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

Abstract

Summary. 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 mutationconfirmed 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 ¼ 0.001), with a positive correlation between repeat number and longest r-r interval duration (P ¼ 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 ¼ 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 ¼ 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.

Molecular genetics of congenital central hypoventilation syndrome and Haddad syndrome

“…They also showed that phenotype severity increased with increasing polyalanine expansion size. Increased repeat length was associated with severe respiratory symptoms, a long R-R interval in Holter monitoring, and facial phenotypes [34,35]. Results by Trochet et al [8] strongly supported this genotypephenotype interaction.…”

“…Review of these results demonstrated that HSCR and neural crest tumors were more frequently associated with missense or frameshift mutations of PHOX2B than with the polyalanine expansion. This led to the conclusion that missense or frameshift mutations produce more severe dysfunction in PHOX2B [8,[32][33][34][35]. How ever, the relationship was not strict, and further study of additional cases is needed to confirm the hypothesis.…”

Pupillometry in congenital central hypoventilation syndrome (CCHS): quantitative evidence of autonomic nervous system dysregulation

“…This includes the potential for pupillometry to predict risk for other pathology (i.e., risk for cardiac sinus pauses) as a sign of cardiac ANSD (10). Accordingly, future steps would include systematic investigation of which, if any, phenotypic features in CCHS are associated with the various pupillary measurements.…”

“…Missense, nonsense, frameshift, and stop codon mutations in the PHOX2B gene, referred to as nonpolyalanine repeat expansion mutations (NPARMs), account for the remaining mutations in CCHS. Quantitative assessment of the respiratory control and ANSD features of CCHS by PHOX2B genotype has identified a graded genotype-phenotype relationship between mutation repeat length and ventilatory requirements (3,4), Hirschsprung disease (8,9), neural crest tumors (8,9), and cardiac sinus pauses (10).…”

Congenital Central Hypoventilation Syndrome: A Comprehensive Review and Future Challenges

“…Chest X-ray and potential chest CT, comprehensive neurological evaluation, potential muscle biopsy, and echocardiogram should exclude as a primary lung disease, ventilatory muscle weakness and cardiac disease. Seventytwo hours of Holter monitoring may determine aberrant cardiac rhythm abnormalities including decreased beat-tobeat heart rate variability [72]. Causative gross anatomic brain/brainstem lesions should be ruled out following a CT or/and MRI scan [73].…”