Congenital Central Hypoventilation Syndrome (CCHS) is a rare neurocristopathy characterized by absence of automatic control of respiration, decreased sensibility to hypoxia and hypercapnia mainly during sleep, and autosomal dominant inheritance due to heterozygous polyalanine expansions and frameshift mutations in the PHOX2B gene. Because the congenital central hypoventilation syndrome phenotype could hide other neurological diseases, the American Thoracic Society established that the initial evaluation of suspected Congenital Central Hypoventilation Syndrome should exclude neuro-anatomic impairments as the structural basis of the reduced autonomic system function. In this work, we describe the clinical history of two unrelated patients with hypoventilation during sleep and harboring hypoplasia of the pons and a Chiari I malformation, respectively. In both patients, congenital central hypoventilation syndrome was diagnosed by detection of PHOX2B polyalanine expansion, suggesting that the American Thoracic Society diagnostic criteria may be too restrictive. Moreover, in order to exclude a putative role of PHOX2B in non-CCHS neurological diseases, we have performed PHOX2B mutation screening in a group of individuals with Chiari I malformation, confirming the exclusive role of PHOX2B in the pathogenesis of Congenital Central Hypoventilation Syndrome.