Congenital Central Hypoventilation Syndrome Clinical Presentation

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

History

Sleep-dependent hypoventilation in the absence of neuromuscular, cardiac, metabolic, or pulmonary disease is the hallmark of congenital central hypoventilation syndrome (CCHS). In severe cases, hypoventilation is also present during wakefulness. The clinical presentation of patients with CCHS may vary and depends on the severity of the hypoventilation.

Some infants do not breathe at birth and require assisted ventilation in the newborn nursery. Most infants who present in this manner do not spontaneously breathe during the first few months of life but may mature and have a pattern of adequate breathing during wakefulness over time; however, apnea or central hypoventilation persists during sleep. This apparent improvement over the first few months of life is believed to result from normal maturation of the respiratory system and does not represent a true change in the basic deficit in respiratory control.

Other infants may present at a later age, with cyanosis, edema, and signs of right-sided heart failure as the first indications of CCHS. These symptoms in infants have often been mistaken for those of cyanotic congenital heart disease; however, cardiac catheterization reveals only pulmonary hypertension. Infants with less severe CCHS may present with tachycardia, diaphoresis, and/or cyanosis during sleep.

Presumably, if the diagnosis is not made, right-sided heart failure develops as a consequence of repeated hypoxemic episodes during sleep. Still, others may present with unexplained apnea or an apparent life-threatening event or some may even die and be categorized as having sudden infant death syndrome (SIDS). Thus, the wide spectrum of severity in clinical manifestations dictates the age at which recognition of CCHS takes place.

Late-onset central hypoventilation syndrome has also been described, for which symptoms present in late childhood or adulthood. [20] They may present with hypoventilation or an altered response to hypoxemia or hypercarbia after an inciting event such as respiratory infection, sedation, anesthesia, or sleep apnea.

CCHS patient also have disorders of autonomic nervous system control. They may have cardiac dysfunction in the form of arrhythmias, primary sinus bradycardia and transient asystole, decreased heart rate variability, and alterations in blood pressure. Blood pressure values are lower during wakefulness and higher during sleep, indicating attenuation of the normal sleep-related blood pressure decrement in CCHS. They may also exhibit dysfunction in thermoregulation such as profuse sweating, decreased body temperature, or inability to mount a fever during an infection. They may also have blunted pupillary light responses.

About 20% of patients with CCHS also have Hirschsprung disease, which is referred to as Haddad syndrome. [21]

Neural crest tumors, such as neuroblastoma, are seen in 5-10% of CCHS patients.

Mild intellectual or cognitive deficits are also common. [22] However, the range of functioning defects makes it likely that environmental factors may also be playing a role. [23] There did not appear to be any correlation with PHOX2B genotype and disease severity. However, a study by Charnay et al that reported on neurodevelopmental impairment in preschool patients with CCHS found that among the children with the three most common polyalanine repeat expansion mutation genotypes, the motor and mental scored varied with normal scores reported in children with the 20/25 genotype but lower scores in the other genotype groups. These lower scores were associated with severe breath-holding spells, prolonged sinus pauses, and need for 24 h/d artificial ventilation, and seizures. [24]

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Physical

A characteristic facies has been described in patients with congenital central hypoventilation syndrome (CCHS) between the ages of 2 years and early adulthood that is characterized by a shorter and flatter face. This characteristic box-shaped face is seen in patients with polyalanine repeat expansion mutations (PARMs).

Infants may be hypotonic, display thermal lability, and have occasional and sudden hypotensive events that are unexplainable based on the surrounding circumstances. These manifestations usually improve over time. Autonomic nervous system dysfunction may also be seen with dysrhythmias, alterations in blood pressure, and ophthalmic findings.

Ocular findings (eg, abnormal pupils that are miotic, anisocoric, or abnormally responsive to light) can be found in 70% of cases. Abnormal irides (60% of cases); strabismus (50% of cases); and, on occasion, lack of tears during crying, can also be found. Thus, referring children with CCHS for a thorough ophthalmologic evaluation is important.

The severity of respiratory dysfunction may range from relatively mild hypoventilation during quiet sleep with fairly good alveolar ventilation during wakefulness to complete apnea during sleep with severe hypoventilation during wakefulness.

Gastroesophageal reflux and decreased intestinal motility with constipation are often present in younger patients.

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Causes

PHOX2B is the main disease-causing gene for primary congenital central hypoventilation syndrome (CCHS), an autosomal dominant disorder with incomplete penetrance. However, about 20 patients have been identified with CCHS with mutations in other genes, usually in genes involved in the development of neural crest cells or components of the endothelin pathway. In some cases, non-PHOX2B gene mutations were accompanied by PHOX2B mutations, suggesting a role as modifier genes. [25]

Secondary central hypoventilation syndrome may result from other conditions or occurrences (eg, brainstem tumor or other space-occupying lesions, vascular malformations, CNS infection, stroke, neurosurgical procedures to the brain stem).

Patients with CCHS who develop malignant neural crest–derived tumors have either a missense or a frameshift heterozygous mutation in the PHOX2B gene. Therefore, a subset of patients with CCHS who are at risk for developing malignant tumors may be identified.

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