CENTRAL HYPOVENTILATION SYNDROME
Jean-Paul Praud
Departments of Pediatrics and Physiology
Université de Sherbrooke
Corresponding author:
Jean-Paul Praud MD PhD
Tel: (819) 346-1110, ext 14851
Departments of Pediatrics and Physiology
Fax: (819) 564-5215
Université de Sherbrooke
email: Jean-Paul.Praud@USherbrooke.ca
J1H 5N4, QC Canada
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INTRODUCTION
Central hypoventilation syndrome (CHS) is defined as the presence of persistent
alveolar hypoventilation and/or apnoea during sleep and impaired ventilatory responses
to hypercapnia. This syndrome was initially described in association with traumatic,
vascular, infectious or tumour events. Between 1970 and 2010, idiopathic CHS, either
congenital (CCHS) or late-onset (LO-CHS), has been described in about 1000 patients
worldwide. In addition, CHS has been increasingly reported in various other diseases
involving autonomic dysfunction, such as Rapid Onset Obesity with Hypothalamic
Dysfunction,
Hypoventilation, and
Autonomic
Dysregulation
(ROHHAD),
Chiari
malformation, Prader-Willi syndrome, familial dysautonomia, achondroplasia and Leigh’s
disease.
A- CONGENITAL CENTRAL HYPOVENTILATION SYNDROME (CCHS)
1- The typical CCHS patient
Classically, CCHS is diagnosed in a newborn presenting with severe hypoventilation,
which is more prominent during sleep than wakefulness and must be treated by
mechanical ventilation. Hypoventilation cannot be explained by neuromuscular or
cardiopulmonary disorders, anatomic anomalies of the brainstem or metabolic disorders.
Polysomnography shows that hypoventilation culminates in NREM sleep along with the
absence
of
ventilatory
and
arousal
response
to
hypercapnia
and
hypoxia.
Simultaneously, a complex autonomic nervous system dysregulation is present,
including very low heart rate and respiratory rate variability, abrupt asystoles, abnormal
pupillary reactivity, temperature dysregulation, profuse sweating, swallowing difficulties
and/or oesophageal dysmotility. Hirschprung disease is present in 20% and neural
tumours (e.g., neuroblastoma, ganglioneuroblastoma or ganglioneuroma) in 5-10% of
CCHS patients. The finding of a PHOX2B gene mutation confirms diagnosis.
Paired-like homeobox gene PHOX2B, the disease-defining gene
A heterozygous mutation in exon 3 of the paired-like homeobox gene PHOX2B is found
in 100% of CCHS patients 1. The PHOX2B gene encodes a key transcription factor in
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the development of the autonomic nervous system, including important medullary sites
for integration/relay of chemosensory drive to respiratory centres.
The normal protein encoded by the PHOX2B gene has a repeat of 20 alanines (20/20
genotype). In contrast, 92% of CCHS cases are heterozygous for a PHOX2B in-frame
polyalanine repeat expansion mutation (PARM) coding for 24 to 33 alanines in the
mutated protein (20/24 to 20/33 genotype). The remaining CCHS patients have a
heterozygous missense, nonsense or frameshift mutation in the PHOX2B gene.
Phenotype-genotype relationships. Of key importance is the existence of an
association between polyalanine expansion length and severity of autonomic
dysfunction, such that patients with the 20/25 genotype rarely require 24-hour per day
ventilatory support, in contrast to those with 20/27 to 20/33 genotypes. Moreover, an
increased number of polyalanine repeats is associated with an increased number of
symptoms of ANS dysregulation.
CCHS patients with a non-PARM have a higher frequency of 24h-hour per day
ventilatory support, Hirschprung disease (87-100% vs. 13-20% in PARM patients) and
tumours from neural crest origin (50% vs. 1% in PARM patients).
Inheritance of CCHS. While most PARMs occur de novo in CCHS, 5 to 10% are
inherited from a mosaic unaffected parent. In contrast, CCHS patients have a 50%
chance of transmitting the mutation to each child according to an autosomal dominant
pattern. Genetic counselling must take into consideration that penetrance of the milder
PARMs (20/24 and 20/25 genotypes) and milder NPARMs is incomplete. Furthermore,
as a mosaic germline PHOX2B mutation cannot be completely ruled out, prenatal testing
is indicated for all subsequent pregnancies in parents of a CCHS child.
2- Late-onset CCHS
Late-onset CCHS (LO-CCHS) presents beyond the neonatal period and as late as
during adulthood (3 months to 55 years). Respiratory infection or anaesthesia apparently
triggers the need for permanent nocturnal ventilator support. Review of the medical chart
however often shows prior chronic pulmonary hypertension or right heart failure, or
respiratory infections leading to seizures or transient need for mechanical ventilation.
Late-onset CCHS reflects the variable penetrance of the mildest PHOX2B PARMs
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(20/24 and 20/25 genotypes) or NPARMs, which may require an environmental cofactor
to become symptomatic.
3- Diagnosis of congenital central hypoventilation syndrome
Suspicion of CCHS must first lead to ruling out primary lung or cardiac disease,
ventilatory muscle weakness, anatomic brain/brainstem lesions and inborn errors of
metabolism. Diagnosis of CCHS is established by means of a blood sample using the
PHOX2B Screening Test, which identifies the mutation in 95% of CCHS cases. In
clinically-suggestive cases with a negative screening test, the PHOX2B Sequencing
Test should be performed 2.
According to the recent ATS clinical policy statement 1, Hirschprung disease or neural
tumours should be investigated in CCHS patients with susceptible genotype (see
above). Furthermore, CCHS patients should be tested for autonomic dysregulation. In
particular, 72–hour Holter monitoring must be performed annually to detect aberrant
cardiac rhythms and/or sinus pauses, which may require bipolar cardiac pacemaker
implantation. Likewise, echocardiogram, haematocrit and reticulocyte counts must be
performed at least annually for detection of unrecognized recurrent hypoxemia. Biannual
and then annual in-hospital comprehensive physiological studies during sleep and
wakefulness should assess ventilatory needs during varying levels of activity and
concentration.
Hypoventilation and incidence. Typically, severe central hypoventilation due to
decreased tidal volume (no apnoea) culminates in non-REM sleep, while a milder
degree of hypoventilation is present in REM sleep and wakefulness, necessitating
ventilatory support at sleep time only. However, central hypoventilation ranges in
severity from significant hypoventilation during non–REM sleep with adequate ventilation
during wakefulness to complete apnoea during sleep and severe hypoventilation during
wakefulness (20/27 to 20/33 genotypes and most NPARMs).
4- Ventilatory Management
Congenital central hypoventilation syndrome does not improve with advancing age and
does not respond to pharmacologic stimulants. Oxygen administration alone is
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inadequate to treat hypoventilation, and chronic home ventilatory support is necessary,
at least during sleep. According to the recent ATS statement 1, intermittent positive
pressure ventilation must be instituted via tracheostomy in the typical CCHS newborn.
Non-invasive ventilation via a nasal mask using a bilevel positive airway pressure
ventilator is not a consideration until 6 to 8 years of age at the earliest and has been
successful in a limited number of stable patients with CCHS requiring ventilatory support
only during sleep. In some selected CCHS children presenting with 24h dependency on
ventilatory support, bilateral diaphragm pacing can be used to assist ventilation during
wakefulness, as a complement to mechanical ventilation via tracheostomy during sleep.
With constant monitoring and maintenance of SpO2 above 95% and PCO2 between 35
and 40 mmHg, most children with CCHS can be expected to graduate from college, get
married and maintain employment.
B-
RAPID
ONSET
OBESITY
WITH
HYPOTHALAMIC
DYSFUNCTION,
HYPOVENTILATION AND AUTONOMIC DYSREGULATION (ROHHAD)
First described in 1965 as late onset central hypoventilation with hypothalamic
dysfunction, ROHHAD was recently renamed to account for the chronology of clinical
presentation and to enable its distinction from CCHS 3. A total of 75 cases have now
been described worldwide. Typically, following apparent normality in the first 1.5 to 7
years of life, various evidences of hypothalamic dysfunction, including rapid-onset
obesity, suddenly develop. Subsequently, signs of autonomic dysregulation, such as low
body temperature, cold hands and feet, severe bradycardia and/or decreased pain
perception, will become apparent. Likewise, after a variable time interval, central
alveolar hypoventilation will manifest after an acute viral illness. Behavioural disorders,
strabismus, and abnormal pupillary responses can be present. Though non-invasive
ventilation at sleep is sufficient in many ROHHAD cases, some children require 24hr/day
mechanical ventilation via a tracheostomy. Of note, ROHHAD children have a high
incidence of cardiorespiratory arrests with acute viral infection. Furthermore,
approximately half of the patients will develop a neural crest tumour at any time in the
course of the disease.
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Diagnosis is made on the typical course of clinical signs and the absence of PHOX2B
mutation. An associated gene has yet to be discovered, and the mechanism of central
hypoventilation/decreased response to carbon dioxide is unknown.
The prognosis of ROHHAD is poor, due to sudden death following cardiorespiratory
arrest and numerous psychosocial impairments. Early diagnosis and optimal
management of central hypoventilation and hypothalamic dysfunction are treatment
cornerstones.
C- OTHER PEDIATRIC CENTRAL HYPOVENTILATION SYNDROMES
1. Chiari malformation
Chiari malformation is the commonest anomaly of the craniovertebral junction involving
both the skeletal and neural structures. Chiari type 1 is defined as cerebellar tonsil
herniation through the foramen magnum. Central sleep apnoea has been well
documented in Chiari type 1.
Chiari type 2 is defined as caudal herniation of the cerebellar vermis, brainstem and
fourth ventricle through the foramen magnum 4. It is typically associated to
myelomeningocele. Varying degrees of respiratory control disorders are present in
children with Chiari 2, including abnormal responses to hypercapnia and hypoxia, and
central and obstructive apnoeas. Pathogenesis involves dysgenesis of neural structures
in the brainstem and/or brainstem damage by compression in the foramen magnum or
by hydrocephalus.
Surgical posterior fossa decompression and/or shunt surgery in case of hydrocephalus
can be helpful, especially on central apnoeas. Positive pressure ventilation, either noninvasive or via tracheostomy, should be discussed in the most severely affected Chiari 2
children.
2. Prader-Willi syndrome
Prader-Willi syndrome is characterized by obesity, muscular hypotonia, mental
retardation, short stature, hypogonadotropic hypogonadism and small hands and feet. It
is an autosomal dominant disorder usually caused by deletion or disruption of one or
several genes on the paternal chromosome 15. Most infants and children have an
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increased apnoea/hypopnoea index, mainly of central origin. Obstructive sleep
disordered breathing is more frequent in obese children. Growth hormone treatment
tends to decrease central apnoeas but increases obstructive apnoeas in some patients,
due to adenotonsillar hypertrophy.
Central hypoventilation pathogenesis in Prader-Willi patients is unclear and involves
hypothalamic dysfunction, blunted response to chemical stimuli and diminished thyroid
function 5.
3. Familial dysautonomia
Familial dysautonomia (Riley-Day syndrome) is an inherited disorder caused by a
mutation of the IKBKAP gene on chromosome 9 that affects neuronal development and
survival, including autonomic (mainly sympathetic) neurons. Inheritance follows an
autosomal recessive pattern, and Ashkenazi Jews have a high carrier rate. A high rate
of sudden death is present. Abnormalities of breathing control are frequent and include
decreased ventilatory, blood pressure and heart rate response to hypoxia. Severe
breath-holding spells and episodes of sleep apnoeas and hypoxemia occur repeatedly
during children. Sleep hypoventilation incidence has not yet been systematically
studied 4.
4. Achondroplasia
Achondroplasia is the most frequent form of short-limb dwarfism and is caused by a
mutation in the fibroblast growth factor receptor-3 gene (FGFR3) located on
chromosome 4. Diminished growth of the skull base can result in a narrow foramen
magnum and medullary compression, which can manifest by central apnoea and sudden
death. In addition, obstructive sleep disordered breathing can result from mid-face
hypoplasia.
5. Leigh’s disease
Leigh’s disease is a group of neurodegenerative brainstem disorders caused by
mutations in mitochondrial DNA or by deficiencies in pyruvate dehydrogenase. Affected
infants present with central hypoventilation and developmental regression such as loss
of head control, sucking ability and motor skills. No specific treatment exists.
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6. Acquired central hypoventilation syndromes
Varying degrees of central hypoventilation can result from brain tumour, brain infection,
head trauma, vascular malformation, neurosurgical procedure and cranial irradiation.
Central hypoventilation usually worsens during sleep. Ventilatory muscle weakness can
further increase respiratory abnormalities.
REFERENCES
1. Weese-Mayer DE, Berry-Kravis EM, Ceccherini I, Keens TG, Loghmanee DA,
Trang H. An Official ATS Clinical Policy Statement: Congenital Central
Hypoventilation Syndrome. Genetic Basis, Diagnosis, and Management. Am J
Respir Crit Care Med 2010; 181:626–644.
2. <http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/clinical_disease_id/217354?db
=genetests>
3. Ize-Ludlow D, Gray JA, Sperling MA et al. Rapid-onset obesity with hypothalamic
dysfunction,
hypoventilation,
and
autonomic
dysregulation
presenting
in
childhood. Pediatrics 2007; 120:e179-188.
4. Lesser DJ, Ward SL, Kun SS, Keens TG. Congenital hypoventilation syndromes.
Semin Respir Crit Care Med 2009; 30:339-347.
5. Zanella S, Tauber M, Muscatelli F. Breathing deficits of the Prader-Willi
syndrome. Respir Physiol Neurobiol 2009; 168:119-124.
ACKNOWLEDGMENTS
Jean-Paul Praud holds the Canada Research Chair in Neonatal Respiratory Physiology.
The author’s work is supported by an operating grant from the Canadian Institutes of
Health Research. Dr. Praud is a member of the Fonds de la recherche en santésponsored Centre de recherche clinique Étienne-Le Bel, Centre hospitalier universitaire
de Sherbrooke.
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