CCHS is a disease of the autonomic nervous system that is not as rare as previously thought, with an estimated incidence of one per 200,000 live births [1, 3, 7]. Classically, it presents as sudden death in infancy because of a failure of autonomic control of ventilation during sleep (Ondine curse) [1, 2, 5]. Infants with CCHS typically do not breathe spontaneously for the first few months of life, but can develop breathing patterns while awake over time. The hypoventilation associated with CCHS is more severe in non-rapid eye sleep, which contrasts with other respiratory disorders . Untreated, this may result in pulmonary hypertension, cor pulmonale and central nervous system hypoxic damage [1, 5]. Other clinical manifestations of CCHS as a result of generalized autonomic nervous system dysfunction include cardiac arrhythmias, orthostatic hypotension, episodes of profuse diaphoresis, pupillary abnormalities, severe constipation, HSCR and neural crest tumors . CCHS is diagnosed in newborns as clinical symptoms develop in the absence of any neuromuscular, cardiovascular or respiratory system abnormalities [1, 3, 5].
Late-onset CCHS (LO-CCHS) is diagnosed in adults who present with signs of central alveolar hypoventilation. They are at risk for polycythemia and pulmonary hypertension. Most adults with LO-CCHS carry a smaller expansion in PHOX2B when compared with infants with classic CCHS, but NPARMs have also occasionally been reported [1, 2, 5, 9].
HSCR is a developmental disorder of the enteric system that is characterized by aganglionosis in the distal colon causing bowel obstruction. It occurs in approximately one out of every 5000 live births . It generally presents as a failure to pass meconium as a neonate or, later in childhood, as chronic constipation, abdominal distension and emesis. Although HSCR can arise as an isolated finding, it can also be an associated feature in 16% to 50% of cases of CCHS [1, 4, 6, 7, 10].
CCHS is an autosomal dominant disorder caused by mutations in the PHOX2B gene on chromosome 4 [1, 3]. This gene was originally identified in mice with abnormalities of the autonomic nervous system. Most cases are associated with PARMs in exon three . Normal individuals carry a 20-alanine repeat sequence, while those with classic CCHS have expansions in the +5 to +13 range. Studies have demonstrated a direct correlation between the repeat number and disease severity. Individuals with small expansions (25 repeats) have LO-CCHS and rarely require ventilation, while those with larger expansions (27 to 33 repeats) often require continuous ventilatory support [1, 3–5]. Less common are the NPARMs (frameshift and nonsense mutations) in PHOX2B. These are commonly associated with a more severe clinical phenotype including the need for continuous ventilatory support, tumors of neural crest origin and HSCR . As with many autosomal dominant conditions, CCHS demonstrates variable expressivity and reduced penetrance. The family in our case was unusual in that most family members were relatively mildly affected and only identified later in childhood or as adults after the diagnosis was made in the proband (III-3), despite carrying an NPARM that is usually associated with more severe disease. This again confirms the highly variable clinical presentation for CCHS and the importance of sleep studies in apparently asymptomatic family members . Phenotypic differences previously described in monozygotic twins with CCHS suggest a role for non-genetic factors in clinical variability and disease severity . Reduced penetrance and variable expressivity has also been described in LO-CCHS [9, 13].
PHOX2B mutation carriers are at risk for chronic hypoventilation and arrhythmias and must be assessed and managed by specialists familiar with CCHS. The American Thoracic Society has issued a clinical policy statement on diagnosis and treatment of CCHS that is largely based on expert opinion . The primary goal of treatment is to ensure optimal ventilation and oxygenation through the use of mechanical assisted ventilation. Most individuals require at least nocturnal ventilation and some may need continuous ventilator support to avoid the long-term complications of chronic hypoxemia. In newborns and children, expert opinion recommends positive pressure ventilation via tracheostomy. In all cases, close monitoring is necessary to maintain normal oxygen levels for various activities and to minimize deleterious effects on cognitive development. Sedatives and central nervous system depressants should be avoided as they can depress ventilatory drive and, in the absence of ventilatory support, can lead to death.
Individuals with CCHS can survive to adulthood with appropriate management. The cause of death in individuals with CCHS relates to suboptimal ventilation, the use of substances that depress ventilatory control and cardiac arrhythmias. Screening recommendations for individuals with CCHS based on genotype are published . Presymptomatic and prenatal diagnostic testing are available in instances where the disease-causing PHOX2B mutation has been identified.