Congenital Central Hypoventilation Syndrome Workup

Updated: Jun 02, 2017
  • Author: Terry W Chin, MD, PhD; Chief Editor: Girish D Sharma, MD, FCCP, FAAP  more...
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Laboratory Studies

Many commercial laboratories are now performing PHOX2B screening testing via fragment analysis or sequencing tests. However, if the screening test is negative and the patient’s clinical manifestations support the diagnosis of congenital central hypoventilation syndrome (CCHS), one can contact Rush University Genetics Laboratory to perform the actual sequencing to identify the subset of nonpolyalanine repeat expansion mutation (NPARM). Because more than 90-95% of individuals with CCHS have a PHOX2B polyalanine expansion mutation (PARM) and because PHOX2B polyalanine expansion testing is a more sensitive test for detection of mosaicism, such testing should be performed first.

Multiplex ligation-dependent probe amplification was introduced by Rush University to identify those patients with alveolar hypoventilation or suspicious apparent life-threatening events who test negative for PARM and NPARM. [26] Multiplex ligation-dependent probe amplification has been used to identify specific exon or whole-gene deletions in the PHOX2B gene that have not been detected by current means of commercial screening. Four cases of either single exon or complete PHOX2B gene deletion have been reported, suggesting that a subset of patients may demonstrate a degree of alveolar hypoventilation without the full spectrum of autonomic dysregulation characteristic in CCHS.

Urine collection for amino acids and organic acids may be considered for evaluation of metabolic disorders.

A hypercoagulability workup is indicated if neural imaging shows evidence of thrombosis.


Imaging Studies

Imaging studies of the CNS are strongly recommended to rule out causative gross anatomic brain or brainstem lesions.

The American Thoracic Society (ATS) recommends performing imaging for neural crest tumors in individuals at greatest risk based on PHOX2B mutation. [1]

Obtain chest radiography and CT scanning to evaluate for a primary pulmonary problem.

As part of the cardiac evaluation, obtain an echocardiogram.

Perform diaphragm fluoroscopy, ultrasonography, or both to rule out unilateral or bilateral diaphragmatic paralysis or paresis.


Other Tests

Polysomnography is useful in determining respiratory patterning and gas-exchange abnormalities during different sleep 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. It is important to periodically repeat these studies because significant developmental changes occur in sleep and respiratory patterns during the first year of life. Therefore, a repeat sleep study should 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 diagnostic criteria, they are a component for the diagnosis of CCHS. 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 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.

Recently, two case reports have described a tentative diagnosis of CCHS made by measuring the electrical activity of the diaphragm using a catheter with a sensor placed just above the gastroesophageal junction. During sleep, the electrical activity of the diaphragm was low, if not absent, indicating central apnea, but there was a good diaphragmatic activity while awake. [27, 28]

If extensive hypotonia is present, nerve conduction studies and electromyography (EMG) may be appropriate 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.



If extensive hypotonia is present, muscle biopsy may be required after extensive clinical neurologic assessment.

If Hirschsprung disease is suspected, consider rectal biopsy.