Central hypoventilation syndrome

Jean-Paul Praud

Departments of Pediatrics and Physiology

Université de Sherbrooke

Corresponding author:

Jean-Paul Praud MD PhDTel: (819) 346-1110, ext 14851

Departments of Pediatrics and PhysiologyFax: (819) 564-5215

Université de Sherbrookeemail:

J1H 5N4, QC Canada

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 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 thatpatients 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 toan 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 (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 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.

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 magnum4. 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 non-invasive or via tracheostomy, should be discussed in the most severely affected Chiari 2 children.

  1. 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 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.

  1. 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 studied4.

  1. 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.

  1. 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.

  1. 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.
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  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 santé-sponsored Centre de recherche clinique Étienne-Le Bel, Centre hospitalier universitaire de Sherbrooke.

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