Facial phenotype in children and young adults with PHOX2B-determined congenital central hypoventilation syndrome: Quantitative pattern of dysmorphology

Congenital central hypoventilation syndrome (CCHS) is caused by mutations in PHOX2B, which is essential for maturation of the neural crest into the autonomic nervous system and is expressed in the dorsal rhombencephalon, a region that gives rise to facial structures. Digital photographs of 45 individuals with PHOX2B-confirmed CCHS, and 45 matched controls were analyzed for 17 linear and 6 angular measurements, and 9 derived indices. Paired t tests were used to compare group means, correlation was calculated between PHOX2B polyalanine expansion number and facial measures, and stepwise logistic regression was used to predict case-control and genotype status. CCHS cases differed significantly from controls on 13 variables (6 after p value correction: nasolabial angle, upper lip height, lateral lip height, facial index, upper facial index, and presence of inferior inflection of the lateral segment of the upper lip vermillion border). Five variables were able to predict correctly 85.7% of CCHS cases and 82.2% of controls: upper lip height, biocular width, upper facial height, nasal tip protrusion, and inferior inflection of the upper lip vermillion border. A negative relationship between number of repeats and four anthropometric measures was observed: mandible breadth, nasolabial angle, lateral lip height, and mandible-face width index. These results suggest a characteristic facial phenotype in children and young adults with CCHS, due to an expansion mutation in PHOX2B.