Late-onset congenital central hypoventilation syndrome and a rare PHOX2B gene mutation

Congenital central hypoventilation syndrome (CCHS) is a rare lifelong disorder characterized by an abnormal ventilatory response with persistent hypercapnia and hypoxia, which worsen during sleep. About 90 % of CCHS individuals are heterozygous for a mutation in the exon 3 of the PHOX2B gene. With higher awareness and better diagnostic tools, cases are identified in late childhood and adulthood, often with distinct mutations.

The authors present a 4-year-old girl admitted to the intensive care unit at 9, 11 and 13 months suffering from severe hypercapnic respiratory failure during viral respiratory infections. Hypercapnia during sleep improved with wakefulness. CCHS was confirmed genetically (heterozygous insertion of an adenine at position 23, leading to a premature stop codon in exon 1 of the PHOX2B gene). The parents' DNA showed no PHOX2B mutations. Hypoventilation was observed by polysomnography, with no autonomic response to declining oxygen or increasing carbon dioxide values. A subsequent sleep study showed less hypoxia and hypercapnia. The patient has been on non-invasive ventilation during sleep, showing good growth and neurocognitive development.

A greater awareness is required to diagnose late-onset CCHS. A respiratory infection can trigger the disease, with a significant difference in CO2 between sleep and wakefulness as the warning signal. Given the clinical suspicion, a genetic study should be performed. Polysomnography is essential for patient characterization. Follow-up and ventilator support adjustment prevent serious hypoxia and hypercapnia, which impair cardiovascular and neurocognitive functions. This patient's mutation has not been previously described; hence, clinical evolution cannot be predicted.