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At a glance

Rare congenital failure of autonomic control of breathing during sleep. Other features include Hirschsprung disease and reduced esophageal motility.

Synonyms

Congenital Central Hypoventilation Syndrome (CCHS); Ondine-Hirschsprung Disease; Ondine Curse.

History

The name of this syndrome originates from Old French and German mythology about the water nymph Ondine (Undine). Nymphs are known to be very beautiful, and Ondine was certainly no exception. Nevertheless, she was very wary of men because they are a threat to a nymph’s immortality. Whenever a nymph falls in love with a man, she loses her immortality and begins to age and eventually dies. However, all this was forgotten when Ondine discovered Sir Huldbrecht (also Hans), a young knight, near her lily pond. Sir Huldbrecht, too, was captured by Ondine’s beauty, and soon the two fell in love and married. From this very moment, however, Ondine started to age. Her stunning beauty slowly fading away, Sir Huldbrecht soon found himself looking for a younger and prettier woman. One afternoon, Ondine caught Sir Huldbrecht happily in the arms of a young woman. Having sacrificed her immortality for this man who had sworn love and faithfulness to her, Ondine demanded retaliation. With her magic still powerful enough for vengeance, she cursed Sir Huldbrecht: “As long as you are awake, you shall have your breath, however, as soon as you fall asleep, your breath will be taken from you!” It didn’t take long until Sir Huldbrecht fell asleep from exhaustion and died shortly thereafter. This myth illustrates the problem of the patient suffering from congenital central hypoventilation. First description by John W. Severinghans and Robert A. Mitchell in 1962.

Incidence

Very rare, estimated to be 1:50,000 to 1:200,000 live births.

Genetic inheritance

Autosomal recessive or autosomal dominant (90%) with reduced penetrance.

Pathophysiology

Ondine Syndrome is most likely caused by a heterozygous mutation—either a polyalanine repeat mutation or nonpolyalanine repeat mutation—in the paired-like homeobox2B (PHO2XB) gene on chromosome 4p13. PHO2XB codes for a transcription factor responsible for regulating the expression of genes crucial to the development of the neural crest. Probable anomaly of integration in the central nervous system (CNS) of afferent stimuli from peripheral chemoreceptors. The resulting hypoventilation is most pronounced during non-REM (rapid eye movement) sleep, with relative insensitivity to hypercarbia and a lesser insensitivity to hypoxia. The frequent association of CCHS with Hirschsprung disease indicates that Ondine Syndrome is a form of neural crest disease.

Diagnosis

Ondine Syndrome is diagnosed in the absence of cardiac disease, neuromuscular disease, or any identifiable brainstem lesion, and shallow breathing during sleep. Polysomnographic recordings show decreased minute ventilation during sleep with hypoxemia and hypercarbia. Acquired causes of alveolar hypoventilation should be excluded: central nervous system infection, metabolic disease, ...

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