Congenital central hypoventilation syndrome (CCHS) – also known
as Ondine’s curse – is a rare congenital condition in which
there is an abnormality of control of respiration in the absence of any
identifiable primary central nervous system, neuromuscular, lung or cardiac
disease. There is an estimated prevalence of approximately 300 cases
The precise pathophysiological mechanisms underlying CCHS are unclear.
Systematic detailed neuroimaging of children with CCHS has not demonstrated
any structural defect. Recent genetic studies have identified a heterozygous
mutation of the PHOX2B gene in the majority of children with CCHS and
consider this a disease defining mutation. Most mutations consist of
5 – 9 alanine expansions within a 20-residue polyalanine tract.
Some investigators have claimed an association between the repeat mutation
length and the severity of the disease. Mutations of other genes acting
as modifiers may explain the heterogeneity of the condition.
Affected children show hypoventilation during sleep, especially non-rapid-eye
movement (non-REM) sleep. There is a wide range of phenotypic expression.
More severely affected children may also demonstrate hypoventilation
whilst awake. Children typically present in the newborn period with
cyanosis when falling asleep and no increase in respiratory effort.
A clear association of hypoventilation with sleep may only manifest
after 2 – 3 months of age. In the most severely affected children,
spontaneous ventilation can be troublesome during waking hours as well.
The increase in severity during non-REM sleep helps differentiate CCHS
from other causes of hypoventilation which is usually more noticeable
during non-REM sleep
If not recognised as a neonate, children with the milder forms
may present with cyanosis, oedema, right heart failure or apparent
life threatening events.
CCHS is associated with a number of other conditions affecting
the autonomic nervous system. These included Hirschprung’s
disease and neural crest tumours. Other clinical associations
include seizures, gastro-oesophageal reflux, cardiac arrhythmias
and lack or circadian temperature variation.
The diagnosis requires the following criteria:
1. Persistent evidence of hypoventilation during sleep
2. Onset of symptoms usually in the first year of life
3. Absence or primary pulmonary or neuromuscular disease
4. No evidence of primary heart disease
Initial assessment includes a detailed history, examination, chest imaging.
ECG, EEG and MRI of brain and brain stem. Additional assessments may
also include metabolic evaluations, exclusion of Hirschprungs disease
and additional neuromuscular tests including diaphragmatic function.
The sleep study will require the recording of adequate periods of sleep
spent in non-REM and REM states. Full polysomnography is recommended
and the measurements or end-tidal and blood gas measurements may be required
for objective evidence of hypoxaemia and hypercarbia. CCHS children have
an absent or negligible response to hypercarbia.
There is now a DNA test for the diagnosis of CCHS. If the test is negative
and the physician is confident that the child has the phenotype for CCHS,
then sequencing of the PHOX2b gene should be performed. Because of the
autosomal dominant inheritance pattern, it would be advisable to perform
the test on parents of CCHS probands and on probands with CCHS who are
pregnant. Prenatal testing for CCHS can be done on cultured chorionic
villus sampled tissue or amniocytes if the PHOX2b mutation in the family
CCHS is a life long condition Respiratory stimulants are ineffective
in CCHS. The management requires a multidisciplinary approach to provide
long term home ventilatory support tailored to the child’s individual
needs. The organisation of home ventilation will require the expertise
of a team experienced in the discharge and management of home ventilation.
Home pulse oximetry monitoring is recommended. There are some children
who are able to have ventilation delivered via a non-invasive approach
using either mask or negative pressure thoracic devices. The vast majority
of young children however require a tracheostomy to deliver ventilatory
. Long-term survival is dependent on the optimal maintenance of oxygenation
and ventilation. Regular follow up is required with sleep studies to
determine that the ventilation remains sufficient. The ventilatory needs
can change during childhood and adolescence with some children seemingly
appearing to “acquire” awake hypoventilation - especially
in the toddler age group. For children with day-time involvement, phrenic
nerve pacing has been suggested.
1. Congenital Central Hypoventilation Syndrome: an
Ped Pulmonology 1998;26:273-282.
2. Central chemoreceptor function in children.
Ped Pulmonology 2001 supplement 23:110 – 113.
3. Noninvasive ventilator strategies in the management
of a newborn infant and three children with congenital
central hypoventilation syndrome .
Tibbals J, Henning RD.
Ped Pulmonolgy 2003; 36:544-548.
4. Idiopathic congenital central hypoventilation syndrome:
diagnosis and management.
American Thoracic Society
Am J Respir Crit Care Med 1999:160;368-373.
5. Genetics of congenital hypoventilation syndrome:
lessons from a seemingly orphan disease.
Weese-Mayer DE, Berry-Kravis EM.
Am J Respir Crit Care Med 2004:170;16.
Download this text as a .PDF HERE