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nord_885_5
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Diagnosis of Nocardiosis
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Physical examination usually reveals decreased breath sounds in the lungs and crackles or rales in the infected lung. Cultures of the sputum and/or the fluid in the lungs will prove positive for the Norcardia bacteria. Chest X-rays, CT scans and viewing the lungs through an optical filament (bronchoscopy) can confirm the diagnosis and determine whether abscesses are present.
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Diagnosis of Nocardiosis. Physical examination usually reveals decreased breath sounds in the lungs and crackles or rales in the infected lung. Cultures of the sputum and/or the fluid in the lungs will prove positive for the Norcardia bacteria. Chest X-rays, CT scans and viewing the lungs through an optical filament (bronchoscopy) can confirm the diagnosis and determine whether abscesses are present.
| 885 |
Nocardiosis
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nord_885_6
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Therapies of Nocardiosis
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TreatmentNocardia organisms are usually resistant to penicillin. Sulfonamide drugs may be prescribed. However, since most cases respond slowly, treatment with sulfonamide drugs must be continued for several months. Trimethoprim-sulfamethoxazole is often prescribed for immunosuppressed patients. Recurrent infection is common.Other drugs sometimes prescribed are Imipenem and cilastatin (Primaxin), Meropenem (Merrem IV), Cefotaxime (Claforan), Ceftriaxone (Rocephin) ampicillin, minocycline, and amikacin. Without treatment the disease can be fatal, so proper and prompt diagnosis is essential.If infection occurs and spreads, surgery may be needed to remove and/or drain the infected areas.
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Therapies of Nocardiosis. TreatmentNocardia organisms are usually resistant to penicillin. Sulfonamide drugs may be prescribed. However, since most cases respond slowly, treatment with sulfonamide drugs must be continued for several months. Trimethoprim-sulfamethoxazole is often prescribed for immunosuppressed patients. Recurrent infection is common.Other drugs sometimes prescribed are Imipenem and cilastatin (Primaxin), Meropenem (Merrem IV), Cefotaxime (Claforan), Ceftriaxone (Rocephin) ampicillin, minocycline, and amikacin. Without treatment the disease can be fatal, so proper and prompt diagnosis is essential.If infection occurs and spreads, surgery may be needed to remove and/or drain the infected areas.
| 885 |
Nocardiosis
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nord_886_0
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Overview of Non-24-Hour Sleep-Wake Disorder
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Non-24-hour sleep-wake disorder (N24) is a circadian rhythm sleep disorder in which an individual's biological clock fails to synchronize to a 24-hour day. Instead of sleeping at roughly the same time every day, someone with N24 will typically find their sleep time gradually delaying by minutes to hours every day. They will sleep at later and later clock times until their sleep periods go all the way around the clock. (In extremely rare cases the sleep rhythm will gradually advance rather than delay.) Patients' cycles of body temperature and hormone rhythms also follow a non-24-hour rhythm. Attempts to fight against this internal rhythm and sleep on a typical schedule result in severe and cumulative sleep deprivation. N24 occurs in 55-70% of completely blind people, but also occurs in an unknown number of sighted people.
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Overview of Non-24-Hour Sleep-Wake Disorder. Non-24-hour sleep-wake disorder (N24) is a circadian rhythm sleep disorder in which an individual's biological clock fails to synchronize to a 24-hour day. Instead of sleeping at roughly the same time every day, someone with N24 will typically find their sleep time gradually delaying by minutes to hours every day. They will sleep at later and later clock times until their sleep periods go all the way around the clock. (In extremely rare cases the sleep rhythm will gradually advance rather than delay.) Patients' cycles of body temperature and hormone rhythms also follow a non-24-hour rhythm. Attempts to fight against this internal rhythm and sleep on a typical schedule result in severe and cumulative sleep deprivation. N24 occurs in 55-70% of completely blind people, but also occurs in an unknown number of sighted people.
| 886 |
Non-24-Hour Sleep-Wake Disorder
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nord_886_1
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Symptoms of Non-24-Hour Sleep-Wake Disorder
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As most people are required to keep a regular schedule for work, school, or other social obligations, the first symptoms of N24 usually noticed are periodic night-time insomnia and excessive daytime sleepiness. Due to the cyclical nature of the disorder, some affected persons will tend to feel normal for periods of days to weeks when their body’s rhythm is synchronized with the rhythm of society around them. As the individual’s body once again desynchronizes from the rhythms of the light-dark cycle (or day-night cycle) and the obligations the individual with N24 is trying to maintain, the insomnia and excessive daytime sleepiness will return.The sleep cycle of persons with N24 usually ranges from just over 24 hours (e.g. 24.1 hours) to as many as 28-30 hours in extreme cases. Cases with cycles less than 24 hours (which would be expected to result in a gradually advancing rhythm) are extremely rare.When allowed to sleep on their own cycle, some individuals with N24 will find relief of their symptoms of insomnia and fatigue, at the cost of the ability to maintain a schedule required for social and occupational requirements. However, some people with N24 will continue to experience fatigue, grogginess, malaise and disrupted sleep on any schedule, possibly because of continued desynchronization of their internal circadian rhythms. Recent research has documented that in addition to the central clock in the brain, virtually every cell in the body has a molecular clock, and scientists speculate that desynchronization of multitude of clocks is what underlies these symptoms.If N24 is not detected and addressed, and the person attempts to stay on a 24-hour schedule, the symptoms of chronic sleep deprivation will accumulate, such as excessive daytime sleepiness, fatigue, depression, difficulty concentrating, and memory problems. N24 can be severely disabling as it causes extreme difficulty for the individual attempting to maintain social and career obligations. Isolation and loneliness can also be issues due to periodically being awake when others are asleep.
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Symptoms of Non-24-Hour Sleep-Wake Disorder. As most people are required to keep a regular schedule for work, school, or other social obligations, the first symptoms of N24 usually noticed are periodic night-time insomnia and excessive daytime sleepiness. Due to the cyclical nature of the disorder, some affected persons will tend to feel normal for periods of days to weeks when their body’s rhythm is synchronized with the rhythm of society around them. As the individual’s body once again desynchronizes from the rhythms of the light-dark cycle (or day-night cycle) and the obligations the individual with N24 is trying to maintain, the insomnia and excessive daytime sleepiness will return.The sleep cycle of persons with N24 usually ranges from just over 24 hours (e.g. 24.1 hours) to as many as 28-30 hours in extreme cases. Cases with cycles less than 24 hours (which would be expected to result in a gradually advancing rhythm) are extremely rare.When allowed to sleep on their own cycle, some individuals with N24 will find relief of their symptoms of insomnia and fatigue, at the cost of the ability to maintain a schedule required for social and occupational requirements. However, some people with N24 will continue to experience fatigue, grogginess, malaise and disrupted sleep on any schedule, possibly because of continued desynchronization of their internal circadian rhythms. Recent research has documented that in addition to the central clock in the brain, virtually every cell in the body has a molecular clock, and scientists speculate that desynchronization of multitude of clocks is what underlies these symptoms.If N24 is not detected and addressed, and the person attempts to stay on a 24-hour schedule, the symptoms of chronic sleep deprivation will accumulate, such as excessive daytime sleepiness, fatigue, depression, difficulty concentrating, and memory problems. N24 can be severely disabling as it causes extreme difficulty for the individual attempting to maintain social and career obligations. Isolation and loneliness can also be issues due to periodically being awake when others are asleep.
| 886 |
Non-24-Hour Sleep-Wake Disorder
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nord_886_2
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Causes of Non-24-Hour Sleep-Wake Disorder
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All life on earth has evolved in conditions of a 24-hour day-night (light-dark) cycle. Organisms have evolved mechanisms to time their cellular and metabolic processes to anticipate this daily rhythm. As a result, within nearly all cells of the human body there is a biological clock based on a cycle of DNA and protein synthesis. Clock gene activity has been found within white blood cells and cells of the heart, brain, liver and many other tissues.The individual cellular clocks run on a cycle that is close to 24 hours. This is known as a circadian rhythm (“circa-” = about and “dian” = pertaining to a day). But because the clocks are not exact, the clocks of individual cells can drift apart from each other or from the earth’s day-night cycle. To keep these clocks in time there is a master clock located in the brain. In the same way that the conductor of an orchestra keeps the musicians playing in time with each other, this master clock keeps the body’s cellular clocks to the same time cycle.The master clock is located in what is called the suprachiasmatic nucleus (SCN), located in a part of the brain called the hypothalamus which regulates many basic body functions. The SCN is composed of about 20,000 closely networked cells whose rhythms are coordinated so that the firing rate of the cells varies together in a near-24-hour rhythm. The firing of SCN cells is then transmitted directly and indirectly to many other regions of the brain which then pass on this clock signal to the rest of the body by neurochemical and hormonal means.Two of the best characterized rhythms driven by the clock signal are the body temperature cycle and the production of the hormone melatonin. The SCN regulates body temperature via connections to other areas of the hypothalamus. Body temperature varies in a wave-like pattern, which reaches a maximum during the day and a minimum (or nadir) during the night.The SCN also sends a nerve signal that follows a complex poly-synaptic pathway via the cervical spinal ganglia to regulate the activity of the pineal gland, which is responsible for the production of melatonin. Melatonin, sometimes called “the hormone of darkness,” is produced during the dark at night. It is secreted by the pineal into the cerebrospinal fluid and then travels in the bloodstream to reach the cells of the body. It acts upon specific melatonin receptors to directly regulate cell functions. It also reinforces the temperature cycle by facilitating the nocturnal drop in body temperature. Among other effects, this drop in body temperature helps ready the brain and body for sleep.While the SCN serves to coordinate the cell clocks throughout the body, there is still a need to coordinate the SCN clock to the earth’s 24-hour period. If left to itself, the SCN keeps a rhythm that is close to but not exactly 24 hours. In healthy humans the intrinsic period of the SCN clock averages about 24.2 hours. If there were no way to correct this cycle to equal 24 hours the clock in the SCN would drift by several minutes each day until it no longer kept correct time or stayed “entrained.”The primary means to keep the SCN clock set properly is via light-dark exposure. Specialized cells in the retina of the eye, which are different from the cells used for vision, register the exposure to light and dark and transmit this signal by a nerve path known as the retinohypothalamic tract to the SCN. When the eyes are exposed to light in the early morning hours this sends a signal that advances the clock in the SCN to an earlier time, thereby providing the necessary daily entrainment. When light falls on the eyes late at night, a delay signal is sent to the SCN. A graph of the effect of light at different times of day and night is known as a phase-response curve and can be used to predict the effects of light on the biological clock. If the SCN clock runs longer than 24 hours, it tends to become delayed relative to the day-night cycle, but morning light exposure will reset it. If the SCN clock runs shorter than 24 hours, late night light exposure will delay it a bit. By this means, the SCN clock is kept in time with the light and dark cycle of day and night. In healthy individuals routine exposure to morning light works to keep circadian rhythms entrained.The retinal cells that register light for circadian functions use a pigment known as melanopsin as a light sensor. Because melanopsin is particularly sensitive to blue light, light of that color has a greater effect in circadian rhythms. Red, orange and yellow light have much less effect. Green light can also affect rhythms under certain circumstances.Among the most important of the body rhythms controlled by the SCN is that of the sleep-wake cycle. This cycle is controlled by two processes known as the homeostatic process and the circadian process. During sleep the brain and body repair themselves and accumulate energy and metabolic resources for the activities of the day. During the day, while the person is awake, these resources are gradually consumed. The gradual loss of energy during the day produces a drive to sleep in order to restore that energy. This is known as the homeostatic sleep drive. If the homeostatic process were the only one involved, a person would wake up fully energized and then gradually wind down over the course of the day, like a battery losing power. This would mean an uneven level of alertness during the day, with dangerously low alertness in the afternoon and evening. To counterbalance this, the SCN also regulates alertness by what is known as the circadian process. As the day goes on, and energy winds down, the SCN compensates for this by sending a stronger alertness signal to the brain and body. This alertness signal reaches a peak in the two hours just before bedtime. This zone of maximum alertness is known as the “forbidden zone for sleep” since the alertness signal makes sleep nearly impossible during that zone. When the usual bedtime is reached, the SCN begins to turn down its alertness signal to allow the body to sleep. In order to prevent early awakening, before the night’s sleep is done, the circadian alertness signal declines further across the night.This complex interplay between the circadian process and the homeostatic process allows the human organism to have a relatively level state of alertness during the day (with the occasional exception of a mid-afternoon nap period) and allows a 7-9 hour period of consolidated sleep at night.When all is working well, light signals registered in the eyes keep the SCN on track with the 24-hour day-night cycle and the SCN in turn coordinates the clocks in the pineal gland and in cells throughout the body. All the clocks keep a 24-hour cycle in sync with each other like the members of a well-conducted orchestra. The circadian alertness signal then combines with the homeostatic process resulting in an individual who can sleep through the night and maintain alertness during the day.But there are a number of things that can go wrong with this system and result in a circadian disorder such as N24.1. Blindness. The most well-understood cause of N24 is what occurs in blind individuals. Persons who are completely blind (no perception of light) will not register the light signals which are needed to fine-tune the body clock to a 24-hour day. If the SCN clock starts to drift away from 24 hours, a blind person has no intrinsic way to bring it back in sync without medical treatment. Since the inherent rhythm of the SCN is not always precisely 24 hours, a blind person’s circadian timing system will slowly drift over time. They will cycle over time between periods of nighttime sleep and periods of daytime sleep. In the vast majority of cases the sleep rhythm gradually delays so the period is over 24 hours, but there are a few cases of gradual advances and a less-than-24-hour period. The length of the circadian period in blind persons with N24 is typically in the range of 23.8 to 25 hours.2. Alterations in Light Sensitivity. In some sighted individuals there may be a subsensitivity or insensitivity to the effects of light on the circadian system. The vision-producing areas of the eye and brain may function well, but the separate cell pathway that transmits the circadian light signal may not. If they are totally insensitive to the circadian effects of light, their condition, from a circadian point of view, is not different from that of a blind person. If they are subsensitive to light, light may produce some effect on their rhythms but it may not be strong enough to correct circadian drift in their particular lighting environment.Conversely, some patients with delayed sleep phase disorder, a condition related to N24, have been shown to be supersensitive to the effects of light. If they are exposed to normal room light in the evening it may produce an exaggerated delay in their circadian rhythms. If this delay becomes cumulative, the result is N24.3. Environment. Environmental exposure to light may also play a role. Healthy individuals, when kept in isolation without time cues and allowed to turn their lights on and off when they choose, will often fall into a non-24-hour rhythm. The length of the rhythm is not only longer than the intrinsic 24.2-hour cycle of the SCN, but may be up to 25 hours or more in length. This is because self-selected light exposure late in the day has a delaying effect. However, this cannot be the sole cause of N24 since light does not lead to N24 in all persons in a non-isolated environment. In contrast, persons with N24 cannot maintain a 24-hour schedule even in a non-isolated environment with normal time cues.4. Hormonal Factors. In some cases the hormone melatonin may be involved in the development or perpetuation of N24. Some patients with N24 produce less melatonin than normal, which can be problematic since melatonin helps link sleep to the day-night cycle. On the other hand, too much melatonin may also cause problems. The antidepressant fluvoxamine, which greatly increases melatonin levels by inhibiting its metabolism, has been reported to cause DSPD, which is closely related to N24. Some individuals have an abnormality in their ability to metabolize melatonin, which can lead to higher-than-normal daytime levels that may result in circadian clock dysfunction.5. Differences in Cellular Clock Function. Other studies of the causes of circadian rhythm disorders have focused on the cellular clock itself. Studies in healthy subjects show a correlation between the period of the cellular clock and the phase of entrainment. Morning persons have a shorter clock period than evening persons. N24 may be an extension of extreme “eveningness” in which the cellular rhythm may be too far from 24 hours for normal light exposure to correct it, a situation known as being “outside the range of entrainment”.The period of the human biological clock can be measured in two ways. First one may examine the period under the usual living conditions of the subject. Under those conditions the period of a normal person is 24 hours. The timing of their sleep wake cycle does not change over time. A person with N24 by definition will have a period that is longer than 24 hours, sometimes as long as 25-26 hours.Under normal circumstances the circadian clock is affected by outside factors, especially light. But under special experimental conditions (constant routines and forced desynchrony) scientists can cancel out these outside effects and find what is called the intrinsic period of the clock. This is the time the clock would keep if it were isolated from outside influences. For normal subjects the intrinsic period of the clock is around 24.2 hours. Daily exposure to normal light compensates for the 0.2 difference and allows normal subjects to stay on a 24-hour day.Three small studies have looked at the intrinsic period of N24 patients. One study of 6 patients found a 24.5 hour period, a study of 4 patients reported 24.9 hours, and a case report of a single patient also found a 24.5 hour period. Thus these N24 patients require an adjustment of at least 0.5 to 0.9 hours per day to remain in a 24-hour cycle. Normal light exposure may not be enough to make this adjustment. When combined with other factors that push the clock later this may make entrainment to a 24-hour day impossible.Other studies have also looked at the clock within muscle cells (fibroblasts) extracted and grown in culture. The period of cells in culture is correlated with the intrinsic period of the person from whom the cells were sampled. This shows that the clock period is determined on a cellular level. For N24 patients this suggests that at least some may be manifesting a fundamental malfunction of the biochemical basis of the circadian clock, which results in a longer intrinsic period.While the intrinsic period of N24 patients is longer than average, it overlaps with the period found in a few extreme evening type subjects who do not have clinical N24. Thus, while the long intrinsic period is clearly a major contributing factor to the development of N24, there may also be additional factors involved, which make the difference between an extreme evening chronotype and free-running N24.6. Differences in the Regulation of Sleep. Another possible set of causes of N24 is related to the homeostatic and circadian regulation of sleep. On average patients with N24 have a slightly greater sleep requirement than normal. In some cases this can be extreme. While a healthy person may sleep 8 hours and be awake for 16 hours, if someone needs 12 hours of sleep and then is awake for a normal 16 hours, their day will last 28 hours total. The change in the sleep cycle will in turn change the timing of light exposure, perpetuating an N24 cycle. Similarly, if someone is deficient in the homeostatic drive for sleep they may sleep a normal 8 hours but require 20 hours of awake time before sufficient homeostatic pressure accumulates to permit sleep, again resulting in a 28 hour day.The timing of sleep in relation to internal circadian rhythms, also known as the phase angle between sleep and circadian rhythms, is abnormal in many cases of N24. Here phase angle is described in terms of the relationship between sleep timing and the circadian rhythm of body temperature. In healthy individuals the body temperature starts to drop shortly before sleep onset and reaches a minimum late in the sleep period — usually about 2 hours before waking. Persons with N24 tend to fall asleep very late relative to their temperature cycle and so the time between the temperature minimum and time of waking (sleep offset) may be 4 hours or more, even up to 8 hours in extreme cases. Since the body’s response to light-dark exposure is synched with the internal rhythms (such as core temperature) rather than the sleep-cycle per se, N24s with an abnormal relationship between sleep and circadian rhythms will sleep through the phase advance portion of their clock and not get the light they need on a daily basis to reset their clock. At the same time since they are awake late relative to their temperature cycle, they are exposed to light during the phase delay portion of the phase response curve. This tends to push their circadian rhythm in the direction of a much longer than normal day. This amplifies the effect of the already prolonged intrinsic period of N24 patients.The circadian regulation of sleepiness is also important. Even healthy individuals have a “forbidden zone for sleep” that occurs an hour or two before normal bedtime and is associated with the maximum circadian alertness signal. In persons with N24 this forbidden zone occurs too late in the day and is too strong to permit sleep on a 24-hour cycle.This pattern may be reinforced by certain effects of sleep and wake on alertness. When individuals wake after a prolonged period of sleep, they are often in a state of reduced alertness known as sleep inertia. In people with N24 this state of sluggishness and grogginess may be very powerful and persist for many hours. The longer they are awake the more alert they become. (This may be explained by an observation that brain cell circuits become more excitable with longer time awake.) When it comes time for them to sleep (if they are trying to stay on a 24-hour cycle) their alertness will have reached a high point and their heightened state of energy, even if brief, will not permit them to fall asleep at a normal time. In addition, patients with N24 may not want to try to fall asleep at this time because they finally feel awake, alert and productive.7. Development. Development of the brain, and in particular the circadian and sleep centers, is another factor. In pervasive developmental disorders such as autism a relatively high frequency of occurrence of N24 and other circadian rhythm and sleep disorders has been noted. It is assumed that the circadian and sleep centers of the brain did not properly develop or are affected by other neurochemical or anatomical deficits. It may be that other N24s who do not have pervasive developmental disorders may have impaired development limited to the sleep and circadian brain centers.8. Trauma. Physical damage to the brain, such as occurs from head injury has been noted to lead to N24 in previously healthy individuals. It is assumed that the head injury damages the sleep and circadian centers of the brain such as the hypothalamus or pineal gland. Similarly, brain tumors have been noted to lead to the development of N24. Circadian sleep disorders have been noted in survivors of tumors affecting the pons and the hypothalamus. Craniopharyngiomas are particularly likely to lead to sleep disorders. In some cases the damage is due to the tumor itself and in other cases to the effects of radiation treatment to the head. In one case an aneurysm near the SCN resulted in transient N24. There has also been a report of N24 following chemotherapy for Hodgkin’s lymphoma.Under the heading of physical abnormalities, any factor that leads to total blindness, whether via genes, disease or injury, can lead to secondary N24.9. Iatrogenic. N24 can also arise from attempts at treatment of the more common disorder, delayed sleep phase disorder (DSPD). One of the widely used treatments for DSPD is chronotherapy, in which the patient is instructed to gradually delay their bedtime and wake time up to three hours a day until they go around the clock to a more socially acceptable sleep-wake schedule. In essence this means temporarily adopting an N24 schedule. Unfortunately, in some patients, once an N24 schedule has been established it becomes nearly impossible to break. They have exchanged one circadian rhythm disorder, DSPD, for an even more disabling one, N24. There are several reasons why the N24 pattern is hard to break out of once established. One involves the timing of sleep relative to the temperature rhythm mentioned above. The other involves what is called the plasticity of the circadian system. That means that once an organism has been placed on a particular cycle, including a non-24-hour cycle, the circadian clock remembers that cycle and tries to continue it. The risk of N24 after chronotherapy has been known since the 1990s but many doctors continue to be unaware of the risk when recommending chronotherapy.10. Genetics. There is increasing evidence of a genetic component to N24. In most cases it is not a simple inherited genetic condition (Medelian inheritance). Most patients with N24 do not have parents or close relatives with the condition. However, there do seem to be several genetic factors which can predispose someone to the development of N24.One study found specific genetic changes (single nucleotide polymorphisms, SNPs) in the gene BHLHE40 in 4 patients with N24. As this gene encodes components of the cellular clock, such mutations may affect clock function leading to the abnormalities noted in N24.A separate study of 67 N24 patients found an association with polymorphisms in the PER3 gene. PER3 also encodes a crucial component of the circadian clock. The same polymorphisms were associated with extreme evening chronotype – a genetic predisposition to functioning better late in the day, a tendency which is also noted in Non-24s. Variations in the PER3 gene (both SNPs and repeat numbers) are believed to affect free-running period (in animals), the homeostatic drive for sleep (in humans) and the response to light (in humans). All of these factors have been hypothesized, with some evidence, to be abnormal in N24.DSPD, a condition related to N24, has been linked to the presence of a mutation in the CRY1 gene, which plays a role in the circadian clock, in a study of one family.Several genome-wide association studies – genetic screenings of over 100,000 persons — have shown genetic associations with human chronotypes. While these studies did not involve N24 patients specifically, N24 is closely related to extreme evening chronotype, suggesting some of the same genetic factors may be relevant.Taken together, both the specific studies of genes in Non-24 and the more general genetic studies of circadian rhythms strongly suggest that some individuals may have a genetic predisposition to the development of N24.
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Causes of Non-24-Hour Sleep-Wake Disorder. All life on earth has evolved in conditions of a 24-hour day-night (light-dark) cycle. Organisms have evolved mechanisms to time their cellular and metabolic processes to anticipate this daily rhythm. As a result, within nearly all cells of the human body there is a biological clock based on a cycle of DNA and protein synthesis. Clock gene activity has been found within white blood cells and cells of the heart, brain, liver and many other tissues.The individual cellular clocks run on a cycle that is close to 24 hours. This is known as a circadian rhythm (“circa-” = about and “dian” = pertaining to a day). But because the clocks are not exact, the clocks of individual cells can drift apart from each other or from the earth’s day-night cycle. To keep these clocks in time there is a master clock located in the brain. In the same way that the conductor of an orchestra keeps the musicians playing in time with each other, this master clock keeps the body’s cellular clocks to the same time cycle.The master clock is located in what is called the suprachiasmatic nucleus (SCN), located in a part of the brain called the hypothalamus which regulates many basic body functions. The SCN is composed of about 20,000 closely networked cells whose rhythms are coordinated so that the firing rate of the cells varies together in a near-24-hour rhythm. The firing of SCN cells is then transmitted directly and indirectly to many other regions of the brain which then pass on this clock signal to the rest of the body by neurochemical and hormonal means.Two of the best characterized rhythms driven by the clock signal are the body temperature cycle and the production of the hormone melatonin. The SCN regulates body temperature via connections to other areas of the hypothalamus. Body temperature varies in a wave-like pattern, which reaches a maximum during the day and a minimum (or nadir) during the night.The SCN also sends a nerve signal that follows a complex poly-synaptic pathway via the cervical spinal ganglia to regulate the activity of the pineal gland, which is responsible for the production of melatonin. Melatonin, sometimes called “the hormone of darkness,” is produced during the dark at night. It is secreted by the pineal into the cerebrospinal fluid and then travels in the bloodstream to reach the cells of the body. It acts upon specific melatonin receptors to directly regulate cell functions. It also reinforces the temperature cycle by facilitating the nocturnal drop in body temperature. Among other effects, this drop in body temperature helps ready the brain and body for sleep.While the SCN serves to coordinate the cell clocks throughout the body, there is still a need to coordinate the SCN clock to the earth’s 24-hour period. If left to itself, the SCN keeps a rhythm that is close to but not exactly 24 hours. In healthy humans the intrinsic period of the SCN clock averages about 24.2 hours. If there were no way to correct this cycle to equal 24 hours the clock in the SCN would drift by several minutes each day until it no longer kept correct time or stayed “entrained.”The primary means to keep the SCN clock set properly is via light-dark exposure. Specialized cells in the retina of the eye, which are different from the cells used for vision, register the exposure to light and dark and transmit this signal by a nerve path known as the retinohypothalamic tract to the SCN. When the eyes are exposed to light in the early morning hours this sends a signal that advances the clock in the SCN to an earlier time, thereby providing the necessary daily entrainment. When light falls on the eyes late at night, a delay signal is sent to the SCN. A graph of the effect of light at different times of day and night is known as a phase-response curve and can be used to predict the effects of light on the biological clock. If the SCN clock runs longer than 24 hours, it tends to become delayed relative to the day-night cycle, but morning light exposure will reset it. If the SCN clock runs shorter than 24 hours, late night light exposure will delay it a bit. By this means, the SCN clock is kept in time with the light and dark cycle of day and night. In healthy individuals routine exposure to morning light works to keep circadian rhythms entrained.The retinal cells that register light for circadian functions use a pigment known as melanopsin as a light sensor. Because melanopsin is particularly sensitive to blue light, light of that color has a greater effect in circadian rhythms. Red, orange and yellow light have much less effect. Green light can also affect rhythms under certain circumstances.Among the most important of the body rhythms controlled by the SCN is that of the sleep-wake cycle. This cycle is controlled by two processes known as the homeostatic process and the circadian process. During sleep the brain and body repair themselves and accumulate energy and metabolic resources for the activities of the day. During the day, while the person is awake, these resources are gradually consumed. The gradual loss of energy during the day produces a drive to sleep in order to restore that energy. This is known as the homeostatic sleep drive. If the homeostatic process were the only one involved, a person would wake up fully energized and then gradually wind down over the course of the day, like a battery losing power. This would mean an uneven level of alertness during the day, with dangerously low alertness in the afternoon and evening. To counterbalance this, the SCN also regulates alertness by what is known as the circadian process. As the day goes on, and energy winds down, the SCN compensates for this by sending a stronger alertness signal to the brain and body. This alertness signal reaches a peak in the two hours just before bedtime. This zone of maximum alertness is known as the “forbidden zone for sleep” since the alertness signal makes sleep nearly impossible during that zone. When the usual bedtime is reached, the SCN begins to turn down its alertness signal to allow the body to sleep. In order to prevent early awakening, before the night’s sleep is done, the circadian alertness signal declines further across the night.This complex interplay between the circadian process and the homeostatic process allows the human organism to have a relatively level state of alertness during the day (with the occasional exception of a mid-afternoon nap period) and allows a 7-9 hour period of consolidated sleep at night.When all is working well, light signals registered in the eyes keep the SCN on track with the 24-hour day-night cycle and the SCN in turn coordinates the clocks in the pineal gland and in cells throughout the body. All the clocks keep a 24-hour cycle in sync with each other like the members of a well-conducted orchestra. The circadian alertness signal then combines with the homeostatic process resulting in an individual who can sleep through the night and maintain alertness during the day.But there are a number of things that can go wrong with this system and result in a circadian disorder such as N24.1. Blindness. The most well-understood cause of N24 is what occurs in blind individuals. Persons who are completely blind (no perception of light) will not register the light signals which are needed to fine-tune the body clock to a 24-hour day. If the SCN clock starts to drift away from 24 hours, a blind person has no intrinsic way to bring it back in sync without medical treatment. Since the inherent rhythm of the SCN is not always precisely 24 hours, a blind person’s circadian timing system will slowly drift over time. They will cycle over time between periods of nighttime sleep and periods of daytime sleep. In the vast majority of cases the sleep rhythm gradually delays so the period is over 24 hours, but there are a few cases of gradual advances and a less-than-24-hour period. The length of the circadian period in blind persons with N24 is typically in the range of 23.8 to 25 hours.2. Alterations in Light Sensitivity. In some sighted individuals there may be a subsensitivity or insensitivity to the effects of light on the circadian system. The vision-producing areas of the eye and brain may function well, but the separate cell pathway that transmits the circadian light signal may not. If they are totally insensitive to the circadian effects of light, their condition, from a circadian point of view, is not different from that of a blind person. If they are subsensitive to light, light may produce some effect on their rhythms but it may not be strong enough to correct circadian drift in their particular lighting environment.Conversely, some patients with delayed sleep phase disorder, a condition related to N24, have been shown to be supersensitive to the effects of light. If they are exposed to normal room light in the evening it may produce an exaggerated delay in their circadian rhythms. If this delay becomes cumulative, the result is N24.3. Environment. Environmental exposure to light may also play a role. Healthy individuals, when kept in isolation without time cues and allowed to turn their lights on and off when they choose, will often fall into a non-24-hour rhythm. The length of the rhythm is not only longer than the intrinsic 24.2-hour cycle of the SCN, but may be up to 25 hours or more in length. This is because self-selected light exposure late in the day has a delaying effect. However, this cannot be the sole cause of N24 since light does not lead to N24 in all persons in a non-isolated environment. In contrast, persons with N24 cannot maintain a 24-hour schedule even in a non-isolated environment with normal time cues.4. Hormonal Factors. In some cases the hormone melatonin may be involved in the development or perpetuation of N24. Some patients with N24 produce less melatonin than normal, which can be problematic since melatonin helps link sleep to the day-night cycle. On the other hand, too much melatonin may also cause problems. The antidepressant fluvoxamine, which greatly increases melatonin levels by inhibiting its metabolism, has been reported to cause DSPD, which is closely related to N24. Some individuals have an abnormality in their ability to metabolize melatonin, which can lead to higher-than-normal daytime levels that may result in circadian clock dysfunction.5. Differences in Cellular Clock Function. Other studies of the causes of circadian rhythm disorders have focused on the cellular clock itself. Studies in healthy subjects show a correlation between the period of the cellular clock and the phase of entrainment. Morning persons have a shorter clock period than evening persons. N24 may be an extension of extreme “eveningness” in which the cellular rhythm may be too far from 24 hours for normal light exposure to correct it, a situation known as being “outside the range of entrainment”.The period of the human biological clock can be measured in two ways. First one may examine the period under the usual living conditions of the subject. Under those conditions the period of a normal person is 24 hours. The timing of their sleep wake cycle does not change over time. A person with N24 by definition will have a period that is longer than 24 hours, sometimes as long as 25-26 hours.Under normal circumstances the circadian clock is affected by outside factors, especially light. But under special experimental conditions (constant routines and forced desynchrony) scientists can cancel out these outside effects and find what is called the intrinsic period of the clock. This is the time the clock would keep if it were isolated from outside influences. For normal subjects the intrinsic period of the clock is around 24.2 hours. Daily exposure to normal light compensates for the 0.2 difference and allows normal subjects to stay on a 24-hour day.Three small studies have looked at the intrinsic period of N24 patients. One study of 6 patients found a 24.5 hour period, a study of 4 patients reported 24.9 hours, and a case report of a single patient also found a 24.5 hour period. Thus these N24 patients require an adjustment of at least 0.5 to 0.9 hours per day to remain in a 24-hour cycle. Normal light exposure may not be enough to make this adjustment. When combined with other factors that push the clock later this may make entrainment to a 24-hour day impossible.Other studies have also looked at the clock within muscle cells (fibroblasts) extracted and grown in culture. The period of cells in culture is correlated with the intrinsic period of the person from whom the cells were sampled. This shows that the clock period is determined on a cellular level. For N24 patients this suggests that at least some may be manifesting a fundamental malfunction of the biochemical basis of the circadian clock, which results in a longer intrinsic period.While the intrinsic period of N24 patients is longer than average, it overlaps with the period found in a few extreme evening type subjects who do not have clinical N24. Thus, while the long intrinsic period is clearly a major contributing factor to the development of N24, there may also be additional factors involved, which make the difference between an extreme evening chronotype and free-running N24.6. Differences in the Regulation of Sleep. Another possible set of causes of N24 is related to the homeostatic and circadian regulation of sleep. On average patients with N24 have a slightly greater sleep requirement than normal. In some cases this can be extreme. While a healthy person may sleep 8 hours and be awake for 16 hours, if someone needs 12 hours of sleep and then is awake for a normal 16 hours, their day will last 28 hours total. The change in the sleep cycle will in turn change the timing of light exposure, perpetuating an N24 cycle. Similarly, if someone is deficient in the homeostatic drive for sleep they may sleep a normal 8 hours but require 20 hours of awake time before sufficient homeostatic pressure accumulates to permit sleep, again resulting in a 28 hour day.The timing of sleep in relation to internal circadian rhythms, also known as the phase angle between sleep and circadian rhythms, is abnormal in many cases of N24. Here phase angle is described in terms of the relationship between sleep timing and the circadian rhythm of body temperature. In healthy individuals the body temperature starts to drop shortly before sleep onset and reaches a minimum late in the sleep period — usually about 2 hours before waking. Persons with N24 tend to fall asleep very late relative to their temperature cycle and so the time between the temperature minimum and time of waking (sleep offset) may be 4 hours or more, even up to 8 hours in extreme cases. Since the body’s response to light-dark exposure is synched with the internal rhythms (such as core temperature) rather than the sleep-cycle per se, N24s with an abnormal relationship between sleep and circadian rhythms will sleep through the phase advance portion of their clock and not get the light they need on a daily basis to reset their clock. At the same time since they are awake late relative to their temperature cycle, they are exposed to light during the phase delay portion of the phase response curve. This tends to push their circadian rhythm in the direction of a much longer than normal day. This amplifies the effect of the already prolonged intrinsic period of N24 patients.The circadian regulation of sleepiness is also important. Even healthy individuals have a “forbidden zone for sleep” that occurs an hour or two before normal bedtime and is associated with the maximum circadian alertness signal. In persons with N24 this forbidden zone occurs too late in the day and is too strong to permit sleep on a 24-hour cycle.This pattern may be reinforced by certain effects of sleep and wake on alertness. When individuals wake after a prolonged period of sleep, they are often in a state of reduced alertness known as sleep inertia. In people with N24 this state of sluggishness and grogginess may be very powerful and persist for many hours. The longer they are awake the more alert they become. (This may be explained by an observation that brain cell circuits become more excitable with longer time awake.) When it comes time for them to sleep (if they are trying to stay on a 24-hour cycle) their alertness will have reached a high point and their heightened state of energy, even if brief, will not permit them to fall asleep at a normal time. In addition, patients with N24 may not want to try to fall asleep at this time because they finally feel awake, alert and productive.7. Development. Development of the brain, and in particular the circadian and sleep centers, is another factor. In pervasive developmental disorders such as autism a relatively high frequency of occurrence of N24 and other circadian rhythm and sleep disorders has been noted. It is assumed that the circadian and sleep centers of the brain did not properly develop or are affected by other neurochemical or anatomical deficits. It may be that other N24s who do not have pervasive developmental disorders may have impaired development limited to the sleep and circadian brain centers.8. Trauma. Physical damage to the brain, such as occurs from head injury has been noted to lead to N24 in previously healthy individuals. It is assumed that the head injury damages the sleep and circadian centers of the brain such as the hypothalamus or pineal gland. Similarly, brain tumors have been noted to lead to the development of N24. Circadian sleep disorders have been noted in survivors of tumors affecting the pons and the hypothalamus. Craniopharyngiomas are particularly likely to lead to sleep disorders. In some cases the damage is due to the tumor itself and in other cases to the effects of radiation treatment to the head. In one case an aneurysm near the SCN resulted in transient N24. There has also been a report of N24 following chemotherapy for Hodgkin’s lymphoma.Under the heading of physical abnormalities, any factor that leads to total blindness, whether via genes, disease or injury, can lead to secondary N24.9. Iatrogenic. N24 can also arise from attempts at treatment of the more common disorder, delayed sleep phase disorder (DSPD). One of the widely used treatments for DSPD is chronotherapy, in which the patient is instructed to gradually delay their bedtime and wake time up to three hours a day until they go around the clock to a more socially acceptable sleep-wake schedule. In essence this means temporarily adopting an N24 schedule. Unfortunately, in some patients, once an N24 schedule has been established it becomes nearly impossible to break. They have exchanged one circadian rhythm disorder, DSPD, for an even more disabling one, N24. There are several reasons why the N24 pattern is hard to break out of once established. One involves the timing of sleep relative to the temperature rhythm mentioned above. The other involves what is called the plasticity of the circadian system. That means that once an organism has been placed on a particular cycle, including a non-24-hour cycle, the circadian clock remembers that cycle and tries to continue it. The risk of N24 after chronotherapy has been known since the 1990s but many doctors continue to be unaware of the risk when recommending chronotherapy.10. Genetics. There is increasing evidence of a genetic component to N24. In most cases it is not a simple inherited genetic condition (Medelian inheritance). Most patients with N24 do not have parents or close relatives with the condition. However, there do seem to be several genetic factors which can predispose someone to the development of N24.One study found specific genetic changes (single nucleotide polymorphisms, SNPs) in the gene BHLHE40 in 4 patients with N24. As this gene encodes components of the cellular clock, such mutations may affect clock function leading to the abnormalities noted in N24.A separate study of 67 N24 patients found an association with polymorphisms in the PER3 gene. PER3 also encodes a crucial component of the circadian clock. The same polymorphisms were associated with extreme evening chronotype – a genetic predisposition to functioning better late in the day, a tendency which is also noted in Non-24s. Variations in the PER3 gene (both SNPs and repeat numbers) are believed to affect free-running period (in animals), the homeostatic drive for sleep (in humans) and the response to light (in humans). All of these factors have been hypothesized, with some evidence, to be abnormal in N24.DSPD, a condition related to N24, has been linked to the presence of a mutation in the CRY1 gene, which plays a role in the circadian clock, in a study of one family.Several genome-wide association studies – genetic screenings of over 100,000 persons — have shown genetic associations with human chronotypes. While these studies did not involve N24 patients specifically, N24 is closely related to extreme evening chronotype, suggesting some of the same genetic factors may be relevant.Taken together, both the specific studies of genes in Non-24 and the more general genetic studies of circadian rhythms strongly suggest that some individuals may have a genetic predisposition to the development of N24.
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Non-24-Hour Sleep-Wake Disorder
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nord_886_3
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Affects of Non-24-Hour Sleep-Wake Disorder
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While the total number of people living with N24 is unknown, researchers assume that more blind people are affected than sighted people. It is estimated that 55-70% of all people who are totally blind have N24. People who lack any light perception (for example those whose eyes are enucleated) are more likely to be affected than those with some retinal function. The frequency of N24 among the sighted is unknown but the world-wide medical literature provides case studies of roughly 100 sighted individuals with N24. Fifty-seven of these cases appear in a single Japanese study. The Circadian Sleep Disorders Network (see under “organizations”) has 98 members who have indicated they or a family member have N24. The Facebook N24 group has over 500 members but it is not known how many are actual patients. As the condition is not widely known, there may be a significant number of undiagnosed cases.In published cases of sighted patients, around 75% are male, although it is not known if this is representative of the ratio in the overall patient population. Studies in healthy adults show that on average men have longer circadian periods than women. Among support groups the numbers of male and female patients are roughly equal. The most frequent age of onset is late teens or early twenties, although N24 can manifest at a much younger or older age. The disorder appears to be life-long. Insufficient data exists to determine whether N24 is progressive. Anecdotal evidence offered by long-term sufferers indicates a worsening of symptoms with age, along with an increase in the day length, however this may be due to the interaction between N24 and age-induced sleep disruptions. Clinical research on changes in the manifestation of N24 throughout the life cycle is absent at present.N24 was first described in the medical literature by Eliott, Mills, and Waterhouse in 1970.
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Affects of Non-24-Hour Sleep-Wake Disorder. While the total number of people living with N24 is unknown, researchers assume that more blind people are affected than sighted people. It is estimated that 55-70% of all people who are totally blind have N24. People who lack any light perception (for example those whose eyes are enucleated) are more likely to be affected than those with some retinal function. The frequency of N24 among the sighted is unknown but the world-wide medical literature provides case studies of roughly 100 sighted individuals with N24. Fifty-seven of these cases appear in a single Japanese study. The Circadian Sleep Disorders Network (see under “organizations”) has 98 members who have indicated they or a family member have N24. The Facebook N24 group has over 500 members but it is not known how many are actual patients. As the condition is not widely known, there may be a significant number of undiagnosed cases.In published cases of sighted patients, around 75% are male, although it is not known if this is representative of the ratio in the overall patient population. Studies in healthy adults show that on average men have longer circadian periods than women. Among support groups the numbers of male and female patients are roughly equal. The most frequent age of onset is late teens or early twenties, although N24 can manifest at a much younger or older age. The disorder appears to be life-long. Insufficient data exists to determine whether N24 is progressive. Anecdotal evidence offered by long-term sufferers indicates a worsening of symptoms with age, along with an increase in the day length, however this may be due to the interaction between N24 and age-induced sleep disruptions. Clinical research on changes in the manifestation of N24 throughout the life cycle is absent at present.N24 was first described in the medical literature by Eliott, Mills, and Waterhouse in 1970.
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Non-24-Hour Sleep-Wake Disorder
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nord_886_4
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Related disorders of Non-24-Hour Sleep-Wake Disorder
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Symptoms of the following disorders can be similar to those of N24. Comparisons may be useful for differential diagnosis.Delayed sleep-wake phase disorder (DSPD) is a circadian rhythm disorder, far more common than N24, in which the body’s time of sleep onset and natural awakening are shifted several hours later than that of unaffected individuals.The difference between DSPD and N24 is that those with DSPD have a delay in their sleep phase that remains roughly constant from day to day, while the sleep time of someone with N24 is constantly shifting later. For example someone with DSPD might go to bed around 4 am most nights. The exact time may fluctuate from day to day (e.g. 3am one day or 5am another) but the delay is not cumulative. Someone with N24 will fall asleep at 4am one day, 5am the next, then 6am, 7am, etc., all the way around the clock.Researchers have theorized that some persons who suffer from DSPD have biological clocks set to a much longer circadian rhythm than normal, just like persons suffering from N24, but the former still have the ability to entrain to a 24-hour day. According to this theory, it is the longer circadian rhythm that causes the biological clock of the individual with DSPD to shift entrainment to a later time. Persons with DSPD sometimes later develop N24, either as a progression of their disorder or as the consequence of chronotherapy (see under “causes”), supporting the idea that the underlying biology is the same in some cases.Irregular sleep-wake rhythm disorder (ISWRD) is characterized by the lack of a clearly defined circadian rhythm of sleep and wake. Sufferers sleep at variable times throughout the day and night with little or no apparent pattern. There are often 3 or more sleep periods of variable length during a typical 24-hour day. ISWRD is different from N24 in that individuals with the latter have a defined rhythmic pattern to their sleep but the period of their rhythm exceeds 24-hours. ISWRD patients have little or no rhythmic pattern of any kind. Patients with long-standing N24 have been observed to have more disorganized sleep as the disorder progresses, but usually retain at least some rhythmic pattern, which distinguishes them from ISWRD. ISWRD is most common among children with developmental disabilities and elderly patients with dementia. It also can result from head injury or brain tumors. ISWRD is also known as circadian rhythm sleep disorder, irregular sleep type.Sleep apnea is a common sleep disorder characterized by temporary, recurrent interruptions of breathing during sleep. Symptoms of the disorder include frequent interruptions of sleep during the night, excessive sleepiness during the day, loud snoring, irritability, poor concentration and/or cognition. Obesity, including a large neck and a narrow or crowded airway are commonly associated with sleep apnea. In obstructive sleep apnea syndrome, the most common form of sleep apnea, labored breathing is interrupted by airway collapse. Partial awakening may then occur and the person may gasp for air. Untreated sleep apnea is associated with high blood pressure, irregular heart-beats, and increased risks for heart attack, heart failure, stroke and diabetes. Since obstructive sleep apnea is so common, affecting approximately 24% of men and 9% of women, it would not be unusual for someone with N24 to have comorbid sleep apnea.Idiopathic hypersomnia is a rare condition that may be misdiagnosed as N24 or may be co-morbid to N24. While N24 normally manifests as a “day” longer than 24 hours due to an abnormally long wake period, chronic, ongoing hypersomnia may also cause an individual to exhibit a sleep onset time that shifts later daily if the individual remains awake for a normal amount of time while sleeping for an abnormally longer period of time. Idiopathic hypersomnia is characterized by episodes of extreme sleepiness that occur for no identifiable reason (idiopathic). Episodes may be chronic or constant. Some individuals with idiopathic hypersomnia sleep for long periods (e.g. more than 10 hours); others sleep for shorter periods (e.g. fewer than 10 hours). Idiopathic hypersomnia can disrupt many aspects of life. Behavioral modification and medications are used to treat the disorder.Narcolepsy is a neurological sleep disorder characterized by chronic, excessive attacks of drowsiness during the day, sometimes called excessive daytime sleepiness (EDS). Attacks of drowsiness may persist for only a few seconds or several minutes. These episodes vary in frequency from a few incidents to several during a single day. Nighttime (nocturnal) sleep patterns may also be disrupted. Three additional symptoms often associated with narcolepsy are sudden extreme muscle weakness (cataplexy), a specific type of hallucination that occurs just before falling asleep or upon awakening, and brief episodes of paralysis while waking up. Narcolepsy also may be associated with “automatic behavior”, i.e. doing something automatically without any memory afterward. (For more information choose “Narcolepsy” as your search term in the Rare Disease Database.)Kleine-Levin syndrome is a rare disorder characterized by the need for excessive amounts of sleep (hypersomnolence), (i.e. up to 20 hours a day); excessive food intake (compulsive hyperphagia); and behavioral changes such as an abnormally uninhibited sexual drive. When awake, affected individuals may exhibit irritability, lack of energy (lethargy), and/or lack of emotions (apathy). They may also appear confused (disoriented) and experience hallucinations. Symptoms of Kleine-Levin syndrome are cyclical. An affected individual may go for weeks or months without experiencing symptoms. When present, symptoms may persist for days to weeks. In some cases, the symptoms associated with Kleine-Levin syndrome eventually disappear with advancing age. However, episodes may recur later during life. The exact cause of Kleine-Levin syndrome is not known. (For more information, choose “Kleine-Levin” as your search term in the Rare Disease Database.)Additionally, hypothyroidism, periodic limb movement disorder, depression, hypoglycemia, and other conditions can also cause excessive daytime sleepiness. Conditions linked to excessive nocturia such as heart conditions, diabetes, prostate disorders, congestive heart failure, interstitial cystitis, cystoceles, and other bladder issues may also lead to symptoms of disturbed sleep and wake patterns as well as excessive daytime sleepiness.
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Related disorders of Non-24-Hour Sleep-Wake Disorder. Symptoms of the following disorders can be similar to those of N24. Comparisons may be useful for differential diagnosis.Delayed sleep-wake phase disorder (DSPD) is a circadian rhythm disorder, far more common than N24, in which the body’s time of sleep onset and natural awakening are shifted several hours later than that of unaffected individuals.The difference between DSPD and N24 is that those with DSPD have a delay in their sleep phase that remains roughly constant from day to day, while the sleep time of someone with N24 is constantly shifting later. For example someone with DSPD might go to bed around 4 am most nights. The exact time may fluctuate from day to day (e.g. 3am one day or 5am another) but the delay is not cumulative. Someone with N24 will fall asleep at 4am one day, 5am the next, then 6am, 7am, etc., all the way around the clock.Researchers have theorized that some persons who suffer from DSPD have biological clocks set to a much longer circadian rhythm than normal, just like persons suffering from N24, but the former still have the ability to entrain to a 24-hour day. According to this theory, it is the longer circadian rhythm that causes the biological clock of the individual with DSPD to shift entrainment to a later time. Persons with DSPD sometimes later develop N24, either as a progression of their disorder or as the consequence of chronotherapy (see under “causes”), supporting the idea that the underlying biology is the same in some cases.Irregular sleep-wake rhythm disorder (ISWRD) is characterized by the lack of a clearly defined circadian rhythm of sleep and wake. Sufferers sleep at variable times throughout the day and night with little or no apparent pattern. There are often 3 or more sleep periods of variable length during a typical 24-hour day. ISWRD is different from N24 in that individuals with the latter have a defined rhythmic pattern to their sleep but the period of their rhythm exceeds 24-hours. ISWRD patients have little or no rhythmic pattern of any kind. Patients with long-standing N24 have been observed to have more disorganized sleep as the disorder progresses, but usually retain at least some rhythmic pattern, which distinguishes them from ISWRD. ISWRD is most common among children with developmental disabilities and elderly patients with dementia. It also can result from head injury or brain tumors. ISWRD is also known as circadian rhythm sleep disorder, irregular sleep type.Sleep apnea is a common sleep disorder characterized by temporary, recurrent interruptions of breathing during sleep. Symptoms of the disorder include frequent interruptions of sleep during the night, excessive sleepiness during the day, loud snoring, irritability, poor concentration and/or cognition. Obesity, including a large neck and a narrow or crowded airway are commonly associated with sleep apnea. In obstructive sleep apnea syndrome, the most common form of sleep apnea, labored breathing is interrupted by airway collapse. Partial awakening may then occur and the person may gasp for air. Untreated sleep apnea is associated with high blood pressure, irregular heart-beats, and increased risks for heart attack, heart failure, stroke and diabetes. Since obstructive sleep apnea is so common, affecting approximately 24% of men and 9% of women, it would not be unusual for someone with N24 to have comorbid sleep apnea.Idiopathic hypersomnia is a rare condition that may be misdiagnosed as N24 or may be co-morbid to N24. While N24 normally manifests as a “day” longer than 24 hours due to an abnormally long wake period, chronic, ongoing hypersomnia may also cause an individual to exhibit a sleep onset time that shifts later daily if the individual remains awake for a normal amount of time while sleeping for an abnormally longer period of time. Idiopathic hypersomnia is characterized by episodes of extreme sleepiness that occur for no identifiable reason (idiopathic). Episodes may be chronic or constant. Some individuals with idiopathic hypersomnia sleep for long periods (e.g. more than 10 hours); others sleep for shorter periods (e.g. fewer than 10 hours). Idiopathic hypersomnia can disrupt many aspects of life. Behavioral modification and medications are used to treat the disorder.Narcolepsy is a neurological sleep disorder characterized by chronic, excessive attacks of drowsiness during the day, sometimes called excessive daytime sleepiness (EDS). Attacks of drowsiness may persist for only a few seconds or several minutes. These episodes vary in frequency from a few incidents to several during a single day. Nighttime (nocturnal) sleep patterns may also be disrupted. Three additional symptoms often associated with narcolepsy are sudden extreme muscle weakness (cataplexy), a specific type of hallucination that occurs just before falling asleep or upon awakening, and brief episodes of paralysis while waking up. Narcolepsy also may be associated with “automatic behavior”, i.e. doing something automatically without any memory afterward. (For more information choose “Narcolepsy” as your search term in the Rare Disease Database.)Kleine-Levin syndrome is a rare disorder characterized by the need for excessive amounts of sleep (hypersomnolence), (i.e. up to 20 hours a day); excessive food intake (compulsive hyperphagia); and behavioral changes such as an abnormally uninhibited sexual drive. When awake, affected individuals may exhibit irritability, lack of energy (lethargy), and/or lack of emotions (apathy). They may also appear confused (disoriented) and experience hallucinations. Symptoms of Kleine-Levin syndrome are cyclical. An affected individual may go for weeks or months without experiencing symptoms. When present, symptoms may persist for days to weeks. In some cases, the symptoms associated with Kleine-Levin syndrome eventually disappear with advancing age. However, episodes may recur later during life. The exact cause of Kleine-Levin syndrome is not known. (For more information, choose “Kleine-Levin” as your search term in the Rare Disease Database.)Additionally, hypothyroidism, periodic limb movement disorder, depression, hypoglycemia, and other conditions can also cause excessive daytime sleepiness. Conditions linked to excessive nocturia such as heart conditions, diabetes, prostate disorders, congestive heart failure, interstitial cystitis, cystoceles, and other bladder issues may also lead to symptoms of disturbed sleep and wake patterns as well as excessive daytime sleepiness.
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Non-24-Hour Sleep-Wake Disorder
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nord_886_5
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Diagnosis of Non-24-Hour Sleep-Wake Disorder
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Initial diagnosis is based on home sleep logs kept by the patient that show a non-24-hour sleep pattern. This is usually more easily distinguished if the patient’s sleep times are not constrained by social or occupational obligations.Confirmation of diagnosis may be obtained by the use of an actigraph, a device worn on the wrist that registers movement which is used to track the timing of sleep. The actigraph should be worn for sufficient time for the sleep cycle to complete at least one pass around the clock, typically several weeks.Documenting a non-24-hour pattern of melatonin secretion may be a useful confirmation of the diagnosis, though this procedure is currently more commonly used for research purposes.Clinical Testing and Work-Up
Sleep logs and actigraphy are the main means for initial work up and follow up. Polysomnography (an overnight sleep study) is not necessary for diagnosis of N24 but may be used to rule out related disorders. For polysomnography to be useful, it must be done at a time when the patient’s cycle allows him or her to sleep.
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Diagnosis of Non-24-Hour Sleep-Wake Disorder. Initial diagnosis is based on home sleep logs kept by the patient that show a non-24-hour sleep pattern. This is usually more easily distinguished if the patient’s sleep times are not constrained by social or occupational obligations.Confirmation of diagnosis may be obtained by the use of an actigraph, a device worn on the wrist that registers movement which is used to track the timing of sleep. The actigraph should be worn for sufficient time for the sleep cycle to complete at least one pass around the clock, typically several weeks.Documenting a non-24-hour pattern of melatonin secretion may be a useful confirmation of the diagnosis, though this procedure is currently more commonly used for research purposes.Clinical Testing and Work-Up
Sleep logs and actigraphy are the main means for initial work up and follow up. Polysomnography (an overnight sleep study) is not necessary for diagnosis of N24 but may be used to rule out related disorders. For polysomnography to be useful, it must be done at a time when the patient’s cycle allows him or her to sleep.
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Non-24-Hour Sleep-Wake Disorder
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nord_886_6
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Therapies of Non-24-Hour Sleep-Wake Disorder
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Treatment
In 2014, The U.S. Food and Drug Administration (FDA) approved Hetlioz (tasimelteon), a melatonin receptor agonist, to treat N24. Hetlioz, manufactured by Vanda Pharmaceuticals, Inc., is the first FDA approved treatment for the disorder. The effectiveness of Hetlioz was evaluated in two clinical trials of totally blind individuals with N24.The most widely recommended treatments for sighted patients involve exposure to specific regimens of light (phototherapy) and dark (scototherapy).Phototherapy usually involves the use of a lightbox. The lightbox is used in the early morning, typically for a duration of 2 hours, in order to stabilize the sleep cycle. Light treatment is best started when the patient’s cycle already has them arising at the desired wake time. Light is registered by special cells in the retina of the eye which send a signal to the brain via the retinohypothalamic tract. This signal suppresses the output of melatonin and shifts the timing of sleep. A phase-response curve determines the best time for light exposure.Dark therapy (scototherapy) is accomplished by avoiding light exposure late in the day. Even ordinary room light may have phase-delaying effect so patients should remain in dim light or use special dark goggles that reduce light exposure during the evening and night.A combination of light and dark therapy is believed to be more effective than either alone. If entrainment to a 24-hour cycle is achieved with light and dark therapy, the patient must maintain the treatment regimen or entrainment will be lost.The hormone melatonin may be used to stabilize the sleep-wake cycle. Melatonin is usually taken about 4-6 hours before the desired sleep time. While melatonin is often effective in blind patients with N24, it is rarely successful as the sole treatment in sighted patients.
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Therapies of Non-24-Hour Sleep-Wake Disorder. Treatment
In 2014, The U.S. Food and Drug Administration (FDA) approved Hetlioz (tasimelteon), a melatonin receptor agonist, to treat N24. Hetlioz, manufactured by Vanda Pharmaceuticals, Inc., is the first FDA approved treatment for the disorder. The effectiveness of Hetlioz was evaluated in two clinical trials of totally blind individuals with N24.The most widely recommended treatments for sighted patients involve exposure to specific regimens of light (phototherapy) and dark (scototherapy).Phototherapy usually involves the use of a lightbox. The lightbox is used in the early morning, typically for a duration of 2 hours, in order to stabilize the sleep cycle. Light treatment is best started when the patient’s cycle already has them arising at the desired wake time. Light is registered by special cells in the retina of the eye which send a signal to the brain via the retinohypothalamic tract. This signal suppresses the output of melatonin and shifts the timing of sleep. A phase-response curve determines the best time for light exposure.Dark therapy (scototherapy) is accomplished by avoiding light exposure late in the day. Even ordinary room light may have phase-delaying effect so patients should remain in dim light or use special dark goggles that reduce light exposure during the evening and night.A combination of light and dark therapy is believed to be more effective than either alone. If entrainment to a 24-hour cycle is achieved with light and dark therapy, the patient must maintain the treatment regimen or entrainment will be lost.The hormone melatonin may be used to stabilize the sleep-wake cycle. Melatonin is usually taken about 4-6 hours before the desired sleep time. While melatonin is often effective in blind patients with N24, it is rarely successful as the sole treatment in sighted patients.
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Non-24-Hour Sleep-Wake Disorder
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nord_887_0
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Overview of Nonketotic Hyperglycinemia
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Non-ketotic hyperglycinemia (NKH) is a rare, genetic, metabolic disorder caused by a defect in the enzyme system that breaks down the amino acid glycine, resulting in an accumulation of glycine in the body's tissues and fluids. There is a classical form of NKH and a variant form of NKH. The classical form is then further divided into severe disorder or an attenuated form (mild form).
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Overview of Nonketotic Hyperglycinemia. Non-ketotic hyperglycinemia (NKH) is a rare, genetic, metabolic disorder caused by a defect in the enzyme system that breaks down the amino acid glycine, resulting in an accumulation of glycine in the body's tissues and fluids. There is a classical form of NKH and a variant form of NKH. The classical form is then further divided into severe disorder or an attenuated form (mild form).
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Nonketotic Hyperglycinemia
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Symptoms of Nonketotic Hyperglycinemia
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The severe classic form of NKH typically presents in the first week of life with low muscle tone, lethargy, seizures, coma, and apnea requiring ventilator support. The ventilator is typically needed for a period of 10-20 days before the apnea resolves. A portion of individuals with severe classical NKH die during the neonatal period, often due to withdrawal of intensive care supports. All children with severe classical NKH who survive the neonatal period have severe developmental delay. Most individuals do not reach milestones past those reached by the typical 6-week-old infant. Seizures gradually worsen and can be difficult to control. Feeding difficulties and orthopedic problems can occur. Airway maintenance becomes poor over time due to low muscle tone, and is often the cause of death. Individuals with attenuated classic NKH can present in the neonatal period or later in infancy. Presentation in the neonatal period resembles that of severe classic NKH. Those who present in infancy can have low muscle tone, lethargy, and seizures. Individuals with attenuated classic NKH have variable developmental progress. Developmental delays can range from mild to profound. They can often walk and achieve various motor skills. They often have hyperactivity and behavioral problems. The clinical picture of individuals with variant NKH is rapidly evolving. Presentation varies depending upon what gene is mutated and the specific mutation itself. Particular symptoms can include: problems with spasticity or balance, problems with the nerve of the eye (optic neuropathy), problems with the white matter of the brain, heart weakness, increased resistance to blood flow in the lungs, accumulation of acid in the blood, loss of skills that the child had achieved, or seizures. Most children have only some of these problems.
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Symptoms of Nonketotic Hyperglycinemia. The severe classic form of NKH typically presents in the first week of life with low muscle tone, lethargy, seizures, coma, and apnea requiring ventilator support. The ventilator is typically needed for a period of 10-20 days before the apnea resolves. A portion of individuals with severe classical NKH die during the neonatal period, often due to withdrawal of intensive care supports. All children with severe classical NKH who survive the neonatal period have severe developmental delay. Most individuals do not reach milestones past those reached by the typical 6-week-old infant. Seizures gradually worsen and can be difficult to control. Feeding difficulties and orthopedic problems can occur. Airway maintenance becomes poor over time due to low muscle tone, and is often the cause of death. Individuals with attenuated classic NKH can present in the neonatal period or later in infancy. Presentation in the neonatal period resembles that of severe classic NKH. Those who present in infancy can have low muscle tone, lethargy, and seizures. Individuals with attenuated classic NKH have variable developmental progress. Developmental delays can range from mild to profound. They can often walk and achieve various motor skills. They often have hyperactivity and behavioral problems. The clinical picture of individuals with variant NKH is rapidly evolving. Presentation varies depending upon what gene is mutated and the specific mutation itself. Particular symptoms can include: problems with spasticity or balance, problems with the nerve of the eye (optic neuropathy), problems with the white matter of the brain, heart weakness, increased resistance to blood flow in the lungs, accumulation of acid in the blood, loss of skills that the child had achieved, or seizures. Most children have only some of these problems.
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Nonketotic Hyperglycinemia
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Causes of Nonketotic Hyperglycinemia
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Classic NKH is caused by genetic variants (mutations) in the genes that encode the components of the glycine cleavage enzyme system. This enzyme system is responsible for breaking down the amino acid glycine in the body. When it is not working properly, glycine accumulates in the body, resulting in the symptoms associated with NKH. The glycine cleavage enzyme system is composed of 4 proteins, the P-protein encoded by the GLDC gene, the H-protein encoded by the GCSH gene, the T-protein encoded by the AMT gene, and the L-protein. Mutations in GLDC or AMT cause classic NKH. The majority of individuals with classic NKH have mutations within the GLDC gene. No mutations have been identified in the GCSH gene.Individuals with deficient enzyme activity, but no mutation in GLDC or AMT, have variant NKH. Many genes have been described in variant NKH including LIAS, BOLA3, GLRX5, NFU1, ISCA2, IBA56, LIPT1 and LIPT2.NKH is inherited in an autosomal recessive inheritance pattern, meaning that an individual must have pathogenic variants in both copies of the causative gene in order to be affected. Individuals with a pathogenic variant in only one copy of the gene are carriers for the disorder, and are not affected themselves, but could potentially have an affected child if their partner is also a carrier. If both parents are carriers for NKH, then there is a 1 in 4 chance, with each pregnancy, of the child being affected with NKH.
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Causes of Nonketotic Hyperglycinemia. Classic NKH is caused by genetic variants (mutations) in the genes that encode the components of the glycine cleavage enzyme system. This enzyme system is responsible for breaking down the amino acid glycine in the body. When it is not working properly, glycine accumulates in the body, resulting in the symptoms associated with NKH. The glycine cleavage enzyme system is composed of 4 proteins, the P-protein encoded by the GLDC gene, the H-protein encoded by the GCSH gene, the T-protein encoded by the AMT gene, and the L-protein. Mutations in GLDC or AMT cause classic NKH. The majority of individuals with classic NKH have mutations within the GLDC gene. No mutations have been identified in the GCSH gene.Individuals with deficient enzyme activity, but no mutation in GLDC or AMT, have variant NKH. Many genes have been described in variant NKH including LIAS, BOLA3, GLRX5, NFU1, ISCA2, IBA56, LIPT1 and LIPT2.NKH is inherited in an autosomal recessive inheritance pattern, meaning that an individual must have pathogenic variants in both copies of the causative gene in order to be affected. Individuals with a pathogenic variant in only one copy of the gene are carriers for the disorder, and are not affected themselves, but could potentially have an affected child if their partner is also a carrier. If both parents are carriers for NKH, then there is a 1 in 4 chance, with each pregnancy, of the child being affected with NKH.
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Nonketotic Hyperglycinemia
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Affects of Nonketotic Hyperglycinemia
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The incidence of NKH is predicted to be approximately 1:76,000. NKH can occur in individuals of any ancestry.
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Affects of Nonketotic Hyperglycinemia. The incidence of NKH is predicted to be approximately 1:76,000. NKH can occur in individuals of any ancestry.
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Nonketotic Hyperglycinemia
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Related disorders of Nonketotic Hyperglycinemia
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Symptoms of the following disorders can be similar to those of non-ketotic hyperglycinemia. Comparisons may be useful for a differential diagnosis:Ketotic hyperglycinemia: propionic acidemia, methlymalonic acidemia, isovalerica acidema and B-ketothiolase deficiency. These patients have elevated glycine due to interference with the glycine cleavage enzyme system, but do not resemble NKH clinically.Hyperglycinuria: familial iminoglycinuria and benign hyperglycinuria. These patients have elevated glycine in urine.Disorders of pyridoxal-phosphate, such as pyridoxal-phosphate dependent encephalopathy. These children resemble NKH and can have elevated glycine levels. They lack active vitamin B6 (called pyridoxal-phosphate), which is a necessary compound for the activity of the glycine cleavage enzyme.Transient NKH: Some children with severe injury to the brain have temporarily elevated glycine levels. They do not have a genetic deficiency in the glycine cleavage enzyme system. Their glycine levels come down spontaneously as they recover from the injury. Hypoxic-ischemic injury is one of the more common reasons for this.Some children have been identified on newborn screening as having very elevated levels of glycine in blood. They have no symptoms. They do not have a deficiency in the glycine cleavage enzyme activity or have mutations in GLDC or AMT. They remain asymptomatic. The cause for this phenomenon is currently unknown.
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Related disorders of Nonketotic Hyperglycinemia. Symptoms of the following disorders can be similar to those of non-ketotic hyperglycinemia. Comparisons may be useful for a differential diagnosis:Ketotic hyperglycinemia: propionic acidemia, methlymalonic acidemia, isovalerica acidema and B-ketothiolase deficiency. These patients have elevated glycine due to interference with the glycine cleavage enzyme system, but do not resemble NKH clinically.Hyperglycinuria: familial iminoglycinuria and benign hyperglycinuria. These patients have elevated glycine in urine.Disorders of pyridoxal-phosphate, such as pyridoxal-phosphate dependent encephalopathy. These children resemble NKH and can have elevated glycine levels. They lack active vitamin B6 (called pyridoxal-phosphate), which is a necessary compound for the activity of the glycine cleavage enzyme.Transient NKH: Some children with severe injury to the brain have temporarily elevated glycine levels. They do not have a genetic deficiency in the glycine cleavage enzyme system. Their glycine levels come down spontaneously as they recover from the injury. Hypoxic-ischemic injury is one of the more common reasons for this.Some children have been identified on newborn screening as having very elevated levels of glycine in blood. They have no symptoms. They do not have a deficiency in the glycine cleavage enzyme activity or have mutations in GLDC or AMT. They remain asymptomatic. The cause for this phenomenon is currently unknown.
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Nonketotic Hyperglycinemia
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Diagnosis of Nonketotic Hyperglycinemia
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Cerebral spinal fluid (CSF) and plasma glycine levels are used in the diagnosis of NKH. Deficient enzyme activity causes elevated glycine levels in plasma and CSF, and an elevated CSF:plasma glycine ratio. High glycine levels in plasma and urine are not exclusive to NKH. Increased CSF glycine is highly indicative of NKH, however contamination of CSF with blood or serum can cause a false elevation of CSF glycine. CSF glycine is the preferred diagnostic test. Molecular analysis is an excellent confirmatory test. With sequencing and deletion/duplication analysis, 98% of alleles are detected. Brain MRI imaging can also be helpful because there is a specific pattern of changes seen in individuals with NKH.Prenatal diagnosis is available when familial mutations are known.
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Diagnosis of Nonketotic Hyperglycinemia. Cerebral spinal fluid (CSF) and plasma glycine levels are used in the diagnosis of NKH. Deficient enzyme activity causes elevated glycine levels in plasma and CSF, and an elevated CSF:plasma glycine ratio. High glycine levels in plasma and urine are not exclusive to NKH. Increased CSF glycine is highly indicative of NKH, however contamination of CSF with blood or serum can cause a false elevation of CSF glycine. CSF glycine is the preferred diagnostic test. Molecular analysis is an excellent confirmatory test. With sequencing and deletion/duplication analysis, 98% of alleles are detected. Brain MRI imaging can also be helpful because there is a specific pattern of changes seen in individuals with NKH.Prenatal diagnosis is available when familial mutations are known.
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Nonketotic Hyperglycinemia
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Therapies of Nonketotic Hyperglycinemia
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TreatmentThere is no curative treatment for NKH. However, there are treatments that can improve outcomes. Sodium benzoate is used to reduce serum glycine levels. Benzoate binds to glycine in the body to form hippurate, which is excreted in the urine. This treatment reduces seizures and improves alertness. Plasma glycine levels must be monitored closely to ensure sodium benzoate is at an effective and non-toxic level. Dextromethorphan is commonly used to reduce seizures and improve alertness. Dextromethorphan binds to NMDA receptors in the brain. These receptors are over-stimulated in individuals with NKH due to increased glycine levels in the brain. Glutamate is the neurotransmitter that predominately binds to these receptors. Dextromethorphan binds to the NMDA receptors, blocking glutamate from binding to the receptor. Ketamine is another NMDA receptor blocker that is also used. In patients with attenuated NKH, use of dextromethorphan can help with attention and chorea, and if treated early together with benzoate, can improve development and seizures.Seizure management in individuals with severe classic NKH is difficult and usually requires multiple anticonvulsants. Valproate is not recommended for patients with NKH as it inhibits the residual glycine cleavage enzyme activity. Vigabatrin should rarely be used as many children with NKH have had adverse reactions to it.
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Therapies of Nonketotic Hyperglycinemia. TreatmentThere is no curative treatment for NKH. However, there are treatments that can improve outcomes. Sodium benzoate is used to reduce serum glycine levels. Benzoate binds to glycine in the body to form hippurate, which is excreted in the urine. This treatment reduces seizures and improves alertness. Plasma glycine levels must be monitored closely to ensure sodium benzoate is at an effective and non-toxic level. Dextromethorphan is commonly used to reduce seizures and improve alertness. Dextromethorphan binds to NMDA receptors in the brain. These receptors are over-stimulated in individuals with NKH due to increased glycine levels in the brain. Glutamate is the neurotransmitter that predominately binds to these receptors. Dextromethorphan binds to the NMDA receptors, blocking glutamate from binding to the receptor. Ketamine is another NMDA receptor blocker that is also used. In patients with attenuated NKH, use of dextromethorphan can help with attention and chorea, and if treated early together with benzoate, can improve development and seizures.Seizure management in individuals with severe classic NKH is difficult and usually requires multiple anticonvulsants. Valproate is not recommended for patients with NKH as it inhibits the residual glycine cleavage enzyme activity. Vigabatrin should rarely be used as many children with NKH have had adverse reactions to it.
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Nonketotic Hyperglycinemia
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Overview of Nontuberculous Mycobacterial Lung Disease
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Nontuberculous mycobacterial (NTM) lung disease is a general term for a group of disorders characterized by exposure to specific bacterial germs known as mycobacteria. These germs are found in the water and soil and are common throughout the environment as a whole. They usually do not cause illness. The term ‘nontuberculous’ is used to differentiate these disorders from the mycobacterium that cause tuberculosis (i.e. mycobacterium tuberculosis complex). These disorders also exclude Mycobacterium leprae, the mycobacterium that causes leprosy. In NTM disorders, the severity of infection and the disease course can vary greatly from one person to another. The most common symptoms include a persistent cough, fatigue, weight loss, night sweats, and occasionally shortness of breath (dyspnea) and coughing up of blood (hemoptysis). Less often, NTM infection can cause skin or soft tissue infections or infection and inflammation of the lymph nodes (lymphadenitis). Most evidence indicates that these infections are not transmitted from one person to another, but are acquired from the environment. NTM lung disease most commonly affects people with an underlying lung disease such as chronic obstructive pulmonary disease (COPD), bronchiectasis, cystic fibrosis, primary ciliary dyskinesia, and alpha-1-antitrypsin disease, but individuals with no prior history of lung disease can also be affected. Less severe infections may not require treatment. In other cases, the infection can become chronic requiring ongoing treatment.
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Overview of Nontuberculous Mycobacterial Lung Disease. Nontuberculous mycobacterial (NTM) lung disease is a general term for a group of disorders characterized by exposure to specific bacterial germs known as mycobacteria. These germs are found in the water and soil and are common throughout the environment as a whole. They usually do not cause illness. The term ‘nontuberculous’ is used to differentiate these disorders from the mycobacterium that cause tuberculosis (i.e. mycobacterium tuberculosis complex). These disorders also exclude Mycobacterium leprae, the mycobacterium that causes leprosy. In NTM disorders, the severity of infection and the disease course can vary greatly from one person to another. The most common symptoms include a persistent cough, fatigue, weight loss, night sweats, and occasionally shortness of breath (dyspnea) and coughing up of blood (hemoptysis). Less often, NTM infection can cause skin or soft tissue infections or infection and inflammation of the lymph nodes (lymphadenitis). Most evidence indicates that these infections are not transmitted from one person to another, but are acquired from the environment. NTM lung disease most commonly affects people with an underlying lung disease such as chronic obstructive pulmonary disease (COPD), bronchiectasis, cystic fibrosis, primary ciliary dyskinesia, and alpha-1-antitrypsin disease, but individuals with no prior history of lung disease can also be affected. Less severe infections may not require treatment. In other cases, the infection can become chronic requiring ongoing treatment.
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Nontuberculous Mycobacterial Lung Disease
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Symptoms of Nontuberculous Mycobacterial Lung Disease
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The symptoms and severity can vary greatly from one person to another. The reason for this variability is not fully understood. Chronic lung infection is the most common complication affecting approximately 94% of individuals. The symptoms are usually nonspecific and similar to the symptoms seen in other lung or respiratory infections. Such symptoms include cough, fatigue, shortness of breath (dyspnea), coughing up of blood (hemoptysis), excessive mucus (sputum) production, fever, night sweats, loss of appetite, and unintended weight loss. Wheezing and chest pain may also occur. Affected individuals may experience recurrent respiratory infections. In some cases, these infections can cause progressive damage to the lungs and, eventually, the lungs will not function as well as they should (impaired lung function).There are two main clinical presentations for NTM infection, which means that the symptoms and signs associated with this disorder are expressed in two specific ways. The less severe form is known as nodular bronchiectasis, in which the airways of the lungs become damaged, and subsequently dilate and become scarred. The airways can lose their ability to clear mucus and the mucus that accumulates within the airways can serve as a nutrient source and home for NTM, helping it to evade the immune system. Infiltrates can accumulate in the lungs particularly in the right middle lobe or the lingula, a small tongue-like projection from the upper left lobe of the lungs. Infiltrates is a nonspecific term describing substances that abnormally accumulate in the lungs or airways. Infiltrates can be pus, blood, or protein-rich fluid. Nodular bronchiectasis predominantly affects older women of Caucasian or Asian descent without a history of lung disease.The second presentation is known as cavitary disease, in which scarring (fibrosis) or cavities form in the lungs (cavitation) particularly in the upper lobes of the lungs. This form is more severe and, if left untreated, can cause progressive cavitation and fibrosis, ultimately resulting in respiratory failure.There are less common presentations of NTM infection. In some individuals, the disease will present as a single or multiple small masses in the lungs (single or multiple pulmonary nodules) or as hypersensitivity pneumonitis, a condition characterized by inflammation of the lungs after being exposed to NTM. In hypersensitivity pneumonitis cough, fever and shortness of breath are the most common symptoms.Although pulmonary symptoms are the most common way NTM disease affects humans, these infections can also involve the skin, bones, and lymph nodes. Specific symptoms vary depending on the exact areas of the body affected. An infection can be widespread (disseminated) throughout the body and, without proper treatment, can prove fatal. Disseminated NTM infection occurs almost entirely in individuals whose immune system’s ability to fight infection is severely compromised or absent (immunocompromised individuals).
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Symptoms of Nontuberculous Mycobacterial Lung Disease. The symptoms and severity can vary greatly from one person to another. The reason for this variability is not fully understood. Chronic lung infection is the most common complication affecting approximately 94% of individuals. The symptoms are usually nonspecific and similar to the symptoms seen in other lung or respiratory infections. Such symptoms include cough, fatigue, shortness of breath (dyspnea), coughing up of blood (hemoptysis), excessive mucus (sputum) production, fever, night sweats, loss of appetite, and unintended weight loss. Wheezing and chest pain may also occur. Affected individuals may experience recurrent respiratory infections. In some cases, these infections can cause progressive damage to the lungs and, eventually, the lungs will not function as well as they should (impaired lung function).There are two main clinical presentations for NTM infection, which means that the symptoms and signs associated with this disorder are expressed in two specific ways. The less severe form is known as nodular bronchiectasis, in which the airways of the lungs become damaged, and subsequently dilate and become scarred. The airways can lose their ability to clear mucus and the mucus that accumulates within the airways can serve as a nutrient source and home for NTM, helping it to evade the immune system. Infiltrates can accumulate in the lungs particularly in the right middle lobe or the lingula, a small tongue-like projection from the upper left lobe of the lungs. Infiltrates is a nonspecific term describing substances that abnormally accumulate in the lungs or airways. Infiltrates can be pus, blood, or protein-rich fluid. Nodular bronchiectasis predominantly affects older women of Caucasian or Asian descent without a history of lung disease.The second presentation is known as cavitary disease, in which scarring (fibrosis) or cavities form in the lungs (cavitation) particularly in the upper lobes of the lungs. This form is more severe and, if left untreated, can cause progressive cavitation and fibrosis, ultimately resulting in respiratory failure.There are less common presentations of NTM infection. In some individuals, the disease will present as a single or multiple small masses in the lungs (single or multiple pulmonary nodules) or as hypersensitivity pneumonitis, a condition characterized by inflammation of the lungs after being exposed to NTM. In hypersensitivity pneumonitis cough, fever and shortness of breath are the most common symptoms.Although pulmonary symptoms are the most common way NTM disease affects humans, these infections can also involve the skin, bones, and lymph nodes. Specific symptoms vary depending on the exact areas of the body affected. An infection can be widespread (disseminated) throughout the body and, without proper treatment, can prove fatal. Disseminated NTM infection occurs almost entirely in individuals whose immune system’s ability to fight infection is severely compromised or absent (immunocompromised individuals).
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Nontuberculous Mycobacterial Lung Disease
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Causes of Nontuberculous Mycobacterial Lung Disease
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Nontuberculous mycobacterial lung disease is caused by infection with specific bacterial germs known as mycobacteria. These germs are commonly found throughout the environment. Most people do not become sick when exposed to these germs. More than 120 species of mycobacteria have been identified that can cause disease in humans. The most common are Mycobacterium avium complex or MAC. MAC encompasses three mycobacterial species known as M. avium,M. intracellulare, and M. chimaera. Collectively, these species account for approximately half of all mycobacterial infections.Additional species that can cause infection in humans include M. abscessus, M. kansasii, M. fortuitum, M. xenopi, M. malmoense, M. szulgai, and M. simiae.The underlying reason why some people become sick when exposed to these bacteria and other people do not is not fully understood. There may be certain risk or predisposing factors that, when present, make it more likely for infection to occur. However, in some people no predisposing or risk factor can be identified. Two main theories exist to explain individual susceptibility to NTM infection. Abnormalities in airway defenses or the ability of the airways to clear out normal secretions can lead to lung disease in individuals infected with NTM. In widespread (disseminated) NTM infection, an underlying problem with the immune system is suspected.There are different predisposing factors for the different forms and species of NTM. Individuals with the cavitary form of infection are often prior smokers with underlying chronic obstructive pulmonary disease (COPD) or have pre-existing structural lung disease such as bronchiectasis.Individuals with the nodular bronchiectatic form of MAC or with M. abscessus infection are often thin, middle aged or elderly females, and over half have no prior history of smoking or underlying lung disease. They may have other associated findings, including a sunken chest (pectus excavatum), abnormal curvature of the spine (scoliosis), improper closure of the valve between the upper left and lower left chambers of the heart (mitral valve prolapse) and heterozygous mutations in the cystic fibrosis transmemberane regulator gene (which means individuals have a mutation in one copy of the gene, rather than in both copies).Individuals with cystic fibrosis (CF) and non-CF bronchiectasis are at increased risk for developing NTM infections, most commonly MAC or M. abscessus.M. kansasii is more common in males and in individuals with underlying COPD or immune suppression from medications, HIV infection or malignancy.Individuals with certain immune defects, including interferon gamma receptor deficiencies, auto-antibodies to interferon gamma, STAT-1 deficiency and GATA2 deficiency also have increased risk of developing NTM, including disseminated disease. Therapy with tumor necrosis factor alpha antagonist drugs, such as is used to treat rheumatoid arthritis and other connective tissue diseases, is also a risk factor for NTM infection. Marfan syndrome, hyper-IgE syndrome, and congenital contractural arachnodactyly have also been associated with pulmonary NTM disease. NORD has more information on some of these disorders (use the specific disorder name, as your search term in the Rare Disease Database).
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Causes of Nontuberculous Mycobacterial Lung Disease. Nontuberculous mycobacterial lung disease is caused by infection with specific bacterial germs known as mycobacteria. These germs are commonly found throughout the environment. Most people do not become sick when exposed to these germs. More than 120 species of mycobacteria have been identified that can cause disease in humans. The most common are Mycobacterium avium complex or MAC. MAC encompasses three mycobacterial species known as M. avium,M. intracellulare, and M. chimaera. Collectively, these species account for approximately half of all mycobacterial infections.Additional species that can cause infection in humans include M. abscessus, M. kansasii, M. fortuitum, M. xenopi, M. malmoense, M. szulgai, and M. simiae.The underlying reason why some people become sick when exposed to these bacteria and other people do not is not fully understood. There may be certain risk or predisposing factors that, when present, make it more likely for infection to occur. However, in some people no predisposing or risk factor can be identified. Two main theories exist to explain individual susceptibility to NTM infection. Abnormalities in airway defenses or the ability of the airways to clear out normal secretions can lead to lung disease in individuals infected with NTM. In widespread (disseminated) NTM infection, an underlying problem with the immune system is suspected.There are different predisposing factors for the different forms and species of NTM. Individuals with the cavitary form of infection are often prior smokers with underlying chronic obstructive pulmonary disease (COPD) or have pre-existing structural lung disease such as bronchiectasis.Individuals with the nodular bronchiectatic form of MAC or with M. abscessus infection are often thin, middle aged or elderly females, and over half have no prior history of smoking or underlying lung disease. They may have other associated findings, including a sunken chest (pectus excavatum), abnormal curvature of the spine (scoliosis), improper closure of the valve between the upper left and lower left chambers of the heart (mitral valve prolapse) and heterozygous mutations in the cystic fibrosis transmemberane regulator gene (which means individuals have a mutation in one copy of the gene, rather than in both copies).Individuals with cystic fibrosis (CF) and non-CF bronchiectasis are at increased risk for developing NTM infections, most commonly MAC or M. abscessus.M. kansasii is more common in males and in individuals with underlying COPD or immune suppression from medications, HIV infection or malignancy.Individuals with certain immune defects, including interferon gamma receptor deficiencies, auto-antibodies to interferon gamma, STAT-1 deficiency and GATA2 deficiency also have increased risk of developing NTM, including disseminated disease. Therapy with tumor necrosis factor alpha antagonist drugs, such as is used to treat rheumatoid arthritis and other connective tissue diseases, is also a risk factor for NTM infection. Marfan syndrome, hyper-IgE syndrome, and congenital contractural arachnodactyly have also been associated with pulmonary NTM disease. NORD has more information on some of these disorders (use the specific disorder name, as your search term in the Rare Disease Database).
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Nontuberculous Mycobacterial Lung Disease
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Affects of Nontuberculous Mycobacterial Lung Disease
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In North America, the incidence of nontuberculous mycobacterial lung disease is rising, particularly among the elderly. Generally, NTM infection is more common in Caucasians, Asians and individuals with a compromised immune system. The incidence and prevalence rates reported in the medical literature varies and because many cases may go undiagnosed or misdiagnosed determining the true frequency of NTM infections in the general population is difficult.
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Affects of Nontuberculous Mycobacterial Lung Disease. In North America, the incidence of nontuberculous mycobacterial lung disease is rising, particularly among the elderly. Generally, NTM infection is more common in Caucasians, Asians and individuals with a compromised immune system. The incidence and prevalence rates reported in the medical literature varies and because many cases may go undiagnosed or misdiagnosed determining the true frequency of NTM infections in the general population is difficult.
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Nontuberculous Mycobacterial Lung Disease
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Related disorders of Nontuberculous Mycobacterial Lung Disease
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Symptoms of the following disorders can be similar to those of nontuberculous mycobacterial lung disease. Comparisons may be useful for a differential diagnosis.There are many conditions that are associated with the same nonspecific symptoms that can characterize NTM lung disease. Such conditions include recurrent aspiration pneumonitis, bronchiectasis, tuberculosis, lung cancer, aspergillosis, and fungal diseases such as blastomycosis, histoplasmosis, and coccidioidomycosis. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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Related disorders of Nontuberculous Mycobacterial Lung Disease. Symptoms of the following disorders can be similar to those of nontuberculous mycobacterial lung disease. Comparisons may be useful for a differential diagnosis.There are many conditions that are associated with the same nonspecific symptoms that can characterize NTM lung disease. Such conditions include recurrent aspiration pneumonitis, bronchiectasis, tuberculosis, lung cancer, aspergillosis, and fungal diseases such as blastomycosis, histoplasmosis, and coccidioidomycosis. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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Nontuberculous Mycobacterial Lung Disease
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Diagnosis of Nontuberculous Mycobacterial Lung Disease
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A diagnosis of nontuberculous mycobacterial lung disease is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. However, the diagnosis can be challenging because the characteristic signs and symptoms are highly variable and nonspecific. A diagnosis of NTM includes ruling out other diseases such as tuberculosis or lung cancer.The American Thoracic Society (ATS) and Infectious Disease Society of America (IDSA) have published joint guidelines (Griffith et al. 2007) outlining the diagnostic criteria for pulmonary NTM infection. The criteria used are a best fit for infection with Mycobacterium avium complex, Mycobacterium kansasii, and Mycobacterium abscessus. These guidelines require that an affected individual meet clinical, radiographic, and microbiologic criteria to establish a diagnosis of NTM lung disease:X-ray studies (e.g. chest x-ray) and high resolution computed tomography (HRCT) scans can be used to examine the lungs. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissues structures such as lung tissue. HRCT gives sharper, more detailed pictures of the lungs than traditional x-rays or conventional CT scanning.A sputum culture is a test that can detect and identify bacteria that are infecting the lungs and various breathing passageways (airways). Sputum is a thick fluid produced within the lungs and breathing passageways of the respiratory tract, usually in response to infection or inflammation. Sputum is mainly made up of mucus and saliva. A sputum culture can be obtained directly from affected individuals by having them cough up a sample. A sputum sample can also be obtained through bronchoscopy. During bronchoscopy, a thin, flexible tube (bronchoscope) is inserted through the nose or mouth, allowing a physician to examine the throat, larynx, trachea and lower airways. During this procedure, a physician can also obtain a bronchoalveolar lavage (BAL), which is a deeper fluid sample from the alveoli (lung sacs) for examination. A bronchoscopy may be necessary for diagnosis in individuals who are unable to produce an adequate sputum sample.During a lung biopsy, a small sample of affected lung tissue is surgically cut out, removed and studied under a microscope. In most cases, a lung biopsy is not necessary for a diagnosis of NTM infection.NTM infections have traditionally been classified into rapidly growing and slowly growing mycobacteria. M. abscessus, M. chelonae, and M. fortuitum are rapidly growing mycobacteria, and usually grow in culture within one week. The slowly growing mycobacteria, which include the most common species, MAC, typically take 10-14 days to grow in a liquid medium, and 2-4 weeks to grow in solid medium. A liquid or solid medium is a liquid or gel designed to support the growth of microorganisms like bacteria. Once growth is evident, nucleic acid probes can be performed for rapid identification of M. tuberculosis, M. kansasii and MAC.
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Diagnosis of Nontuberculous Mycobacterial Lung Disease. A diagnosis of nontuberculous mycobacterial lung disease is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. However, the diagnosis can be challenging because the characteristic signs and symptoms are highly variable and nonspecific. A diagnosis of NTM includes ruling out other diseases such as tuberculosis or lung cancer.The American Thoracic Society (ATS) and Infectious Disease Society of America (IDSA) have published joint guidelines (Griffith et al. 2007) outlining the diagnostic criteria for pulmonary NTM infection. The criteria used are a best fit for infection with Mycobacterium avium complex, Mycobacterium kansasii, and Mycobacterium abscessus. These guidelines require that an affected individual meet clinical, radiographic, and microbiologic criteria to establish a diagnosis of NTM lung disease:X-ray studies (e.g. chest x-ray) and high resolution computed tomography (HRCT) scans can be used to examine the lungs. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissues structures such as lung tissue. HRCT gives sharper, more detailed pictures of the lungs than traditional x-rays or conventional CT scanning.A sputum culture is a test that can detect and identify bacteria that are infecting the lungs and various breathing passageways (airways). Sputum is a thick fluid produced within the lungs and breathing passageways of the respiratory tract, usually in response to infection or inflammation. Sputum is mainly made up of mucus and saliva. A sputum culture can be obtained directly from affected individuals by having them cough up a sample. A sputum sample can also be obtained through bronchoscopy. During bronchoscopy, a thin, flexible tube (bronchoscope) is inserted through the nose or mouth, allowing a physician to examine the throat, larynx, trachea and lower airways. During this procedure, a physician can also obtain a bronchoalveolar lavage (BAL), which is a deeper fluid sample from the alveoli (lung sacs) for examination. A bronchoscopy may be necessary for diagnosis in individuals who are unable to produce an adequate sputum sample.During a lung biopsy, a small sample of affected lung tissue is surgically cut out, removed and studied under a microscope. In most cases, a lung biopsy is not necessary for a diagnosis of NTM infection.NTM infections have traditionally been classified into rapidly growing and slowly growing mycobacteria. M. abscessus, M. chelonae, and M. fortuitum are rapidly growing mycobacteria, and usually grow in culture within one week. The slowly growing mycobacteria, which include the most common species, MAC, typically take 10-14 days to grow in a liquid medium, and 2-4 weeks to grow in solid medium. A liquid or solid medium is a liquid or gel designed to support the growth of microorganisms like bacteria. Once growth is evident, nucleic acid probes can be performed for rapid identification of M. tuberculosis, M. kansasii and MAC.
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Nontuberculous Mycobacterial Lung Disease
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Therapies of Nontuberculous Mycobacterial Lung Disease
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Treatment
The decision to begin treatment for NTM infection is a challenging and difficult one. Treatment with a combination of antibiotic drugs (drug regimen) is the mainstay of therapy for these diseases. However, these drugs carry certain risks (side effects) and are often poorly tolerated, have a high cost, and require individuals to remain on the medications for a lengthy period of time. These risks must be weighed against the potential benefits for each individual based upon the severity of their disease and specific symptoms that are present. If a decision is made not to treat, then an affected individual should be closely monitored to promptly detect any progression of the infection.Specific drug regimens will vary depending upon multiple factors including the susceptibility of the bacterial species in question to specific drugs as well as unique factors regarding the affected individual (age, overall health, specific symptoms, personal preference, and interactions with other medications). Treatment should be continued for 12 months after sputum cultures change from positive for infection to negative.The ATS/IDSA guidelines (Griffith et al. 2007) include detailed treatment recommendations for individuals with NTM infections. These guidelines detail specific drug regimens including frequency, duration and dosage, monitoring for drug toxicity, and prophylactic treatment recommendations. The treatment regimens vary by species with the most important distinction being how to treat slow-growing versus rapid-growing NTM infection.In specific cases such as in individuals with localized bronchiectasis, cavitary disease, or coughing up blood that does not improve with treatment (refractory hemoptysis), surgical removal of the affected tissue may be recommended. However, determining the best candidates and timing for surgical therapy is unknown.There are additional measures that can be taken to help treat individuals with NTM infection. Various techniques that help to expel mucus from the lungs may be recommended for affected individuals. Such techniques include sterile, extra-salty water delivered as a mist (nebulized hypertonic saline), physical therapy of the chest, devices that loosen mucus in the airways (flutter devices, high frequency chest wall oscillation), a specific way of coughing that helps bring up mucus (huff cough), and aerobic exercise. Proper nutrition and weight maintenance are also important.In 2018, Arikayce (amikacin liposome inhalation suspension) was approved for the treatment of lung disease caused by Mycobacterium avium complex (MAC) bacteria in a limited population of patients with the disease who do not respond to conventional treatment. Arikayce is manufactured by Insmed, Inc.There are steps that affected individuals can take to lessen the chance of re-infection from the environment including the avoidance of hot-tubs, the avoidance of using tap water in humidifiers and CPAP machines, taking care in regard to environmental exposure to tap water and soil, and the use of specialized filtration systems in household plumbing. Since it is unknown whether individuals acquire NTM through inhalation (for example, from the shower spray) or from ingestion of tap water and subsequent reflux and aspiration of NTM-infected water into the lungs, consideration may be given to minimizing time spent in the shower and to boiling tap water prior to drinking.
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Therapies of Nontuberculous Mycobacterial Lung Disease. Treatment
The decision to begin treatment for NTM infection is a challenging and difficult one. Treatment with a combination of antibiotic drugs (drug regimen) is the mainstay of therapy for these diseases. However, these drugs carry certain risks (side effects) and are often poorly tolerated, have a high cost, and require individuals to remain on the medications for a lengthy period of time. These risks must be weighed against the potential benefits for each individual based upon the severity of their disease and specific symptoms that are present. If a decision is made not to treat, then an affected individual should be closely monitored to promptly detect any progression of the infection.Specific drug regimens will vary depending upon multiple factors including the susceptibility of the bacterial species in question to specific drugs as well as unique factors regarding the affected individual (age, overall health, specific symptoms, personal preference, and interactions with other medications). Treatment should be continued for 12 months after sputum cultures change from positive for infection to negative.The ATS/IDSA guidelines (Griffith et al. 2007) include detailed treatment recommendations for individuals with NTM infections. These guidelines detail specific drug regimens including frequency, duration and dosage, monitoring for drug toxicity, and prophylactic treatment recommendations. The treatment regimens vary by species with the most important distinction being how to treat slow-growing versus rapid-growing NTM infection.In specific cases such as in individuals with localized bronchiectasis, cavitary disease, or coughing up blood that does not improve with treatment (refractory hemoptysis), surgical removal of the affected tissue may be recommended. However, determining the best candidates and timing for surgical therapy is unknown.There are additional measures that can be taken to help treat individuals with NTM infection. Various techniques that help to expel mucus from the lungs may be recommended for affected individuals. Such techniques include sterile, extra-salty water delivered as a mist (nebulized hypertonic saline), physical therapy of the chest, devices that loosen mucus in the airways (flutter devices, high frequency chest wall oscillation), a specific way of coughing that helps bring up mucus (huff cough), and aerobic exercise. Proper nutrition and weight maintenance are also important.In 2018, Arikayce (amikacin liposome inhalation suspension) was approved for the treatment of lung disease caused by Mycobacterium avium complex (MAC) bacteria in a limited population of patients with the disease who do not respond to conventional treatment. Arikayce is manufactured by Insmed, Inc.There are steps that affected individuals can take to lessen the chance of re-infection from the environment including the avoidance of hot-tubs, the avoidance of using tap water in humidifiers and CPAP machines, taking care in regard to environmental exposure to tap water and soil, and the use of specialized filtration systems in household plumbing. Since it is unknown whether individuals acquire NTM through inhalation (for example, from the shower spray) or from ingestion of tap water and subsequent reflux and aspiration of NTM-infected water into the lungs, consideration may be given to minimizing time spent in the shower and to boiling tap water prior to drinking.
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Nontuberculous Mycobacterial Lung Disease
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Overview of Noonan Syndrome
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Noonan syndrome is a genetic disorder that is typically evident at birth (congenital). The disorder is characterized by a wide spectrum of symptoms and physical features that vary greatly in range and severity. In many affected individuals, associated abnormalities include a distinctive facial appearance; a broad or webbed neck; a low posterior hairline; a typical chest deformity and short stature. Characteristic features of the head and facial (craniofacial) area may include widely set eyes (ocular hypertelorism); skin folds that may cover the eyes' inner corners (epicanthal folds); drooping of the upper eyelids (ptosis); a small jaw (micrognathia); a depressed nasal root; a short nose with broad base; and low-set, posteriorly rotated ears (pinnae). Distinctive skeletal malformations are also typically present, such as abnormalities of the breastbone (sternum), curvature of the spine (kyphosis and/or scoliosis), and outward deviation of the elbows (cubitus valgus). Many infants with Noonan syndrome also have heart (cardiac) defects, such as obstruction of proper blood flow from the lower right chamber of the heart to the lungs (pulmonary valvular stenosis) and thickening of the ventricular heart muscle (hypertrophic cardiomyopathy). Additional abnormalities may include malformations of certain blood and lymph vessels, blood clotting and platelet deficiencies, learning difficulties or mild intellectual disability, failure of the testes to descend into the scrotum (cryptorchidism) by the first year of life in affected males, and/or other symptoms and findings.In the majority of cases Noonan syndrome is an autosomal dominant genetic disorder caused by abnormalities (mutations) in more than eight genes. The five most commonly involved genes are: PTPN11 (50%), SOS1 (10-13%), RAF1 (5%), RIT1 (5%), and KRAS (less than 5%). Fewer individuals have a mutation in NRAS, BRAF, MEK2, RRAS, RASA2, A2ML1, and SOS2. Noonan-like disorders are found in association with mutations in SHOC2 and CBL. Noonan syndrome caused by pathogenic variants in LZTR1 can be inherited in either an autosomal dominant or an autosomal recessive manner.
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Overview of Noonan Syndrome. Noonan syndrome is a genetic disorder that is typically evident at birth (congenital). The disorder is characterized by a wide spectrum of symptoms and physical features that vary greatly in range and severity. In many affected individuals, associated abnormalities include a distinctive facial appearance; a broad or webbed neck; a low posterior hairline; a typical chest deformity and short stature. Characteristic features of the head and facial (craniofacial) area may include widely set eyes (ocular hypertelorism); skin folds that may cover the eyes' inner corners (epicanthal folds); drooping of the upper eyelids (ptosis); a small jaw (micrognathia); a depressed nasal root; a short nose with broad base; and low-set, posteriorly rotated ears (pinnae). Distinctive skeletal malformations are also typically present, such as abnormalities of the breastbone (sternum), curvature of the spine (kyphosis and/or scoliosis), and outward deviation of the elbows (cubitus valgus). Many infants with Noonan syndrome also have heart (cardiac) defects, such as obstruction of proper blood flow from the lower right chamber of the heart to the lungs (pulmonary valvular stenosis) and thickening of the ventricular heart muscle (hypertrophic cardiomyopathy). Additional abnormalities may include malformations of certain blood and lymph vessels, blood clotting and platelet deficiencies, learning difficulties or mild intellectual disability, failure of the testes to descend into the scrotum (cryptorchidism) by the first year of life in affected males, and/or other symptoms and findings.In the majority of cases Noonan syndrome is an autosomal dominant genetic disorder caused by abnormalities (mutations) in more than eight genes. The five most commonly involved genes are: PTPN11 (50%), SOS1 (10-13%), RAF1 (5%), RIT1 (5%), and KRAS (less than 5%). Fewer individuals have a mutation in NRAS, BRAF, MEK2, RRAS, RASA2, A2ML1, and SOS2. Noonan-like disorders are found in association with mutations in SHOC2 and CBL. Noonan syndrome caused by pathogenic variants in LZTR1 can be inherited in either an autosomal dominant or an autosomal recessive manner.
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Noonan Syndrome
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Symptoms of Noonan Syndrome
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Individuals with Noonan syndrome have associated symptoms and physical findings that vary greatly in range and severity from person to person. Some affected individuals have only minor facial abnormalities; others may have the majority of symptoms and findings associated with the disorder, such as distinctive features of the head and facial (craniofacial) area, a broad or webbed neck, short stature, skeletal malformations, congenital heart defects, malformations of certain blood and lymph vessels, blood clotting and platelet deficiencies, attention issues, mild intellectual disability, and/or other abnormalities.Most infants with Noonan syndrome have characteristic craniofacial features. In many cases, the head appears relatively large. Affected infants may have several findings affecting the eyes including widely set eyes (ocular hypertelorism) that are unusually prominent; drooping of the upper eyelids (ptosis) and/or unusually thick, “hooded” eyelids; an eye that turns in or turns out (strabismus); downwardly slanting eyelids (palpebral fissures); skin folds (epicanthal folds) that may cover the eyes’ inner corners; and/or strikingly blue or bluish green colored portions of the eyes (irides).Many infants with Noonan syndrome also have additional craniofacial features. These may include an unusually deep vertical groove in the middle of the upper lip (philtrum); and/or a small chin. Affected infants may also have a small jaw (micrognathia); crowding of the lower teeth, low-set, posteriorly rotated external ears (pinnae); and/or distinctive abnormalities of the nose including a depressed nasal root, a wide base, and a rounded (bulbous) tip. Affected infants also often have excessive skin in the neck area (nuchal skin) and a low hairline at the back of the neck (low posterior hairline).The facial features of individuals with Noonan syndrome tend to change in a predictable manner with age. During later childhood, the face may appear relatively coarse and begin to appear more triangular in shape; in addition, the neck lengthens, causing the webbing of the neck (pterygium colli) to appear more pronounced and/or the large, triangular muscles of the upper back and shoulders (trapezius) to appear more prominent. During adolescence, the nasal bridge is thinner and higher, with a “pinched” root and wide base, and the eyes appear less prominent. During older adulthood, characteristic features may include an abnormally high hairline on the forehead; wrinkled, unusually transparent skin; and unusually prominent folds between the nose and the lips (nasolabial folds). In addition, individuals with Noonan syndrome may have wispy scalp hair during infancy that typically becomes more wooly or curly during later childhood or adolescence. Many affected individuals also have distinctive eyebrows that appear highly arched and/or “diamond shaped.”Many newborns with Noonan syndrome attain normal birth weight. However, in some newborns, the birth weight may be increased due to abnormal accumulations of fluid between layers of tissue under the skin (subcutaneous edema). For example, swelling of the back of the hands and top of the feet (peripheral lymphedema) is common in newborns with Noonan syndrome; in such cases, edema affecting the fingers may result in an increased number of whorls on the fingertips (abnormal dermatoglyphics). Such edema may be due to improper or late development of certain lymph vessels (congenital lymphatic dysplasia).Some infants with Noonan syndrome may experience feeding problems and fail to grow and gain weight at the expected rate (failure to thrive). In addition, children with the disorder tend to be short for their age, and approximately 20 percent experience delayed bone maturation. Most affected children have a relatively normal growth rate (velocity) before puberty; however, the growth spurt that is typically experienced during puberty may be reduced or absent in some adolescents. Average adult height is approximately five feet, four inches (162.5 cm) in males with Noonan syndrome and approximately five feet (152.7 cm) in females with the disorder. Individuals with the disorder typically reach their adult height by the end of the second decade of life. Growth patterns are influenced by the molecular genetic cause of NS. People with NS harboring mutations in RAF1 and SHOC2 are shorter than other genotypes, whereas those with SOS1 and BRAF mutations have more preserved growth.Some males and females with Noonan syndrome may also experience abnormalities in the development of secondary sexual characteristics. In approximately 60 to 75 percent of males with Noonan syndrome, one or both testes fail to descend into the scrotum (unilateral or bilateral cryptorchidism) before birth or during the first year of life. If not corrected surgically, male reproductive cells (spermatozoa) may fail to develop properly within the testes (deficient spermatogenesis), and some affected males may experience infertility (sterility). Other males with Noonan syndrome may experience a delayed yet normal acquisition of secondary sexual characteristics (e.g., increased growth of the testes, scrotum, and penis; appearance of facial and pubic hair; etc.). According to the medical literature, puberty may be delayed an average of two years in such cases. Other males with Noonan syndrome may experience normal pubertal development. Even in the absence of a history of cryptorchidism, adult males appear to have decreased fertility. In females with the disorder, the acquisition of secondary sexual characteristics (e.g., the appearance of pubic hair, breast development, and menstruation) may be mildly delayed but is more often normal. Most females with Noonan syndrome have normal fertility.Many individuals with Noonan syndrome also have skeletal abnormalities. Approximately 70 percent of affected children have a distinctive chest malformation characterized by abnormal protrusion of the upper (superior) portion of the breastbone (sternum) and/or abnormal depression of the lower (inferior) portion of the breastbone (pectus carinatum and/or pectus excavatum, respectively). In addition, the chest may be unusually broad, and the nipples may appear low set. Some affected individuals may have additional skeletal malformations including rounded shoulders; outward deviation of the elbows (cubitus valgus); abnormally short fingers (brachydactyly) with blunt fingertips; and/or front-to-back and/or sideways curvature of the spine (kyphoscoliosis and/or scoliosis respectively). Children with NS have a significantly lower total body bone mineral density when evaluated by DEXA scan putting them at risk for fractures. There is also an increased incidence of serious cervical spine disorders, including cervical stenosis, Arnold-Chiari malformation, and syringomyelia.Approximately two thirds of infants with Noonan syndrome also have heart (cardiac) abnormalities at birth (congenital heart defects). In about half of such cases, affected infants have obstruction of the normal flow of blood from the lower right chamber (ventricle) of the heart to the lungs (pulmonary stenosis). In those with pulmonary stenosis, the heart must work harder to send blood to the lungs for oxygenation. The symptoms resulting from pulmonary stenosis will vary, depending on the severity of the stenosis and any other associated findings. In some severe cases, an affected infant’s heart may begin to enlarge immediately after birth (i.e., upon initiation of breathing in the newborn). In such cases, the heart may be unable to pump blood effectively (heart failure) to the lungs and throughout the body. Associated symptoms and findings may include bluish discoloration of the skin and mucous membranes (cyanosis) due to abnormally low levels of circulating oxygen (hypoxia), breathlessness, swelling of the abdomen, feeding difficulties, and/or other abnormalities. Potentially life-threatening complications may result without appropriate treatment. In less severe cases of pulmonary stenosis, symptoms may not become apparent until later childhood. Such symptoms may include breathlessness, easy fatigability, and/or other abnormalities. In other cases, pulmonary stenosis may be mild and symptoms may not occur (asymptomatic).In approximately 30 percent of infants with Noonan syndrome, there may be an abnormal opening in the fibrous partition (septum) that divides the two upper chambers (atria) of the heart (atrial septal defects). Another 20 percent of those with congenital heart defects may have enlargement (hypertrophy) of the partition that separates the left and right ventricles (interventricular septum) and, in some patients, of the left ventricular wall (hypertrophic cardiomyopathy). Less often, other congenital heart defects may be present (e.g., ventricular septal defects, patent ductus arteriosus, atrioventricular canal defect). According to the medical literature, most individuals with Noonan syndrome have a single heart defect. However, some affected individuals may have pulmonary stenosis in combination with either an atrial septal defect or hypertrophic cardiomyopathy, for example.Atrial septal defects occur in approximately 30 percent of those with Noonan syndrome who have congenital heart defects. In the normal heart, a small opening is present between the two atria (foramen ovale) at birth. Shortly after birth, the atrial septum gradually closes and covers this opening. In infants with atrial septal defects, however, the atrial septum may not close properly or may be malformed during fetal development. As a result, the opening between the atria persists long after it should be closed, causing an increase in the workload on the right side of the heart and associated enlargement of the right ventricle, the right atrium, and the main pulmonary artery. The size, location, and nature of an atrial septal defect and any associated abnormalities determine the severity of symptoms.Many children with atrial septal defects have no symptoms. However, in some cases, associated symptoms may include poor weight gain, mild growth delays, and an increased susceptibility to repeated respiratory infections (e.g., pneumonia) and bacterial infections of the lining of the heart (endocarditis) and the heart valves. In rare cases, severely affected children may also experience breathlessness, easy fatigability with exercise, heart failure, and/or irregular heartbeats (arrhythmias).Approximately 20 percent of affected infants with heart defects experience hypertrophic cardiomyopathy. In most cases, such abnormal enlargement (hypertrophy) affects a localized area of the fibrous partition separating the left and right ventricles (anterior interventricular septal hypertrophy); in other cases, the entire septum and the wall of the left ventricle may be affected. Hypertrophic cardiomyopathy may cause reduced cardiac output. Associated symptoms and findings may include fatigue, brief fainting episodes (syncope) during exertion or exercise, and heart failure. Without appropriate treatment, life-threatening complications may result in some cases. Patients with NS with HCM have a worse risk profile at presentation compared with other children with HCM, resulting in significant early mortality (22% at 1 year). Rarely, hypertrophic cardiomyopathy can also develop later in life.Some infants with Noonan syndrome may also have malformations of certain blood vessels, such as the presence of abnormal passages (fistulas) involving the arteries that supply blood to heart muscle (coronary arteries). The coronary arteries may also be dilated (ectatic) and/or curved (tortuous) in contour. In addition, some affected infants may have malformations of certain lymph vessels (congenital lymphatic dysplasia). Lymph, a bodily fluid that contains white blood cells (lymphocytes), fats, and proteins, accumulates outside blood vessels in spaces between cells in tissues and flows back into the bloodstream via lymph vessels. In some infants with Noonan syndrome, lymphatic system malformations may include underdevelopment (hypoplasia) of certain channels within lymph tissue through which lymph enters lymph vessels; abnormal widening (dilatation) of lymph vessels within the lungs (pulmonary lymphangiectasis); and/or widening (dilatation) of intestinal lymph vessels (intestinal lymphangiectasis), particularly the vessels that transport chyle, the milky fluid that is absorbed from food during digestion. Intestinal lymphangiectasis may result in loss of protein during intestinal absorption (protein-losing enteropathy), abnormally low levels of certain circulating white blood cells (lymphopenia), and loose, foul smelling stools that contain an excessive amount of fat (steatorrhea). During the teenage years, some individuals with Noonan syndrome develop swelling of the lower extremities (lymphedema).In utero, some affected infants may have an abnormal cystic swelling beneath the skin in the neck area (cystic hygroma). There may, in addition, may more amniotic fluid around the baby than usual (polyhydramnios). Due to lymphatic system malformations and associated obstruction of normal lymph flow into the bloodstream, affected infants may have an abnormal accumulation of lymph fluid in certain tissues (lymphedema). In some cases, edema may affect tissues and cavities throughout the body (hydrops fetalis).Approximately 20 to 33 percent of individuals with Noonan syndrome also have various blood clotting defects (coagulation factor deficiencies), low levels of circulating platelets in the blood (thrombocytopenia), and/or improper function of blood platelets. Platelets are specialized blood cells that help prevent and stop bleeding. Affected individuals may have low levels of certain substances in the blood (coagulation factors) that are essential in the normal blood clotting process, a complex process that is necessary to stop bleeding (hemostatis). In individuals with Noonan syndrome, such deficiencies may include low levels of coagulation factor XI and/or, in some cases, factors XII and/or VIII. Some affected individuals may have von Willebrand disease; an inherited condition characterized by deficiency of coagulation factor VIII, prolonged bleeding time, and impaired adhesion of platelets. In addition, in rare cases, affected individuals’ urine may have an abnormally “fishy” smell (trimethylaminuria), a finding that may be associated with platelet dysfunction. Due to coagulation factor deficiencies, platelet dysfunction, and/or thrombocytopenia, affected individuals may have a history of abnormal and easy bruising and bleeding. They should avoid aspirin-containing medications.Some individuals with Noonan syndrome may also abnormal skin discolorations. In approximately one quarter of affected individuals, pigmented moles (nevi) may be present. In rare cases, there may be pale tan or light brown patches (café-au-lait spots) and/or black, darkish tan or brown “freckle-like” spots (lentigines) on the skin.Up to 35 percent of individuals with Noonan syndrome may also have mild intellectual disability. However, many affected individuals have a normal I.Q. (intelligence quotient). In addition, affected individuals may experience abnormal delays in the acquisition of skills requiring the coordination of mental and muscular activity (psychomotor retardation), learning disabilities, and language delays that may potentially be due to hypotonia, difficulties speaking and/or, in some individuals, mild hearing loss. Inattention and challenges with executive functioning have also been reported. A lowered speed of information processing and relatively intact functioning in other cognitive domains characterizes the cognitive profile of many adults with NS.
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Symptoms of Noonan Syndrome. Individuals with Noonan syndrome have associated symptoms and physical findings that vary greatly in range and severity from person to person. Some affected individuals have only minor facial abnormalities; others may have the majority of symptoms and findings associated with the disorder, such as distinctive features of the head and facial (craniofacial) area, a broad or webbed neck, short stature, skeletal malformations, congenital heart defects, malformations of certain blood and lymph vessels, blood clotting and platelet deficiencies, attention issues, mild intellectual disability, and/or other abnormalities.Most infants with Noonan syndrome have characteristic craniofacial features. In many cases, the head appears relatively large. Affected infants may have several findings affecting the eyes including widely set eyes (ocular hypertelorism) that are unusually prominent; drooping of the upper eyelids (ptosis) and/or unusually thick, “hooded” eyelids; an eye that turns in or turns out (strabismus); downwardly slanting eyelids (palpebral fissures); skin folds (epicanthal folds) that may cover the eyes’ inner corners; and/or strikingly blue or bluish green colored portions of the eyes (irides).Many infants with Noonan syndrome also have additional craniofacial features. These may include an unusually deep vertical groove in the middle of the upper lip (philtrum); and/or a small chin. Affected infants may also have a small jaw (micrognathia); crowding of the lower teeth, low-set, posteriorly rotated external ears (pinnae); and/or distinctive abnormalities of the nose including a depressed nasal root, a wide base, and a rounded (bulbous) tip. Affected infants also often have excessive skin in the neck area (nuchal skin) and a low hairline at the back of the neck (low posterior hairline).The facial features of individuals with Noonan syndrome tend to change in a predictable manner with age. During later childhood, the face may appear relatively coarse and begin to appear more triangular in shape; in addition, the neck lengthens, causing the webbing of the neck (pterygium colli) to appear more pronounced and/or the large, triangular muscles of the upper back and shoulders (trapezius) to appear more prominent. During adolescence, the nasal bridge is thinner and higher, with a “pinched” root and wide base, and the eyes appear less prominent. During older adulthood, characteristic features may include an abnormally high hairline on the forehead; wrinkled, unusually transparent skin; and unusually prominent folds between the nose and the lips (nasolabial folds). In addition, individuals with Noonan syndrome may have wispy scalp hair during infancy that typically becomes more wooly or curly during later childhood or adolescence. Many affected individuals also have distinctive eyebrows that appear highly arched and/or “diamond shaped.”Many newborns with Noonan syndrome attain normal birth weight. However, in some newborns, the birth weight may be increased due to abnormal accumulations of fluid between layers of tissue under the skin (subcutaneous edema). For example, swelling of the back of the hands and top of the feet (peripheral lymphedema) is common in newborns with Noonan syndrome; in such cases, edema affecting the fingers may result in an increased number of whorls on the fingertips (abnormal dermatoglyphics). Such edema may be due to improper or late development of certain lymph vessels (congenital lymphatic dysplasia).Some infants with Noonan syndrome may experience feeding problems and fail to grow and gain weight at the expected rate (failure to thrive). In addition, children with the disorder tend to be short for their age, and approximately 20 percent experience delayed bone maturation. Most affected children have a relatively normal growth rate (velocity) before puberty; however, the growth spurt that is typically experienced during puberty may be reduced or absent in some adolescents. Average adult height is approximately five feet, four inches (162.5 cm) in males with Noonan syndrome and approximately five feet (152.7 cm) in females with the disorder. Individuals with the disorder typically reach their adult height by the end of the second decade of life. Growth patterns are influenced by the molecular genetic cause of NS. People with NS harboring mutations in RAF1 and SHOC2 are shorter than other genotypes, whereas those with SOS1 and BRAF mutations have more preserved growth.Some males and females with Noonan syndrome may also experience abnormalities in the development of secondary sexual characteristics. In approximately 60 to 75 percent of males with Noonan syndrome, one or both testes fail to descend into the scrotum (unilateral or bilateral cryptorchidism) before birth or during the first year of life. If not corrected surgically, male reproductive cells (spermatozoa) may fail to develop properly within the testes (deficient spermatogenesis), and some affected males may experience infertility (sterility). Other males with Noonan syndrome may experience a delayed yet normal acquisition of secondary sexual characteristics (e.g., increased growth of the testes, scrotum, and penis; appearance of facial and pubic hair; etc.). According to the medical literature, puberty may be delayed an average of two years in such cases. Other males with Noonan syndrome may experience normal pubertal development. Even in the absence of a history of cryptorchidism, adult males appear to have decreased fertility. In females with the disorder, the acquisition of secondary sexual characteristics (e.g., the appearance of pubic hair, breast development, and menstruation) may be mildly delayed but is more often normal. Most females with Noonan syndrome have normal fertility.Many individuals with Noonan syndrome also have skeletal abnormalities. Approximately 70 percent of affected children have a distinctive chest malformation characterized by abnormal protrusion of the upper (superior) portion of the breastbone (sternum) and/or abnormal depression of the lower (inferior) portion of the breastbone (pectus carinatum and/or pectus excavatum, respectively). In addition, the chest may be unusually broad, and the nipples may appear low set. Some affected individuals may have additional skeletal malformations including rounded shoulders; outward deviation of the elbows (cubitus valgus); abnormally short fingers (brachydactyly) with blunt fingertips; and/or front-to-back and/or sideways curvature of the spine (kyphoscoliosis and/or scoliosis respectively). Children with NS have a significantly lower total body bone mineral density when evaluated by DEXA scan putting them at risk for fractures. There is also an increased incidence of serious cervical spine disorders, including cervical stenosis, Arnold-Chiari malformation, and syringomyelia.Approximately two thirds of infants with Noonan syndrome also have heart (cardiac) abnormalities at birth (congenital heart defects). In about half of such cases, affected infants have obstruction of the normal flow of blood from the lower right chamber (ventricle) of the heart to the lungs (pulmonary stenosis). In those with pulmonary stenosis, the heart must work harder to send blood to the lungs for oxygenation. The symptoms resulting from pulmonary stenosis will vary, depending on the severity of the stenosis and any other associated findings. In some severe cases, an affected infant’s heart may begin to enlarge immediately after birth (i.e., upon initiation of breathing in the newborn). In such cases, the heart may be unable to pump blood effectively (heart failure) to the lungs and throughout the body. Associated symptoms and findings may include bluish discoloration of the skin and mucous membranes (cyanosis) due to abnormally low levels of circulating oxygen (hypoxia), breathlessness, swelling of the abdomen, feeding difficulties, and/or other abnormalities. Potentially life-threatening complications may result without appropriate treatment. In less severe cases of pulmonary stenosis, symptoms may not become apparent until later childhood. Such symptoms may include breathlessness, easy fatigability, and/or other abnormalities. In other cases, pulmonary stenosis may be mild and symptoms may not occur (asymptomatic).In approximately 30 percent of infants with Noonan syndrome, there may be an abnormal opening in the fibrous partition (septum) that divides the two upper chambers (atria) of the heart (atrial septal defects). Another 20 percent of those with congenital heart defects may have enlargement (hypertrophy) of the partition that separates the left and right ventricles (interventricular septum) and, in some patients, of the left ventricular wall (hypertrophic cardiomyopathy). Less often, other congenital heart defects may be present (e.g., ventricular septal defects, patent ductus arteriosus, atrioventricular canal defect). According to the medical literature, most individuals with Noonan syndrome have a single heart defect. However, some affected individuals may have pulmonary stenosis in combination with either an atrial septal defect or hypertrophic cardiomyopathy, for example.Atrial septal defects occur in approximately 30 percent of those with Noonan syndrome who have congenital heart defects. In the normal heart, a small opening is present between the two atria (foramen ovale) at birth. Shortly after birth, the atrial septum gradually closes and covers this opening. In infants with atrial septal defects, however, the atrial septum may not close properly or may be malformed during fetal development. As a result, the opening between the atria persists long after it should be closed, causing an increase in the workload on the right side of the heart and associated enlargement of the right ventricle, the right atrium, and the main pulmonary artery. The size, location, and nature of an atrial septal defect and any associated abnormalities determine the severity of symptoms.Many children with atrial septal defects have no symptoms. However, in some cases, associated symptoms may include poor weight gain, mild growth delays, and an increased susceptibility to repeated respiratory infections (e.g., pneumonia) and bacterial infections of the lining of the heart (endocarditis) and the heart valves. In rare cases, severely affected children may also experience breathlessness, easy fatigability with exercise, heart failure, and/or irregular heartbeats (arrhythmias).Approximately 20 percent of affected infants with heart defects experience hypertrophic cardiomyopathy. In most cases, such abnormal enlargement (hypertrophy) affects a localized area of the fibrous partition separating the left and right ventricles (anterior interventricular septal hypertrophy); in other cases, the entire septum and the wall of the left ventricle may be affected. Hypertrophic cardiomyopathy may cause reduced cardiac output. Associated symptoms and findings may include fatigue, brief fainting episodes (syncope) during exertion or exercise, and heart failure. Without appropriate treatment, life-threatening complications may result in some cases. Patients with NS with HCM have a worse risk profile at presentation compared with other children with HCM, resulting in significant early mortality (22% at 1 year). Rarely, hypertrophic cardiomyopathy can also develop later in life.Some infants with Noonan syndrome may also have malformations of certain blood vessels, such as the presence of abnormal passages (fistulas) involving the arteries that supply blood to heart muscle (coronary arteries). The coronary arteries may also be dilated (ectatic) and/or curved (tortuous) in contour. In addition, some affected infants may have malformations of certain lymph vessels (congenital lymphatic dysplasia). Lymph, a bodily fluid that contains white blood cells (lymphocytes), fats, and proteins, accumulates outside blood vessels in spaces between cells in tissues and flows back into the bloodstream via lymph vessels. In some infants with Noonan syndrome, lymphatic system malformations may include underdevelopment (hypoplasia) of certain channels within lymph tissue through which lymph enters lymph vessels; abnormal widening (dilatation) of lymph vessels within the lungs (pulmonary lymphangiectasis); and/or widening (dilatation) of intestinal lymph vessels (intestinal lymphangiectasis), particularly the vessels that transport chyle, the milky fluid that is absorbed from food during digestion. Intestinal lymphangiectasis may result in loss of protein during intestinal absorption (protein-losing enteropathy), abnormally low levels of certain circulating white blood cells (lymphopenia), and loose, foul smelling stools that contain an excessive amount of fat (steatorrhea). During the teenage years, some individuals with Noonan syndrome develop swelling of the lower extremities (lymphedema).In utero, some affected infants may have an abnormal cystic swelling beneath the skin in the neck area (cystic hygroma). There may, in addition, may more amniotic fluid around the baby than usual (polyhydramnios). Due to lymphatic system malformations and associated obstruction of normal lymph flow into the bloodstream, affected infants may have an abnormal accumulation of lymph fluid in certain tissues (lymphedema). In some cases, edema may affect tissues and cavities throughout the body (hydrops fetalis).Approximately 20 to 33 percent of individuals with Noonan syndrome also have various blood clotting defects (coagulation factor deficiencies), low levels of circulating platelets in the blood (thrombocytopenia), and/or improper function of blood platelets. Platelets are specialized blood cells that help prevent and stop bleeding. Affected individuals may have low levels of certain substances in the blood (coagulation factors) that are essential in the normal blood clotting process, a complex process that is necessary to stop bleeding (hemostatis). In individuals with Noonan syndrome, such deficiencies may include low levels of coagulation factor XI and/or, in some cases, factors XII and/or VIII. Some affected individuals may have von Willebrand disease; an inherited condition characterized by deficiency of coagulation factor VIII, prolonged bleeding time, and impaired adhesion of platelets. In addition, in rare cases, affected individuals’ urine may have an abnormally “fishy” smell (trimethylaminuria), a finding that may be associated with platelet dysfunction. Due to coagulation factor deficiencies, platelet dysfunction, and/or thrombocytopenia, affected individuals may have a history of abnormal and easy bruising and bleeding. They should avoid aspirin-containing medications.Some individuals with Noonan syndrome may also abnormal skin discolorations. In approximately one quarter of affected individuals, pigmented moles (nevi) may be present. In rare cases, there may be pale tan or light brown patches (café-au-lait spots) and/or black, darkish tan or brown “freckle-like” spots (lentigines) on the skin.Up to 35 percent of individuals with Noonan syndrome may also have mild intellectual disability. However, many affected individuals have a normal I.Q. (intelligence quotient). In addition, affected individuals may experience abnormal delays in the acquisition of skills requiring the coordination of mental and muscular activity (psychomotor retardation), learning disabilities, and language delays that may potentially be due to hypotonia, difficulties speaking and/or, in some individuals, mild hearing loss. Inattention and challenges with executive functioning have also been reported. A lowered speed of information processing and relatively intact functioning in other cognitive domains characterizes the cognitive profile of many adults with NS.
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Noonan Syndrome
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Causes of Noonan Syndrome
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Noonan syndrome is most often an autosomal dominant genetic disorder caused by abnormalities (mutations) in several different genes, the main ones being: PTPN11, KRAS, SOS1 RIT1 and RAF1. PTPN11 mutations have been found in approximately 50% of affected individuals; KRAS mutations have been found in fewer than 5% of those affected; SOS1 mutations have been seen in approximately 13% of people with Noonan syndrome; RIT1 mutations have been seen in approximately 5% of people with Noonan syndrome, and RAF1 mutations are observed in 5% of those affected. Additional genes associated with Noonan syndrome have been identified in fewer cases: NRAS, BRAF, MEK2, RRAS, RASA2, A2ML1, and SOS2. Two conditions with overlap are newly described in association with mutations in SHOC2 and CBL. Noonan syndrome caused by pathogenic variants in LZTR1 can be inherited in either an autosomal dominant or an autosomal recessive manner.Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. Approximately 50% of affected individuals have an affected parent. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.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 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25 percent. The risk is the same for males and females.
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Causes of Noonan Syndrome. Noonan syndrome is most often an autosomal dominant genetic disorder caused by abnormalities (mutations) in several different genes, the main ones being: PTPN11, KRAS, SOS1 RIT1 and RAF1. PTPN11 mutations have been found in approximately 50% of affected individuals; KRAS mutations have been found in fewer than 5% of those affected; SOS1 mutations have been seen in approximately 13% of people with Noonan syndrome; RIT1 mutations have been seen in approximately 5% of people with Noonan syndrome, and RAF1 mutations are observed in 5% of those affected. Additional genes associated with Noonan syndrome have been identified in fewer cases: NRAS, BRAF, MEK2, RRAS, RASA2, A2ML1, and SOS2. Two conditions with overlap are newly described in association with mutations in SHOC2 and CBL. Noonan syndrome caused by pathogenic variants in LZTR1 can be inherited in either an autosomal dominant or an autosomal recessive manner.Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. Approximately 50% of affected individuals have an affected parent. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.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 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25 percent. The risk is the same for males and females.
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Noonan Syndrome
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Affects of Noonan Syndrome
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Noonan syndrome appears to affect more males than females and is thought to affect approximately one in 1,000 to one in 2,500 people. However, other reports indicate that the disorder may affect more than one in 1,000 newborns in the general population. Since Noonan syndrome was originally reported in 1883 (O. Kobylinski) and more thoroughly described in 1963 (J.A. Noonan and D.A. Ehmke), more than 500 patients shave been discussed in the medical literature. Because Noonan syndrome is extremely variable and therefore may be under- or misdiagnosed, it may be difficult to determine the true frequency of the disorder in the general population.
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Affects of Noonan Syndrome. Noonan syndrome appears to affect more males than females and is thought to affect approximately one in 1,000 to one in 2,500 people. However, other reports indicate that the disorder may affect more than one in 1,000 newborns in the general population. Since Noonan syndrome was originally reported in 1883 (O. Kobylinski) and more thoroughly described in 1963 (J.A. Noonan and D.A. Ehmke), more than 500 patients shave been discussed in the medical literature. Because Noonan syndrome is extremely variable and therefore may be under- or misdiagnosed, it may be difficult to determine the true frequency of the disorder in the general population.
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Noonan Syndrome
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Related disorders of Noonan Syndrome
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Symptoms of the following disorders may be similar to those of Noonan syndrome. Comparisons may be useful for a differential diagnosis:Cardiofaciocutaneous (CFC) syndrome, an extremely rare genetic disorder, is characterized by a distinctive facial appearance similar to that seen in children with Noonan syndrome. Additional primary characteristics may include unusually sparse, brittle, curly hair; skin abnormalities; heart malformations that are present at birth (congenital heart defects); growth delays; and moderate to severe intellectual disability. Individuals with cardiofaciocutaneous syndrome typically have an unusually large head (macrocephaly), a prominent forehead, and abnormal narrowing of both sides of the forehead (bitemporal constriction); a short, upturned nose with a depressed nasal root; eye findings including downwardly slanting eyelids (palpebral fissures), widely spaced eyes (ocular hypertelorism), and/or drooping of the upper eyelids (ptosis). In most patients, congenital heart defects are also present, particularly obstruction of the normal flow of blood from the lower right chamber (ventricle) of the heart to the lungs (pulmonary valve stenosis) and/or an abnormal opening in the fibrous partition (septum) that divides the two upper chambers (atria) of the heart (atrial septal defects). Thickening of the heart muscle (hypertrophic cardiomyopathy) can also be found. In addition, most individuals with the disorder experience growth delays, moderate to severe intellectual disability, and abnormal delays in the acquisition of skills requiring the coordination of mental and muscular activity (psychomotor retardation). Cardiofaciocutaneous syndrome is caused by mutations in several genes: BRAF, MEK1 and 2, and KRAS. (For more information choose “CFC Syndrome” as your search term in the Rare Disease Database.)Turner syndrome is a chromosomal disorder that has some similarities to Noonan syndrome. In fact, because some individuals with Noonan syndrome may superficially resemble those with Turner syndrome (due to certain findings that may be associated with both disorders, such as short stature, webbed neck, etc.), Noonan syndrome has in the past been referred to as “male Turner syndrome,” “female pseudo-Turner syndrome,” or “Turner phenotype with normal chromosomes”. However, there are many important differences between the two disorders. Noonan syndrome affects both males and females, and there is a normal chromosomal makeup (karyotype). Only females are affected by Turner syndrome, which is characterized by abnormalities affecting the X chromosome.Females with Turner syndrome may have a short, webbed neck with a low posterior hairline; short stature; drooping of the upper eyelids (ptosis) and/or widely spaced eyes (ocular hypertelorism); widely spaced, inverted, and/or underdeveloped (hypoplastic) nipples; congenital heart defects, especially coarctation; and/or kidney abnormalities. In almost all cases, immature (streak) ovaries are present that cannot produce the female hormone estrogen. As a result, normal secondary sexual characteristics, such as the appearance of pubic hair, breast development, and menstruation (primary amenorrhea) fail to develop during puberty. Almost all affected females are infertile. Although intellectual abilities are usually normal, some individuals may experience difficulties with visual-spatial relationships (e.g., right-left disorientation). (For more information on Turner syndrome, please choose “Turner” as your search term in the Rare Disease Database.)Costello syndrome is a rare genetic disorder characterized by growth delay after birth (postnatal), leading to short stature; a distinctive facial appearance; excessive, loose skin on the neck, palms of the hands, fingers, and soles of the feet; development of benign (non-cancerous) growths (papillomata) around the mouth (perioral), nostrils (nares) and anus; and mild to moderate intellectual disability. Newborns with the disorder may have an abnormal accumulation of lymph fluid in tissues throughout the body (generalized lymphedema) and high birth weight. In addition, affected infants often have severe feeding and swallowing difficulties and may fail to grow and gain weight at the expected rate (failure to thrive).
Characteristic craniofacial abnormalities associated with the disorder may include an unusually large head (macrocephaly) and wide forehead; a large, depressed nasal root; abnormally wide nostrils; skin folds (epicanthal folds) that may cover the eyes’ inner corners; low-set ears with large, thick lobes; and/or unusually thick lips. Other physical features may include the development of dry, hardened, thickened skin on the palms of the hands and the soles of the feet (palmoplantar hyperkeratosis) and/or abnormally deep creases on the palms and soles. Many affected individuals may also have congenital heart defects similar to those found in Noonan and CFC syndromes. More distinctive is the presence of unusual and chaotic rhythms in about a third. Most cases of Costello syndrome occur sporadically, with no family history of the disorder, and are caused by mutations in HRAS. (For more information on this disorder, choose “Costello” as your search term in the Rare Disease Database.)Multiple giant cell lesions are abnormal cysts (lesions) involving certain large cells (giant cells) within bone and soft tissue of the jaw. They are found in Noonan syndrome and other overlapping disorders such as CFC syndrome and are usually diagnosed in the first two decades.Neurofibromatosis-Noonan syndrome is characterized by the occurrence of neurofibromatosis type I in association with some manifestations of Noonan syndrome. Associated symptoms and findings may include multiple benign tumors of the nerves and skin, short stature, webbing of the neck (pterygium colli), muscle weakness, and/or learning disabilities. Affected individuals may also have certain craniofacial abnormalities associated with Noonan syndrome including drooping of the upper eyelids (ptosis), low-set ears, and/or unusually prominent folds between the nose and the lips (nasolabial folds). In addition, congenital heart defects often seen in Noonan syndrome may be present, such as obstruction of the normal outflow of blood from the lower right chamber (ventricle) of the heart (pulmonary stenosis) and/or an abnormal opening in the fibrous partition (septum) between the upper chambers (atria) of the heart (atrial septal defect). Neurofibromatosis-Noonan syndrome can be due to the chance occurrence of both disorders in the same individuals, can be a phenotype of neurofibromatosis type I, or can be a separate disease entity caused by mutations in the NF1 gene but without some of the characteristic features of NF1.Noonan syndrome with multiple lentigines (NSML, formerly known as LEOPARD syndrome) is a rare inherited disorder characterized by abnormalities of the skin, the structure and function of the heart, the inner ear, the head and facial (craniofacial) area, and/or the genitals. In individuals with the disorder, the range and severity of symptoms and physical characteristics may vary from person to person.Some of the most common features include lentigines (multiple black or dark brown spots on the skin); electrocardiographic conduction defects (abnormalities of the electrical activity and the coordination of proper contractions of the heart); hypertrophic cardiomyopathy, ocular hypertelorism (widely-spaced eyes); pulmonary stenosis (obstruction of the normal outflow of blood from the right ventricle of the heart); abnormalities of the genitals (in boys usually undescended testes (cryptorchidism); slowed growth resulting in short stature, delayed development; and deafness or hearing loss due to malfunction of the inner ear (sensorineural deafness). NSML is an autosomal dominant genetic disorder caused by a mutation in one of two genes: PTPN11 or RAF1. (For more information choose “LEOPARD Syndrome” as your search term in the Rare Disease Database.)
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Related disorders of Noonan Syndrome. Symptoms of the following disorders may be similar to those of Noonan syndrome. Comparisons may be useful for a differential diagnosis:Cardiofaciocutaneous (CFC) syndrome, an extremely rare genetic disorder, is characterized by a distinctive facial appearance similar to that seen in children with Noonan syndrome. Additional primary characteristics may include unusually sparse, brittle, curly hair; skin abnormalities; heart malformations that are present at birth (congenital heart defects); growth delays; and moderate to severe intellectual disability. Individuals with cardiofaciocutaneous syndrome typically have an unusually large head (macrocephaly), a prominent forehead, and abnormal narrowing of both sides of the forehead (bitemporal constriction); a short, upturned nose with a depressed nasal root; eye findings including downwardly slanting eyelids (palpebral fissures), widely spaced eyes (ocular hypertelorism), and/or drooping of the upper eyelids (ptosis). In most patients, congenital heart defects are also present, particularly obstruction of the normal flow of blood from the lower right chamber (ventricle) of the heart to the lungs (pulmonary valve stenosis) and/or an abnormal opening in the fibrous partition (septum) that divides the two upper chambers (atria) of the heart (atrial septal defects). Thickening of the heart muscle (hypertrophic cardiomyopathy) can also be found. In addition, most individuals with the disorder experience growth delays, moderate to severe intellectual disability, and abnormal delays in the acquisition of skills requiring the coordination of mental and muscular activity (psychomotor retardation). Cardiofaciocutaneous syndrome is caused by mutations in several genes: BRAF, MEK1 and 2, and KRAS. (For more information choose “CFC Syndrome” as your search term in the Rare Disease Database.)Turner syndrome is a chromosomal disorder that has some similarities to Noonan syndrome. In fact, because some individuals with Noonan syndrome may superficially resemble those with Turner syndrome (due to certain findings that may be associated with both disorders, such as short stature, webbed neck, etc.), Noonan syndrome has in the past been referred to as “male Turner syndrome,” “female pseudo-Turner syndrome,” or “Turner phenotype with normal chromosomes”. However, there are many important differences between the two disorders. Noonan syndrome affects both males and females, and there is a normal chromosomal makeup (karyotype). Only females are affected by Turner syndrome, which is characterized by abnormalities affecting the X chromosome.Females with Turner syndrome may have a short, webbed neck with a low posterior hairline; short stature; drooping of the upper eyelids (ptosis) and/or widely spaced eyes (ocular hypertelorism); widely spaced, inverted, and/or underdeveloped (hypoplastic) nipples; congenital heart defects, especially coarctation; and/or kidney abnormalities. In almost all cases, immature (streak) ovaries are present that cannot produce the female hormone estrogen. As a result, normal secondary sexual characteristics, such as the appearance of pubic hair, breast development, and menstruation (primary amenorrhea) fail to develop during puberty. Almost all affected females are infertile. Although intellectual abilities are usually normal, some individuals may experience difficulties with visual-spatial relationships (e.g., right-left disorientation). (For more information on Turner syndrome, please choose “Turner” as your search term in the Rare Disease Database.)Costello syndrome is a rare genetic disorder characterized by growth delay after birth (postnatal), leading to short stature; a distinctive facial appearance; excessive, loose skin on the neck, palms of the hands, fingers, and soles of the feet; development of benign (non-cancerous) growths (papillomata) around the mouth (perioral), nostrils (nares) and anus; and mild to moderate intellectual disability. Newborns with the disorder may have an abnormal accumulation of lymph fluid in tissues throughout the body (generalized lymphedema) and high birth weight. In addition, affected infants often have severe feeding and swallowing difficulties and may fail to grow and gain weight at the expected rate (failure to thrive).
Characteristic craniofacial abnormalities associated with the disorder may include an unusually large head (macrocephaly) and wide forehead; a large, depressed nasal root; abnormally wide nostrils; skin folds (epicanthal folds) that may cover the eyes’ inner corners; low-set ears with large, thick lobes; and/or unusually thick lips. Other physical features may include the development of dry, hardened, thickened skin on the palms of the hands and the soles of the feet (palmoplantar hyperkeratosis) and/or abnormally deep creases on the palms and soles. Many affected individuals may also have congenital heart defects similar to those found in Noonan and CFC syndromes. More distinctive is the presence of unusual and chaotic rhythms in about a third. Most cases of Costello syndrome occur sporadically, with no family history of the disorder, and are caused by mutations in HRAS. (For more information on this disorder, choose “Costello” as your search term in the Rare Disease Database.)Multiple giant cell lesions are abnormal cysts (lesions) involving certain large cells (giant cells) within bone and soft tissue of the jaw. They are found in Noonan syndrome and other overlapping disorders such as CFC syndrome and are usually diagnosed in the first two decades.Neurofibromatosis-Noonan syndrome is characterized by the occurrence of neurofibromatosis type I in association with some manifestations of Noonan syndrome. Associated symptoms and findings may include multiple benign tumors of the nerves and skin, short stature, webbing of the neck (pterygium colli), muscle weakness, and/or learning disabilities. Affected individuals may also have certain craniofacial abnormalities associated with Noonan syndrome including drooping of the upper eyelids (ptosis), low-set ears, and/or unusually prominent folds between the nose and the lips (nasolabial folds). In addition, congenital heart defects often seen in Noonan syndrome may be present, such as obstruction of the normal outflow of blood from the lower right chamber (ventricle) of the heart (pulmonary stenosis) and/or an abnormal opening in the fibrous partition (septum) between the upper chambers (atria) of the heart (atrial septal defect). Neurofibromatosis-Noonan syndrome can be due to the chance occurrence of both disorders in the same individuals, can be a phenotype of neurofibromatosis type I, or can be a separate disease entity caused by mutations in the NF1 gene but without some of the characteristic features of NF1.Noonan syndrome with multiple lentigines (NSML, formerly known as LEOPARD syndrome) is a rare inherited disorder characterized by abnormalities of the skin, the structure and function of the heart, the inner ear, the head and facial (craniofacial) area, and/or the genitals. In individuals with the disorder, the range and severity of symptoms and physical characteristics may vary from person to person.Some of the most common features include lentigines (multiple black or dark brown spots on the skin); electrocardiographic conduction defects (abnormalities of the electrical activity and the coordination of proper contractions of the heart); hypertrophic cardiomyopathy, ocular hypertelorism (widely-spaced eyes); pulmonary stenosis (obstruction of the normal outflow of blood from the right ventricle of the heart); abnormalities of the genitals (in boys usually undescended testes (cryptorchidism); slowed growth resulting in short stature, delayed development; and deafness or hearing loss due to malfunction of the inner ear (sensorineural deafness). NSML is an autosomal dominant genetic disorder caused by a mutation in one of two genes: PTPN11 or RAF1. (For more information choose “LEOPARD Syndrome” as your search term in the Rare Disease Database.)
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Noonan Syndrome
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Diagnosis of Noonan Syndrome
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In some cases, Noonan syndrome may be suspected before birth (prenatally) based upon results of fetal ultrasonography, a specializing imaging technique in which sound waves are used to create an image of the developing fetus. A diagnosis of Noonan syndrome may be considered due to abnormal maternal serum triple screen, detection of excessive amniotic fluid surrounding the fetus within the amniotic sac (polyhydramnios), the presence of an abnormal cystic swelling consisting of dilated lymph vessels in the neck area (cystic hygroma), a structural heart difference, other fetal anomalies, and confirmation of a normal chromosomal makeup (karyotype). However, in many cases, Noonan syndrome is diagnosed at birth or early infancy based upon a thorough clinical evaluation, identification of characteristic physical findings, and a variety of specialized tests. If Noonan syndrome is suspected prenatally, molecular genetic testing is available by amniotic fluid or cell free fetal DNA analysis.It is important to note that, in some cases, individuals who have only minor, subtle characteristics associated with Noonan syndrome may not receive a diagnosis. Physicians who specialize in diagnosing and treating heart abnormalities (cardiologists) should suspect the possibility of Noonan syndrome in any individuals who have congenital pulmonary valve stenosis. Because Noonan syndrome may be difficult to confirm in such cases (particularly if there is no family history of the disorder), Noonan syndrome should be strongly considered as a possible diagnosis in any individuals with pulmonary valve stenosis and certain eye abnormalities typically found even in the more mild cases (e.g., ptosis, epicanthal folds, ocular hypertelorism). In addition, in such cases, all immediate (first-degree) relatives should be examined for mild facial abnormalities and cardiac defects potentially occurring in association with Noonan syndrome.In many individuals with the disorder, certain advanced imaging techniques and laboratory tests may be used to detect, confirm, and/or characterize specific abnormalities that may be associated with Noonan syndrome.Congenital heart defects that occur in association with Noonan syndrome may be detected and/or confirmed by a thorough clinical examination and specialized tests that allow physicians to evaluate the structure and function of the heart. Clinical examination may include a physician’s evaluation of heart and lung sounds through use of a stethoscope. In mild asymptomatic cases of pulmonary stenosis, the condition may initially be detected through an abnormal heart murmur heard during such stethoscopic evaluation.Specialized cardiac tests may include electrocardiography (EKG), echocardiography, and/or cardiac catheterization. An EKG, which records the electrical activities of the heart muscle, may reveal abnormal electrical patterns (e.g., left axis deviation, left anterior hemiblock, deep S wave). During an echocardiogram, sound waves are directed toward the heart, enabling physicians to study cardiac function and motion. During cardiac catheterization, a small hollow tube (catheter) is inserted into a large vein and threaded through the blood vessels leading to the heart.This procedure allows physicians to determine the rate of blood flow through the heart, measure the pressure within the heart, and/or thoroughly identify anatomical abnormalities. In addition, physicians may also closely evaluate respiratory (ventilatory) capabilities since associated heart defects may result in inadequate blood supply to the lungs and breathlessness.Specialized blood tests may be performed to detect potential coagulation factor deficiencies and/or platelet dysfunction.Molecular genetic testing for mutations in the associated genes is available to confirm the diagnosis and for prenatal diagnosis.
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Diagnosis of Noonan Syndrome. In some cases, Noonan syndrome may be suspected before birth (prenatally) based upon results of fetal ultrasonography, a specializing imaging technique in which sound waves are used to create an image of the developing fetus. A diagnosis of Noonan syndrome may be considered due to abnormal maternal serum triple screen, detection of excessive amniotic fluid surrounding the fetus within the amniotic sac (polyhydramnios), the presence of an abnormal cystic swelling consisting of dilated lymph vessels in the neck area (cystic hygroma), a structural heart difference, other fetal anomalies, and confirmation of a normal chromosomal makeup (karyotype). However, in many cases, Noonan syndrome is diagnosed at birth or early infancy based upon a thorough clinical evaluation, identification of characteristic physical findings, and a variety of specialized tests. If Noonan syndrome is suspected prenatally, molecular genetic testing is available by amniotic fluid or cell free fetal DNA analysis.It is important to note that, in some cases, individuals who have only minor, subtle characteristics associated with Noonan syndrome may not receive a diagnosis. Physicians who specialize in diagnosing and treating heart abnormalities (cardiologists) should suspect the possibility of Noonan syndrome in any individuals who have congenital pulmonary valve stenosis. Because Noonan syndrome may be difficult to confirm in such cases (particularly if there is no family history of the disorder), Noonan syndrome should be strongly considered as a possible diagnosis in any individuals with pulmonary valve stenosis and certain eye abnormalities typically found even in the more mild cases (e.g., ptosis, epicanthal folds, ocular hypertelorism). In addition, in such cases, all immediate (first-degree) relatives should be examined for mild facial abnormalities and cardiac defects potentially occurring in association with Noonan syndrome.In many individuals with the disorder, certain advanced imaging techniques and laboratory tests may be used to detect, confirm, and/or characterize specific abnormalities that may be associated with Noonan syndrome.Congenital heart defects that occur in association with Noonan syndrome may be detected and/or confirmed by a thorough clinical examination and specialized tests that allow physicians to evaluate the structure and function of the heart. Clinical examination may include a physician’s evaluation of heart and lung sounds through use of a stethoscope. In mild asymptomatic cases of pulmonary stenosis, the condition may initially be detected through an abnormal heart murmur heard during such stethoscopic evaluation.Specialized cardiac tests may include electrocardiography (EKG), echocardiography, and/or cardiac catheterization. An EKG, which records the electrical activities of the heart muscle, may reveal abnormal electrical patterns (e.g., left axis deviation, left anterior hemiblock, deep S wave). During an echocardiogram, sound waves are directed toward the heart, enabling physicians to study cardiac function and motion. During cardiac catheterization, a small hollow tube (catheter) is inserted into a large vein and threaded through the blood vessels leading to the heart.This procedure allows physicians to determine the rate of blood flow through the heart, measure the pressure within the heart, and/or thoroughly identify anatomical abnormalities. In addition, physicians may also closely evaluate respiratory (ventilatory) capabilities since associated heart defects may result in inadequate blood supply to the lungs and breathlessness.Specialized blood tests may be performed to detect potential coagulation factor deficiencies and/or platelet dysfunction.Molecular genetic testing for mutations in the associated genes is available to confirm the diagnosis and for prenatal diagnosis.
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Noonan Syndrome
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Therapies of Noonan Syndrome
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TreatmentThe treatment of Noonan syndrome is directed toward the specific complications that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, physicians who diagnose and treat heart abnormalities (cardiologists), physicians who diagnose and treat disorders of the blood and blood-forming tissues (hematologists), physicians who diagnose and treat disorders of growth (endocrinologists) and/or other health care professionals may need to systematically and comprehensively plan an affected child’s treatment.In some individuals with congenital heart defects, treatment with certain medications, surgical intervention, and/or other techniques may be necessary. In such cases, any surgical procedures performed will depend upon the location, severity, and/or combination of anatomical abnormalities and their associated symptoms. Cardiac, arteriovenous, and/or lymphatic malformations that may be present must be taken into consideration during decisions concerning surgical procedures. For example, during certain types of surgery performed on lymphangiomas, there is an increased risk that chyle may escape from the largest lymph channel in the body (thoracic duct) into the cavity between the neck and the diaphragm (thoracic cavity), potentially causing life-threatening complications (chylothorax).For those who also have thrombocytopenia, platelet dysfunction, and/or coagulation factor deficiencies, physicians, dentists, and/or other health care workers may recommend certain preventive measures before or take certain supportive measures during surgery to prevent, lower the risk of, or control abnormal bleeding.Respiratory infections should be treated promptly and vigorously. Because of the potentially increased risk of bacterial infection of the lining of the heart (endocarditis) and the heart valves, affected individuals with certain heart defects may be given medication prior to any surgical procedures, including dental procedures, such as tooth extractions.In affected males with cryptorchidism, surgery should be performed to move undescended testes into the scrotum and attach them in a fixed position (orchiopexy). Such surgery is typically performed between 12 and 24 months of age to help prevent the risk of associated infertility.In addition, appropriate supportive measures may be used in affected individuals with lymphedema.Early intervention may be important in helping children with Noonan syndrome reach their potential. Special services that may be beneficial to affected children may include special remedial education, speech therapy, physical therapy, and other medical, social, and/or vocational services. The short stature in patients with Noonan syndrome can be treated with growth hormone which has been shown to improve final adult height.Genetic counseling is recommended for affected individuals and their families. As mentioned earlier, thorough clinical evaluations may be important in family members of diagnosed individuals to detect any symptoms and physical characteristics that may be associated with Noonan syndrome. Other treatment for the disorder is symptomatic and supportive.
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Therapies of Noonan Syndrome. TreatmentThe treatment of Noonan syndrome is directed toward the specific complications that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, physicians who diagnose and treat heart abnormalities (cardiologists), physicians who diagnose and treat disorders of the blood and blood-forming tissues (hematologists), physicians who diagnose and treat disorders of growth (endocrinologists) and/or other health care professionals may need to systematically and comprehensively plan an affected child’s treatment.In some individuals with congenital heart defects, treatment with certain medications, surgical intervention, and/or other techniques may be necessary. In such cases, any surgical procedures performed will depend upon the location, severity, and/or combination of anatomical abnormalities and their associated symptoms. Cardiac, arteriovenous, and/or lymphatic malformations that may be present must be taken into consideration during decisions concerning surgical procedures. For example, during certain types of surgery performed on lymphangiomas, there is an increased risk that chyle may escape from the largest lymph channel in the body (thoracic duct) into the cavity between the neck and the diaphragm (thoracic cavity), potentially causing life-threatening complications (chylothorax).For those who also have thrombocytopenia, platelet dysfunction, and/or coagulation factor deficiencies, physicians, dentists, and/or other health care workers may recommend certain preventive measures before or take certain supportive measures during surgery to prevent, lower the risk of, or control abnormal bleeding.Respiratory infections should be treated promptly and vigorously. Because of the potentially increased risk of bacterial infection of the lining of the heart (endocarditis) and the heart valves, affected individuals with certain heart defects may be given medication prior to any surgical procedures, including dental procedures, such as tooth extractions.In affected males with cryptorchidism, surgery should be performed to move undescended testes into the scrotum and attach them in a fixed position (orchiopexy). Such surgery is typically performed between 12 and 24 months of age to help prevent the risk of associated infertility.In addition, appropriate supportive measures may be used in affected individuals with lymphedema.Early intervention may be important in helping children with Noonan syndrome reach their potential. Special services that may be beneficial to affected children may include special remedial education, speech therapy, physical therapy, and other medical, social, and/or vocational services. The short stature in patients with Noonan syndrome can be treated with growth hormone which has been shown to improve final adult height.Genetic counseling is recommended for affected individuals and their families. As mentioned earlier, thorough clinical evaluations may be important in family members of diagnosed individuals to detect any symptoms and physical characteristics that may be associated with Noonan syndrome. Other treatment for the disorder is symptomatic and supportive.
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Noonan Syndrome
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Overview of Noonan Syndrome with Multiple Lentigines
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SummaryNoonan syndrome with multiple lentigines (NSML) is a rare genetic disorder characterized by abnormalities of the skin, the structure and function of the heart, the inner ear, the head and facial (craniofacial) area, and/or the genitals. In individuals with the disorder, the range and severity of symptoms and physical characteristics may vary from person to person.LEOPARD is an acronym for the characteristic abnormalities associated with the disorder: L stands for (L)entigines (multiple black or dark brown spots on the skin); (E)lectrocardiographic conduction defects (abnormalities of the electrical activity and the coordination of proper contractions of the heart); (0)cular hypertelorism (widely-spaced eyes); (P)ulmonary stenosis (obstruction of the normal outflow of blood from the right ventricle of the heart); (A)bnormalities of the genitals; (R)etarded growth resulting in short stature; and (D)eafness or hearing loss due to malfunction of the inner ear (sensorineural deafness). Some affected individuals may also exhibit mild intellectual disability, speech difficulties, and/or, in some cases, additional physical abnormalities.NSML is an autosomal dominant genetic disorder. NSML and Noonan syndrome are both caused by mutations in the PTPN11 and RAF1 genes.
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Overview of Noonan Syndrome with Multiple Lentigines. SummaryNoonan syndrome with multiple lentigines (NSML) is a rare genetic disorder characterized by abnormalities of the skin, the structure and function of the heart, the inner ear, the head and facial (craniofacial) area, and/or the genitals. In individuals with the disorder, the range and severity of symptoms and physical characteristics may vary from person to person.LEOPARD is an acronym for the characteristic abnormalities associated with the disorder: L stands for (L)entigines (multiple black or dark brown spots on the skin); (E)lectrocardiographic conduction defects (abnormalities of the electrical activity and the coordination of proper contractions of the heart); (0)cular hypertelorism (widely-spaced eyes); (P)ulmonary stenosis (obstruction of the normal outflow of blood from the right ventricle of the heart); (A)bnormalities of the genitals; (R)etarded growth resulting in short stature; and (D)eafness or hearing loss due to malfunction of the inner ear (sensorineural deafness). Some affected individuals may also exhibit mild intellectual disability, speech difficulties, and/or, in some cases, additional physical abnormalities.NSML is an autosomal dominant genetic disorder. NSML and Noonan syndrome are both caused by mutations in the PTPN11 and RAF1 genes.
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Noonan Syndrome with Multiple Lentigines
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Symptoms of Noonan Syndrome with Multiple Lentigines
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The symptoms and physical characteristics associated with NSML are highly variable. However, most affected individuals tend to exhibit characteristic abnormalities of the skin, the structure and function of the heart, the head and facial (craniofacial) area, and/or the genitals.Children with NSML may exhibit numerous black or dark brown “freckle-like” spots on the skin (multiple lentigines). However, most individuals with NSML do not exhibit lentigines during the first few years of life. Lentigines increase in number with age, usually until puberty. Many affected individuals may exhibit thousands of such lentigines. Although these small, flat discolorations (macules) resemble freckles, they tend to be darker, range from approximately one to five millimeters (mm) in size, and do not darken upon exposure to sunlight. The lentigines tend to be most numerous on the neck and upper chest area (trunk), be less concentrated below the knees, and involve only the skin, not the mucous membranes. However, they may appear anywhere on the skin of the body including the scalp, face, upper arms and/or upper legs, palms of the hands, soles of the feet, and/or genitals. In approximately 20 percent of affected individuals, larger, dark brown discolorations (café-au-lait spots) may also appear on the skin.Many individuals with NSML also have cardiac anomalies. Such heart defects, which are often apparent during infancy or early childhood, may include the abnormal transmission of electrical impulses that coordinate contractions of the heart (electrocardiographic conduction defects). In many cases of NSML, there may be an interruption of the normal passage of electrical impulses (heart block) through the heart’s conducting system. As a result, although the two upper chambers of the heart (atria) may beat normally, the two lower chambers (ventricles) may contract less often or “fall behind” the atria.The effects of such electrocardiographic conduction defects in individuals with NSML may be highly variable, ranging from no apparent symptoms (asymptomatic) in some affected individuals to potentially serious complications in others. For example, those who exhibit prolonged P-R intervals may not exhibit any associated symptoms. Observable symptoms may also not occur in affected individuals who experience dropped beats. In more severe cases of heart block, however, if there is inadequate blood output from the ventricles, affected individuals may experience breathlessness due to the heart’s inability to pump blood effectively (heart failure), fatigue, or experience fainting episodes. If the ventricular beat slows dramatically or stops, affected individuals may black out, experience seizures, or exhibit life-threatening symptoms.In addition, individuals with NSML may also have structural (anatomical) malformations of the heart. The most common cardiac malformation appears to be overgrowth (hypertrophy) of the cardiac muscle in the ventricular wall(s) (hypertrophic obstructive cardiomyopathy), particularly the left ventricle. This condition may cause reduced cardiac output, potentially resulting in fatigue; fainting episodes (syncope), particularly during physical activity; and/or, in some cases, potentially life-threatening symptoms (e.g., arrhythmias, etc.)The second most common abnormality is the obstruction of the normal outflow of blood from the lower right chamber (ventricle) of the heart to the lungs (isolated valvar pulmonary stenosis). Such obstruction may be due to abnormal narrowing (stenosis) of the pulmonary artery, which carries blood from the right ventricle to the lungs; stenosis of the pulmonary valve, the valve that controls the regular flow of deoxygenated blood through the pulmonary artery and on to the lungs; abnormal narrowing of the upper portion of the right ventricle; and/or other causes. In individuals with pulmonary stenosis, the heart must work harder to send blood to the lungs for oxygenation.In most individuals with NSML, pulmonary stenosis tends to be mild and symptoms may not occur (asymptomatic). In those cases when symptoms do occur, they often may not appear until later in childhood.In some people, hypertrophic cardiomyopathy and pulmonary stenosis may be associated.Some affected individuals with pulmonary stenosis may also exhibit abnormal narrowing (stenosis) of the aorta, the main artery of the body. Aortic stenosis may result in obstruction of blood flow from the left ventricle to the aorta and abnormal thickening of cardiac muscle in the wall of the left ventricle. As a result, aortic stenosis may contribute to such symptoms as fatigue, chest pain (angina pectoris) during exertion, breathlessness, and/or fainting episodes.Many individuals with NSML exhibit widely spaced eyes (ocular hypertelorism), with or without additional malformations of the head and facial (craniofacial) area. These may include a triangular-shaped face, drooping of the upper eyelids (ptosis), the presence of abnormal folds of skin over the inner corners of the eye (epicanthal folds), abnormal protrusion of the lower jaw (mandibular prognathism), and/or low-set, unusually prominent ears. Some affected individuals may also exhibit additional abnormalities including crossing of the eyes (strabismus) and/or mild webbing of the neck (pterygium colli).Many individuals with NSML also have genital abnormalities. Affected males may exhibit abnormal placement of the urinary opening (meatus) on the underside of the penis (hypospadias), unusual smallness of the penis (micropenis), and/or failure of one or both testes to descend into the scrotum (unilateral or bilateral cryptorchidism). Affected females may exhibit underdevelopment (hypoplasia) or absence (agenesis) of an ovary. Abnormally decreased function of the gonads (i.e., testes in males, ovaries in females) may result in delayed development of secondary sexual characteristics (puberty) in some affected males and females.Individuals with NSML may also exhibit growth retardation that results in short stature. Affected individuals may also have additional skeletal abnormalities. These may include malformations of the chest (thoracic deformity) such as abnormal depression of the bone forming the center of the chest (sternum), known as “funnel chest” or pectus excavatum, or abnormal protrusion of the sternum, known as “keeled chest” or pectus carinatum. Some individuals with NSML may exhibit additional skeletal abnormalities such as unusually prominent shoulder blades (winged scapula), abnormal sideways curvature of the spine (scoliosis), and/or the development of abnormal front-to-back spinal curvature (kyphosis) during later life.Some individuals with NSML may also exhibit mild to severe hearing loss due to malfunction of the inner ears (sensorineural deafness). In some people, such hearing loss may be apparent at birth or during early childhood. However, other affected individuals may have normal hearing in early childhood yet eventually exhibit hearing loss at a later age. Hearing impairment may contribute to speech difficulties in many people. Although most affected individuals have normal intelligence, others may exhibit mild intellectual disability.
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Symptoms of Noonan Syndrome with Multiple Lentigines. The symptoms and physical characteristics associated with NSML are highly variable. However, most affected individuals tend to exhibit characteristic abnormalities of the skin, the structure and function of the heart, the head and facial (craniofacial) area, and/or the genitals.Children with NSML may exhibit numerous black or dark brown “freckle-like” spots on the skin (multiple lentigines). However, most individuals with NSML do not exhibit lentigines during the first few years of life. Lentigines increase in number with age, usually until puberty. Many affected individuals may exhibit thousands of such lentigines. Although these small, flat discolorations (macules) resemble freckles, they tend to be darker, range from approximately one to five millimeters (mm) in size, and do not darken upon exposure to sunlight. The lentigines tend to be most numerous on the neck and upper chest area (trunk), be less concentrated below the knees, and involve only the skin, not the mucous membranes. However, they may appear anywhere on the skin of the body including the scalp, face, upper arms and/or upper legs, palms of the hands, soles of the feet, and/or genitals. In approximately 20 percent of affected individuals, larger, dark brown discolorations (café-au-lait spots) may also appear on the skin.Many individuals with NSML also have cardiac anomalies. Such heart defects, which are often apparent during infancy or early childhood, may include the abnormal transmission of electrical impulses that coordinate contractions of the heart (electrocardiographic conduction defects). In many cases of NSML, there may be an interruption of the normal passage of electrical impulses (heart block) through the heart’s conducting system. As a result, although the two upper chambers of the heart (atria) may beat normally, the two lower chambers (ventricles) may contract less often or “fall behind” the atria.The effects of such electrocardiographic conduction defects in individuals with NSML may be highly variable, ranging from no apparent symptoms (asymptomatic) in some affected individuals to potentially serious complications in others. For example, those who exhibit prolonged P-R intervals may not exhibit any associated symptoms. Observable symptoms may also not occur in affected individuals who experience dropped beats. In more severe cases of heart block, however, if there is inadequate blood output from the ventricles, affected individuals may experience breathlessness due to the heart’s inability to pump blood effectively (heart failure), fatigue, or experience fainting episodes. If the ventricular beat slows dramatically or stops, affected individuals may black out, experience seizures, or exhibit life-threatening symptoms.In addition, individuals with NSML may also have structural (anatomical) malformations of the heart. The most common cardiac malformation appears to be overgrowth (hypertrophy) of the cardiac muscle in the ventricular wall(s) (hypertrophic obstructive cardiomyopathy), particularly the left ventricle. This condition may cause reduced cardiac output, potentially resulting in fatigue; fainting episodes (syncope), particularly during physical activity; and/or, in some cases, potentially life-threatening symptoms (e.g., arrhythmias, etc.)The second most common abnormality is the obstruction of the normal outflow of blood from the lower right chamber (ventricle) of the heart to the lungs (isolated valvar pulmonary stenosis). Such obstruction may be due to abnormal narrowing (stenosis) of the pulmonary artery, which carries blood from the right ventricle to the lungs; stenosis of the pulmonary valve, the valve that controls the regular flow of deoxygenated blood through the pulmonary artery and on to the lungs; abnormal narrowing of the upper portion of the right ventricle; and/or other causes. In individuals with pulmonary stenosis, the heart must work harder to send blood to the lungs for oxygenation.In most individuals with NSML, pulmonary stenosis tends to be mild and symptoms may not occur (asymptomatic). In those cases when symptoms do occur, they often may not appear until later in childhood.In some people, hypertrophic cardiomyopathy and pulmonary stenosis may be associated.Some affected individuals with pulmonary stenosis may also exhibit abnormal narrowing (stenosis) of the aorta, the main artery of the body. Aortic stenosis may result in obstruction of blood flow from the left ventricle to the aorta and abnormal thickening of cardiac muscle in the wall of the left ventricle. As a result, aortic stenosis may contribute to such symptoms as fatigue, chest pain (angina pectoris) during exertion, breathlessness, and/or fainting episodes.Many individuals with NSML exhibit widely spaced eyes (ocular hypertelorism), with or without additional malformations of the head and facial (craniofacial) area. These may include a triangular-shaped face, drooping of the upper eyelids (ptosis), the presence of abnormal folds of skin over the inner corners of the eye (epicanthal folds), abnormal protrusion of the lower jaw (mandibular prognathism), and/or low-set, unusually prominent ears. Some affected individuals may also exhibit additional abnormalities including crossing of the eyes (strabismus) and/or mild webbing of the neck (pterygium colli).Many individuals with NSML also have genital abnormalities. Affected males may exhibit abnormal placement of the urinary opening (meatus) on the underside of the penis (hypospadias), unusual smallness of the penis (micropenis), and/or failure of one or both testes to descend into the scrotum (unilateral or bilateral cryptorchidism). Affected females may exhibit underdevelopment (hypoplasia) or absence (agenesis) of an ovary. Abnormally decreased function of the gonads (i.e., testes in males, ovaries in females) may result in delayed development of secondary sexual characteristics (puberty) in some affected males and females.Individuals with NSML may also exhibit growth retardation that results in short stature. Affected individuals may also have additional skeletal abnormalities. These may include malformations of the chest (thoracic deformity) such as abnormal depression of the bone forming the center of the chest (sternum), known as “funnel chest” or pectus excavatum, or abnormal protrusion of the sternum, known as “keeled chest” or pectus carinatum. Some individuals with NSML may exhibit additional skeletal abnormalities such as unusually prominent shoulder blades (winged scapula), abnormal sideways curvature of the spine (scoliosis), and/or the development of abnormal front-to-back spinal curvature (kyphosis) during later life.Some individuals with NSML may also exhibit mild to severe hearing loss due to malfunction of the inner ears (sensorineural deafness). In some people, such hearing loss may be apparent at birth or during early childhood. However, other affected individuals may have normal hearing in early childhood yet eventually exhibit hearing loss at a later age. Hearing impairment may contribute to speech difficulties in many people. Although most affected individuals have normal intelligence, others may exhibit mild intellectual disability.
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Noonan Syndrome with Multiple Lentigines
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Causes of Noonan Syndrome with Multiple Lentigines
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NSML is an autosomal dominant genetic disorder caused by an abnormality (change) in one of two genes: PTPN11 or RAF1. Mutations in these genes also cause a different genetic condition called Noonan syndrome. Approximately 90% of individuals with NSML have a mutation in the PTPN11 gene and most individuals who do not have a PTPN11 gene mutation have a RAF1 gene mutation. A single patient with a mutation in the BRAF gene, belonging to the same molecular pathway as PTPN11 and RAF1, has been described.Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. It is not known how often NSML is caused by a new mutation. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.
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Causes of Noonan Syndrome with Multiple Lentigines. NSML is an autosomal dominant genetic disorder caused by an abnormality (change) in one of two genes: PTPN11 or RAF1. Mutations in these genes also cause a different genetic condition called Noonan syndrome. Approximately 90% of individuals with NSML have a mutation in the PTPN11 gene and most individuals who do not have a PTPN11 gene mutation have a RAF1 gene mutation. A single patient with a mutation in the BRAF gene, belonging to the same molecular pathway as PTPN11 and RAF1, has been described.Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. It is not known how often NSML is caused by a new mutation. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.
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Noonan Syndrome with Multiple Lentigines
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Affects of Noonan Syndrome with Multiple Lentigines
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NSML is an extremely rare disorder that is believed to affect males and females in equal numbers.
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Affects of Noonan Syndrome with Multiple Lentigines. NSML is an extremely rare disorder that is believed to affect males and females in equal numbers.
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Noonan Syndrome with Multiple Lentigines
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Related disorders of Noonan Syndrome with Multiple Lentigines
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Symptoms of the following disorders may be similar to those of NSML. Comparisons may be useful for a differential diagnosis:Noonan syndrome and NSML are both caused by mutations in the PTPN11 and RAF1 genes. The characteristics seen in both of these conditions include hypertelorism, broad chest, short stature, developmental delay, pulmonic stenosis, hypertrophic cardiomyopathy, and a chest abnormality. Noonan syndrome is an autosomal dominant genetic disorder characterized by a distinctive facial appearance, webbing of the neck (pterygium colli), short stature, chest abnormalities, congenital heart defects, and/or other abnormalities. Characteristic malformations of the head and facial (craniofacial) area may include widely-set eyes (ocular hypertelorism); downwardly slanting eyelid folds (palpebral fissures); drooping of the upper eyelids (ptosis) or unusually thick, “hooded” eyelids; a prominent upper lip; and/or low-set, prominent external ears (pinnae) that are abnormally rotated toward the back of the head (posteriorly angulated). Most affected individuals also have a distinctive chest malformation characterized by abnormal protrusion of the upper (superior) portion of the breastbone (sternum) and/or abnormal depression of the lower (inferior) portion of the breastbone (pectus carinatum and/or pectus excavatum, respectively). In many males with Noonan syndrome, one or both testes may have failed to descend into the scrotum (unilateral or bilateral cryptorchidism). In addition, affected individuals often have congenital heart defects, particularly obstruction of the normal flow of blood from the lower right chamber (ventricle) of the heart to the lungs (valvar pulmonary stenosis).Additional abnormalities associated with Noonan syndrome may include improper development of certain blood vessels; malformation of certain lymph vessels; and/or various blood clotting deficiencies (coagulation factor deficiencies), low levels of circulating platelets in the blood (thrombocytopenia), and improper function of blood platelets, potentially causing abnormal bruising and bleeding. Rarely, affected individuals may have pigmented birthmarks (nevi), small black or dark brown “freckle-like” spots (lentigines), and/or larger, light brown discolorations (“cafe-au-lait” spots) on the skin. Noonan syndrome is associated with mutations in seven genes: PTPN11, KRAS, SOS1 and RAF1, SHOC2, NRAS, CBL. (For more information on this disorder, choose “Noonan” as your search term in the Rare Disease Database.)Centrofacial lentiginosis is an extremely rare inherited disorder characterized by the presence of multiple, small black or dark brown “freckle-like” spots (lentigines) appearing on the skin of the face. Many affected individuals also experience intellectual disability. Centrofacial lentiginosis is inherited as an autosomal dominant genetic condition.Neurofibromatosis type 1 is a rare genetic disorder characterized by the appearance of light brown discolorations (“cafe-au-lait” spots) on the skin; freckling, particularly under the arms (axillary) and/or in the area of the groin (inguinal); multiple benign tumors of the nerves and skin; benign tumor-like nodules on the colored portion of the eyes (iris Lisch nodules); and/or, in some cases, slow-growing tumors of the optic nerve (or optic chiasm). Affected individuals may also have an abnormally large head (macrocephaly), widely spaced eyes (ocular hypertelorism), short stature, abnormal sideways curvature of the spine (scoliosis), and/or other skeletal abnormalities. Some individuals with neurofibromatosis type 1 may also have learning disabilities and speech impairment. Additional physical abnormalities may also be present in many people. Neurofibromatosis type 1 is an autosomal dominant genetic disorder. (For more information on this disorder, choose “neurofibromatosis type 1” as your search term in the Rare Disease Database.)Peutz-Jeghers syndrome (PJS) is an autosomal dominant genetic condition characterized by multiple benign polyps called hamartomas on the mucous lining in the gastrointestinal system. These polyps occur most often in the small intestine but also occur in the stomach and large intestine. Affected individuals also have dark skin discoloration, especially around the eyes, nostrils, mucous membranes of the mouth, perianal area and inside the mouth. Affected individuals have an increased risk for intestinal and other cancers. (For more information on this disorder, choose “Peutz Jeghers” as your search term in the Rare Disease Database.)Carney complex is an autosomal dominant genetic disorder characterized by abnormalities in skin pigment, non-cancerous tumors of the skin, heart and breast called myxomas, and overactivity of endocrine glands and endocrine tumors and tumors in the tissue covering the nerves (schwannomas). (For more information on this disorder, choose “Carney” as your search term in the Rare Disease Database.)
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Related disorders of Noonan Syndrome with Multiple Lentigines. Symptoms of the following disorders may be similar to those of NSML. Comparisons may be useful for a differential diagnosis:Noonan syndrome and NSML are both caused by mutations in the PTPN11 and RAF1 genes. The characteristics seen in both of these conditions include hypertelorism, broad chest, short stature, developmental delay, pulmonic stenosis, hypertrophic cardiomyopathy, and a chest abnormality. Noonan syndrome is an autosomal dominant genetic disorder characterized by a distinctive facial appearance, webbing of the neck (pterygium colli), short stature, chest abnormalities, congenital heart defects, and/or other abnormalities. Characteristic malformations of the head and facial (craniofacial) area may include widely-set eyes (ocular hypertelorism); downwardly slanting eyelid folds (palpebral fissures); drooping of the upper eyelids (ptosis) or unusually thick, “hooded” eyelids; a prominent upper lip; and/or low-set, prominent external ears (pinnae) that are abnormally rotated toward the back of the head (posteriorly angulated). Most affected individuals also have a distinctive chest malformation characterized by abnormal protrusion of the upper (superior) portion of the breastbone (sternum) and/or abnormal depression of the lower (inferior) portion of the breastbone (pectus carinatum and/or pectus excavatum, respectively). In many males with Noonan syndrome, one or both testes may have failed to descend into the scrotum (unilateral or bilateral cryptorchidism). In addition, affected individuals often have congenital heart defects, particularly obstruction of the normal flow of blood from the lower right chamber (ventricle) of the heart to the lungs (valvar pulmonary stenosis).Additional abnormalities associated with Noonan syndrome may include improper development of certain blood vessels; malformation of certain lymph vessels; and/or various blood clotting deficiencies (coagulation factor deficiencies), low levels of circulating platelets in the blood (thrombocytopenia), and improper function of blood platelets, potentially causing abnormal bruising and bleeding. Rarely, affected individuals may have pigmented birthmarks (nevi), small black or dark brown “freckle-like” spots (lentigines), and/or larger, light brown discolorations (“cafe-au-lait” spots) on the skin. Noonan syndrome is associated with mutations in seven genes: PTPN11, KRAS, SOS1 and RAF1, SHOC2, NRAS, CBL. (For more information on this disorder, choose “Noonan” as your search term in the Rare Disease Database.)Centrofacial lentiginosis is an extremely rare inherited disorder characterized by the presence of multiple, small black or dark brown “freckle-like” spots (lentigines) appearing on the skin of the face. Many affected individuals also experience intellectual disability. Centrofacial lentiginosis is inherited as an autosomal dominant genetic condition.Neurofibromatosis type 1 is a rare genetic disorder characterized by the appearance of light brown discolorations (“cafe-au-lait” spots) on the skin; freckling, particularly under the arms (axillary) and/or in the area of the groin (inguinal); multiple benign tumors of the nerves and skin; benign tumor-like nodules on the colored portion of the eyes (iris Lisch nodules); and/or, in some cases, slow-growing tumors of the optic nerve (or optic chiasm). Affected individuals may also have an abnormally large head (macrocephaly), widely spaced eyes (ocular hypertelorism), short stature, abnormal sideways curvature of the spine (scoliosis), and/or other skeletal abnormalities. Some individuals with neurofibromatosis type 1 may also have learning disabilities and speech impairment. Additional physical abnormalities may also be present in many people. Neurofibromatosis type 1 is an autosomal dominant genetic disorder. (For more information on this disorder, choose “neurofibromatosis type 1” as your search term in the Rare Disease Database.)Peutz-Jeghers syndrome (PJS) is an autosomal dominant genetic condition characterized by multiple benign polyps called hamartomas on the mucous lining in the gastrointestinal system. These polyps occur most often in the small intestine but also occur in the stomach and large intestine. Affected individuals also have dark skin discoloration, especially around the eyes, nostrils, mucous membranes of the mouth, perianal area and inside the mouth. Affected individuals have an increased risk for intestinal and other cancers. (For more information on this disorder, choose “Peutz Jeghers” as your search term in the Rare Disease Database.)Carney complex is an autosomal dominant genetic disorder characterized by abnormalities in skin pigment, non-cancerous tumors of the skin, heart and breast called myxomas, and overactivity of endocrine glands and endocrine tumors and tumors in the tissue covering the nerves (schwannomas). (For more information on this disorder, choose “Carney” as your search term in the Rare Disease Database.)
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Noonan Syndrome with Multiple Lentigines
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nord_890_5
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Diagnosis of Noonan Syndrome with Multiple Lentigines
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In some children, the diagnosis of NSML may be suspected soon after birth due to the presence of pale tan or light brown discolorations on the skin (café-au-lait spots), characteristic facial features and hypertrophic cardiomyopathy. Multiple lentigines are usually not apparent before the age of five years. When they are seen in combination with two other related features in the LEOPARD acronym or when an individual has three related features plus a parent or sibling with multiple lentigines, the diagnosis of NSML can be made.Molecular genetic testing for the PTPN11 gene and the RAF1 gene is available to confirm the diagnosis and for prenatal diagnosis.The diagnosis of certain specific abnormalities that may occur in association with NSML may be confirmed by specialized imaging studies and/or additional tests. Examination of skin samples (biopsies) under a microscope that uses light (light microscopy) or an electron beam (electron microscopy) may confirm that pigmented areas of skin represent multiple lentigines as opposed to freckles.Children who exhibit multiple lentigines should receive prompt, thorough cardiac evaluation. If no cardiac abnormalities are revealed during such evaluation, individuals should receive periodic reassessments to detect any heart abnormalities that may develop later.A variety of tests may be conducted to perform such a cardiac assessment. For example, the electrocardiographic conduction defects (e.g., varying degrees of heart block) and/or structural (anatomical) malformations of the heart (e.g., pulmonary and/or aortic stenosis, hypertrophic obstructive cardiomyopathy) may be confirmed by a thorough clinical examination and several specialized tests that allow physicians to evaluate the structure and function of the heart.Clinical examination may include a physician's evaluation of heart and lung sounds through use of a stethoscope. For example, in mild asymptomatic cases of pulmonary stenosis, the condition may initially be suspected through the detection of an abnormal heart murmur during such stethoscopic evaluation. Heart block may initially be identified by detection of a slow, regular heartbeat that fails to increase during exercise.Specialized cardiac tests may include electrocardiography (EKG), echocardiography, cardiac MRI and/or cardiac catheterization. An EKG, which records the electrical activities of the heart muscle, may confirm the presence of abnormal electrical patterns such as those associated with varying degrees of heart block (e.g., prolonged P-R interval, left anterior hemiblock, widening of the QRS complex, complete heart block). During an echocardiogram, sound waves are directed toward the heart, enabling physicians to study cardiac function and motion. Echocardiography may play an essential role in helping to confirm hypertrophic obstructive cardiomyopathy. EKG, echocardiograms, cardiac catheterization, and/or other tests may help to clarify the underlying anatomical cause and/or severity of narrowing associated with pulmonary stenosis.Sonographic and radiological techniques may be conducted to detect and/or confirm certain genital abnormalities in many individuals with NSML (e.g., unilateral or bilateral cryptorchidism in affected males, hypoplastic ovaries in affected females). In addition, because deficiencies of certain hormones (gonadotrophin) may contribute to abnormally decreased function of the gonads (hypogonadism) and delayed puberty in some affected males and females, individuals with NSML may be monitored closely to promptly detect such delays and laboratory tests may be conducted to screen for deficient levels of certain gonadotrophins in the blood.In many individuals with NSML, X-ray studies may also be used to confirm the presence of certain skeletal abnormalities suspected during clinical observation. Growth retardation may not become obvious until early childhood, when there may be an observable decline in the normal growth rate.Thorough, regular hearing (audiological) evaluation should also be conducted in individuals with NSML to promptly detect potential hearing impairment and help ensure early implementation of appropriate supportive measures. If hearing impairment is detected, a scanning procedure, such as computerized tomography or CT scan, may be performed to confirm the underlying cause (e.g., inner ear malformation) and characterize the type of hearing loss (e.g., sensorineural hearing impairment). During a CT scan, a computer and x-rays are used to create a film showing cross-sectional images of the structures of the inner ear.
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Diagnosis of Noonan Syndrome with Multiple Lentigines. In some children, the diagnosis of NSML may be suspected soon after birth due to the presence of pale tan or light brown discolorations on the skin (café-au-lait spots), characteristic facial features and hypertrophic cardiomyopathy. Multiple lentigines are usually not apparent before the age of five years. When they are seen in combination with two other related features in the LEOPARD acronym or when an individual has three related features plus a parent or sibling with multiple lentigines, the diagnosis of NSML can be made.Molecular genetic testing for the PTPN11 gene and the RAF1 gene is available to confirm the diagnosis and for prenatal diagnosis.The diagnosis of certain specific abnormalities that may occur in association with NSML may be confirmed by specialized imaging studies and/or additional tests. Examination of skin samples (biopsies) under a microscope that uses light (light microscopy) or an electron beam (electron microscopy) may confirm that pigmented areas of skin represent multiple lentigines as opposed to freckles.Children who exhibit multiple lentigines should receive prompt, thorough cardiac evaluation. If no cardiac abnormalities are revealed during such evaluation, individuals should receive periodic reassessments to detect any heart abnormalities that may develop later.A variety of tests may be conducted to perform such a cardiac assessment. For example, the electrocardiographic conduction defects (e.g., varying degrees of heart block) and/or structural (anatomical) malformations of the heart (e.g., pulmonary and/or aortic stenosis, hypertrophic obstructive cardiomyopathy) may be confirmed by a thorough clinical examination and several specialized tests that allow physicians to evaluate the structure and function of the heart.Clinical examination may include a physician's evaluation of heart and lung sounds through use of a stethoscope. For example, in mild asymptomatic cases of pulmonary stenosis, the condition may initially be suspected through the detection of an abnormal heart murmur during such stethoscopic evaluation. Heart block may initially be identified by detection of a slow, regular heartbeat that fails to increase during exercise.Specialized cardiac tests may include electrocardiography (EKG), echocardiography, cardiac MRI and/or cardiac catheterization. An EKG, which records the electrical activities of the heart muscle, may confirm the presence of abnormal electrical patterns such as those associated with varying degrees of heart block (e.g., prolonged P-R interval, left anterior hemiblock, widening of the QRS complex, complete heart block). During an echocardiogram, sound waves are directed toward the heart, enabling physicians to study cardiac function and motion. Echocardiography may play an essential role in helping to confirm hypertrophic obstructive cardiomyopathy. EKG, echocardiograms, cardiac catheterization, and/or other tests may help to clarify the underlying anatomical cause and/or severity of narrowing associated with pulmonary stenosis.Sonographic and radiological techniques may be conducted to detect and/or confirm certain genital abnormalities in many individuals with NSML (e.g., unilateral or bilateral cryptorchidism in affected males, hypoplastic ovaries in affected females). In addition, because deficiencies of certain hormones (gonadotrophin) may contribute to abnormally decreased function of the gonads (hypogonadism) and delayed puberty in some affected males and females, individuals with NSML may be monitored closely to promptly detect such delays and laboratory tests may be conducted to screen for deficient levels of certain gonadotrophins in the blood.In many individuals with NSML, X-ray studies may also be used to confirm the presence of certain skeletal abnormalities suspected during clinical observation. Growth retardation may not become obvious until early childhood, when there may be an observable decline in the normal growth rate.Thorough, regular hearing (audiological) evaluation should also be conducted in individuals with NSML to promptly detect potential hearing impairment and help ensure early implementation of appropriate supportive measures. If hearing impairment is detected, a scanning procedure, such as computerized tomography or CT scan, may be performed to confirm the underlying cause (e.g., inner ear malformation) and characterize the type of hearing loss (e.g., sensorineural hearing impairment). During a CT scan, a computer and x-rays are used to create a film showing cross-sectional images of the structures of the inner ear.
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Noonan Syndrome with Multiple Lentigines
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nord_890_6
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Therapies of Noonan Syndrome with Multiple Lentigines
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Treatment
The treatment of NSML is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, physicians who diagnose and treat disorders of the skin (dermatologists), cardiologists, specialists who diagnose and treat skeletal disorders (orthopedists), physicians who specialize in diagnosing and treating disorders of the glands (endocrinologists), specialists who assess and treat hearing problems (audiologists), speech pathologists, and/or other health care professionals may need to systematically and comprehensively plan an affected child's treatment.Specific therapies for NSML are symptomatic and supportive. In affected individuals who exhibit mild forms of cardiac conduction abnormalities, treatment may not be required. However, in more severe cases when associated symptoms occur (e.g., fainting episodes) and in some cases of pulmonary stenosis, hypertrophic obstructive cardiomyopathy, and/or other structural heart abnormalities potentially associated with NSML, treatment with certain medications, surgical intervention, and/or other techniques may be necessary. The surgical procedures performed will depend upon the location and severity of the anatomical abnormalities and their associated symptoms.Other abnormalities potentially associated with NSML may also be corrected surgically. These may include certain craniofacial, skeletal, genital, and/or other malformations. For example, in some affected males with cryptorchidism, hormone treatment may be administered; however, if this treatment is not successful, surgery may be performed to move the undescended testes into the scrotum and attach them in a fixed position to prevent retraction (orchiopexy).In addition, if laboratory and additional tests demonstrate that deficient levels of gonadotrophin (hypogonadotropism) have contributed to abnormally decreased gonadal function (hypogonadism) and delayed puberty in affected males or females, sex hormone replacement therapy may be considered in some cases.If individuals with NSML demonstrate hearing impairment, hearing aids may be beneficial. Appropriate use of hearing aids, other supportive techniques, and speech therapy may help to prevent, improve, and/or correct some speech problems that may result from such hearing impairment.Early intervention is important to ensure that children with NSML reach their potential. Special services that may be beneficial to affected children include special remedial education, special social support, physical therapy, and/or other medical, social, and/or vocational services.Genetic counseling is recommended for individuals with NSML and their families.
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Therapies of Noonan Syndrome with Multiple Lentigines. Treatment
The treatment of NSML is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, physicians who diagnose and treat disorders of the skin (dermatologists), cardiologists, specialists who diagnose and treat skeletal disorders (orthopedists), physicians who specialize in diagnosing and treating disorders of the glands (endocrinologists), specialists who assess and treat hearing problems (audiologists), speech pathologists, and/or other health care professionals may need to systematically and comprehensively plan an affected child's treatment.Specific therapies for NSML are symptomatic and supportive. In affected individuals who exhibit mild forms of cardiac conduction abnormalities, treatment may not be required. However, in more severe cases when associated symptoms occur (e.g., fainting episodes) and in some cases of pulmonary stenosis, hypertrophic obstructive cardiomyopathy, and/or other structural heart abnormalities potentially associated with NSML, treatment with certain medications, surgical intervention, and/or other techniques may be necessary. The surgical procedures performed will depend upon the location and severity of the anatomical abnormalities and their associated symptoms.Other abnormalities potentially associated with NSML may also be corrected surgically. These may include certain craniofacial, skeletal, genital, and/or other malformations. For example, in some affected males with cryptorchidism, hormone treatment may be administered; however, if this treatment is not successful, surgery may be performed to move the undescended testes into the scrotum and attach them in a fixed position to prevent retraction (orchiopexy).In addition, if laboratory and additional tests demonstrate that deficient levels of gonadotrophin (hypogonadotropism) have contributed to abnormally decreased gonadal function (hypogonadism) and delayed puberty in affected males or females, sex hormone replacement therapy may be considered in some cases.If individuals with NSML demonstrate hearing impairment, hearing aids may be beneficial. Appropriate use of hearing aids, other supportive techniques, and speech therapy may help to prevent, improve, and/or correct some speech problems that may result from such hearing impairment.Early intervention is important to ensure that children with NSML reach their potential. Special services that may be beneficial to affected children include special remedial education, special social support, physical therapy, and/or other medical, social, and/or vocational services.Genetic counseling is recommended for individuals with NSML and their families.
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Noonan Syndrome with Multiple Lentigines
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nord_891_0
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Overview of Norrie Disease
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SummaryNorrie disease is characterized by vision loss at birth or a few weeks after an eye lesion such as retinal detachment occurs which threatens vision and can lead to severe visual impairment or loss of vision. Norrie disease mostly occurs in males, but females can show milder symptoms. Norrie disease is progressive through childhood and adolescence. Additional symptoms may occur in some people, although this varies even among individuals in the same family. Most affected males develop hearing loss which is progressive over many years. Some may exhibit cognitive abnormalities such as developmental delays, intellectual disabilities or behavioral issues.Norrie disease is a rare X-linked genetic disorder that occurs due to change (mutation) in the NDP gene. NDP gene mutations are associated with a spectrum of retinopathies and Norrie disease is the most severe. Less severe retinopathies that can be caused by NDP gene mutations include persistent hyperplastic primary vitreous (PHPV), X-linked familial exudative vitreoretinopathy (X-linked-FEVR), and some cases of retinopathy of prematurity (ROP) and Coats disease The ocular manifestations may vary between individuals even within a family.IntroductionNorrie Disease was thought to have first been reported in Denmark in 1927 when Norrie, a Danish ophthalmologist, surveyed the cause of blindness in Denmark and found a disease that only affected males and occurred in several generations. The records were later reviewed by Mete Warburg and the name Norrie was proposed.
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Overview of Norrie Disease. SummaryNorrie disease is characterized by vision loss at birth or a few weeks after an eye lesion such as retinal detachment occurs which threatens vision and can lead to severe visual impairment or loss of vision. Norrie disease mostly occurs in males, but females can show milder symptoms. Norrie disease is progressive through childhood and adolescence. Additional symptoms may occur in some people, although this varies even among individuals in the same family. Most affected males develop hearing loss which is progressive over many years. Some may exhibit cognitive abnormalities such as developmental delays, intellectual disabilities or behavioral issues.Norrie disease is a rare X-linked genetic disorder that occurs due to change (mutation) in the NDP gene. NDP gene mutations are associated with a spectrum of retinopathies and Norrie disease is the most severe. Less severe retinopathies that can be caused by NDP gene mutations include persistent hyperplastic primary vitreous (PHPV), X-linked familial exudative vitreoretinopathy (X-linked-FEVR), and some cases of retinopathy of prematurity (ROP) and Coats disease The ocular manifestations may vary between individuals even within a family.IntroductionNorrie Disease was thought to have first been reported in Denmark in 1927 when Norrie, a Danish ophthalmologist, surveyed the cause of blindness in Denmark and found a disease that only affected males and occurred in several generations. The records were later reviewed by Mete Warburg and the name Norrie was proposed.
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Norrie Disease
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nord_891_1
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Symptoms of Norrie Disease
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The main symptom of Norrie disease is a retinal degeneration which occurs before birth and results in blindness at birth (congenital) or early infancy, usually by 3 months of age. Visual failure in this disorder is characterized by the abnormal development of the neuroretina, the thin layer of nerve cells that lines the back of the eyes. The neuroretina senses light and converts it into nerve signals, which are then relayed to brain through the optic nerve.In Norrie disease, the retinas separate from the underlying, supporting tissue (retinal detachment). This causes a grayish-yellow mass to develop in the back of the eye behind the lens that may be mistaken for a tumor (pseudoglioma). This mass consists of immature retinal cells and may be apparent a few days after birth or may not be noted until weeks or months later. This mass is located behind the lens of the eyes so that in some, instant illumination the pupils appear white, a condition known as leukocoria or “cat’s eye” reflex.The eyes of affected children go through additional progressive changes. The lenses of the eyes of an affected infant may be initially clear. Eventually, clouding (opacity) lens through which light passes may develop, a condition known as a cataract. In addition, as the disorder progresses, shrinking of the eyeball (phthisis bulbi) may occur and is often apparent by ten years of age. Subsequently, the lenses are often completely obscured by cataracts.In addition, the eyes may be abnormally small (microphthalmia) at birth, the pupils may be widened (dilated) and the colored portion of the eyes (irises) may be underdeveloped (hypoplasia) and may stick to the lens (posterior synechiae) or to the cornea (anterior synechiae). The space in the eye behind the cornea and in front of the iris (anterior chamber) may be abnormally shallow and the outflow tracts of the eye may be blocked (occluded), resulting in increased pressure within the eye (intraocular pressure) which may be extremely painful. Other signs of Norrie disease that occur in 80%-99% of individuals with this condition can be found in the facial features. These include abnormally close eyes (hypotelorism), deeply set eyes, a narrow nasal bridge, and larger than normal ears (macrotia). Most individuals with Norrie disease develop progressive hearing loss due to vascular abnormalities in the cochlea (inner ear). Hearing loss usually begins in early childhood and may be mild at first and slowly progressive. By the third or fourth decade there may be significant functional loss but can usually be aide assisted. Speech discrimination is relatively well preserved. The development and severity of hearing loss varies greatly even among members of the same family. In some patients, hearing loss may not develop until adulthood.Approximately 30-50 percent of individuals with Norrie disease may experience cognitive abnormalities including delays in reaching developmental milestones disproportional to vision loss. Patients could also show behavioral problems including psychosis, aggressive behavior and cognitive regression. Intellectual disabilities have been reported in 20-30% of patients. Dementia is rare but may occur in late adulthood.Norrie disease has been associated with disease of the peripheral blood vessels in some people. Patients have been reported with venous stasis ulcers. In more complex molecular genetic cases (NDP gene deletion), other clinical features may occur including seizures, growth failure and endocrine abnormalities.
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Symptoms of Norrie Disease. The main symptom of Norrie disease is a retinal degeneration which occurs before birth and results in blindness at birth (congenital) or early infancy, usually by 3 months of age. Visual failure in this disorder is characterized by the abnormal development of the neuroretina, the thin layer of nerve cells that lines the back of the eyes. The neuroretina senses light and converts it into nerve signals, which are then relayed to brain through the optic nerve.In Norrie disease, the retinas separate from the underlying, supporting tissue (retinal detachment). This causes a grayish-yellow mass to develop in the back of the eye behind the lens that may be mistaken for a tumor (pseudoglioma). This mass consists of immature retinal cells and may be apparent a few days after birth or may not be noted until weeks or months later. This mass is located behind the lens of the eyes so that in some, instant illumination the pupils appear white, a condition known as leukocoria or “cat’s eye” reflex.The eyes of affected children go through additional progressive changes. The lenses of the eyes of an affected infant may be initially clear. Eventually, clouding (opacity) lens through which light passes may develop, a condition known as a cataract. In addition, as the disorder progresses, shrinking of the eyeball (phthisis bulbi) may occur and is often apparent by ten years of age. Subsequently, the lenses are often completely obscured by cataracts.In addition, the eyes may be abnormally small (microphthalmia) at birth, the pupils may be widened (dilated) and the colored portion of the eyes (irises) may be underdeveloped (hypoplasia) and may stick to the lens (posterior synechiae) or to the cornea (anterior synechiae). The space in the eye behind the cornea and in front of the iris (anterior chamber) may be abnormally shallow and the outflow tracts of the eye may be blocked (occluded), resulting in increased pressure within the eye (intraocular pressure) which may be extremely painful. Other signs of Norrie disease that occur in 80%-99% of individuals with this condition can be found in the facial features. These include abnormally close eyes (hypotelorism), deeply set eyes, a narrow nasal bridge, and larger than normal ears (macrotia). Most individuals with Norrie disease develop progressive hearing loss due to vascular abnormalities in the cochlea (inner ear). Hearing loss usually begins in early childhood and may be mild at first and slowly progressive. By the third or fourth decade there may be significant functional loss but can usually be aide assisted. Speech discrimination is relatively well preserved. The development and severity of hearing loss varies greatly even among members of the same family. In some patients, hearing loss may not develop until adulthood.Approximately 30-50 percent of individuals with Norrie disease may experience cognitive abnormalities including delays in reaching developmental milestones disproportional to vision loss. Patients could also show behavioral problems including psychosis, aggressive behavior and cognitive regression. Intellectual disabilities have been reported in 20-30% of patients. Dementia is rare but may occur in late adulthood.Norrie disease has been associated with disease of the peripheral blood vessels in some people. Patients have been reported with venous stasis ulcers. In more complex molecular genetic cases (NDP gene deletion), other clinical features may occur including seizures, growth failure and endocrine abnormalities.
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Norrie Disease
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nord_891_2
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Causes of Norrie Disease
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Norrie disease occurs due to a mutation of the NDP gene located on the X chromosome. The NDP gene encodes a protein known as norrin which plays a role in cell and tissue development. It is believed to be essential for the proper development of blood vessels (angiogenesis), especially those that supply blood to the retina and the cochlea of the inner ear. Norrin is an essential ligand for the frizzled-4 receptor of the Wnt cascade pathway, which contributes to cell development and specialization. Mutations in the NDP gene can prevent the protein from working correctly. Norrie disease is inherited in an X-linked recessive pattern. X-linked recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome. Females who have a disease gene present on one of their X chromosomes are carriers for that disorder, meaning they can pass on the chromosome to their children. Carrier females usually do not display symptoms of the disorder because the functional X chromosome will mask the symptoms of the disease. Males have only one X chromosome inherited from their mothers. When the transmitted X chromosome they receive contains a disease gene, they will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers, but cannot pass it to any of their sons. 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.Heterozygous females who have a single copy of a mutated NDP gene may, rarely exhibit some of the symptoms of ND such as visual impairment.
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Causes of Norrie Disease. Norrie disease occurs due to a mutation of the NDP gene located on the X chromosome. The NDP gene encodes a protein known as norrin which plays a role in cell and tissue development. It is believed to be essential for the proper development of blood vessels (angiogenesis), especially those that supply blood to the retina and the cochlea of the inner ear. Norrin is an essential ligand for the frizzled-4 receptor of the Wnt cascade pathway, which contributes to cell development and specialization. Mutations in the NDP gene can prevent the protein from working correctly. Norrie disease is inherited in an X-linked recessive pattern. X-linked recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome. Females who have a disease gene present on one of their X chromosomes are carriers for that disorder, meaning they can pass on the chromosome to their children. Carrier females usually do not display symptoms of the disorder because the functional X chromosome will mask the symptoms of the disease. Males have only one X chromosome inherited from their mothers. When the transmitted X chromosome they receive contains a disease gene, they will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers, but cannot pass it to any of their sons. 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.Heterozygous females who have a single copy of a mutated NDP gene may, rarely exhibit some of the symptoms of ND such as visual impairment.
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Norrie Disease
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nord_891_3
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Affects of Norrie Disease
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The incidence and prevalence rates for Norrie disease are unknown. The disorder has been reported in all ethnic groups.
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Affects of Norrie Disease. The incidence and prevalence rates for Norrie disease are unknown. The disorder has been reported in all ethnic groups.
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Norrie Disease
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nord_891_4
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Related disorders of Norrie Disease
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Symptoms of the following disorders can be similar to those of Norrie disease. Comparisons may be useful for a differential diagnosis. Common differential diagnoses include retinoblastoma with unilateral pseudoglioma, retinopathy as a result of prematurity, persistent hyperplastic primary vitreous and familial exudative vitreoretinopathy.Retinoblastoma is an extremely rare malignant tumor that develops in the nerve-rich layers that line the back of the eyes (retina). It occurs most commonly in children under the age of three. The most suggestive and earliest clinical sign associated with retinoblastoma is the reflection of light off a tumor behind the lens of the eye, which causes the pupil to appear white, the so called “cat’s eye reflex” (leukocoria). In addition, the eyes may be crossed (strabismus). In some affected children, the eye(s) may become red and/or painful. The presence of a retinoblastoma may cause a rise in the pressure in the eyeball (glaucoma). Retinoblastoma may affect one eye (unilateral) or both eyes (bilateral). In most cases, retinoblastoma occurs as a sporadic disease but familial forms with autosomal dominant inheritance account for about 40% of cases. (For more information on this disorder, choose “retinoblastoma” as your search term in the Rare Disease Database).Retinopathy of prematurity (ROP) is a potentially blinding disease affecting the retinas in premature infants. The retinas are the light-sensitive linings of the insides of the eyes. In infants born prematurely, the blood vessels that supply the retina are not yet completely developed. ROP may cause blood vessels to develop in an abnormal, disorganized pattern. In some affected infants, the changes associated with ROP spontaneously subside. However, in others, ROP may lead to bleeding, scarring of the retina, retinal detachment and visual loss. Even in cases in which ROP changes cease or regress spontaneously, affected children may have an increased risk of certain eye (ocular) abnormalities, including nearsightedness (myopia), misalignment of the eyes (strabismus), and/or future retinal detachment. The two major risk factors for ROP are a low birth weight and premature delivery. (For more information on this disorder, choose “retinopathy of prematurity” as your search term in the Rare Disease Database.)Persistent hyperplastic primary vitreous (PHPV) is a developmental disorder affecting the eye that is present at birth (congenital). The disorder is characterized by abnormalities of certain eye structures and loss of vision. Specific symptoms may include abnormally small eyes (microphthalmia), cataracts, and the formation of a white membrane or mass in the pupil area behind the lens of the eyes (leukocoria). This later feature causes the pupil to appear white when light reflects off it. In a limited number of some cases of bilateral PHPV, gene mutations have been identified including mutations of the NDP gene. Familial exudative vitreoretinopathy (FEVR) is a genetic disorder involving retinal detachment caused by retinal dysfunction or dysfunction of the blood vessel bearing tissue of the eye (choroids). These conditions disturb the outer blood-retinal barrier – known as the retinal pigment epithelium (RPE) – or inner blood-retinal barrier. The X-linked form of this disorder (X-linked FEVR) may be caused by mutations in the NDP gene. Coats disease is a rare disorder characterized by abnormal development of the blood vessels of the nerve-rich membrane lining the eyes (retina). Affected individuals may experience loss of vision and detachment of the retina. In most patients, only one eye is affected (unilateral).Rarely, both eyes (bilateral) may be affected. In these bilateral cases, one eye may be affected more than the other (asymmetric Coats disease). Some cases of Coats disease have occurred due to mutations of the NDP gene. (For more information on this disorder, choose “Coats” as your search term in the Rare Disease Database.)Lenz microphthalmia is a rare X-linked disorder with multisystem involvement. This includes bilateral microphthalmia and missing eyes (anophthalmia), anomalies of the digits, ear, skeleton and genitourinary tract. Mild to severe intellectual disability and other neurological impairment are often present. Lenz microphthalmia is inherited in an X-linked recessive pattern and caused by mutations in the NAA10 gene. (For more information on this disorder, choose “Lenz microphthalmia” as your search term in the Rare Disease Database).
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Related disorders of Norrie Disease. Symptoms of the following disorders can be similar to those of Norrie disease. Comparisons may be useful for a differential diagnosis. Common differential diagnoses include retinoblastoma with unilateral pseudoglioma, retinopathy as a result of prematurity, persistent hyperplastic primary vitreous and familial exudative vitreoretinopathy.Retinoblastoma is an extremely rare malignant tumor that develops in the nerve-rich layers that line the back of the eyes (retina). It occurs most commonly in children under the age of three. The most suggestive and earliest clinical sign associated with retinoblastoma is the reflection of light off a tumor behind the lens of the eye, which causes the pupil to appear white, the so called “cat’s eye reflex” (leukocoria). In addition, the eyes may be crossed (strabismus). In some affected children, the eye(s) may become red and/or painful. The presence of a retinoblastoma may cause a rise in the pressure in the eyeball (glaucoma). Retinoblastoma may affect one eye (unilateral) or both eyes (bilateral). In most cases, retinoblastoma occurs as a sporadic disease but familial forms with autosomal dominant inheritance account for about 40% of cases. (For more information on this disorder, choose “retinoblastoma” as your search term in the Rare Disease Database).Retinopathy of prematurity (ROP) is a potentially blinding disease affecting the retinas in premature infants. The retinas are the light-sensitive linings of the insides of the eyes. In infants born prematurely, the blood vessels that supply the retina are not yet completely developed. ROP may cause blood vessels to develop in an abnormal, disorganized pattern. In some affected infants, the changes associated with ROP spontaneously subside. However, in others, ROP may lead to bleeding, scarring of the retina, retinal detachment and visual loss. Even in cases in which ROP changes cease or regress spontaneously, affected children may have an increased risk of certain eye (ocular) abnormalities, including nearsightedness (myopia), misalignment of the eyes (strabismus), and/or future retinal detachment. The two major risk factors for ROP are a low birth weight and premature delivery. (For more information on this disorder, choose “retinopathy of prematurity” as your search term in the Rare Disease Database.)Persistent hyperplastic primary vitreous (PHPV) is a developmental disorder affecting the eye that is present at birth (congenital). The disorder is characterized by abnormalities of certain eye structures and loss of vision. Specific symptoms may include abnormally small eyes (microphthalmia), cataracts, and the formation of a white membrane or mass in the pupil area behind the lens of the eyes (leukocoria). This later feature causes the pupil to appear white when light reflects off it. In a limited number of some cases of bilateral PHPV, gene mutations have been identified including mutations of the NDP gene. Familial exudative vitreoretinopathy (FEVR) is a genetic disorder involving retinal detachment caused by retinal dysfunction or dysfunction of the blood vessel bearing tissue of the eye (choroids). These conditions disturb the outer blood-retinal barrier – known as the retinal pigment epithelium (RPE) – or inner blood-retinal barrier. The X-linked form of this disorder (X-linked FEVR) may be caused by mutations in the NDP gene. Coats disease is a rare disorder characterized by abnormal development of the blood vessels of the nerve-rich membrane lining the eyes (retina). Affected individuals may experience loss of vision and detachment of the retina. In most patients, only one eye is affected (unilateral).Rarely, both eyes (bilateral) may be affected. In these bilateral cases, one eye may be affected more than the other (asymmetric Coats disease). Some cases of Coats disease have occurred due to mutations of the NDP gene. (For more information on this disorder, choose “Coats” as your search term in the Rare Disease Database.)Lenz microphthalmia is a rare X-linked disorder with multisystem involvement. This includes bilateral microphthalmia and missing eyes (anophthalmia), anomalies of the digits, ear, skeleton and genitourinary tract. Mild to severe intellectual disability and other neurological impairment are often present. Lenz microphthalmia is inherited in an X-linked recessive pattern and caused by mutations in the NAA10 gene. (For more information on this disorder, choose “Lenz microphthalmia” as your search term in the Rare Disease Database).
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Norrie Disease
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Diagnosis of Norrie Disease
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A diagnosis of Norrie disease is suspected based upon a detailed patient history, a thorough clinical evaluation, and identification of characteristic findings. There may be a family history supporting X-linked inheritance. There are no biochemical or functional assays available for diagnosis. A diagnosis may be confirmed by molecular genetic testing in which a mutation in the NDP gene is identified.
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Diagnosis of Norrie Disease. A diagnosis of Norrie disease is suspected based upon a detailed patient history, a thorough clinical evaluation, and identification of characteristic findings. There may be a family history supporting X-linked inheritance. There are no biochemical or functional assays available for diagnosis. A diagnosis may be confirmed by molecular genetic testing in which a mutation in the NDP gene is identified.
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Norrie Disease
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Therapies of Norrie Disease
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TreatmentThe treatment of Norrie disease may require the coordinated efforts of a team of specialists. Pediatricians, specialists who assess and treat eye abnormalities (ophthalmologists), specialists who assess and treat hearing loss (audiologists), and other healthcare professionals may need to systematically and comprehensively plan an affected child's treatment. Regular follow-ups are necessary, even if there is no light perception, to prevent painful eye pressure. The treatment of individuals with Norrie disease is directed toward the specific symptoms that are apparent in each individual. There is no standard of care yet, but early surgical intervention may preserve some vision. Surgery may be necessary to remove cataracts and reattach retinas. These efforts may prevent shrinkage of the eyeballs, but will not improve vision. Treatment for patients with less than complete retinal detachment includes surgery or laser surgery to preserve eyesight if done at an early age. Intraocular pressure, which is pressure in the eye, may require surgery to remove. Very rarely does the eye need to be removed. For patients who have complete retinal detachment at birth, surgery is not an option. Hearing aids may be of benefit for individuals with hearing loss and is usually successful in middle or late adulthood. When hearing is significantly impaired, a cochlear implant may be helpful. Other treatment is symptomatic and supportive.Early intervention and appropriate specialized education are important in ensuring that children with Norrie disease reach their highest potential. Services that may be beneficial include special remedial or personalized education, other medical, social, and/or vocational services. Individualized educational plans should also be implemented early in pre-schools. Genetic counseling is recommended for affected individual and their family members.
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Therapies of Norrie Disease. TreatmentThe treatment of Norrie disease may require the coordinated efforts of a team of specialists. Pediatricians, specialists who assess and treat eye abnormalities (ophthalmologists), specialists who assess and treat hearing loss (audiologists), and other healthcare professionals may need to systematically and comprehensively plan an affected child's treatment. Regular follow-ups are necessary, even if there is no light perception, to prevent painful eye pressure. The treatment of individuals with Norrie disease is directed toward the specific symptoms that are apparent in each individual. There is no standard of care yet, but early surgical intervention may preserve some vision. Surgery may be necessary to remove cataracts and reattach retinas. These efforts may prevent shrinkage of the eyeballs, but will not improve vision. Treatment for patients with less than complete retinal detachment includes surgery or laser surgery to preserve eyesight if done at an early age. Intraocular pressure, which is pressure in the eye, may require surgery to remove. Very rarely does the eye need to be removed. For patients who have complete retinal detachment at birth, surgery is not an option. Hearing aids may be of benefit for individuals with hearing loss and is usually successful in middle or late adulthood. When hearing is significantly impaired, a cochlear implant may be helpful. Other treatment is symptomatic and supportive.Early intervention and appropriate specialized education are important in ensuring that children with Norrie disease reach their highest potential. Services that may be beneficial include special remedial or personalized education, other medical, social, and/or vocational services. Individualized educational plans should also be implemented early in pre-schools. Genetic counseling is recommended for affected individual and their family members.
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Norrie Disease
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Overview of NORSE (New Onset Refractory Status Epilepticus) and FIRES (Febrile Infection-Related Epilepsy Syndrome)
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Definitions and SummaryNew-onset refractory status epilepticus (NORSE) is defined as a condition, not a specific diagnosis, with new onset of refractory status epilepticus without a clear acute or active structural, toxic or metabolic cause in a patient without active epilepsy. Status epilepticus (SE) is a condition of prolonged seizure activity or repeated seizures without full recovery in between. Status epilepticus that persists despite at least two standard anti-seizure medications is termed refractory status epilepticus (RSE). Most of the common causes of RSE can be identified within 24-72 hours of presentation.Febrile infection-related epilepsy syndrome (FIRES) is a subcategory of NORSE that requires a prior febrile infection starting between 2 weeks and 24 hours prior to onset of refractory status epilepticus, with or without fever at onset of status epilepticus.In up to half of the cases of NORSE, a possible or probable cause is ultimately found, most often autoimmune or paraneoplastic encephalitis, with infectious causes less common. In the remaining half or more, no cause is identified despite an extensive work-up. These cases are referred to as cryptogenic NORSE or NORSE of unknown etiology. In cryptogenic cases, and likely in other cases, seizures are thought to be caused or exacerbated by an excess of pro-inflammatory molecules in the brain, perhaps triggered by a typical minor infection in a susceptible individual, although no clear cause—or even risk factor–has been demonstrated. Affected individuals are most often treated for weeks in an intensive care unit because they require prolonged anesthesia with coma-inducing drugs to control their seizures. NORSE carries a high rate of complications and mortality, but a significant proportion of patients do eventually recover. Epilepsy (a life-long predisposition to unprovoked seizures), cognitive and psychological issues are common among survivors although a minority of them eventually return to a normal lifestyle.IntroductionStatus epilepticus (SE) is defined as a prolonged seizure (>5 minutes if convulsive, >10 minutes if not) or a cluster of seizures without recovery in between. Status epilepticus that persists despite administration of at least two appropriately selected and dosed parenteral medications is termed refractory status epilepticus (RSE). Most of the causes of RSE can be identified within 24-72 hours of presentation, as it is commonly due to an obvious acute brain injury (stroke, trauma, etc.) or serious acute medical illness. RSE may also occur in people with epilepsy (also known as a seizure disorder). In a substantial minority of cases, however, RSE strikes out of the blue without a clear acute or active structural, toxic or metabolic cause, in a healthy patient without active epilepsy. These cases are known as new-onset refractory status epilepticus, or NORSE. In half of the cases, a cause is ultimately identified, most often autoimmune or paraneoplastic, followed by infections (mostly viral, although mycoplasma is not rare). In the remaining half or more, however, no cause is identified despite an extensive work-up. These cases are referred to as cryptogenic NORSE or NORSE of unknown etiology.Febrile infection-related epilepsy syndrome (FIRES) is a subtype of NORSE preceded by a febrile infection, with fever starting between 2 weeks and 24 hours prior to onset of refractory status epilepticus. Fever may or may not be present at the time of onset of status epilepticus. The syndrome has been mostly described in school-aged children but occurs in adults as well. Previously, the term FIRES was only used in the pediatric population while NORSE was mainly used in adults. According to recent consensus definitions, FIRES is now considered a subtype of NORSE and both conditions now have no age limits. Children can have NORSE and adults can have FIRES. Everyone with FIRES also has NORSE, by definition. The distinguishing feature of FIRES is the preceding fever. Although the term NORSE includes the subcategory of FIRES, both terms are used here because the recent integration of the two disorders is still being disseminated in the literature and public.
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Overview of NORSE (New Onset Refractory Status Epilepticus) and FIRES (Febrile Infection-Related Epilepsy Syndrome). Definitions and SummaryNew-onset refractory status epilepticus (NORSE) is defined as a condition, not a specific diagnosis, with new onset of refractory status epilepticus without a clear acute or active structural, toxic or metabolic cause in a patient without active epilepsy. Status epilepticus (SE) is a condition of prolonged seizure activity or repeated seizures without full recovery in between. Status epilepticus that persists despite at least two standard anti-seizure medications is termed refractory status epilepticus (RSE). Most of the common causes of RSE can be identified within 24-72 hours of presentation.Febrile infection-related epilepsy syndrome (FIRES) is a subcategory of NORSE that requires a prior febrile infection starting between 2 weeks and 24 hours prior to onset of refractory status epilepticus, with or without fever at onset of status epilepticus.In up to half of the cases of NORSE, a possible or probable cause is ultimately found, most often autoimmune or paraneoplastic encephalitis, with infectious causes less common. In the remaining half or more, no cause is identified despite an extensive work-up. These cases are referred to as cryptogenic NORSE or NORSE of unknown etiology. In cryptogenic cases, and likely in other cases, seizures are thought to be caused or exacerbated by an excess of pro-inflammatory molecules in the brain, perhaps triggered by a typical minor infection in a susceptible individual, although no clear cause—or even risk factor–has been demonstrated. Affected individuals are most often treated for weeks in an intensive care unit because they require prolonged anesthesia with coma-inducing drugs to control their seizures. NORSE carries a high rate of complications and mortality, but a significant proportion of patients do eventually recover. Epilepsy (a life-long predisposition to unprovoked seizures), cognitive and psychological issues are common among survivors although a minority of them eventually return to a normal lifestyle.IntroductionStatus epilepticus (SE) is defined as a prolonged seizure (>5 minutes if convulsive, >10 minutes if not) or a cluster of seizures without recovery in between. Status epilepticus that persists despite administration of at least two appropriately selected and dosed parenteral medications is termed refractory status epilepticus (RSE). Most of the causes of RSE can be identified within 24-72 hours of presentation, as it is commonly due to an obvious acute brain injury (stroke, trauma, etc.) or serious acute medical illness. RSE may also occur in people with epilepsy (also known as a seizure disorder). In a substantial minority of cases, however, RSE strikes out of the blue without a clear acute or active structural, toxic or metabolic cause, in a healthy patient without active epilepsy. These cases are known as new-onset refractory status epilepticus, or NORSE. In half of the cases, a cause is ultimately identified, most often autoimmune or paraneoplastic, followed by infections (mostly viral, although mycoplasma is not rare). In the remaining half or more, however, no cause is identified despite an extensive work-up. These cases are referred to as cryptogenic NORSE or NORSE of unknown etiology.Febrile infection-related epilepsy syndrome (FIRES) is a subtype of NORSE preceded by a febrile infection, with fever starting between 2 weeks and 24 hours prior to onset of refractory status epilepticus. Fever may or may not be present at the time of onset of status epilepticus. The syndrome has been mostly described in school-aged children but occurs in adults as well. Previously, the term FIRES was only used in the pediatric population while NORSE was mainly used in adults. According to recent consensus definitions, FIRES is now considered a subtype of NORSE and both conditions now have no age limits. Children can have NORSE and adults can have FIRES. Everyone with FIRES also has NORSE, by definition. The distinguishing feature of FIRES is the preceding fever. Although the term NORSE includes the subcategory of FIRES, both terms are used here because the recent integration of the two disorders is still being disseminated in the literature and public.
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NORSE (New Onset Refractory Status Epilepticus) and FIRES (Febrile Infection-Related Epilepsy Syndrome)
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Symptoms of NORSE (New Onset Refractory Status Epilepticus) and FIRES (Febrile Infection-Related Epilepsy Syndrome)
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In two-thirds of NORSE cases, the course of the syndrome begins with a mild febrile illness, associated with malaise, fatigue and symptoms of upper respiratory tract or gastro-intestinal tract infection. Symptoms of meningeal inflammation, such as headache and photophobia, are uncommon. Behavioral and cognitive symptoms, such as apathy or agitation, amnesia, and sometimes hallucinations can be observed. The presence of hallucinations may suggest an autoimmune etiology, especially anti-NMDA receptor encephalitis.This initial phase lasts a few days to a week or two and is followed by the progressive onset of seizures. Both focal seizures with impaired awareness (previously known as complex partial seizures, and typically described as staring episodes) and bilateral tonic-clonic seizures (often referred to as “grand mal” in non-medical terms) can occur. They are initially intermittent but become increasingly more frequent and the patient’s consciousness declines as he/she transitions into status epilepticus.This acute phase usually lasts days to several weeks and in some cases can even last several months. During this phase, the patient remains comatose due to the effect of the seizures and anesthetic treatment and can develop any of the complications associated with prolonged unconsciousness and mechanical ventilation. The mortality rate reaches 30% and is higher in adults than children.Once SE is controlled and anesthetic treatment is discontinued, the patients progressively regain consciousness and can be discharged from the ICU and the hospital. At least one half of the surviving patients are left with long-term cognitive and functional disability and many will have epilepsy, requiring prolonged (or lifelong) treatment with anti-seizure medications. A small minority, however, will be able to resume their previously normal lifestyle.The infantile hemiconvulsion‐hemiplegia and epilepsy syndrome (IHHE) is a specific syndrome that also qualifies as NORSE. IHHE occurs in a patient <2 years old, presenting as NORSE with unilateral motor seizures, high‐grade fever persisting at the time of onset of refractory status epilepticus, and unilaterally abnormal acute imaging, followed by hemiparesis lasting at least 24 hours, and excluding definite infectious encephalitis.
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Symptoms of NORSE (New Onset Refractory Status Epilepticus) and FIRES (Febrile Infection-Related Epilepsy Syndrome). In two-thirds of NORSE cases, the course of the syndrome begins with a mild febrile illness, associated with malaise, fatigue and symptoms of upper respiratory tract or gastro-intestinal tract infection. Symptoms of meningeal inflammation, such as headache and photophobia, are uncommon. Behavioral and cognitive symptoms, such as apathy or agitation, amnesia, and sometimes hallucinations can be observed. The presence of hallucinations may suggest an autoimmune etiology, especially anti-NMDA receptor encephalitis.This initial phase lasts a few days to a week or two and is followed by the progressive onset of seizures. Both focal seizures with impaired awareness (previously known as complex partial seizures, and typically described as staring episodes) and bilateral tonic-clonic seizures (often referred to as “grand mal” in non-medical terms) can occur. They are initially intermittent but become increasingly more frequent and the patient’s consciousness declines as he/she transitions into status epilepticus.This acute phase usually lasts days to several weeks and in some cases can even last several months. During this phase, the patient remains comatose due to the effect of the seizures and anesthetic treatment and can develop any of the complications associated with prolonged unconsciousness and mechanical ventilation. The mortality rate reaches 30% and is higher in adults than children.Once SE is controlled and anesthetic treatment is discontinued, the patients progressively regain consciousness and can be discharged from the ICU and the hospital. At least one half of the surviving patients are left with long-term cognitive and functional disability and many will have epilepsy, requiring prolonged (or lifelong) treatment with anti-seizure medications. A small minority, however, will be able to resume their previously normal lifestyle.The infantile hemiconvulsion‐hemiplegia and epilepsy syndrome (IHHE) is a specific syndrome that also qualifies as NORSE. IHHE occurs in a patient <2 years old, presenting as NORSE with unilateral motor seizures, high‐grade fever persisting at the time of onset of refractory status epilepticus, and unilaterally abnormal acute imaging, followed by hemiparesis lasting at least 24 hours, and excluding definite infectious encephalitis.
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NORSE (New Onset Refractory Status Epilepticus) and FIRES (Febrile Infection-Related Epilepsy Syndrome)
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Causes of NORSE (New Onset Refractory Status Epilepticus) and FIRES (Febrile Infection-Related Epilepsy Syndrome)
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The most common causes of NORSE and FIRES are autoimmune/paraneoplastic disorders, such as encephalitis associated with anti-neuronal antibodies (anti-NMDA receptor, anti-voltage-gated potassium channel complex, etc.), followed by viral encephalitis. Genetic epilepsy syndromes associated with sensitivity to fever do not represent a major cause of NORSE and FIRES, as suggested by one study in children that did not find mutations in the SCN1A (the gene mostly associated with Dravet syndrome), PCDH19 or POLG1 (Alpers syndrome) genes. However, studies found genetic polymorphisms in the SCN2A gene (another gene involved in Dravet syndrome) and in the IL1RN gene (a gene coding for an immunomodulatory protein) in children with FIRES. These data are still very limited and further studies are required to fully explore the hypothesis of a genetic predisposition. As the term “cryptogenic” implies, the cause of cryptogenic NORSE and FIRES is thus unknown. The frequent occurrence of a mild febrile illness in the days preceding seizures, the presence of inflammatory markers in the cerebrospinal fluid (CSF) (though usually only mild), and genetic polymorphisms in genes coding for immunomodulatory proteins of patients with NORSE and FIRES suggest that it might be due to an excess of pro-inflammatory molecules in the brain, perhaps triggered by a viral infection. This hypothesis is supported by experimental evidence that inflammatory molecules are powerful triggers of seizures in animals and by the fact that well established autoimmune disorders affecting the brain can lead to refractory SE. Furthermore, there is some evidence from uncontrolled case series that early immune-suppressing medications may be helpful, at least in some cases. Finally, it is possible that a direct infection of the brain by an undetected and/or unknown pathogen can be responsible for some cases of NORSE and FIRES.
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Causes of NORSE (New Onset Refractory Status Epilepticus) and FIRES (Febrile Infection-Related Epilepsy Syndrome). The most common causes of NORSE and FIRES are autoimmune/paraneoplastic disorders, such as encephalitis associated with anti-neuronal antibodies (anti-NMDA receptor, anti-voltage-gated potassium channel complex, etc.), followed by viral encephalitis. Genetic epilepsy syndromes associated with sensitivity to fever do not represent a major cause of NORSE and FIRES, as suggested by one study in children that did not find mutations in the SCN1A (the gene mostly associated with Dravet syndrome), PCDH19 or POLG1 (Alpers syndrome) genes. However, studies found genetic polymorphisms in the SCN2A gene (another gene involved in Dravet syndrome) and in the IL1RN gene (a gene coding for an immunomodulatory protein) in children with FIRES. These data are still very limited and further studies are required to fully explore the hypothesis of a genetic predisposition. As the term “cryptogenic” implies, the cause of cryptogenic NORSE and FIRES is thus unknown. The frequent occurrence of a mild febrile illness in the days preceding seizures, the presence of inflammatory markers in the cerebrospinal fluid (CSF) (though usually only mild), and genetic polymorphisms in genes coding for immunomodulatory proteins of patients with NORSE and FIRES suggest that it might be due to an excess of pro-inflammatory molecules in the brain, perhaps triggered by a viral infection. This hypothesis is supported by experimental evidence that inflammatory molecules are powerful triggers of seizures in animals and by the fact that well established autoimmune disorders affecting the brain can lead to refractory SE. Furthermore, there is some evidence from uncontrolled case series that early immune-suppressing medications may be helpful, at least in some cases. Finally, it is possible that a direct infection of the brain by an undetected and/or unknown pathogen can be responsible for some cases of NORSE and FIRES.
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NORSE (New Onset Refractory Status Epilepticus) and FIRES (Febrile Infection-Related Epilepsy Syndrome)
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Affects of NORSE (New Onset Refractory Status Epilepticus) and FIRES (Febrile Infection-Related Epilepsy Syndrome)
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NORSE and FIRES can occur at any age but preferentially affect young adults and school-age children, with a second peak occurring around age 65. In adults, females are more likely to be affected than males, but probably not in children. The idiopathic hemiconvulsion-hemiplegia and epilepsy syndrome (IHHE) is a related syndrome seen only in infants as discussed above. As NORSE and FIRES are not always clearly reported per se in series of patients with SE, but often as either “unknown cause” or “possible brain infection”, it is difficult to provide an accurate estimate of their incidence. However, it is likely that it is responsible for at least 10 to 20% of cases of refractory SE. This proportion can reach 50 to 70% when considering only cases of SE that persists or recurs despite appropriate anesthetic treatment or recurs after withdrawal of anesthesia (known as “super-refractory” SE), or that persists for at least 7 days (known as “prolonged” RSE).In the United States, SE occurs in approximately 14 individuals/100,000 per year. Refractory SE represents approximately a third of all SE cases and NORSE represents approximately 20% of all RSE cases; thus NORSE represents approximately 7% of cases of SE, or close to 1/100,000 per year. Thus it can be estimated that about 3,200 cases of NORSE, including FIRES, occur each year in the United States.
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Affects of NORSE (New Onset Refractory Status Epilepticus) and FIRES (Febrile Infection-Related Epilepsy Syndrome). NORSE and FIRES can occur at any age but preferentially affect young adults and school-age children, with a second peak occurring around age 65. In adults, females are more likely to be affected than males, but probably not in children. The idiopathic hemiconvulsion-hemiplegia and epilepsy syndrome (IHHE) is a related syndrome seen only in infants as discussed above. As NORSE and FIRES are not always clearly reported per se in series of patients with SE, but often as either “unknown cause” or “possible brain infection”, it is difficult to provide an accurate estimate of their incidence. However, it is likely that it is responsible for at least 10 to 20% of cases of refractory SE. This proportion can reach 50 to 70% when considering only cases of SE that persists or recurs despite appropriate anesthetic treatment or recurs after withdrawal of anesthesia (known as “super-refractory” SE), or that persists for at least 7 days (known as “prolonged” RSE).In the United States, SE occurs in approximately 14 individuals/100,000 per year. Refractory SE represents approximately a third of all SE cases and NORSE represents approximately 20% of all RSE cases; thus NORSE represents approximately 7% of cases of SE, or close to 1/100,000 per year. Thus it can be estimated that about 3,200 cases of NORSE, including FIRES, occur each year in the United States.
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NORSE (New Onset Refractory Status Epilepticus) and FIRES (Febrile Infection-Related Epilepsy Syndrome)
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Related disorders of NORSE (New Onset Refractory Status Epilepticus) and FIRES (Febrile Infection-Related Epilepsy Syndrome)
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Several epilepsy syndromes in infants and children share many similarities with NORSE and FIRES, and many are likely different terms for the same condition. All these syndromes have in common an acute onset, a prolonged course of refractory SE, and inflammatory features in the CSF. These related disorders include:Refractory SE can also occur in patients with a known history of epilepsy or with an acute brain injury (trauma, stroke, etc.). These cases are easily identified and distinguished from NORSE on the basis of clinical history and/or brain imaging. As discussed above, NORSE and FIRES can be the manifestation of brain infections or autoimmune disorders. A thorough work-up will need to rule out these treatable conditions.
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Related disorders of NORSE (New Onset Refractory Status Epilepticus) and FIRES (Febrile Infection-Related Epilepsy Syndrome). Several epilepsy syndromes in infants and children share many similarities with NORSE and FIRES, and many are likely different terms for the same condition. All these syndromes have in common an acute onset, a prolonged course of refractory SE, and inflammatory features in the CSF. These related disorders include:Refractory SE can also occur in patients with a known history of epilepsy or with an acute brain injury (trauma, stroke, etc.). These cases are easily identified and distinguished from NORSE on the basis of clinical history and/or brain imaging. As discussed above, NORSE and FIRES can be the manifestation of brain infections or autoimmune disorders. A thorough work-up will need to rule out these treatable conditions.
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NORSE (New Onset Refractory Status Epilepticus) and FIRES (Febrile Infection-Related Epilepsy Syndrome)
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Diagnosis of NORSE (New Onset Refractory Status Epilepticus) and FIRES (Febrile Infection-Related Epilepsy Syndrome)
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The diagnosis of NORSE or FIRES, as a clinical presentation, is usually made on clinical grounds in patients who develop refractory SE once obvious causes of SE have been excluded. The diagnosis of cryptogenic NORSE or FIRES can only be made once uncommon causes of SE have been carefully excluded (see Clinical Testing and Work-Up section below), which typically takes several weeks to complete.Clinical Testing and Work-Up
The clinical work-up should aim at identifying treatable causes of refractory SE. Brain CT and MRI scans are required to rule out stroke and other conditions with a characteristic appearance on imaging. In some cases of cryptogenic NORSE and FIRES, brain MRI can reveal leptomeningeal enhancement, bilateral claustrum hyperintensity or progressive mesial temporal lobe atrophy. Cerebrospinal fluid studies and blood tests should be performed to rule out infectious and known metabolic, infectious, inflammatory and autoimmune conditions. In selected cases, additional tests can be performed to identify other very rare causes of SE (a suggested diagnostic evaluation can be found on the NORSE Institute website at http://www.norseinstitute.org/definitions/). Electroencephalography (EEG) and continuous EEG monitoring are usually required to detect seizures, as they frequently become increasingly subtler clinically, then undetectable, during the course of the disease.
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Diagnosis of NORSE (New Onset Refractory Status Epilepticus) and FIRES (Febrile Infection-Related Epilepsy Syndrome). The diagnosis of NORSE or FIRES, as a clinical presentation, is usually made on clinical grounds in patients who develop refractory SE once obvious causes of SE have been excluded. The diagnosis of cryptogenic NORSE or FIRES can only be made once uncommon causes of SE have been carefully excluded (see Clinical Testing and Work-Up section below), which typically takes several weeks to complete.Clinical Testing and Work-Up
The clinical work-up should aim at identifying treatable causes of refractory SE. Brain CT and MRI scans are required to rule out stroke and other conditions with a characteristic appearance on imaging. In some cases of cryptogenic NORSE and FIRES, brain MRI can reveal leptomeningeal enhancement, bilateral claustrum hyperintensity or progressive mesial temporal lobe atrophy. Cerebrospinal fluid studies and blood tests should be performed to rule out infectious and known metabolic, infectious, inflammatory and autoimmune conditions. In selected cases, additional tests can be performed to identify other very rare causes of SE (a suggested diagnostic evaluation can be found on the NORSE Institute website at http://www.norseinstitute.org/definitions/). Electroencephalography (EEG) and continuous EEG monitoring are usually required to detect seizures, as they frequently become increasingly subtler clinically, then undetectable, during the course of the disease.
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Therapies of NORSE (New Onset Refractory Status Epilepticus) and FIRES (Febrile Infection-Related Epilepsy Syndrome)
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Treatment
The treatment of SE initially consists of benzodiazepines (lorazepam, diazepam, or clonazepam), followed by a standard anti-seizure medication, as in most cases of SE. Preference is given to drugs that are available in IV form (valproic acid, phenytoin, fosphenytoin, levetiracetam, phenobarbital, lacosamide, and, more recently, brivaracetam).By definition, NORSE and FIRES do not respond to at least two lines of treatment, and additional drugs are required. The two options are either to try additional anti-seizure medications and/or to induce pharmacological coma with an anesthetic drug. In the former case, medications available in an IV formulation are often favored but others (e.g., topiramate, pregabalin, clobazam, perampanel) are sometimes used later as add-on therapy via nasogastric tube. Anesthetic agents utilized most commonly include infusions of midazolam, propofol and barbiturates (pentobarbital in the USA and thiopental in Europe). Of the three, midazolam likely has the best safety profile but may be associated with a higher risk of recurrent seizures. Barbiturates are associated with more prolonged coma and need for mechanical ventilation, with a higher rate of complications. Propofol carries a small risk of propofol infusion related syndrome (PRIS), a potentially lethal syndrome of metabolic acidosis, kidney and heart failure.When an underlying cause is identified it should be appropriately treated.There is currently no known specific therapy for cryptogenic NORSE and FIRES and studies are urgently needed to determine the best treatment options.Given the putative causal role of inflammation in cryptogenic NORSE and FIRES, it is common to use approaches that modulate the immune system. These options include IV steroids, IV immunoglobulins, plasma exchange therapy (plasmapheresis) and some monoclonal antibodies against inflammatory cells (e.g., rituximab). The efficacy of these strategies is suggested by small case series, though never investigated in controlled trials. Emerging therapies, such as anakinra (recombinant Il-1 receptor antagonist), tocilizumab (Il-6 receptor blocking humanized antibody), and cannabinoids, have been used in NORSE and FIRES in case reports and small case series. The ketogenic diet, a therapy for chronic drug-resistant epilepsy, has shown some efficacy in both pediatric and, more recently, adult cases.
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Therapies of NORSE (New Onset Refractory Status Epilepticus) and FIRES (Febrile Infection-Related Epilepsy Syndrome). Treatment
The treatment of SE initially consists of benzodiazepines (lorazepam, diazepam, or clonazepam), followed by a standard anti-seizure medication, as in most cases of SE. Preference is given to drugs that are available in IV form (valproic acid, phenytoin, fosphenytoin, levetiracetam, phenobarbital, lacosamide, and, more recently, brivaracetam).By definition, NORSE and FIRES do not respond to at least two lines of treatment, and additional drugs are required. The two options are either to try additional anti-seizure medications and/or to induce pharmacological coma with an anesthetic drug. In the former case, medications available in an IV formulation are often favored but others (e.g., topiramate, pregabalin, clobazam, perampanel) are sometimes used later as add-on therapy via nasogastric tube. Anesthetic agents utilized most commonly include infusions of midazolam, propofol and barbiturates (pentobarbital in the USA and thiopental in Europe). Of the three, midazolam likely has the best safety profile but may be associated with a higher risk of recurrent seizures. Barbiturates are associated with more prolonged coma and need for mechanical ventilation, with a higher rate of complications. Propofol carries a small risk of propofol infusion related syndrome (PRIS), a potentially lethal syndrome of metabolic acidosis, kidney and heart failure.When an underlying cause is identified it should be appropriately treated.There is currently no known specific therapy for cryptogenic NORSE and FIRES and studies are urgently needed to determine the best treatment options.Given the putative causal role of inflammation in cryptogenic NORSE and FIRES, it is common to use approaches that modulate the immune system. These options include IV steroids, IV immunoglobulins, plasma exchange therapy (plasmapheresis) and some monoclonal antibodies against inflammatory cells (e.g., rituximab). The efficacy of these strategies is suggested by small case series, though never investigated in controlled trials. Emerging therapies, such as anakinra (recombinant Il-1 receptor antagonist), tocilizumab (Il-6 receptor blocking humanized antibody), and cannabinoids, have been used in NORSE and FIRES in case reports and small case series. The ketogenic diet, a therapy for chronic drug-resistant epilepsy, has shown some efficacy in both pediatric and, more recently, adult cases.
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NORSE (New Onset Refractory Status Epilepticus) and FIRES (Febrile Infection-Related Epilepsy Syndrome)
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Overview of Ocular Albinism
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Ocular albinism type I (OA1), or X-linked ocular albinism, is the most common form of ocular albinism. Ocular albinism is a genetic disorder characterized by vision abnormalities in affected males. Vision deficits are present at birth and do not become more severe over time. Affected individuals have normal skin and hair pigmentation. Ocular albinism is inherited as an X-linked recessive genetic condition and caused by mutations in the G protein-coupled receptor 143 (GPR143) gene.
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Overview of Ocular Albinism. Ocular albinism type I (OA1), or X-linked ocular albinism, is the most common form of ocular albinism. Ocular albinism is a genetic disorder characterized by vision abnormalities in affected males. Vision deficits are present at birth and do not become more severe over time. Affected individuals have normal skin and hair pigmentation. Ocular albinism is inherited as an X-linked recessive genetic condition and caused by mutations in the G protein-coupled receptor 143 (GPR143) gene.
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Symptoms of Ocular Albinism
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Ocular albinism primarily affects pigment production in the eyes. Several vision problems can occur with ocular albinism including an involuntary movement of eyes back and forth (nystagmus), reduced iris pigment in some individuals, reduced retinal pigment, lack of development of the fovea (foveal hypoplasia) leading to blurred vision, and abnormal connections in the nerves from the retina to the brain that prevents the eyes from tracking together and reduces depth perception. Crossed eyes (strabismus) and sensitivity to light (photophobia) are also common. Typically individuals have normal hair and skin pigmentation.Congenital motor nystagmus is a genetic condition characterized by an involuntary movement of eyes back and forth (nystagmus). Affected individuals will often turn or bob their head to try to improve vision clarity. Pigmentation in the eye is normal. There is preliminary evidence that some mutations of GPR143 result in X-linked congenital nystagmus in males. This has been seen in several different Chinese families. Affected males have congenital nystagmus but they do not have the additional changes typically seen in individuals with classical X-linked ocular albinism including a reduction in retinal pigmentation and pathological changes to the fundus. Female carriers appear to be unaffected. Further research needs to be done to understand how mutations in the same gene can result in different outcomes.
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Symptoms of Ocular Albinism. Ocular albinism primarily affects pigment production in the eyes. Several vision problems can occur with ocular albinism including an involuntary movement of eyes back and forth (nystagmus), reduced iris pigment in some individuals, reduced retinal pigment, lack of development of the fovea (foveal hypoplasia) leading to blurred vision, and abnormal connections in the nerves from the retina to the brain that prevents the eyes from tracking together and reduces depth perception. Crossed eyes (strabismus) and sensitivity to light (photophobia) are also common. Typically individuals have normal hair and skin pigmentation.Congenital motor nystagmus is a genetic condition characterized by an involuntary movement of eyes back and forth (nystagmus). Affected individuals will often turn or bob their head to try to improve vision clarity. Pigmentation in the eye is normal. There is preliminary evidence that some mutations of GPR143 result in X-linked congenital nystagmus in males. This has been seen in several different Chinese families. Affected males have congenital nystagmus but they do not have the additional changes typically seen in individuals with classical X-linked ocular albinism including a reduction in retinal pigmentation and pathological changes to the fundus. Female carriers appear to be unaffected. Further research needs to be done to understand how mutations in the same gene can result in different outcomes.
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Causes of Ocular Albinism
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Mutations in the G protein-coupled receptor 143 (GPR143) gene on the X chromosome encoding a protein of 404 amino acids and are associated with ocular albinism type I (OA1). This protein is expressed in the retinal pigment epithelium (RPE) of the eye and melanocytes. GPR143 interacts with the premelanosomal protein MART1 which also plays a role in the regulation of melanin pigment formation. MART1 may act as a chaperone protein for GPR143. Mutations in GPR143 result in enlarged aberrant premelanosomes with aberrant fibril formation. There is also a decrease in melanin pigment synthesis in the premelanosome. The premelanosome is the intracellular location of melanin pigment production in the pigment cell. Aberrations of melanosomes in the skin are also present, but do not seem to reduce the amount of skin and hair pigment. GPR143 is also thought to be a receptor for L-DOPA (L-3,4-dihydroxyphenylalanine), an intermediate metabolite in the melanin pigment pathway, and may be involved in intracellular signaling in the retina.Most mutations associated with OA1 have been missense mutations, but nonsense, frameshift and splice site mutations have also been reported. Several large deletions including one or multiple exons have also been reported. In some cases flanking genes such as SHROOM2 may also be involved, but these additional genes have not been shown to be associated with alterations in pigmentation but could be involved in ocular albinism type 1 syndrome.Ocular albinism is inherited as an X-linked recessive genetic condition. X-linked recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome. Females have two X chromosomes but one of the X chromosomes is “turned off” and most of the genes on that chromosome are inactivated. Females who have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms of the disorder because inactivation of the X chromosome is random and usually half of the cells in the eye have the normal X chromosome activated resulting in normal vision. A male has one X chromosome and if he inherits an X chromosome that contains a disease gene, he will develop the disease. Males with X-linked disorders 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 to male offspring. 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.
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Causes of Ocular Albinism. Mutations in the G protein-coupled receptor 143 (GPR143) gene on the X chromosome encoding a protein of 404 amino acids and are associated with ocular albinism type I (OA1). This protein is expressed in the retinal pigment epithelium (RPE) of the eye and melanocytes. GPR143 interacts with the premelanosomal protein MART1 which also plays a role in the regulation of melanin pigment formation. MART1 may act as a chaperone protein for GPR143. Mutations in GPR143 result in enlarged aberrant premelanosomes with aberrant fibril formation. There is also a decrease in melanin pigment synthesis in the premelanosome. The premelanosome is the intracellular location of melanin pigment production in the pigment cell. Aberrations of melanosomes in the skin are also present, but do not seem to reduce the amount of skin and hair pigment. GPR143 is also thought to be a receptor for L-DOPA (L-3,4-dihydroxyphenylalanine), an intermediate metabolite in the melanin pigment pathway, and may be involved in intracellular signaling in the retina.Most mutations associated with OA1 have been missense mutations, but nonsense, frameshift and splice site mutations have also been reported. Several large deletions including one or multiple exons have also been reported. In some cases flanking genes such as SHROOM2 may also be involved, but these additional genes have not been shown to be associated with alterations in pigmentation but could be involved in ocular albinism type 1 syndrome.Ocular albinism is inherited as an X-linked recessive genetic condition. X-linked recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome. Females have two X chromosomes but one of the X chromosomes is “turned off” and most of the genes on that chromosome are inactivated. Females who have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms of the disorder because inactivation of the X chromosome is random and usually half of the cells in the eye have the normal X chromosome activated resulting in normal vision. A male has one X chromosome and if he inherits an X chromosome that contains a disease gene, he will develop the disease. Males with X-linked disorders 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 to male offspring. 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.
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Affects of Ocular Albinism
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The prevalence of ocular albinism has been reported to be one male in 20,000 births.
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Affects of Ocular Albinism. The prevalence of ocular albinism has been reported to be one male in 20,000 births.
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Related disorders of Ocular Albinism
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Symptoms of the following disorders can be similar to those of ocular albinism. Comparisons may be useful for a differential diagnosis:Oculocutaneous albinism is a group of rare inherited disorders characterized by a reduced amount or complete lack of color (pigmentation) in the skin, hair, and eyes. These conditions are caused by mutations in specific genes that are necessary for the production of melanin pigment. Abnormal or insufficient melanin pigment results in vision abnormalities and light skin that is very susceptible to damage from the sun. In some cases, individuals with oculocutaneous albinism can have near normal skin and hair pigmentation as seen in ocular albinism, making it appear to be X-linked ocular albinism, but these individuals are usually born with reduced skin and hair pigmentation and accumulate pigment with time unlike individuals with ocular albinism who are born with normal skin and hair pigmentation. Oculocutaneous albinism is inherited as an autosomal recessive genetic condition. (For more information on this disorder, choose “oculocutaneous albinism” as your search term in the Rare Disease Database.)Ocular albinism with sensorineural deafness is a condition that includes the vision abnormalities of ocular albinism as well as deafness and balance problems. Some affected individuals have different colored eyes and a white forelock of hair. Ocular albinism with sensorineural deafness is inherited as an autosomal dominant genetic condition. This is also termed Waardenburg syndrome.
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Related disorders of Ocular Albinism. Symptoms of the following disorders can be similar to those of ocular albinism. Comparisons may be useful for a differential diagnosis:Oculocutaneous albinism is a group of rare inherited disorders characterized by a reduced amount or complete lack of color (pigmentation) in the skin, hair, and eyes. These conditions are caused by mutations in specific genes that are necessary for the production of melanin pigment. Abnormal or insufficient melanin pigment results in vision abnormalities and light skin that is very susceptible to damage from the sun. In some cases, individuals with oculocutaneous albinism can have near normal skin and hair pigmentation as seen in ocular albinism, making it appear to be X-linked ocular albinism, but these individuals are usually born with reduced skin and hair pigmentation and accumulate pigment with time unlike individuals with ocular albinism who are born with normal skin and hair pigmentation. Oculocutaneous albinism is inherited as an autosomal recessive genetic condition. (For more information on this disorder, choose “oculocutaneous albinism” as your search term in the Rare Disease Database.)Ocular albinism with sensorineural deafness is a condition that includes the vision abnormalities of ocular albinism as well as deafness and balance problems. Some affected individuals have different colored eyes and a white forelock of hair. Ocular albinism with sensorineural deafness is inherited as an autosomal dominant genetic condition. This is also termed Waardenburg syndrome.
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Diagnosis of Ocular Albinism
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The diagnosis of ocular albinism is based on the characteristic eye findings. Female relatives who carry the gene for ocular albinism will have some retinal pigment abnormalities (seen as mild iris transillumination) but usually will not have the visual changes observed in affected males. Very rarely females can be affected with the hallmarks of OA1 including nystagmus and foveal hypoplasia with reduced visual acuity. Molecular genetic testing for GPR143 gene detects mutations in approximately 90% of affected males and is available to confirm the diagnosis.
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Diagnosis of Ocular Albinism. The diagnosis of ocular albinism is based on the characteristic eye findings. Female relatives who carry the gene for ocular albinism will have some retinal pigment abnormalities (seen as mild iris transillumination) but usually will not have the visual changes observed in affected males. Very rarely females can be affected with the hallmarks of OA1 including nystagmus and foveal hypoplasia with reduced visual acuity. Molecular genetic testing for GPR143 gene detects mutations in approximately 90% of affected males and is available to confirm the diagnosis.
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Therapies of Ocular Albinism
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TreatmentIndividuals diagnosed with ocular albinism should be evaluated by an ophthalmologist at the time of diagnosis to determine the extent of the disease and have ongoing ophthalmologic examinations annually. Glasses or contact lenses can greatly improve vision. Dark glasses or a hat with a brim can help to reduce sun sensitivity (photophobia).
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Therapies of Ocular Albinism. TreatmentIndividuals diagnosed with ocular albinism should be evaluated by an ophthalmologist at the time of diagnosis to determine the extent of the disease and have ongoing ophthalmologic examinations annually. Glasses or contact lenses can greatly improve vision. Dark glasses or a hat with a brim can help to reduce sun sensitivity (photophobia).
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Overview of Ocular Melanoma
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Ocular melanoma is an extremely rare form of cancer that affects the eye with an incidence of 5 per million adults. Although rare, it is the most common primary cancer of the eye in adults. Primary means that the cancer began at that site (in this case the eye) and did not spread there from another part of the body. In most people, this cancer arises in a part of the eye known as the uveal tract. The uveal tract is the colored (pigmented) layer of tissue that is found beneath the white of the eye (sclera) and is composed of normally pigmented cells and blood vessels. In the front of the eye, the uvea is made up of the colored part of the eye (iris) and a circle of muscle tissue (ciliary body) that releases a transparent fluid (aqueous humor) into the eye and helps to control the shape of the lens. The largest area of the uveal tract is in the back part of the eye (choroid) which is located beneath the retina, the vision sensing portion of the eye. In most instances, ocular melanomas arise within the choroid. Ocular melanoma arises from cells called melanocytes, which are the cells of the body that produce pigment. Ocular melanoma is a cancerous (malignant) tumor that can potentially spread (metastasize) to other parts of the body, most often to the liver. The exact cause of this disorder is unknown, but several risk factors have been identified.Although these choroidal melanocytes are similar to those cells found in the skin that produce skin pigment, when choroidal melanocytes transform into cancerous cells it is called choroidal (or uveal) melanoma. However, cutaneous (skin) melanoma and uveal (ocular) melanoma are distinct conditions which share the same name but are biologically and genetically very different diseases. It is extremely rare for skin melanoma to spread into the eye and nearly unheard of for ocular melanoma to spread to the skin.
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Overview of Ocular Melanoma. Ocular melanoma is an extremely rare form of cancer that affects the eye with an incidence of 5 per million adults. Although rare, it is the most common primary cancer of the eye in adults. Primary means that the cancer began at that site (in this case the eye) and did not spread there from another part of the body. In most people, this cancer arises in a part of the eye known as the uveal tract. The uveal tract is the colored (pigmented) layer of tissue that is found beneath the white of the eye (sclera) and is composed of normally pigmented cells and blood vessels. In the front of the eye, the uvea is made up of the colored part of the eye (iris) and a circle of muscle tissue (ciliary body) that releases a transparent fluid (aqueous humor) into the eye and helps to control the shape of the lens. The largest area of the uveal tract is in the back part of the eye (choroid) which is located beneath the retina, the vision sensing portion of the eye. In most instances, ocular melanomas arise within the choroid. Ocular melanoma arises from cells called melanocytes, which are the cells of the body that produce pigment. Ocular melanoma is a cancerous (malignant) tumor that can potentially spread (metastasize) to other parts of the body, most often to the liver. The exact cause of this disorder is unknown, but several risk factors have been identified.Although these choroidal melanocytes are similar to those cells found in the skin that produce skin pigment, when choroidal melanocytes transform into cancerous cells it is called choroidal (or uveal) melanoma. However, cutaneous (skin) melanoma and uveal (ocular) melanoma are distinct conditions which share the same name but are biologically and genetically very different diseases. It is extremely rare for skin melanoma to spread into the eye and nearly unheard of for ocular melanoma to spread to the skin.
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Symptoms of Ocular Melanoma
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Ocular melanoma may or may not cause symptoms. This generally depends on the exact location, size of the tumor within the eye, and if the tumor is causing secondary effects to the retina. An ocular melanoma may not cause any symptoms (clinically silent) for many years before symptoms begin. When symptoms develop they can include blurred vision, double vision (diplopia), irritation, pain, a perception of flashes of light in the eye (photopsia), a reduction in the total field of vision, and loss of vision. Additional symptoms that have been reported include a sensation of a foreign body like a speck of dust in the field of vision (floaters), redness, bulging or displacement of the eye (proptosis), a change in the shape of the pupil, and pressure within the eye. Some individuals may develop metamorphopsia, a distortion of vision where, when a person looks at a grid of straight lines, the lines appear wavy and parts of the grid appears blank.When an ocular melanoma occurs in the choroid, this can lead to detachment of the retina, the nerve-rich membrane lining the back of the eyes. When an ocular melanoma occurs in the ciliary body, it can displace the lens of the eye causing blurry vision from cataract or a rapid change in eyeglass prescription (astigmatism).An ocular melanoma has the potential to spread (metastasize) to other areas of the body. The liver is the most common organ in the body affected by metastasis of an ocular melanoma (80% of cases) but less often may involve the lungs, skin or soft tissue, and bone. Some estimates suggest that in 40-50% of individuals, an ocular melanoma will metastasize. Based on the aggressiveness of the particular tumor, as defined by clinical and genetic features, metastasis may be detected as early as 2-3 years after diagnosis and rarely as late as decades after treatment. Symptoms will depend upon what part of the body is affected and how long the metastasis has been present. Metastasis is a severe complication of the disease that has a high mortality rare due to lack of definitive treatments to eradicate all metastasis, though recent advances have shown success in certain instances.There are some differences in metastatic risk based on where in the uveal tract the ocular melanoma develops. For example, iris melanomas have a very low rate of metastasis compared to ciliary body and choroidal melanomas. Advances in genetic testing of individual ocular melanoma tumors has helped to better customize a patient’s risk of developing metastasis independent of the tumor location or tumor size.
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Symptoms of Ocular Melanoma. Ocular melanoma may or may not cause symptoms. This generally depends on the exact location, size of the tumor within the eye, and if the tumor is causing secondary effects to the retina. An ocular melanoma may not cause any symptoms (clinically silent) for many years before symptoms begin. When symptoms develop they can include blurred vision, double vision (diplopia), irritation, pain, a perception of flashes of light in the eye (photopsia), a reduction in the total field of vision, and loss of vision. Additional symptoms that have been reported include a sensation of a foreign body like a speck of dust in the field of vision (floaters), redness, bulging or displacement of the eye (proptosis), a change in the shape of the pupil, and pressure within the eye. Some individuals may develop metamorphopsia, a distortion of vision where, when a person looks at a grid of straight lines, the lines appear wavy and parts of the grid appears blank.When an ocular melanoma occurs in the choroid, this can lead to detachment of the retina, the nerve-rich membrane lining the back of the eyes. When an ocular melanoma occurs in the ciliary body, it can displace the lens of the eye causing blurry vision from cataract or a rapid change in eyeglass prescription (astigmatism).An ocular melanoma has the potential to spread (metastasize) to other areas of the body. The liver is the most common organ in the body affected by metastasis of an ocular melanoma (80% of cases) but less often may involve the lungs, skin or soft tissue, and bone. Some estimates suggest that in 40-50% of individuals, an ocular melanoma will metastasize. Based on the aggressiveness of the particular tumor, as defined by clinical and genetic features, metastasis may be detected as early as 2-3 years after diagnosis and rarely as late as decades after treatment. Symptoms will depend upon what part of the body is affected and how long the metastasis has been present. Metastasis is a severe complication of the disease that has a high mortality rare due to lack of definitive treatments to eradicate all metastasis, though recent advances have shown success in certain instances.There are some differences in metastatic risk based on where in the uveal tract the ocular melanoma develops. For example, iris melanomas have a very low rate of metastasis compared to ciliary body and choroidal melanomas. Advances in genetic testing of individual ocular melanoma tumors has helped to better customize a patient’s risk of developing metastasis independent of the tumor location or tumor size.
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Causes of Ocular Melanoma
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As with many forms of cancer, the exact, underlying cause of ocular melanoma is unknown. Researchers speculate that 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. In ocular melanoma, cancer arises from changes or errors in the DNA of cells called melanocytes (or pigment cells). Investigators are conducting ongoing basic research to learn more about the many factors that may result in cancer.Several risk factors have been identified in individuals with ocular melanoma including light- colored eyes, fair skin, and an inability to tan or skin that sunburns easily. People who have another disorder called dysplastic nevus syndrome (also called atypical mole syndrome) are at a greater risk of developing melanoma including ocular melanoma than people who do not have the disorder. Other conditions that increase the risk of developing ocular melanoma include atypical cutaneous nevi, common cutaneous nevi, cutaneous freckles, and iris nevi. Nevus or nevi are growths or marks on tissue such as the skin that are usually discolored and sometimes raised. They are sometimes described as an “eye freckle.” The concern with ocular nevi is whether there is a risk of the abnormal tissue becoming cancerous. Patients with a strong family history of systemic and ocular cancers may have a rare genetic mutation called the BAP1 cancer predisposition syndrome which may increase the risk of developing ocular melanoma.Melanoma of the skin has been linked to exposure to ultraviolet (UV) rays from the sun. However, research on whether exposure to UV rays contributes to ocular melanoma is inconclusive. If UV rays do influence the development of an ocular melanoma, their impact is significantly less than in the development of melanoma of the skin.Changes in a few genes have been noted to occur in some affected individuals than in people without an ocular melanoma. Researchers have shown that abnormalities on chromosomes 3, 6, 8, and 1 are common in these tumors. Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females.In approximately 50% of people there is a loss (deletion or monosomy) of genetic material on one chromosome 3. About 70% of people who experience the spread of cancer outside of the uvea (metastasis), have this monosomy. There is a gene located on chromosome 3 called the BAP1 gene. Sometimes, people with uveal melanoma do not have a monosomy of chromosome 3, but they have an altered (mutated) version of this gene. The BAP1 gene is a tumor suppressor gene, which is a gene that slows down cell division, repairs damage to the DNA of cells, and tells cells when to die, a normal process called apoptosis. Patients with an altered BAP1 gene tend to have larger tumor diameters, and higher rates of metastasis than people without this alteration. Ciliary body tumors are also more highly associated with BAP1 changes.Researchers have also determined that other genes, namely EIF1AX and a SRSF2/SF3B1 combination gene also occur with greater frequency in individuals with ocular melanomas. Other genes that have been shown to occur with greater frequency in ocular melanoma than otherwise would be expected include the GNAQ, GNA11, PLCB4, and CYSLTR2 genes.The genetics involving uveal melanoma are not fully understood and investigators are conducting research to better understand the underlying factors that contribute to tumor formation and growth in this disorder. As researchers uncover the genetic components of uveal melanomas this should lead to better, more targeted therapies.
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Causes of Ocular Melanoma. As with many forms of cancer, the exact, underlying cause of ocular melanoma is unknown. Researchers speculate that 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. In ocular melanoma, cancer arises from changes or errors in the DNA of cells called melanocytes (or pigment cells). Investigators are conducting ongoing basic research to learn more about the many factors that may result in cancer.Several risk factors have been identified in individuals with ocular melanoma including light- colored eyes, fair skin, and an inability to tan or skin that sunburns easily. People who have another disorder called dysplastic nevus syndrome (also called atypical mole syndrome) are at a greater risk of developing melanoma including ocular melanoma than people who do not have the disorder. Other conditions that increase the risk of developing ocular melanoma include atypical cutaneous nevi, common cutaneous nevi, cutaneous freckles, and iris nevi. Nevus or nevi are growths or marks on tissue such as the skin that are usually discolored and sometimes raised. They are sometimes described as an “eye freckle.” The concern with ocular nevi is whether there is a risk of the abnormal tissue becoming cancerous. Patients with a strong family history of systemic and ocular cancers may have a rare genetic mutation called the BAP1 cancer predisposition syndrome which may increase the risk of developing ocular melanoma.Melanoma of the skin has been linked to exposure to ultraviolet (UV) rays from the sun. However, research on whether exposure to UV rays contributes to ocular melanoma is inconclusive. If UV rays do influence the development of an ocular melanoma, their impact is significantly less than in the development of melanoma of the skin.Changes in a few genes have been noted to occur in some affected individuals than in people without an ocular melanoma. Researchers have shown that abnormalities on chromosomes 3, 6, 8, and 1 are common in these tumors. Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females.In approximately 50% of people there is a loss (deletion or monosomy) of genetic material on one chromosome 3. About 70% of people who experience the spread of cancer outside of the uvea (metastasis), have this monosomy. There is a gene located on chromosome 3 called the BAP1 gene. Sometimes, people with uveal melanoma do not have a monosomy of chromosome 3, but they have an altered (mutated) version of this gene. The BAP1 gene is a tumor suppressor gene, which is a gene that slows down cell division, repairs damage to the DNA of cells, and tells cells when to die, a normal process called apoptosis. Patients with an altered BAP1 gene tend to have larger tumor diameters, and higher rates of metastasis than people without this alteration. Ciliary body tumors are also more highly associated with BAP1 changes.Researchers have also determined that other genes, namely EIF1AX and a SRSF2/SF3B1 combination gene also occur with greater frequency in individuals with ocular melanomas. Other genes that have been shown to occur with greater frequency in ocular melanoma than otherwise would be expected include the GNAQ, GNA11, PLCB4, and CYSLTR2 genes.The genetics involving uveal melanoma are not fully understood and investigators are conducting research to better understand the underlying factors that contribute to tumor formation and growth in this disorder. As researchers uncover the genetic components of uveal melanomas this should lead to better, more targeted therapies.
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Ocular Melanoma
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Affects of Ocular Melanoma
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Ocular melanoma is the most common primary cancer affecting the eye. However, it is a rare disorder and is estimated to be diagnosed in about 2,500 people in the United States each year. The incidence is unknown, but one estimate places it at about 5-6 people per every 1,000,000 people in the general population. This cancer can affect men and women and individuals of all ethnic or racial groups. It occurs most commonly in older individuals with the highest incidence in the seventh and eighth decade of life. However, ocular melanoma has been reported in children as well. The disorder occurs more often in people who are fair skinned and have lighter colored eyes. The rate of occurrence is 8-10 times higher in Caucasian individuals compared to people of African descent. Ocular melanoma accounts for about 3-4% of all people with melanoma and is less common than melanoma of the skin.
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Affects of Ocular Melanoma. Ocular melanoma is the most common primary cancer affecting the eye. However, it is a rare disorder and is estimated to be diagnosed in about 2,500 people in the United States each year. The incidence is unknown, but one estimate places it at about 5-6 people per every 1,000,000 people in the general population. This cancer can affect men and women and individuals of all ethnic or racial groups. It occurs most commonly in older individuals with the highest incidence in the seventh and eighth decade of life. However, ocular melanoma has been reported in children as well. The disorder occurs more often in people who are fair skinned and have lighter colored eyes. The rate of occurrence is 8-10 times higher in Caucasian individuals compared to people of African descent. Ocular melanoma accounts for about 3-4% of all people with melanoma and is less common than melanoma of the skin.
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Ocular Melanoma
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Related disorders of Ocular Melanoma
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Symptoms of the following disorders can be similar to those of ocular melanoma. Comparisons may be useful for a differential diagnosis.There are other types of cancer that can affect the eye. An orbital lymphoma is the most common primary form of cancer affecting the orbit, which is the bony cavity that protects the eyes. Other intraocular or choroidal tumors can be benign such as a choroidal hemangioma (collection of blood vessels) or choroidal osteoma (atypical bone formation in the eye). Rare uveal tumors may also resemble ocular melanomas including leiomyosarcomas, leiomyomas, and rhabdomyosarcomas. In children, the most common intraocular tumor is called a retinoblastoma.As an ocular melanoma arises from its benign counterpart called a choroidal nevus, it is important to differentiate a benign nevus from a high-risk nevus which may grow into a melanoma. A variety of clinical features and parameters detected in a nevus may help determine whether a nevus or nevus-like lesion is at risk for growth or has already changed into an early melanoma. Differentiating pigmented nevi from an ocular melanoma sometimes can be challenging. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)Secondary cancer of the eye must also be differentiated from ocular melanoma. Secondary cancer is when cancer begins in another part of the body, then spreads to another part, in this instance, the eye. Lung and breast cancers are known to spread to the eye more commonly compared to other cancers.Finally, lesions may develop in the eye that have the appearance of an ocular melanoma but are not cancerous. These include atypical bleeding conditions within the choroid that create a “blood blister” which may resemble an ocular melanoma. Other situations when fluid collects underneath the retina (retinal detachment) may also resemble an elevated ocular melanoma. Careful examination techniques can help distinguish these conditions.Conjunctival melanoma is a rare form of eye cancer and is much rarer than a melanoma affecting the uveal tract. A melanoma affecting the orbit is even rarer. The underlying genetic (molecular) abnormalities associated with conjunctival melanoma is different from uveal melanoma. More than 95% of eye melanomas affect the uveal tract. A conjunctival melanoma is usually treated with surgery, although the use of cold to destroy affected tissue (cryotherapy) has also been used.
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Related disorders of Ocular Melanoma. Symptoms of the following disorders can be similar to those of ocular melanoma. Comparisons may be useful for a differential diagnosis.There are other types of cancer that can affect the eye. An orbital lymphoma is the most common primary form of cancer affecting the orbit, which is the bony cavity that protects the eyes. Other intraocular or choroidal tumors can be benign such as a choroidal hemangioma (collection of blood vessels) or choroidal osteoma (atypical bone formation in the eye). Rare uveal tumors may also resemble ocular melanomas including leiomyosarcomas, leiomyomas, and rhabdomyosarcomas. In children, the most common intraocular tumor is called a retinoblastoma.As an ocular melanoma arises from its benign counterpart called a choroidal nevus, it is important to differentiate a benign nevus from a high-risk nevus which may grow into a melanoma. A variety of clinical features and parameters detected in a nevus may help determine whether a nevus or nevus-like lesion is at risk for growth or has already changed into an early melanoma. Differentiating pigmented nevi from an ocular melanoma sometimes can be challenging. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)Secondary cancer of the eye must also be differentiated from ocular melanoma. Secondary cancer is when cancer begins in another part of the body, then spreads to another part, in this instance, the eye. Lung and breast cancers are known to spread to the eye more commonly compared to other cancers.Finally, lesions may develop in the eye that have the appearance of an ocular melanoma but are not cancerous. These include atypical bleeding conditions within the choroid that create a “blood blister” which may resemble an ocular melanoma. Other situations when fluid collects underneath the retina (retinal detachment) may also resemble an elevated ocular melanoma. Careful examination techniques can help distinguish these conditions.Conjunctival melanoma is a rare form of eye cancer and is much rarer than a melanoma affecting the uveal tract. A melanoma affecting the orbit is even rarer. The underlying genetic (molecular) abnormalities associated with conjunctival melanoma is different from uveal melanoma. More than 95% of eye melanomas affect the uveal tract. A conjunctival melanoma is usually treated with surgery, although the use of cold to destroy affected tissue (cryotherapy) has also been used.
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Ocular Melanoma
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Diagnosis of Ocular Melanoma
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A diagnosis of ocular melanoma is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. In many individuals, an ocular melanoma is discovered during a routine eye examination by an optometrist or general ophthalmologist without any symptoms being present, but is confirmed by an ocular oncologist who specializes in the diagnosis and treatment of eye cancer.Clinical Testing and Workup
An eye doctor may suspect ocular melanoma following a routine eye exam. Individuals may visit an eye doctor because of problems with vision or soreness in one eye. An eye doctor can detect a melanoma with a routine piece of equipment called an ophthalmoscope, a handheld instrument that contains a perforated mirror and lens and allows a physician to view structures of the eye. In other situations, special pictures are taken of the eye to assess general eye health which may detect an asymptomatic lesion which then requires further examination.A physician may order a specialized ocular ultrasound examination of the eye. An ultrasound is a test that uses high frequency sounds waves to create pieces of organs and tissues of the body. A small device is rubbed over the skin by the eye or the eyelid. This device produces sound waves which bounce back (or echo) and are recorded and then converted into images by a computer.Sometimes, a test called a fluorescein angiography may be used to aid in a diagnosis. During this test, a colored dye called fluorescein is injected into a vein in an arm. This dye will travel via the bloodstream to blood vessels in the eye. A small camera with special filters is used to take a series of pictures of the eye. The filters can detect the dye, which enables doctors to form a picture of structures of the eye to detect any damage or presence of a tumor.Optical coherence tomography (OCT) is a noninvasive imaging test performed routinely. The computer detects alterations in light waves that give a cross sectional image of the retina and parts of the choroid. This can help determine the location and associated features of a choroidal nevus or a small choroidal melanoma.Fine needle aspiration biopsy is used in some cases to confirm the diagnosis of an ocular tumor as well as to try and determine the underlying genetic abnormalities associated with the tumor, which can help doctors predict the risk of the cancer spreading (metastasizing) and help identify high risk patients. This test involves passing a thin, hollow needle through into the eye tumor through a delicate surgical procedure. The specimen can then be analyzed for with a variety of tests to determine the exact type of cancer cells and specific genetic testing.
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Diagnosis of Ocular Melanoma. A diagnosis of ocular melanoma is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. In many individuals, an ocular melanoma is discovered during a routine eye examination by an optometrist or general ophthalmologist without any symptoms being present, but is confirmed by an ocular oncologist who specializes in the diagnosis and treatment of eye cancer.Clinical Testing and Workup
An eye doctor may suspect ocular melanoma following a routine eye exam. Individuals may visit an eye doctor because of problems with vision or soreness in one eye. An eye doctor can detect a melanoma with a routine piece of equipment called an ophthalmoscope, a handheld instrument that contains a perforated mirror and lens and allows a physician to view structures of the eye. In other situations, special pictures are taken of the eye to assess general eye health which may detect an asymptomatic lesion which then requires further examination.A physician may order a specialized ocular ultrasound examination of the eye. An ultrasound is a test that uses high frequency sounds waves to create pieces of organs and tissues of the body. A small device is rubbed over the skin by the eye or the eyelid. This device produces sound waves which bounce back (or echo) and are recorded and then converted into images by a computer.Sometimes, a test called a fluorescein angiography may be used to aid in a diagnosis. During this test, a colored dye called fluorescein is injected into a vein in an arm. This dye will travel via the bloodstream to blood vessels in the eye. A small camera with special filters is used to take a series of pictures of the eye. The filters can detect the dye, which enables doctors to form a picture of structures of the eye to detect any damage or presence of a tumor.Optical coherence tomography (OCT) is a noninvasive imaging test performed routinely. The computer detects alterations in light waves that give a cross sectional image of the retina and parts of the choroid. This can help determine the location and associated features of a choroidal nevus or a small choroidal melanoma.Fine needle aspiration biopsy is used in some cases to confirm the diagnosis of an ocular tumor as well as to try and determine the underlying genetic abnormalities associated with the tumor, which can help doctors predict the risk of the cancer spreading (metastasizing) and help identify high risk patients. This test involves passing a thin, hollow needle through into the eye tumor through a delicate surgical procedure. The specimen can then be analyzed for with a variety of tests to determine the exact type of cancer cells and specific genetic testing.
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Ocular Melanoma
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Therapies of Ocular Melanoma
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Treatment
The therapeutic management of individuals with ocular melanoma may require the coordinated efforts of a team of medical professionals, such as specialists in the diagnosis and treatment of eye disorders (ocular oncologists who are specially trained ophthalmologists), eye surgeons, physicians who specialize in the diagnosis and treatment of cancer (medical oncologists), physicians who use radiation to treat cancer (radiation oncologists), and other healthcare specialists. Psychosocial support for the entire family is essential as well.Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease stage; tumor size; specific location of the tumor within the eye; the presence or absence of certain symptoms; an individual’s age and general health; and/or other elements. Decisions concerning the use of radiation therapy, experimental therapies, 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.Very small melanomas may not require treatment, and physicians may recommend watch and wait. Watch and wait refers to when physicians follow a patient with a slow-growing disorder without giving treatment until progression of the disease occurs. This allows some people to avoid undergoing therapies for many years. However, there is an increasing trend to treat even small melanomas earlier in many centers around the world.Historically, the main therapeutic options have been radiation therapy or surgery. Procedures that use local radiation to destroy tissue and cancer cells (radiotherapy) such as brachytherapy are often used, especially for small- or medium-sized ocular melanomas. Radiation therapy produces damage to the tumor cells causing them to die and the tumor to slowly shrink in size. The most common method of treating the eye with radiation therapy is a process called brachytherapy, which may also be known as “plaque therapy,” endocurietherapy, or sealed source radiotherapy. During brachytherapy, radioactive material (implant) is placed on a small disk called a plaque. This disk is inserted into the eye socket next to or near the base of a tumor and secured to the outside of the eye. The disk is left in place for several days and then removed. Sometimes, external beam radiotherapy may be used with a specialized technique called proton beam radiation. This procedure uses a machine outside of the body that delivers laser beams to the eye to destroy cancer cells. There are different types of external beam radiotherapy. Both plaque brachytherapy and proton therapy are effective treatments for ocular melanoma.In 2022, the U.S. Food and Drug Administration (FDA) approved tebentafusp-tebn (Kimmtrak) for adult patients with uveal melanoma that has spread (metastasized) or cannot be surgically removed. In order receive this therapy, a patient must have a blood test to determine if they have a specific human leukocyte antigen (HLA) called HLA-A*02:01.Other procedures that have been used to treat ocular melanoma include the use of an intense, focused light (e.g. laser therapy) to heat and destroy tissue and cancer cells (laser photocoagulation) or the use of a different type of laser to heat and destroy tissue and cancer cells (transpupillary thermotherapy).There are a variety of surgical techniques that are also used to treat ocular melanoma. Sometimes, physicians will recommend surgical removal (resection) of the entire affected eye (enucleation). Other times, physicians may recommendation surgical removal of the tissue that is affected by the disease (local resection). For example, an iris melanoma is often treated by surgical removal (resection) of the affected tissue.
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Therapies of Ocular Melanoma. Treatment
The therapeutic management of individuals with ocular melanoma may require the coordinated efforts of a team of medical professionals, such as specialists in the diagnosis and treatment of eye disorders (ocular oncologists who are specially trained ophthalmologists), eye surgeons, physicians who specialize in the diagnosis and treatment of cancer (medical oncologists), physicians who use radiation to treat cancer (radiation oncologists), and other healthcare specialists. Psychosocial support for the entire family is essential as well.Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease stage; tumor size; specific location of the tumor within the eye; the presence or absence of certain symptoms; an individual’s age and general health; and/or other elements. Decisions concerning the use of radiation therapy, experimental therapies, 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.Very small melanomas may not require treatment, and physicians may recommend watch and wait. Watch and wait refers to when physicians follow a patient with a slow-growing disorder without giving treatment until progression of the disease occurs. This allows some people to avoid undergoing therapies for many years. However, there is an increasing trend to treat even small melanomas earlier in many centers around the world.Historically, the main therapeutic options have been radiation therapy or surgery. Procedures that use local radiation to destroy tissue and cancer cells (radiotherapy) such as brachytherapy are often used, especially for small- or medium-sized ocular melanomas. Radiation therapy produces damage to the tumor cells causing them to die and the tumor to slowly shrink in size. The most common method of treating the eye with radiation therapy is a process called brachytherapy, which may also be known as “plaque therapy,” endocurietherapy, or sealed source radiotherapy. During brachytherapy, radioactive material (implant) is placed on a small disk called a plaque. This disk is inserted into the eye socket next to or near the base of a tumor and secured to the outside of the eye. The disk is left in place for several days and then removed. Sometimes, external beam radiotherapy may be used with a specialized technique called proton beam radiation. This procedure uses a machine outside of the body that delivers laser beams to the eye to destroy cancer cells. There are different types of external beam radiotherapy. Both plaque brachytherapy and proton therapy are effective treatments for ocular melanoma.In 2022, the U.S. Food and Drug Administration (FDA) approved tebentafusp-tebn (Kimmtrak) for adult patients with uveal melanoma that has spread (metastasized) or cannot be surgically removed. In order receive this therapy, a patient must have a blood test to determine if they have a specific human leukocyte antigen (HLA) called HLA-A*02:01.Other procedures that have been used to treat ocular melanoma include the use of an intense, focused light (e.g. laser therapy) to heat and destroy tissue and cancer cells (laser photocoagulation) or the use of a different type of laser to heat and destroy tissue and cancer cells (transpupillary thermotherapy).There are a variety of surgical techniques that are also used to treat ocular melanoma. Sometimes, physicians will recommend surgical removal (resection) of the entire affected eye (enucleation). Other times, physicians may recommendation surgical removal of the tissue that is affected by the disease (local resection). For example, an iris melanoma is often treated by surgical removal (resection) of the affected tissue.
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Ocular Melanoma
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Overview of Ocular Motor Apraxia, Cogan Type
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Overview of Ocular Motor Apraxia, Cogan Type.
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Ocular Motor Apraxia, Cogan Type
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Symptoms of Ocular Motor Apraxia, Cogan Type
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Cogan type ocular motor apraxia is a rare congenital disorder characterized by a defect in side-to-side (horizontal) eye movements. The eyes do not move properly in response to stimuli or voluntarily. When affected infants are asked to fixate on an object to the side, their eyes will lag and then move in the opposite direction. In order to compensate for this, the infants will sharply jerk their heads past the desired object in an effort to bring the eyes to a position where they can view the object. When the eyes fixate on the object, the head will return to its normal position. These jerking head movements are the most noticeable sign of Cogan type ocular motor apraxia and are usually recognized three to four months after birth. Before these head jerkings occur, an infant's inability to fixate on an object may sometimes be mistaken for blindness.Infants with Cogan type ocular motor apraxia will also be unable to follow rapid movements across their fields of vision, such as focusing on a moving train (opticokinetic nystagmus). The disorder can also be associated with mild developmental delay and speech difficulties.In other rare cases of Cogan type ocular motor apraxia, individuals exhibit an inability to fixate on objects to one particular side of the body (unilateral ocular motor apraxia). In some of these cases, individuals may demonstrate improper eye movements and/or an inability to track an object with the other eye. Cogan type ocular motor apraxia is not progressive and many affected individuals eventually learn to compensate for the disorder by overshooting the eyes instead of jerking the head. The number and severity of symptoms varies widely among affected individuals.Some individuals with Cogan type ocular motor apraxia have a brain abnormality such as underdevelopment (hypoplasia) of the corpus callosum, hypoplasia of the cerebellum, or an abnormality in the grey matter. (For more information on agenesis of corpus callosum, see the Related Disorders section of this report.)
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Symptoms of Ocular Motor Apraxia, Cogan Type. Cogan type ocular motor apraxia is a rare congenital disorder characterized by a defect in side-to-side (horizontal) eye movements. The eyes do not move properly in response to stimuli or voluntarily. When affected infants are asked to fixate on an object to the side, their eyes will lag and then move in the opposite direction. In order to compensate for this, the infants will sharply jerk their heads past the desired object in an effort to bring the eyes to a position where they can view the object. When the eyes fixate on the object, the head will return to its normal position. These jerking head movements are the most noticeable sign of Cogan type ocular motor apraxia and are usually recognized three to four months after birth. Before these head jerkings occur, an infant's inability to fixate on an object may sometimes be mistaken for blindness.Infants with Cogan type ocular motor apraxia will also be unable to follow rapid movements across their fields of vision, such as focusing on a moving train (opticokinetic nystagmus). The disorder can also be associated with mild developmental delay and speech difficulties.In other rare cases of Cogan type ocular motor apraxia, individuals exhibit an inability to fixate on objects to one particular side of the body (unilateral ocular motor apraxia). In some of these cases, individuals may demonstrate improper eye movements and/or an inability to track an object with the other eye. Cogan type ocular motor apraxia is not progressive and many affected individuals eventually learn to compensate for the disorder by overshooting the eyes instead of jerking the head. The number and severity of symptoms varies widely among affected individuals.Some individuals with Cogan type ocular motor apraxia have a brain abnormality such as underdevelopment (hypoplasia) of the corpus callosum, hypoplasia of the cerebellum, or an abnormality in the grey matter. (For more information on agenesis of corpus callosum, see the Related Disorders section of this report.)
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Ocular Motor Apraxia, Cogan Type
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Causes of Ocular Motor Apraxia, Cogan Type
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Cogan type ocular motor apraxia is a genetic condition for which the inheritance pattern has not been well established. It is not clear if it is inherited as an autosomal recessive genetic trait or an autosomal dominant genetic trait. 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 and be genetically normal for that particular trait is 25%. The risk is the same for males and females.Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.
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Causes of Ocular Motor Apraxia, Cogan Type. Cogan type ocular motor apraxia is a genetic condition for which the inheritance pattern has not been well established. It is not clear if it is inherited as an autosomal recessive genetic trait or an autosomal dominant genetic trait. 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 and be genetically normal for that particular trait is 25%. The risk is the same for males and females.Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.
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Ocular Motor Apraxia, Cogan Type
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Affects of Ocular Motor Apraxia, Cogan Type
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Cogan type ocular motor apraxia affects males approximately twice as often as females. Symptoms are present at birth (congenital). The jerking-head movements associated with this disorder usually appear by the third or fourth month of life. Approximately 50 cases have been reported in the medical literature.
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Affects of Ocular Motor Apraxia, Cogan Type. Cogan type ocular motor apraxia affects males approximately twice as often as females. Symptoms are present at birth (congenital). The jerking-head movements associated with this disorder usually appear by the third or fourth month of life. Approximately 50 cases have been reported in the medical literature.
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Ocular Motor Apraxia, Cogan Type
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Related disorders of Ocular Motor Apraxia, Cogan Type
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Symptoms of the following disorders can be similar to those of Cogan type ocular motor apraxia. Comparisons may be useful for a differential diagnosis:Balint's syndrome is a rare eye disorder characterized by the inability to voluntarily look at objects to the side (peripherally). An affected individual may also have trouble grasping objects due to difficulties with hand-to-eye coordination and may be unable to follow objects across the eyes' field of vision. Although the exact cause of Balint's syndrome is not known, it is thought that symptoms may be caused by improper development of part of the brain. Ataxia-telangiectasia is a rare inherited form of cerebellar ataxia that usually begins during infancy. It is characterized by loss of coordination of the limbs, the head, and the eyes, and a lower than normal immune response against infections. Rapid eye blinking, abnormal eye movements, and head thrusting may develop gradually. Ataxia-telangiectasia may be confused with Cogan type ocular motor apraxia prior to the development of visible widened (dilated) blood vessels (telangiectasias). However, unlike individuals with Cogan type ocular motor apraxia, individuals with ataxia-telangiectasia have defective up-and-down (vertical) as well as side-to-side (horizontal) eye movements. Ocular telangiectasias, which lead to a bloodshot appearance, usually begin between three and six years of age but may occur earlier. Ataxia-telangiectasia is inherited as an autosomal recessive genetic trait. (For more information on this disorder, choose “ataxia-telangiectasia” as your search term in the Rare Disease Database.) The following disorder may precede the development of Cogan type ocular motor apraxia. It can be useful in identifying an underlying cause of some forms of this disorder: Agenesis of corpus callosum (ACC) is a rare neurological disorder that is present at birth (congenital). It is characterized by a partial or complete absence (agenesis) of the area of the brain that connects the two cerebral hemispheres. Symptoms of this disorder include seizures and delays in the ability to properly sit, stand, or walk (developmental delays). Agenesis of corpus callosum is usually inherited as either an autosomal recessive trait or an X-linked dominant trait. (For more information on this disorder, choose “agenesis of corpus callosum” as your search term in the Rare Disease Database.)
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Related disorders of Ocular Motor Apraxia, Cogan Type. Symptoms of the following disorders can be similar to those of Cogan type ocular motor apraxia. Comparisons may be useful for a differential diagnosis:Balint's syndrome is a rare eye disorder characterized by the inability to voluntarily look at objects to the side (peripherally). An affected individual may also have trouble grasping objects due to difficulties with hand-to-eye coordination and may be unable to follow objects across the eyes' field of vision. Although the exact cause of Balint's syndrome is not known, it is thought that symptoms may be caused by improper development of part of the brain. Ataxia-telangiectasia is a rare inherited form of cerebellar ataxia that usually begins during infancy. It is characterized by loss of coordination of the limbs, the head, and the eyes, and a lower than normal immune response against infections. Rapid eye blinking, abnormal eye movements, and head thrusting may develop gradually. Ataxia-telangiectasia may be confused with Cogan type ocular motor apraxia prior to the development of visible widened (dilated) blood vessels (telangiectasias). However, unlike individuals with Cogan type ocular motor apraxia, individuals with ataxia-telangiectasia have defective up-and-down (vertical) as well as side-to-side (horizontal) eye movements. Ocular telangiectasias, which lead to a bloodshot appearance, usually begin between three and six years of age but may occur earlier. Ataxia-telangiectasia is inherited as an autosomal recessive genetic trait. (For more information on this disorder, choose “ataxia-telangiectasia” as your search term in the Rare Disease Database.) The following disorder may precede the development of Cogan type ocular motor apraxia. It can be useful in identifying an underlying cause of some forms of this disorder: Agenesis of corpus callosum (ACC) is a rare neurological disorder that is present at birth (congenital). It is characterized by a partial or complete absence (agenesis) of the area of the brain that connects the two cerebral hemispheres. Symptoms of this disorder include seizures and delays in the ability to properly sit, stand, or walk (developmental delays). Agenesis of corpus callosum is usually inherited as either an autosomal recessive trait or an X-linked dominant trait. (For more information on this disorder, choose “agenesis of corpus callosum” as your search term in the Rare Disease Database.)
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Ocular Motor Apraxia, Cogan Type
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nord_895_5
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Diagnosis of Ocular Motor Apraxia, Cogan Type
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Diagnosis of Cogan type ocular motor apraxia may be made upon observing the jerking-head movements that an infant will make in order to view an object to the side. Infants who exhibit jerking-head movements and the inability to fixate on an object should have a thorough eye examination by a qualified physician. Magnetic Resonance Imaging (MRI), CT Scan, or Positron Emission Tomography (PET) may be used to determine whether any associated brain abnormalities (i.e., underdevelopment of the corpus callosum or improper development of the cerebellar vermis) are present.
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Diagnosis of Ocular Motor Apraxia, Cogan Type. Diagnosis of Cogan type ocular motor apraxia may be made upon observing the jerking-head movements that an infant will make in order to view an object to the side. Infants who exhibit jerking-head movements and the inability to fixate on an object should have a thorough eye examination by a qualified physician. Magnetic Resonance Imaging (MRI), CT Scan, or Positron Emission Tomography (PET) may be used to determine whether any associated brain abnormalities (i.e., underdevelopment of the corpus callosum or improper development of the cerebellar vermis) are present.
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Ocular Motor Apraxia, Cogan Type
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nord_895_6
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Therapies of Ocular Motor Apraxia, Cogan Type
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TreatmentA supportive team approach for children with ocular motor apraxia may be of benefit and may include special education services, physical therapy, speech therapy, and other medical, social, or vocational services.Cogan type ocular motor apraxia has been associated with progressive kidney failure (nephronophthisis) in some individuals. It has been suggested that affected individuals have routine screening to determine if their kidneys are functioning normally.Genetic counseling may be of benefit for patients and their families. Other treatment is symptomatic and supportive.
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Therapies of Ocular Motor Apraxia, Cogan Type. TreatmentA supportive team approach for children with ocular motor apraxia may be of benefit and may include special education services, physical therapy, speech therapy, and other medical, social, or vocational services.Cogan type ocular motor apraxia has been associated with progressive kidney failure (nephronophthisis) in some individuals. It has been suggested that affected individuals have routine screening to determine if their kidneys are functioning normally.Genetic counseling may be of benefit for patients and their families. Other treatment is symptomatic and supportive.
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Ocular Motor Apraxia, Cogan Type
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nord_896_0
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Overview of Oculo-Auriculo-Vertebral Spectrum
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Oculo-auriculo-vertebral spectrum (OAVS) refers to three rare disorders that many clinicians believe to be intimately related to one another and which represent the range of severity of the same disorder. These disorders are apparent at birth (congenital). As the name suggests, they involve malformations of the eyes, ears and spine.Oculo-auriculo-vertebral disorder (OAVD) represents the mildest form of the disorder, while Goldenhar syndrome presents frequently as the most severe form. Hemifacial microstomia appears to be an intermediate form.The disorder is characterized by a wide spectrum of symptoms and physical features that may vary greatly in range and severity from case to case. However, such abnormalities tend to involve the cheekbones, jaw, mouth, ears, eyes, and/or bones of the spinal column (vertebrae). Although, in most cases (about 60%), such malformations affect one side of the body (unilateral), approximately 10 to 33 percent of affected individuals have such malformations on both sides of the body (bilateral), with one side typically more affected than the other (asymmetry). In the majority of such cases, the right side is more severely affected than the left.In most cases OAVS appears to occur randomly, with no apparent cause (sporadic). However, in some cases, family histories suggest autosomal dominant or recessive inheritance. In addition, some researchers suggest that the disorder may be caused by the interaction of many genes, possibly in combination with environmental factors (multifactorial inheritance).
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Overview of Oculo-Auriculo-Vertebral Spectrum. Oculo-auriculo-vertebral spectrum (OAVS) refers to three rare disorders that many clinicians believe to be intimately related to one another and which represent the range of severity of the same disorder. These disorders are apparent at birth (congenital). As the name suggests, they involve malformations of the eyes, ears and spine.Oculo-auriculo-vertebral disorder (OAVD) represents the mildest form of the disorder, while Goldenhar syndrome presents frequently as the most severe form. Hemifacial microstomia appears to be an intermediate form.The disorder is characterized by a wide spectrum of symptoms and physical features that may vary greatly in range and severity from case to case. However, such abnormalities tend to involve the cheekbones, jaw, mouth, ears, eyes, and/or bones of the spinal column (vertebrae). Although, in most cases (about 60%), such malformations affect one side of the body (unilateral), approximately 10 to 33 percent of affected individuals have such malformations on both sides of the body (bilateral), with one side typically more affected than the other (asymmetry). In the majority of such cases, the right side is more severely affected than the left.In most cases OAVS appears to occur randomly, with no apparent cause (sporadic). However, in some cases, family histories suggest autosomal dominant or recessive inheritance. In addition, some researchers suggest that the disorder may be caused by the interaction of many genes, possibly in combination with environmental factors (multifactorial inheritance).
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Oculo-Auriculo-Vertebral Spectrum
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nord_896_1
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Symptoms of Oculo-Auriculo-Vertebral Spectrum
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Oculo-auriculo-vertebral spectrum represents three rare disorders that are apparent at birth (congenital), and are characterized by a wide spectrum of symptoms and physical features that may vary greatly in range and severity from case to case. However, such abnormalities tend to involve the cheekbones, jaws, mouth, ears, eyes, and/or bones of the spinal column (vertebrae). In about 60 percent of the cases, such malformations involve one side of the body (unilateral). Yet, in approximately 10 to 33 percent of affected individuals, both sides of the body may be involved (bilateral), with one side usually more affected than the other (asymmetry). In many such cases, the right side is more severely affected than the left.For unknown reasons, hemifacial microsomia (HFM) tends to affect only the right side of the face. IN HFM, both the jaw and the eye may be substantially smaller on the affected side. The cheek on the affected side may appear to be flatter due to under development of the cheekbones on that side. The external ear may be smaller (microtia) or even absent (anotia). There may also be hearing loss. Intelligence is not affected.People with the Goldenhar variant of OAVS present with most if not all of the signs of HFM, but in 10 to 33 percent of the cases, the symptoms affect both sides of the face (bilateral). A cleft lip and/or cleft palate may be present but the presence of a cleft palate alone is more common. The muscles of the tongue and cheeks may cause severe difficulties with speech. Some tissue(s) of the eye may fail to close, presenting as a notch (coloboma) of varying size. In about one-third of cases, the patient presents with a cyst on the eye (dermoids cyst). Further, patients with Goldenhar syndrome can present with heart defects as well as kidney problems. People with Goldenhar syndrome may have underdeveloped kidneys on one side or even the lack of a kidney on the affected side. Two or more vertebrae may be fused or knitted together. Intelligence is not affected.
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Symptoms of Oculo-Auriculo-Vertebral Spectrum. Oculo-auriculo-vertebral spectrum represents three rare disorders that are apparent at birth (congenital), and are characterized by a wide spectrum of symptoms and physical features that may vary greatly in range and severity from case to case. However, such abnormalities tend to involve the cheekbones, jaws, mouth, ears, eyes, and/or bones of the spinal column (vertebrae). In about 60 percent of the cases, such malformations involve one side of the body (unilateral). Yet, in approximately 10 to 33 percent of affected individuals, both sides of the body may be involved (bilateral), with one side usually more affected than the other (asymmetry). In many such cases, the right side is more severely affected than the left.For unknown reasons, hemifacial microsomia (HFM) tends to affect only the right side of the face. IN HFM, both the jaw and the eye may be substantially smaller on the affected side. The cheek on the affected side may appear to be flatter due to under development of the cheekbones on that side. The external ear may be smaller (microtia) or even absent (anotia). There may also be hearing loss. Intelligence is not affected.People with the Goldenhar variant of OAVS present with most if not all of the signs of HFM, but in 10 to 33 percent of the cases, the symptoms affect both sides of the face (bilateral). A cleft lip and/or cleft palate may be present but the presence of a cleft palate alone is more common. The muscles of the tongue and cheeks may cause severe difficulties with speech. Some tissue(s) of the eye may fail to close, presenting as a notch (coloboma) of varying size. In about one-third of cases, the patient presents with a cyst on the eye (dermoids cyst). Further, patients with Goldenhar syndrome can present with heart defects as well as kidney problems. People with Goldenhar syndrome may have underdeveloped kidneys on one side or even the lack of a kidney on the affected side. Two or more vertebrae may be fused or knitted together. Intelligence is not affected.
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Oculo-Auriculo-Vertebral Spectrum
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nord_896_2
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Causes of Oculo-Auriculo-Vertebral Spectrum
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In most cases, oculo-auriculo-vertebral spectrum occurs randomly, with no apparent cause (sporadic). However, in some cases, positive family histories have been identified that have suggested autosomal dominant, or, less frequently, autosomal recessive inheritance. In addition, many researchers suggest that OAVS may be caused by the interaction of many genes, possibly in combination with environmental factors (multifactorial inheritance). For as yet unexplained reasons, it appears that women who have been exposed to certain medications (e.g., certain acne drugs with retinoic acid) or conditions (e.g., diabetes) during pregnancy have had children with abnormalities characteristic of OAVS. In addition, distinctive features associated with OAVS have also occurred in association with several chromosomal disorders. (For more information, see the Related Disorders section below.) The implications of such findings are not fully understood.
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Causes of Oculo-Auriculo-Vertebral Spectrum. In most cases, oculo-auriculo-vertebral spectrum occurs randomly, with no apparent cause (sporadic). However, in some cases, positive family histories have been identified that have suggested autosomal dominant, or, less frequently, autosomal recessive inheritance. In addition, many researchers suggest that OAVS may be caused by the interaction of many genes, possibly in combination with environmental factors (multifactorial inheritance). For as yet unexplained reasons, it appears that women who have been exposed to certain medications (e.g., certain acne drugs with retinoic acid) or conditions (e.g., diabetes) during pregnancy have had children with abnormalities characteristic of OAVS. In addition, distinctive features associated with OAVS have also occurred in association with several chromosomal disorders. (For more information, see the Related Disorders section below.) The implications of such findings are not fully understood.
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Oculo-Auriculo-Vertebral Spectrum
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nord_896_3
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Affects of Oculo-Auriculo-Vertebral Spectrum
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OAVS affects males more frequently than females by an approximate 3:2 ratio. There is some disagreement in the medical literature concerning the disorder's rate of occurrence. Reported estimates range from one in 3000 to 5000 live births up to one in 25,000-40,000 live births. Most of the physical characteristics associated with OAVS are apparent at birth (congenital), with the possible exception of facial asymmetry, which may not become apparent until approximately four years of age in many cases.
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Affects of Oculo-Auriculo-Vertebral Spectrum. OAVS affects males more frequently than females by an approximate 3:2 ratio. There is some disagreement in the medical literature concerning the disorder's rate of occurrence. Reported estimates range from one in 3000 to 5000 live births up to one in 25,000-40,000 live births. Most of the physical characteristics associated with OAVS are apparent at birth (congenital), with the possible exception of facial asymmetry, which may not become apparent until approximately four years of age in many cases.
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Oculo-Auriculo-Vertebral Spectrum
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nord_896_4
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Related disorders of Oculo-Auriculo-Vertebral Spectrum
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Symptoms of the following disorders may be similar to those of oculo-auriculo-vertebral spectrum. Comparisons may be useful for a differential diagnosis:Treacher Collins syndrome is an extremely rare genetic disorder characterized by distinctive abnormalities of the craniofacial area due to underdevelopment (hypoplasia) of certain portions of the skull (e.g., supraorbital rims and zygomatic arches) and lower jaw. Although the symptoms and physical characteristics associated with Treacher Collins syndrome may vary greatly in severity from case to case, craniofacial abnormalities tend to involve the cheekbones, jaws, mouth, ears, and/or eyes. Such craniofacial malformations may include underdeveloped (hypoplastic) or absent cheekbones; an incompletely developed, abnormally small lower jaw (mandibular hypoplasia and micrognathia); an unusually large mouth (macrostomia); malformations of the roof of the mouth (palate); and/or dental abnormalities such as misaligned teeth (malocclusion). Affected infants may also have underdeveloped (hypoplastic) and/or malformed (microtic) outer ears with blind ending or absent external ear canals (atresia), resulting in hearing impairment (conductive hearing loss). In addition, infants with the disorder may have downwardly slanting eyelid folds (palpebral fissues), partial or total absence of tissue (colobomas) from the outer third of the lower eyelids, and/or additional eye abnormalities. In approximately 40 percent of cases, Treacher Collins syndrome has autosomal dominant inheritance. However, in about 60 percent of cases, a positive family history is not found. Research suggests that such cases represent new genetic changes (mutations) that occur randomly, with no apparent cause (sporadic). (For more information on this disorder, choose “Treacher Collins” as your search term in the Rare Disease Database.) CHARGE association, a rare disorder that results from several defects during early fetal development, is characterized by abnormalities affecting several organ systems of the body. CHARGE is an acronym representing (C)oloboma of the eye, particularly of the colored portion of the eye (iris), giving the iris an abnormal “keyhole” shape; (H)eart defects, including Tetralogy of Fallot, ventricular and/or atrial septal defects, and patent ductus arteriosus; (A)tresia of the choanae, a condition in which the passages, or choanae, connecting the back of the nose to the throat may be narrowed or blocked, preventing normal nasal breathing; (R)etardation of growth and development, as well as mental and psychomotor retardation in some cases; (G)enital and urinary anomalies; and (E)ar abnormalities such as malformation of the outer ears and bones of the middle ears, improper functioning of the eustachian tubes, obstruction of the ear canals, and/or hearing loss. Four of these characteristic findings must be present to confirm the diagnosis of CHARGE association. In addition to the classic features, individuals with CHARGE Association may also exhibit craniofacial abnormalities, renal and central nervous system malformations, and/or other abnormalities such as tracheoesophageal fistula and/or imperforate anus. The exact cause of CHARGE association is not known; however, most cases are thought to occur randomly, with no apparent cause (sporadic). (For more information on this disorder, choose “CHARGE” as your search term in the Rare Disease Database.) VACTERL association, a rare disorder resulting from fetal development defects, is characterized by congenital abnormalities affecting several organ systems of the body. VACTERL is an acronym representing (V)ertebral abnormalities including hemivertebrae and malformation of the lower vertebrae (sacrum); (A)nal atresia, a condition in which there is absence of the anal opening; (C)ardiac defects, particularly ventricular septal defects; (T)racheo(E)sophageal fistula; (R)enal abnormalities including absence of the kidney and hydronephrosis; and improper development of one of the forearm bones (radial dysplasia) and other (L)imb defects. Symptoms may occur in various combinations and may be manifestations of several recognized disorders. Affected individuals may also exhibit additional abnormalities involving other systems of the body. In most cases, VACTERL association is thought to occur randomly, for no apparent reason (sporadic); however, researchers suggest that some cases may be inherited as an X-linked or autosomal recessive genetic trait. (For more information on this disorder, choose “VACTERL” as your search term in the Rare Disease Database.)Townes-Brocks syndrome is a rare inherited disorder that is apparent at birth (congenital). Although symptoms and physical characteristics associated with the disorder may vary greatly in range and severity from case to case, abnormalities tend to involve the face, ears, arms and legs (limbs), gastrointestinal system, and kidneys. In individuals with the disorder, one side of the face may appear smaller than the other (hemifacial microsomia). Ear abnormalities may include malformation of the outer ears, excess tags of skin and/or indentations in front of the ears (preauricular tags and/or pits), and/or hearing impairment due to abnormalities of the internal ear (sensorineural hearing loss). Affected individuals may also have malformations of the thumbs, extra fingers (polydactyly), webbing between two or more fingers and/or toes (syndactyly), and/or other limb irregularities. In addition, individuals with Townes-Brocks syndrome may exhibit absence of the anal opening (imperforate anus); abnormal passages between the rectum and the genitals (rectovaginal or rectoperineal fistula); underdeveloped kidneys (renal hypoplasia); a condition in which urine flows backwards from the bladder into a ureter (vesicoureteral reflux); and/or other related abnormalities. In addition, in some cases, affected individuals may also have abnormalities of the heart and the reproductive organs. Townes-Brocks syndrome has autosomal dominant inheritance. (For more information on this disorder, choose “Townes Brocks” as your search term in the Rare Disease Database.) Branchio-oto-renal (BOR) syndrome is a rare inherited disorder characterized by abnormalities primarily affecting the ears, neck and throat, and the kidneys. Affected individuals may exhibit excess tags of skin in front of the ears (preauricular tags), malformation of the middle and inner ear, malformed outer ears, and mild to severe conductive and/or sensorineural hearing loss. Additional abnormalities may include an abnormal passage from the throat to the outside surface of the neck (branchial fistula); an abnormal opening, cyst, or mass in the tonsil area; narrowing (stenosis) and/or absence (aplasia) of the tear ducts (lacrimal ducts); and/or craniofacial abnormalities including a long, narrow face, incomplete closure of the roof of the mouth (cleft palate), a deep overbite, and/or paralysis of certain muscles of the face. Individuals with BOR syndrome also often have mild to severe kidney (renal) abnormalities, including unusually shaped kidneys, duplication of the collecting system of the kidneys, and/or underdevelopment (hypoplasia) of the kidneys. branchio-oto-renal syndrome is inherited as an autosomal dominant genetic trait. (For more information on this disorder, choose “Branchio Oto Renal” as your search term in the Rare Disease Database.)
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Related disorders of Oculo-Auriculo-Vertebral Spectrum. Symptoms of the following disorders may be similar to those of oculo-auriculo-vertebral spectrum. Comparisons may be useful for a differential diagnosis:Treacher Collins syndrome is an extremely rare genetic disorder characterized by distinctive abnormalities of the craniofacial area due to underdevelopment (hypoplasia) of certain portions of the skull (e.g., supraorbital rims and zygomatic arches) and lower jaw. Although the symptoms and physical characteristics associated with Treacher Collins syndrome may vary greatly in severity from case to case, craniofacial abnormalities tend to involve the cheekbones, jaws, mouth, ears, and/or eyes. Such craniofacial malformations may include underdeveloped (hypoplastic) or absent cheekbones; an incompletely developed, abnormally small lower jaw (mandibular hypoplasia and micrognathia); an unusually large mouth (macrostomia); malformations of the roof of the mouth (palate); and/or dental abnormalities such as misaligned teeth (malocclusion). Affected infants may also have underdeveloped (hypoplastic) and/or malformed (microtic) outer ears with blind ending or absent external ear canals (atresia), resulting in hearing impairment (conductive hearing loss). In addition, infants with the disorder may have downwardly slanting eyelid folds (palpebral fissues), partial or total absence of tissue (colobomas) from the outer third of the lower eyelids, and/or additional eye abnormalities. In approximately 40 percent of cases, Treacher Collins syndrome has autosomal dominant inheritance. However, in about 60 percent of cases, a positive family history is not found. Research suggests that such cases represent new genetic changes (mutations) that occur randomly, with no apparent cause (sporadic). (For more information on this disorder, choose “Treacher Collins” as your search term in the Rare Disease Database.) CHARGE association, a rare disorder that results from several defects during early fetal development, is characterized by abnormalities affecting several organ systems of the body. CHARGE is an acronym representing (C)oloboma of the eye, particularly of the colored portion of the eye (iris), giving the iris an abnormal “keyhole” shape; (H)eart defects, including Tetralogy of Fallot, ventricular and/or atrial septal defects, and patent ductus arteriosus; (A)tresia of the choanae, a condition in which the passages, or choanae, connecting the back of the nose to the throat may be narrowed or blocked, preventing normal nasal breathing; (R)etardation of growth and development, as well as mental and psychomotor retardation in some cases; (G)enital and urinary anomalies; and (E)ar abnormalities such as malformation of the outer ears and bones of the middle ears, improper functioning of the eustachian tubes, obstruction of the ear canals, and/or hearing loss. Four of these characteristic findings must be present to confirm the diagnosis of CHARGE association. In addition to the classic features, individuals with CHARGE Association may also exhibit craniofacial abnormalities, renal and central nervous system malformations, and/or other abnormalities such as tracheoesophageal fistula and/or imperforate anus. The exact cause of CHARGE association is not known; however, most cases are thought to occur randomly, with no apparent cause (sporadic). (For more information on this disorder, choose “CHARGE” as your search term in the Rare Disease Database.) VACTERL association, a rare disorder resulting from fetal development defects, is characterized by congenital abnormalities affecting several organ systems of the body. VACTERL is an acronym representing (V)ertebral abnormalities including hemivertebrae and malformation of the lower vertebrae (sacrum); (A)nal atresia, a condition in which there is absence of the anal opening; (C)ardiac defects, particularly ventricular septal defects; (T)racheo(E)sophageal fistula; (R)enal abnormalities including absence of the kidney and hydronephrosis; and improper development of one of the forearm bones (radial dysplasia) and other (L)imb defects. Symptoms may occur in various combinations and may be manifestations of several recognized disorders. Affected individuals may also exhibit additional abnormalities involving other systems of the body. In most cases, VACTERL association is thought to occur randomly, for no apparent reason (sporadic); however, researchers suggest that some cases may be inherited as an X-linked or autosomal recessive genetic trait. (For more information on this disorder, choose “VACTERL” as your search term in the Rare Disease Database.)Townes-Brocks syndrome is a rare inherited disorder that is apparent at birth (congenital). Although symptoms and physical characteristics associated with the disorder may vary greatly in range and severity from case to case, abnormalities tend to involve the face, ears, arms and legs (limbs), gastrointestinal system, and kidneys. In individuals with the disorder, one side of the face may appear smaller than the other (hemifacial microsomia). Ear abnormalities may include malformation of the outer ears, excess tags of skin and/or indentations in front of the ears (preauricular tags and/or pits), and/or hearing impairment due to abnormalities of the internal ear (sensorineural hearing loss). Affected individuals may also have malformations of the thumbs, extra fingers (polydactyly), webbing between two or more fingers and/or toes (syndactyly), and/or other limb irregularities. In addition, individuals with Townes-Brocks syndrome may exhibit absence of the anal opening (imperforate anus); abnormal passages between the rectum and the genitals (rectovaginal or rectoperineal fistula); underdeveloped kidneys (renal hypoplasia); a condition in which urine flows backwards from the bladder into a ureter (vesicoureteral reflux); and/or other related abnormalities. In addition, in some cases, affected individuals may also have abnormalities of the heart and the reproductive organs. Townes-Brocks syndrome has autosomal dominant inheritance. (For more information on this disorder, choose “Townes Brocks” as your search term in the Rare Disease Database.) Branchio-oto-renal (BOR) syndrome is a rare inherited disorder characterized by abnormalities primarily affecting the ears, neck and throat, and the kidneys. Affected individuals may exhibit excess tags of skin in front of the ears (preauricular tags), malformation of the middle and inner ear, malformed outer ears, and mild to severe conductive and/or sensorineural hearing loss. Additional abnormalities may include an abnormal passage from the throat to the outside surface of the neck (branchial fistula); an abnormal opening, cyst, or mass in the tonsil area; narrowing (stenosis) and/or absence (aplasia) of the tear ducts (lacrimal ducts); and/or craniofacial abnormalities including a long, narrow face, incomplete closure of the roof of the mouth (cleft palate), a deep overbite, and/or paralysis of certain muscles of the face. Individuals with BOR syndrome also often have mild to severe kidney (renal) abnormalities, including unusually shaped kidneys, duplication of the collecting system of the kidneys, and/or underdevelopment (hypoplasia) of the kidneys. branchio-oto-renal syndrome is inherited as an autosomal dominant genetic trait. (For more information on this disorder, choose “Branchio Oto Renal” as your search term in the Rare Disease Database.)
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Oculo-Auriculo-Vertebral Spectrum
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nord_896_5
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Diagnosis of Oculo-Auriculo-Vertebral Spectrum
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Rarely, oculo-auriculo-vertebral spectrum may be detected before birth (prenatally) by specialized tests such as ultrasound imaging. In fetal ultrasonography, reflected sound waves may be used to create an image of the developing fetus, revealing characteristic findings. In the case of OAVS, such findings depend on the presence or absence of bone in the lower jaw (mandible), severe abnormalities of the outer ears, cleft palate, and/or cleft lip.OAVS may also be diagnosed and/or confirmed after birth (postnatally) by a thorough clinical evaluation, identification of characteristic physical findings, and advanced imaging techniques.A variety of specialized tests may be conducted to confirm specific abnormalities potentially associated with oculo-auriculo-vertebral spectrum disorders. For example, computer-assisted tomography (CT) scanning may be an essential aid in the detection of middle ear abnormalities that may contribute to hearing loss. Advanced imaging techniques may also be helpful in detecting and/or confirming other potential abnormalities of the skull, spinal column, lungs, and/or kidneys. In some cases, additional specialized tests (e.g., echocardiograms, electrocardio-grams, cardiac catheterization, specialized x-ray studies, etc.) may be conducted to detect and/or confirm the presence of congenital heart defects that may be associated with the disorder.Examination with an instrument (opthalmoscope) that visualizes the interior of the eye may also be conducted to detect, confirm, and/or characterize certain eye (ocular) abnormalities, such as microphthalmia or anophthalmia, epibulbar dermoids and lipodermoids, strabismus, etc.Swallowing and feeding difficulties in newborns with OAVS may suggest abnormalities such as esophageal atresia and tracheoesophageal fistula. These abnormalities may be detected by means of a flexible, hollow tube used to inject fluid into or drain fluid from the body (catheter). If it cannot pass from the mouth to the stomach, congenital malformations may be present.
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Diagnosis of Oculo-Auriculo-Vertebral Spectrum. Rarely, oculo-auriculo-vertebral spectrum may be detected before birth (prenatally) by specialized tests such as ultrasound imaging. In fetal ultrasonography, reflected sound waves may be used to create an image of the developing fetus, revealing characteristic findings. In the case of OAVS, such findings depend on the presence or absence of bone in the lower jaw (mandible), severe abnormalities of the outer ears, cleft palate, and/or cleft lip.OAVS may also be diagnosed and/or confirmed after birth (postnatally) by a thorough clinical evaluation, identification of characteristic physical findings, and advanced imaging techniques.A variety of specialized tests may be conducted to confirm specific abnormalities potentially associated with oculo-auriculo-vertebral spectrum disorders. For example, computer-assisted tomography (CT) scanning may be an essential aid in the detection of middle ear abnormalities that may contribute to hearing loss. Advanced imaging techniques may also be helpful in detecting and/or confirming other potential abnormalities of the skull, spinal column, lungs, and/or kidneys. In some cases, additional specialized tests (e.g., echocardiograms, electrocardio-grams, cardiac catheterization, specialized x-ray studies, etc.) may be conducted to detect and/or confirm the presence of congenital heart defects that may be associated with the disorder.Examination with an instrument (opthalmoscope) that visualizes the interior of the eye may also be conducted to detect, confirm, and/or characterize certain eye (ocular) abnormalities, such as microphthalmia or anophthalmia, epibulbar dermoids and lipodermoids, strabismus, etc.Swallowing and feeding difficulties in newborns with OAVS may suggest abnormalities such as esophageal atresia and tracheoesophageal fistula. These abnormalities may be detected by means of a flexible, hollow tube used to inject fluid into or drain fluid from the body (catheter). If it cannot pass from the mouth to the stomach, congenital malformations may be present.
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Oculo-Auriculo-Vertebral Spectrum
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Therapies of Oculo-Auriculo-Vertebral Spectrum
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TreatmentThe treatment of OAVS is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists who may need to work together to ensure a comprehensive, systematic approach to treatment. Such specialists may include pediatricians; physicians who diagnose and treat disorders of the ears, nose, and throat (otolaryngologists); eye specialists (ophthalmologists); neurologists; heart (cardiologists) and/or lung (cardiothoracic) surgeons; physicians who specialize in the diagnosis and treatment of disorders of the kidneys (nephrologists), urinary tract (urologists), and digestive tract (gastroenterologists); plastic surgeons; specialists who assess and treat hearing problems (audiologists); speech pathologists; and/or other health care professionals.
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Therapies of Oculo-Auriculo-Vertebral Spectrum. TreatmentThe treatment of OAVS is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists who may need to work together to ensure a comprehensive, systematic approach to treatment. Such specialists may include pediatricians; physicians who diagnose and treat disorders of the ears, nose, and throat (otolaryngologists); eye specialists (ophthalmologists); neurologists; heart (cardiologists) and/or lung (cardiothoracic) surgeons; physicians who specialize in the diagnosis and treatment of disorders of the kidneys (nephrologists), urinary tract (urologists), and digestive tract (gastroenterologists); plastic surgeons; specialists who assess and treat hearing problems (audiologists); speech pathologists; and/or other health care professionals.
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Oculo-Auriculo-Vertebral Spectrum
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nord_897_0
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Overview of Oculo-Dento-Digital Dysplasia
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Oculo-dento-digital dysplasia is a rare disorder that may be inherited as an autosomal dominant trait or be caused by a new change in the genes that occurs for no apparent reason (mutation). There also have been a few instances in which it is thought to have been inherited as an autosomal recessive trait. Major symptoms of cculo-dento-digital dysplasia are webbing of the fourth and fifth fingers, an abnormally small transparent part of the eye (microcornea), a slender nose with narrow nostrils, underdevelopment of the outer flaring wall of each nostril (alae), defective enamel and dry hair that grows slowly.
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Overview of Oculo-Dento-Digital Dysplasia. Oculo-dento-digital dysplasia is a rare disorder that may be inherited as an autosomal dominant trait or be caused by a new change in the genes that occurs for no apparent reason (mutation). There also have been a few instances in which it is thought to have been inherited as an autosomal recessive trait. Major symptoms of cculo-dento-digital dysplasia are webbing of the fourth and fifth fingers, an abnormally small transparent part of the eye (microcornea), a slender nose with narrow nostrils, underdevelopment of the outer flaring wall of each nostril (alae), defective enamel and dry hair that grows slowly.
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Oculo-Dento-Digital Dysplasia
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Symptoms of Oculo-Dento-Digital Dysplasia
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Oculo-dento-digital dysplasia is a rare disorder characterized by webbing of the fourth and fifth fingers, an abnormally small transparent front part of the eye (cornea), a slender nose, underdeveloped outer walls of each nostril, narrowing of the nostrils, defective enamel of the teeth and dry hair that grows slowly.Other symptoms that may be present in some patients with oculo-dento-digital dysplasia are: a thick lower jaw; an abnormally small head; permanent bending of the fourth and fifth fingers; webbing and/or permanent bending of the second third and fourth toes; abnormally small teeth; eyes that do not look in the same direction (strabismus); a build-up of fluid pressure in the eyeball (glaucoma); a short, narrow opening between the upper and lower eyelids; a vertical fold over the inner corner of the eye; atrophy of the eye; cleft lip and/or palate; and bone abnormalities in the toes and fifth finger.It is felt that there may be another form of oculo-dento-digital dysplasia in which the eye and skeletal changes are more severe. There have only been a few cases of this severe form documented and it is thought they may have been inherited as an autosomal recessive trait. The eyes are smaller than normal, slanted, set wide apart and blindness may occur. Skeletal abnormalities include overgrowth of the lower jaw, excessive thickening of bone tissue in the skull, an abnormally wide collarbone, and calcium deposits in the lobes of the ear.Other symptoms found in patients with autosomal recessive oculo-dento-digital dysplasia are a long narrow nose with underdeveloped outer flaring walls of the nostrils, irregular teeth with abnormal enamel, and webbing of the fourth and fifth fingers.
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Symptoms of Oculo-Dento-Digital Dysplasia. Oculo-dento-digital dysplasia is a rare disorder characterized by webbing of the fourth and fifth fingers, an abnormally small transparent front part of the eye (cornea), a slender nose, underdeveloped outer walls of each nostril, narrowing of the nostrils, defective enamel of the teeth and dry hair that grows slowly.Other symptoms that may be present in some patients with oculo-dento-digital dysplasia are: a thick lower jaw; an abnormally small head; permanent bending of the fourth and fifth fingers; webbing and/or permanent bending of the second third and fourth toes; abnormally small teeth; eyes that do not look in the same direction (strabismus); a build-up of fluid pressure in the eyeball (glaucoma); a short, narrow opening between the upper and lower eyelids; a vertical fold over the inner corner of the eye; atrophy of the eye; cleft lip and/or palate; and bone abnormalities in the toes and fifth finger.It is felt that there may be another form of oculo-dento-digital dysplasia in which the eye and skeletal changes are more severe. There have only been a few cases of this severe form documented and it is thought they may have been inherited as an autosomal recessive trait. The eyes are smaller than normal, slanted, set wide apart and blindness may occur. Skeletal abnormalities include overgrowth of the lower jaw, excessive thickening of bone tissue in the skull, an abnormally wide collarbone, and calcium deposits in the lobes of the ear.Other symptoms found in patients with autosomal recessive oculo-dento-digital dysplasia are a long narrow nose with underdeveloped outer flaring walls of the nostrils, irregular teeth with abnormal enamel, and webbing of the fourth and fifth fingers.
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Oculo-Dento-Digital Dysplasia
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nord_897_2
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Causes of Oculo-Dento-Digital Dysplasia
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Oculo-dento-digital dysplasia may be inherited as an autosomal dominant trait. In these cases, it occurs as a result of a change (mutation) in a gene on the long arm of chromosome 6 (6q21-q23.2). An autosomal recessive form is also thought to exist, but the associated gene has not been identified. Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 16q21-q23.2” refers to a region between bands 21 and 23.2 on the long arm of chromosome 6. The numbered bands specify the location of the thousands of genes that are present on each chromosome.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. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.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 and be genetically normal for that particular trait 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 Oculo-Dento-Digital Dysplasia. Oculo-dento-digital dysplasia may be inherited as an autosomal dominant trait. In these cases, it occurs as a result of a change (mutation) in a gene on the long arm of chromosome 6 (6q21-q23.2). An autosomal recessive form is also thought to exist, but the associated gene has not been identified. Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 16q21-q23.2” refers to a region between bands 21 and 23.2 on the long arm of chromosome 6. The numbered bands specify the location of the thousands of genes that are present on each chromosome.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. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.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 and be genetically normal for that particular trait 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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Oculo-Dento-Digital Dysplasia
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Affects of Oculo-Dento-Digital Dysplasia
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Oculo-dento-digital dysplasia is a very rare disorder that appears to affect males and females in equal numbers. There have been approximately eighty-five cases reported in the medical literature.The autosomal recessive form of this disorder has only been documented in about 5 cases.
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Affects of Oculo-Dento-Digital Dysplasia. Oculo-dento-digital dysplasia is a very rare disorder that appears to affect males and females in equal numbers. There have been approximately eighty-five cases reported in the medical literature.The autosomal recessive form of this disorder has only been documented in about 5 cases.
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Oculo-Dento-Digital Dysplasia
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Related disorders of Oculo-Dento-Digital Dysplasia
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Symptoms of the following disorders can be similar to those of oculo-dento-digital dysplasia. Comparisons may be useful for a differential diagnosis:Amelogenesis imperfecta is a rare genetic disorder characterized by a developmental defect of the tooth enamel. Secondary effects of this disorder may be early tooth loss, heightened susceptibility to disease of the tissues surrounding the teeth and increased sensitivity of the teeth to hot and cold. There are multiple types of this disorder and it is inherited through various modes of transmission. (For more information on this disorder, choose “Amelogenesis Imperfecta” as your search term in the Rare Disease Database.)The ectodermal dysplasias are a group of hereditary, nonprogressive syndromes in which the affected tissue derives primarily from the ectodermal germ layer. The skin, it's derivatives, and some other organs are involved. Patients have abnormal enamel on their teeth or missing teeth, and absent or unusual hair on their head. (For more information on this disorder choose “Ectodermal Dysplasias” as your search term in the Rare Disease Database.)Oro-cranio-digital syndrome is a very rare disorder that is thought to possibly be inherited as an autosomal recessive trait. Symptoms of this disorder may be an abnormally small head, abnormalities of the thumbs and toes, growth retardation and cleft lip and/or palate. This disorder affects females slightly more often than males.Saethre-Chotzen syndrome is a rare disorder thought to be inherited as an autosomal dominant trait. This disorder involves various craniofacial and skeletal malformations with abnormalities of the skin on the toes and finger. Short stature, and in some cases, mild to moderate mental retardation may also occur. (For more information on this disorder, choose “Saethre-Chotzen Syndrome” as your search term in the Rare Disease Database.)
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Related disorders of Oculo-Dento-Digital Dysplasia. Symptoms of the following disorders can be similar to those of oculo-dento-digital dysplasia. Comparisons may be useful for a differential diagnosis:Amelogenesis imperfecta is a rare genetic disorder characterized by a developmental defect of the tooth enamel. Secondary effects of this disorder may be early tooth loss, heightened susceptibility to disease of the tissues surrounding the teeth and increased sensitivity of the teeth to hot and cold. There are multiple types of this disorder and it is inherited through various modes of transmission. (For more information on this disorder, choose “Amelogenesis Imperfecta” as your search term in the Rare Disease Database.)The ectodermal dysplasias are a group of hereditary, nonprogressive syndromes in which the affected tissue derives primarily from the ectodermal germ layer. The skin, it's derivatives, and some other organs are involved. Patients have abnormal enamel on their teeth or missing teeth, and absent or unusual hair on their head. (For more information on this disorder choose “Ectodermal Dysplasias” as your search term in the Rare Disease Database.)Oro-cranio-digital syndrome is a very rare disorder that is thought to possibly be inherited as an autosomal recessive trait. Symptoms of this disorder may be an abnormally small head, abnormalities of the thumbs and toes, growth retardation and cleft lip and/or palate. This disorder affects females slightly more often than males.Saethre-Chotzen syndrome is a rare disorder thought to be inherited as an autosomal dominant trait. This disorder involves various craniofacial and skeletal malformations with abnormalities of the skin on the toes and finger. Short stature, and in some cases, mild to moderate mental retardation may also occur. (For more information on this disorder, choose “Saethre-Chotzen Syndrome” as your search term in the Rare Disease Database.)
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Oculo-Dento-Digital Dysplasia
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Diagnosis of Oculo-Dento-Digital Dysplasia
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Diagnosis of Oculo-Dento-Digital Dysplasia.
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Oculo-Dento-Digital Dysplasia
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Therapies of Oculo-Dento-Digital Dysplasia
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Patients with oculo-dento-digital dysplasia may benefit from surgery to repair the webbed fingers and bone malformations.Full crown restorations may be used to correct the defect in the enamel of the teeth.The crossed eyes (strabismus) may be corrected by wearing a patch over the strong eye in order to strengthen the weak eye. This procedure must be done at a young age in order to be affective. Surgery may also be performed in some cases.In older people whose strabismus is beyond the age of correction, the orphan drug Oculinum can be injected around the eye muscles to correct the crossed eyes. Injections must be repeated every few months.Genetic counseling may be of benefit for patients and their families. Other treatment is symptomatic and supportive.
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Therapies of Oculo-Dento-Digital Dysplasia. Patients with oculo-dento-digital dysplasia may benefit from surgery to repair the webbed fingers and bone malformations.Full crown restorations may be used to correct the defect in the enamel of the teeth.The crossed eyes (strabismus) may be corrected by wearing a patch over the strong eye in order to strengthen the weak eye. This procedure must be done at a young age in order to be affective. Surgery may also be performed in some cases.In older people whose strabismus is beyond the age of correction, the orphan drug Oculinum can be injected around the eye muscles to correct the crossed eyes. Injections must be repeated every few months.Genetic counseling may be of benefit for patients and their families. Other treatment is symptomatic and supportive.
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Oculo-Dento-Digital Dysplasia
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nord_898_0
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Overview of Oculocerebral Syndrome with Hypopigmentation
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Oculocerebral Syndrome with Hypopigmentation is an extremely rare inherited disorder characterized by the lack of normal color (hypopigmentation) of the skin and hair and abnormalities of the central nervous system that affect the eyes and certain parts of the brain (oculocerebral). Physical findings at birth include unusually light skin color and silvery-gray hair. Abnormal findings associated with the central nervous system may include abnormal smallness of one or both eyes (microphthalmia); clouding (opacities) of the front, clear portion of the eye through which light passes (cornea); and/or rapid, involuntary eye movements (nystagmus). Additional symptoms that may develop during infancy include involuntary muscle contractions, associated loss of muscle function (spastic paraplegia), developmental delays, and/or mental retardation. Oculocerebral Syndrome with Hypopigmentation is believed to be inherited as an autosomal recessive genetic trait.
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Overview of Oculocerebral Syndrome with Hypopigmentation. Oculocerebral Syndrome with Hypopigmentation is an extremely rare inherited disorder characterized by the lack of normal color (hypopigmentation) of the skin and hair and abnormalities of the central nervous system that affect the eyes and certain parts of the brain (oculocerebral). Physical findings at birth include unusually light skin color and silvery-gray hair. Abnormal findings associated with the central nervous system may include abnormal smallness of one or both eyes (microphthalmia); clouding (opacities) of the front, clear portion of the eye through which light passes (cornea); and/or rapid, involuntary eye movements (nystagmus). Additional symptoms that may develop during infancy include involuntary muscle contractions, associated loss of muscle function (spastic paraplegia), developmental delays, and/or mental retardation. Oculocerebral Syndrome with Hypopigmentation is believed to be inherited as an autosomal recessive genetic trait.
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Oculocerebral Syndrome with Hypopigmentation
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nord_898_1
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Symptoms of Oculocerebral Syndrome with Hypopigmentation
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Oculocerebral Syndrome with Hypopigmentation, also known as Cross Syndrome, is an extremely rare inherited disorder that may be apparent at birth (congenital) or during early infancy. The first visible signs of the disorder are decreased color (hypopigmentation) or total lack of color (depigmentation) of the skin and hair. The skin is usually very light and may be extremely sensitive to exposure to the sun. In most cases, the hair is often silvery or silvery-gray in color at birth. In addition, infants with Oculocerebral Syndrome with Hypopigmentation may be abnormally sensitive to light (photosensitivity). Later during infancy, affected infants may begin to exhibit more serious abnormalities. By three months of age, an infant with Oculocerebral Syndrome with Hypopigmentation may exhibit symptoms associated with abnormalities of the central nervous system (i.e., affecting parts of the brain and the eyes). These symptoms may include slow involuntary purposeless movements of various muscles, especially those in the hands (athetoid movements); impaired ability to coordinate voluntary movements (ataxia); movement of the head beyond the normal range of motion (hyperextension), and/or increased rigidity in some muscles causing stiffness and limitation of movement. In more severe cases, children may experience lack of voluntary movements of the arms and legs (spastic tetraplegia). Other neurological symptoms may include exaggerated reflexes and/or fixation of several joints in a permanently flexed position (joint contractures). The legs, arms, shoulders, and hips are the sites that are most often involved. Affected individuals may also have a high-pitched cry or make constant sucking sounds.Infants with Oculocerebral Syndrome with Hypopigmentation may also have abnormalities of the eyes including abnormal smallness of one or both eyes (microphthalmia). In some cases, the front clear portion of the eyes through which light passes (corneas) may also be unusually small (microcornea). Affected infants may also exhibit abnormal clouding (opacity) of the corneas; rapid side-to-side involuntary eye movements (horizontal nystagmus); an outward turning of the eyelids, exposing the delicate membranes that line the inside of the eyelids (ectropion palpebral conjunctivae); loss of transparency (opacity) of the lenses of the eyes (cataracts); and/or wasting away (atrophy) of the iris and/or the optic nerve (optic atrophy). Such eye abnormalities may result in varying degrees of visual impairment or, in some cases, blindness. The degree of visual impairment depends upon the severity and/or combination of eye abnormalities present.Children with Oculocerebral Syndrome with Hypopigmentation may also exhibit mental retardation, abnormally slow physical development (growth retardation), a delay in reaching developmental milestones (e.g., holding up their heads, sitting, walking, etc.), and/or a delay in the acquisition of skills requiring the coordination of muscular and mental activity (psychomotor retardation). Between the ages of six months to three years, when the baby teeth emerge from the gums, most infants with this disorder may develop abnormally large gums (gingival fibromatosis). The overgrown gums may be pink and leathery and have small pebble-like bumps on the surface. In rare cases, the gums may completely cover the teeth and protrude from the mouth. If not corrected, enlargement of the gums may cause speech problems, or in severe cases, may interfere with breathing and swallowing. Other findings in children with Oculocerebral Syndrome with Hypopigmentation may include an abnormally long appearance to the head (dolichocephaly), a highly-arched roof of the mouth (palate), widely spaced teeth, and/or underdevelopment of a muscle (diaphragm) that is necessary for proper breathing (oligophrenia). Oligophrenia may cause respiratory difficulties. In one case reported in the medical literature, urinary tract abnormalities were present.
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Symptoms of Oculocerebral Syndrome with Hypopigmentation. Oculocerebral Syndrome with Hypopigmentation, also known as Cross Syndrome, is an extremely rare inherited disorder that may be apparent at birth (congenital) or during early infancy. The first visible signs of the disorder are decreased color (hypopigmentation) or total lack of color (depigmentation) of the skin and hair. The skin is usually very light and may be extremely sensitive to exposure to the sun. In most cases, the hair is often silvery or silvery-gray in color at birth. In addition, infants with Oculocerebral Syndrome with Hypopigmentation may be abnormally sensitive to light (photosensitivity). Later during infancy, affected infants may begin to exhibit more serious abnormalities. By three months of age, an infant with Oculocerebral Syndrome with Hypopigmentation may exhibit symptoms associated with abnormalities of the central nervous system (i.e., affecting parts of the brain and the eyes). These symptoms may include slow involuntary purposeless movements of various muscles, especially those in the hands (athetoid movements); impaired ability to coordinate voluntary movements (ataxia); movement of the head beyond the normal range of motion (hyperextension), and/or increased rigidity in some muscles causing stiffness and limitation of movement. In more severe cases, children may experience lack of voluntary movements of the arms and legs (spastic tetraplegia). Other neurological symptoms may include exaggerated reflexes and/or fixation of several joints in a permanently flexed position (joint contractures). The legs, arms, shoulders, and hips are the sites that are most often involved. Affected individuals may also have a high-pitched cry or make constant sucking sounds.Infants with Oculocerebral Syndrome with Hypopigmentation may also have abnormalities of the eyes including abnormal smallness of one or both eyes (microphthalmia). In some cases, the front clear portion of the eyes through which light passes (corneas) may also be unusually small (microcornea). Affected infants may also exhibit abnormal clouding (opacity) of the corneas; rapid side-to-side involuntary eye movements (horizontal nystagmus); an outward turning of the eyelids, exposing the delicate membranes that line the inside of the eyelids (ectropion palpebral conjunctivae); loss of transparency (opacity) of the lenses of the eyes (cataracts); and/or wasting away (atrophy) of the iris and/or the optic nerve (optic atrophy). Such eye abnormalities may result in varying degrees of visual impairment or, in some cases, blindness. The degree of visual impairment depends upon the severity and/or combination of eye abnormalities present.Children with Oculocerebral Syndrome with Hypopigmentation may also exhibit mental retardation, abnormally slow physical development (growth retardation), a delay in reaching developmental milestones (e.g., holding up their heads, sitting, walking, etc.), and/or a delay in the acquisition of skills requiring the coordination of muscular and mental activity (psychomotor retardation). Between the ages of six months to three years, when the baby teeth emerge from the gums, most infants with this disorder may develop abnormally large gums (gingival fibromatosis). The overgrown gums may be pink and leathery and have small pebble-like bumps on the surface. In rare cases, the gums may completely cover the teeth and protrude from the mouth. If not corrected, enlargement of the gums may cause speech problems, or in severe cases, may interfere with breathing and swallowing. Other findings in children with Oculocerebral Syndrome with Hypopigmentation may include an abnormally long appearance to the head (dolichocephaly), a highly-arched roof of the mouth (palate), widely spaced teeth, and/or underdevelopment of a muscle (diaphragm) that is necessary for proper breathing (oligophrenia). Oligophrenia may cause respiratory difficulties. In one case reported in the medical literature, urinary tract abnormalities were present.
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Oculocerebral Syndrome with Hypopigmentation
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nord_898_2
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Causes of Oculocerebral Syndrome with Hypopigmentation
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Oculocerebral Syndrome with Hypopigmentation is believed to be inherited as an autosomal recessive genetic trait. Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother. In recessive disorders, the condition does not appear unless a person inherits the same defective 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 of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is 25 percent. Fifty percent of their children risk being carriers of the disease, but generally will not show symptoms of the disorder. Twenty-five percent of their children may receive both normal genes, one from each parent, and will be genetically normal (for that particular trait). The risk is the same for each pregnancy.Parents of several individuals with the disorder have been closely related by blood (consanguineous). In these cases, there is a higher than normal chance that both parents carry, and consequently may pass on, the genes necessary for development of the disorder.
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Causes of Oculocerebral Syndrome with Hypopigmentation. Oculocerebral Syndrome with Hypopigmentation is believed to be inherited as an autosomal recessive genetic trait. Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother. In recessive disorders, the condition does not appear unless a person inherits the same defective 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 of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is 25 percent. Fifty percent of their children risk being carriers of the disease, but generally will not show symptoms of the disorder. Twenty-five percent of their children may receive both normal genes, one from each parent, and will be genetically normal (for that particular trait). The risk is the same for each pregnancy.Parents of several individuals with the disorder have been closely related by blood (consanguineous). In these cases, there is a higher than normal chance that both parents carry, and consequently may pass on, the genes necessary for development of the disorder.
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Oculocerebral Syndrome with Hypopigmentation
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nord_898_3
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Affects of Oculocerebral Syndrome with Hypopigmentation
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Oculocerebral Syndrome with Hypopigmentation is an extremely rare disorder that affects males and females in equal numbers. Fewer than 15 cases have been reported in the medical literature. Most of these observed cases occurred within families. Abnormally small eyes and lack of skin and hair color are usually apparent at birth (congenital). Neurological abnormalities (e.g., athetoid movements, ataxia, etc.) may become apparent by three months of age. Some affected infants exhibit abnormally enlarged gums (gingival fibromatosis) when the first teeth emerge from the gums (at age six months to three years). Other symptoms (e.g., developmental delays, mental retardation, etc.) may become apparent later during infancy or childhood.
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Affects of Oculocerebral Syndrome with Hypopigmentation. Oculocerebral Syndrome with Hypopigmentation is an extremely rare disorder that affects males and females in equal numbers. Fewer than 15 cases have been reported in the medical literature. Most of these observed cases occurred within families. Abnormally small eyes and lack of skin and hair color are usually apparent at birth (congenital). Neurological abnormalities (e.g., athetoid movements, ataxia, etc.) may become apparent by three months of age. Some affected infants exhibit abnormally enlarged gums (gingival fibromatosis) when the first teeth emerge from the gums (at age six months to three years). Other symptoms (e.g., developmental delays, mental retardation, etc.) may become apparent later during infancy or childhood.
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Oculocerebral Syndrome with Hypopigmentation
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nord_898_4
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Related disorders of Oculocerebral Syndrome with Hypopigmentation
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Symptoms of the following disorders can be similar to those of Oculocerebral Syndrome with Hypopigmentation. Comparisons may be useful for a differential diagnosis:Chediak-Higashi Syndrome is a rare inherited disorder characterized by the lack of normal color of the skin and eyes (oculocutaneous albinism), visual difficulties, and/or abnormalities affecting certain white blood cells (leukocytes) that may result in immune system deficiencies. The hair is typically blond or light brown with a silvery tint. Affected infants may also exhibit abnormal sensitivity to light (photosensitivity), rapid involuntary eye movements (nystagmus), and/or an impaired ability to coordinate voluntary movements (ataxia). Chediak-Higashi Syndrome is inherited as an autosomal recessive genetic trait. (For more information on this disorder, choose “Chediak Higashi” as your search term in the Rare Disease Database.)Hermansky-Pudlak Syndrome is a rare inherited disorder characterized by: lack of normal skin pigmentation (albinism), blood platelet dysfunction with prolonged bleeding, visual impairment, and abnormal storage of a fatty-like substance in various tissues of the body. In individuals with Hermansky-Pudlak Syndrome, the skin, hair, and eyes may vary in color from very pale to almost normal coloring. Other symptoms of Hermansky-Pudlak Syndrome may include easy bruising, bleeding gums, and excessive bleeding after surgery or accidents. Hermansky-Pudlak Syndrome is inherited as an autosomal recessive genetic trait. (For more information on this disorder, choose “Hermansky Pudlak” as your search term in the Rare Disease Database.)Albinism is a group of rare inherited disorders characterized by decreased color (hypopigmentation) or complete absence of color (depigmentation) in the skin, hair, and eyes at birth. Albinism may be associated with many different syndromes. In individuals with Albinism, the skin and the eyes are generally extremely pale or white. This may result in abnormal sensitivity to light, abnormal eye movements, crossed eyes, and/or nearsightedness (myopia). Some people with Albinism may be at an increased risk of developing skin cancer. The range and severity of symptoms and physical characteristics associated with Albinism depend upon the type of Albinism present. (For more information on this disorder, choose “Albinism” as your search term in the Rare Disease Database.)Menkes Disease is a rare genetic disorder of copper metabolism beginning before birth. Copper accumulates in excessive amounts in the liver, and is deficient in most other tissues of the body. Structural changes occur in the hair, brain, bones, liver and arteries. Physical findings may include poorly pigmented, frail hair and lack of normal skin color (hypopigmentation). (For more information on this disorder, choose “Menkes” as your search term in the Rare Disease Database.)
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Related disorders of Oculocerebral Syndrome with Hypopigmentation. Symptoms of the following disorders can be similar to those of Oculocerebral Syndrome with Hypopigmentation. Comparisons may be useful for a differential diagnosis:Chediak-Higashi Syndrome is a rare inherited disorder characterized by the lack of normal color of the skin and eyes (oculocutaneous albinism), visual difficulties, and/or abnormalities affecting certain white blood cells (leukocytes) that may result in immune system deficiencies. The hair is typically blond or light brown with a silvery tint. Affected infants may also exhibit abnormal sensitivity to light (photosensitivity), rapid involuntary eye movements (nystagmus), and/or an impaired ability to coordinate voluntary movements (ataxia). Chediak-Higashi Syndrome is inherited as an autosomal recessive genetic trait. (For more information on this disorder, choose “Chediak Higashi” as your search term in the Rare Disease Database.)Hermansky-Pudlak Syndrome is a rare inherited disorder characterized by: lack of normal skin pigmentation (albinism), blood platelet dysfunction with prolonged bleeding, visual impairment, and abnormal storage of a fatty-like substance in various tissues of the body. In individuals with Hermansky-Pudlak Syndrome, the skin, hair, and eyes may vary in color from very pale to almost normal coloring. Other symptoms of Hermansky-Pudlak Syndrome may include easy bruising, bleeding gums, and excessive bleeding after surgery or accidents. Hermansky-Pudlak Syndrome is inherited as an autosomal recessive genetic trait. (For more information on this disorder, choose “Hermansky Pudlak” as your search term in the Rare Disease Database.)Albinism is a group of rare inherited disorders characterized by decreased color (hypopigmentation) or complete absence of color (depigmentation) in the skin, hair, and eyes at birth. Albinism may be associated with many different syndromes. In individuals with Albinism, the skin and the eyes are generally extremely pale or white. This may result in abnormal sensitivity to light, abnormal eye movements, crossed eyes, and/or nearsightedness (myopia). Some people with Albinism may be at an increased risk of developing skin cancer. The range and severity of symptoms and physical characteristics associated with Albinism depend upon the type of Albinism present. (For more information on this disorder, choose “Albinism” as your search term in the Rare Disease Database.)Menkes Disease is a rare genetic disorder of copper metabolism beginning before birth. Copper accumulates in excessive amounts in the liver, and is deficient in most other tissues of the body. Structural changes occur in the hair, brain, bones, liver and arteries. Physical findings may include poorly pigmented, frail hair and lack of normal skin color (hypopigmentation). (For more information on this disorder, choose “Menkes” as your search term in the Rare Disease Database.)
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Oculocerebral Syndrome with Hypopigmentation
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Diagnosis of Oculocerebral Syndrome with Hypopigmentation
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Diagnosis of Oculocerebral Syndrome with Hypopigmentation.
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Oculocerebral Syndrome with Hypopigmentation
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Therapies of Oculocerebral Syndrome with Hypopigmentation
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The diagnosis of Oculocerebral Syndrome with Hypopigmentation may be confirmed based upon a thorough clinical evaluation and detailed patient history, characteristic physical findings, specialized laboratory tests, imaging techniques, and/or genetic testing. Oculocerebral Syndrome with Hypopigmentation may be suspected in infants with characteristic neurological and ocular abnormalities occurring in association with the presence of abnormally light skin and silvery-gray hair.Abnormal lack of skin color (cutaneous hypopigmentation) and abnormally small eye(s) are usually obvious at birth or in early infancy. Ultrasonography may be used to confirm a diagnosis of microphthalmia. Ultrasonography, a testing method that creates an image of internal structures by measuring the reflection of sound waves, may demonstrate that the length from the front to the back of the eye (anteroposterior axis) is smaller than normal (microphthalmia). Horizontal side-to-side eye movements (nystagmus) and outward turning of the eyelids (ectropion palpebral conjunctivae) may also be observed at birth. Enlarged gums (gingival fibromatosis) may develop when the first teeth emerge from the gums (usually around six months to three years of age). Neurological abnormalities, such as athetoid movements and ataxia, may become apparent around three months of age. Other symptoms (e.g., developmental delays, mental retardation, etc.) may not become apparent until late infancy or childhood.Internal abnormalities such as an underdeveloped diaphragm (oligophrenia) may be detected through a combination of observation and internal imaging techniques, such as computerized tomography (CT) scanning. CT scanning is an imaging technique in which a computer and x-rays are used to create a film showing cross-sectional images of certain organs.The treatment of Oculocerebral Syndrome with Hypopigmentation is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, dentists, physicians who specialize in disorders of the eyes (ophthamologists), physicians who specialize in skin disorders (dermatologists), and other health care professionals may need to systematically and comprehensively plan an affected child's treatment.Specific therapies for the treatment of Oculocerebral Syndrome with Hypopigmentation are symptomatic and supportive. Due to lack of normal skin color, an affected child's skin may be highly sensitive to sun exposure; therefore, sunscreen, hats, and long sleeves may be recommended to avoid sunburn. Wearing sunglasses and other preventative measures may also be recommended to protect affected individuals from the sun.Corrective glasses or contact lenses may be used to help improve vision. In some cases, eye surgery may be performed.The size of the gums may be reduced with surgery. However, the enlargement may recur as more teeth emerge and/or when secondary teeth grow in, requiring subsequent surgery.Early intervention is important to ensure that affected children with Oculocerebral Syndrome with Hypopigmentation reach their potential. Special services that may be beneficial to affected children may include special remedial education and other medical, social, and/or vocational services.
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Therapies of Oculocerebral Syndrome with Hypopigmentation. The diagnosis of Oculocerebral Syndrome with Hypopigmentation may be confirmed based upon a thorough clinical evaluation and detailed patient history, characteristic physical findings, specialized laboratory tests, imaging techniques, and/or genetic testing. Oculocerebral Syndrome with Hypopigmentation may be suspected in infants with characteristic neurological and ocular abnormalities occurring in association with the presence of abnormally light skin and silvery-gray hair.Abnormal lack of skin color (cutaneous hypopigmentation) and abnormally small eye(s) are usually obvious at birth or in early infancy. Ultrasonography may be used to confirm a diagnosis of microphthalmia. Ultrasonography, a testing method that creates an image of internal structures by measuring the reflection of sound waves, may demonstrate that the length from the front to the back of the eye (anteroposterior axis) is smaller than normal (microphthalmia). Horizontal side-to-side eye movements (nystagmus) and outward turning of the eyelids (ectropion palpebral conjunctivae) may also be observed at birth. Enlarged gums (gingival fibromatosis) may develop when the first teeth emerge from the gums (usually around six months to three years of age). Neurological abnormalities, such as athetoid movements and ataxia, may become apparent around three months of age. Other symptoms (e.g., developmental delays, mental retardation, etc.) may not become apparent until late infancy or childhood.Internal abnormalities such as an underdeveloped diaphragm (oligophrenia) may be detected through a combination of observation and internal imaging techniques, such as computerized tomography (CT) scanning. CT scanning is an imaging technique in which a computer and x-rays are used to create a film showing cross-sectional images of certain organs.The treatment of Oculocerebral Syndrome with Hypopigmentation is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, dentists, physicians who specialize in disorders of the eyes (ophthamologists), physicians who specialize in skin disorders (dermatologists), and other health care professionals may need to systematically and comprehensively plan an affected child's treatment.Specific therapies for the treatment of Oculocerebral Syndrome with Hypopigmentation are symptomatic and supportive. Due to lack of normal skin color, an affected child's skin may be highly sensitive to sun exposure; therefore, sunscreen, hats, and long sleeves may be recommended to avoid sunburn. Wearing sunglasses and other preventative measures may also be recommended to protect affected individuals from the sun.Corrective glasses or contact lenses may be used to help improve vision. In some cases, eye surgery may be performed.The size of the gums may be reduced with surgery. However, the enlargement may recur as more teeth emerge and/or when secondary teeth grow in, requiring subsequent surgery.Early intervention is important to ensure that affected children with Oculocerebral Syndrome with Hypopigmentation reach their potential. Special services that may be beneficial to affected children may include special remedial education and other medical, social, and/or vocational services.
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Oculocerebral Syndrome with Hypopigmentation
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nord_899_0
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Overview of Oculocerebrocutaneous Syndrome
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Oculocerebrocutaneous (OCC) syndrome is a rare genetic disorder that is apparent at birth (congenital). The disorder is characterized primarily by eye (ocular), brain (e.g., cerebral) and skin (cutaneous) malformations. For example, many affected infants have semisolid or fluid-filled swellings (cysts) within the cavities of the skull (orbits) that accommodate the eyeballs and associated structures. In most patients, the eye on the affected side or sides is also abnormally small (microphthalmos). Brain abnormalities associated with OCC syndrome may include enlargement of the ventricular system, multiple fluid-filled spaces within and malformations of the outer region of the cerebral hemispheres (cerebral cortex), absence of the band of nerve fibers that joins the brain’s hemispheres (agenesis of the corpus callosum) and a typical malformation of mid- and hindbrain. Affected infants and children often have intellectual disability and episodes of uncontrolled electrical activity in the brain (seizures). In addition, OCC syndrome is characterized by underdevelopment or absence of skin in certain localized regions (focal dermal hypoplasia or aplasia), and most have protruding, flesh-colored or brownish outgrowths of skin (cutaneous tags) within certain facial areas, including around the eyelids, on the cheeks, or near the ears. In all individuals with OCC syndrome known so far, the disorder occurs sporadically (with no family history of similar disorders).
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Overview of Oculocerebrocutaneous Syndrome. Oculocerebrocutaneous (OCC) syndrome is a rare genetic disorder that is apparent at birth (congenital). The disorder is characterized primarily by eye (ocular), brain (e.g., cerebral) and skin (cutaneous) malformations. For example, many affected infants have semisolid or fluid-filled swellings (cysts) within the cavities of the skull (orbits) that accommodate the eyeballs and associated structures. In most patients, the eye on the affected side or sides is also abnormally small (microphthalmos). Brain abnormalities associated with OCC syndrome may include enlargement of the ventricular system, multiple fluid-filled spaces within and malformations of the outer region of the cerebral hemispheres (cerebral cortex), absence of the band of nerve fibers that joins the brain’s hemispheres (agenesis of the corpus callosum) and a typical malformation of mid- and hindbrain. Affected infants and children often have intellectual disability and episodes of uncontrolled electrical activity in the brain (seizures). In addition, OCC syndrome is characterized by underdevelopment or absence of skin in certain localized regions (focal dermal hypoplasia or aplasia), and most have protruding, flesh-colored or brownish outgrowths of skin (cutaneous tags) within certain facial areas, including around the eyelids, on the cheeks, or near the ears. In all individuals with OCC syndrome known so far, the disorder occurs sporadically (with no family history of similar disorders).
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Oculocerebrocutaneous Syndrome
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Symptoms of Oculocerebrocutaneous Syndrome
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OCC syndrome is characterized by distinctive eye (ocular), brain (e.g., cerebral) and skin (cutaneous) malformations. Most infants with the disorder have fluid-filled or semisolid swellings (cysts) within the cavities of the skull (orbits) that accommodate the eyeballs. The eye on the affected side or sides is characteristically small (microphthalmos). In some patients, the orbital cysts may contain benign (noncancerous), tumor-like nodules (hamartomas) consisting of ocular tissue. Affected infants may have additional ocular abnormalities, such as absence or defects (notches) of tissue (colobomas) of the upper eyelids, the lower eyelids, or the colored part of the eye(s) (irises) or abnormal persistence of the embryonic blood vessel (the hyaloid artery system) that supplies certain regions of the eyes (persistent fetal vasculature, the hyaloid artery usually disappears during the ninth month of fetal development.)Infants with OCC syndrome may also have skeletal abnormalities. These may include underdevelopment (hypoplasia) of the orbits or other bones of the skull (e.g., zygomas); malformation of certain ribs or of the bones of the spinal column (vertebrae); and/or abnormal curvature of the spine (scoliosis).OCC syndrome is also characterized by abnormalities of the brain. These malformations include the presence of malformations of the cerebral hemispheres (cerebral cortex), mainly polymicrogyria or periventricular heterotopia; abnormal, fluid-filled spaces in the outer region of the cerebral cortex; absence of the band of nerve fibers that joins the brain’s hemispheres (agenesis of the corpus callosum); and a very characteristic malformation of the mid- and hindbrain with a giant tectum and missing or hypoplastic vermis of the cerebellum. The ventricles (fluid filled cavities) in the brain may be enlarged and obstructive hydrocephalus may occur, a condition in which there is obstructed flow of the fluid surrounding the brain and spinal cord (cerebrospinal fluid [CSF]), resulting in increasing fluid pressure in the brain leading to rapid enlargement of the head and other symptoms. Many affected infants have intellectual disability, substantial delay in the acquisition of skills requiring the coordination of mental and physical activities (psychomotor impairment), and episodes of uncontrolled electrical activity in the brain (seizures). In rare cases, infants with OCC syndrome may have protrusion of a portion of the brain and its surrounding membranes (meninges) through a defect in the back of the skull (occipital meningoencephalocele).OCC syndrome also has distinctive skin (cutaneous) abnormalities. Most infants with the disorder have multiple localized areas in which the skin is underdeveloped (hypoplastic), absent (aplastic), or characterized by a “punched-out “appearance in some cases, involved areas appear as abnormal depressions in the skin. Although these lesions primarily affect the head, face, and trunk, they may occur anywhere on the body. Many affected infants also have protruding, brownish or flesh-colored outgrowths of skin (skin or cutaneous tags). Such cutaneous outgrowths usually appear around the eyes (periorbital). However, they may occur in other facial regions, such as the cheeks or near the ears, or, more rarely, in other bodily areas.In some infants with OCC syndrome, the various cutaneous, ocular, orbital, or other malformations may involve one side of the body (unilateral). In those with unilateral involvement, the left side has been affected more often than the right. As a result, the face appears different on one side from the other (facial asymmetry). Less commonly, due to the presence of certain skeletal abnormalities, such as those mentioned above, one side of the body may appear different from the other (generalized body asymmetry).Rarely, infants with OCC syndrome may have other signs, including undescended testes, incomplete closure of the roof of the mouth (cleft palate), clefts involving larger parts of the face or other physical features.
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Symptoms of Oculocerebrocutaneous Syndrome. OCC syndrome is characterized by distinctive eye (ocular), brain (e.g., cerebral) and skin (cutaneous) malformations. Most infants with the disorder have fluid-filled or semisolid swellings (cysts) within the cavities of the skull (orbits) that accommodate the eyeballs. The eye on the affected side or sides is characteristically small (microphthalmos). In some patients, the orbital cysts may contain benign (noncancerous), tumor-like nodules (hamartomas) consisting of ocular tissue. Affected infants may have additional ocular abnormalities, such as absence or defects (notches) of tissue (colobomas) of the upper eyelids, the lower eyelids, or the colored part of the eye(s) (irises) or abnormal persistence of the embryonic blood vessel (the hyaloid artery system) that supplies certain regions of the eyes (persistent fetal vasculature, the hyaloid artery usually disappears during the ninth month of fetal development.)Infants with OCC syndrome may also have skeletal abnormalities. These may include underdevelopment (hypoplasia) of the orbits or other bones of the skull (e.g., zygomas); malformation of certain ribs or of the bones of the spinal column (vertebrae); and/or abnormal curvature of the spine (scoliosis).OCC syndrome is also characterized by abnormalities of the brain. These malformations include the presence of malformations of the cerebral hemispheres (cerebral cortex), mainly polymicrogyria or periventricular heterotopia; abnormal, fluid-filled spaces in the outer region of the cerebral cortex; absence of the band of nerve fibers that joins the brain’s hemispheres (agenesis of the corpus callosum); and a very characteristic malformation of the mid- and hindbrain with a giant tectum and missing or hypoplastic vermis of the cerebellum. The ventricles (fluid filled cavities) in the brain may be enlarged and obstructive hydrocephalus may occur, a condition in which there is obstructed flow of the fluid surrounding the brain and spinal cord (cerebrospinal fluid [CSF]), resulting in increasing fluid pressure in the brain leading to rapid enlargement of the head and other symptoms. Many affected infants have intellectual disability, substantial delay in the acquisition of skills requiring the coordination of mental and physical activities (psychomotor impairment), and episodes of uncontrolled electrical activity in the brain (seizures). In rare cases, infants with OCC syndrome may have protrusion of a portion of the brain and its surrounding membranes (meninges) through a defect in the back of the skull (occipital meningoencephalocele).OCC syndrome also has distinctive skin (cutaneous) abnormalities. Most infants with the disorder have multiple localized areas in which the skin is underdeveloped (hypoplastic), absent (aplastic), or characterized by a “punched-out “appearance in some cases, involved areas appear as abnormal depressions in the skin. Although these lesions primarily affect the head, face, and trunk, they may occur anywhere on the body. Many affected infants also have protruding, brownish or flesh-colored outgrowths of skin (skin or cutaneous tags). Such cutaneous outgrowths usually appear around the eyes (periorbital). However, they may occur in other facial regions, such as the cheeks or near the ears, or, more rarely, in other bodily areas.In some infants with OCC syndrome, the various cutaneous, ocular, orbital, or other malformations may involve one side of the body (unilateral). In those with unilateral involvement, the left side has been affected more often than the right. As a result, the face appears different on one side from the other (facial asymmetry). Less commonly, due to the presence of certain skeletal abnormalities, such as those mentioned above, one side of the body may appear different from the other (generalized body asymmetry).Rarely, infants with OCC syndrome may have other signs, including undescended testes, incomplete closure of the roof of the mouth (cleft palate), clefts involving larger parts of the face or other physical features.
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Oculocerebrocutaneous Syndrome
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Causes of Oculocerebrocutaneous Syndrome
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In all reported individuals with OCC syndrome, there is no family history of the disorder. Therefore, geneticists suggest that OCC syndrome is caused by a genetic change (variant or mutation) that appears to be present in some of the cells of the body only (somatic mosaicism) and is thought to be the consequence of a randomly occurring, new event in one of the cells present at a very early embryonic stage.A few affected individuals have had relatives with conditions distantly similar but probably unrelated to OCC syndrome. For example, the mother of one affected individual had defects of ocular tissue affecting both eyes (bilateral colobomas), and a cousin of another had an ocular cyst.The exact cause of OCC is still unknown and difficult to determine.
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Causes of Oculocerebrocutaneous Syndrome. In all reported individuals with OCC syndrome, there is no family history of the disorder. Therefore, geneticists suggest that OCC syndrome is caused by a genetic change (variant or mutation) that appears to be present in some of the cells of the body only (somatic mosaicism) and is thought to be the consequence of a randomly occurring, new event in one of the cells present at a very early embryonic stage.A few affected individuals have had relatives with conditions distantly similar but probably unrelated to OCC syndrome. For example, the mother of one affected individual had defects of ocular tissue affecting both eyes (bilateral colobomas), and a cousin of another had an ocular cyst.The exact cause of OCC is still unknown and difficult to determine.
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Oculocerebrocutaneous Syndrome
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Affects of Oculocerebrocutaneous Syndrome
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OCC syndrome has been reported more frequently in males than in females; however, the prevalence is unknown. Since the disorder was originally described in 1981 (JW Delleman & JWE Oorthuys), approximately 40 patients have been reported in the medical literature.
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Affects of Oculocerebrocutaneous Syndrome. OCC syndrome has been reported more frequently in males than in females; however, the prevalence is unknown. Since the disorder was originally described in 1981 (JW Delleman & JWE Oorthuys), approximately 40 patients have been reported in the medical literature.
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Oculocerebrocutaneous Syndrome
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Related disorders of Oculocerebrocutaneous Syndrome
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Symptoms of the following disorders may be similar to those of oculocerebrocutaneous syndrome. Comparisons may be useful for a differential diagnosis:Microphthalmia with linear skin defects syndrome is a rare genetic disorder that is caused by an alteration on the X chromosome (most often a missing piece in chromosome region Xp22.2 that includes the HCCS gene) which affects only females. The disorder is characterized by eye (ocular) defects, including abnormally small size of the eyes (microphthalmia); and clouding of the front, usually transparent surface of the eyes (corneal opacities). These ocular defects typically occur in association with underdevelopment or absence of skin in “streak-like” (linear) patterns, primarily affecting the head and neck region and healing into hyperpigmented areas with age. Some affected females may have additional abnormalities, including congenital heart defects, a small head (microcephaly), absence of the band of nerve fibers that joins the two hemispheres of the brain (agenesis of the septum pellucidum), seizures, or intellectual disability.Focal dermal hypoplasia is also a rare genetic X-linked disorder caused by a change (mutation) in the PORCN gene. The condition is characterized by distinctive abnormalities of the skin, the fingers and toes, the eyes, and other bodily regions. Primary cutaneous abnormalities include underdevelopment of localized areas of skin (focal dermal hypoplasia) with protrusion of fat (herniation); red streaking of the skin; and multiple benign (noncancerous) tumors (papillomas) of the skin or mucous membranes (including the esophagus and the larynx). Most affected females also have ocular defects, such as small eyes (microphthalmia); absence or defects of ocular tissues (colobomas of the iris or the choroid); or abnormal malalignment of one eye in relation to the other (strabismus, usually turned in or esotropia). Limb malformations may include webbing or fusion (syndactyly) of certain fingers or toes; permanent flexion of one or more digits (camptodactyly); additional fingers or toes (polydactyly); or absence of certain digits (usually in the middle of the hand). Also present are skeletal abnormalities, such as an unusually small, rounded skull; malformations of bones in the spinal column (vertebrae); unusual streaks (striations) in the long bones or abnormal curvature of the spine. Many affected individuals also have abnormal eruption, irregular spacing, defective enamel, or absence of some teeth (hypodontia); an abnormal vertical notch in the upper lip (cleft lip); incomplete closure of the roof of the mouth (cleft palate); or other physical abnormalities. Most individuals with the disorder have intellectual disability. (For further information on this disorder, choose “focal dermal hypoplasia” as your search term in the Rare Disease Database.)Encephalocraniocutaneous lipomatosis is a rare genetic disorder that is typically characterized by skin abnormalities, ocular defects and multiple benign fatty tumors (lipomas) in the brain or along the spinal cord. ECCL may involve one or both sides of the body (unilateral or bilateral). It can be associated with a normal development or mild to severe intellectual disability and may lead to episodes of uncontrolled electrical activity in the brain (seizures). Affected individuals have multiple subcutaneous lipomas and other benign tumor-like lesions (hamartomas), involving the surface of the eye (epibulbar dermoids), and may show protruding outgrowths of skin (skin tags) that may involve the eyelids, the nose, or other regions. They may also show areas localized loss of scalp hair (alopecia) possibly with underlying fatty tissue (so-called nevus psiloliparus), and areas of underdeveloped (hypoplastic) or absent (aplastic) scalp. Additional findings in the brain include fluid-filled spaces in the brain (porencephalic cysts), anomalies of the vessels and of the protective membranes surrounding the brain and spinal cord (i.e., leptomeninges). Affected individuals may have a large head (macrocephaly); congenital malformation of the aorta; cystic bone lesions that may be progressive. Sometimes, they develop jaw tumors and a particular brain tumor (low-grade gliomas). To date, all individuals with ECCL are the only individuals in their families with the disorder (isolated). In some patients, somatic mosaic mutations in the FGFR1 gene or the KRAS gene have been identified, meaning that the mutation (genetic change) is only present in part of the cells of the body (somatic mosaicism). This is the consequence of a randomly occurring, new event in one of the cells present at a very early embryonic stage.Goldenhar syndrome, a term used synonymously with “oculo-auriculo-vertebral (OAV) spectrum,” is a rare genetic disorder apparent at birth (congenital). The disorder is characterized by a wide spectrum of signs and physical features that vary greatly in extent and severity from patient to patient. However, the abnormalities tend to involve the cheekbones, jaws, mouth, ears, eyes, and bones of the spinal column (vertebrae). Although the malformations usually affect one side of the body (unilateral), some affected individuals have such abnormalities on both sides (bilateral) in which one side is more affected than the other. Due to these malformations, the face usually appears smaller on one side (hemifacial microsomia). Craniofacial abnormalities include underdevelopment of the cheekbones (malar hypoplasia), bones of the upper and lower jaws, and bones forming a portion of the lower skull (temporal hypoplasia); incomplete development of certain muscles of the face; an abnormally wide mouth (macrostomia); incomplete closure of the roof of the mouth (cleft palate); an abnormal groove in the upper lip (cleft lip); and/or abnormalities of the teeth. Malformation (microtia) or absence (anotia) of the outer ears (auricles or pinnae) also occurs; narrow, blind ending, or absent external ear canals (atresia); abnormal outgrowths of skin and cartilage on or in front of the ears (preauricular tags); or abnormalities affecting the middle or inner ears, resulting in hearing impairment (either conductive or sensorineural hearing loss). Eye abnormalities may include the formation of solid benign tumors on the surface of the eyeball(s) (epibulbar dermoids and lipodermoids), partial absence of tissue (coloboma) from the upper eyelids, abnormally small eye(s) (microphthalmia), narrowing of the openings (palpebral fissures) between the upper and lower eyelids (blepharophimosis), or other ocular abnormalities. In some individuals, additional physical malformations and/or mild intellectual disability may occur. Goldenhar syndrome is usually an isolated event with no family history. A few reports imply a positive family history, suggesting autosomal dominant or autosomal recessive inheritance. In addition, some investigators have suggested that the disorder may be caused by the combined interaction of a few genes (oligogenic inheritance). (For further information on this disorder, choose “Goldenhar” as your search term in the Rare Disease Database.)Aicardi syndrome is a rare disorder affecting females only. Individuals with Aicardi syndrome have underdeveloped or absent tissue connecting the left and the right halves of the brain (agenesis corpus callosum) in combination with a multitude of other brain lesions. These brain lesions overlap substantially with those seen in OCC syndrome although the typical mid-hindbrain malformation seen in OCC syndrome is unknown in Aicardi syndrome. Affected individuals show severe intellectual disability, infantile spasms and other types of seizures. Examination of the eyes typically shows holes in the retina (chorioretinal lacunae), but the eye anomalies known in OCC syndrome may be seen occasionally. Anomalies of the ribs, the spine, and the skin may be associated. Aicardi syndrome occurs sporadically. The underlying gene has not yet been identified.
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Related disorders of Oculocerebrocutaneous Syndrome. Symptoms of the following disorders may be similar to those of oculocerebrocutaneous syndrome. Comparisons may be useful for a differential diagnosis:Microphthalmia with linear skin defects syndrome is a rare genetic disorder that is caused by an alteration on the X chromosome (most often a missing piece in chromosome region Xp22.2 that includes the HCCS gene) which affects only females. The disorder is characterized by eye (ocular) defects, including abnormally small size of the eyes (microphthalmia); and clouding of the front, usually transparent surface of the eyes (corneal opacities). These ocular defects typically occur in association with underdevelopment or absence of skin in “streak-like” (linear) patterns, primarily affecting the head and neck region and healing into hyperpigmented areas with age. Some affected females may have additional abnormalities, including congenital heart defects, a small head (microcephaly), absence of the band of nerve fibers that joins the two hemispheres of the brain (agenesis of the septum pellucidum), seizures, or intellectual disability.Focal dermal hypoplasia is also a rare genetic X-linked disorder caused by a change (mutation) in the PORCN gene. The condition is characterized by distinctive abnormalities of the skin, the fingers and toes, the eyes, and other bodily regions. Primary cutaneous abnormalities include underdevelopment of localized areas of skin (focal dermal hypoplasia) with protrusion of fat (herniation); red streaking of the skin; and multiple benign (noncancerous) tumors (papillomas) of the skin or mucous membranes (including the esophagus and the larynx). Most affected females also have ocular defects, such as small eyes (microphthalmia); absence or defects of ocular tissues (colobomas of the iris or the choroid); or abnormal malalignment of one eye in relation to the other (strabismus, usually turned in or esotropia). Limb malformations may include webbing or fusion (syndactyly) of certain fingers or toes; permanent flexion of one or more digits (camptodactyly); additional fingers or toes (polydactyly); or absence of certain digits (usually in the middle of the hand). Also present are skeletal abnormalities, such as an unusually small, rounded skull; malformations of bones in the spinal column (vertebrae); unusual streaks (striations) in the long bones or abnormal curvature of the spine. Many affected individuals also have abnormal eruption, irregular spacing, defective enamel, or absence of some teeth (hypodontia); an abnormal vertical notch in the upper lip (cleft lip); incomplete closure of the roof of the mouth (cleft palate); or other physical abnormalities. Most individuals with the disorder have intellectual disability. (For further information on this disorder, choose “focal dermal hypoplasia” as your search term in the Rare Disease Database.)Encephalocraniocutaneous lipomatosis is a rare genetic disorder that is typically characterized by skin abnormalities, ocular defects and multiple benign fatty tumors (lipomas) in the brain or along the spinal cord. ECCL may involve one or both sides of the body (unilateral or bilateral). It can be associated with a normal development or mild to severe intellectual disability and may lead to episodes of uncontrolled electrical activity in the brain (seizures). Affected individuals have multiple subcutaneous lipomas and other benign tumor-like lesions (hamartomas), involving the surface of the eye (epibulbar dermoids), and may show protruding outgrowths of skin (skin tags) that may involve the eyelids, the nose, or other regions. They may also show areas localized loss of scalp hair (alopecia) possibly with underlying fatty tissue (so-called nevus psiloliparus), and areas of underdeveloped (hypoplastic) or absent (aplastic) scalp. Additional findings in the brain include fluid-filled spaces in the brain (porencephalic cysts), anomalies of the vessels and of the protective membranes surrounding the brain and spinal cord (i.e., leptomeninges). Affected individuals may have a large head (macrocephaly); congenital malformation of the aorta; cystic bone lesions that may be progressive. Sometimes, they develop jaw tumors and a particular brain tumor (low-grade gliomas). To date, all individuals with ECCL are the only individuals in their families with the disorder (isolated). In some patients, somatic mosaic mutations in the FGFR1 gene or the KRAS gene have been identified, meaning that the mutation (genetic change) is only present in part of the cells of the body (somatic mosaicism). This is the consequence of a randomly occurring, new event in one of the cells present at a very early embryonic stage.Goldenhar syndrome, a term used synonymously with “oculo-auriculo-vertebral (OAV) spectrum,” is a rare genetic disorder apparent at birth (congenital). The disorder is characterized by a wide spectrum of signs and physical features that vary greatly in extent and severity from patient to patient. However, the abnormalities tend to involve the cheekbones, jaws, mouth, ears, eyes, and bones of the spinal column (vertebrae). Although the malformations usually affect one side of the body (unilateral), some affected individuals have such abnormalities on both sides (bilateral) in which one side is more affected than the other. Due to these malformations, the face usually appears smaller on one side (hemifacial microsomia). Craniofacial abnormalities include underdevelopment of the cheekbones (malar hypoplasia), bones of the upper and lower jaws, and bones forming a portion of the lower skull (temporal hypoplasia); incomplete development of certain muscles of the face; an abnormally wide mouth (macrostomia); incomplete closure of the roof of the mouth (cleft palate); an abnormal groove in the upper lip (cleft lip); and/or abnormalities of the teeth. Malformation (microtia) or absence (anotia) of the outer ears (auricles or pinnae) also occurs; narrow, blind ending, or absent external ear canals (atresia); abnormal outgrowths of skin and cartilage on or in front of the ears (preauricular tags); or abnormalities affecting the middle or inner ears, resulting in hearing impairment (either conductive or sensorineural hearing loss). Eye abnormalities may include the formation of solid benign tumors on the surface of the eyeball(s) (epibulbar dermoids and lipodermoids), partial absence of tissue (coloboma) from the upper eyelids, abnormally small eye(s) (microphthalmia), narrowing of the openings (palpebral fissures) between the upper and lower eyelids (blepharophimosis), or other ocular abnormalities. In some individuals, additional physical malformations and/or mild intellectual disability may occur. Goldenhar syndrome is usually an isolated event with no family history. A few reports imply a positive family history, suggesting autosomal dominant or autosomal recessive inheritance. In addition, some investigators have suggested that the disorder may be caused by the combined interaction of a few genes (oligogenic inheritance). (For further information on this disorder, choose “Goldenhar” as your search term in the Rare Disease Database.)Aicardi syndrome is a rare disorder affecting females only. Individuals with Aicardi syndrome have underdeveloped or absent tissue connecting the left and the right halves of the brain (agenesis corpus callosum) in combination with a multitude of other brain lesions. These brain lesions overlap substantially with those seen in OCC syndrome although the typical mid-hindbrain malformation seen in OCC syndrome is unknown in Aicardi syndrome. Affected individuals show severe intellectual disability, infantile spasms and other types of seizures. Examination of the eyes typically shows holes in the retina (chorioretinal lacunae), but the eye anomalies known in OCC syndrome may be seen occasionally. Anomalies of the ribs, the spine, and the skin may be associated. Aicardi syndrome occurs sporadically. The underlying gene has not yet been identified.
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Oculocerebrocutaneous Syndrome
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nord_899_5
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Diagnosis of Oculocerebrocutaneous Syndrome
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OCC syndrome may be diagnosed at or shortly after birth based upon a thorough clinical evaluation, identification of characteristic physical findings, and specialized imaging techniques. Some investigators have suggested that minimal diagnostic criteria for OCC syndrome must include the presence of characteristic findings in at least two of the three systems typically involved (eye, skin, brain).Specialized tests detect and/or characterize certain abnormalities associated with the disorder, including ocular defects, cerebral malformations, and seizure activity. These may include advanced imaging techniques, such as computed tomography (CT), magnetic resonance imaging (MRI); or electroencephalography (EEG).
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Diagnosis of Oculocerebrocutaneous Syndrome. OCC syndrome may be diagnosed at or shortly after birth based upon a thorough clinical evaluation, identification of characteristic physical findings, and specialized imaging techniques. Some investigators have suggested that minimal diagnostic criteria for OCC syndrome must include the presence of characteristic findings in at least two of the three systems typically involved (eye, skin, brain).Specialized tests detect and/or characterize certain abnormalities associated with the disorder, including ocular defects, cerebral malformations, and seizure activity. These may include advanced imaging techniques, such as computed tomography (CT), magnetic resonance imaging (MRI); or electroencephalography (EEG).
| 899 |
Oculocerebrocutaneous Syndrome
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nord_899_6
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Therapies of Oculocerebrocutaneous Syndrome
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TreatmentThe management of OCC syndrome is directed toward the specific signs apparent in each individual. Such treatment may require the coordinated efforts of a team of medical professionals who may need to plan an affected child’s treatment systematically and comprehensively. These professionals may include pediatricians; surgeons; physicians who specialize in disorders of the skin (dermatologists); physicians who diagnose and treat neurological disorders (neurologists and neurosurgeons); eye specialists (ophthalmologists); and/or others.Specific therapies for OCC syndrome are symptomatic and supportive. Intervention may include drainage of orbital cysts; surgical removal (excision) of orbital cysts, hamartomas, or skin tags; or surgical repair of certain abnormalities, such as colobomas of the lids or the cleft palate. The specific surgical interventions will depend on the severity of the anatomical abnormalities, their associated signs, and other factors.Treatment may include medications to prevent, reduce, or control seizures (anticonvulsant drugs). Those with hydrocephalus may have a specialized device (shunt) surgically implanted to drain excess cerebrospinal fluid (CSF) away from the brain and into another part of the body where the CSF can be absorbed.Genetic counseling may be recommended for the families of affected individuals. Other treatment for OCC syndrome is symptomatic and supportive.
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Therapies of Oculocerebrocutaneous Syndrome. TreatmentThe management of OCC syndrome is directed toward the specific signs apparent in each individual. Such treatment may require the coordinated efforts of a team of medical professionals who may need to plan an affected child’s treatment systematically and comprehensively. These professionals may include pediatricians; surgeons; physicians who specialize in disorders of the skin (dermatologists); physicians who diagnose and treat neurological disorders (neurologists and neurosurgeons); eye specialists (ophthalmologists); and/or others.Specific therapies for OCC syndrome are symptomatic and supportive. Intervention may include drainage of orbital cysts; surgical removal (excision) of orbital cysts, hamartomas, or skin tags; or surgical repair of certain abnormalities, such as colobomas of the lids or the cleft palate. The specific surgical interventions will depend on the severity of the anatomical abnormalities, their associated signs, and other factors.Treatment may include medications to prevent, reduce, or control seizures (anticonvulsant drugs). Those with hydrocephalus may have a specialized device (shunt) surgically implanted to drain excess cerebrospinal fluid (CSF) away from the brain and into another part of the body where the CSF can be absorbed.Genetic counseling may be recommended for the families of affected individuals. Other treatment for OCC syndrome is symptomatic and supportive.
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Oculocerebrocutaneous Syndrome
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