Congenital central hypoventilation syndrome (CCHS;
Ondine's Curse) is traditionally defined as the failure of automatic control of breathing. The term ''Ondine's curse'' was initially coined by Severinghaus and Mitchell in 1962 to describe a syndrome manifested in three adult patients after high cervical/brainstem surgery. 11 When awake and summoned to breathe, these patients would do so, but otherwise would require mechanical ventilation for severe central apnea. In 1970, Mellins and colleagues were the first to report an infant with the typical clinical features corresponding to CCHS. 1 Although the cases described by Severinghaus and Mitchell were markedly different from the typical infant with CCHS, the term Ondine's curse gained wide acceptance to denote infants and children with CCHS, and it has been only in recent years that the term has finally and justifiably fallen out of favor.
In CCHS, ventilation is most severely affected during quiet sleep, a state during which automatic neural control is predominant. 5 Ventilatory patterns are also abnormal during active sleep and even during wakefulness, although to a milder degree. 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. Other symptoms indicative of brainstem dysfunction such as poor swallowing may be present, but are not essential to make the diagnosis of CCHS.
The proposed diagnostic criteria for CCHS include all of the following: 10 (1) persistent evidence of hypoventilation during sleep (PaCO 2 > 60 mmHg), (2) the onset of symptoms usually occur during the first year of life, (3) absence of primary pulmonary disease or neuromuscular dysfunction that could explain the hypoventilation, and (4) no evidence of primary heart disease.
PATHOPHYSIOLOGY
The exact pathophysiology of CCHS remains unknown and has been the subject of intense speculation and research. In the following paragraphs, I will briefly summarize the more recent developments and current understanding for this medically challenging syndrome.
GENETIC HYPOTHESES
Although a genetic defect is the probable underlying cause for CCHS when associated with Hirschsprung's disease (HD), it should be stressed that in the absence of HD, the likelihood of a successful search for candidate gene(s) accounting for the majority of CCHS cases seems relatively low at this time.
The rationale for CCHS containing a genetic component is its early manifestation in the newborn period, its occurrence in families, and its association with HD.