Rationale: Late-Onset Central Hypoventilation Syndrome (LO-CHS) is a rare disorder which may manifest as early as infancy or as late as during adulthood. The potential overlap of LO-CHS with Congenital CHS (C-CHS) is under debate, even though both disorders can result from heterozygous PHOX2B gene mutations. Objectives: To characterize the PHOX2B status in a series of 25 patients with LO-CHS referred from 3 months of age to adulthood. Whenever a PHOX2B mutations was identified, we ascertained its germline or somatic origin in both LO-CHS patients and in 15 parents of C-CHS probands found to harbour a PHOX2B mutation. Methods: The PHOX2B gene was analyzed by direct DNA sequencing and origin of the mutation evaluated by genescan analysis. Results: We have identified a heterozygous PHOX2B gene mutation in 17/25 LO-CHS patients. The far most frequent mutation results in a germline +5 alanines expansion in the series of 20 alanines (15 cases) that shows incomplete penetrance and variable expressivity possibly resulting from combined environmental and genetic factors. PHOX2B frameshift and missense mutations have also been identified in patients with LO-CHS. Importantly, one parent found to harbour a somatic mosaic for a +8 alanines expansion developed alveolar hypoventilation in his forties. Conclusions: These data indicate that PHOX2B gene mutations should be systematically examined in any adult with unexplained central hypoventilation and raise the question of the follow-up for apparently healthy parents found to harbour a somatic mosaic for the PHOX2B mutation identified in their child.