allowing the lab to look for genetic variants in several different genes at the same time. Genetic testing is usually done with a blood or saliva sample. It is helpful to speak to a genetics professional prior to having genetic testing to learn more about the risk, benefits and limitations.
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PCSK1 Deficiency
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Therapies of PCSK1 Deficiency
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In early childhood, treatments for obesity may include weight management through diet and behavioral therapies. Gastric bypass surgery has been tried in at least one patient. Several medications are available for treating obesity, although all have limited effectiveness and may have side effects. Most of these treatments do not result in permanent weight loss.Setmelanotide has been approved by the U.S. Food and Drug Administration (FDA) for people six years and older with obesity due to PCSK1 deficiency which has been confirmed by genetic testing. People taking setmelanotide are able to control their appetite, lose weight and maintain weight loss.In addition, growth hormone may be given to increase height and other hormones may be given if they are deficient.People with PCSK1 deficiency may be treated by a variety of different medical specialists, including gastroenterologists, nutritionists and endocrinologists. A psychologist or other mental health professional can help people cope with the symptoms of this condition.
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Therapies of PCSK1 Deficiency. In early childhood, treatments for obesity may include weight management through diet and behavioral therapies. Gastric bypass surgery has been tried in at least one patient. Several medications are available for treating obesity, although all have limited effectiveness and may have side effects. Most of these treatments do not result in permanent weight loss.Setmelanotide has been approved by the U.S. Food and Drug Administration (FDA) for people six years and older with obesity due to PCSK1 deficiency which has been confirmed by genetic testing. People taking setmelanotide are able to control their appetite, lose weight and maintain weight loss.In addition, growth hormone may be given to increase height and other hormones may be given if they are deficient.People with PCSK1 deficiency may be treated by a variety of different medical specialists, including gastroenterologists, nutritionists and endocrinologists. A psychologist or other mental health professional can help people cope with the symptoms of this condition.
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PCSK1 Deficiency
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Overview of Pediatric Cardiomyopathy
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Pediatric cardiomyopathy is a rare heart condition that affects infants and children. Specifically, cardiomyopathy means disease of the heart muscle (myocardium). Several different types of cardiomyopathies exist, and the specific symptoms vary from person to person. In some affected individuals, no symptoms may be present (asymptomatic); in many people, cardiomyopathy is a progressive condition that may result in an impaired ability of the heart to pump blood; fatigue; heart block resulting in a very slow heart rate (bradycardia); irregular or rapid heartbeats (tachycardia); and, potentially, heart failure and sudden cardiac death.Cardiomyopathy may be termed ischemic or nonischemic. Ischemic cardiomyopathy refers to a lack of blood flow and oxygen (ischemia) to the heart and in pediatrics is due to a congenital abnormality of the blood vessels that supply the heart (coronary arteries). Nonischemic cardiomyopathy refers to structural damage or malfunction of the heart muscle due to causes other than coronary artery abnormalities. Nearly all patients with pediatric cardiomyopathy have the nonischemic type. This report deals with nonischemic pediatric cardiomyopathy.Cardiomyopathy may also be termed primary or secondary. Primary cardiomyopathy occurs by itself (no other parts of the body are involved) due to a genetic abnormality or an external cause such as heart muscle inflammation (myocarditis) caused by viral or bacterial infections; exposure to certain toxins such as heavy metals or excessive alcohol use. Some disorders affect the heart in addition to additional organ systems and this is called secondary cardiomyopathy. According to the Pediatric Cardiomyopathy Registry, approximately 79 percent of pediatric cardiomyopathy is idiopathic (that is, the cause is unknown).Cardiomyopathy has traditionally been divided into three basic subtypes based upon the specific changes within the heart. These subtypes are dilated, hypertrophic and restrictive. There are several other less common forms such as arrhythmogenic right ventricular dysplasia, noncompaction and others where it is controversial whether they are subtypes of the three principal forms or should be considered as completely different diseases.
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Overview of Pediatric Cardiomyopathy. Pediatric cardiomyopathy is a rare heart condition that affects infants and children. Specifically, cardiomyopathy means disease of the heart muscle (myocardium). Several different types of cardiomyopathies exist, and the specific symptoms vary from person to person. In some affected individuals, no symptoms may be present (asymptomatic); in many people, cardiomyopathy is a progressive condition that may result in an impaired ability of the heart to pump blood; fatigue; heart block resulting in a very slow heart rate (bradycardia); irregular or rapid heartbeats (tachycardia); and, potentially, heart failure and sudden cardiac death.Cardiomyopathy may be termed ischemic or nonischemic. Ischemic cardiomyopathy refers to a lack of blood flow and oxygen (ischemia) to the heart and in pediatrics is due to a congenital abnormality of the blood vessels that supply the heart (coronary arteries). Nonischemic cardiomyopathy refers to structural damage or malfunction of the heart muscle due to causes other than coronary artery abnormalities. Nearly all patients with pediatric cardiomyopathy have the nonischemic type. This report deals with nonischemic pediatric cardiomyopathy.Cardiomyopathy may also be termed primary or secondary. Primary cardiomyopathy occurs by itself (no other parts of the body are involved) due to a genetic abnormality or an external cause such as heart muscle inflammation (myocarditis) caused by viral or bacterial infections; exposure to certain toxins such as heavy metals or excessive alcohol use. Some disorders affect the heart in addition to additional organ systems and this is called secondary cardiomyopathy. According to the Pediatric Cardiomyopathy Registry, approximately 79 percent of pediatric cardiomyopathy is idiopathic (that is, the cause is unknown).Cardiomyopathy has traditionally been divided into three basic subtypes based upon the specific changes within the heart. These subtypes are dilated, hypertrophic and restrictive. There are several other less common forms such as arrhythmogenic right ventricular dysplasia, noncompaction and others where it is controversial whether they are subtypes of the three principal forms or should be considered as completely different diseases.
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Pediatric Cardiomyopathy
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Symptoms of Pediatric Cardiomyopathy
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The specific symptoms of pediatric cardiomyopathy depend upon the type of cardiomyopathy present. Many individuals with cardiomyopathy will not exhibit any symptoms (asymptomatic) throughout life. Common symptoms of cardiomyopathy that may occur include fatigue, shortness of breath (dyspnea) especially with exertion and chest pain. Additional symptoms potentially associated with all forms of cardiomyopathy include irregular heartbeats (arrhythmias) such as abnormally fast (tachycardia) or slow (bradycardia) heartbeats. In some individuals, cardiomyopathy may progress to cause congestive heart failure, cardiac arrest and sudden death. Cardiomyopathy can be present at birth or have new onset at any age, and even in the presence of cardiomyopathy symptoms may or may not be present.The normal heart has four chambers. The two upper chambers, known as atria, are separated from each other by a fibrous partition known as the atrial septum. The two lower chambers are known as ventricles and are separated from each other by muscular wall (the ventricular septum). Valves connect the atria (left and right) to their respective ventricles. The valves allow for blood to be pumped through the chambers and prevent the flow from going backwards. Blood travels from the right ventricle through the pulmonary artery to the lungs where it receives oxygen. The blood returns to the heart through pulmonary veins and enters the left ventricle. The left ventricle sends the now oxygen-filled blood into the main artery of the body (aorta). The aorta distributes the blood throughout the body.The various forms of nonischemic cardiomyopathy occur because of structural damage and malfunction of the heart muscle itself. For most people with nonischemic cardiomyopathy, the main pumping chamber of the heart (left ventricle) is affected. However, the right ventricle and the atria may also become involved.Dilated Cardiomyopathy
Dilated cardiomyopathy is characterized by abnormal enlargement (dilatation) of the left and/or right ventricle because of a weakening of the heart muscle, reducing the strength of the pumping action. This results in a limited ability to circulate blood to the lungs and the rest of the body which may result in fluid buildup in the lungs and various body tissues, a condition known as congestive heart failure. In some individuals, all four chambers of the heart may be affected. Symptoms of congestive heart failure may depend upon an affected child’s age and other factors. In young children, for example, heart failure may manifest as fatigue and shortness of breath (dyspnea) upon exertion. Additional symptoms may include swelling of the legs and feet and, in some people, chest pain. Initial symptoms of dilated cardiomyopathy in infants and children may include irritability, a persistent cough, shortness of breath and poor feeding resulting in the failure to gain weight at the expected rate (failure to thrive). Affected individuals may also experience excessive sweating, fatigue, wheezing and paleness of the skin (pallor). More serious complications may include fainting episodes (syncope), abdominal pain, irregular heartbeats and fluid accumulation within the lungs (pulmonary congestion) resulting in a persistent cough.Hypertrophic Cardiomyopathy
Hypertrophic cardiomyopathy is a disease of the heart muscle characterized by abnormal thickening of the walls of the heart potentially resulting in obstruction of blood flow in and out of the heart. In most patients, the left ventricle is primarily affected. The symptoms of hypertrophic cardiomyopathy vary widely among affected individuals. In many cases, affected individuals have no symptoms. Affected infants and children may experience shortness of breath upon exertion, fatigue, excessive sweating and poor appetite and weight gain resulting in growth failure. As affected children age, they may experience chest pain or discomfort, irregular heartbeats, dizziness or fainting episodes (syncope) usually upon heavy exertion, and some eventually develop congestive heart failure and fluid accumulation within the lungs. In some cases, affected individuals may experience sudden cardiac arrest and, potentially, sudden death.Restrictive Cardiomyopathy
Restrictive cardiomyopathy is extremely rare in children. In this form of cardiomyopathy, the muscular walls of the heart become stiff, impeding blood flow into the heart. Symptoms associated with restrictive cardiomyopathy in infants and children include shortness of breath, fatigue, chest pain and poor appetite and weight gain, resulting in growth failure. Additional symptoms may include fluid collection in the abdomen (ascites) and feet, congestion of the lungs and an abnormally large liver (hepatomegaly). Irregular heartbeats, the formation of blood clots and heart block may also occur. Restrictive cardiomyopathy may progress to cause congestive heart failure and sudden death.Arrhythmogenic Right Ventricular Dysplasia
Arrhythmogenic right ventricular dysplasia (ARVD) is a rare form of nonischemic cardiomyopathy in which the normal muscular tissue of the right ventricle is replaced by fatty tissue and may also occasionally affect the left ventricle. The symptoms of ARVD vary greatly. Symptoms may develop during childhood, but in most people do not appear until their 30s or 40s. Symptoms associated with ARVD may include irregular heartbeats (arrhythmias), shortness of breath, swollen neck veins, abdominal discomfort and fainting episodes (syncope). In some patients, no symptoms are apparent until an affected individual goes into cardiac arrest and possibly sudden death.
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Symptoms of Pediatric Cardiomyopathy. The specific symptoms of pediatric cardiomyopathy depend upon the type of cardiomyopathy present. Many individuals with cardiomyopathy will not exhibit any symptoms (asymptomatic) throughout life. Common symptoms of cardiomyopathy that may occur include fatigue, shortness of breath (dyspnea) especially with exertion and chest pain. Additional symptoms potentially associated with all forms of cardiomyopathy include irregular heartbeats (arrhythmias) such as abnormally fast (tachycardia) or slow (bradycardia) heartbeats. In some individuals, cardiomyopathy may progress to cause congestive heart failure, cardiac arrest and sudden death. Cardiomyopathy can be present at birth or have new onset at any age, and even in the presence of cardiomyopathy symptoms may or may not be present.The normal heart has four chambers. The two upper chambers, known as atria, are separated from each other by a fibrous partition known as the atrial septum. The two lower chambers are known as ventricles and are separated from each other by muscular wall (the ventricular septum). Valves connect the atria (left and right) to their respective ventricles. The valves allow for blood to be pumped through the chambers and prevent the flow from going backwards. Blood travels from the right ventricle through the pulmonary artery to the lungs where it receives oxygen. The blood returns to the heart through pulmonary veins and enters the left ventricle. The left ventricle sends the now oxygen-filled blood into the main artery of the body (aorta). The aorta distributes the blood throughout the body.The various forms of nonischemic cardiomyopathy occur because of structural damage and malfunction of the heart muscle itself. For most people with nonischemic cardiomyopathy, the main pumping chamber of the heart (left ventricle) is affected. However, the right ventricle and the atria may also become involved.Dilated Cardiomyopathy
Dilated cardiomyopathy is characterized by abnormal enlargement (dilatation) of the left and/or right ventricle because of a weakening of the heart muscle, reducing the strength of the pumping action. This results in a limited ability to circulate blood to the lungs and the rest of the body which may result in fluid buildup in the lungs and various body tissues, a condition known as congestive heart failure. In some individuals, all four chambers of the heart may be affected. Symptoms of congestive heart failure may depend upon an affected child’s age and other factors. In young children, for example, heart failure may manifest as fatigue and shortness of breath (dyspnea) upon exertion. Additional symptoms may include swelling of the legs and feet and, in some people, chest pain. Initial symptoms of dilated cardiomyopathy in infants and children may include irritability, a persistent cough, shortness of breath and poor feeding resulting in the failure to gain weight at the expected rate (failure to thrive). Affected individuals may also experience excessive sweating, fatigue, wheezing and paleness of the skin (pallor). More serious complications may include fainting episodes (syncope), abdominal pain, irregular heartbeats and fluid accumulation within the lungs (pulmonary congestion) resulting in a persistent cough.Hypertrophic Cardiomyopathy
Hypertrophic cardiomyopathy is a disease of the heart muscle characterized by abnormal thickening of the walls of the heart potentially resulting in obstruction of blood flow in and out of the heart. In most patients, the left ventricle is primarily affected. The symptoms of hypertrophic cardiomyopathy vary widely among affected individuals. In many cases, affected individuals have no symptoms. Affected infants and children may experience shortness of breath upon exertion, fatigue, excessive sweating and poor appetite and weight gain resulting in growth failure. As affected children age, they may experience chest pain or discomfort, irregular heartbeats, dizziness or fainting episodes (syncope) usually upon heavy exertion, and some eventually develop congestive heart failure and fluid accumulation within the lungs. In some cases, affected individuals may experience sudden cardiac arrest and, potentially, sudden death.Restrictive Cardiomyopathy
Restrictive cardiomyopathy is extremely rare in children. In this form of cardiomyopathy, the muscular walls of the heart become stiff, impeding blood flow into the heart. Symptoms associated with restrictive cardiomyopathy in infants and children include shortness of breath, fatigue, chest pain and poor appetite and weight gain, resulting in growth failure. Additional symptoms may include fluid collection in the abdomen (ascites) and feet, congestion of the lungs and an abnormally large liver (hepatomegaly). Irregular heartbeats, the formation of blood clots and heart block may also occur. Restrictive cardiomyopathy may progress to cause congestive heart failure and sudden death.Arrhythmogenic Right Ventricular Dysplasia
Arrhythmogenic right ventricular dysplasia (ARVD) is a rare form of nonischemic cardiomyopathy in which the normal muscular tissue of the right ventricle is replaced by fatty tissue and may also occasionally affect the left ventricle. The symptoms of ARVD vary greatly. Symptoms may develop during childhood, but in most people do not appear until their 30s or 40s. Symptoms associated with ARVD may include irregular heartbeats (arrhythmias), shortness of breath, swollen neck veins, abdominal discomfort and fainting episodes (syncope). In some patients, no symptoms are apparent until an affected individual goes into cardiac arrest and possibly sudden death.
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Pediatric Cardiomyopathy
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Causes of Pediatric Cardiomyopathy
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Most cases of pediatric cardiomyopathy occur for unknown reasons (idiopathic). Pediatric cardiomyopathy may be inherited or acquired. In recent years, investigators have determined that the cause of pediatric cardiomyopathy in many children may be changes (variants or mutations) of certain genes. Researchers have discovered more than 300 different gene variants that may play a role in the development of different forms of cardiomyopathy, and this number continues to grow.In most patients, the cause of dilated cardiomyopathy is unknown (idiopathic). However, dilated cardiomyopathy may be acquired or inherited. The development of dilated cardiomyopathy has been linked to excessive alcohol use, viral or bacterial infections that result in inflammation of the heart muscle (myocarditis), autoimmune disease and metabolic deficiencies. Exposure to certain toxins including heavy metals (e.g., cobalt or lead) and certain chemotherapy drugs may lead to the development of the disorder. Dilated cardiomyopathy may also occur as part of certain endocrine, blood (hematological), and collagen vascular disorders. It can also occur because of congenital heart malformations or acquired heart valve abnormalities that result in an excess workload on the heart.Dilated cardiomyopathy may also occur secondary to a generalized genetic disorder such as one of the muscular dystrophies, certain metabolic disorders or rare genetic disorders such as Barth syndrome. In some cases, dilated cardiomyopathy may be inherited as an isolated genetic condition (familial dilated cardiomyopathy). It has been estimated that genetic factors play a role in more than 30 percent of dilated cardiomyopathy. Most are inherited in an autosomal dominant pattern, but autosomal recessive or X-linked inheritance has also been reported.Dominant genetic disorders occur when only a single copy of a mutated gene is necessary to cause the disease. The mutated gene can be inherited from either parent or can be the result of a changed gene in the affected individual. The risk of passing the mutated gene from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females. Recessive genetic disorders occur when an individual inherits a mutated gene from each parent. If an individual receives one normal gene and one mutated gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the mutated gene and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females. X-linked genetic disorders are conditions caused by a mutated gene on the X chromosome and mostly affect males. Females who have a mutated gene on one of their X chromosomes are carriers for that disorder. Carrier females usually do not have symptoms because females have two X chromosomes and only one carries the mutated gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a mutated gene, he will develop the disease. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son. If a male with an X-linked disorder can reproduce, he will pass the mutated gene to all his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male children. Hypertrophic cardiomyopathy is inherited as an autosomal dominant condition in more than 50 percent of patients. In some people, there is no apparent family history of the disorder. In some of these individuals, hypertrophic cardiomyopathy may be caused by a new gene change that occurs spontaneously for unknown reasons (sporadically). These gene variants may be passed onto future generations in an autosomal dominant pattern. Non-genetic factors, in combination with genetic factors, may play a role in determining who develops hypertrophic cardiomyopathy. In other cases, the cause of hypertrophic cardiomyopathy is unknown (idiopathic).In most patients, restrictive cardiomyopathy occurs secondary to a systemic disorder such as amyloidosis, sarcoidosis or hemochromatosis. In amyloidosis, specific proteins (amyloids) accumulate in the heart resulting in stiffening of the ventricles, which impedes normal filling and contraction of the heart. In sarcoidosis, certain white blood cells abnormally accumulate in the heart. In hemochromatosis, iron accumulates in the heart and facilitates oxygen damage to the heart muscle. Some people with restrictive cardiomyopathy have certain connective tissue diseases.Restrictive cardiomyopathy may also occur because of scarring from open-heart surgery or exposure of the chest to radiation. In a rare subset of cases, restrictive cardiomyopathy has occurred in multiple family members, suggesting that genetic factors may play a role in the development of the disorder. In children, the cause of restrictive cardiomyopathy is unknown in more than 90% of those affected.Genetic factors play a role for most individuals affected with ARVD. For many people, the disorder is inherited in an autosomal dominant pattern. Some people with ARVD may have had an infection of the heart muscle.
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Causes of Pediatric Cardiomyopathy. Most cases of pediatric cardiomyopathy occur for unknown reasons (idiopathic). Pediatric cardiomyopathy may be inherited or acquired. In recent years, investigators have determined that the cause of pediatric cardiomyopathy in many children may be changes (variants or mutations) of certain genes. Researchers have discovered more than 300 different gene variants that may play a role in the development of different forms of cardiomyopathy, and this number continues to grow.In most patients, the cause of dilated cardiomyopathy is unknown (idiopathic). However, dilated cardiomyopathy may be acquired or inherited. The development of dilated cardiomyopathy has been linked to excessive alcohol use, viral or bacterial infections that result in inflammation of the heart muscle (myocarditis), autoimmune disease and metabolic deficiencies. Exposure to certain toxins including heavy metals (e.g., cobalt or lead) and certain chemotherapy drugs may lead to the development of the disorder. Dilated cardiomyopathy may also occur as part of certain endocrine, blood (hematological), and collagen vascular disorders. It can also occur because of congenital heart malformations or acquired heart valve abnormalities that result in an excess workload on the heart.Dilated cardiomyopathy may also occur secondary to a generalized genetic disorder such as one of the muscular dystrophies, certain metabolic disorders or rare genetic disorders such as Barth syndrome. In some cases, dilated cardiomyopathy may be inherited as an isolated genetic condition (familial dilated cardiomyopathy). It has been estimated that genetic factors play a role in more than 30 percent of dilated cardiomyopathy. Most are inherited in an autosomal dominant pattern, but autosomal recessive or X-linked inheritance has also been reported.Dominant genetic disorders occur when only a single copy of a mutated gene is necessary to cause the disease. The mutated gene can be inherited from either parent or can be the result of a changed gene in the affected individual. The risk of passing the mutated gene from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females. Recessive genetic disorders occur when an individual inherits a mutated gene from each parent. If an individual receives one normal gene and one mutated gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the mutated gene and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females. X-linked genetic disorders are conditions caused by a mutated gene on the X chromosome and mostly affect males. Females who have a mutated gene on one of their X chromosomes are carriers for that disorder. Carrier females usually do not have symptoms because females have two X chromosomes and only one carries the mutated gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a mutated gene, he will develop the disease. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son. If a male with an X-linked disorder can reproduce, he will pass the mutated gene to all his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male children. Hypertrophic cardiomyopathy is inherited as an autosomal dominant condition in more than 50 percent of patients. In some people, there is no apparent family history of the disorder. In some of these individuals, hypertrophic cardiomyopathy may be caused by a new gene change that occurs spontaneously for unknown reasons (sporadically). These gene variants may be passed onto future generations in an autosomal dominant pattern. Non-genetic factors, in combination with genetic factors, may play a role in determining who develops hypertrophic cardiomyopathy. In other cases, the cause of hypertrophic cardiomyopathy is unknown (idiopathic).In most patients, restrictive cardiomyopathy occurs secondary to a systemic disorder such as amyloidosis, sarcoidosis or hemochromatosis. In amyloidosis, specific proteins (amyloids) accumulate in the heart resulting in stiffening of the ventricles, which impedes normal filling and contraction of the heart. In sarcoidosis, certain white blood cells abnormally accumulate in the heart. In hemochromatosis, iron accumulates in the heart and facilitates oxygen damage to the heart muscle. Some people with restrictive cardiomyopathy have certain connective tissue diseases.Restrictive cardiomyopathy may also occur because of scarring from open-heart surgery or exposure of the chest to radiation. In a rare subset of cases, restrictive cardiomyopathy has occurred in multiple family members, suggesting that genetic factors may play a role in the development of the disorder. In children, the cause of restrictive cardiomyopathy is unknown in more than 90% of those affected.Genetic factors play a role for most individuals affected with ARVD. For many people, the disorder is inherited in an autosomal dominant pattern. Some people with ARVD may have had an infection of the heart muscle.
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Pediatric Cardiomyopathy
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Affects of Pediatric Cardiomyopathy
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The exact prevalence of pediatric cardiomyopathy in the general population is unknown and estimates vary within the medical literature. However, because children who are asymptomatic often go unrecognized, pediatric cardiomyopathy is under-diagnosed, making it difficult to determine the true frequency of these disorders in the pediatric population.According to the national Pediatric Cardiomyopathy Registry, 1 in every 100,000 children in the United States under the age of 18 is diagnosed with primary cardiomyopathy. This estimate, however, excludes children affected by secondary cardiomyopathy and potentially children who are undiagnosed because they are asymptomatic. Within the pediatric population, cardiomyopathy occurs in approximately 12 children out of every million. Approximately 1,000 to 5,000 children are diagnosed each year in the United States.The estimated incidence of dilated cardiomyopathy is 36.5 per 100,000 children. According to the Pediatric Cardiomyopathy Registry, the estimated incidence of hypertrophic cardiomyopathy is 5 per 1 million children. The overall prevalence of hypertrophic cardiomyopathy is estimated to be less than 0.2 percent of the general population. The prevalence of restrictive cardiomyopathy is unknown. According to one estimate, ARVD occurs in 1 out of 5,000 people in the general population.
Children are much more likely to develop cardiomyopathy early in life. Children are 10 times more likely to develop cardiomyopathy before the age of one than between ages two through 18 combined.Dilated and restrictive cardiomyopathies affect males and females in equal numbers. Hypertrophic cardiomyopathy is slightly more common in males. ARVD affects more males than females. Cardiomyopathy continues to be the leading reason for heart transplants in children.
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Affects of Pediatric Cardiomyopathy. The exact prevalence of pediatric cardiomyopathy in the general population is unknown and estimates vary within the medical literature. However, because children who are asymptomatic often go unrecognized, pediatric cardiomyopathy is under-diagnosed, making it difficult to determine the true frequency of these disorders in the pediatric population.According to the national Pediatric Cardiomyopathy Registry, 1 in every 100,000 children in the United States under the age of 18 is diagnosed with primary cardiomyopathy. This estimate, however, excludes children affected by secondary cardiomyopathy and potentially children who are undiagnosed because they are asymptomatic. Within the pediatric population, cardiomyopathy occurs in approximately 12 children out of every million. Approximately 1,000 to 5,000 children are diagnosed each year in the United States.The estimated incidence of dilated cardiomyopathy is 36.5 per 100,000 children. According to the Pediatric Cardiomyopathy Registry, the estimated incidence of hypertrophic cardiomyopathy is 5 per 1 million children. The overall prevalence of hypertrophic cardiomyopathy is estimated to be less than 0.2 percent of the general population. The prevalence of restrictive cardiomyopathy is unknown. According to one estimate, ARVD occurs in 1 out of 5,000 people in the general population.
Children are much more likely to develop cardiomyopathy early in life. Children are 10 times more likely to develop cardiomyopathy before the age of one than between ages two through 18 combined.Dilated and restrictive cardiomyopathies affect males and females in equal numbers. Hypertrophic cardiomyopathy is slightly more common in males. ARVD affects more males than females. Cardiomyopathy continues to be the leading reason for heart transplants in children.
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Pediatric Cardiomyopathy
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Related disorders of Pediatric Cardiomyopathy
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Related disorders of Pediatric Cardiomyopathy.
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Pediatric Cardiomyopathy
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Diagnosis of Pediatric Cardiomyopathy
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Pediatric cardiomyopathy may be diagnosed based upon a thorough clinical evaluation, identification of characteristic physical findings, a complete patient and family history and a variety of specialized tests. Such tests may include x-ray studies (e.g., computed tomography), electrocardiography (EKG) or echocardiography. An EKG, which records the electrical activities of heart muscle, may reveal abnormal electrical patterns (e.g., resulting in arrhythmias). During an echocardiogram, sound waves are bounced off the heart (echoes), enabling physicians to study cardiac function and structure.Three additional tests that may be performed for evaluation of heart disease are cardiac catheterization, cardiac magnetic resonance imaging (MRI) and radionuclide ventriculogram. During the cardiac catheterization, a small hollow tube (catheter) is inserted into a large vein and threaded through the blood vessels leading to the heart. Cardiac catheterization may enable physicians to withdraw blood to assess oxygen content, measure blood pressure in the heart, evaluate heart function, obtain small samples of myocardial tissue for microscopic evaluation, or thoroughly identify certain anatomical abnormalities. Cardiac MRI generates images of the heart similar to echocardiography but uses magnetic waves instead of sound waves. During radionuclide ventriculogram, tiny amounts of low-dose radioactive materials (tracers) are injected into to a vein and travel into the heart. Tracers release energy that is used by special cameras to produce pictures of the heart chambers.Because certain forms of cardiomyopathy may occur as part of a larger genetic disorder, infants and young children with a diagnosis of cardiomyopathy should receive specific tests to rule out any potentially associated disorders such as metabolic disorders.
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Diagnosis of Pediatric Cardiomyopathy. Pediatric cardiomyopathy may be diagnosed based upon a thorough clinical evaluation, identification of characteristic physical findings, a complete patient and family history and a variety of specialized tests. Such tests may include x-ray studies (e.g., computed tomography), electrocardiography (EKG) or echocardiography. An EKG, which records the electrical activities of heart muscle, may reveal abnormal electrical patterns (e.g., resulting in arrhythmias). During an echocardiogram, sound waves are bounced off the heart (echoes), enabling physicians to study cardiac function and structure.Three additional tests that may be performed for evaluation of heart disease are cardiac catheterization, cardiac magnetic resonance imaging (MRI) and radionuclide ventriculogram. During the cardiac catheterization, a small hollow tube (catheter) is inserted into a large vein and threaded through the blood vessels leading to the heart. Cardiac catheterization may enable physicians to withdraw blood to assess oxygen content, measure blood pressure in the heart, evaluate heart function, obtain small samples of myocardial tissue for microscopic evaluation, or thoroughly identify certain anatomical abnormalities. Cardiac MRI generates images of the heart similar to echocardiography but uses magnetic waves instead of sound waves. During radionuclide ventriculogram, tiny amounts of low-dose radioactive materials (tracers) are injected into to a vein and travel into the heart. Tracers release energy that is used by special cameras to produce pictures of the heart chambers.Because certain forms of cardiomyopathy may occur as part of a larger genetic disorder, infants and young children with a diagnosis of cardiomyopathy should receive specific tests to rule out any potentially associated disorders such as metabolic disorders.
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Pediatric Cardiomyopathy
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Therapies of Pediatric Cardiomyopathy
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TreatmentThe treatment of pediatric cardiomyopathy is directed toward the specific symptoms that are apparent in each individual. Such treatment may require the coordinated efforts of a team of medical professionals, such as pediatricians; physicians who specialize in childhood heart disease (pediatric cardiologists); specialists in the study of the blood and blood-forming tissues (hematologists); pediatric cardiothoracic surgeons; geneticists, physical therapists; occupational therapists and/or other health care professionals. Individuals with pediatric cardiomyopathy may be treated by lifestyle changes, dietary restrictions, various medications and surgery.It is important to note that many drug therapies and surgical techniques used to treat cardiomyopathy have predominantly been used and tested in adults. Only limited information exists detailing the effectiveness of such therapies in children with cardiomyopathy. More research is necessary to determine the long-term safety and effectiveness of such therapies in the pediatric population.Specific therapeutic procedures and interventions may vary, depending upon numerous factors such as the specific type of cardiomyopathy present; the progression of the disease upon diagnosis; an affected individual’s age; associated health conditions; an individual’s tolerance to certain medications; and additional factors.Individuals with dilated cardiomyopathy may be treated with a variety of medications including drugs that reduce abnormal fluid retention by promoting the production and excretion of urine (diuretics); drugs that reduce the workload of the heart by blocking certain substances from binding to structures within the heart (beta blockers); and digitalis medications such as digoxin, which increase the efficiency of heart muscle contractions and produce a more regular heartbeat. Another type of medication used to treat individuals with dilated cardiomyopathy is vasodilators, which relax blood vessels, thereby lowering the blood pressure and minimizing the effort needed by the heart to pump blood throughout the body. Angiotensin-converting enzyme (ACE) inhibitors are a type of vasodilator.Children with more serious dilated cardiomyopathy may need surgery to implant a device that helps maintain normal heart rhythm through electrical stimulation (pacemakers or defibrillators. If drug therapy fails, some individuals may require a cardiac assistance device and possibly a heart transplant (see below).Individuals with hypertrophic cardiomyopathy may be treated with a variety of drugs including beta-blockers, calcium channel blockers, drugs that regulate irregular heartbeats (anti-arrhythmics), and most recently drugs that reduce the strength of the muscular contractions. If drug therapy does not work, a permanent pacemaker or defibrillator may be implanted to help control irregular heartbeats. In some patients where drug therapy does not work, the blockage of flow that may result from the abnormal thickening of the heart muscle that can restrict blood flow as is common in hypertrophic cardiomyopathy may be treated with surgery. Surgical techniques may include septal myectomy (removal of some of the excess muscle) and modification of the mitral valve.Septal myectomy is a type of open-heart surgery, in which a portion of the abnormally thick and stiff ventricular septum (the partition that separates the left and right ventricles) is removed. This procedure allows for improved blood flow and reduces the symptoms associated with severe hypertrophic cardiomyopathy. In some cases of hypertrophic cardiomyopathy, a heart transplant may ultimately be necessary (see below).Restrictive cardiomyopathy may be treated with diuretics and drugs that prevent blood clotting (anticoagulants). A pacemaker or defibrillator may be implanted to help control irregular heartbeats. In most cases, heart transplantation will be necessary. Some physicians recommend that affected children be listed for transplant as soon as the diagnosis is made.ARVD may be treated by avoidance of severe physical and emotional stress; drugs that help regulate heart rhythms and/or the implantation of a defibrillator.In many children with pediatric cardiomyopathy, the disorder progresses to the point where medications and surgical treatment options are ineffective. In such cases, affected children may require a heart transplant, a form of open-heart surgery in which a severely diseased heart is replaced with a healthy donor heart. Pediatric cardiomyopathy is the leading cause of heart transplantation in children. A heart transplant is considered a last resort for individuals with end-stage heart failure. Drawbacks of heart transplantation include the potential for rejection and the limited availability of a suitable donor.Genetic counseling may be recommended for affected individuals and their families. Other treatment is symptomatic and supportive.
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Therapies of Pediatric Cardiomyopathy. TreatmentThe treatment of pediatric cardiomyopathy is directed toward the specific symptoms that are apparent in each individual. Such treatment may require the coordinated efforts of a team of medical professionals, such as pediatricians; physicians who specialize in childhood heart disease (pediatric cardiologists); specialists in the study of the blood and blood-forming tissues (hematologists); pediatric cardiothoracic surgeons; geneticists, physical therapists; occupational therapists and/or other health care professionals. Individuals with pediatric cardiomyopathy may be treated by lifestyle changes, dietary restrictions, various medications and surgery.It is important to note that many drug therapies and surgical techniques used to treat cardiomyopathy have predominantly been used and tested in adults. Only limited information exists detailing the effectiveness of such therapies in children with cardiomyopathy. More research is necessary to determine the long-term safety and effectiveness of such therapies in the pediatric population.Specific therapeutic procedures and interventions may vary, depending upon numerous factors such as the specific type of cardiomyopathy present; the progression of the disease upon diagnosis; an affected individual’s age; associated health conditions; an individual’s tolerance to certain medications; and additional factors.Individuals with dilated cardiomyopathy may be treated with a variety of medications including drugs that reduce abnormal fluid retention by promoting the production and excretion of urine (diuretics); drugs that reduce the workload of the heart by blocking certain substances from binding to structures within the heart (beta blockers); and digitalis medications such as digoxin, which increase the efficiency of heart muscle contractions and produce a more regular heartbeat. Another type of medication used to treat individuals with dilated cardiomyopathy is vasodilators, which relax blood vessels, thereby lowering the blood pressure and minimizing the effort needed by the heart to pump blood throughout the body. Angiotensin-converting enzyme (ACE) inhibitors are a type of vasodilator.Children with more serious dilated cardiomyopathy may need surgery to implant a device that helps maintain normal heart rhythm through electrical stimulation (pacemakers or defibrillators. If drug therapy fails, some individuals may require a cardiac assistance device and possibly a heart transplant (see below).Individuals with hypertrophic cardiomyopathy may be treated with a variety of drugs including beta-blockers, calcium channel blockers, drugs that regulate irregular heartbeats (anti-arrhythmics), and most recently drugs that reduce the strength of the muscular contractions. If drug therapy does not work, a permanent pacemaker or defibrillator may be implanted to help control irregular heartbeats. In some patients where drug therapy does not work, the blockage of flow that may result from the abnormal thickening of the heart muscle that can restrict blood flow as is common in hypertrophic cardiomyopathy may be treated with surgery. Surgical techniques may include septal myectomy (removal of some of the excess muscle) and modification of the mitral valve.Septal myectomy is a type of open-heart surgery, in which a portion of the abnormally thick and stiff ventricular septum (the partition that separates the left and right ventricles) is removed. This procedure allows for improved blood flow and reduces the symptoms associated with severe hypertrophic cardiomyopathy. In some cases of hypertrophic cardiomyopathy, a heart transplant may ultimately be necessary (see below).Restrictive cardiomyopathy may be treated with diuretics and drugs that prevent blood clotting (anticoagulants). A pacemaker or defibrillator may be implanted to help control irregular heartbeats. In most cases, heart transplantation will be necessary. Some physicians recommend that affected children be listed for transplant as soon as the diagnosis is made.ARVD may be treated by avoidance of severe physical and emotional stress; drugs that help regulate heart rhythms and/or the implantation of a defibrillator.In many children with pediatric cardiomyopathy, the disorder progresses to the point where medications and surgical treatment options are ineffective. In such cases, affected children may require a heart transplant, a form of open-heart surgery in which a severely diseased heart is replaced with a healthy donor heart. Pediatric cardiomyopathy is the leading cause of heart transplantation in children. A heart transplant is considered a last resort for individuals with end-stage heart failure. Drawbacks of heart transplantation include the potential for rejection and the limited availability of a suitable donor.Genetic counseling may be recommended for affected individuals and their families. Other treatment is symptomatic and supportive.
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Pediatric Cardiomyopathy
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Overview of Pediatric Crohn’s Disease
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Summary
Pediatric Crohn’s disease is a rare, inflammatory bowel disease characterized by severe, chronic inflammation of the intestinal wall or any portion of the gastrointestinal tract. The gastrointestinal tract is a group of organs that are connected by tubes that run from the mouth to the anus. The organs that make up the gastrointestinal tract are the esophagus, stomach, small intestine, large intestine and anus. The esophagus is the muscular tube that runs from the back of the throat to the stomach. The small intestine is a long, narrow, folded tube that extends from the stomach to the large intestine. It is the area where most of the digestion and absorption of nutrients occurs within the body. When the small intestine is damaged or lost (e.g., due to surgery), affected individuals may lose the ability to absorb enough water, vitamins, and other nutrients from food. The large intestine, also known as the colon, is a long, narrow folded tube that connects the small intestine to the anus. The large intestine absorbs water and minerals and is where the formation and temporary storage of solid waste (feces) occurs. The anus is a small opening at the end of the intestines through which solid waste exits the body. The last segment of the large intestine that connects to the anus is called the rectum. Pediatric Crohn’s disease can affect any area of the gastrointestinal tract.The two areas most often affected are the ileum and the large intestine. The ileum is the last section of the small intestine and connects to the large intestine. Common symptoms often include diarrhea (sometimes bloody), abdominal pain, fever, and weight loss. In children, poor linear growth and lack of adequate weight gain can often be the presenting concerns; in these instances, proper diagnosis is often delayed. Symptoms may come and go (relapsing and remitting). Crohn’s disease is more commonly diagnosed in adults, but approximately 25% of patients are diagnosed as children and teenagers (pediatric population). Children and adolescents are less likely than adults to have disease that is limited to the small intestine. The exact cause of pediatric Crohn’s disease is not fully understood, but this is thought to develop because of multiple different factors occurring together including genetic, immunologic and environmental triggers.
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Overview of Pediatric Crohn’s Disease. Summary
Pediatric Crohn’s disease is a rare, inflammatory bowel disease characterized by severe, chronic inflammation of the intestinal wall or any portion of the gastrointestinal tract. The gastrointestinal tract is a group of organs that are connected by tubes that run from the mouth to the anus. The organs that make up the gastrointestinal tract are the esophagus, stomach, small intestine, large intestine and anus. The esophagus is the muscular tube that runs from the back of the throat to the stomach. The small intestine is a long, narrow, folded tube that extends from the stomach to the large intestine. It is the area where most of the digestion and absorption of nutrients occurs within the body. When the small intestine is damaged or lost (e.g., due to surgery), affected individuals may lose the ability to absorb enough water, vitamins, and other nutrients from food. The large intestine, also known as the colon, is a long, narrow folded tube that connects the small intestine to the anus. The large intestine absorbs water and minerals and is where the formation and temporary storage of solid waste (feces) occurs. The anus is a small opening at the end of the intestines through which solid waste exits the body. The last segment of the large intestine that connects to the anus is called the rectum. Pediatric Crohn’s disease can affect any area of the gastrointestinal tract.The two areas most often affected are the ileum and the large intestine. The ileum is the last section of the small intestine and connects to the large intestine. Common symptoms often include diarrhea (sometimes bloody), abdominal pain, fever, and weight loss. In children, poor linear growth and lack of adequate weight gain can often be the presenting concerns; in these instances, proper diagnosis is often delayed. Symptoms may come and go (relapsing and remitting). Crohn’s disease is more commonly diagnosed in adults, but approximately 25% of patients are diagnosed as children and teenagers (pediatric population). Children and adolescents are less likely than adults to have disease that is limited to the small intestine. The exact cause of pediatric Crohn’s disease is not fully understood, but this is thought to develop because of multiple different factors occurring together including genetic, immunologic and environmental triggers.
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Pediatric Crohn’s Disease
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Symptoms of Pediatric Crohn’s Disease
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The signs and symptoms can vary from one person to another. Symptoms can appear suddenly, or they may build slowly over time. Symptoms may be triggered by trauma, illness or stress. Sometimes, symptoms occur with no identifiable triggering event.Common symptoms of pediatric Crohn’s disease are cramping, abdominal pain and chronic episodes of watery diarrhea; blood may at times be seen in the diarrhea. Sometimes, affected individuals will have an urgent need to go to the bathroom and move their bowels. Some affected individuals may feel tired a lot and experience fever, nausea or loss of appetite. Loss of appetite may cause some children to fail to gain weight and grow as would be expected for their age and sex. Affected individuals may exhibit malnutrition because of reduced intake of calories, and some may have difficulty absorbing nutrients in the intestines (malabsorption). As a result, they may fall behind their peers in growth. Some children may experience a delay in reaching puberty.Some affected children may develop bleeding within the gastrointestinal system. This bleeding may not be seen with the naked eye. Sometimes, anemia may develop. Anemia is a condition in which there are low levels of circulating red blood cells. Red blood cells deliver oxygen throughout the body. Anemia is associated with fatigue, pale skin color (pallor), lightheadedness and other symptoms.About 30% of children and adolescents develop perianal disease, which affects the area around the anus. This can make it painful for children to go to the bathroom. Affected individuals may develop fissures or tears, abscesses or a fistula in the perianal region. A fistula is a small, abnormal passageway that connects the skin to the inside of the anus. Fistulae can be associated with abscesses. Some individuals develop skin tags, which are raised areas or bumps off of the anus.Some affected children develop narrowing of the affected area of the gastrointestinal tract. Over time, scar tissue can form around the narrowing, resulting in a stricture. This can hinder or block the passage of food through the large or small intestine and cause obstruction. A bowel obstruction can cause cramping, vomiting, and constipation.Extraintestinal Symptoms
Some affected individuals develop signs and symptoms outside of the gastrointestinal tract. These signs and symptoms may be called extraintestinal symptoms. About 40% of children or adolescents eventually develop lesions on or in the mouth, including lesions on the mucous membrane lining the inside of the mouth and on the gums (mucogingivitis), canker sores of the mouth (aphthous ulcers) or swelling.In rare instances, children with pediatric Crohn’s disease develop lesions of the mouth and the perianal region, but with limited or mild intestinal disease.There are additional symptoms that can occur in some children and adolescents with pediatric Crohn’s disease including an inflammatory skin condition called erythema nodosum, in which small, raised, reddish bumps develop on the skin. These bumps are often painful and occur most commonly on the shins. Some affected individuals may experience inflammation in the eyes, causing burning or itching eyes. Some affected individuals develop joint pain (arthralgia) or joint inflammation (arthritis).
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Symptoms of Pediatric Crohn’s Disease. The signs and symptoms can vary from one person to another. Symptoms can appear suddenly, or they may build slowly over time. Symptoms may be triggered by trauma, illness or stress. Sometimes, symptoms occur with no identifiable triggering event.Common symptoms of pediatric Crohn’s disease are cramping, abdominal pain and chronic episodes of watery diarrhea; blood may at times be seen in the diarrhea. Sometimes, affected individuals will have an urgent need to go to the bathroom and move their bowels. Some affected individuals may feel tired a lot and experience fever, nausea or loss of appetite. Loss of appetite may cause some children to fail to gain weight and grow as would be expected for their age and sex. Affected individuals may exhibit malnutrition because of reduced intake of calories, and some may have difficulty absorbing nutrients in the intestines (malabsorption). As a result, they may fall behind their peers in growth. Some children may experience a delay in reaching puberty.Some affected children may develop bleeding within the gastrointestinal system. This bleeding may not be seen with the naked eye. Sometimes, anemia may develop. Anemia is a condition in which there are low levels of circulating red blood cells. Red blood cells deliver oxygen throughout the body. Anemia is associated with fatigue, pale skin color (pallor), lightheadedness and other symptoms.About 30% of children and adolescents develop perianal disease, which affects the area around the anus. This can make it painful for children to go to the bathroom. Affected individuals may develop fissures or tears, abscesses or a fistula in the perianal region. A fistula is a small, abnormal passageway that connects the skin to the inside of the anus. Fistulae can be associated with abscesses. Some individuals develop skin tags, which are raised areas or bumps off of the anus.Some affected children develop narrowing of the affected area of the gastrointestinal tract. Over time, scar tissue can form around the narrowing, resulting in a stricture. This can hinder or block the passage of food through the large or small intestine and cause obstruction. A bowel obstruction can cause cramping, vomiting, and constipation.Extraintestinal Symptoms
Some affected individuals develop signs and symptoms outside of the gastrointestinal tract. These signs and symptoms may be called extraintestinal symptoms. About 40% of children or adolescents eventually develop lesions on or in the mouth, including lesions on the mucous membrane lining the inside of the mouth and on the gums (mucogingivitis), canker sores of the mouth (aphthous ulcers) or swelling.In rare instances, children with pediatric Crohn’s disease develop lesions of the mouth and the perianal region, but with limited or mild intestinal disease.There are additional symptoms that can occur in some children and adolescents with pediatric Crohn’s disease including an inflammatory skin condition called erythema nodosum, in which small, raised, reddish bumps develop on the skin. These bumps are often painful and occur most commonly on the shins. Some affected individuals may experience inflammation in the eyes, causing burning or itching eyes. Some affected individuals develop joint pain (arthralgia) or joint inflammation (arthritis).
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Pediatric Crohn’s Disease
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Causes of Pediatric Crohn’s Disease
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The exact cause of pediatric Crohn’s disease is not fully understood. Most likely, pediatric Crohn’s disease is a multifactorial disorder, which means that multiple factors must occur together for the disorder to develop. These factors can include genetic, immunological and environmental factors.It is likely that pediatric Crohn’s disease develops, in part, because of malfunctioning of the body’s immune system. The immune system is the body’s natural defense system against foreign or invading organisms or substances. The immune system is a complex network of cells, tissues, organs, and proteins that work together to keep the body healthy. In pediatric Crohn’s disease, the immune system responds to a stimulus or ‘trigger’, often an infection, but the response is abnormal. The immune system does not shut off as it is supposed to and instead mistakenly targets the gastrointestinal system, and the large and small intestines, in particular. This sustained and abnormal immune system activity causes chronic inflammation and irritation of the tissues of the gastrointestinal tract, resulting in the signs and symptoms of pediatric Crohn’s disease. Researchers are not sure why the immune system malfunctions, or why the gastrointestinal system is affected in pediatric Crohn’s disease.Genetic factors play a role in some people with pediatric Crohn’s disease. If a family member has Crohn’s disease, relatives of the child have a greater chance of developing the disorder than people in the general population. Pediatric Crohn’s disease runs in the family in about 15% of affected individuals. When someone has a genetic factor for a disorder, it is called a genetic predisposition. A genetic predisposition is when a person has a gene or genes associated with a particular disorder, but who will not develop the disorder unless other factors such as environmental or immunological ones are also present.Changes (variants) in several different genes have been found more often in children and adolescents with pediatric Crohn’s disease including the NOD2, ATG16L1, IL23R, and IRGM genes. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a gene is altered, the protein product may be faulty, inefficient, absent or overproduced. The genes involved with pediatric Crohn’s disease are all involved with the function of the immune system.Researchers have determined that there are more than 200 different genes that can be associated with Crohn’s disease and ulcerative colitis, another form of inflammatory bowel disease. Sometimes, the specific gene or genes involved in a disorder influence the specific signs or symptoms. This is called genotype-phenotype correlation. Researchers are still trying to determine whether there are any specific genotype-phenotype correlations in pediatric Crohn’s disease. If specific correlations can be made, this may help physicians predict disease course and help determine the most effective treatments.Researchers have determined that genes that are involved with the interleukin 10 signaling pathway can cause a severe form of Crohn’s disease that is often present at or shortly after birth. An interleukin is a type of cytokine. Cytokines are specialized proteins secreted from certain immune system cells that either stimulate or inhibit the function of other immune system cells. Interleukin 10 is a cytokine that blocks inflammation in the body (anti-inflammatory). When genes in this pathway are altered, it may contribute to the unregulated inflammation seen in the gastrointestinal tract.Environmental factors may include bacterial or viral infections. Environmental factors may directly damage the gastrointestinal tract, or they may trigger the immune system to act, which then mistakenly damages the gastrointestinal tract. Other risk factors that may be associated with an increased risk of developing Crohn’s disease include frequent antibiotic use, consumption of a more Westernized diet and history of smoking.The intestines and stomach contain bacteria, which contribute to the gut microbiota. Researchers believe that some of these bacteria are beneficial to the body and help the immune system protect the body. When the gut microbiota is imbalanced – too little helpful bacteria, or too much unhelpful bacteria – it may increase the risk of an inflammatory bowel disease like pediatric Crohn’s disease. Why these shifts in the gut microbiota occur and how, specifically, they contribute to the development of pediatric Crohn’s disease is not fully understood.
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Causes of Pediatric Crohn’s Disease. The exact cause of pediatric Crohn’s disease is not fully understood. Most likely, pediatric Crohn’s disease is a multifactorial disorder, which means that multiple factors must occur together for the disorder to develop. These factors can include genetic, immunological and environmental factors.It is likely that pediatric Crohn’s disease develops, in part, because of malfunctioning of the body’s immune system. The immune system is the body’s natural defense system against foreign or invading organisms or substances. The immune system is a complex network of cells, tissues, organs, and proteins that work together to keep the body healthy. In pediatric Crohn’s disease, the immune system responds to a stimulus or ‘trigger’, often an infection, but the response is abnormal. The immune system does not shut off as it is supposed to and instead mistakenly targets the gastrointestinal system, and the large and small intestines, in particular. This sustained and abnormal immune system activity causes chronic inflammation and irritation of the tissues of the gastrointestinal tract, resulting in the signs and symptoms of pediatric Crohn’s disease. Researchers are not sure why the immune system malfunctions, or why the gastrointestinal system is affected in pediatric Crohn’s disease.Genetic factors play a role in some people with pediatric Crohn’s disease. If a family member has Crohn’s disease, relatives of the child have a greater chance of developing the disorder than people in the general population. Pediatric Crohn’s disease runs in the family in about 15% of affected individuals. When someone has a genetic factor for a disorder, it is called a genetic predisposition. A genetic predisposition is when a person has a gene or genes associated with a particular disorder, but who will not develop the disorder unless other factors such as environmental or immunological ones are also present.Changes (variants) in several different genes have been found more often in children and adolescents with pediatric Crohn’s disease including the NOD2, ATG16L1, IL23R, and IRGM genes. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a gene is altered, the protein product may be faulty, inefficient, absent or overproduced. The genes involved with pediatric Crohn’s disease are all involved with the function of the immune system.Researchers have determined that there are more than 200 different genes that can be associated with Crohn’s disease and ulcerative colitis, another form of inflammatory bowel disease. Sometimes, the specific gene or genes involved in a disorder influence the specific signs or symptoms. This is called genotype-phenotype correlation. Researchers are still trying to determine whether there are any specific genotype-phenotype correlations in pediatric Crohn’s disease. If specific correlations can be made, this may help physicians predict disease course and help determine the most effective treatments.Researchers have determined that genes that are involved with the interleukin 10 signaling pathway can cause a severe form of Crohn’s disease that is often present at or shortly after birth. An interleukin is a type of cytokine. Cytokines are specialized proteins secreted from certain immune system cells that either stimulate or inhibit the function of other immune system cells. Interleukin 10 is a cytokine that blocks inflammation in the body (anti-inflammatory). When genes in this pathway are altered, it may contribute to the unregulated inflammation seen in the gastrointestinal tract.Environmental factors may include bacterial or viral infections. Environmental factors may directly damage the gastrointestinal tract, or they may trigger the immune system to act, which then mistakenly damages the gastrointestinal tract. Other risk factors that may be associated with an increased risk of developing Crohn’s disease include frequent antibiotic use, consumption of a more Westernized diet and history of smoking.The intestines and stomach contain bacteria, which contribute to the gut microbiota. Researchers believe that some of these bacteria are beneficial to the body and help the immune system protect the body. When the gut microbiota is imbalanced – too little helpful bacteria, or too much unhelpful bacteria – it may increase the risk of an inflammatory bowel disease like pediatric Crohn’s disease. Why these shifts in the gut microbiota occur and how, specifically, they contribute to the development of pediatric Crohn’s disease is not fully understood.
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Pediatric Crohn’s Disease
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Affects of Pediatric Crohn’s Disease
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Crohn’s disease is a common disorder, affecting as many as 780,000 people in the United States. The disorder is most common in individuals between 15-35, with approximately 25% diagnosed by age 20. There is another increase in frequency among individuals between 60-80 years of age. The frequency of pediatric Crohn’s disease is increasing; in particular, there has been a recent increase in the incidence of Crohn’s disease in children less than 6 years old; this is called very early onset (VEO) inflammatory bowel disease. Although more females are affected by Crohn’s disease than males, pediatric Crohn’s disease is more common in boys than girls. Pediatric Crohn’s disease is more common in Caucasians than in people of African descent. It is rare in people of Asian and Hispanic descent. Generally, Crohn’s disease is more severe among children and adolescents than in adults.
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Affects of Pediatric Crohn’s Disease. Crohn’s disease is a common disorder, affecting as many as 780,000 people in the United States. The disorder is most common in individuals between 15-35, with approximately 25% diagnosed by age 20. There is another increase in frequency among individuals between 60-80 years of age. The frequency of pediatric Crohn’s disease is increasing; in particular, there has been a recent increase in the incidence of Crohn’s disease in children less than 6 years old; this is called very early onset (VEO) inflammatory bowel disease. Although more females are affected by Crohn’s disease than males, pediatric Crohn’s disease is more common in boys than girls. Pediatric Crohn’s disease is more common in Caucasians than in people of African descent. It is rare in people of Asian and Hispanic descent. Generally, Crohn’s disease is more severe among children and adolescents than in adults.
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Pediatric Crohn’s Disease
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Related disorders of Pediatric Crohn’s Disease
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Symptoms of the following disorders can be similar to those of pediatric Crohn’s disease. Comparisons may be useful for a differential diagnosis.Ulcerative colitis is an inflammatory bowel disease (IBD) of unknown cause. It is characterized by chronic inflammation and open sores (ulceration) of the lining of some or all of the large intestine (colon). In the least affected individuals, the lowest region of the large intestine, known as the rectum, is initially affected. However, particularly inchildren, the entire large intestine can be affected. Although associated symptoms and findings usually become apparent during adolescence or young adulthood, some individuals may experience an initial episode between ages 50 to 70. In other people, symptom onset may occur as early as the first year of life. Ulcerative colitis is usually a chronic disease with repeated episodes of symptoms and remission (relapsing-remitting). However, some affected individuals may have few episodes, whereas others may have severe, continuous symptoms. During an episode, affected individuals may experience attacks of watery diarrhea that may contain pus, blood, and/or mucus; abdominal pain; fever and chills; weight loss and/or other symptoms and findings. Severely affected individuals may be at risk for certain serious complications. The specific underlying cause of ulcerative colitis is unknown. However, genetic, immunologic, infectious, and/or psychological factors are thought to play some causative role.Some children and adolescents have what doctors called ‘indeterminate’ inflammatory bowel disease. These children have signs and symptoms of both Crohn’s disease and ulcerative colitis, and one disorder cannot be distinguished from the other.There are numerous additional disorders and conditions that can cause signs and symptoms similar to pediatric Crohn’s disease including various gastrointestinal infections, lactose intolerance, celiac disease, peptic ulcer disease, functional diarrhea, irritable bowel syndrome, various disorders where the immune system does not function properly (immunodeficiencies) and intestinal tuberculosis. Additional disorders include Behcet syndrome, pediatric graft-versus-host disease, Henoch-Schonlein purpura, chronic granulomatous disease and pediatric forms of colorectal cancer.
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Related disorders of Pediatric Crohn’s Disease. Symptoms of the following disorders can be similar to those of pediatric Crohn’s disease. Comparisons may be useful for a differential diagnosis.Ulcerative colitis is an inflammatory bowel disease (IBD) of unknown cause. It is characterized by chronic inflammation and open sores (ulceration) of the lining of some or all of the large intestine (colon). In the least affected individuals, the lowest region of the large intestine, known as the rectum, is initially affected. However, particularly inchildren, the entire large intestine can be affected. Although associated symptoms and findings usually become apparent during adolescence or young adulthood, some individuals may experience an initial episode between ages 50 to 70. In other people, symptom onset may occur as early as the first year of life. Ulcerative colitis is usually a chronic disease with repeated episodes of symptoms and remission (relapsing-remitting). However, some affected individuals may have few episodes, whereas others may have severe, continuous symptoms. During an episode, affected individuals may experience attacks of watery diarrhea that may contain pus, blood, and/or mucus; abdominal pain; fever and chills; weight loss and/or other symptoms and findings. Severely affected individuals may be at risk for certain serious complications. The specific underlying cause of ulcerative colitis is unknown. However, genetic, immunologic, infectious, and/or psychological factors are thought to play some causative role.Some children and adolescents have what doctors called ‘indeterminate’ inflammatory bowel disease. These children have signs and symptoms of both Crohn’s disease and ulcerative colitis, and one disorder cannot be distinguished from the other.There are numerous additional disorders and conditions that can cause signs and symptoms similar to pediatric Crohn’s disease including various gastrointestinal infections, lactose intolerance, celiac disease, peptic ulcer disease, functional diarrhea, irritable bowel syndrome, various disorders where the immune system does not function properly (immunodeficiencies) and intestinal tuberculosis. Additional disorders include Behcet syndrome, pediatric graft-versus-host disease, Henoch-Schonlein purpura, chronic granulomatous disease and pediatric forms of colorectal cancer.
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Pediatric Crohn’s Disease
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Diagnosis of Pediatric Crohn’s Disease
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A diagnosis of pediatric Crohn’s disease is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. Pediatric Crohn’s disease may be suspected in children or adolescents with chronic abdominal pain, diarrhea, weight loss and anemia.Clinical Testing and Workup
Children and adolescents suspected to have pediatric Crohn’s disease will receive a complete blood count. A complete blood count is a test that evaluates the cells in a person’s blood. In children and adolescents with pediatric Crohn’s disease there may be low levels of red blood cells (anemia), as well as high levels of white blood cells and platelets, which can indicate an inflammatory process in the body. A blood sample can also be used to determine an elevated erythrocyte sedimentation rate. This is a test that measures how long it takes red blood cells (erythrocytes) to settle in a test tube over a given period and is a measure of inflammation. Another test that can be run on a blood sample is a C-reactive protein test. C-reactive protein is released into the blood stream from the liver in response to inflammation within the body, including the inflammation that characterizes pediatric Crohn’s disease. Some affected individuals may have low levels of a protein called albumin in the blood (hypoalbuminemia). Although these tests can be positive in pediatric Crohn’s disease, there can be other causes for a positive result. These tests, in an of themselves, are not diagnostic. In addition, some affected children will be negative for these tests, meaning that if these tests are normal, it doesn’t rule out the pediatric Crohn’s disease.
Doctors may request a stool sample. This sample can be tested to see if gastrointestinal symptoms are caused by a bacterial infection or parasite. A stool sample can also show that blood loss has occurred somewhere in the gastrointestinal tract. A stool sample can also be tested to detect the presence of a protein called calprotectin. Fecal calprotectin is a biomarker for inflammation of the mucosa, the mucous membranes that lines various organs and areas of the body. Biomarkers are measurable substances that can indicate the presence of disease; in this case, intestinal mucosal inflammation, which is indicative of an inflammatory bowel disease like pediatric Crohn’s disease.Doctors may order traditional X-rays or specialized imaging techniques. Such imaging techniques may include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). During CT scanning, a computer and X-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of organs and bodily tissues. These specialized x-ray tests can be used to assess and evaluate the health of the small and large intestines. A specific type of MRI called magnetic resonance enterography (MRE) can produce detailed images of the small intestine. An MRE is taken with an oral contrast and can reveal inflammation, bleeding and other issues. A special type of CT scan called computed tomography enterography (CTE) is also taken with an oral contrast and can also produce detailed pictures of the small intestine. An oral contrast is a liquid that helps to produce detailed images of internal structures.Some clinical centers use ultrasonography to produce images of the small intestine. Ultrasounds use high-frequency radio waves to create a picture or image (sonogram) of specific structures like internal organs. The radio waves bounce off internal structures within the body and the echoes are recorded to create a sonogram.Diagnostic testing for pediatric Crohn’s disease also includes direct visual examination of the gastrointestinal tract. Doctors may order an upper endoscopy examination. This examination allows doctors to view the upper portion of the digestive tract including the esophagus, the stomach, and the first section of the small intestine called the duodenum. During this examination, doctors will run a thin, flexible tube (endoscope) down a person’s throat, then into the stomach, and eventually into the first part of the small intestine. This tube has a tiny camera attached to it that allows doctors to visually inspect these areas. This examination can reveal abnormal inflammation, irritation or swelling in these areas. An endoscopy examination also allows doctors to remove a small sample of tissue to be studied for microscopic areas of inflammation. A colonoscopy involves using a colonoscope inserted through the anus to view the rectum, colon, and often the last part of the small intestine (terminal ileum); this exam can show inflammation, irritation or swelling in these areas. Doctors can also take a biopsy sample during a colonoscopy.The U.S. Food and Drug Administration (FDA) has approved the use of video capsule endoscopy in children over the age of 2. This test can help to diagnose Crohn’s disease as well as determine the severity of the disorder. Unlike an upper endoscopy, this exam allows physicians to exam the entire small intestine. A patient will swallow a small capsule that contains a tiny camera. If the capsule cannot be swallowed, then it can be placed during an upper endoscopy. As the capsule moves through the gastrointestinal tract, it snaps pictures at a rate of about two pictures per second. The pictures are wirelessly sent to a receiver. The capsule takes about eight-to-twelve hours to move through the gastrointestinal tract and permits doctors to view a length of the small intestine that cannot be reach by upper endoscopy or colonoscopy but does not allow for biopsy samples to be obtained.
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Diagnosis of Pediatric Crohn’s Disease. A diagnosis of pediatric Crohn’s disease is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. Pediatric Crohn’s disease may be suspected in children or adolescents with chronic abdominal pain, diarrhea, weight loss and anemia.Clinical Testing and Workup
Children and adolescents suspected to have pediatric Crohn’s disease will receive a complete blood count. A complete blood count is a test that evaluates the cells in a person’s blood. In children and adolescents with pediatric Crohn’s disease there may be low levels of red blood cells (anemia), as well as high levels of white blood cells and platelets, which can indicate an inflammatory process in the body. A blood sample can also be used to determine an elevated erythrocyte sedimentation rate. This is a test that measures how long it takes red blood cells (erythrocytes) to settle in a test tube over a given period and is a measure of inflammation. Another test that can be run on a blood sample is a C-reactive protein test. C-reactive protein is released into the blood stream from the liver in response to inflammation within the body, including the inflammation that characterizes pediatric Crohn’s disease. Some affected individuals may have low levels of a protein called albumin in the blood (hypoalbuminemia). Although these tests can be positive in pediatric Crohn’s disease, there can be other causes for a positive result. These tests, in an of themselves, are not diagnostic. In addition, some affected children will be negative for these tests, meaning that if these tests are normal, it doesn’t rule out the pediatric Crohn’s disease.
Doctors may request a stool sample. This sample can be tested to see if gastrointestinal symptoms are caused by a bacterial infection or parasite. A stool sample can also show that blood loss has occurred somewhere in the gastrointestinal tract. A stool sample can also be tested to detect the presence of a protein called calprotectin. Fecal calprotectin is a biomarker for inflammation of the mucosa, the mucous membranes that lines various organs and areas of the body. Biomarkers are measurable substances that can indicate the presence of disease; in this case, intestinal mucosal inflammation, which is indicative of an inflammatory bowel disease like pediatric Crohn’s disease.Doctors may order traditional X-rays or specialized imaging techniques. Such imaging techniques may include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). During CT scanning, a computer and X-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of organs and bodily tissues. These specialized x-ray tests can be used to assess and evaluate the health of the small and large intestines. A specific type of MRI called magnetic resonance enterography (MRE) can produce detailed images of the small intestine. An MRE is taken with an oral contrast and can reveal inflammation, bleeding and other issues. A special type of CT scan called computed tomography enterography (CTE) is also taken with an oral contrast and can also produce detailed pictures of the small intestine. An oral contrast is a liquid that helps to produce detailed images of internal structures.Some clinical centers use ultrasonography to produce images of the small intestine. Ultrasounds use high-frequency radio waves to create a picture or image (sonogram) of specific structures like internal organs. The radio waves bounce off internal structures within the body and the echoes are recorded to create a sonogram.Diagnostic testing for pediatric Crohn’s disease also includes direct visual examination of the gastrointestinal tract. Doctors may order an upper endoscopy examination. This examination allows doctors to view the upper portion of the digestive tract including the esophagus, the stomach, and the first section of the small intestine called the duodenum. During this examination, doctors will run a thin, flexible tube (endoscope) down a person’s throat, then into the stomach, and eventually into the first part of the small intestine. This tube has a tiny camera attached to it that allows doctors to visually inspect these areas. This examination can reveal abnormal inflammation, irritation or swelling in these areas. An endoscopy examination also allows doctors to remove a small sample of tissue to be studied for microscopic areas of inflammation. A colonoscopy involves using a colonoscope inserted through the anus to view the rectum, colon, and often the last part of the small intestine (terminal ileum); this exam can show inflammation, irritation or swelling in these areas. Doctors can also take a biopsy sample during a colonoscopy.The U.S. Food and Drug Administration (FDA) has approved the use of video capsule endoscopy in children over the age of 2. This test can help to diagnose Crohn’s disease as well as determine the severity of the disorder. Unlike an upper endoscopy, this exam allows physicians to exam the entire small intestine. A patient will swallow a small capsule that contains a tiny camera. If the capsule cannot be swallowed, then it can be placed during an upper endoscopy. As the capsule moves through the gastrointestinal tract, it snaps pictures at a rate of about two pictures per second. The pictures are wirelessly sent to a receiver. The capsule takes about eight-to-twelve hours to move through the gastrointestinal tract and permits doctors to view a length of the small intestine that cannot be reach by upper endoscopy or colonoscopy but does not allow for biopsy samples to be obtained.
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Therapies of Pediatric Crohn’s Disease
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Treatment
Treatment may require the coordinated efforts of a team of specialists. The treatment of pediatric Crohn’s disease is directed toward the specific symptoms that are apparent in each individual. Pediatricians, physicians who specialize in diagnosing and treating gastrointestinal disorders in children (pediatric gastroenterologists), pediatric surgeons, psychologists, dieticians, nutritionists and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment.Psychosocial support for the entire family is essential, as well. Several of the organizations listed in the Resources section provide support and information on inflammatory bowel diseases like Crohn’s disease. There is no cure for Crohn’s disease, but with proper treatment and support the disease can be effectively managed and may go into remission for long periods of time. Affected children can lead normal lives.Specific therapeutic procedures and interventions may vary, depending upon numerous factors including the severity of the disease. Children will respond differently to therapy and the best therapy for one child may not be the same for another child. Decisions concerning the use of drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient (and parents) based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference and other appropriate factors.The treatment options for pediatric Crohn’s disease can include medications, nutritional and diet therapy and surgery. These therapies are often used in combination, with surgery being recommended when other therapies haven’t worked. The goals of therapy are to relieve symptoms and reduce inflammation, improve and optimize growth and well-being and induce a remission to help prevent future complications.Some children with mild or moderate disease will be given a drug called 5-aminosalicylic acid (5-ASA). In children with moderate or severe disease, doctors may try stronger anti-inflammatory drugs called corticosteroids, which are effective in treating active disease and achieving remission.Some doctors may recommend antibiotics to treat bacteria found in the gut, which may be a contributing factor to the development of Crohn’s disease. Antibiotics are often used for mild or moderate disease as well as to treat infection associated with perianal disease, fistulae and abscesses.Drugs that modify the response of the immune system called immunomodulators may be used to induce or prolong remissions. Immunomodulator drugs most utilized in the treatment of Crohn’s disease include 6-mercaptopurine and azathioprine, as well as methotrexate.Drugs known as biologics can also be used to treat pediatric Crohn’s disease. Biologics are usually complex molecules that contain living organisms or are produced from living organisms. Biologic medications for pediatric Crohn’s disease include the following:In 2006, the FDA approved infliximab (Remicade) for the treatment of moderate to severe active Crohn’s disease in children aged 6-17 in whom other treatments have not been effective. Infliximab can reduce signs and symptoms and help to achieve and maintain remission.In 2014, the FDA approved adalimumab (Humira) for the treatment of moderate to severe Crohn’s disease in children 6 years and older in whom certain other treatments haven’t been effective. Adalimumab reduces the signs and symptoms of pediatric Crohn’s disease and helps to achieve and maintain a remission.Three other medications, called vedolizumab (Entyvio), ustekinumab (Stelara) and (Skyrizi) have been approved by the FDA for the treatment of adult Crohn’s disease. These medications are sometimes used off-label in the treatment of pediatric Crohn’s disease.Diet and Nutrition
Diet modifications and nutrition are important elements of treating pediatric Crohn’s disease. Although no specific diet has been proven to be most effective, there are foods that doctors may recommend avoiding because they are difficult to digest and could result in an obstruction in a narrowed segment of bowel. These foods include popcorn, uncooked vegetables and nuts. Additionally, some food, such as milk, certain spices, or spicy foods, may worsen symptoms for particular individuals.The inflammation of the gastrointestinal tract that characterizes pediatric Crohn’s disease may make it difficult for the body to absorb nutrients. Affected children may then be unable to gain weight or grow properly. Sometimes, exclusive enteral nutrition (EEN) may be recommended. This involves consuming all calories from a special formula instead of a regular diet. Often, this requires introducing the formula directly to the stomach through a nasogastric tube. A nasogastric tube is a thin tube that is inserted into the nostrils and runs down the throat to the stomach. The amount of time children will need exclusive enteral nutrition varies depending upon their specific symptoms and disease severity. While this can be helpful for improving nutritional status, EEN can also lead to remission of active disease.Surgery
Surgery may be necessary in children in whom previous medical therapies such as medications and diet and nutrition have failed. Surgery usually involves removing the diseased tissue, but the disease often recurs in nearby tissue and as many as 50% of children who undergo surgery require a second surgery at some point during their lives. In some children, severe disease that is resistant to therapy may require a larger portion of intestines to be removed. This can result in short bowel syndrome. Short bowel syndrome is a complex disease that occurs due to the physical loss or the loss of function of a portion of the small and/or large intestine. NORD has a separate report on short bowel syndrome.Surgery may also be indicated for severe narrowing or obstruction of the intestines, bleeding that can’t be stopped by other means (intractable hemorrhaging), intestinal fistulae, and perforation, which is when a hole forms in the intestinal wall. Surgery may also be used to drain an abscess.
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Therapies of Pediatric Crohn’s Disease. Treatment
Treatment may require the coordinated efforts of a team of specialists. The treatment of pediatric Crohn’s disease is directed toward the specific symptoms that are apparent in each individual. Pediatricians, physicians who specialize in diagnosing and treating gastrointestinal disorders in children (pediatric gastroenterologists), pediatric surgeons, psychologists, dieticians, nutritionists and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment.Psychosocial support for the entire family is essential, as well. Several of the organizations listed in the Resources section provide support and information on inflammatory bowel diseases like Crohn’s disease. There is no cure for Crohn’s disease, but with proper treatment and support the disease can be effectively managed and may go into remission for long periods of time. Affected children can lead normal lives.Specific therapeutic procedures and interventions may vary, depending upon numerous factors including the severity of the disease. Children will respond differently to therapy and the best therapy for one child may not be the same for another child. Decisions concerning the use of drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient (and parents) based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference and other appropriate factors.The treatment options for pediatric Crohn’s disease can include medications, nutritional and diet therapy and surgery. These therapies are often used in combination, with surgery being recommended when other therapies haven’t worked. The goals of therapy are to relieve symptoms and reduce inflammation, improve and optimize growth and well-being and induce a remission to help prevent future complications.Some children with mild or moderate disease will be given a drug called 5-aminosalicylic acid (5-ASA). In children with moderate or severe disease, doctors may try stronger anti-inflammatory drugs called corticosteroids, which are effective in treating active disease and achieving remission.Some doctors may recommend antibiotics to treat bacteria found in the gut, which may be a contributing factor to the development of Crohn’s disease. Antibiotics are often used for mild or moderate disease as well as to treat infection associated with perianal disease, fistulae and abscesses.Drugs that modify the response of the immune system called immunomodulators may be used to induce or prolong remissions. Immunomodulator drugs most utilized in the treatment of Crohn’s disease include 6-mercaptopurine and azathioprine, as well as methotrexate.Drugs known as biologics can also be used to treat pediatric Crohn’s disease. Biologics are usually complex molecules that contain living organisms or are produced from living organisms. Biologic medications for pediatric Crohn’s disease include the following:In 2006, the FDA approved infliximab (Remicade) for the treatment of moderate to severe active Crohn’s disease in children aged 6-17 in whom other treatments have not been effective. Infliximab can reduce signs and symptoms and help to achieve and maintain remission.In 2014, the FDA approved adalimumab (Humira) for the treatment of moderate to severe Crohn’s disease in children 6 years and older in whom certain other treatments haven’t been effective. Adalimumab reduces the signs and symptoms of pediatric Crohn’s disease and helps to achieve and maintain a remission.Three other medications, called vedolizumab (Entyvio), ustekinumab (Stelara) and (Skyrizi) have been approved by the FDA for the treatment of adult Crohn’s disease. These medications are sometimes used off-label in the treatment of pediatric Crohn’s disease.Diet and Nutrition
Diet modifications and nutrition are important elements of treating pediatric Crohn’s disease. Although no specific diet has been proven to be most effective, there are foods that doctors may recommend avoiding because they are difficult to digest and could result in an obstruction in a narrowed segment of bowel. These foods include popcorn, uncooked vegetables and nuts. Additionally, some food, such as milk, certain spices, or spicy foods, may worsen symptoms for particular individuals.The inflammation of the gastrointestinal tract that characterizes pediatric Crohn’s disease may make it difficult for the body to absorb nutrients. Affected children may then be unable to gain weight or grow properly. Sometimes, exclusive enteral nutrition (EEN) may be recommended. This involves consuming all calories from a special formula instead of a regular diet. Often, this requires introducing the formula directly to the stomach through a nasogastric tube. A nasogastric tube is a thin tube that is inserted into the nostrils and runs down the throat to the stomach. The amount of time children will need exclusive enteral nutrition varies depending upon their specific symptoms and disease severity. While this can be helpful for improving nutritional status, EEN can also lead to remission of active disease.Surgery
Surgery may be necessary in children in whom previous medical therapies such as medications and diet and nutrition have failed. Surgery usually involves removing the diseased tissue, but the disease often recurs in nearby tissue and as many as 50% of children who undergo surgery require a second surgery at some point during their lives. In some children, severe disease that is resistant to therapy may require a larger portion of intestines to be removed. This can result in short bowel syndrome. Short bowel syndrome is a complex disease that occurs due to the physical loss or the loss of function of a portion of the small and/or large intestine. NORD has a separate report on short bowel syndrome.Surgery may also be indicated for severe narrowing or obstruction of the intestines, bleeding that can’t be stopped by other means (intractable hemorrhaging), intestinal fistulae, and perforation, which is when a hole forms in the intestinal wall. Surgery may also be used to drain an abscess.
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Overview of Pediatric Non-Small Cell Lung Cancer
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SummaryPediatric non-small cell lung cancer is the occurrence of non-small cell lung cancer (NSCLC) in children and adolescents (i.e. the pediatric population). This cancer is rare in individuals under 40 years of age and extremely rare in children and adolescents. NSCLC is the most common form of lung cancer; it is a general term for several different types of cancer in the lungs including adenocarcinoma, squamous cell carcinoma, large cell (undifferentiated) carcinoma, and other rare forms. ALK-positive NSCLC is a specific subtype generally associated with a younger age of onset than other forms of NSCLC and affected individuals have no history of smoking or a limited history of smoking. These tumors are usually adenocarcinomas. Because of the small number of children and adolescents that have been diagnosed with NSCLC, not much is known about this cancer in the pediatric population or how it differs from the adult population. Most of the literature and the treatment information and recommendations are based on research into adults. The treatment of NSCLC can include surgery, chemotherapy, and radiation therapy.
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Overview of Pediatric Non-Small Cell Lung Cancer. SummaryPediatric non-small cell lung cancer is the occurrence of non-small cell lung cancer (NSCLC) in children and adolescents (i.e. the pediatric population). This cancer is rare in individuals under 40 years of age and extremely rare in children and adolescents. NSCLC is the most common form of lung cancer; it is a general term for several different types of cancer in the lungs including adenocarcinoma, squamous cell carcinoma, large cell (undifferentiated) carcinoma, and other rare forms. ALK-positive NSCLC is a specific subtype generally associated with a younger age of onset than other forms of NSCLC and affected individuals have no history of smoking or a limited history of smoking. These tumors are usually adenocarcinomas. Because of the small number of children and adolescents that have been diagnosed with NSCLC, not much is known about this cancer in the pediatric population or how it differs from the adult population. Most of the literature and the treatment information and recommendations are based on research into adults. The treatment of NSCLC can include surgery, chemotherapy, and radiation therapy.
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Symptoms of Pediatric Non-Small Cell Lung Cancer
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The clinical course and signs and symptoms associated with NSCLC lung cancer in children is unclear because so few children have been described in the medical literature. Sometimes, especially early in the disease, no symptoms may be present (asymptomatic). Common symptoms associated with lung cancer include a cough that doesn’t get better and doesn’t go away, chest pain that is worse when coughing, laughing or taking a deep breath, shortness of breath, coughing up of blood (hemoptysis), and the development of hoarseness or wheezing. Some affected individuals can develop loss of appetite, unintended weight loss, fatigue, and recurrent episodes of lung infections such as pneumonia or bronchitis, which is an infection that causes inflammation of the lining of the lungs or its airways. NSCLC can potentially spread (metastasize) to affect other areas of the body. Specific signs and symptoms depend upon the exact location where the cancer has spread and the size of the tumor(s). Sometimes, symptoms of metastatic spread including bone pain, anemia, or unintended weight loss are the initial signs of pediatric NSCLC.
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Symptoms of Pediatric Non-Small Cell Lung Cancer. The clinical course and signs and symptoms associated with NSCLC lung cancer in children is unclear because so few children have been described in the medical literature. Sometimes, especially early in the disease, no symptoms may be present (asymptomatic). Common symptoms associated with lung cancer include a cough that doesn’t get better and doesn’t go away, chest pain that is worse when coughing, laughing or taking a deep breath, shortness of breath, coughing up of blood (hemoptysis), and the development of hoarseness or wheezing. Some affected individuals can develop loss of appetite, unintended weight loss, fatigue, and recurrent episodes of lung infections such as pneumonia or bronchitis, which is an infection that causes inflammation of the lining of the lungs or its airways. NSCLC can potentially spread (metastasize) to affect other areas of the body. Specific signs and symptoms depend upon the exact location where the cancer has spread and the size of the tumor(s). Sometimes, symptoms of metastatic spread including bone pain, anemia, or unintended weight loss are the initial signs of pediatric NSCLC.
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Causes of Pediatric Non-Small Cell Lung Cancer
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The exact underlying cause of pediatric non-small cell lung cancer is unknown. The exact reason normal cells become cancerous is not known. Most likely, multiple factors including genetic and environmental ones play a role in the disorder’s development. Current research suggests that abnormalities of DNA (deoxyribonucleic acid), which is the carrier of the body’s genetic code, are the underlying basis of cellular malignant transformation. Smoking is the major risk factor for NSCLC, but children and adolescents do not have decades or years of smoking in their medical history, meaning that other factors play a role in the development of this cancer in children and adolescents. In NSCLC, genetic changes can affect oncogenes or tumor suppressor genes. These gene changes are acquired during life; they are not inherited. They are acquired because of exposure to environmental factors like smoking or they occur randomly for no known reason (spontaneously). These gene changes are altered or incomplete versions of ordinary genes that normally regulate cell growth and division. An altered oncogene promotes out-of-control growth (cancer). Tumor suppressor genes normally limit or stop the growth of cells. When the tumor suppressor genes are inactivated (mutated), cells can multiply (proliferate) wildly, causing cancer. The two genes most often associated with adenocarcinoma of the lungs are the EGFR gene and the KRAS gene which, when mutated, function as oncogenes. Some affected children and adolescents have ALK-positive NSCLC. This form of lung cancer is associated with a specific genetic alteration, in which a segment of chromosome 2 is rearranged causing pieces of the chromosome to breakoff and reattach in the wrong areas. This causes two different genes to “fuse” together to form one abnormal gene. The two genes affected are the echinoderm microtubule-associated protein-like 4 (EML4) gene and the anaplastic lymphoma kinase (ALK) gene. This results in a “fusion” gene that produces an abnormal protein product. Researchers believe that this abnormal protein product may contribute to the growth and spread of cancer in such instances. A few drugs have been created that block the protein product of this fusion gene; they are called ALK inhibitors. Research is ongoing to determine more genetic factors that can play a role in the development of NSCLC. As more gene or gene(s) are identified that contribute to lung cancer development and growth, the greater potential there will be for the development of targeted therapies.There are reports of NSCLC developing in adolescents as a secondary cancer. Secondary cancer is one that develops as a late-effect of cancer treatment from years earlier for a different, unrelated cancer. Some teen-agers who received chemotherapy or radiation therapy during their childhood have been shown to develop lung cancer years later. This is known as a late effect of cancer treatment in children.
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Causes of Pediatric Non-Small Cell Lung Cancer. The exact underlying cause of pediatric non-small cell lung cancer is unknown. The exact reason normal cells become cancerous is not known. Most likely, multiple factors including genetic and environmental ones play a role in the disorder’s development. Current research suggests that abnormalities of DNA (deoxyribonucleic acid), which is the carrier of the body’s genetic code, are the underlying basis of cellular malignant transformation. Smoking is the major risk factor for NSCLC, but children and adolescents do not have decades or years of smoking in their medical history, meaning that other factors play a role in the development of this cancer in children and adolescents. In NSCLC, genetic changes can affect oncogenes or tumor suppressor genes. These gene changes are acquired during life; they are not inherited. They are acquired because of exposure to environmental factors like smoking or they occur randomly for no known reason (spontaneously). These gene changes are altered or incomplete versions of ordinary genes that normally regulate cell growth and division. An altered oncogene promotes out-of-control growth (cancer). Tumor suppressor genes normally limit or stop the growth of cells. When the tumor suppressor genes are inactivated (mutated), cells can multiply (proliferate) wildly, causing cancer. The two genes most often associated with adenocarcinoma of the lungs are the EGFR gene and the KRAS gene which, when mutated, function as oncogenes. Some affected children and adolescents have ALK-positive NSCLC. This form of lung cancer is associated with a specific genetic alteration, in which a segment of chromosome 2 is rearranged causing pieces of the chromosome to breakoff and reattach in the wrong areas. This causes two different genes to “fuse” together to form one abnormal gene. The two genes affected are the echinoderm microtubule-associated protein-like 4 (EML4) gene and the anaplastic lymphoma kinase (ALK) gene. This results in a “fusion” gene that produces an abnormal protein product. Researchers believe that this abnormal protein product may contribute to the growth and spread of cancer in such instances. A few drugs have been created that block the protein product of this fusion gene; they are called ALK inhibitors. Research is ongoing to determine more genetic factors that can play a role in the development of NSCLC. As more gene or gene(s) are identified that contribute to lung cancer development and growth, the greater potential there will be for the development of targeted therapies.There are reports of NSCLC developing in adolescents as a secondary cancer. Secondary cancer is one that develops as a late-effect of cancer treatment from years earlier for a different, unrelated cancer. Some teen-agers who received chemotherapy or radiation therapy during their childhood have been shown to develop lung cancer years later. This is known as a late effect of cancer treatment in children.
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Affects of Pediatric Non-Small Cell Lung Cancer
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Non-small cell lung cancer is the most common form of lung cancer. There are about 230,000 people diagnosed each year in the United States with lung cancer, and about 80%-85% of all lung cancers are NSCLC. The majority of these individuals are over the age of 45. This cancer is rare in people under 45 years of age, and extremely rare in children and adolescents. The number of children and adolescents who have NSCLC is unknown. The number of children and adolescents described in the medical literature with NSCLC has increased, but it is unclear whether this is due to an actual increase in the amount of people with this cancer or because of better recognition and diagnosis.
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Affects of Pediatric Non-Small Cell Lung Cancer. Non-small cell lung cancer is the most common form of lung cancer. There are about 230,000 people diagnosed each year in the United States with lung cancer, and about 80%-85% of all lung cancers are NSCLC. The majority of these individuals are over the age of 45. This cancer is rare in people under 45 years of age, and extremely rare in children and adolescents. The number of children and adolescents who have NSCLC is unknown. The number of children and adolescents described in the medical literature with NSCLC has increased, but it is unclear whether this is due to an actual increase in the amount of people with this cancer or because of better recognition and diagnosis.
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Related disorders of Pediatric Non-Small Cell Lung Cancer
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Symptoms of the following disorders can be similar to those of pediatric non-small cell lung cancer. Comparisons may be useful for a differential diagnosis.Pleuropulmonary blastoma (PPB) is a rare childhood cancer occurring in the chest, specifically in the lungs or in the coverings of the lungs called “pleura”. Three subtypes of PPB exist and are called Type I, Type II, and Type III PPB. Type I PPB takes the form of one or more cysts in the lungs (air-filled pockets) and may be found in very young children with PPB (from birth to about 2 years of age). Type III PPB is entirely solid tumor. Type II PPB includes both cystic and solid parts. Types II and III PPB tend to be found more often after 2 years of age. Type Ir (the “r” stands for regressed/ regressing) is another type of PPB. Under the microscope Type Ir is similar to Type I PPB, but it does not have cancerous cells. Type I, II, and III PPB are usually found in children under the age of approximately 7-8 years; PPB occurs rarely in older children or teenagers, and even more rarely in adults, but Type Ir PPB may be found at any age. Children with Type I have a better outlook (“prognosis”) than children with Types II and III PPB; most Type I PPB patients are cured (89%) but Type I PPB can sometimes recur (“come back”) as Type II or III PPB. Treatment for Type I consists of surgery and possibly chemotherapy. Treatment for Types II and III PPB consists of surgery and chemotherapy and possibly radiation therapy. At present, about 50-70% of children with Types II and III PPB are cured. (For more information on this disorder, choose “pleuropulmonary blastoma” as your search term in the Rare Disease Database.)Although pleuropulmonary blastoma is the most common form of lung cancer in children, there are other types of cancers that can develop in the lungs of children and adolescents including carcinoid tumors and sarcomas. These can be tumors that originate in the lungs or develop in the lungs after spreading there from somewhere else in the body. Leukemia, lymphoma, neuroblastoma, rhabdomyosarcoma, osteosarcoma, and Wilms tumor are childhood cancers that can spread to the lungs. Initial symptoms of lung cancer are often vague and can be mistaken for more common conditions such as asthma or other inflammatory, infectious, or reactive processes. There a common malformations of the lungs that are present at birth (congenital) or that develop during childhood that can result in the formation of a mass or masses that can be mistaken for a tumor. These conditions include bronchogenic cysts; narrowing (atresia) of certain airways of the lungs (segmental bronchial atresia); and a mass of lung tissue that does not connect to the other airways (tracheobronchial tree) and receives arterial blood supply from another source (pulmonary sequestration).
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Related disorders of Pediatric Non-Small Cell Lung Cancer. Symptoms of the following disorders can be similar to those of pediatric non-small cell lung cancer. Comparisons may be useful for a differential diagnosis.Pleuropulmonary blastoma (PPB) is a rare childhood cancer occurring in the chest, specifically in the lungs or in the coverings of the lungs called “pleura”. Three subtypes of PPB exist and are called Type I, Type II, and Type III PPB. Type I PPB takes the form of one or more cysts in the lungs (air-filled pockets) and may be found in very young children with PPB (from birth to about 2 years of age). Type III PPB is entirely solid tumor. Type II PPB includes both cystic and solid parts. Types II and III PPB tend to be found more often after 2 years of age. Type Ir (the “r” stands for regressed/ regressing) is another type of PPB. Under the microscope Type Ir is similar to Type I PPB, but it does not have cancerous cells. Type I, II, and III PPB are usually found in children under the age of approximately 7-8 years; PPB occurs rarely in older children or teenagers, and even more rarely in adults, but Type Ir PPB may be found at any age. Children with Type I have a better outlook (“prognosis”) than children with Types II and III PPB; most Type I PPB patients are cured (89%) but Type I PPB can sometimes recur (“come back”) as Type II or III PPB. Treatment for Type I consists of surgery and possibly chemotherapy. Treatment for Types II and III PPB consists of surgery and chemotherapy and possibly radiation therapy. At present, about 50-70% of children with Types II and III PPB are cured. (For more information on this disorder, choose “pleuropulmonary blastoma” as your search term in the Rare Disease Database.)Although pleuropulmonary blastoma is the most common form of lung cancer in children, there are other types of cancers that can develop in the lungs of children and adolescents including carcinoid tumors and sarcomas. These can be tumors that originate in the lungs or develop in the lungs after spreading there from somewhere else in the body. Leukemia, lymphoma, neuroblastoma, rhabdomyosarcoma, osteosarcoma, and Wilms tumor are childhood cancers that can spread to the lungs. Initial symptoms of lung cancer are often vague and can be mistaken for more common conditions such as asthma or other inflammatory, infectious, or reactive processes. There a common malformations of the lungs that are present at birth (congenital) or that develop during childhood that can result in the formation of a mass or masses that can be mistaken for a tumor. These conditions include bronchogenic cysts; narrowing (atresia) of certain airways of the lungs (segmental bronchial atresia); and a mass of lung tissue that does not connect to the other airways (tracheobronchial tree) and receives arterial blood supply from another source (pulmonary sequestration).
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Pediatric Non-Small Cell Lung Cancer
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Diagnosis of Pediatric Non-Small Cell Lung Cancer
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A diagnosis of pediatric non-small cell lung cancer is based upon identification of characteristic symptoms, a detailed family and patient history, a thorough clinical evaluation and a variety of specialized tests. Because NSCLC is extremely rare in children, the diagnosis is often not suspected in children with unexplained symptoms of lung disease and diagnosis is often delayed until more common diagnoses such as asthma are ruled out. Clinical Testing and Workup
Most methods and tests developed or used for NSCLC have been studied in adults. Many of the same methods are used in pediatric patients. Some doctors will use a test called sputum cytology. This is a test in which sputum, the mucus that is coughed up from the lungs, is studied under a microscopic to look for abnormal, cancerous cells. A plain x-ray (radiography) of the chest can show a tumor or mass in the lungs. Specialized imaging techniques can be used to determine whether cancer is present, the extent of the disease, and whether the cancer has spread to other areas. Such imaging techniques may include computerized tomography (CT), positron emission tomography (PET) scanning and magnetic resonance imaging (MRI). During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. A CT scan of the lungs can show smaller tumors that do not show up on conventional x-rays and can also show whether cancer has spread to nearby lymph nodes. A CT scan of other areas of the body can show whether cancer has spread (metastasized) to specific areas. Another advanced imaging technique known as positron emission tomography or PET scan may also be used. During a PET scan, a radioactive sugar is injected into the body. This sugar will collect in areas of the body where there is a higher demand for energy. Tumors require a lot of energy to keep growing and spreading, and will soak up the radioactive sugar. When the x-ray (scan) is taken, areas that take up the radioactive sugar including NSCLC may show up as bright spots on the film. A PET scan is often used to help show whether NSCLC has spread or how well it is responding to treatment. A PET scan can determine whether cancer has spread to the bones. In the past, this required a bone scan, but when a PET scan is used, a bone scan is no longer necessary. During a bone scan, a relatively harmless radioactive dye is injected into the affected bone. A special camera that can track the dye as it travels through the bone is used to create a picture of the skeleton and determine all affected areas and can help determine whether NSCLC has spread to other areas of the body. Sometimes, doctors will recommend a combined PET/CT scan. This scan gathers information about how much metabolic activity (glucose uptake, measured by PET) a cancer has at the same time as mapping the adjacent body structures (CT). An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. An MRI of the brain may be ordered to determine whether cancer has spread to the brain. Advanced imaging techniques are also used to help to stage NSCLC and to help plan and guide treatment. Surgical removal (biopsy) of affected lung tissue can also be performed. In order to obtain a lung sample, physicians may recommend a bronchoscopy or fine-needle aspiration. During a bronchoscopy, a physician inserts a bronchoscope through the mouth and down an affected individual’s throat and obtains a sample of tissue to be analyzed (biopsy). Fine needle aspiration is another type of biopsy. It involves a thinner, hollow needle, which is inserted into the tumor to remove tissue. The needle is attached to a syringe, which is used to draw out (aspirate) a sample of tissue and fluid from the mass or tumor. During video thoracoscopy, a thin tube with a built-in camera (thoracoscope) is inserted into the chest through a small surgical cut (incision) allowing a physician to view the lungs and obtain tissue samples. This is usually a formal operative procedure performed in an operating room, or similar setting, and may require a general anesthetic with a temporary breathing tube.Sometimes, doctors may order a mediastinoscopy. This involves making a small cut near the top of the breastbone, which is the thin bone that runs down the center of the chest. A small thin tube called a mediastinoscope is passed through to allow doctors to view and take tissue samples from the mediastinum, which is the area between the lungs in the central region of the chest.Distinguishing ALK-positive NSCLC from other forms is extremely important as there are targeted therapies for this form of cancer. A test known as fluorescent in situ hybridization or FISH may also be used to help diagnose specific subtypes. During a FISH exam, probes marked by a specific color of fluorescent dye are attached to a specific chromosome allowing to view a specific region of that chromosome. The test allows physicians to detect alterations in the genetic material of chromosomes including inversions such as the inversion on chromosome 2 that results in the fusion gene that causes EML4-ALK-positive NSCLC. Staging
The International Association of the Study of Lung Cancer has proposed that physicians should adopt a different staging system called the Tumor Node Metastasis (TNM) Staging System, which is a common staging system for cancer developed by the American Joint Committee on Cancer. This system is based on the extent of the tumor, whether and to what extent cancer has spread to the lymph nodes, and whether cancer has spread (metastasized) to other areas of the body. It is a complex staging system. For more information on this staging system for NSCLC, visit the American Cancer Society: https://www.cancer.org/cancer/non-small-cell-lung-cancer/detection-diagnosis-staging/staging.html It is important to note that prognostic information and survival rates for NSCLC are based on older adults since the majority of people with this cancer are over the age of 45. Many of these individuals have other health concerns that affect these percentages. Because NSCLC is so rare in the pediatric population, there are no prognostic or survival data for this age group.
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Diagnosis of Pediatric Non-Small Cell Lung Cancer. A diagnosis of pediatric non-small cell lung cancer is based upon identification of characteristic symptoms, a detailed family and patient history, a thorough clinical evaluation and a variety of specialized tests. Because NSCLC is extremely rare in children, the diagnosis is often not suspected in children with unexplained symptoms of lung disease and diagnosis is often delayed until more common diagnoses such as asthma are ruled out. Clinical Testing and Workup
Most methods and tests developed or used for NSCLC have been studied in adults. Many of the same methods are used in pediatric patients. Some doctors will use a test called sputum cytology. This is a test in which sputum, the mucus that is coughed up from the lungs, is studied under a microscopic to look for abnormal, cancerous cells. A plain x-ray (radiography) of the chest can show a tumor or mass in the lungs. Specialized imaging techniques can be used to determine whether cancer is present, the extent of the disease, and whether the cancer has spread to other areas. Such imaging techniques may include computerized tomography (CT), positron emission tomography (PET) scanning and magnetic resonance imaging (MRI). During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. A CT scan of the lungs can show smaller tumors that do not show up on conventional x-rays and can also show whether cancer has spread to nearby lymph nodes. A CT scan of other areas of the body can show whether cancer has spread (metastasized) to specific areas. Another advanced imaging technique known as positron emission tomography or PET scan may also be used. During a PET scan, a radioactive sugar is injected into the body. This sugar will collect in areas of the body where there is a higher demand for energy. Tumors require a lot of energy to keep growing and spreading, and will soak up the radioactive sugar. When the x-ray (scan) is taken, areas that take up the radioactive sugar including NSCLC may show up as bright spots on the film. A PET scan is often used to help show whether NSCLC has spread or how well it is responding to treatment. A PET scan can determine whether cancer has spread to the bones. In the past, this required a bone scan, but when a PET scan is used, a bone scan is no longer necessary. During a bone scan, a relatively harmless radioactive dye is injected into the affected bone. A special camera that can track the dye as it travels through the bone is used to create a picture of the skeleton and determine all affected areas and can help determine whether NSCLC has spread to other areas of the body. Sometimes, doctors will recommend a combined PET/CT scan. This scan gathers information about how much metabolic activity (glucose uptake, measured by PET) a cancer has at the same time as mapping the adjacent body structures (CT). An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. An MRI of the brain may be ordered to determine whether cancer has spread to the brain. Advanced imaging techniques are also used to help to stage NSCLC and to help plan and guide treatment. Surgical removal (biopsy) of affected lung tissue can also be performed. In order to obtain a lung sample, physicians may recommend a bronchoscopy or fine-needle aspiration. During a bronchoscopy, a physician inserts a bronchoscope through the mouth and down an affected individual’s throat and obtains a sample of tissue to be analyzed (biopsy). Fine needle aspiration is another type of biopsy. It involves a thinner, hollow needle, which is inserted into the tumor to remove tissue. The needle is attached to a syringe, which is used to draw out (aspirate) a sample of tissue and fluid from the mass or tumor. During video thoracoscopy, a thin tube with a built-in camera (thoracoscope) is inserted into the chest through a small surgical cut (incision) allowing a physician to view the lungs and obtain tissue samples. This is usually a formal operative procedure performed in an operating room, or similar setting, and may require a general anesthetic with a temporary breathing tube.Sometimes, doctors may order a mediastinoscopy. This involves making a small cut near the top of the breastbone, which is the thin bone that runs down the center of the chest. A small thin tube called a mediastinoscope is passed through to allow doctors to view and take tissue samples from the mediastinum, which is the area between the lungs in the central region of the chest.Distinguishing ALK-positive NSCLC from other forms is extremely important as there are targeted therapies for this form of cancer. A test known as fluorescent in situ hybridization or FISH may also be used to help diagnose specific subtypes. During a FISH exam, probes marked by a specific color of fluorescent dye are attached to a specific chromosome allowing to view a specific region of that chromosome. The test allows physicians to detect alterations in the genetic material of chromosomes including inversions such as the inversion on chromosome 2 that results in the fusion gene that causes EML4-ALK-positive NSCLC. Staging
The International Association of the Study of Lung Cancer has proposed that physicians should adopt a different staging system called the Tumor Node Metastasis (TNM) Staging System, which is a common staging system for cancer developed by the American Joint Committee on Cancer. This system is based on the extent of the tumor, whether and to what extent cancer has spread to the lymph nodes, and whether cancer has spread (metastasized) to other areas of the body. It is a complex staging system. For more information on this staging system for NSCLC, visit the American Cancer Society: https://www.cancer.org/cancer/non-small-cell-lung-cancer/detection-diagnosis-staging/staging.html It is important to note that prognostic information and survival rates for NSCLC are based on older adults since the majority of people with this cancer are over the age of 45. Many of these individuals have other health concerns that affect these percentages. Because NSCLC is so rare in the pediatric population, there are no prognostic or survival data for this age group.
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Pediatric Non-Small Cell Lung Cancer
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Therapies of Pediatric Non-Small Cell Lung Cancer
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Treatment
Treatment may require the coordinated efforts of a team of specialists. Physicians who specialize in the diagnosis and treatment of cancer in children (pediatric oncologists), physicians who specialize in the treatment of cancer with radiation (radiation oncologists), physicians who specialize in examining tissues and cells to find disease and determine what disease is present (pathologists), surgeons who specialize in removing cancer by surgery (thoracic surgeon), physicians who specialize in the diagnosis and treatment of lung disease (pulmonologists); nurses who specialize in the car and treatment of cancer (oncology nurses), psychiatrists, nutritionists, and other healthcare professionals may need to systematically and comprehensively plan treatment.Psychosocial support for the entire family is essential as well. Several of the organizations listed in the Resources section provide support and information on lung cancer or lung disease. Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease stage; tumor size; specific cancer subtype; the presence or absence of certain symptoms; an individual’s age and general health; and/or other elements. Decisions concerning the use of particular drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.Because pediatric NSCLC is so rare, most treatment options are based on studies done on adult patients. The effectiveness of these treatment options, the optimal dosage, and the overall best treatment protocol for pediatric patients is unknown. Generally, there are three main treatment options: surgery, chemotherapy, and radiation therapy. Surgery may be option for some individuals, especially those in whom the tumor that has not spread to other nearby lymph nodes. Surgical removal of the tumor may be curative, but there is a risk of recurrence of the cancer. If surgery is not an option or the cancer has already spread to other areas of the body, then chemotherapy and radiation therapy, either separately or combined, will be recommended. Chemotherapy is the use of certain medications to slow down or stop the growth of cancer cells. Cancers cells grow and divide rapidly, which makes them susceptible to chemotherapy medications. Different combinations of medications may be used; this is called a chemotherapy regimen. The most common chemotherapeutic drugs used in adults are etoposide combined with cisplatin or carboplatin. This may be referred to as platinum-based chemotherapy because and carboplatin and cisplatin a platinum-containing compounds. Radiation therapy is also often used to treat individuals with limited stage NSCLC. Radiation therapy uses x-rays or similar forms of radiation to directly destroy cancer cells. Radiation therapy is directed at the chest (thoracic radiotherapy) and is sometimes given at the same time as chemotherapy (chemoradiotherapy).There is a risk of recurrence of NSCLC following successfully treatment with chemotherapy and radiation therapy. According to the Genetic and Rare Diseases Information Center (GARD), there are three drugs that have been approved by the Food and Drug Administration (FDA) for childhood NSCLC (https://rarediseases.info.nih.gov/diseases/9343/non-small-cell-lung-cancer-childhood). These drugs are brigatinib (Alunbrig®), Crizotinib (Xalkori®), and Ceritinib (Zykadia®). These drugs are ALK-inhibitors, which means that they block the protein product from the EML4-ALK fusion gene. These drugs are approved for individuals with ALK-positive NSCLC.
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Therapies of Pediatric Non-Small Cell Lung Cancer. Treatment
Treatment may require the coordinated efforts of a team of specialists. Physicians who specialize in the diagnosis and treatment of cancer in children (pediatric oncologists), physicians who specialize in the treatment of cancer with radiation (radiation oncologists), physicians who specialize in examining tissues and cells to find disease and determine what disease is present (pathologists), surgeons who specialize in removing cancer by surgery (thoracic surgeon), physicians who specialize in the diagnosis and treatment of lung disease (pulmonologists); nurses who specialize in the car and treatment of cancer (oncology nurses), psychiatrists, nutritionists, and other healthcare professionals may need to systematically and comprehensively plan treatment.Psychosocial support for the entire family is essential as well. Several of the organizations listed in the Resources section provide support and information on lung cancer or lung disease. Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease stage; tumor size; specific cancer subtype; the presence or absence of certain symptoms; an individual’s age and general health; and/or other elements. Decisions concerning the use of particular drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.Because pediatric NSCLC is so rare, most treatment options are based on studies done on adult patients. The effectiveness of these treatment options, the optimal dosage, and the overall best treatment protocol for pediatric patients is unknown. Generally, there are three main treatment options: surgery, chemotherapy, and radiation therapy. Surgery may be option for some individuals, especially those in whom the tumor that has not spread to other nearby lymph nodes. Surgical removal of the tumor may be curative, but there is a risk of recurrence of the cancer. If surgery is not an option or the cancer has already spread to other areas of the body, then chemotherapy and radiation therapy, either separately or combined, will be recommended. Chemotherapy is the use of certain medications to slow down or stop the growth of cancer cells. Cancers cells grow and divide rapidly, which makes them susceptible to chemotherapy medications. Different combinations of medications may be used; this is called a chemotherapy regimen. The most common chemotherapeutic drugs used in adults are etoposide combined with cisplatin or carboplatin. This may be referred to as platinum-based chemotherapy because and carboplatin and cisplatin a platinum-containing compounds. Radiation therapy is also often used to treat individuals with limited stage NSCLC. Radiation therapy uses x-rays or similar forms of radiation to directly destroy cancer cells. Radiation therapy is directed at the chest (thoracic radiotherapy) and is sometimes given at the same time as chemotherapy (chemoradiotherapy).There is a risk of recurrence of NSCLC following successfully treatment with chemotherapy and radiation therapy. According to the Genetic and Rare Diseases Information Center (GARD), there are three drugs that have been approved by the Food and Drug Administration (FDA) for childhood NSCLC (https://rarediseases.info.nih.gov/diseases/9343/non-small-cell-lung-cancer-childhood). These drugs are brigatinib (Alunbrig®), Crizotinib (Xalkori®), and Ceritinib (Zykadia®). These drugs are ALK-inhibitors, which means that they block the protein product from the EML4-ALK fusion gene. These drugs are approved for individuals with ALK-positive NSCLC.
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Pediatric Non-Small Cell Lung Cancer
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Overview of Peeling Skin Syndrome
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Peeling skin syndrome (PSS) is a group of rare inherited skin disorders in which the normal gradual process of invisible shedding of the outermost skin layers is hastened and/or aggravated. PSS is characterized by painless, continual, spontaneous skin peeling (exfoliation) due to a separation of the outermost layer of the epidermis (stratum corneum) from the underlying layers. Other findings may include blistering and/or reddening of the skin (erythema) and itching (pruritus). Symptoms may be present from birth or appear in early childhood and are often exacerbated by friction, heat or other external factors. Based on the extent of skin involvement, PSS may involve the skin of the entire body (generalized form), or is limited to the extremities, mostly hands and feet (localized form). Generalized PSS can be distinguished into an inflammatory type which is associated with erythema, involves other organ systems and is more severe, and a milder, non-inflammatory type. PSS may be caused by disease-causing variants in multiple genes encoding proteins with crucial functions for cell-cell adhesion: structural proteins forming cell-cell adhesion points (desmosomes, corneodesmosomes) and inhibitors of epidermal proteases that control skin shedding.
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Overview of Peeling Skin Syndrome. Peeling skin syndrome (PSS) is a group of rare inherited skin disorders in which the normal gradual process of invisible shedding of the outermost skin layers is hastened and/or aggravated. PSS is characterized by painless, continual, spontaneous skin peeling (exfoliation) due to a separation of the outermost layer of the epidermis (stratum corneum) from the underlying layers. Other findings may include blistering and/or reddening of the skin (erythema) and itching (pruritus). Symptoms may be present from birth or appear in early childhood and are often exacerbated by friction, heat or other external factors. Based on the extent of skin involvement, PSS may involve the skin of the entire body (generalized form), or is limited to the extremities, mostly hands and feet (localized form). Generalized PSS can be distinguished into an inflammatory type which is associated with erythema, involves other organ systems and is more severe, and a milder, non-inflammatory type. PSS may be caused by disease-causing variants in multiple genes encoding proteins with crucial functions for cell-cell adhesion: structural proteins forming cell-cell adhesion points (desmosomes, corneodesmosomes) and inhibitors of epidermal proteases that control skin shedding.
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Peeling Skin Syndrome
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Symptoms of Peeling Skin Syndrome
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Peeling skin syndrome belongs to the groups of congenital ichthyosis and skin fragility disorders with autosomal recessive inheritance. Most forms of PSS manifest at birth or during infancy with shedding or peeling of the outermost layer of the skin (horny layer, aka stratum corneum). Skin peeling occurs spontaneous, is painless, and may persist lifelong with gradual improvements. Often, affected individuals and/or their caregivers can remove sheets of skin manually, comparable to skin peeling after a severe sunburn.Other findings associated with this disorder may include blistering and skin fragility, itching, short stature, and/or newly formed hairs that can be plucked out more easily than normal. Skin peeling is often exacerbated by mechanical irritation of the skin, heat, sweat or water exposure or other external factors.In the localized types, individuals develop blisters and erosions on hands and feet at birth or during infancy, which is reminiscent of another blistering skin disorder, epidermolysis bullosa simplex. The generalized inflammatory types, such as SAM syndrome or Netherton syndrome may be associated with generalized inflammation of the skin (erythroderma) or localized thickened, red plaques (erythrokeratoderma), immunodysfunction with elevated IgE levels, allergies, and susceptibility to infections, failure to thrive or metabolic wasting. In some patients, these disorders may be life-threatening, especially during the newborn period. Due to the variable clinical presentations of PSS, its often mild features and gradual improvement with age, PSS may be underdiagnosed and underreported.
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Symptoms of Peeling Skin Syndrome. Peeling skin syndrome belongs to the groups of congenital ichthyosis and skin fragility disorders with autosomal recessive inheritance. Most forms of PSS manifest at birth or during infancy with shedding or peeling of the outermost layer of the skin (horny layer, aka stratum corneum). Skin peeling occurs spontaneous, is painless, and may persist lifelong with gradual improvements. Often, affected individuals and/or their caregivers can remove sheets of skin manually, comparable to skin peeling after a severe sunburn.Other findings associated with this disorder may include blistering and skin fragility, itching, short stature, and/or newly formed hairs that can be plucked out more easily than normal. Skin peeling is often exacerbated by mechanical irritation of the skin, heat, sweat or water exposure or other external factors.In the localized types, individuals develop blisters and erosions on hands and feet at birth or during infancy, which is reminiscent of another blistering skin disorder, epidermolysis bullosa simplex. The generalized inflammatory types, such as SAM syndrome or Netherton syndrome may be associated with generalized inflammation of the skin (erythroderma) or localized thickened, red plaques (erythrokeratoderma), immunodysfunction with elevated IgE levels, allergies, and susceptibility to infections, failure to thrive or metabolic wasting. In some patients, these disorders may be life-threatening, especially during the newborn period. Due to the variable clinical presentations of PSS, its often mild features and gradual improvement with age, PSS may be underdiagnosed and underreported.
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Peeling Skin Syndrome
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Causes of Peeling Skin Syndrome
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To date, genetic changes in several distinct genes have been reported to cause PSS. These genes encode either structural proteins of corneocytes, the cells of the outermost skin layer (CDSN; DSG1; FLG2; DSC3; JUP) or inhibitors of epidermal proteases (SPINK5, CSTA; CAST; SERINB8), which are crucial regulators for the degradation of corneodesmosomes and shedding of corneocytes. Generalized non-inflammatory typeFLG2: The filaggrin 2 gene (FLG2) is co-expressed with corneodesmosin (CDSN, see below) in the outermost layers of the skin, where it is cleaved into multiple small repeat units and is crucial for maintaining cell-cell adhesion. Complete or almost complete filaggrin 2 deficiency due to loss-of-function variants in FLG2 results in decreased expression of CDSN, and generalized, non-inflammatory PSS. The generalized dryness and peeling of the skin typically improves with age but can be triggered or aggravated by heat exposure, mechanical trauma to the skin and other external factors. Rarely, formation of blisters has been reported. CAST: This gene encodes calpastatin, an endogenous protease inhibitor of calpain, which plays a role in various cell functions such as cell proliferation, differentiation, mobility, cell cycle progression, and apoptosis. Several homozygous loss-of-function variants in the CAST gene have been reported in association with PLACK syndrome, an autosomal recessive form of generalized peeling skin syndrome associated with leukonychia (white nails), acral punctate keratoses and knuckle pads (small, callus-like plaques of thickened skin on palms and soles and over knuckles), and angular cheilitis (inflammation on the corners of the mouth). Skin peeling manifests in infancy and improves over time, although it may worsen with heat exposure in the summer. The features may overlap with pachyonychia congenita, including oral leukokeratosis (whitish thickened plaques inside the mouth), and more diffuse plantar keratoderma. SERPINB8: The SERPINB8 gene codes for an epidermal serine protease inhibitor, which is, similar to SPINK5 involved in Netherton syndrome, crucial for balance between cell-cell adhesion and shedding of corneocytes. Different homozygous variants in the SERPINB8 gene have been reported in three unrelated families with autosomal recessive peeling skin syndrome, with evidence of reduced protein expression and altered cell adhesion in affected skin. The affected individuals presented in infancy with peeling of the skin of varying severity, with or without erythema or hyperkeratotic plaques on the palms and soles.CHST8: Function of the carbohydrate sulfotransferase gene CHST8 and its role in human disease have not been completely established. A homozygous missense variant in the CHST8 gene has been reported in multiple individuals with generalized non-inflammatory peeling skin syndrome from a single large consanguineous family. While initial studies suggested that the reported variant results in decreased expression and loss of function, these findings were not confirmed by functional follow-up studies, suggesting another, not yet identified, genetic cause of PSS in that family.Generalized inflammatory typeCDSN: PSS1 is caused by deleterious loss-of-function changes in the corneodesmosin gene, CDSN. Corneodesmosin is a secreted glycoprotein and main component of cell-cell adhesion structures called corneodesmosomes within the stratum corneum and is also found in hair follicles. While complete loss of corneodesmosin due to variants on both alleles of the gene (bi-allelic) results in generalized peeling skin syndrome, abnormal corneodesmosin (due to sequence changes on only one copy of the gene) have been described in the autosomal dominant hair disorder ‘hypotrichosis simplex (MIM146520)’. In Japanese individuals, a particularly common cause of PSS1 is a genomic deletion of 6 genes including the entire CDSN gene. DSG1: DSG1 codes for desmoglein 1, a major structural protein of desmosomal plaques and corneodesmosomes forming adhesion junctions between cells. Complete loss of desmoglein 1 due to bi-allelic pathogenic variants in DSG1 typically causes SAM syndrome, characterized by severe skin dermatitis, multiple allergies and metabolic wasting, which can be life-threatening. Nevertheless, there is a broad range of features and severity, and some DSG1 variants, especially those in the repeat unit domain, may result in a milder phenotype with features of PSS. SPINK5: Features of generalized inflammatory peeling skin syndrome may be present in individuals with Netherton syndrome, which is caused by bi-allelic loss-of-function variants in the SPINK5 gene. NTS is characterized by a triad of erythema and peeling of the skin associated with characteristic hair shaft abnormalities (“bamboo hair’), and immunodysregulation with elevated IgE levels, atopy and allergies. SPINK5 codes for the multidomain protease inhibitor LEKTI, crucial for checking proteolytical activity of several epidermal serine proteases. Its loss leads to increased degradation of corneodesmosomes and excessive shedding of corneocytes, abnormal formation of the lipid envelope, and to a severe skin barrier dysfunction aggravated by a loss of crucial anti-inflammatory and anti-microbial protection normally provided by LEKTI. Localized typeTGM5: The transglutaminase-5 (TGM5) gene is responsible for the acral, localized form of peeling skin syndrome. Bi-allelic disease-causing genetic variants in TGM5 result in loss of function of this important cross-linking enzyme in the upper skin layers. Acral PSS presents with superficial blistering and peeling on the inner and outer surfaces of hands and feet, sometimes resembling the blistering skin disorder epidermolysis bullosa simplex. The majority of affected individuals reported to date harbor the common missense variant p.Gly113Cys in the TGM1 gene, either in a heterozygous or homozygous state. This recurrent variant is especially common and disseminated across the European continent, and has also been observed homozygously in the general population, suggesting that acral PSS is more common and underdiagnosed due to its mild features. CSTA: The cystatin A gene encodes a cysteine proteinase inhibitor expressed in the outermost skin layers. This enzyme is, similar to other protease inhibitors, an important player in cell-cell adhesion. Biallelic loss-of-function variants in CSTA may also cause acral peeling skin syndrome. Major features are dry, scaly skin with hyperhidrosis, erythroderma, and peeling on palms and soles aggravated by heat, friction, and water or sweat exposure. All known forms of peeling skin syndrome are inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits two abnormal copies of the disease gene, usually one from each parent. If an individual receives one normal gene copy and one abnormal gene copy for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene copy and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females. All individuals are thought to be carriers for at least 4-5 abnormal recessive genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
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Causes of Peeling Skin Syndrome. To date, genetic changes in several distinct genes have been reported to cause PSS. These genes encode either structural proteins of corneocytes, the cells of the outermost skin layer (CDSN; DSG1; FLG2; DSC3; JUP) or inhibitors of epidermal proteases (SPINK5, CSTA; CAST; SERINB8), which are crucial regulators for the degradation of corneodesmosomes and shedding of corneocytes. Generalized non-inflammatory typeFLG2: The filaggrin 2 gene (FLG2) is co-expressed with corneodesmosin (CDSN, see below) in the outermost layers of the skin, where it is cleaved into multiple small repeat units and is crucial for maintaining cell-cell adhesion. Complete or almost complete filaggrin 2 deficiency due to loss-of-function variants in FLG2 results in decreased expression of CDSN, and generalized, non-inflammatory PSS. The generalized dryness and peeling of the skin typically improves with age but can be triggered or aggravated by heat exposure, mechanical trauma to the skin and other external factors. Rarely, formation of blisters has been reported. CAST: This gene encodes calpastatin, an endogenous protease inhibitor of calpain, which plays a role in various cell functions such as cell proliferation, differentiation, mobility, cell cycle progression, and apoptosis. Several homozygous loss-of-function variants in the CAST gene have been reported in association with PLACK syndrome, an autosomal recessive form of generalized peeling skin syndrome associated with leukonychia (white nails), acral punctate keratoses and knuckle pads (small, callus-like plaques of thickened skin on palms and soles and over knuckles), and angular cheilitis (inflammation on the corners of the mouth). Skin peeling manifests in infancy and improves over time, although it may worsen with heat exposure in the summer. The features may overlap with pachyonychia congenita, including oral leukokeratosis (whitish thickened plaques inside the mouth), and more diffuse plantar keratoderma. SERPINB8: The SERPINB8 gene codes for an epidermal serine protease inhibitor, which is, similar to SPINK5 involved in Netherton syndrome, crucial for balance between cell-cell adhesion and shedding of corneocytes. Different homozygous variants in the SERPINB8 gene have been reported in three unrelated families with autosomal recessive peeling skin syndrome, with evidence of reduced protein expression and altered cell adhesion in affected skin. The affected individuals presented in infancy with peeling of the skin of varying severity, with or without erythema or hyperkeratotic plaques on the palms and soles.CHST8: Function of the carbohydrate sulfotransferase gene CHST8 and its role in human disease have not been completely established. A homozygous missense variant in the CHST8 gene has been reported in multiple individuals with generalized non-inflammatory peeling skin syndrome from a single large consanguineous family. While initial studies suggested that the reported variant results in decreased expression and loss of function, these findings were not confirmed by functional follow-up studies, suggesting another, not yet identified, genetic cause of PSS in that family.Generalized inflammatory typeCDSN: PSS1 is caused by deleterious loss-of-function changes in the corneodesmosin gene, CDSN. Corneodesmosin is a secreted glycoprotein and main component of cell-cell adhesion structures called corneodesmosomes within the stratum corneum and is also found in hair follicles. While complete loss of corneodesmosin due to variants on both alleles of the gene (bi-allelic) results in generalized peeling skin syndrome, abnormal corneodesmosin (due to sequence changes on only one copy of the gene) have been described in the autosomal dominant hair disorder ‘hypotrichosis simplex (MIM146520)’. In Japanese individuals, a particularly common cause of PSS1 is a genomic deletion of 6 genes including the entire CDSN gene. DSG1: DSG1 codes for desmoglein 1, a major structural protein of desmosomal plaques and corneodesmosomes forming adhesion junctions between cells. Complete loss of desmoglein 1 due to bi-allelic pathogenic variants in DSG1 typically causes SAM syndrome, characterized by severe skin dermatitis, multiple allergies and metabolic wasting, which can be life-threatening. Nevertheless, there is a broad range of features and severity, and some DSG1 variants, especially those in the repeat unit domain, may result in a milder phenotype with features of PSS. SPINK5: Features of generalized inflammatory peeling skin syndrome may be present in individuals with Netherton syndrome, which is caused by bi-allelic loss-of-function variants in the SPINK5 gene. NTS is characterized by a triad of erythema and peeling of the skin associated with characteristic hair shaft abnormalities (“bamboo hair’), and immunodysregulation with elevated IgE levels, atopy and allergies. SPINK5 codes for the multidomain protease inhibitor LEKTI, crucial for checking proteolytical activity of several epidermal serine proteases. Its loss leads to increased degradation of corneodesmosomes and excessive shedding of corneocytes, abnormal formation of the lipid envelope, and to a severe skin barrier dysfunction aggravated by a loss of crucial anti-inflammatory and anti-microbial protection normally provided by LEKTI. Localized typeTGM5: The transglutaminase-5 (TGM5) gene is responsible for the acral, localized form of peeling skin syndrome. Bi-allelic disease-causing genetic variants in TGM5 result in loss of function of this important cross-linking enzyme in the upper skin layers. Acral PSS presents with superficial blistering and peeling on the inner and outer surfaces of hands and feet, sometimes resembling the blistering skin disorder epidermolysis bullosa simplex. The majority of affected individuals reported to date harbor the common missense variant p.Gly113Cys in the TGM1 gene, either in a heterozygous or homozygous state. This recurrent variant is especially common and disseminated across the European continent, and has also been observed homozygously in the general population, suggesting that acral PSS is more common and underdiagnosed due to its mild features. CSTA: The cystatin A gene encodes a cysteine proteinase inhibitor expressed in the outermost skin layers. This enzyme is, similar to other protease inhibitors, an important player in cell-cell adhesion. Biallelic loss-of-function variants in CSTA may also cause acral peeling skin syndrome. Major features are dry, scaly skin with hyperhidrosis, erythroderma, and peeling on palms and soles aggravated by heat, friction, and water or sweat exposure. All known forms of peeling skin syndrome are inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits two abnormal copies of the disease gene, usually one from each parent. If an individual receives one normal gene copy and one abnormal gene copy for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene copy and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females. All individuals are thought to be carriers for at least 4-5 abnormal recessive genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
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Affects of Peeling Skin Syndrome
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Peeling skin syndrome is a rare inherited disorder that, in theory, affects males and females in equal numbers. More than 100 cases have been reported in the medical literature from different population groups. Peeling skin syndrome due to variants in the CHST8 and CSTA genes were reported in consanguineous Pakistani and in Bedouin families, respectively. In Japanese individuals, a particularly common deletion involving CDSN has been reported. In Europeans, acral PSS due to TMG5 variants is more common.
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Affects of Peeling Skin Syndrome. Peeling skin syndrome is a rare inherited disorder that, in theory, affects males and females in equal numbers. More than 100 cases have been reported in the medical literature from different population groups. Peeling skin syndrome due to variants in the CHST8 and CSTA genes were reported in consanguineous Pakistani and in Bedouin families, respectively. In Japanese individuals, a particularly common deletion involving CDSN has been reported. In Europeans, acral PSS due to TMG5 variants is more common.
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Related disorders of Peeling Skin Syndrome
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Symptoms of the following disorders can be similar to those of peeling skin syndrome. Comparisons may be useful for a differential diagnosis:Exfoliative dermatitis refers to a scaling skin disorder accompanied by distinct reddening (erythematous dermatitis) involving 90% or more of the skin surface. It is characterized by erythema and scaling involving the skin’s surface that often obscures the primary lesions. It is frequently difficult for clinicians to find the cause of exfoliative dermatitis even though the history of illness prior to erythema and scaling is obtained. Often, biopsies and blood studies are required. The term red man syndrome is reserved for idiopathic exfoliative dermatitis in which no primary cause can be found, notwithstanding a variety of examinations and tests. This form of the disorder is characterized by marked hardening of the skin of the palms and soles, swelling (lymphadenopathy), and raised levels of immunoglobulin E. Keratolysis exfoliativa congenital (also known as dyshidrosis lamellosa sicca) is limited to palms and soles with small, air-filled blisters and collarette-like scaling. It has been debated to be a subtype of dyshidrotic eczema, due to fungal infection, or drug reaction. Although this disorder shows microscopic evidence for premature falling-apart of the components of the outer horny layer of the epidermis (corneodesmolysis), no mutations were identified in TGM5 and other candidate genes, indicating that it is a distinct disorder from acral peeling skin syndrome.Netherton syndrome is a rare type of autosomal recessive congenital ichthyosis characterized either by scaly plaques with a peculiar, double-edged border (so-called “ichthyosis linearis circumflexa”) or by persistent, generalized redness, scaling, or, sometimes, peeling. The hair is often fragile and sparse due to a structural defect of the hair shafts that results in a ball-in-socket or bamboo stick-like appearance (trichorrhexis invaginata, “bamboo hair”). Another characteristic of Netherton syndrome is a predisposition to allergies such as asthma, or food allergies that cause skin eruptions. (For more information, choose “Netherton” as your search term in the Rare Disease Database.)PSS might also show minimal clinical overlap to disorders caused by other desmosomal genes, such as DSC3 and JUP. Rarely, mutations in these genes have been implicated in lethal congenital epidermolysis bullosa (JUP, plakoglobin), cardiomyopathy with alopecia and palmoplantar keratoderma (JUP, plakoglobin), and hypotrichosis with scalp vesicles (DSC3, desmocollin 3).
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Related disorders of Peeling Skin Syndrome. Symptoms of the following disorders can be similar to those of peeling skin syndrome. Comparisons may be useful for a differential diagnosis:Exfoliative dermatitis refers to a scaling skin disorder accompanied by distinct reddening (erythematous dermatitis) involving 90% or more of the skin surface. It is characterized by erythema and scaling involving the skin’s surface that often obscures the primary lesions. It is frequently difficult for clinicians to find the cause of exfoliative dermatitis even though the history of illness prior to erythema and scaling is obtained. Often, biopsies and blood studies are required. The term red man syndrome is reserved for idiopathic exfoliative dermatitis in which no primary cause can be found, notwithstanding a variety of examinations and tests. This form of the disorder is characterized by marked hardening of the skin of the palms and soles, swelling (lymphadenopathy), and raised levels of immunoglobulin E. Keratolysis exfoliativa congenital (also known as dyshidrosis lamellosa sicca) is limited to palms and soles with small, air-filled blisters and collarette-like scaling. It has been debated to be a subtype of dyshidrotic eczema, due to fungal infection, or drug reaction. Although this disorder shows microscopic evidence for premature falling-apart of the components of the outer horny layer of the epidermis (corneodesmolysis), no mutations were identified in TGM5 and other candidate genes, indicating that it is a distinct disorder from acral peeling skin syndrome.Netherton syndrome is a rare type of autosomal recessive congenital ichthyosis characterized either by scaly plaques with a peculiar, double-edged border (so-called “ichthyosis linearis circumflexa”) or by persistent, generalized redness, scaling, or, sometimes, peeling. The hair is often fragile and sparse due to a structural defect of the hair shafts that results in a ball-in-socket or bamboo stick-like appearance (trichorrhexis invaginata, “bamboo hair”). Another characteristic of Netherton syndrome is a predisposition to allergies such as asthma, or food allergies that cause skin eruptions. (For more information, choose “Netherton” as your search term in the Rare Disease Database.)PSS might also show minimal clinical overlap to disorders caused by other desmosomal genes, such as DSC3 and JUP. Rarely, mutations in these genes have been implicated in lethal congenital epidermolysis bullosa (JUP, plakoglobin), cardiomyopathy with alopecia and palmoplantar keratoderma (JUP, plakoglobin), and hypotrichosis with scalp vesicles (DSC3, desmocollin 3).
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Diagnosis of Peeling Skin Syndrome
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A good history and physical exam are often sufficient to make the diagnosis, although specialized tests including surgical removal and microscopic evaluation (biopsy) of affected tissue may be necessary at times. The continual shedding of large sheets of skin distinguishes peeling skin syndrome from Netherton syndrome and from other types of autosomal recessive congenital ichthyosis, such as congenital ichthyosiform erythroderma. The skin of so-called “collodion babies” peels off after a few weeks and does not return, in contrast to patients with peeling skin syndrome whose symptoms return time after time.
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Diagnosis of Peeling Skin Syndrome. A good history and physical exam are often sufficient to make the diagnosis, although specialized tests including surgical removal and microscopic evaluation (biopsy) of affected tissue may be necessary at times. The continual shedding of large sheets of skin distinguishes peeling skin syndrome from Netherton syndrome and from other types of autosomal recessive congenital ichthyosis, such as congenital ichthyosiform erythroderma. The skin of so-called “collodion babies” peels off after a few weeks and does not return, in contrast to patients with peeling skin syndrome whose symptoms return time after time.
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Therapies of Peeling Skin Syndrome
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Treatment
Treating peeling skin syndrome by applying skin softening (emollient) ointments, especially after a bath while the skin is moist, may offer some relief. Plain petroleum jelly or Vaseline is preferred. None of the corticosteroids or systemic retinoids (vitamin A derivatives) is indicated or effective and all may have serious side effects or adverse reactions.To discuss the risk of having children with this disorder and the possibility of genetic testing, genetic counseling is recommended for affected individuals and their families.
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Therapies of Peeling Skin Syndrome. Treatment
Treating peeling skin syndrome by applying skin softening (emollient) ointments, especially after a bath while the skin is moist, may offer some relief. Plain petroleum jelly or Vaseline is preferred. None of the corticosteroids or systemic retinoids (vitamin A derivatives) is indicated or effective and all may have serious side effects or adverse reactions.To discuss the risk of having children with this disorder and the possibility of genetic testing, genetic counseling is recommended for affected individuals and their families.
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Overview of Pelizaeus-Merzbacher Disease
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SummaryPelizaeus-Merzbacher disease (PMD) is a rare X-linked genetic disorder affecting the central nervous system that is associated with abnormalities of the white matter of the brain and spinal cord. It is one of the leukodystrophies in which disease is due to abnormal development of one or more components (predominantly fats or proteins) that make up the white matter (myelin sheath) of the brain. The myelin sheath is the protective covering of the nerve and nerves cannot function normally without it. In PMD, many areas of the central nervous system may be affected, including the deep portions of the cerebrum (subcortical), cerebellum, brain stem and spinal cord. Signs may include the impaired ability to coordinate movement (ataxia), involuntary muscle spasms (spasticity) that result in slow, stiff movements of the legs, delays in reaching developmental milestones, late onset loss of motor abilities, and progressive deterioration of intellectual function. The neurologic signs of PMD are usually slowly progressive.PMD is associated with abnormalities (mutations or variants) in the PLP1 gene. Several forms of the disorder have been identified including classic PMD; connatal (meaning “at birth”) PMD; transitional PMD; and PLP1 null syndrome (no PLP1 protein). Forms of complicated spastic paraparesis and pure spastic paraparesis (designated SPG2) and hypomyelination of early myelinating structures (HEMS) are also caused by variants of the PLP1 gene.
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Overview of Pelizaeus-Merzbacher Disease. SummaryPelizaeus-Merzbacher disease (PMD) is a rare X-linked genetic disorder affecting the central nervous system that is associated with abnormalities of the white matter of the brain and spinal cord. It is one of the leukodystrophies in which disease is due to abnormal development of one or more components (predominantly fats or proteins) that make up the white matter (myelin sheath) of the brain. The myelin sheath is the protective covering of the nerve and nerves cannot function normally without it. In PMD, many areas of the central nervous system may be affected, including the deep portions of the cerebrum (subcortical), cerebellum, brain stem and spinal cord. Signs may include the impaired ability to coordinate movement (ataxia), involuntary muscle spasms (spasticity) that result in slow, stiff movements of the legs, delays in reaching developmental milestones, late onset loss of motor abilities, and progressive deterioration of intellectual function. The neurologic signs of PMD are usually slowly progressive.PMD is associated with abnormalities (mutations or variants) in the PLP1 gene. Several forms of the disorder have been identified including classic PMD; connatal (meaning “at birth”) PMD; transitional PMD; and PLP1 null syndrome (no PLP1 protein). Forms of complicated spastic paraparesis and pure spastic paraparesis (designated SPG2) and hypomyelination of early myelinating structures (HEMS) are also caused by variants of the PLP1 gene.
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Symptoms of Pelizaeus-Merzbacher Disease
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The signs of PMD may vary widely from person to person. The signs of the classical form of PMD usually begin during early infancy, typically before 2 months of age. Initially, affected infants may fail to develop normal control of the head and eyes, specifically abnormal head bobbing and rapid, involuntary, jerky eye movements (nystagmus). Abnormally slow growth may also be an early sign. As affected infants and children age, additional signs may become apparent, including muscle tremors, weakness, facial grimacing, lack of muscle tone (hypotonia), impaired ability to coordinate voluntary movements (ataxia), and/or impairment in the acquisition of skills requiring the coordination of muscular and mental activities (psychomotor retardation) including delays in reaching developmental milestones such as sitting, standing, and walking. Affected individuals may also develop involuntary muscle spasms (spasticity) that result in slow, stiff movements of the legs and potentially partial paralysis of the arms and legs (spastic quadriparesis); abnormal, permanent fixation of certain joints (contractures); progressive degeneration of the nerves that lead to the eyes (optic atrophy); and/or difficulty speaking (dysarthria). As some affected children age, nystagmus may disappear. Some children may also develop skeletal deformities secondary to the severe spasticity that typically develops over time. The signs of connatal PMD are present at birth or are observed during the first few weeks of life. This form of the disorder is characterized by weakness, spasticity, high-pitched sound when breathing (stridor), nystagmus, and seizures. Severe difficulty while swallowing (dysphagia) may also occur, necessitating gastrostomy feeding. Affected infants may also exhibit deterioration of mental functions and failure to reach developmental milestones such as speaking and walking. The progression of this form of PMD is more rapid and severe than the classic form and is often fatal during childhood. Transitional PMD is a form of disease that is intermediate between the classical and connatal forms. The signs are similar to those of the classical and connatal forms of the disorder. However, the rate of progression is faster than the classical form but slower than the connatal form. The PLP1 null syndrome is characterized by mild spastic quadriparesis, mild ataxia, absence of nystagmus during infancy and a mild demyelinating peripheral neuropathy. Patients with this form typically learn to walk, but deteriorate more rapidly beginning in late adolescence or early adulthood. Female carriers of PMD-related PLP1 variants may have mild to moderate signs of the disease. In some cases, these signs resolve with age.
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Symptoms of Pelizaeus-Merzbacher Disease. The signs of PMD may vary widely from person to person. The signs of the classical form of PMD usually begin during early infancy, typically before 2 months of age. Initially, affected infants may fail to develop normal control of the head and eyes, specifically abnormal head bobbing and rapid, involuntary, jerky eye movements (nystagmus). Abnormally slow growth may also be an early sign. As affected infants and children age, additional signs may become apparent, including muscle tremors, weakness, facial grimacing, lack of muscle tone (hypotonia), impaired ability to coordinate voluntary movements (ataxia), and/or impairment in the acquisition of skills requiring the coordination of muscular and mental activities (psychomotor retardation) including delays in reaching developmental milestones such as sitting, standing, and walking. Affected individuals may also develop involuntary muscle spasms (spasticity) that result in slow, stiff movements of the legs and potentially partial paralysis of the arms and legs (spastic quadriparesis); abnormal, permanent fixation of certain joints (contractures); progressive degeneration of the nerves that lead to the eyes (optic atrophy); and/or difficulty speaking (dysarthria). As some affected children age, nystagmus may disappear. Some children may also develop skeletal deformities secondary to the severe spasticity that typically develops over time. The signs of connatal PMD are present at birth or are observed during the first few weeks of life. This form of the disorder is characterized by weakness, spasticity, high-pitched sound when breathing (stridor), nystagmus, and seizures. Severe difficulty while swallowing (dysphagia) may also occur, necessitating gastrostomy feeding. Affected infants may also exhibit deterioration of mental functions and failure to reach developmental milestones such as speaking and walking. The progression of this form of PMD is more rapid and severe than the classic form and is often fatal during childhood. Transitional PMD is a form of disease that is intermediate between the classical and connatal forms. The signs are similar to those of the classical and connatal forms of the disorder. However, the rate of progression is faster than the classical form but slower than the connatal form. The PLP1 null syndrome is characterized by mild spastic quadriparesis, mild ataxia, absence of nystagmus during infancy and a mild demyelinating peripheral neuropathy. Patients with this form typically learn to walk, but deteriorate more rapidly beginning in late adolescence or early adulthood. Female carriers of PMD-related PLP1 variants may have mild to moderate signs of the disease. In some cases, these signs resolve with age.
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Causes of Pelizaeus-Merzbacher Disease
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PMD is inherited as an X-linked recessive genetic disorder that affects mostly males. X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome. Females that have a disease gene present on one of their two X chromosomes are carriers for that disorder. Female carriers usually do not display symptoms because one of their two X chromosomes is inactivated so that the genes on that chromosome are nonfunctioning. It is usually the X chromosome with the abnormal gene that is inactivated. Males have one X chromosome that is inherited from their mother, and if a male inherits an X chromosome that contains a disease gene, he will develop the disease. Female carriers of PMD have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son. Females from families where males have a milder phenotype, such as SPG2 or the PLP1 null syndrome, should be more cautiously counseled. In some of these families, the disorder behaves more like an X-linked dominant disorder with reduced penetrance in which females can be affected but less severely than the affected males in the family. Male PMD patients usually do not reproduce, but males with X-linked disorders who do reproduce pass the disease gene to all of their daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome with the PLP1 gene on it to male offspring. The only gene that has been found to be associated with PMD is located on the X chromosome and called the proteolipid protein gene or PLP1. Approximately 5 to 20% of males with a syndrome consistent with PMD do not have a variant in the PLP1 gene. Some of these patients have a variant of the GJC2 gene (autosomal recessive) that causes a Pelizaeus-Merzbacher-like disease (PMLD), which is clinically indistinguishable from PMD. Others have variants in a growing list of other leukodystrophy genes that are being discovered (see Related Disorders). Spastic paraplegia 2 (SPG2), hypomyelination of early myelinating structures (HEMS) and PMD result from different variants of the same gene (allelic disorders) on the X chromosome, the PLP1 gene.
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Causes of Pelizaeus-Merzbacher Disease. PMD is inherited as an X-linked recessive genetic disorder that affects mostly males. X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome. Females that have a disease gene present on one of their two X chromosomes are carriers for that disorder. Female carriers usually do not display symptoms because one of their two X chromosomes is inactivated so that the genes on that chromosome are nonfunctioning. It is usually the X chromosome with the abnormal gene that is inactivated. Males have one X chromosome that is inherited from their mother, and if a male inherits an X chromosome that contains a disease gene, he will develop the disease. Female carriers of PMD have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son. Females from families where males have a milder phenotype, such as SPG2 or the PLP1 null syndrome, should be more cautiously counseled. In some of these families, the disorder behaves more like an X-linked dominant disorder with reduced penetrance in which females can be affected but less severely than the affected males in the family. Male PMD patients usually do not reproduce, but males with X-linked disorders who do reproduce pass the disease gene to all of their daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome with the PLP1 gene on it to male offspring. The only gene that has been found to be associated with PMD is located on the X chromosome and called the proteolipid protein gene or PLP1. Approximately 5 to 20% of males with a syndrome consistent with PMD do not have a variant in the PLP1 gene. Some of these patients have a variant of the GJC2 gene (autosomal recessive) that causes a Pelizaeus-Merzbacher-like disease (PMLD), which is clinically indistinguishable from PMD. Others have variants in a growing list of other leukodystrophy genes that are being discovered (see Related Disorders). Spastic paraplegia 2 (SPG2), hypomyelination of early myelinating structures (HEMS) and PMD result from different variants of the same gene (allelic disorders) on the X chromosome, the PLP1 gene.
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Affects of Pelizaeus-Merzbacher Disease
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The classical and connatal forms of PMD affect males far more often than females. In rare cases, heterozygous females will exhibit some of the signs associated with the disorder. However, in the milder forms of PMD and the allelic SPG2 and HEMS, carrier females may be affected. PMD is a rare disorder. Its prevalence in the general population is unknown but estimated as approximately 1 in 100,000 in the USA.
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Affects of Pelizaeus-Merzbacher Disease. The classical and connatal forms of PMD affect males far more often than females. In rare cases, heterozygous females will exhibit some of the signs associated with the disorder. However, in the milder forms of PMD and the allelic SPG2 and HEMS, carrier females may be affected. PMD is a rare disorder. Its prevalence in the general population is unknown but estimated as approximately 1 in 100,000 in the USA.
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Related disorders of Pelizaeus-Merzbacher Disease
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Symptoms of the following disorders can be similar to those of PMD. Comparisons may be useful for a differential diagnosis: SPG2, HEMS, and PMD result from different variants of the same gene (allelic disorders) on the X chromosome. SPG2 is characterized by progressive weakness (paraplegia) and increased muscle tone and stiffness (spasticity) of leg muscles. Initial findings typically include stiffness and relatively mild weakness of leg muscles, balance difficulties, involuntary eye movements (nystagmus), gradual deterioration of the nerves of the eyes (optic atrophy, and an unusually “clumsy” manner of walking). As the disorder progresses, walking may become increasingly difficult, and patients progress to walker and then wheelchair. HEMS is similar to SPG2, but a characteristic lack of myelination of the structures of the brain that should myelinate early in development is seen on magnetic resonance imaging (MRI). PMLD (mentioned above) and the following diseases are caused by variants of different genes from the one that causes PMD. Comparisons may be useful for a differential diagnosis: Allan-Herndon-Dudley syndrome (AHDS) is caused by variants of the SLC16A2/MCT8 gene (X-linked recessive). Hypomyelinating Leukodystrophy 7 with or without oligodontia and/or hypogonotropic hypogonadism (HLD7) is caused by variants of the POLR3A gene (autosomal recessive). Hypomyelinating Leukodystrophy 8 with or without oligodontia and/or hypogonotropic hypogonadism (HLD8), is caused by variants of the POLR3B gene (autosomal recessive). Hypomyelination with congenital cataract (HCC) is caused by variants of the FAM126A gene (autosomal recessive). Hypomyelination with atrophy of the basal ganglia and cerebellum (HABC) is caused by variants of the TUBB4A gene (autosomal dominant). Autosomal dominant adult-onset leukodystrophy (ADLD) is caused by genomic duplication of the LMN1B gene (autosomal dominant). Other leukodystrophy genes are: AIMP1, HSPD1, RARS, PYCR2, POLR1C, AARS, DARS. PMD can be misdiagnosed as cerebral palsy, multiple sclerosis and spinal muscular atrophy. For more information on these disorders use them as search terms in the NORD Rare Disease Database.
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Related disorders of Pelizaeus-Merzbacher Disease. Symptoms of the following disorders can be similar to those of PMD. Comparisons may be useful for a differential diagnosis: SPG2, HEMS, and PMD result from different variants of the same gene (allelic disorders) on the X chromosome. SPG2 is characterized by progressive weakness (paraplegia) and increased muscle tone and stiffness (spasticity) of leg muscles. Initial findings typically include stiffness and relatively mild weakness of leg muscles, balance difficulties, involuntary eye movements (nystagmus), gradual deterioration of the nerves of the eyes (optic atrophy, and an unusually “clumsy” manner of walking). As the disorder progresses, walking may become increasingly difficult, and patients progress to walker and then wheelchair. HEMS is similar to SPG2, but a characteristic lack of myelination of the structures of the brain that should myelinate early in development is seen on magnetic resonance imaging (MRI). PMLD (mentioned above) and the following diseases are caused by variants of different genes from the one that causes PMD. Comparisons may be useful for a differential diagnosis: Allan-Herndon-Dudley syndrome (AHDS) is caused by variants of the SLC16A2/MCT8 gene (X-linked recessive). Hypomyelinating Leukodystrophy 7 with or without oligodontia and/or hypogonotropic hypogonadism (HLD7) is caused by variants of the POLR3A gene (autosomal recessive). Hypomyelinating Leukodystrophy 8 with or without oligodontia and/or hypogonotropic hypogonadism (HLD8), is caused by variants of the POLR3B gene (autosomal recessive). Hypomyelination with congenital cataract (HCC) is caused by variants of the FAM126A gene (autosomal recessive). Hypomyelination with atrophy of the basal ganglia and cerebellum (HABC) is caused by variants of the TUBB4A gene (autosomal dominant). Autosomal dominant adult-onset leukodystrophy (ADLD) is caused by genomic duplication of the LMN1B gene (autosomal dominant). Other leukodystrophy genes are: AIMP1, HSPD1, RARS, PYCR2, POLR1C, AARS, DARS. PMD can be misdiagnosed as cerebral palsy, multiple sclerosis and spinal muscular atrophy. For more information on these disorders use them as search terms in the NORD Rare Disease Database.
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Diagnosis of Pelizaeus-Merzbacher Disease
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A diagnosis of PMD may be suspected based upon a thorough clinical evaluation, a detailed patient history, and a variety of specialized tests such as magnetic resonance imaging (MRI) to detect deficiency of white matter. Recognition of early myelination defects, such as lack of myelination in the cerebellum and brainstem, may aide in early diagnosis of the severe forms of PMD. Molecular genetic testing for the PLP1 gene is available to confirm the diagnosis. Carrier testing is possible if a disease-causing variant in the PLP1 gene has been identified in an affected family member. Prenatal diagnosis and preimplantation genetic diagnosis is available if a PLP1 gene variant is identified in an affected family member.
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Diagnosis of Pelizaeus-Merzbacher Disease. A diagnosis of PMD may be suspected based upon a thorough clinical evaluation, a detailed patient history, and a variety of specialized tests such as magnetic resonance imaging (MRI) to detect deficiency of white matter. Recognition of early myelination defects, such as lack of myelination in the cerebellum and brainstem, may aide in early diagnosis of the severe forms of PMD. Molecular genetic testing for the PLP1 gene is available to confirm the diagnosis. Carrier testing is possible if a disease-causing variant in the PLP1 gene has been identified in an affected family member. Prenatal diagnosis and preimplantation genetic diagnosis is available if a PLP1 gene variant is identified in an affected family member.
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Therapies of Pelizaeus-Merzbacher Disease
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TreatmentThere is no standard treatment method or regimen for individuals with PMD. Treatment is based upon specific symptoms present such as medications that prevent seizures or those used for movement disorders. Supportive care, including emotional support for family members, is recommended as needed. Genetic Counseling is recommended for individuals affected with PMD and their families.
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Therapies of Pelizaeus-Merzbacher Disease. TreatmentThere is no standard treatment method or regimen for individuals with PMD. Treatment is based upon specific symptoms present such as medications that prevent seizures or those used for movement disorders. Supportive care, including emotional support for family members, is recommended as needed. Genetic Counseling is recommended for individuals affected with PMD and their families.
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Overview of Pemphigus and Pemphigoid
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Pemphigus and pemphigoid are rare autoimmune blistering diseases of the skin and/or mucous membranes. Pemphigus affects the outer layer of the skin (epidermis) and causes lesions and blisters that easily rupture. Pemphigoid affects a lower layer of the skin, between the epidermis and the dermis, creating tense blisters that do not break easily. Sometimes pemphigoid may look like hives or eczema without blisters.The term “pemphigus” is used in a very specific way to describe blistering disorders caused by autoantibodies such as desmoglein 1 and desmoglein 3 that recognize components of the epidermis and lead to disruption of the intercellular junctions, loss of integrity and formation of blisters.Pemphigoid is a group of subepidermal, blistering autoimmune diseases that primarily affect the skin, especially in the lower abdomen, groin and flexor surfaces of the extremities. Here, autoantibodies (anti-BPA-2 and anti-BPA-1) are directed against the basal layer of the epidermis and mucosa.The patient’s immune system makes antibodies, which attack viruses and harmful bacteria. In the context of pemphigus and pemphigoid, the immune system is over-active, and antibodies instead attack healthy cells in the skin or mucous membranes. As a result, skin cells separate from each other, fluid collects between skin layers and blisters form and may cover a large area of skin.
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Overview of Pemphigus and Pemphigoid. Pemphigus and pemphigoid are rare autoimmune blistering diseases of the skin and/or mucous membranes. Pemphigus affects the outer layer of the skin (epidermis) and causes lesions and blisters that easily rupture. Pemphigoid affects a lower layer of the skin, between the epidermis and the dermis, creating tense blisters that do not break easily. Sometimes pemphigoid may look like hives or eczema without blisters.The term “pemphigus” is used in a very specific way to describe blistering disorders caused by autoantibodies such as desmoglein 1 and desmoglein 3 that recognize components of the epidermis and lead to disruption of the intercellular junctions, loss of integrity and formation of blisters.Pemphigoid is a group of subepidermal, blistering autoimmune diseases that primarily affect the skin, especially in the lower abdomen, groin and flexor surfaces of the extremities. Here, autoantibodies (anti-BPA-2 and anti-BPA-1) are directed against the basal layer of the epidermis and mucosa.The patient’s immune system makes antibodies, which attack viruses and harmful bacteria. In the context of pemphigus and pemphigoid, the immune system is over-active, and antibodies instead attack healthy cells in the skin or mucous membranes. As a result, skin cells separate from each other, fluid collects between skin layers and blisters form and may cover a large area of skin.
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Pemphigus and Pemphigoid
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Symptoms of Pemphigus and Pemphigoid
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There are several different types of pemphigus.Pemphigus Vulgaris (PV)
PV is the most common of these conditions. Blisters are soft and fragile and may form at the mouth first and then spread to the skin and even the genitals. Blisters are frequently painful but not itchy, and in the mouth make chewing and swallowing difficult. PV does not cause permanent scarring unless there is an infection associated with the sore.Pemphigus Foliaceus (PF)
PF is a less severe type. Blisters may form on the scalp and face first and then spread to the chest and back. Blisters do not occur in the mouth. Blisters are not usually painful and are superficial and form crusts.Pemphigus Vegetans
This type results in thicker sores, mainly in the groin and under the arms.IgA Pemphigus
This type is caused by the IgA antibody binding to epidermal cell proteins. It may resemble pemphigus foliaceus or may appear as small pustules.Paraneoplastic Pemphigus (PNP)
PNP is associated with certain forms of cancer. Blisters form inside the mouth and may affect the lungs, leading to a fatal outcome. Sores of the mouth, lips and esophagus are almost always present and skin lesions of different types occur. PNP can affect the lungs. In some patients, the diagnosis will prompt doctors to search for a hidden tumor. In some patients, the tumor will be benign, and the disease will improve if the tumor is surgically removed.Mucous Membrane Pemphigoid (MMP)
MMP affects the eyes, mouth and throat. A clinical form called ocular cicatricial pemphigoid (OCP) can result in blindness if it involves the eyes and respiratory compromise if it involves the deeper parts of the throat.Bullous Pemphigoid (BP)
BP is frequently limited to the skin with blisters presenting predominantly on the abdomen, groin, back, arms and legs. The blisters may itch and be painful.Gestational Pemphigoid (GP)
GP is characterized by a blistering rash starting around the navel and spreading to the entire body, typically in the second or third trimester of pregnancy.Epidermolysis Bullosa Acquisita (EBA)
EBA involves a blistering rash on the skin and/or mucosal surfaces. Blisters are usually smaller than in pemphigoid.
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Symptoms of Pemphigus and Pemphigoid. There are several different types of pemphigus.Pemphigus Vulgaris (PV)
PV is the most common of these conditions. Blisters are soft and fragile and may form at the mouth first and then spread to the skin and even the genitals. Blisters are frequently painful but not itchy, and in the mouth make chewing and swallowing difficult. PV does not cause permanent scarring unless there is an infection associated with the sore.Pemphigus Foliaceus (PF)
PF is a less severe type. Blisters may form on the scalp and face first and then spread to the chest and back. Blisters do not occur in the mouth. Blisters are not usually painful and are superficial and form crusts.Pemphigus Vegetans
This type results in thicker sores, mainly in the groin and under the arms.IgA Pemphigus
This type is caused by the IgA antibody binding to epidermal cell proteins. It may resemble pemphigus foliaceus or may appear as small pustules.Paraneoplastic Pemphigus (PNP)
PNP is associated with certain forms of cancer. Blisters form inside the mouth and may affect the lungs, leading to a fatal outcome. Sores of the mouth, lips and esophagus are almost always present and skin lesions of different types occur. PNP can affect the lungs. In some patients, the diagnosis will prompt doctors to search for a hidden tumor. In some patients, the tumor will be benign, and the disease will improve if the tumor is surgically removed.Mucous Membrane Pemphigoid (MMP)
MMP affects the eyes, mouth and throat. A clinical form called ocular cicatricial pemphigoid (OCP) can result in blindness if it involves the eyes and respiratory compromise if it involves the deeper parts of the throat.Bullous Pemphigoid (BP)
BP is frequently limited to the skin with blisters presenting predominantly on the abdomen, groin, back, arms and legs. The blisters may itch and be painful.Gestational Pemphigoid (GP)
GP is characterized by a blistering rash starting around the navel and spreading to the entire body, typically in the second or third trimester of pregnancy.Epidermolysis Bullosa Acquisita (EBA)
EBA involves a blistering rash on the skin and/or mucosal surfaces. Blisters are usually smaller than in pemphigoid.
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Causes of Pemphigus and Pemphigoid
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Pemphigus and pemphigoid are not inherited but there can be a genetic predisposition to develop the disease. A person who is genetically predisposed to a disorder carries a gene (or genes) for the disease, but it may not be expressed unless it is triggered or “activated” under certain circumstances, such as due to particular environmental factors. It is not currently possible to predict who may get these diseases.
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Causes of Pemphigus and Pemphigoid. Pemphigus and pemphigoid are not inherited but there can be a genetic predisposition to develop the disease. A person who is genetically predisposed to a disorder carries a gene (or genes) for the disease, but it may not be expressed unless it is triggered or “activated” under certain circumstances, such as due to particular environmental factors. It is not currently possible to predict who may get these diseases.
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Affects of Pemphigus and Pemphigoid
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Males and females are equally affected. The conditions are known to affect people from all racial and cultural backgrounds. However, there are certain groups of people (Ashkenazi Jews, people of Mediterranean, North Indian and Persian decent) who have a higher incidence of pemphigus.
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Affects of Pemphigus and Pemphigoid. Males and females are equally affected. The conditions are known to affect people from all racial and cultural backgrounds. However, there are certain groups of people (Ashkenazi Jews, people of Mediterranean, North Indian and Persian decent) who have a higher incidence of pemphigus.
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Related disorders of Pemphigus and Pemphigoid
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Related disorders of Pemphigus and Pemphigoid.
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Pemphigus and Pemphigoid
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Diagnosis of Pemphigus and Pemphigoid
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Pemphigus and pemphigoid are diagnosed through special testing and clinical presentation. Types of testing include:Lesion biopsy — a sample of skin is removed by biopsy and examined under the microscope. Additionally, the layer of skin in which cell-to-cell separation occurs can be determined.Direct immunofluorescence — the skin sample is treated to detect desmoglein autoantibodies in the skin. The presence of these antibodies indicates pemphigus. In pemphigoid and other basement membrane autoimmune blistering diseases, other autoantibodies can be detected.Indirect immunofluorescence or antibody titer test — this measures desmoglein autoantibodies in the blood serum in pemphigus. In bullous pemphigoid BP180 and BP230 antibodies can be measured in the serum. Anti-type VII collagen is found in EBA. It may be used to obtain a more complete understanding of the course of the disease.
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Diagnosis of Pemphigus and Pemphigoid. Pemphigus and pemphigoid are diagnosed through special testing and clinical presentation. Types of testing include:Lesion biopsy — a sample of skin is removed by biopsy and examined under the microscope. Additionally, the layer of skin in which cell-to-cell separation occurs can be determined.Direct immunofluorescence — the skin sample is treated to detect desmoglein autoantibodies in the skin. The presence of these antibodies indicates pemphigus. In pemphigoid and other basement membrane autoimmune blistering diseases, other autoantibodies can be detected.Indirect immunofluorescence or antibody titer test — this measures desmoglein autoantibodies in the blood serum in pemphigus. In bullous pemphigoid BP180 and BP230 antibodies can be measured in the serum. Anti-type VII collagen is found in EBA. It may be used to obtain a more complete understanding of the course of the disease.
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Pemphigus and Pemphigoid
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Therapies of Pemphigus and Pemphigoid
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Treatment
There is currently no cure for pemphigus or pemphigoid, but these conditions can usually be controlled. A decrease in or disappearance of signs and symptoms (remission) is possible. The treatment of pemphigus and pemphigoid is directed toward suppressing the skin and mucosal lesions of the disease and preventing complications potentially associated with its treatment. Most patients will eventually enter a complete remission in which they are off all therapy and there is no evidence of the disease. Generally, the less widespread the pemphigus is, the easier it is to control. The development, severity and progression of the diseases are not uniform and the response to therapies can vary among individuals. Consequently, physicians will take several different factors into account when planning an individual’s treatment, which will be tailored to the individual’s specific needs and situation.Treatment is usually separated into phases: control, consolidation and maintenance. In the control phase, high-intensity therapy is used to bring the disorder under control by initiating the clearance of current lesions, reducing or suppressing new lesion formation, and improving other symptoms such as itch relief. In the consolidation phase, a consistent dose of medication is used until a significant portion of lesions have healed. In the maintenance phase, the dose of medication is gradually reduced until a minimal level is achieved that is successful in preventing the development of new lesions.The mainstay of treatment is the use of corticosteroids such as prednisone, which are anti-inflammatory medications that also suppress the normal function of the immune system. Steroids may be applied directly to the affected areas (topically) or may be taken by mouth or given by injection (systemic steroids). Topical therapy is generally given to reduce pain and prevent or treat infection. Most individuals will receive systemic steroids to bring about control of pemphigus. The dose of steroids used can be tapered once control of the disorder is achieved.Rituximab is now considered a first-line therapy for pemphigus, and it was recently approved by the FDA for this indication. Rituximab can prevent new autoantibodies from forming. It takes 3-4 months for the existing autoantibody levels to fall, during which time some dose of steroids may be required.Other medications that may be used in combination with corticosteroids to treat individuals with pemphigus include drugs that suppress the immune system (immunosuppressive drugs) such as mycophenolate mofetil, azathioprine, methotrexate or cyclophosphamide; drugs that modify or regulate the immune system (immunomodulatory drugs) dapsone; or antibiotics such as doxycycline. These medications may be used to allow physicians to lower the overall dose of steroids. Some individuals respond to therapy quickly; others respond more slowly or do not respond at all. In severe cases or in cases where individuals fail to respond to other therapies, pulse steroids, plasmapheresis or intravenous immunoglobulin therapy (IVIG) may be used.Research has indicated that IVIG therapy can markedly decrease levels of the abnormal antibodies associated with pemphigus without decreasing the levels of normal, healthy antibodies. IVIG is normally given with other therapy such as steroids and immunosuppressive drugs, to prevent rebound of disease as the therapy is tapered.Pulse-steroid therapy refers to the administration of extremely high levels of steroids given for a short period of time. Plasmapheresis is a method for removing unwanted substances (e.g., autoantibodies) from the blood, and is not used as much now because of increased risk of infections. Blood is removed from the patient and blood cells are separated from plasma. The patient’s plasma is then replaced with other human plasma and the blood is transfused into the patient. These approaches are most frequently used now only if rituximab is not tolerated or is ineffective.The conditions themselves are rarely fatal, and most deaths occur from infections of compromised tissues. If left untreated, these diseases may be fatal.
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Therapies of Pemphigus and Pemphigoid. Treatment
There is currently no cure for pemphigus or pemphigoid, but these conditions can usually be controlled. A decrease in or disappearance of signs and symptoms (remission) is possible. The treatment of pemphigus and pemphigoid is directed toward suppressing the skin and mucosal lesions of the disease and preventing complications potentially associated with its treatment. Most patients will eventually enter a complete remission in which they are off all therapy and there is no evidence of the disease. Generally, the less widespread the pemphigus is, the easier it is to control. The development, severity and progression of the diseases are not uniform and the response to therapies can vary among individuals. Consequently, physicians will take several different factors into account when planning an individual’s treatment, which will be tailored to the individual’s specific needs and situation.Treatment is usually separated into phases: control, consolidation and maintenance. In the control phase, high-intensity therapy is used to bring the disorder under control by initiating the clearance of current lesions, reducing or suppressing new lesion formation, and improving other symptoms such as itch relief. In the consolidation phase, a consistent dose of medication is used until a significant portion of lesions have healed. In the maintenance phase, the dose of medication is gradually reduced until a minimal level is achieved that is successful in preventing the development of new lesions.The mainstay of treatment is the use of corticosteroids such as prednisone, which are anti-inflammatory medications that also suppress the normal function of the immune system. Steroids may be applied directly to the affected areas (topically) or may be taken by mouth or given by injection (systemic steroids). Topical therapy is generally given to reduce pain and prevent or treat infection. Most individuals will receive systemic steroids to bring about control of pemphigus. The dose of steroids used can be tapered once control of the disorder is achieved.Rituximab is now considered a first-line therapy for pemphigus, and it was recently approved by the FDA for this indication. Rituximab can prevent new autoantibodies from forming. It takes 3-4 months for the existing autoantibody levels to fall, during which time some dose of steroids may be required.Other medications that may be used in combination with corticosteroids to treat individuals with pemphigus include drugs that suppress the immune system (immunosuppressive drugs) such as mycophenolate mofetil, azathioprine, methotrexate or cyclophosphamide; drugs that modify or regulate the immune system (immunomodulatory drugs) dapsone; or antibiotics such as doxycycline. These medications may be used to allow physicians to lower the overall dose of steroids. Some individuals respond to therapy quickly; others respond more slowly or do not respond at all. In severe cases or in cases where individuals fail to respond to other therapies, pulse steroids, plasmapheresis or intravenous immunoglobulin therapy (IVIG) may be used.Research has indicated that IVIG therapy can markedly decrease levels of the abnormal antibodies associated with pemphigus without decreasing the levels of normal, healthy antibodies. IVIG is normally given with other therapy such as steroids and immunosuppressive drugs, to prevent rebound of disease as the therapy is tapered.Pulse-steroid therapy refers to the administration of extremely high levels of steroids given for a short period of time. Plasmapheresis is a method for removing unwanted substances (e.g., autoantibodies) from the blood, and is not used as much now because of increased risk of infections. Blood is removed from the patient and blood cells are separated from plasma. The patient’s plasma is then replaced with other human plasma and the blood is transfused into the patient. These approaches are most frequently used now only if rituximab is not tolerated or is ineffective.The conditions themselves are rarely fatal, and most deaths occur from infections of compromised tissues. If left untreated, these diseases may be fatal.
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Overview of Pendred Syndrome
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SummaryPendred syndrome is an uncommon genetic disease in children. Patients usually have hearing loss in both ears (often at birth) and a goiter, which is an enlarged thyroid gland in the neck. The goiter typically grows in the teenage years but may present earlier or later. Pendred syndrome is caused by the lack of a protein called pendrin, which is important in the kidney, ear and thyroid to keep salt levels balanced. Without enough pendrin, the ion levels become unbalanced and cause hearing and balance issues, a swollen thyroid and less commonly electrolyte imbalances. There is no specific treatment, but the symptoms can be managed with thyroid hormone supplements and hearing aids.
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Overview of Pendred Syndrome. SummaryPendred syndrome is an uncommon genetic disease in children. Patients usually have hearing loss in both ears (often at birth) and a goiter, which is an enlarged thyroid gland in the neck. The goiter typically grows in the teenage years but may present earlier or later. Pendred syndrome is caused by the lack of a protein called pendrin, which is important in the kidney, ear and thyroid to keep salt levels balanced. Without enough pendrin, the ion levels become unbalanced and cause hearing and balance issues, a swollen thyroid and less commonly electrolyte imbalances. There is no specific treatment, but the symptoms can be managed with thyroid hormone supplements and hearing aids.
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Symptoms of Pendred Syndrome
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The most common symptoms of Pendred syndrome include:
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Symptoms of Pendred Syndrome. The most common symptoms of Pendred syndrome include:
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Pendred Syndrome
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Causes of Pendred Syndrome
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Pendred syndrome is caused by changes (mutations) in three genes (SLC26A4, FOXI1, or KCNJ10) in about 50% of patients, and the other half are due to unknown causes. Mutations in SLC26A4 (also known as PDS), which encodes the protein pendrin, are the most common identifiable causes of Pendred syndrome. Pendrin is found in the inner ear (responsible for hearing and balance), the thyroid (a butterfly-shaped organ in the lower neck which is responsible for controlling metabolism) and kidneys (responsible for filtering waste and controlling salt levels). Pendrin pumps chloride and iodide to maintain their ion balance in the inner ear, thyroid and kidney. Mutations in these genes result in a lack of pendrin, so the ion levels become unbalanced and cause hearing and balance issues, a swollen thyroid and less commonly electrolyte imbalances.Pendred syndrome is an autosomal recessive genetic condition. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.
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Causes of Pendred Syndrome. Pendred syndrome is caused by changes (mutations) in three genes (SLC26A4, FOXI1, or KCNJ10) in about 50% of patients, and the other half are due to unknown causes. Mutations in SLC26A4 (also known as PDS), which encodes the protein pendrin, are the most common identifiable causes of Pendred syndrome. Pendrin is found in the inner ear (responsible for hearing and balance), the thyroid (a butterfly-shaped organ in the lower neck which is responsible for controlling metabolism) and kidneys (responsible for filtering waste and controlling salt levels). Pendrin pumps chloride and iodide to maintain their ion balance in the inner ear, thyroid and kidney. Mutations in these genes result in a lack of pendrin, so the ion levels become unbalanced and cause hearing and balance issues, a swollen thyroid and less commonly electrolyte imbalances.Pendred syndrome is an autosomal recessive genetic condition. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.
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Pendred Syndrome
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Affects of Pendred Syndrome
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Pendred syndrome affects approximately 2-3 per 1,000 children. This condition is not known to occur more often in people with different racial/ethnic backgrounds.
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Affects of Pendred Syndrome. Pendred syndrome affects approximately 2-3 per 1,000 children. This condition is not known to occur more often in people with different racial/ethnic backgrounds.
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Pendred Syndrome
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Related disorders of Pendred Syndrome
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Congenital cytomegaloviral infection (cCMV) – may also cause hearing loss at birth due to a viral infection during pregnancyX-linked deafness 2 (DFNX2) – causes a different type of hearing loss at birth, affecting the bone rather than the nervous system
Goiter – an enlarged thyroid gland due to other causes such as iodine deficiency, pregnancy, or thyroid cancerEnlarged vestibular aqueduct – a congenital malformation of the inner ear that can be seen on imaging (CT or MRI) which can cause hearing loss. Head trauma can cause significant hearing loss in these patients.
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Related disorders of Pendred Syndrome. Congenital cytomegaloviral infection (cCMV) – may also cause hearing loss at birth due to a viral infection during pregnancyX-linked deafness 2 (DFNX2) – causes a different type of hearing loss at birth, affecting the bone rather than the nervous system
Goiter – an enlarged thyroid gland due to other causes such as iodine deficiency, pregnancy, or thyroid cancerEnlarged vestibular aqueduct – a congenital malformation of the inner ear that can be seen on imaging (CT or MRI) which can cause hearing loss. Head trauma can cause significant hearing loss in these patients.
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Diagnosis of Pendred Syndrome
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Hearing loss at birth or during childhood is usually the first sign of this disease. An MRI scan of the inner ear may show an enlarged vestibular aqueduct or an abnormal cochlea. Genetic testing for the pendrin gene is the most common test leading to a diagnosis of Pendred syndrome.Clinical Testing and Work-up
Abnormal hearing tests lead to the initial suspicion of congenital hearing loss. If possible, an MRI scan of the inner ear may be performed to look for malformations. An MRI does not emit radiation but requires the child to sit still for an extended period. A perchlorate discharge test and thyroid function test may be used to determine how well the thyroid is functioning. The results of these tests will help determine whether the patient needs thyroid hormone supplements or other treatments.
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Diagnosis of Pendred Syndrome. Hearing loss at birth or during childhood is usually the first sign of this disease. An MRI scan of the inner ear may show an enlarged vestibular aqueduct or an abnormal cochlea. Genetic testing for the pendrin gene is the most common test leading to a diagnosis of Pendred syndrome.Clinical Testing and Work-up
Abnormal hearing tests lead to the initial suspicion of congenital hearing loss. If possible, an MRI scan of the inner ear may be performed to look for malformations. An MRI does not emit radiation but requires the child to sit still for an extended period. A perchlorate discharge test and thyroid function test may be used to determine how well the thyroid is functioning. The results of these tests will help determine whether the patient needs thyroid hormone supplements or other treatments.
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Pendred Syndrome
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Therapies of Pendred Syndrome
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Treatment
There is no specific treatment for Pendred syndrome and supportive therapies are typically aimed at correcting hearing loss and thyroid dysfunction.Depending on the extent of hearing loss and thyroid dysfunction, patients with Pendred syndrome may need hearing aids, therapy or thyroid supplements. Patients should be very careful to avoid head injuries, since the inner ear is extra sensitive, and some patients have noted worsened hearing impairment or vertigo after minor head trauma.
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Therapies of Pendred Syndrome. Treatment
There is no specific treatment for Pendred syndrome and supportive therapies are typically aimed at correcting hearing loss and thyroid dysfunction.Depending on the extent of hearing loss and thyroid dysfunction, patients with Pendred syndrome may need hearing aids, therapy or thyroid supplements. Patients should be very careful to avoid head injuries, since the inner ear is extra sensitive, and some patients have noted worsened hearing impairment or vertigo after minor head trauma.
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Pendred Syndrome
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Overview of Penta X Syndrome
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Penta X syndrome is an extremely rare chromosomal disorder in which females have three extra X chromosomes. Typically, females have only two X chromosomes, resulting in a 46,XX karyotype. However, in those with penta X syndrome, there are a total of five X chromosomes, resulting in a karyotype of 49,XXXXX. The condition is typically characterized by moderate to severe intellectual disability, short stature, upslanting eyelid folds (palpebral fissures), a flat nasal bridge, malformed ears, and a short neck with a low hairline. Penta X syndrome may also be characterized by mild angulation of the fifth finger (pinky) toward the fourth finger (ring finger) (clinodactyly) or permanent flexion (camptodactyly) of the fifth fingers, heart and/or kidney defects, and deficient development of the ovaries and uterus. The disorder results from random errors during the division of reproductive cells in one of the parents. While the exact incidence of this disorder is unknown, researchers believe it occurs in close to one in 85,000 live births, comparable to the male equivalence (49,XXXXY).
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Overview of Penta X Syndrome. Penta X syndrome is an extremely rare chromosomal disorder in which females have three extra X chromosomes. Typically, females have only two X chromosomes, resulting in a 46,XX karyotype. However, in those with penta X syndrome, there are a total of five X chromosomes, resulting in a karyotype of 49,XXXXX. The condition is typically characterized by moderate to severe intellectual disability, short stature, upslanting eyelid folds (palpebral fissures), a flat nasal bridge, malformed ears, and a short neck with a low hairline. Penta X syndrome may also be characterized by mild angulation of the fifth finger (pinky) toward the fourth finger (ring finger) (clinodactyly) or permanent flexion (camptodactyly) of the fifth fingers, heart and/or kidney defects, and deficient development of the ovaries and uterus. The disorder results from random errors during the division of reproductive cells in one of the parents. While the exact incidence of this disorder is unknown, researchers believe it occurs in close to one in 85,000 live births, comparable to the male equivalence (49,XXXXY).
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Symptoms of Penta X Syndrome
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Penta X syndrome is characteristically associated with growth delays before birth (prenatal growth deficiency), failure to grow and gain weight at the expected rate after birth (failure to thrive), and short stature. In addition, infants and children with penta X syndrome typically have delays in the acquisition of skills requiring the coordination of mental and physical activities (psychomotor deficits) and are affected by moderate to severe intellectual disability.There are several physical features this disorder is characterized by, with the most common being short stature, facial differences and clinodactyly. Because penta X is so rare, there is still much unknown about the phenotype, and associated symptoms vary. It is important to note that affected individuals may not have all of the symptoms discussed below.Females with 49,XXXXX typically have distinctive facial features. These often include a small head (microcephaly), a round face, upslanting eyelid folds (palpebral fissures), a flat nasal bridge, low-set malformed ears, and/or a short neck with a low hairline. Some affected individuals may also have additional eye (ocular) abnormalities, such as widely spaced eyes (ocular hypertelorism), vertical skin folds that may cover the eyes’ inner corners (epicanthal folds), drooping of the upper eyelids (ptosis), and/or partial absence of tissue from the irides or the colored regions of the eyes (iris colobomas). Additional craniofacial features reported in association with penta X syndrome have included abnormal, rudimentary outgrowths of tissue in front of the external ears (preauricular tags), a small jaw (micrognathia), thick lips, and/or incomplete closure of the roof of the mouth (cleft palate). Dental abnormalities have been reported in females with 49,XXXXX such as abnormal contact of the upper jaw teeth with those of the lower jaw (malocclusion), unusually shaped molars with large pulp spaces (taurodontism), and/or enamel defects, potentially resulting in premature loss of certain “baby” (deciduous or primary) teeth.Females with penta X syndrome may have various musculoskeletal defects, such as abnormal fusion of the forearm bones (radioulnar synostosis), narrow shoulders, and/or unusually small hands with abnormal deviation (clinodactyly) or permanent flexion (camptodactyly) of the fifth fingers. Additional findings may include overlapping toes, a foot deformity in which the sole is turned inward (metatarsus varus), and/or an abnormality in which the knees are unusually close together and the space between the ankles is increased (“knock knees” [genua valga]). Some affected females also have overflexion, bending (i.e., hyperflexion), or dislocations of multiple joints, including those of the fingers, wrists, shoulders, elbows, and/or hips. Further, reports indicate that some affected individuals may have abnormal skin ridge patterns (dermatoglyphics) on the fingers and palms of the hands.In some cases, penta X syndrome may be associated with certain structural malformations of the heart at birth (congenital heart defects). Such defects may include an abnormal opening in the fibrous partition (septum) that normally separates the two lower chambers of the heart (ventricular septal defect [VSD]), and/or patent ductus arteriosus (PDA). In PDA, the channel that is present between the aorta and the pulmonary artery during fetal development fails to close after birth, leaving an abnormal opening between the arteries and affecting the supply of oxygenated blood to body tissues.Some females with penta X syndrome may also have certain kidney (renal) abnormalities, such as underdevelopment of the kidneys (renal hypoplasia) and/or a congenital abnormality in which the two kidneys are joined at the base (horseshoe kidney).Less often, affected females may have an unusually small uterus, and/or deficient development of the ovaries. Delayed puberty has also been reported.
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Symptoms of Penta X Syndrome. Penta X syndrome is characteristically associated with growth delays before birth (prenatal growth deficiency), failure to grow and gain weight at the expected rate after birth (failure to thrive), and short stature. In addition, infants and children with penta X syndrome typically have delays in the acquisition of skills requiring the coordination of mental and physical activities (psychomotor deficits) and are affected by moderate to severe intellectual disability.There are several physical features this disorder is characterized by, with the most common being short stature, facial differences and clinodactyly. Because penta X is so rare, there is still much unknown about the phenotype, and associated symptoms vary. It is important to note that affected individuals may not have all of the symptoms discussed below.Females with 49,XXXXX typically have distinctive facial features. These often include a small head (microcephaly), a round face, upslanting eyelid folds (palpebral fissures), a flat nasal bridge, low-set malformed ears, and/or a short neck with a low hairline. Some affected individuals may also have additional eye (ocular) abnormalities, such as widely spaced eyes (ocular hypertelorism), vertical skin folds that may cover the eyes’ inner corners (epicanthal folds), drooping of the upper eyelids (ptosis), and/or partial absence of tissue from the irides or the colored regions of the eyes (iris colobomas). Additional craniofacial features reported in association with penta X syndrome have included abnormal, rudimentary outgrowths of tissue in front of the external ears (preauricular tags), a small jaw (micrognathia), thick lips, and/or incomplete closure of the roof of the mouth (cleft palate). Dental abnormalities have been reported in females with 49,XXXXX such as abnormal contact of the upper jaw teeth with those of the lower jaw (malocclusion), unusually shaped molars with large pulp spaces (taurodontism), and/or enamel defects, potentially resulting in premature loss of certain “baby” (deciduous or primary) teeth.Females with penta X syndrome may have various musculoskeletal defects, such as abnormal fusion of the forearm bones (radioulnar synostosis), narrow shoulders, and/or unusually small hands with abnormal deviation (clinodactyly) or permanent flexion (camptodactyly) of the fifth fingers. Additional findings may include overlapping toes, a foot deformity in which the sole is turned inward (metatarsus varus), and/or an abnormality in which the knees are unusually close together and the space between the ankles is increased (“knock knees” [genua valga]). Some affected females also have overflexion, bending (i.e., hyperflexion), or dislocations of multiple joints, including those of the fingers, wrists, shoulders, elbows, and/or hips. Further, reports indicate that some affected individuals may have abnormal skin ridge patterns (dermatoglyphics) on the fingers and palms of the hands.In some cases, penta X syndrome may be associated with certain structural malformations of the heart at birth (congenital heart defects). Such defects may include an abnormal opening in the fibrous partition (septum) that normally separates the two lower chambers of the heart (ventricular septal defect [VSD]), and/or patent ductus arteriosus (PDA). In PDA, the channel that is present between the aorta and the pulmonary artery during fetal development fails to close after birth, leaving an abnormal opening between the arteries and affecting the supply of oxygenated blood to body tissues.Some females with penta X syndrome may also have certain kidney (renal) abnormalities, such as underdevelopment of the kidneys (renal hypoplasia) and/or a congenital abnormality in which the two kidneys are joined at the base (horseshoe kidney).Less often, affected females may have an unusually small uterus, and/or deficient development of the ovaries. Delayed puberty has also been reported.
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Penta X Syndrome
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Causes of Penta X Syndrome
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Penta X syndrome is a chromosomal disorder characterized by the presence of three extra X chromosomes in females. Chromosomes are found in the nucleus of all body cells and carry the genetic characteristics of each individual. There are 46 human chromosomes arranged into 23 pairs, with the 23rd pair determining the sex of the individual. Females with a normal chromosomal make-up (karyotype) have two X chromosomes (46,XX karyotype), receiving one chromosome from the mother and one from the father in each of the 23 pairs.However, females with penta X syndrome have 49 chromosomes, five of which are X chromosomes (49,XXXXX karyotype). The presence of the three additional X chromosomes results from sporadic, random errors during the division of reproductive cells in one of the parents (nondisjunction during meiosis). Research suggests that the extra X chromosomes are typically derived from the mother, and the risk of such errors may increase with advanced maternal age.
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Causes of Penta X Syndrome. Penta X syndrome is a chromosomal disorder characterized by the presence of three extra X chromosomes in females. Chromosomes are found in the nucleus of all body cells and carry the genetic characteristics of each individual. There are 46 human chromosomes arranged into 23 pairs, with the 23rd pair determining the sex of the individual. Females with a normal chromosomal make-up (karyotype) have two X chromosomes (46,XX karyotype), receiving one chromosome from the mother and one from the father in each of the 23 pairs.However, females with penta X syndrome have 49 chromosomes, five of which are X chromosomes (49,XXXXX karyotype). The presence of the three additional X chromosomes results from sporadic, random errors during the division of reproductive cells in one of the parents (nondisjunction during meiosis). Research suggests that the extra X chromosomes are typically derived from the mother, and the risk of such errors may increase with advanced maternal age.
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Penta X Syndrome
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Affects of Penta X Syndrome
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Penta X syndrome is a rare chromosomal disorder that affects only females. Since the syndrome was originally described in 1963 by Kesaree and Wooley, only approximately 40 cases have been reported in the medical literature. The exact incidence of 49,XXXXX is still unknown, however, researchers believe it is close to that of 49,XXXXY (1:85,000).Some females with penta X syndrome were originally thought to be affected by Down syndrome due to the presence of certain features sometimes associated with the latter disorder. (For further information, please see the “Related Disorders” section of this report below.)
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Affects of Penta X Syndrome. Penta X syndrome is a rare chromosomal disorder that affects only females. Since the syndrome was originally described in 1963 by Kesaree and Wooley, only approximately 40 cases have been reported in the medical literature. The exact incidence of 49,XXXXX is still unknown, however, researchers believe it is close to that of 49,XXXXY (1:85,000).Some females with penta X syndrome were originally thought to be affected by Down syndrome due to the presence of certain features sometimes associated with the latter disorder. (For further information, please see the “Related Disorders” section of this report below.)
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Related disorders of Penta X Syndrome
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Certain symptoms of the following disorders may be similar to those of penta X syndrome. Comparisons may be useful for a differential diagnosis.
Unlike penta X syndrome, Down syndrome is a disorder that affects both females and males with a slightly higher incidence in males, and is considered the most common chromosomal syndrome. As noted above, some females with penta X syndrome were initially thought to have Down syndrome due to detection of certain overlapping symptoms. In females and males with Down syndrome, all or a portion of chromosome 21 appears three times (trisomy) rather than twice in cells of the body. In some cases, only a percentage of cells may contain the chromosomal abnormality (mosaicism). In most cases, duplication of chromosome 21 appears to result from random errors during the division of reproductive cells in one of the parents. Triple X syndrome is a chromosomal abnormality in which females have an extra X chromosome (47,XXX karyotype). Though the phenotype for this disorder varies widely, many affected females appear to have no or very few associated symptoms, with 90% remaining undiagnosed throughout life. However, typical physical features include tall stature, relatively small heads, vertical skin folds that may cover the eyes’ inner corners (epicanthal folds), and/or abnormal development of the ovaries and/or the uterus. Research indicates that triple X syndrome is a relatively common cause of learning difficulties, particularly language-based disabilities (e.g., dyslexia), in females. Evidence suggests that females with 47,XXX typically have poor coordination, normal or average intelligence, and a high incidence of anxiety and attention deficit hyperactivity disorder (ADHD-inattentive subtype). Infants and children with 47,XXX syndrome may tend to have delayed acquisition of certain motor skills as well as delayed language and speech development. Triple X Syndrome results from random errors during the division of reproductive cells in one of the parents. (For further information, please choose “Triple X” as your search term in the Rare Disease Database.)Tetra X syndrome is a rare chromosomal abnormality in which females have two extra X chromosomes (48,XXXX karyotype). As with triple X syndrome, the phenotypic outcome associated with this chromosomal abnormality varies widely. However, mild to moderate (or, more rarely, severe) intellectual disability appears to be a consistent finding. Affected females also commonly have speech difficulties due to verbal and motor dysfunction in association with developmental dyspraxia and childhood of apraxia (CAS), as well as behavioral difficulties. In some cases, tetra X syndrome may be associated with certain craniofacial abnormalities, such as widely set eyes (ocular hypertelorism), upslanting eyelid folds (palpebral fissures), vertical skin folds that may cover the eyes’ inner corners (epicanthal folds), and/or a relatively small jaw (micrognathia). Other associated features may include abnormal angle (clinodactyly) of the fifth fingers, fusion of the forearm bones (radioulnar synostosis), and/or webbing of the neck. Inconsistent with penta X, affected females may have incomplete development of secondary sexual characteristics, such as sparse pubic and underarm hair, small breasts, absence or irregularity of menstrual cycles, and, in some cases, underdevelopment of external genitalia. Tetra X syndrome also results from random errors during the division of a parent’s reproductive cells (nondisjunction during meiosis).Turner syndrome, a sex chromosomal disorder that affects females, is characterized by absence of all or a portion, or impaired functioning, of one of the X chromosomes (45,X karyotype). In some cases, some cells may have the normal pair of X chromosomes while other cells do not (45,X/46,XX mosaicism). In addition, evidence suggests that some affected individuals have Y chromosomal material in addition to the X chromosome in some or all cells. Females with Turner syndrome may have a short, webbed neck with a low hairline, short stature, widely spaced, inverted, and/or underdeveloped (hypoplastic) nipples, heart defects, and/or kidney abnormalities. In addition, some affected females may have certain craniofacial abnormalities, such as a small jaw (micrognathia), a narrow roof of the mouth (palate), droopy upper eyelids (ptosis), and/or widely spaced eyes (ocular hypertelorism). In many cases, immature (streak) ovaries are present that cannot produce the female hormone estrogen. As a result, normal secondary sexual characteristics may fail to develop (e.g., the appearance of pubic hair, breast development, menstruation [primary amenorrhea]). Intellectual abilities are usually normal, though some individuals may have problems with visual-spatial relations and poor coordination. Turner syndrome is thought to result from random errors during the division of a parent’s reproductive cells. (For more information on this disorder, choose “Turner” as your search term in the Rare Disease Database.)
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Related disorders of Penta X Syndrome. Certain symptoms of the following disorders may be similar to those of penta X syndrome. Comparisons may be useful for a differential diagnosis.
Unlike penta X syndrome, Down syndrome is a disorder that affects both females and males with a slightly higher incidence in males, and is considered the most common chromosomal syndrome. As noted above, some females with penta X syndrome were initially thought to have Down syndrome due to detection of certain overlapping symptoms. In females and males with Down syndrome, all or a portion of chromosome 21 appears three times (trisomy) rather than twice in cells of the body. In some cases, only a percentage of cells may contain the chromosomal abnormality (mosaicism). In most cases, duplication of chromosome 21 appears to result from random errors during the division of reproductive cells in one of the parents. Triple X syndrome is a chromosomal abnormality in which females have an extra X chromosome (47,XXX karyotype). Though the phenotype for this disorder varies widely, many affected females appear to have no or very few associated symptoms, with 90% remaining undiagnosed throughout life. However, typical physical features include tall stature, relatively small heads, vertical skin folds that may cover the eyes’ inner corners (epicanthal folds), and/or abnormal development of the ovaries and/or the uterus. Research indicates that triple X syndrome is a relatively common cause of learning difficulties, particularly language-based disabilities (e.g., dyslexia), in females. Evidence suggests that females with 47,XXX typically have poor coordination, normal or average intelligence, and a high incidence of anxiety and attention deficit hyperactivity disorder (ADHD-inattentive subtype). Infants and children with 47,XXX syndrome may tend to have delayed acquisition of certain motor skills as well as delayed language and speech development. Triple X Syndrome results from random errors during the division of reproductive cells in one of the parents. (For further information, please choose “Triple X” as your search term in the Rare Disease Database.)Tetra X syndrome is a rare chromosomal abnormality in which females have two extra X chromosomes (48,XXXX karyotype). As with triple X syndrome, the phenotypic outcome associated with this chromosomal abnormality varies widely. However, mild to moderate (or, more rarely, severe) intellectual disability appears to be a consistent finding. Affected females also commonly have speech difficulties due to verbal and motor dysfunction in association with developmental dyspraxia and childhood of apraxia (CAS), as well as behavioral difficulties. In some cases, tetra X syndrome may be associated with certain craniofacial abnormalities, such as widely set eyes (ocular hypertelorism), upslanting eyelid folds (palpebral fissures), vertical skin folds that may cover the eyes’ inner corners (epicanthal folds), and/or a relatively small jaw (micrognathia). Other associated features may include abnormal angle (clinodactyly) of the fifth fingers, fusion of the forearm bones (radioulnar synostosis), and/or webbing of the neck. Inconsistent with penta X, affected females may have incomplete development of secondary sexual characteristics, such as sparse pubic and underarm hair, small breasts, absence or irregularity of menstrual cycles, and, in some cases, underdevelopment of external genitalia. Tetra X syndrome also results from random errors during the division of a parent’s reproductive cells (nondisjunction during meiosis).Turner syndrome, a sex chromosomal disorder that affects females, is characterized by absence of all or a portion, or impaired functioning, of one of the X chromosomes (45,X karyotype). In some cases, some cells may have the normal pair of X chromosomes while other cells do not (45,X/46,XX mosaicism). In addition, evidence suggests that some affected individuals have Y chromosomal material in addition to the X chromosome in some or all cells. Females with Turner syndrome may have a short, webbed neck with a low hairline, short stature, widely spaced, inverted, and/or underdeveloped (hypoplastic) nipples, heart defects, and/or kidney abnormalities. In addition, some affected females may have certain craniofacial abnormalities, such as a small jaw (micrognathia), a narrow roof of the mouth (palate), droopy upper eyelids (ptosis), and/or widely spaced eyes (ocular hypertelorism). In many cases, immature (streak) ovaries are present that cannot produce the female hormone estrogen. As a result, normal secondary sexual characteristics may fail to develop (e.g., the appearance of pubic hair, breast development, menstruation [primary amenorrhea]). Intellectual abilities are usually normal, though some individuals may have problems with visual-spatial relations and poor coordination. Turner syndrome is thought to result from random errors during the division of a parent’s reproductive cells. (For more information on this disorder, choose “Turner” as your search term in the Rare Disease Database.)
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Diagnosis of Penta X Syndrome
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Penta X syndrome may be suspected upon thorough clinical examination and the detection of characteristic physical findings. However, a diagnosis may be confirmed by chromosomal analysis performed on blood samples that can reveal the presence of three extra X chromosomes in body cells. In some instances, the abnormality may be detected before birth (prenatally) based on non-invasive prenatal testing (NIPT), which screens the fetus for chromosomal disorders and determines those at risk. Chromosomal analysis such as amniocentesis or chorionic villus sampling (CVS) will confirm the diagnosis. During amniocentesis, a sample of fluid that surrounds the developing fetus is removed and analyzed, while CVS involves the removal of tissue samples from a portion of the placenta.
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Diagnosis of Penta X Syndrome. Penta X syndrome may be suspected upon thorough clinical examination and the detection of characteristic physical findings. However, a diagnosis may be confirmed by chromosomal analysis performed on blood samples that can reveal the presence of three extra X chromosomes in body cells. In some instances, the abnormality may be detected before birth (prenatally) based on non-invasive prenatal testing (NIPT), which screens the fetus for chromosomal disorders and determines those at risk. Chromosomal analysis such as amniocentesis or chorionic villus sampling (CVS) will confirm the diagnosis. During amniocentesis, a sample of fluid that surrounds the developing fetus is removed and analyzed, while CVS involves the removal of tissue samples from a portion of the placenta.
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Penta X Syndrome
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Therapies of Penta X Syndrome
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Treatment
Due to the wide variability in phenotypic outcome, the treatment of penta X syndrome is directed toward the specific symptoms that are apparent in each individual. Such treatment may require the coordinated efforts of a team of medical professionals, such as clinical geneticists, clinical psychologists, pediatric speech therapists, physical therapists, and speech and language pathologists. If there are other abnormalities noted then appropriate pediatric medical specialists should be seen.For some affected individuals with congenital heart defects, treatment with certain medications, surgical intervention, and/or other measures may be necessary. The specific surgical procedures performed will depend upon the severity and location of the anatomical abnormalities and their associated symptoms.Early intervention is important in ensuring that all girls with penta X reach their optimal outcome. Special services that may be beneficial include special education, pediatric physical, speech, occupational, and developmental therapy, counseling, and/or medical, social, and vocational services. Genetic counseling will also be of benefit for affected individuals and their families.
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Therapies of Penta X Syndrome. Treatment
Due to the wide variability in phenotypic outcome, the treatment of penta X syndrome is directed toward the specific symptoms that are apparent in each individual. Such treatment may require the coordinated efforts of a team of medical professionals, such as clinical geneticists, clinical psychologists, pediatric speech therapists, physical therapists, and speech and language pathologists. If there are other abnormalities noted then appropriate pediatric medical specialists should be seen.For some affected individuals with congenital heart defects, treatment with certain medications, surgical intervention, and/or other measures may be necessary. The specific surgical procedures performed will depend upon the severity and location of the anatomical abnormalities and their associated symptoms.Early intervention is important in ensuring that all girls with penta X reach their optimal outcome. Special services that may be beneficial include special education, pediatric physical, speech, occupational, and developmental therapy, counseling, and/or medical, social, and vocational services. Genetic counseling will also be of benefit for affected individuals and their families.
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Penta X Syndrome
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Overview of Pentalogy of Cantrell
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Pentalogy of Cantrell is a rare disorder that is present at birth (congenital). Pentalogy of Cantrell is characterized by a combination of birth defects. These birth defects can potentially involve the breastbone (sternum), the muscle that separates the chest cavity from the abdomen and aids in breathing (diaphragm), the thin membrane that lines the heart (pericardium), the abdominal wall, and the heart. Pentalogy of Cantrell occurs with varying degrees of severity, potentially causing severe, life-threatening complications. Most infants do not develop all of the potential defects, which may be referred to as incomplete pentalogy of Cantrell. When all five defects are present, this is referred to as complete pentalogy of Cantrell. The variability of the disorder from one individual to another can be significant. The exact cause of pentalogy of Cantrell is unknown. Most cases are believed to occur sporadically.
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Overview of Pentalogy of Cantrell. Pentalogy of Cantrell is a rare disorder that is present at birth (congenital). Pentalogy of Cantrell is characterized by a combination of birth defects. These birth defects can potentially involve the breastbone (sternum), the muscle that separates the chest cavity from the abdomen and aids in breathing (diaphragm), the thin membrane that lines the heart (pericardium), the abdominal wall, and the heart. Pentalogy of Cantrell occurs with varying degrees of severity, potentially causing severe, life-threatening complications. Most infants do not develop all of the potential defects, which may be referred to as incomplete pentalogy of Cantrell. When all five defects are present, this is referred to as complete pentalogy of Cantrell. The variability of the disorder from one individual to another can be significant. The exact cause of pentalogy of Cantrell is unknown. Most cases are believed to occur sporadically.
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Pentalogy of Cantrell
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Symptoms of Pentalogy of Cantrell
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The specific symptoms and severity of pentalogy of Cantrell can vary dramatically from one person to another. Some infants may have mild defects with incomplete expression of the disorder. Other infants may have serious, life-threatening complications. It is important to note that affected individuals will not necessarily have all of the symptoms discussed below. Parents of caregivers of individuals with this condition should talk to their physician and medical team about their specific case, associated symptoms, and overall prognosis. The most severe expression of pentalogy of Cantrell presents at birth with ectopia cordis and omphalocele. Ectopia cordis is a severe condition in which the heart is completely or partially displaced outside of the thoracic cavity and therefore not protected by the chest wall. Ectopia cordis is frequently, but not always associated with pentalogy of Cantrell. Omphalocele is an abdominal wall defect in which part of an infant's intestines and abdominal organs protrude or stick out through the bellybutton. The intestines and organs are covered by a thin membrane or sac. An omphalocele may be small, in which the intestines protrude, or large, in which both intestines and abdominal organs protrude. In some cases, omphalocele may not be present. Other forms of abdominal wall defects that can occur in pentalogy of Cantrell include wide separation (diastasis) of certain abdominal muscles or, less frequently, the intestines may protrude through a defect to either side of the umbilical cord (gastroschisis). Abnormalities affecting the sternum can range from complete absence of the cartilage prominence at the end of the sternum (xiphoid) to complete absence of the sternum. In some cases, the sternum may be cleft or abnormally short. Defects of the thin membranous, fluid-filled sac that lines the heart (pericardium) may occur in pentalogy of Cantrell, specifically in the lower portion where it meets the diaphragm. Affected infants may also have a hole in the diaphragm allowing the contents of the abdomen to protrude into the chest (congenital diaphragmatic hernia). Infants with pentalogy of Cantrell can have a wide variety of congenital heart defects including a “hole in the heart” between the two lower chambers (ventricles) of the heart (ventricular septal defects), a “hole in the heart” between the two upper chambers (atria) of the heart (atrial septal defects), abnormal location of the heart on the right side of chest instead of the left (dextrocardia), and tetralogy of Fallot, a condition in which four anatomical defects of the heart occur together. (For more information on these heart defects, choose the specific name as your search term in the Rare Disease Database.) Other complex congenital heart abnormalities may also be identified. The type and severity of congenital heart defects can vary from one infant to another. The various defects potentially associated with pentalogy of Cantrell can cause a wide variety of serious issues including underdevelopment of the lungs, breathing (respiratory) difficulties, embolism (plugged blood vessel), and impaired function of the heart. Infants with pentalogy of Cantrell are at risk of developing widespread internal infection of the abdominal cavity. Additional anomalies have been reported in some infants with pentalogy of Cantrell. Such anomalies include cleft lip, cleft palate, malformation (dysplasia) of the kidneys, a fluid-filled mass or sac in the head or neck area (cystic hygroma), limb defects (club feet, absent bones in the arms or legs) and birth defects of the brain and spinal cord (neural tube defects).
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Symptoms of Pentalogy of Cantrell. The specific symptoms and severity of pentalogy of Cantrell can vary dramatically from one person to another. Some infants may have mild defects with incomplete expression of the disorder. Other infants may have serious, life-threatening complications. It is important to note that affected individuals will not necessarily have all of the symptoms discussed below. Parents of caregivers of individuals with this condition should talk to their physician and medical team about their specific case, associated symptoms, and overall prognosis. The most severe expression of pentalogy of Cantrell presents at birth with ectopia cordis and omphalocele. Ectopia cordis is a severe condition in which the heart is completely or partially displaced outside of the thoracic cavity and therefore not protected by the chest wall. Ectopia cordis is frequently, but not always associated with pentalogy of Cantrell. Omphalocele is an abdominal wall defect in which part of an infant's intestines and abdominal organs protrude or stick out through the bellybutton. The intestines and organs are covered by a thin membrane or sac. An omphalocele may be small, in which the intestines protrude, or large, in which both intestines and abdominal organs protrude. In some cases, omphalocele may not be present. Other forms of abdominal wall defects that can occur in pentalogy of Cantrell include wide separation (diastasis) of certain abdominal muscles or, less frequently, the intestines may protrude through a defect to either side of the umbilical cord (gastroschisis). Abnormalities affecting the sternum can range from complete absence of the cartilage prominence at the end of the sternum (xiphoid) to complete absence of the sternum. In some cases, the sternum may be cleft or abnormally short. Defects of the thin membranous, fluid-filled sac that lines the heart (pericardium) may occur in pentalogy of Cantrell, specifically in the lower portion where it meets the diaphragm. Affected infants may also have a hole in the diaphragm allowing the contents of the abdomen to protrude into the chest (congenital diaphragmatic hernia). Infants with pentalogy of Cantrell can have a wide variety of congenital heart defects including a “hole in the heart” between the two lower chambers (ventricles) of the heart (ventricular septal defects), a “hole in the heart” between the two upper chambers (atria) of the heart (atrial septal defects), abnormal location of the heart on the right side of chest instead of the left (dextrocardia), and tetralogy of Fallot, a condition in which four anatomical defects of the heart occur together. (For more information on these heart defects, choose the specific name as your search term in the Rare Disease Database.) Other complex congenital heart abnormalities may also be identified. The type and severity of congenital heart defects can vary from one infant to another. The various defects potentially associated with pentalogy of Cantrell can cause a wide variety of serious issues including underdevelopment of the lungs, breathing (respiratory) difficulties, embolism (plugged blood vessel), and impaired function of the heart. Infants with pentalogy of Cantrell are at risk of developing widespread internal infection of the abdominal cavity. Additional anomalies have been reported in some infants with pentalogy of Cantrell. Such anomalies include cleft lip, cleft palate, malformation (dysplasia) of the kidneys, a fluid-filled mass or sac in the head or neck area (cystic hygroma), limb defects (club feet, absent bones in the arms or legs) and birth defects of the brain and spinal cord (neural tube defects).
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Causes of Pentalogy of Cantrell
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The exact cause of pentalogy of Cantrell is unknown. Most cases occur randomly for no apparent reason (sporadically). One theory suggests that the symptoms of pentalogy of Cantrell occur due to an abnormality in the development of midline embryonic tissue fourteen to eighteen days after conception. Several familial cases have been reported, and some researchers have suggested that genetic factors may play a role in the development of the disorder. More research is necessary to determine the exact, underlying cause(s) of pentalogy of Cantrell.
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Causes of Pentalogy of Cantrell. The exact cause of pentalogy of Cantrell is unknown. Most cases occur randomly for no apparent reason (sporadically). One theory suggests that the symptoms of pentalogy of Cantrell occur due to an abnormality in the development of midline embryonic tissue fourteen to eighteen days after conception. Several familial cases have been reported, and some researchers have suggested that genetic factors may play a role in the development of the disorder. More research is necessary to determine the exact, underlying cause(s) of pentalogy of Cantrell.
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Affects of Pentalogy of Cantrell
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Pentalogy of Cantrell affects males and females in equal numbers. The exact prevalence is unknown, but estimated to be 5.5 in 1 million live births. The symptoms of pentalogy of Cantrell are present at birth (congenital).
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Affects of Pentalogy of Cantrell. Pentalogy of Cantrell affects males and females in equal numbers. The exact prevalence is unknown, but estimated to be 5.5 in 1 million live births. The symptoms of pentalogy of Cantrell are present at birth (congenital).
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Related disorders of Pentalogy of Cantrell
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Symptoms of the following disorders can be similar to those of pentalogy of Cantrell. Comparisons may be useful for a differential diagnosis. Amniotic band syndrome is a well-known condition potentially associated with a variety of different birth defects. Ectopia cordis may occur with this condition. However, the arms and legs are most often affected. The head and face and, in some cases, various internal organs can also be affected. It is important to note that no two cases of amniotic band syndrome are exactly alike and that the associated symptoms are highly variable. The severity of amniotic band syndrome can range from a single, isolated finding to multiple, disfiguring complications. The exact cause of amniotic band syndrome is unknown and controversial. (For more information on this disorder, choose “amniotic band syndrome” as your search term in the Rare Disease Database.) Additionally, many of these birth defects, i.e., omphalocoele and ectopia cordis, may also occur as isolated defects.
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Related disorders of Pentalogy of Cantrell. Symptoms of the following disorders can be similar to those of pentalogy of Cantrell. Comparisons may be useful for a differential diagnosis. Amniotic band syndrome is a well-known condition potentially associated with a variety of different birth defects. Ectopia cordis may occur with this condition. However, the arms and legs are most often affected. The head and face and, in some cases, various internal organs can also be affected. It is important to note that no two cases of amniotic band syndrome are exactly alike and that the associated symptoms are highly variable. The severity of amniotic band syndrome can range from a single, isolated finding to multiple, disfiguring complications. The exact cause of amniotic band syndrome is unknown and controversial. (For more information on this disorder, choose “amniotic band syndrome” as your search term in the Rare Disease Database.) Additionally, many of these birth defects, i.e., omphalocoele and ectopia cordis, may also occur as isolated defects.
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Diagnosis of Pentalogy of Cantrell
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A diagnosis of pentalogy of Cantrell can often be made before birth (prenatally) sometimes using a fetal ultrasound. An ultrasound is an exam that uses high-frequency sound waves to produce an image of the developing fetus. A fetal ultrasound can detect some of the defects associated with pentalogy of Cantrell. An echocardiography is usually performed to evaluate the extent of the involvement of the heart. An echocardiography is an exam that uses sound waves to produce images of the heartMagnetic resonance imaging (MRI) may also be performed to assess the degree of certain anomalies such as abdominal wall and pericardial defects. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues.
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Diagnosis of Pentalogy of Cantrell. A diagnosis of pentalogy of Cantrell can often be made before birth (prenatally) sometimes using a fetal ultrasound. An ultrasound is an exam that uses high-frequency sound waves to produce an image of the developing fetus. A fetal ultrasound can detect some of the defects associated with pentalogy of Cantrell. An echocardiography is usually performed to evaluate the extent of the involvement of the heart. An echocardiography is an exam that uses sound waves to produce images of the heartMagnetic resonance imaging (MRI) may also be performed to assess the degree of certain anomalies such as abdominal wall and pericardial defects. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues.
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Pentalogy of Cantrell
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Therapies of Pentalogy of Cantrell
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TreatmentThe treatment of pentalogy of Cantrell is directed toward the specific symptoms that are apparent in each individual. Surgical intervention for cardiac, diaphragmatic and other associated defects is necessary. Affected infants will require complex medical care and may require surgical intervention. In most cases, pentalogy of Cantrell is fatal without surgical intervention. However, in some cases, the defects are so severe that the individual dies regardless of the medical or surgical interventions received.The specific treatment strategy will vary from one infant to another based upon various factors, including the size and type of abdominal wall defect, the specific cardiac anomalies that are present, and the particular type of ectopia cordis. Surgical procedures that may be required shortly after birth include repair of an omphalocele. At this time, physicians may also attempt to repair certain other defects including defects of the sternum, diaphragm and the pericardium.In severe cases, some physicians advocate for a staged repair of the defects associated with pentalogy of Cantrell. The initial operation immediately after birth provides separation of the peritoneal and pericardial cavities, coverage of the midline defect and repair of the omphalocele. After appropriate growth of the thoracic cavity and lungs, the second stage consists of the repair of cardiac defects and return of the heart to the chest. Eventually, usually by age 2 or 3, reconstruction of the lower sternum or epigastrium may be necessary.Other treatment of pentalogy of Cantrell is symptomatic and supportive.
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Therapies of Pentalogy of Cantrell. TreatmentThe treatment of pentalogy of Cantrell is directed toward the specific symptoms that are apparent in each individual. Surgical intervention for cardiac, diaphragmatic and other associated defects is necessary. Affected infants will require complex medical care and may require surgical intervention. In most cases, pentalogy of Cantrell is fatal without surgical intervention. However, in some cases, the defects are so severe that the individual dies regardless of the medical or surgical interventions received.The specific treatment strategy will vary from one infant to another based upon various factors, including the size and type of abdominal wall defect, the specific cardiac anomalies that are present, and the particular type of ectopia cordis. Surgical procedures that may be required shortly after birth include repair of an omphalocele. At this time, physicians may also attempt to repair certain other defects including defects of the sternum, diaphragm and the pericardium.In severe cases, some physicians advocate for a staged repair of the defects associated with pentalogy of Cantrell. The initial operation immediately after birth provides separation of the peritoneal and pericardial cavities, coverage of the midline defect and repair of the omphalocele. After appropriate growth of the thoracic cavity and lungs, the second stage consists of the repair of cardiac defects and return of the heart to the chest. Eventually, usually by age 2 or 3, reconstruction of the lower sternum or epigastrium may be necessary.Other treatment of pentalogy of Cantrell is symptomatic and supportive.
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Overview of PEPCK Deficiency
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PEPCK deficiency is an extremely rare disorder characterized by episodes of low blood sugar (hypoglycemia). It is a disorder of carbohydrate metabolism caused by a deficiency in the enzyme called phosphoenolpyruvate carboxykinase or PEPCK. This enzyme normally converts proteins and fats to glucose during times of fasting, in a process called gluconeogenesis. The glucose is used as a source of energy by the body. PEPCK deficiency is inherited in an autosomal recessive pattern.The treatment for this disorder is avoidance of fasting and consumption of extra carbohydrates during exercise, illness or other periods when the body needs additional sources of energy.
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Overview of PEPCK Deficiency. PEPCK deficiency is an extremely rare disorder characterized by episodes of low blood sugar (hypoglycemia). It is a disorder of carbohydrate metabolism caused by a deficiency in the enzyme called phosphoenolpyruvate carboxykinase or PEPCK. This enzyme normally converts proteins and fats to glucose during times of fasting, in a process called gluconeogenesis. The glucose is used as a source of energy by the body. PEPCK deficiency is inherited in an autosomal recessive pattern.The treatment for this disorder is avoidance of fasting and consumption of extra carbohydrates during exercise, illness or other periods when the body needs additional sources of energy.
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Symptoms of PEPCK Deficiency
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There are two forms of PEPCK deficiency: PEPCK1 deficiency (cytosolic) and PEPCK2 deficiency (mitochondrial).Both forms represent an inherited deficiency of the PEPCK enzymes. These enzymes are part of a process of converting proteins and fat to glucose (gluconeogenesis) that occurs primarily in the liver. This process is activated when dietary intake of glucose is insufficient, such as fasting or when extra energy is needed, such as during periods of intense exercise. Glucose is essential as the body’s source of energy, and for the functioning of many organs and systems in the body, especially the brain.The main symptom of this disorder is an abnormally low blood sugar level (hypoglycemia) during times of insufficient glucose intake. Hypoglycemia can present with drowsiness, confusion or loss of consciousness. Severe cases may exhibit loss of muscle tone (hypotonia); abnormal enlargement of the liver (hepatomegaly) inability to gain appropriate weight and grow normally (failure to thrive), small head size and developmental delay. Poor appetite, vomiting, seizures and coma may also occur. If hypoglycemia is not treated, the disease can progress to multiorgan system damage or acute liver failure. Sometimes the presence of excess acid in the circulating blood (lactic acidemia) is noticed.At birth, babies with PEPCK deficiency may present with hypoglycemia, and may have an enlarged liver, and apneas. Many babies do not show any symptoms, however. Typically, PEPCK deficiency presents in early childhood with symptoms noted during infections or after vigorous exercise, especially after a period of overnight fasting, when gluconeogenesis would normally be activated. These individuals tend to present with fasting hypoglycemia (low blood sugar) and may show shakiness, irritability or even lethargy. Liver impairment may occur and results in abnormal liver enzyme levels found in the blood. Abnormal amounts of other metabolites in the blood or urine can give a diagnostic clue (glutamine, or fumarate and other metabolites of tricarboxylic acid cycle). The symptoms of PEPCK deficiency vary among patients, and not all will exhibit every symptom. Many children develop normally despite episodes of hypoglycemia. The course of this disorder can be very rapid, however, if hypoglycemia is not treated.
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Symptoms of PEPCK Deficiency. There are two forms of PEPCK deficiency: PEPCK1 deficiency (cytosolic) and PEPCK2 deficiency (mitochondrial).Both forms represent an inherited deficiency of the PEPCK enzymes. These enzymes are part of a process of converting proteins and fat to glucose (gluconeogenesis) that occurs primarily in the liver. This process is activated when dietary intake of glucose is insufficient, such as fasting or when extra energy is needed, such as during periods of intense exercise. Glucose is essential as the body’s source of energy, and for the functioning of many organs and systems in the body, especially the brain.The main symptom of this disorder is an abnormally low blood sugar level (hypoglycemia) during times of insufficient glucose intake. Hypoglycemia can present with drowsiness, confusion or loss of consciousness. Severe cases may exhibit loss of muscle tone (hypotonia); abnormal enlargement of the liver (hepatomegaly) inability to gain appropriate weight and grow normally (failure to thrive), small head size and developmental delay. Poor appetite, vomiting, seizures and coma may also occur. If hypoglycemia is not treated, the disease can progress to multiorgan system damage or acute liver failure. Sometimes the presence of excess acid in the circulating blood (lactic acidemia) is noticed.At birth, babies with PEPCK deficiency may present with hypoglycemia, and may have an enlarged liver, and apneas. Many babies do not show any symptoms, however. Typically, PEPCK deficiency presents in early childhood with symptoms noted during infections or after vigorous exercise, especially after a period of overnight fasting, when gluconeogenesis would normally be activated. These individuals tend to present with fasting hypoglycemia (low blood sugar) and may show shakiness, irritability or even lethargy. Liver impairment may occur and results in abnormal liver enzyme levels found in the blood. Abnormal amounts of other metabolites in the blood or urine can give a diagnostic clue (glutamine, or fumarate and other metabolites of tricarboxylic acid cycle). The symptoms of PEPCK deficiency vary among patients, and not all will exhibit every symptom. Many children develop normally despite episodes of hypoglycemia. The course of this disorder can be very rapid, however, if hypoglycemia is not treated.
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Causes of PEPCK Deficiency
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Changes (mutations) in the PCK1 gene cause the cytosolic (soluble) form of PEPCK deficiency (PEPCK1) and mutations in the PCK2 gene cause the mitochondrial form of PEPCK deficiency (PEPCK2). Mutations in these genes result in a reduced amount or absence of the PEPCK enzyme. Researchers believe that the severity of disease is based upon the amount of residual enzyme activity that remains.PEPCK deficiencies, in both forms, are very rare disorders that are inherited in an autosomal recessive pattern, where two copies of the abnormal gene must be present in order for the disease to develop.Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.
Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.All individuals carry a few abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
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Causes of PEPCK Deficiency. Changes (mutations) in the PCK1 gene cause the cytosolic (soluble) form of PEPCK deficiency (PEPCK1) and mutations in the PCK2 gene cause the mitochondrial form of PEPCK deficiency (PEPCK2). Mutations in these genes result in a reduced amount or absence of the PEPCK enzyme. Researchers believe that the severity of disease is based upon the amount of residual enzyme activity that remains.PEPCK deficiencies, in both forms, are very rare disorders that are inherited in an autosomal recessive pattern, where two copies of the abnormal gene must be present in order for the disease to develop.Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.
Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.All individuals carry a few abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
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Affects of PEPCK Deficiency
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PEPCK deficiency is extremely rare. Prior to 2007, only 10 cases were reported in the medical literature. Since then, there have been at least 6 new cases reported for a total of 16 cases of PEPCK deficiency. Males and females are equally affected..
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Affects of PEPCK Deficiency. PEPCK deficiency is extremely rare. Prior to 2007, only 10 cases were reported in the medical literature. Since then, there have been at least 6 new cases reported for a total of 16 cases of PEPCK deficiency. Males and females are equally affected..
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Related disorders of PEPCK Deficiency
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Symptoms of the following disorders can be similar to those of PEPCK deficiency disorder. Comparisons may be useful for a differential diagnosis:Patients with fatty acid oxidation disorders such as medium chain acyl-coA dehydrogenase deficiency (MCAD) and long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHAD) and glycogen storage disorders can present with hypoglycemia during fasting, and may have abnormal metabolites in urine. (For more information on these disorders, search the Rare Disease Database.)Fructose-1,6-bisphosphatase deficiency: Fructose 1,6-bisphosphatase (FBPase) (also termed fructose 1,6-diphosphatase) is a key enzyme in gluconeogenesis. It permits glucose production from sources such as amino acids (eg, alanine and glycine), glycerol, or lactate. It causes episodes of buildup of lactate in the body (lactic acidosis) and low blood glucose and ketones present in the urine (ketotic hypoglycemia).Pyruvate carboxylase deficiency is a rare metabolic disorder in which there is a deficiency of the enzyme pyruvate carboxylase. This disorder causes an excess presence of acid in the circulating blood (lactic acidemia), neurologic deterioration, vomiting, irritability, and inactivity, loss of muscle tone, abnormal eye movements, and seizures. The course of this disorder is progressive. It is inherited through an autosomal recessive trait. (For more information on this disorder, choose “pyruvate carboxylase” as your search term in the Rare Disease Database.)Pyruvate dehydrogenase deficiency is a rare disorder of carbohydrate metabolism inherited through an autosomal recessive trait. Symptoms are caused by a deficiency of the enzyme pyruvate dehydrogenase resulting in persistent or recurrent metabolic acidosis (acidemia). The disorder is manifested by mental retardation and other neurological symptoms. (For more information on this disorder, choose “Pyruvate Dehydrogenase” as your search term in the Rare Disease Database.)
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Related disorders of PEPCK Deficiency. Symptoms of the following disorders can be similar to those of PEPCK deficiency disorder. Comparisons may be useful for a differential diagnosis:Patients with fatty acid oxidation disorders such as medium chain acyl-coA dehydrogenase deficiency (MCAD) and long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHAD) and glycogen storage disorders can present with hypoglycemia during fasting, and may have abnormal metabolites in urine. (For more information on these disorders, search the Rare Disease Database.)Fructose-1,6-bisphosphatase deficiency: Fructose 1,6-bisphosphatase (FBPase) (also termed fructose 1,6-diphosphatase) is a key enzyme in gluconeogenesis. It permits glucose production from sources such as amino acids (eg, alanine and glycine), glycerol, or lactate. It causes episodes of buildup of lactate in the body (lactic acidosis) and low blood glucose and ketones present in the urine (ketotic hypoglycemia).Pyruvate carboxylase deficiency is a rare metabolic disorder in which there is a deficiency of the enzyme pyruvate carboxylase. This disorder causes an excess presence of acid in the circulating blood (lactic acidemia), neurologic deterioration, vomiting, irritability, and inactivity, loss of muscle tone, abnormal eye movements, and seizures. The course of this disorder is progressive. It is inherited through an autosomal recessive trait. (For more information on this disorder, choose “pyruvate carboxylase” as your search term in the Rare Disease Database.)Pyruvate dehydrogenase deficiency is a rare disorder of carbohydrate metabolism inherited through an autosomal recessive trait. Symptoms are caused by a deficiency of the enzyme pyruvate dehydrogenase resulting in persistent or recurrent metabolic acidosis (acidemia). The disorder is manifested by mental retardation and other neurological symptoms. (For more information on this disorder, choose “Pyruvate Dehydrogenase” as your search term in the Rare Disease Database.)
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Diagnosis of PEPCK Deficiency
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Diagnosis of PEPCK deficiency may be made shortly after birth based upon the results of the following:
1. Clinical presentation of symptoms
2. Laboratory testing including blood and urine analysis.
3. Molecular genetic testing to confirm mutations of the PCK1 or PCK2 genes
4. Biochemical analysis of fibroblast cells (skin biopsy) Laboratory testing may include a blood test to identify low blood sugar levels (hypoglycemia) and urinalysis can detect the presence of TCA (tricarboxylic acid cycle) metabolites excreted in urine, especially fumarate. The dysfunctional PEPCK enzyme disrupts the metabolic route leading to gluconeogenesis and causes a buildup of these intermediates that are then excreted in urine.
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Diagnosis of PEPCK Deficiency. Diagnosis of PEPCK deficiency may be made shortly after birth based upon the results of the following:
1. Clinical presentation of symptoms
2. Laboratory testing including blood and urine analysis.
3. Molecular genetic testing to confirm mutations of the PCK1 or PCK2 genes
4. Biochemical analysis of fibroblast cells (skin biopsy) Laboratory testing may include a blood test to identify low blood sugar levels (hypoglycemia) and urinalysis can detect the presence of TCA (tricarboxylic acid cycle) metabolites excreted in urine, especially fumarate. The dysfunctional PEPCK enzyme disrupts the metabolic route leading to gluconeogenesis and causes a buildup of these intermediates that are then excreted in urine.
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Therapies of PEPCK Deficiency
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The mainstay of treatment for PEPCK deficiency is avoidance of fasting. Individuals with this disorder may consume extra carbohydrate such as cornstarch to lower the occurrence of symptoms. This is especially important in the evenings before an overnight fast.Individuals may be prescribed glucose polymers (high carbohydrate oral replacement) during rigorous exercise, illness, or other times of fasting. Glucose-containing solutions may also be administered intravenously during times of fasting or illness. Regular contact with a dietician is recommended. The dietician can provide the patient with instructions for a so called sick-day regimen, which tells you how much extra carbohydrate is needed during times of illness.Genetic counseling is recommended for patients and their families. Other treatments of PEPCK deficiency are based upon symptoms presented.
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Therapies of PEPCK Deficiency. The mainstay of treatment for PEPCK deficiency is avoidance of fasting. Individuals with this disorder may consume extra carbohydrate such as cornstarch to lower the occurrence of symptoms. This is especially important in the evenings before an overnight fast.Individuals may be prescribed glucose polymers (high carbohydrate oral replacement) during rigorous exercise, illness, or other times of fasting. Glucose-containing solutions may also be administered intravenously during times of fasting or illness. Regular contact with a dietician is recommended. The dietician can provide the patient with instructions for a so called sick-day regimen, which tells you how much extra carbohydrate is needed during times of illness.Genetic counseling is recommended for patients and their families. Other treatments of PEPCK deficiency are based upon symptoms presented.
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Overview of Perivascular Epithelioid Cell Neoplasm
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SummaryPerivascular epithelioid cell neoplasms (PEComas) are rare soft tissue tumors. They often form around small blood vessels (perivascular spaces) in various body parts such as the lungs, GI tract, kidneys, liver and uterus. PEComas are made up of cells with an epithelioid (cuboidal) shape and have some features that are shared with melanocytes and smooth muscle cells. Melanocytes are cells that are normally found in the skin and produce melanin to give skin its color. PEComa can make some of the same proteins that are used to create pigment. PEComa also make some of the same proteins found in smooth muscle cells, which make up muscles that are not under our conscious control, such as the muscles that make up our internal organs and digestive tract.PEComas are considered to be a group of tumors that share these characteristic features. However, within this group are specific tumors with their own unique features and more likely to form in certain body parts. These specific tumors include angiomyolipomas (AMLs), clear cell sugar tumors, primary extrapulmonary sugar tumor (PEST), lymphangioleiomyomatosis (LAM), clear-cell myomelanocytic tumor (CCMT) of the falciform ligament/ligamentum teres, primary cutaneous PEComa (CCCMT-cutaneous clear cell myomelanocytic tumor) and PEComas not otherwise specified (NOS).Most PEComas are benign but some can be malignant with the potential to spread to other parts of the body.
PEComas can also be associated with the genetic condition tuberous sclerosis complex (TSC). In this condition, multiple tumors form in the body. Intellectual disabilities and seizures may also be present.IntroductionThe name perivascular epithelioid cell tumor was first proposed in the early 1990s after researchers noticed shared cellular features between the various tumors that are now members of the PEComa grouping. These features are considered unique to these types of tumors, distinguishing them from other tumors.
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Overview of Perivascular Epithelioid Cell Neoplasm. SummaryPerivascular epithelioid cell neoplasms (PEComas) are rare soft tissue tumors. They often form around small blood vessels (perivascular spaces) in various body parts such as the lungs, GI tract, kidneys, liver and uterus. PEComas are made up of cells with an epithelioid (cuboidal) shape and have some features that are shared with melanocytes and smooth muscle cells. Melanocytes are cells that are normally found in the skin and produce melanin to give skin its color. PEComa can make some of the same proteins that are used to create pigment. PEComa also make some of the same proteins found in smooth muscle cells, which make up muscles that are not under our conscious control, such as the muscles that make up our internal organs and digestive tract.PEComas are considered to be a group of tumors that share these characteristic features. However, within this group are specific tumors with their own unique features and more likely to form in certain body parts. These specific tumors include angiomyolipomas (AMLs), clear cell sugar tumors, primary extrapulmonary sugar tumor (PEST), lymphangioleiomyomatosis (LAM), clear-cell myomelanocytic tumor (CCMT) of the falciform ligament/ligamentum teres, primary cutaneous PEComa (CCCMT-cutaneous clear cell myomelanocytic tumor) and PEComas not otherwise specified (NOS).Most PEComas are benign but some can be malignant with the potential to spread to other parts of the body.
PEComas can also be associated with the genetic condition tuberous sclerosis complex (TSC). In this condition, multiple tumors form in the body. Intellectual disabilities and seizures may also be present.IntroductionThe name perivascular epithelioid cell tumor was first proposed in the early 1990s after researchers noticed shared cellular features between the various tumors that are now members of the PEComa grouping. These features are considered unique to these types of tumors, distinguishing them from other tumors.
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Symptoms of Perivascular Epithelioid Cell Neoplasm
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Signs and symptoms of PEComas vary quite a bit between patients and depend on tumor location. Some PEComas cause no symptoms and are found when patients undergo imaging for other reasons. For patients with symptoms, PEComas may form a visible painful or painless mass. For women with PEComas in the reproductive tract, these tumors may present with vaginal bleeding. PEComas in the GI tract may present with abdominal pain, bloody stools, constipation/bowel obstruction, weight loss and anemia.Each type of PEComa has unique physical features and potential signs and symptoms associated with it.AngiomyolipomaAngiomyolipomas (AMLs) are rare but are the most common benign tumor of the kidneys. AMLs are composed of blood vessels (angio), smooth muscle cells (myo) and fatty (adipose/lipomatous) tissues.Eighty percent of AML cases are sporadic (occur randomly with no known risk factors) and 20% of cases develop in patients with TSC or LAM (hereditary conditions). In people with TSC, AMLs are especially common, occurring in approximately 75% of these patients. TSC patients are more likely to have AMLs that cause symptoms. AMLs may also develop in patients with LAM. Patients with AMLs who have TSC or LAM are more likely to have multiple, large and more aggressive AMLs.When AMLs cause signs and symptoms, they may include a mass that can easily be felt, pain on one side of the body between the abdomen and back (flank pain), weight loss, blood in the urine, anemia, urinary tract infections or kidney failure. More serious symptoms include bleeding in the abdomen (retroperitoneal hemorrhage) which can lead to shock. This is estimated to occur in less than 15% of AML cases.AMLs can also occur in organs outside of the kidney, such as the liver. These are also usually benign but can be malignant. AMLs can vary in the proportion of cell types they're composed of. AMLs with more epithelioid cells, especially, may become malignant, although this is rare. Larger tumors are also more likely to spread to other parts of the body.Clear Cell Sugar Tumor of the Lung (CCTL)Clear cell “sugar” tumors of the lung are usually benign. They're called clear cell “sugar” tumors because the cells they're composed of have thin walls and high levels of glycogen, a stored version of the body's carbohydrates, or sugars. CCTL is usually around the size of a coin and occurs as a single tumor. It can occur in any lung lobe but tends to affect the lower lungs.Symptoms of CCTL may include fever, cough, coughing up blood and shortness of breath, but patients typically do not have symptoms. CCTL rarely affects tissues outside of the lung.Like other PEComas, CCTLs are also associated with TSC, and it can also occur in patients with LAM without TSC.Primary Extrapulmonary Sugar Tumor (PEST)Primary extrapulmonary sugar tumors are similar in structure and appearance to clear cell sugar tumors of the lungs but instead occur outside of the lung, such as in the rectum, vulva, uterus, pancreas, breast, trachea or heart. Symptoms vary depending on location but can include fatigue, rectal bleeding, shortness of breath and heart rhythm disturbances.Most PESTs are thought to be benign but can be malignant.LymphangioleiomyomatosisLymphangioleiomyomatosis (LAM) is a rare progressive multisystem disorder that predominantly impacts women of reproductive age. LAM is characterized by the spread and uncontrolled growth of specialized cells (smooth muscle-like LAM cells) in certain organs of the body, especially the lungs, kidneys and lymphatics. There are two main types of LAM: sporadic LAM (that occurs spontaneously) and LAM associated with tuberous sclerosis complex (TSC), a genetic condition. Symptoms of LAM vary depending on the organs affected. The most common symptom associated with LAM is difficulty breathing (dyspnea), especially on exertion. Affected individuals may also experience complications including lung collapse (pneumothorax) or fluid accumulation around the lungs (pleural effusion) and in the abdomen and angiomyolipomas. The disorder is progressive and, in some patients, may result in chronic respiratory failure (For more information, search “lymphangioleiomyomatosis” in the Rare Disease Database).Clear Cell Myomelanocytic Tumor of the Falciform Ligament (CCMT)Clear cell myomelanocytic tumors of the falciform ligament form on this ligament usually in the right lobe of the liver. The falciform ligament connects the liver to the front portion of the abdominal wall.CCMTs were first described in 2000. These tumors are usually benign and can be large. Symptoms usually include abdominal pain, but CCMTs can be asymptomatic.Primary Cutaneous PEComa/Cutaneous Clear Cell Myomelanocytic Tumor (CCCMT)Primary cutaneous PEComas are very rare PEComas that arise in the skin. They are more likely to appear on the limbs or the back. These tumors involve the dermis of the skin and the underlying subcutaneous fat. CCCMT may be confused with malignant melanoma.PEComas – Not Otherwise Specified (NOS)PEComas-NOS include tumors composed of perivascular epithelioid cells that do not fit into the other PEComa subtypes based on overall composition and location.PEComas-NOS typically present as a painless mass and usually occur in women.PEComas-NOS have been reported in almost every body site. The uterus is the most commonly reported site for this type of PEComa. PEComas-NOS of the uterus may present with vaginal bleeding. Other common sites include the genitourinary tract, gastrointestinal tract and the back side of the abdomen (retroperitoneum). PEComas-NOS have also been reported in the oral cavity, the orbit (socket that holds the eye) and the skull base.These PEComas can be aggressive, spreading to nearby regions or other organs far from the original tumor. They may also recur after surgical removal.
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Symptoms of Perivascular Epithelioid Cell Neoplasm. Signs and symptoms of PEComas vary quite a bit between patients and depend on tumor location. Some PEComas cause no symptoms and are found when patients undergo imaging for other reasons. For patients with symptoms, PEComas may form a visible painful or painless mass. For women with PEComas in the reproductive tract, these tumors may present with vaginal bleeding. PEComas in the GI tract may present with abdominal pain, bloody stools, constipation/bowel obstruction, weight loss and anemia.Each type of PEComa has unique physical features and potential signs and symptoms associated with it.AngiomyolipomaAngiomyolipomas (AMLs) are rare but are the most common benign tumor of the kidneys. AMLs are composed of blood vessels (angio), smooth muscle cells (myo) and fatty (adipose/lipomatous) tissues.Eighty percent of AML cases are sporadic (occur randomly with no known risk factors) and 20% of cases develop in patients with TSC or LAM (hereditary conditions). In people with TSC, AMLs are especially common, occurring in approximately 75% of these patients. TSC patients are more likely to have AMLs that cause symptoms. AMLs may also develop in patients with LAM. Patients with AMLs who have TSC or LAM are more likely to have multiple, large and more aggressive AMLs.When AMLs cause signs and symptoms, they may include a mass that can easily be felt, pain on one side of the body between the abdomen and back (flank pain), weight loss, blood in the urine, anemia, urinary tract infections or kidney failure. More serious symptoms include bleeding in the abdomen (retroperitoneal hemorrhage) which can lead to shock. This is estimated to occur in less than 15% of AML cases.AMLs can also occur in organs outside of the kidney, such as the liver. These are also usually benign but can be malignant. AMLs can vary in the proportion of cell types they're composed of. AMLs with more epithelioid cells, especially, may become malignant, although this is rare. Larger tumors are also more likely to spread to other parts of the body.Clear Cell Sugar Tumor of the Lung (CCTL)Clear cell “sugar” tumors of the lung are usually benign. They're called clear cell “sugar” tumors because the cells they're composed of have thin walls and high levels of glycogen, a stored version of the body's carbohydrates, or sugars. CCTL is usually around the size of a coin and occurs as a single tumor. It can occur in any lung lobe but tends to affect the lower lungs.Symptoms of CCTL may include fever, cough, coughing up blood and shortness of breath, but patients typically do not have symptoms. CCTL rarely affects tissues outside of the lung.Like other PEComas, CCTLs are also associated with TSC, and it can also occur in patients with LAM without TSC.Primary Extrapulmonary Sugar Tumor (PEST)Primary extrapulmonary sugar tumors are similar in structure and appearance to clear cell sugar tumors of the lungs but instead occur outside of the lung, such as in the rectum, vulva, uterus, pancreas, breast, trachea or heart. Symptoms vary depending on location but can include fatigue, rectal bleeding, shortness of breath and heart rhythm disturbances.Most PESTs are thought to be benign but can be malignant.LymphangioleiomyomatosisLymphangioleiomyomatosis (LAM) is a rare progressive multisystem disorder that predominantly impacts women of reproductive age. LAM is characterized by the spread and uncontrolled growth of specialized cells (smooth muscle-like LAM cells) in certain organs of the body, especially the lungs, kidneys and lymphatics. There are two main types of LAM: sporadic LAM (that occurs spontaneously) and LAM associated with tuberous sclerosis complex (TSC), a genetic condition. Symptoms of LAM vary depending on the organs affected. The most common symptom associated with LAM is difficulty breathing (dyspnea), especially on exertion. Affected individuals may also experience complications including lung collapse (pneumothorax) or fluid accumulation around the lungs (pleural effusion) and in the abdomen and angiomyolipomas. The disorder is progressive and, in some patients, may result in chronic respiratory failure (For more information, search “lymphangioleiomyomatosis” in the Rare Disease Database).Clear Cell Myomelanocytic Tumor of the Falciform Ligament (CCMT)Clear cell myomelanocytic tumors of the falciform ligament form on this ligament usually in the right lobe of the liver. The falciform ligament connects the liver to the front portion of the abdominal wall.CCMTs were first described in 2000. These tumors are usually benign and can be large. Symptoms usually include abdominal pain, but CCMTs can be asymptomatic.Primary Cutaneous PEComa/Cutaneous Clear Cell Myomelanocytic Tumor (CCCMT)Primary cutaneous PEComas are very rare PEComas that arise in the skin. They are more likely to appear on the limbs or the back. These tumors involve the dermis of the skin and the underlying subcutaneous fat. CCCMT may be confused with malignant melanoma.PEComas – Not Otherwise Specified (NOS)PEComas-NOS include tumors composed of perivascular epithelioid cells that do not fit into the other PEComa subtypes based on overall composition and location.PEComas-NOS typically present as a painless mass and usually occur in women.PEComas-NOS have been reported in almost every body site. The uterus is the most commonly reported site for this type of PEComa. PEComas-NOS of the uterus may present with vaginal bleeding. Other common sites include the genitourinary tract, gastrointestinal tract and the back side of the abdomen (retroperitoneum). PEComas-NOS have also been reported in the oral cavity, the orbit (socket that holds the eye) and the skull base.These PEComas can be aggressive, spreading to nearby regions or other organs far from the original tumor. They may also recur after surgical removal.
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Perivascular Epithelioid Cell Neoplasm
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nord_956_2
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Causes of Perivascular Epithelioid Cell Neoplasm
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The cause of sporadic cases of PEComas is not known. PEComas may be associated with the genetic condition tuberous sclerosis complex (TSC), an autosomal dominant genetic disorder.
Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a changed (mutated) gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.TSC is caused by changes (mutations) in the TSC1 or TSC2 genes. These genes encode the proteins hamartin and tuberin, respectively. Normally, these proteins suppress tumor formation by inhibiting the rapamycin (mTOR) pathway. Mutations in the TSC1 or TSC2 genes lead to overactivation of the mTOR pathway, which in turn causes increased cell growth, blood vessel formation and protein synthesis. This is why multiple tumors form in the body of patients with TSC. TSC is more strongly associated with AML, LAM and CCTL.An overactive mTOR pathway is also thought to be involved in sporadic cases of AML and other PEComas.
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Causes of Perivascular Epithelioid Cell Neoplasm. The cause of sporadic cases of PEComas is not known. PEComas may be associated with the genetic condition tuberous sclerosis complex (TSC), an autosomal dominant genetic disorder.
Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a changed (mutated) gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.TSC is caused by changes (mutations) in the TSC1 or TSC2 genes. These genes encode the proteins hamartin and tuberin, respectively. Normally, these proteins suppress tumor formation by inhibiting the rapamycin (mTOR) pathway. Mutations in the TSC1 or TSC2 genes lead to overactivation of the mTOR pathway, which in turn causes increased cell growth, blood vessel formation and protein synthesis. This is why multiple tumors form in the body of patients with TSC. TSC is more strongly associated with AML, LAM and CCTL.An overactive mTOR pathway is also thought to be involved in sporadic cases of AML and other PEComas.
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Perivascular Epithelioid Cell Neoplasm
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nord_956_3
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Affects of Perivascular Epithelioid Cell Neoplasm
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PEComas have been found in people of all ages, from children to older adults. Although they often occur in children with TSC, they also occur sporadically in people with no known risk factors.In general, PEComas are more likely to occur in middle-aged women, with some studies reporting PEComas are 5 to 7 times more likely in females than males.However, average age of onset varies widely depending on the type of tumor. For instance, PEComas-NOS of the uterus have an average age of onset of 54 years of age while CCMTs of the falciform ligament occur more often in young women around the age of 20 years of age.Renal AMLs, the most common and well-described PEComas, have an estimated prevalence of 0.44% in the general population. Sporadic AMLs are more common in women. AMLs associated with TSC affect both females and males equally and appear at a younger age.CCTLs occur most often in middle-aged adults but have been reported in children as young as 8 years old. They are only slightly more common in females than males.LAM affects mostly women of childbearing age. Sporadic LAM is estimated to affect 1 in 400,000 women. TSC-associated LAM is estimated to affect 30 to 40% of female patients with TSC. Overall, LAM is estimated to affect 3.4-7.8/1,000,000 women worldwide.Malignant PEComas are estimated to be diagnosed in 0.12 to 0.24 per one million people.
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Affects of Perivascular Epithelioid Cell Neoplasm. PEComas have been found in people of all ages, from children to older adults. Although they often occur in children with TSC, they also occur sporadically in people with no known risk factors.In general, PEComas are more likely to occur in middle-aged women, with some studies reporting PEComas are 5 to 7 times more likely in females than males.However, average age of onset varies widely depending on the type of tumor. For instance, PEComas-NOS of the uterus have an average age of onset of 54 years of age while CCMTs of the falciform ligament occur more often in young women around the age of 20 years of age.Renal AMLs, the most common and well-described PEComas, have an estimated prevalence of 0.44% in the general population. Sporadic AMLs are more common in women. AMLs associated with TSC affect both females and males equally and appear at a younger age.CCTLs occur most often in middle-aged adults but have been reported in children as young as 8 years old. They are only slightly more common in females than males.LAM affects mostly women of childbearing age. Sporadic LAM is estimated to affect 1 in 400,000 women. TSC-associated LAM is estimated to affect 30 to 40% of female patients with TSC. Overall, LAM is estimated to affect 3.4-7.8/1,000,000 women worldwide.Malignant PEComas are estimated to be diagnosed in 0.12 to 0.24 per one million people.
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Perivascular Epithelioid Cell Neoplasm
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nord_956_4
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Related disorders of Perivascular Epithelioid Cell Neoplasm
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PEComas can be mistaken for other tumors, some of which can be malignant. Different tumors on imaging can appear similar to one another, so a PEComa in one organ may be difficult to distinguish from another tumor that can occur in the same organ. Because they are frequently found on the kidneys, angiomyolipomas may be mistaken for renal cell carcinoma, especially when AMLs contain less fatty tissue. Renal cell carcinoma is the most common cancer of the kidneys in adults and can present with symptoms similar to AMLs. AMLs may also be confused with adrenocortical carcinoma or pheochromocytomas, tumors of the adrenal glands, because of their similar locations. Clear-cell sugar tumors of the lungs can also be mistaken for renal cell carcinoma that has metastasized to the lungs due to a similar composition.PEComas may also appear similar to leiomyosarcomas, another soft tissue tumor that contains smooth muscle markers. Leiomyosarcomas are always malignant, however. Like PEComas-NOS, the uterus is a common location for leiomyosarcomas. Leiomyosarcomas can form in any part of the body where there are soft tissues, similar to the parts of the body where PEComas can form.Because of the presence of melanocytic markers in both, PEComas can also appear similar to malignant melanoma. In other PEComa cases, medical history that includes whether or not there was a primary skin tumor should help differentiate PEComa from melanoma that's spread beyond the skin.PEComa may be mistaken for other cancerous tumors including clear cell sarcoma, alveolar soft part sarcoma and endometrial stromal sarcoma with clear cell features.
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Related disorders of Perivascular Epithelioid Cell Neoplasm. PEComas can be mistaken for other tumors, some of which can be malignant. Different tumors on imaging can appear similar to one another, so a PEComa in one organ may be difficult to distinguish from another tumor that can occur in the same organ. Because they are frequently found on the kidneys, angiomyolipomas may be mistaken for renal cell carcinoma, especially when AMLs contain less fatty tissue. Renal cell carcinoma is the most common cancer of the kidneys in adults and can present with symptoms similar to AMLs. AMLs may also be confused with adrenocortical carcinoma or pheochromocytomas, tumors of the adrenal glands, because of their similar locations. Clear-cell sugar tumors of the lungs can also be mistaken for renal cell carcinoma that has metastasized to the lungs due to a similar composition.PEComas may also appear similar to leiomyosarcomas, another soft tissue tumor that contains smooth muscle markers. Leiomyosarcomas are always malignant, however. Like PEComas-NOS, the uterus is a common location for leiomyosarcomas. Leiomyosarcomas can form in any part of the body where there are soft tissues, similar to the parts of the body where PEComas can form.Because of the presence of melanocytic markers in both, PEComas can also appear similar to malignant melanoma. In other PEComa cases, medical history that includes whether or not there was a primary skin tumor should help differentiate PEComa from melanoma that's spread beyond the skin.PEComa may be mistaken for other cancerous tumors including clear cell sarcoma, alveolar soft part sarcoma and endometrial stromal sarcoma with clear cell features.
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Perivascular Epithelioid Cell Neoplasm
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nord_956_5
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Diagnosis of Perivascular Epithelioid Cell Neoplasm
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PEComas may be detected by imaging with X-ray, CT scan or MRI. Once a tumor is detected, biopsy is needed to examine the cellular make-up and distinguish it from other types of tumors.Tissue samples from biopsies will have a characteristic appearance under the microscope to identify tumors as PEComas and differentiate them from other potential tumors.PEComas typically have mostly epithelioid cells around blood vessels. They also contain protein markers similar to melanocytes (melanin-producing cells) and smooth muscle cells.Malignant PEComas can be detected from biopsy as well. Malignancy is more likely in PEComas that are larger in size, begin to grow into surrounding tissues and have a higher percentage of cells that are actively growing.Genetic testing is available to identify patients with TSC who are at an increased risk of developing PEComas.For patients with LAM, a blood test for detecting increased levels of vascular endothelial growth factor D (VEGF-D) may aid in diagnosing this PEComa subtype. VEGF-D stimulates growth of new blood vessels and high levels may be involved in tumor spread.
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Diagnosis of Perivascular Epithelioid Cell Neoplasm. PEComas may be detected by imaging with X-ray, CT scan or MRI. Once a tumor is detected, biopsy is needed to examine the cellular make-up and distinguish it from other types of tumors.Tissue samples from biopsies will have a characteristic appearance under the microscope to identify tumors as PEComas and differentiate them from other potential tumors.PEComas typically have mostly epithelioid cells around blood vessels. They also contain protein markers similar to melanocytes (melanin-producing cells) and smooth muscle cells.Malignant PEComas can be detected from biopsy as well. Malignancy is more likely in PEComas that are larger in size, begin to grow into surrounding tissues and have a higher percentage of cells that are actively growing.Genetic testing is available to identify patients with TSC who are at an increased risk of developing PEComas.For patients with LAM, a blood test for detecting increased levels of vascular endothelial growth factor D (VEGF-D) may aid in diagnosing this PEComa subtype. VEGF-D stimulates growth of new blood vessels and high levels may be involved in tumor spread.
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Perivascular Epithelioid Cell Neoplasm
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nord_956_6
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Therapies of Perivascular Epithelioid Cell Neoplasm
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Surgery to remove a localized PEComa that has not spread is currently the recommended form of treatment. Surgery may be curative for patients with benign PEComas, although tumor regrowth can occur. If regrowth occurs, surgery is again recommended to remove the regrowth. Surgery is not usually recommended to remove tumors that have spread (metastasized) to other parts of the body. Instead, medical treatment is usually recommended.Regular monitoring of tumors with imaging exams may be recommended in some patients where surgery is not possible or where tumors have a potential for malignancy.For patients with LAM, bronchodilators that help relax and open the airways may be prescribed. Oxygen therapy may also be needed at some point. For more advanced LAM, lung transplants may be recommended.Some PEComas are caused by TSC1 or TSC2 gene mutations. In these cases, patients may benefit from everolimus, an mTOR inhibitor that blocks this overactive pathway thought to lead to tumor formation when these genetic mutations are present. Everolimus is a medication taken by mouth and approved by the U.S. Food and Drug Administration (FDA) to treat AMLs that occur in patients with TSC.Sirolimus is another mTOR inhibitor taken by mouth and developed as an immunosuppressive drug for transplant patients to prevent organ rejection. Sirolimus has been approved by the FDA to treat LAM.Sirolimus protein-bound (previously nab-sirolimus) is a different formulation of sirolimus given intravenously and approved by the FDA to treat malignant PEComa that has spread or cannot be removed surgically.
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Therapies of Perivascular Epithelioid Cell Neoplasm. Surgery to remove a localized PEComa that has not spread is currently the recommended form of treatment. Surgery may be curative for patients with benign PEComas, although tumor regrowth can occur. If regrowth occurs, surgery is again recommended to remove the regrowth. Surgery is not usually recommended to remove tumors that have spread (metastasized) to other parts of the body. Instead, medical treatment is usually recommended.Regular monitoring of tumors with imaging exams may be recommended in some patients where surgery is not possible or where tumors have a potential for malignancy.For patients with LAM, bronchodilators that help relax and open the airways may be prescribed. Oxygen therapy may also be needed at some point. For more advanced LAM, lung transplants may be recommended.Some PEComas are caused by TSC1 or TSC2 gene mutations. In these cases, patients may benefit from everolimus, an mTOR inhibitor that blocks this overactive pathway thought to lead to tumor formation when these genetic mutations are present. Everolimus is a medication taken by mouth and approved by the U.S. Food and Drug Administration (FDA) to treat AMLs that occur in patients with TSC.Sirolimus is another mTOR inhibitor taken by mouth and developed as an immunosuppressive drug for transplant patients to prevent organ rejection. Sirolimus has been approved by the FDA to treat LAM.Sirolimus protein-bound (previously nab-sirolimus) is a different formulation of sirolimus given intravenously and approved by the FDA to treat malignant PEComa that has spread or cannot be removed surgically.
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Perivascular Epithelioid Cell Neoplasm
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nord_957_0
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Overview of Perniosis
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SummaryPerniosis is a seasonal inflammatory disorder that is triggered by prolonged exposure to cold and damp (humid) conditions. It usually occurs when the weather is cold and the humidity is high, especially during late fall and winter. It is a form of inflammation of the small blood vessels (vasculitis) that is characterized by painful, itchy, tender, skin injuries (lesions) on the lower legs, hands, toes, feet, ears and face. The lesions typically appear 12-24 hours after exposure to cold and usually last for two to three weeks. It may last for years if left untreated and cold exposure persists. Some individuals experience complete or partial resolution in the summer months, but in some individuals, symptoms may persist even into the warmer months.
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Overview of Perniosis. SummaryPerniosis is a seasonal inflammatory disorder that is triggered by prolonged exposure to cold and damp (humid) conditions. It usually occurs when the weather is cold and the humidity is high, especially during late fall and winter. It is a form of inflammation of the small blood vessels (vasculitis) that is characterized by painful, itchy, tender, skin injuries (lesions) on the lower legs, hands, toes, feet, ears and face. The lesions typically appear 12-24 hours after exposure to cold and usually last for two to three weeks. It may last for years if left untreated and cold exposure persists. Some individuals experience complete or partial resolution in the summer months, but in some individuals, symptoms may persist even into the warmer months.
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Perniosis
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