eMedicine Specialties > Pediatrics: General Medicine > Pulmonology

Congenital Central Hypoventilation Syndrome: Differential Diagnoses & Workup

Author: Terry Chin, MD, PhD, Associate Professor of Pediatrics, Pediatric Allergy/Immunology/Pulmonology, Department of Pediatrics, University of California Irvine School of Medicine; Associate Director, Miller Children's Hospital at Long Beach Memorial Medical Center
Coauthor(s): Cyrus M Shahriary, MD, Fellow, Pediatric Pulmonology, University of California at Irvine, Miller Children's Hospital; David Gozal, MD, Vice-Chairman of Research and Director, Kosair Children's Hospital Comprehensive Sleep Medicine Center, Professor, Department of Pediatrics, University of Louisville
Contributor Information and Disclosures

Updated: Dec 19, 2008

Differential Diagnoses

Apnea of Prematurity
Obesity
Aspiration Syndromes
Obesity-Hypoventilation Syndrome and Pulmonary Consequences of Obesity
Assisted Ventilation of the Newborn
Obstructive Sleep Apnea Syndrome
Botulism
Sleep Apnea

Other Problems to Be Considered

A structural hindbrain or brainstem abnormality
Congenital myasthenic syndrome
Diaphragm dysfunction
Mobius syndrome

Workup

Laboratory Studies

  • In patients with suspected congenital central hypoventilation syndrome (CCHS), perform urine collection for amino acids and organic acids to evaluate for metabolic disorders that may occur as recurrent apparent life-threatening events or cyanotic spells.
  • For PHOX2B testing, contact Rush University Genetics Laboratory at (312) 942-6298.

Imaging Studies

  • Imaging studies of the CNS are strongly recommended. Computerized axial tomographic scans of the brain have been used in the past but have a low yield in the evaluation of brainstem regions because of bone-air interface reconstruction artifacts. Thus, when congenital central hypoventilation syndrome is suspected, T1 and T2 MRI testing is currently the recommended imaging approach for anatomic evaluation of the CNS. Using a 3.0-Tesla MRI unit, increased mean diffusivity (MD) values suggest regional alterations or injury.
  • Perform cardiac evaluation, including chest radiography and echocardiography.
  • Perform diaphragm fluoroscopy, ultrasonography, or both to rule out unilateral or bilateral diaphragmatic paralysis or paresis. On occasion, measuring maximal transdiaphragmatic pressures against an occluded airway when the patient is crying and breathing 100% oxygen or, preferentially, a mixture that contains 95% oxygen and 5% carbon dioxide may be useful.

Other Tests

  • Although specific methods for establishing the diagnosis of congenital central hypoventilation syndrome vary among medical centers, the following guidelines for evaluation of a patient exemplify a typical approach in a tertiary center:  
    • Administer a polysomnographic study in a well-equipped laboratory to carefully determine respiratory patterning and gas-exchange abnormalities during different behavioral states. Because many infants may not be sufficiently stable to undergo polysomnographic studies while spontaneously breathing, documenting the changes in cardiorespiratory behavior and related consequences by performing brief discontinuations of mechanical ventilatory support during each sleep stage is important. Periodically repeat these studies because significant developmental changes occur in sleep and respiratory patterns during the first year of life. A sleep study needs to be performed every 3-4 months during the first 2 years of life and every 6 months until the child is aged 5-6 years. Annual evaluation after age 6 years is usually adequate if the patient is stable.
    • Although hypercapnic ventilatory challenges are not specifically included in the proposed diagnostic criteria, they are an essential component for the diagnosis of congenital central hypoventilation syndrome. Steady-state or rebreathing approaches are similarly valid. For steady-state challenges, the use of 3%, 5%, and 7% carbon dioxide balance in oxygen for 20-30 minutes at each level is usually appropriate; it is also easier to deliver when patients are mechanically ventilated. In infants, the use of calibrated respiratory inductance plethysmography is helpful to determine, in a semiquantitative fashion, whether a ventilatory increase is apparent during spontaneous breathing, during wakefulness in milder patients, or as a ventilatory change from the stable ventilation provided by the mechanical ventilatory settings.
    • At a later stage, pursue more quantitative measurements with a mask and pneumotachograph if the patient is awake or by incorporating a pneumotachograph to the ventilator circuit if the patient is asleep. These studies must be conducted in each of the defined states (ie, waking, rapid eye movement [REM], non-REM) so they can be incorporated into the polysomnographic evaluation described above.
  • Obtain an electrocardiography as part of the cardiac evaluation.
  • If extensive hypotonia is present, nerve conduction studies and electromyography (EMG) may be required after extensive clinical neurologic assessment.
  • Perform an ophthalmologic examination (ie, careful pupillary assessment) to assess for autonomic ophthalmologic abnormality.
  • Neurocognitive assessment is used to determine baseline function.

Procedures

  • If extensive hypotonia is present, muscle biopsy may be required after extensive clinical neurologic assessment.
  • If Hirschsprung disease is suspected, consider rectal biopsy.

More on Congenital Central Hypoventilation Syndrome

Overview: Congenital Central Hypoventilation Syndrome
Differential Diagnoses & Workup: Congenital Central Hypoventilation Syndrome
Treatment & Medication: Congenital Central Hypoventilation Syndrome
Follow-up: Congenital Central Hypoventilation Syndrome
References
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References

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  2. Berry-Kravis EM, Zhou L, Rand CM, et al. Congenital central hypoventilation syndrome: PHOX2B mutations and phenotype. Am J Respir Crit Care Med. Nov 15 2006;174(10):1139-44. [Medline]. [Full Text].

  3. Weese-Mayer DE, Berry-Kravis EM. Genetics of congenital central hypoventilation syndrome: lessons from a seemingly orphan disease. Am J Respir Crit Care Med. Jul 1 2004;170(1):16-21. [Medline]. [Full Text].

  4. O'Brien LM, Holbrook CR, Vanderlaan M, et al. Autonomic function in children with congenital central hypoventilation syndrome and their families. Chest. Oct 2005;128(4):2478-84. [Medline].

  5. Kumar R, Macey PM, Woo MA, et al. Elevated mean diffusivity in widespread brain regions in congenital central hypoventilation syndrome. J Magn Reson Imaging. Dec 2006;24(6):1252-8. [Medline].

  6. Huang J, Colrain IM, Panitch HB, et al. Effect of sleep stage on breathing in children with central hypoventilation. J Appl Physiol. Jul 2008;105(1):44-53. [Medline].

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  9. Gaultier C, Trang H, Dauger S, et al. Pediatric disorders with autonomic dysfunction: what role for PHOX2B?. Pediatr Res. Jul 2005;58(1):1-6. [Medline]. [Full Text].

  10. Haddad GG, Mazza NM, Defendini R, et al. Congenital failure of automatic control of ventilation, gastrointestinal motility and heart rate. Medicine (Baltimore). Nov 1978;57(6):517-26. [Medline].

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  13. Shaul DB, Danielson PD, McComb JG, et al. Thoracoscopic placement of phrenic nerve electrodes for diaphragmatic pacing in children. J Pediatr Surg. Jul 2002;37(7):974-8; discussion 974-8. [Medline].

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Further Reading

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Keywords

congenital central hypoventilation syndrome, CCHS, Ondine curse, Ondine's curse, sleep-induced apnea, central apnea, central hypoventilation, autonomic nervous system dysregulation, ANS dysregulation, Hirschsprung disease, Hirschsprung's disease, obstructive sleep apnea syndrome, sudden infant death syndrome, Rett syndrome, stunted growth, cor pulmonale, neural crest tumors, apnea, heart failure, apparent life-threatening event, SIDS, neuroblastoma, gastroesophageal reflux

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Contributor Information and Disclosures

Author

Terry Chin, MD, PhD, Associate Professor of Pediatrics, Pediatric Allergy/Immunology/Pulmonology, Department of Pediatrics, University of California Irvine School of Medicine; Associate Director, Miller Children's Hospital at Long Beach Memorial Medical Center
Terry Chin, MD, PhD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Association of Immunologists, American College of Allergy, Asthma and Immunology, American College of Chest Physicians, American Thoracic Society, California Thoracic Society, Clinical Immunology Society, and Western Society for Pediatric Research
Disclosure: Nothing to disclose.

Coauthor(s)

Cyrus M Shahriary, MD, Fellow, Pediatric Pulmonology, University of California at Irvine, Miller Children's Hospital
Cyrus M Shahriary, MD is a member of the following medical societies: American Academy of Pediatrics, Iran Medical Council, and Iranian Society of Pediatrics
Disclosure: Nothing to disclose.

David Gozal, MD, Vice-Chairman of Research and Director, Kosair Children's Hospital Comprehensive Sleep Medicine Center, Professor, Department of Pediatrics, University of Louisville
David Gozal, MD is a member of the following medical societies: Society for Pediatric Research
Disclosure: Nothing to disclose.

Medical Editor

Girish D Sharma, MD, Associate Professor, Department of Pediatrics, Rush University Medical Center, Rush Children's Hospital; Director of Pediatric Pulmonary Section and Rush Cystic Fibrosis Center
Girish D Sharma, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Chest Physicians, American Thoracic Society, and Royal College of Physicians of Ireland
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

Heidi Connolly, MD, Associate Professor of Pediatrics and Psychiatry, University of Rochester; Director, Pediatric Sleep Medicine Services, Strong Sleep Disorders Center
Heidi Connolly, MD is a member of the following medical societies: American Academy of Pediatrics, American Thoracic Society, and Society of Critical Care Medicine
Disclosure: Nothing to disclose.

CME Editor

Mary E Cataletto, MD, Associate Director, Division of Pediatric Pulmonology, Winthrop University Hospital; Professor of Clinical Pediatrics, State University of New York at Stony Brook; Director of Children's Sleep Services, Winthrop University Hospital
Mary E Cataletto, MD is a member of the following medical societies: American Academy of Pediatrics and American College of Chest Physicians
Disclosure: Shering Plough Pharmaceuticals Honoraria Consulting

Chief Editor

Michael R Bye, MD, Professor of Clinical Pediatrics, Division of Pulmonary Medicine, Columbia University College of Physicians and Surgeons; Attending Physician, Pediatric Pulmonary Medicine, Columbia University Medical Center
Michael R Bye, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Chest Physicians, and American Thoracic Society
Disclosure: Merck Honoraria Speaking and teaching

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