Congenital central hypoventilation syndrome: PHOX2B genotype determines risk for sudden death

Objective: Children with Congenital Central Hypoventilation Syndrome (CCHS) have cardiovascular symptoms consistent with the autonomic nervous system dysregulation/dysfunction (ANSD) phenotype. We hypothesized that children with CCHS would have a relationship between PHOX2B genotype and two clinically applicable cardiovascular measures of ANSD: duration of longest r-r interval and longest corrected QT interval (QTc). Materials and Methods: We studied 501 days of Holter recordings from 39 individuals with PHOX2B mutation-confirmed CCHS, and analyzed longest r-r and QTc intervals with respect to PHOX2B genotype. Results: We determined that longest r-r interval varied by genotype (P = 0.001), with a positive correlation between repeat number and longest r-r interval duration (P = 0.0007). Number of children with a longest r-r interval value ≥3 sec varied by genotype (P < 0.0001): 0% with the 20/25 genotype, 19% with the 20/26 genotype, and 83% with the 20/27 genotype. Though longest QTc interval did not vary by genotype (P = 0.09), all children with CCHS had at least one Holter with a QTc interval >450 msec, and percent of time with QTc >450 msec exceeded published values. The proportion of subjects who received a cardiac pacemaker due to prolonged r-r interval was greater for the children with the 20/27 genotype (67%) than the 20/25 (0%) or 20/26 genotype (25%) (P = 0.01). Among three children who did not receive a cardiac pacemaker, but who had r-r intervals ≥3 sec, two died suddenly. Conclusions: These results confirm a disturbance of cardiac autonomic regulation in CCHS, indicate that PHOX2B genotype is related to the severity of dysregulation, predict the need for cardiac pacemaker, and offer the clinician the potential to avert sudden death.