Abstract Rationale Congenital Central Hypoventilation Syndrome (CCHS) is a rare disorder of autonomic nervous system (ANS) regulation caused by mutations in the PHOX2B gene, which supports ANS neuron formation/differentiation. CCHS manifests as hypoventilation, with hypercarbia/hypoxemia, necessitating lifelong, assisted ventilatory life-support asleep and sometimes awake. Individuals with CCHS demonstrate variably reduced neurocognitive functioning relative to population norms. Despite a strong correlation between PHOX2B genotype and pupillary light response, genotype has not consistently predicted neurocognition in CCHS. Clinical variables that influence CCHS neurocognition have been reported, but influence of social predictors has not yet been studied. This study aims to determine a comprehensive set of clinical and social predictors of neurocognitive variability in CCHS. Methods 39 CCHS patients (3-46yrs) completed the NIH Toolbox® Cognition Battery (NTCB), a standardized assessment of cognition that measures Fluid Cognition, Crystallized Cognition, and Total Cognition composites. A 33-patient subset completed a concurrent Behavior Rating Inventory of Executive Function® (BRIEF), a standardized questionnaire assessing impairment of executive functioning through a Global Executive Composite (GEC) score. Patients completed respective age-appropriate test versions. Clinical variables hypothesized to influence neurocognition were collected. Participant zip code data were converted to a Child Opportunity Index (COI) National score measuring neighborhood opportunity levels. Stepwise regressions were conducted to identify the strongest combination of predictors for each of the four composite outcomes (best-fitting model evaluated using AIC, R2, adjusted-R2). Results NTCB Fluid Cognition (p 0.0001) and Total Cognition (p = 0.002) composite scores were downward shifted in CCHS. For the NTCB Fluid Cognition composite, PHOX2B genotype and COI National domain demonstrated significant associations (p = 0.005 and 0.018, respectively), while cyanosis history emerged as the next strongest predictor. For Crystallized Cognition, PHOX2B genotype and neural crest tumor showed the strongest directional effects. For Total Cognition, PHOX2B genotype and COI National emerged as significant predictors (p = 0.009 and 0.033, respectively), with neural crest tumor showing the next largest effect. For BRIEF GEC, neurodevelopmental disorders history and COI National accounted for the largest proportion of explained variance (Table 1). Conclusions These findings demonstrate that neurocognitive functioning in individuals with CCHS is influenced by clinical and social factors. While PHOX2B genotype and clinical phenotypes contribute to cognitive variability, neighborhood opportunity also emerged as a robust predictor across multiple cognitive domains. Identifying both clinical and social predictors highlights the need to integrate environmental context into patient care, providing a more comprehensive framework for targeted interventions with aim to optimize neurodevelopmental outcomes for every individual with CCHS. This abstract is funded by: NIH
Kiang et al. (Fri,) studied this question.