Congenital central hypoventilation syndrome and other causes of sleep-related hypoventilation in children
- Robert T Brouillette, MD
Robert T Brouillette, MD
- Professor and Associate Chair of Pediatrics
- McGill University, Montreal
Hypoventilation (ventilatory insufficiency) can result from disorders of the brain, spinal cord, nerves, muscles, heart, lungs, or airway. Sleep-related hypoventilation is a clinical pattern in which the ventilatory insufficiency occurs primarily during sleep. Affected individuals are at risk for hypoxemia and bradycardia because of the hypoventilation, and require continuous monitoring during sleep to monitor for these problems.
In children, the most common cause of hypoventilation during sleep is obstructive sleep apnea (OSA), which is discussed in separate topic reviews. (See "Evaluation of suspected obstructive sleep apnea in children" and "Management of obstructive sleep apnea in children".)
Non-obstructive sleep-related hypoventilation is much less common, and is usually due to one of several rare genetic or neurologic disorders of ventilatory control, especially congenital central hypoventilation syndrome (CCHS), late onset central hypoventilation syndrome (LO-CHS), or rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) syndrome. These disorders will be discussed in this topic review.
●Hypoventilation refers to a mismatch between elimination of carbon dioxide (CO2) by the ventilatory apparatus and metabolic production of CO2. Conventionally, hypoventilation is defined as arterial blood gas partial pressure of CO2 (pCO2) above the normal levels of 35 to 45 mmHg in an awake patient. Hypoventilation is often, but not always, accompanied by hypoxemia. Clinicians may suspect hypoventilation on the basis of capillary or venous blood gas with unexplained elevations of CO2 (>50 mmHg) and bicarbonate (>25 mEq/L), or pulse oximetry with a baseline oxygen saturation <96 percent at rest.
●Sleep-related hypoventilation refers to hypoventilation that worsens or exclusively occurs during sleep. Because the hypoventilation tends to occur during daytime naps as well as during nocturnal sleep, the term "sleep-related hypoventilation" is preferred over "nocturnal hypoventilation." During sleep, withdrawal of the wakefulness drive to breathe allows a rise in pCO2 in the arterial blood (PaCO2) to as high as 50 mmHg in healthy individuals.
- Berry RB, Brooks R, Gamaldo CE, et al for the American Academy of Sleep Medicine. The AASM Manual for the Scoring of Sleep and Associated Events: Rules, Terminology and Technical Specifications, Version 2.2, www.aasmnet.org, American Academy of Sleep Medicine, Darien, IL 2015.
- Berry RB, Budhiraja R, Gottlieb DJ, et al. Rules for scoring respiratory events in sleep: update of the 2007 AASM Manual for the Scoring of Sleep and Associated Events. Deliberations of the Sleep Apnea Definitions Task Force of the American Academy of Sleep Medicine. J Clin Sleep Med 2012; 8:597.
- Mellins RB, Balfour HH Jr, Turino GM, Winters RW. Failure of automatic control of ventilation (Ondine's curse). Report of an infant born with this syndrome and review of the literature. Medicine (Baltimore) 1970; 49:487.
- Weese-Mayer DE, Berry-Kravis EM, Ceccherini I, et al. An official ATS clinical policy statement: Congenital central hypoventilation syndrome: genetic basis, diagnosis, and management. Am J Respir Crit Care Med 2010; 181:626.
- Amiel J, Laudier B, Attié-Bitach T, et al. Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome. Nat Genet 2003; 33:459.
- Weese-Mayer DE, Berry-Kravis EM, Zhou L, et al. Idiopathic congenital central hypoventilation syndrome: analysis of genes pertinent to early autonomic nervous system embryologic development and identification of mutations in PHOX2b. Am J Med Genet A 2003; 123A:267.
- Weese-Mayer DE, Rand CM, Berry-Kravis EM, et al. Congenital central hypoventilation syndrome from past to future: model for translational and transitional autonomic medicine. Pediatr Pulmonol 2009; 44:521.
- Arai H, Otagiri T, Sasaki A, et al. De novo polyalanine expansion of PHOX2B in congenital central hypoventilation syndrome: unequal sister chromatid exchange during paternal gametogenesis. J Hum Genet 2007; 52:921.
- Arai H, Otagiri T, Sasaki A, et al. Polyalanine expansion of PHOX2B in congenital central hypoventilation syndrome: rs17884724:A>C is associated with 7-alanine expansion. J Hum Genet 2010; 55:4.
- Rand CM, Yu M, Jennings LJ, et al. Germline mosaicism of PHOX2B mutation accounts for familial recurrence of congenital central hypoventilation syndrome (CCHS). Am J Med Genet A 2012; 158A:2297.
- Guyenet PG, Stornetta RL, Abbott SB, et al. The retrotrapezoid nucleus and breathing. Adv Exp Med Biol 2012; 758:115.
- Kumar NN, Velic A, Soliz J, et al. PHYSIOLOGY. Regulation of breathing by CO₂ requires the proton-activated receptor GPR4 in retrotrapezoid nucleus neurons. Science 2015; 348:1255.
- Haddad GG, Mazza NM, Defendini R, et al. Congenital failure of automatic control of ventilation, gastrointestinal motility and heart rate. Medicine (Baltimore) 1978; 57:517.
- Lake JI, Heuckeroth RO. Enteric nervous system development: migration, differentiation, and disease. Am J Physiol Gastrointest Liver Physiol 2013; 305:G1.
- Shannon DC, Marsland DW, Gould JB, et al. Central hypoventilation during quiet sleep in two infants. Pediatrics 1976; 57:342.
- Paton JY, Swaminathan S, Sargent CW, Keens TG. Hypoxic and hypercapnic ventilatory responses in awake children with congenital central hypoventilation syndrome. Am Rev Respir Dis 1989; 140:368.
- Carroll MS, Patwari PP, Kenny AS, et al. Residual chemosensitivity to ventilatory challenges in genotyped congenital central hypoventilation syndrome. J Appl Physiol (1985) 2014; 116:439.
- Gronli JO, Santucci BA, Leurgans SE, et al. Congenital central hypoventilation syndrome: PHOX2B genotype determines risk for sudden death. Pediatr Pulmonol 2008; 43:77.
- Goldberg DS, Ludwig IH. Congenital central hypoventilation syndrome: ocular findings in 37 children. J Pediatr Ophthalmol Strabismus 1996; 33:175.
- Patwari PP, Stewart TM, Rand CM, et al. Pupillometry in congenital central hypoventilation syndrome (CCHS): quantitative evidence of autonomic nervous system dysregulation. Pediatr Res 2012; 71:280.
- Zelko FA, Nelson MN, Leurgans SE, et al. Congenital central hypoventilation syndrome: neurocognitive functioning in school age children. Pediatr Pulmonol 2010; 45:92.
- Charnay AJ, Antisdel-Lomaglio JE, Zelko FA, et al. Congenital Central Hypoventilation Syndrome: Neurocognition Already Reduced in Preschool-Aged Children. Chest 2016; 149:809.
- Weese-Mayer DE, Marazita ML, Rand CM et al. Congenital central hypoventilation syndrome. In: GeneReviews (Internet). Pagon RA, Adam MP, Ardinger HH et al, eds. University of Washington, Seattle. Available at: http://www.ncbi.nlm.nih.gov/books/NBK1427 (Accessed on October 30, 2015).
- Weese-Mayer DE, Brouillette RT, Naidich TP, et al. Magnetic resonance imaging and computerized tomography in central hypoventilation. Am Rev Respir Dis 1988; 137:393.
- Kumar R, Macey PM, Woo MA, et al. Elevated mean diffusivity in widespread brain regions in congenital central hypoventilation syndrome. J Magn Reson Imaging 2006; 24:1252.
- Macey PM, Richard CA, Kumar R, et al. Hippocampal volume reduction in congenital central hypoventilation syndrome. PLoS One 2009; 4:e6436.
- Kumar R, Ahdout R, Macey PM, et al. Reduced caudate nuclei volumes in patients with congenital central hypoventilation syndrome. Neuroscience 2009; 163:1373.
- Kumar R, Woo MS, Macey PM, et al. Progressive gray matter changes in patients with congenital central hypoventilation syndrome. Pediatr Res 2012; 71:701.
- Brouillette RT, Marzocchi M. Diaphragm pacing: clinical and experimental results. Biol Neonate 1994; 65:265.
- Hunt CE, Silvestri JM. Pediatric hypoventilation syndromes. Curr Opin Pulm Med 1997; 3:445.
- Vanderlaan M, Holbrook CR, Wang M, et al. Epidemiologic survey of 196 patients with congenital central hypoventilation syndrome. Pediatr Pulmonol 2004; 37:217.
- Trang H, Dehan M, Beaufils F, et al. The French Congenital Central Hypoventilation Syndrome Registry: general data, phenotype, and genotype. Chest 2005; 127:72.
- Verkaeren E, Brion A, Hurbault A, et al. Health-related quality of life in young adults with congenital central hypoventilation syndrome due to PHOX2B mutations: a cross-sectional study. Respir Res 2015; 16:80.
- Carnevale FA, Alexander E, Davis M, et al. Daily living with distress and enrichment: the moral experience of families with ventilator-assisted children at home. Pediatrics 2006; 117:e48.
- Massie J, Gillam L. Ethical considerations with the management of congenital central hypoventilation syndrome. Pediatr Pulmonol 2015; 50:503.
- Bougnères P, Pantalone L, Linglart A, et al. Endocrine manifestations of the rapid-onset obesity with hypoventilation, hypothalamic, autonomic dysregulation, and neural tumor syndrome in childhood. J Clin Endocrinol Metab 2008; 93:3971.
- FISHMAN LS, SAMSON JH, SPERLING DR. PRIMARY ALVEOLAR HYPOVENTILATION SYNDROME (ONDINE'S CURSE). Am J Dis Child 1965; 110:155.
- duRivage SK, Winter RJ, Brouillette RT, et al. Idiopathic hypothalamic dysfunction and impaired control of breathing. Pediatrics 1985; 75:896.
- Katz ES, McGrath S, Marcus CL. Late-onset central hypoventilation with hypothalamic dysfunction: a distinct clinical syndrome. Pediatr Pulmonol 2000; 29:62.
- 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.
- Patwari PP and Rand CM. Rapid onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysfunction (ROHHAD). In: Principles and Practice of Pediatric Sleep Medicine, 2 ed, Sheldon SH, Kryger MH, Ferber R, Gozal D.. (Eds), Elsevier/Saunders, London 2014. p.307.
- Paz-Priel I, Cooke DW, Chen AR. Cyclophosphamide for rapid-onset obesity, hypothalamic dysfunction, hypoventilation, and autonomic dysregulation syndrome. J Pediatr 2011; 158:337.
- Sartori S, Priante E, Pettenazzo A, et al. Intrathecal synthesis of oligoclonal bands in rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation syndrome: new evidence supporting immunological pathogenesis. J Child Neurol 2014; 29:421.
- Chow C, Fortier MV, Das L, et al. Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) syndrome may have a hypothalamus-periaqueductal gray localization. Pediatr Neurol 2015; 52:521.
- Huppke P, Heise A, Rostasy K, et al. Immunoglobulin therapy in idiopathic hypothalamic dysfunction. Pediatr Neurol 2009; 41:232.
- Davidson AJ, Morton NS, Arnup SJ, et al. Apnea after Awake Regional and General Anesthesia in Infants: The General Anesthesia Compared to Spinal Anesthesia Study--Comparing Apnea and Neurodevelopmental Outcomes, a Randomized Controlled Trial. Anesthesiology 2015; 123:38.
- Lal C, White DR, Joseph JE, et al. Sleep-disordered breathing in Down syndrome. Chest 2015; 147:570.
- Cohen M, Hamilton J, Narang I. Clinically important age-related differences in sleep related disordered breathing in infants and children with Prader-Willi Syndrome. PLoS One 2014; 9:e101012.
- Felix O, Amaddeo A, Olmo Arroyo J, et al. Central sleep apnea in children: experience at a single center. Sleep Med 2016; 25:24.
- Kritzinger FE, Al-Saleh S, Narang I. Descriptive analysis of central sleep apnea in childhood at a single center. Pediatr Pulmonol 2011; 46:1023.
- Waters KA, Forbes P, Morielli A, et al. Sleep-disordered breathing in children with myelomeningocele. J Pediatr 1998; 132:672.
- Mandrell BN, Wise M, Schoumacher RA, et al. Excessive daytime sleepiness and sleep-disordered breathing disturbances in survivors of childhood central nervous system tumors. Pediatr Blood Cancer 2012; 58:746.
- Woughter M, Perkins AM, Baldassari CM. Is MRI Necessary in the Evaluation of Pediatric Central Sleep Apnea? Otolaryngol Head Neck Surg 2015; 153:1031.
- CONGENITAL CENTRAL HYPOVENTILATION SYNDROME
- - Genotypes
- - Inheritance
- - Molecular mechanisms
- Clinical features
- - Presentation
- - Abnormal ventilatory and arousal responses
- - Autonomic abnormalities
- - Ophthalmic abnormalities
- - Cognitive abnormalities
- - Neural crest derived tumors
- - Hirschsprung disease
- - Clinical evaluation
- - Molecular diagnosis
- - Ventilatory support
- - Monitoring and home care
- - Surveillance
- - Burden of illness, quality of life, and long-term outcome
- OTHER HYPOVENTILATION SYNDROMES
- Late-onset central hypoventilation syndrome (LO-CHS)
- Rapid-onset obesity with hypothalamic dysfunction (ROHHAD)
- OTHER CAUSES OF CENTRAL SLEEP APNEA
- SUMMARY AND RECOMMENDATIONS