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What is Congenital Central Hypoventilation
Syndrome?
Congenital Central Hypoventilation Syndrome (CCHS; Ondine's Curse) is a genetic condition which causes problems with the automatic control of breathing. It is congenital because babies appear to be born with this condition although some of them may not present as having problems immediately after birth. It is central because it involves the central nervous system, ie the brain. The breathing centres are at the bottom of the brain (brain stem), which is just above where the spinal cord enters the skull. Hypoventilation essentially means under-breathing, and this is most obvious during sleep - it is demonstrated by rises in carbon dioxide (the waste gas we breathe out) and falls in oxygen levels in the blood.
Problems with breathing may be present sometimes during wakefulness, although usually to a milder degree. The disordered control of breathing may range in severity from being relatively mild under-breathing during quiet sleep and normal breathing when awake, to a complete cessation of breathing during sleep and still severe under-breathing during wakefulness - this may be particularly evident with either feeding (particularly in infancy) or when concentrating.
Why is CCHS sometimes referred to as Ondine's Curse?
Ondine's Curse is an unfortunate name which was given to the condition in 1962. This name for the condition comes from a German legend in which the nymph, Ondine, placed a curse on her unfaithful mortal husband, removing all his automatic functions and thus requiring that he remembered to breathe.
What causes CCHS?
In recent years, we have learnt that CCHS is due to a problem with a specific gene that affects the way nervous tissue in the brain develops early in fetal life. More information about CCHS and genes can be found at the end of this leaflet.
How rare is CCHS?
It is unknown how many children there are with CCHS. It has been estimated that the incidence is somewhere between 1 affected baby in every 50,000 - 200,000 live births, making this a very rare condition. In the United States there may be over 200 children and adults with CCHS, while in the UK there are probably somewhere between 50 and 100. Unfortunately, there is no complete information on where children and adults with CCHS live in the UK, although a pan-European CCHS Registry is currently being set up, as currently exists in France.
What do doctors look for if they suspect a baby has CCHS?
The clinical presentation of CCHS is quite variable and depends on the severity of the condition. Some babies do not breathe at birth, and require assisted ventilation in the delivery room and on the neonatal or special care baby unit. Many of these infants may not breathe at all during the first few months of life, but may mature to a more adequate pattern of breathing when awake, with under-breathing or stopping breathing just persisting during sleep.
Some babies may present at a slightly later age with a blue discolouration of the face, lips and tongue, indicating low levels of blood oxygen. Low oxygen levels also cause irritability, poor feeding and failure to gain weight adequately. Sometimes it is thought that these babies may have a congenital heart problem when they first present, because the low oxygen levels may cause the blood pressure in the lungs to rise, which in turn causes strain on the heart (heart failure).
Some infants present solely because of an observation by a parent or health professional that the baby appears to stop breathing a lot. If this is severe and associated with colour change, poor muscle tone or arousability and requires vigorous stimulation or resuscitation to bring recovery, this is termed an ?apparent life threatening event'.
It is possible that some children may not present until a few months or years of age because they have a milder form of the condition. When their body is no longer able to cope, they may present with heart failure or a severe pneumonia. At this time they may be found to need help with their breathing in the form of mechanical ventilation on an intensive care unit. After a period of treatment, it becomes clear that the patient is unable to be weaned off the ventilator and the diagnosis may then be considered.
How is CCHS diagnosed?
The diagnosis of CCHS depends on documenting that under-breathing occurs during sleep, and that this is not due to a muscle or lung disease, or some other congenital syndrome (ie a different type of genetic disorder). The assessment of under-breathing during sleep is best achieved by continuous monitoring with sensors that stick on to the body surface (non-invasive monitoring). This includes monitors to measure: (1) carbon dioxide, either through the skin (transcutaneous or tcPCO2) or from the expired air (end-tidal, ET-CO2) and (2) blood oxygen levels, using a pulse oximeter (this measures how much the arterial blood is saturated with oxygen, that is the oxygen sat, or SaO2, normal 95-100%).
These measurements can be performed continuously and without discomfort, and help show how well the lungs are inflated (by looking at blood oxygen levels), and how well fresh air (consisting of nitrogen and oxygen) is moved in and out of the lungs over a period of time (removing the waste gas, carbon dioxide levels). Intermittent sampling of blood specimens to assess oxygen or carbon dioxide levels is usually inadequate, as it causes discomfort and arousal, and will not represent true breathing during sleep. However, a blood sample is usually needed at some point to confirm the effects of the raised carbon dioxide, which is to make the blood more acidic.
The diagnosis is now able to be confirmed in >95% of cases by finding the problem with the specific gene - you can find a list of genetic laboratories able to perfor the genetic test in the "european CHS Map" in the homepage
How is CCHS treated?
The treatment of CCHS is essentially to ensure adequate ventilation when the child is unable to breathe on their own. No drugs have been shown to be effective as respiratory stimulants, and hence mechanical ventilation is needed. Mechanical ventilation may be provided by intermittently blowing air at pressure through either:
? a tracheostomy - a whole created in the front of the neck allowing permanent placement of a tube into the trachea or windpipe; sometimes known as trache ventilation, or
? a mask over the nose or face or both, also known as mask ventilation.
Other techniques that are occasionally used include:
? phrenic nerve stimulation - this stimulates the nerves to the diaphragm, the main breathing muscle under the lungs. The phrenic nerve pacing wires have to be implanted surgically and connected to a pacing box outside the body. It is not commonly used in the United Kingdom, because there are few centres used to inserting and following up children with such devices. Furthermore, pacing is mainly applicable to children who need ventilation 16-24 hours / day.
? Negative pressure ventilation - this involves a tank or cuirass (chest shell) that creates intermittent negative pressure (suction) outside the chest. This technique has largely been superseded by mask ventilation.
Children with CCHS may severely under-breathe or stop breathing as soon as they fall asleep. Thus it is important that they receive continuous observation or monitoring, especially in early childhood, so that ventilation may be started at the beginning of sleep. As a minimum form of monitoring, oxygen monitoring must be used during sleep, although giving additional oxygen to breathe would be inadequate treatment alone. Many children also have monitoring of their carbon dioxide levels too and this can allow the ability to modify the settings on the ventilator at home.
Hospital discharge usually takes place once children are stable and are set up with their home ventilator. Parents and any other carers at home need training in how to look after the child's ventilation. The biggest delays to hospital discharge include:
? alterations to housing to ensure there is room for the equipment, and if employed, space for carers, and
? employment of carers - these can take many months to achieve.
As children grow, their need for ventilation may change and hence regular assessment is required. The condition appears to be life-long, as no patient with CCHS has been documented to outgrow this disorder. Despite this many children do well, and may attend a main stream school and have a normal lifestyle while awake.
What other problems are common with CCHS?
The gene that causes CCHS is also associated with the development of nerve cells of an automatic part of the nervous system, called the autonomic nervous system. These nerves control not only breathing, but the heart, gut, blood vessels, sweat glands and so on. Thus some children are affected with problems other than that affecting breathing.
In 15% of cases, there is a failure in the development of nerves that supply the large bowel - this may cause a permanent narrowing of the large bowel (colon), anywhere from just above the rectum and anus (short segment disease) right round the large bowel (long segment disease). This condition is called Hirschsprung's disease and invariably needs surgery to remove the narrowed segment of bowel.
Some children may have problems with the way the brain develops after birth - these may not present in early infancy, but become more apparent as the child grows. Thus infants may have some degree of learning difficulties or develop epilepsy. However, most children with the condition are able to attend main stream schools, with or without extra support.
Some children may have a problem affecting their heart rhythm. This involves episodes in which the normal heart rhythm has stopped for a few seconds. It may present with episodes of dizziness or collapse. Whilst there are other causes for these symptoms, such as breath-holding episodes, simple faints and epileptic seizures, such symptoms warrant recording the heart rhythm (ECG) over a period of 1 to 3 days (Holter recording).
Children with CCHS may also have swallowing difficulties, increased sweating, eye problems (eg squints) and respond in unusual ways to anaesthesia. Children will usually be able to exercise adequately, but they can hold their breath for dangerously long periods underwater when swimming (people with a tracheostomy will not take part in swimming).
Rarely, abnormal growths of nerve cells develop alongside the spine (ganglioneuromas and neuroblastomas), which need surgical removal and treatment if found to be malignant.
What help and support is available to care for my child at home?
Most parents manage to look after their children at home, either alone or with help from carers and community nurses, sitting in the home overnight. The decision to have carers in the home is affected by parental preference, the severity of the child's condition and associated problems, and the willingness of the local health fund holders to pay for night carers.
What equipment is needed at home?
Children will need oxygen monitoring when asleep, and in infancy, when falling asleep, particularly if left unattended. Some families have home carbon dioxide monitors to help ensure adequate ventilation and identify if the child is becoming less well. Most families will have two ventilators and back-up power systems. Despite all the equipment, it is possible for families to organise holidays abroad.
What regular follow up will my child need?
Children with CCHS have regular reviews to check for a number of issues:
? to assess the adequacy of ventilation
? to check the mask fitting or tracheostomy
? to determine whether there have been significant respiratory problems, such as chest infections (reflecting either inadequate ventilation or other lung problems)
? to assess for any of the associated problems
? to check on development and growth, and
? to make sure all care needs are being met. The latter will often be helped by having a local care co-ordinator to oversee the care, and an annual multi-disciplinary meeting to review the care package organised for the family.
What research and education is going on?
As with most conditions that are very rare, there is little funding available for research into the condition. However, in 2009, a pan-European group, including France, Germany, Italy, Poland, Sweden and the UK, was successful in obtaining an EU grant to learn more about the condition and its management. There are now 14 collaborating countries, and the health professionals are aiming to:
? establish a registry of individuals affected by the condition
? develop clinical guidelines for its management
? produce a range of information leaflets for patients and their families
? set up a web site for use by families and professionals, and
? learn more about how the condition is managed by different centres across Europe.
One additional role this group hopes to achieve is the setting up of international research studies to improve understanding and treatment of this rare condition.
Updates on these activities will be provided in CCHS Family Support newsletters.
More information about CCHS and genes
This abnormality is thought to arise in most cases spontaneously at the time of the formation of the new embryo, a situation known as a spontaneous mutation. All cells of the affected infant will have the abnormal gene and parents will usually be unaffected. However, we know that in 5-10% of cases, one parent may carry the genetic abnormality. These parents may have this genetic abnormality in all their body's cells or in only some. This explains in part why some parents have been found to have hypoventilation after positive genetic testing, whereas others do not.
The genetic abnormality affects the control region, called PHOX2b, in one of a pair of genes on chromosome number 4 (there are 23 pairs of chromosomes in each cell of the body). The PHOX2b gene is responsible for development of brain tissue in the early embryo, ie before 8 weeks of pregnancy. At one point of the gene, there is a run of 20 proteins (also known as nucleotides) called alanines, but the affected gene may have anywhere between 25 and 33 alanines - this is called a repeat polyalanine expansion. This abnormality is not found in non-affected individuals. Thus PHOX2b has been described as a disease-defining gene. Experiments in mice have shown that if both genes are affected, the fetuses do not survive the pregnancy.
In those children where the PHOX2b gene is not found, there are sometimes other genetic findings, similar to the PHOX2b mutation.
If an individual with PHOX2B has children, they have a 50% chance of passing the affected gene onto children. If carrying the gene, an individual will be affected to some extent or other, ie there is no silent carrier status. So we are now newly recognising some adults with the condition, in whom it was never suspected earlier in life. If an adult with PHOX2B has a child, detection of the disorder is possible in the affected fetus early in pregnancy.
Related Conditions
Since the onset of genetic testing and the increased awareness of the condition, the following related conditions have also been recognised:
? late-onset central hypoventilation syndrome (LO-CHS) - this is where the condition may not have presented at or shortly after birth, but after a few years. This is thought to be because the condition is milder. It often comes to light in the setting of an infection, which causes a severe pneumonia.
? ROHHAD: Rapid-onset obesity, hypoventilation, hypothalamic disorder and autonomic disorder. This condition is a type of late-onset CHS presenting in mid-childhood with obesity, hormonal problems and under-breathing. It is exceedingly rare.
? adult-onset CHS: this is a mild form of the condition, which has been unrecognised for many years, but sometimes may have been associated with unexplained symptoms such as nocturnal epilepsy or severe pneumonia.
Congenital Central Hypoventilation Syndrome (CCHS; Ondine's Curse) is a genetic condition which causes problems with the automatic control of breathing. It is congenital because babies appear to be born with this condition although some of them may not present as having problems immediately after birth. It is central because it involves the central nervous system, ie the brain. The breathing centres are at the bottom of the brain (brain stem), which is just above where the spinal cord enters the skull. Hypoventilation essentially means under-breathing, and this is most obvious during sleep - it is demonstrated by rises in carbon dioxide (the waste gas we breathe out) and falls in oxygen levels in the blood.
Problems with breathing may be present sometimes during wakefulness, although usually to a milder degree. The disordered control of breathing may range in severity from being relatively mild under-breathing during quiet sleep and normal breathing when awake, to a complete cessation of breathing during sleep and still severe under-breathing during wakefulness - this may be particularly evident with either feeding (particularly in infancy) or when concentrating.
Why is CCHS sometimes referred to as Ondine's Curse?
Ondine's Curse is an unfortunate name which was given to the condition in 1962. This name for the condition comes from a German legend in which the nymph, Ondine, placed a curse on her unfaithful mortal husband, removing all his automatic functions and thus requiring that he remembered to breathe.
What causes CCHS?
In recent years, we have learnt that CCHS is due to a problem with a specific gene that affects the way nervous tissue in the brain develops early in fetal life. More information about CCHS and genes can be found at the end of this leaflet.
How rare is CCHS?
It is unknown how many children there are with CCHS. It has been estimated that the incidence is somewhere between 1 affected baby in every 50,000 - 200,000 live births, making this a very rare condition. In the United States there may be over 200 children and adults with CCHS, while in the UK there are probably somewhere between 50 and 100. Unfortunately, there is no complete information on where children and adults with CCHS live in the UK, although a pan-European CCHS Registry is currently being set up, as currently exists in France.
What do doctors look for if they suspect a baby has CCHS?
The clinical presentation of CCHS is quite variable and depends on the severity of the condition. Some babies do not breathe at birth, and require assisted ventilation in the delivery room and on the neonatal or special care baby unit. Many of these infants may not breathe at all during the first few months of life, but may mature to a more adequate pattern of breathing when awake, with under-breathing or stopping breathing just persisting during sleep.
Some babies may present at a slightly later age with a blue discolouration of the face, lips and tongue, indicating low levels of blood oxygen. Low oxygen levels also cause irritability, poor feeding and failure to gain weight adequately. Sometimes it is thought that these babies may have a congenital heart problem when they first present, because the low oxygen levels may cause the blood pressure in the lungs to rise, which in turn causes strain on the heart (heart failure).
Some infants present solely because of an observation by a parent or health professional that the baby appears to stop breathing a lot. If this is severe and associated with colour change, poor muscle tone or arousability and requires vigorous stimulation or resuscitation to bring recovery, this is termed an ?apparent life threatening event'.
It is possible that some children may not present until a few months or years of age because they have a milder form of the condition. When their body is no longer able to cope, they may present with heart failure or a severe pneumonia. At this time they may be found to need help with their breathing in the form of mechanical ventilation on an intensive care unit. After a period of treatment, it becomes clear that the patient is unable to be weaned off the ventilator and the diagnosis may then be considered.
How is CCHS diagnosed?
The diagnosis of CCHS depends on documenting that under-breathing occurs during sleep, and that this is not due to a muscle or lung disease, or some other congenital syndrome (ie a different type of genetic disorder). The assessment of under-breathing during sleep is best achieved by continuous monitoring with sensors that stick on to the body surface (non-invasive monitoring). This includes monitors to measure: (1) carbon dioxide, either through the skin (transcutaneous or tcPCO2) or from the expired air (end-tidal, ET-CO2) and (2) blood oxygen levels, using a pulse oximeter (this measures how much the arterial blood is saturated with oxygen, that is the oxygen sat, or SaO2, normal 95-100%).
These measurements can be performed continuously and without discomfort, and help show how well the lungs are inflated (by looking at blood oxygen levels), and how well fresh air (consisting of nitrogen and oxygen) is moved in and out of the lungs over a period of time (removing the waste gas, carbon dioxide levels). Intermittent sampling of blood specimens to assess oxygen or carbon dioxide levels is usually inadequate, as it causes discomfort and arousal, and will not represent true breathing during sleep. However, a blood sample is usually needed at some point to confirm the effects of the raised carbon dioxide, which is to make the blood more acidic.
The diagnosis is now able to be confirmed in >95% of cases by finding the problem with the specific gene - you can find a list of genetic laboratories able to perfor the genetic test in the "european CHS Map" in the homepage
How is CCHS treated?
The treatment of CCHS is essentially to ensure adequate ventilation when the child is unable to breathe on their own. No drugs have been shown to be effective as respiratory stimulants, and hence mechanical ventilation is needed. Mechanical ventilation may be provided by intermittently blowing air at pressure through either:
? a tracheostomy - a whole created in the front of the neck allowing permanent placement of a tube into the trachea or windpipe; sometimes known as trache ventilation, or
? a mask over the nose or face or both, also known as mask ventilation.
Other techniques that are occasionally used include:
? phrenic nerve stimulation - this stimulates the nerves to the diaphragm, the main breathing muscle under the lungs. The phrenic nerve pacing wires have to be implanted surgically and connected to a pacing box outside the body. It is not commonly used in the United Kingdom, because there are few centres used to inserting and following up children with such devices. Furthermore, pacing is mainly applicable to children who need ventilation 16-24 hours / day.
? Negative pressure ventilation - this involves a tank or cuirass (chest shell) that creates intermittent negative pressure (suction) outside the chest. This technique has largely been superseded by mask ventilation.
Children with CCHS may severely under-breathe or stop breathing as soon as they fall asleep. Thus it is important that they receive continuous observation or monitoring, especially in early childhood, so that ventilation may be started at the beginning of sleep. As a minimum form of monitoring, oxygen monitoring must be used during sleep, although giving additional oxygen to breathe would be inadequate treatment alone. Many children also have monitoring of their carbon dioxide levels too and this can allow the ability to modify the settings on the ventilator at home.
Hospital discharge usually takes place once children are stable and are set up with their home ventilator. Parents and any other carers at home need training in how to look after the child's ventilation. The biggest delays to hospital discharge include:
? alterations to housing to ensure there is room for the equipment, and if employed, space for carers, and
? employment of carers - these can take many months to achieve.
As children grow, their need for ventilation may change and hence regular assessment is required. The condition appears to be life-long, as no patient with CCHS has been documented to outgrow this disorder. Despite this many children do well, and may attend a main stream school and have a normal lifestyle while awake.
What other problems are common with CCHS?
The gene that causes CCHS is also associated with the development of nerve cells of an automatic part of the nervous system, called the autonomic nervous system. These nerves control not only breathing, but the heart, gut, blood vessels, sweat glands and so on. Thus some children are affected with problems other than that affecting breathing.
In 15% of cases, there is a failure in the development of nerves that supply the large bowel - this may cause a permanent narrowing of the large bowel (colon), anywhere from just above the rectum and anus (short segment disease) right round the large bowel (long segment disease). This condition is called Hirschsprung's disease and invariably needs surgery to remove the narrowed segment of bowel.
Some children may have problems with the way the brain develops after birth - these may not present in early infancy, but become more apparent as the child grows. Thus infants may have some degree of learning difficulties or develop epilepsy. However, most children with the condition are able to attend main stream schools, with or without extra support.
Some children may have a problem affecting their heart rhythm. This involves episodes in which the normal heart rhythm has stopped for a few seconds. It may present with episodes of dizziness or collapse. Whilst there are other causes for these symptoms, such as breath-holding episodes, simple faints and epileptic seizures, such symptoms warrant recording the heart rhythm (ECG) over a period of 1 to 3 days (Holter recording).
Children with CCHS may also have swallowing difficulties, increased sweating, eye problems (eg squints) and respond in unusual ways to anaesthesia. Children will usually be able to exercise adequately, but they can hold their breath for dangerously long periods underwater when swimming (people with a tracheostomy will not take part in swimming).
Rarely, abnormal growths of nerve cells develop alongside the spine (ganglioneuromas and neuroblastomas), which need surgical removal and treatment if found to be malignant.
What help and support is available to care for my child at home?
Most parents manage to look after their children at home, either alone or with help from carers and community nurses, sitting in the home overnight. The decision to have carers in the home is affected by parental preference, the severity of the child's condition and associated problems, and the willingness of the local health fund holders to pay for night carers.
What equipment is needed at home?
Children will need oxygen monitoring when asleep, and in infancy, when falling asleep, particularly if left unattended. Some families have home carbon dioxide monitors to help ensure adequate ventilation and identify if the child is becoming less well. Most families will have two ventilators and back-up power systems. Despite all the equipment, it is possible for families to organise holidays abroad.
What regular follow up will my child need?
Children with CCHS have regular reviews to check for a number of issues:
? to assess the adequacy of ventilation
? to check the mask fitting or tracheostomy
? to determine whether there have been significant respiratory problems, such as chest infections (reflecting either inadequate ventilation or other lung problems)
? to assess for any of the associated problems
? to check on development and growth, and
? to make sure all care needs are being met. The latter will often be helped by having a local care co-ordinator to oversee the care, and an annual multi-disciplinary meeting to review the care package organised for the family.
What research and education is going on?
As with most conditions that are very rare, there is little funding available for research into the condition. However, in 2009, a pan-European group, including France, Germany, Italy, Poland, Sweden and the UK, was successful in obtaining an EU grant to learn more about the condition and its management. There are now 14 collaborating countries, and the health professionals are aiming to:
? establish a registry of individuals affected by the condition
? develop clinical guidelines for its management
? produce a range of information leaflets for patients and their families
? set up a web site for use by families and professionals, and
? learn more about how the condition is managed by different centres across Europe.
One additional role this group hopes to achieve is the setting up of international research studies to improve understanding and treatment of this rare condition.
Updates on these activities will be provided in CCHS Family Support newsletters.
More information about CCHS and genes
This abnormality is thought to arise in most cases spontaneously at the time of the formation of the new embryo, a situation known as a spontaneous mutation. All cells of the affected infant will have the abnormal gene and parents will usually be unaffected. However, we know that in 5-10% of cases, one parent may carry the genetic abnormality. These parents may have this genetic abnormality in all their body's cells or in only some. This explains in part why some parents have been found to have hypoventilation after positive genetic testing, whereas others do not.
The genetic abnormality affects the control region, called PHOX2b, in one of a pair of genes on chromosome number 4 (there are 23 pairs of chromosomes in each cell of the body). The PHOX2b gene is responsible for development of brain tissue in the early embryo, ie before 8 weeks of pregnancy. At one point of the gene, there is a run of 20 proteins (also known as nucleotides) called alanines, but the affected gene may have anywhere between 25 and 33 alanines - this is called a repeat polyalanine expansion. This abnormality is not found in non-affected individuals. Thus PHOX2b has been described as a disease-defining gene. Experiments in mice have shown that if both genes are affected, the fetuses do not survive the pregnancy.
In those children where the PHOX2b gene is not found, there are sometimes other genetic findings, similar to the PHOX2b mutation.
If an individual with PHOX2B has children, they have a 50% chance of passing the affected gene onto children. If carrying the gene, an individual will be affected to some extent or other, ie there is no silent carrier status. So we are now newly recognising some adults with the condition, in whom it was never suspected earlier in life. If an adult with PHOX2B has a child, detection of the disorder is possible in the affected fetus early in pregnancy.
Related Conditions
Since the onset of genetic testing and the increased awareness of the condition, the following related conditions have also been recognised:
? late-onset central hypoventilation syndrome (LO-CHS) - this is where the condition may not have presented at or shortly after birth, but after a few years. This is thought to be because the condition is milder. It often comes to light in the setting of an infection, which causes a severe pneumonia.
? ROHHAD: Rapid-onset obesity, hypoventilation, hypothalamic disorder and autonomic disorder. This condition is a type of late-onset CHS presenting in mid-childhood with obesity, hormonal problems and under-breathing. It is exceedingly rare.
? adult-onset CHS: this is a mild form of the condition, which has been unrecognised for many years, but sometimes may have been associated with unexplained symptoms such as nocturnal epilepsy or severe pneumonia.
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