What is Congenital Central Hypoventilation
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
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
What do doctors look for if they suspect a baby has
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
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
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 /
? 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
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?
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
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
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
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
What regular follow up will my child
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?
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
? 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
? 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
More information about CCHS and genes
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
In those children where the PHOX2b gene is not found, there are
sometimes other genetic findings, similar to the PHOX2b
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.
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