Introduction. CCHS is a rare disorder caused by PHOX2B gene variants. While CCHS hallmarks are hypoventilation and respiratory control dysfunction necessitating lifelong artificial ventilatory support, affected individuals also experience widespread, but less studied, autonomic nervous system (ANS) dysregulation. PHOX2B variants may be divided into moderate and severe groups based upon molecular and in-silico data. The International CCHS Registry is a secure repository for longitudinal data from individuals with a PHOX2B variant-confirmed diagnosis, including information on seven systems served by the ANS (cardiovascular, gastrointestinal, neurological, ophthalmologic, renal/urinary, respiratory, sudomotor). Our objective was to analyze patient-reported symptoms (PRS) across all ANS-served systems and determine their relationship with PHOX2B variant severity. We hypothesized an increase in PRS in all organ systems in individuals with severe variants. Methods. This study focused on completed initial surveys. Descriptive statistics were generated for all PRS, and by variant groups, with statistical comparison using the Wilcoxon Rank-Sum and Fisher’s exact tests. Results. Analysis of 148 surveys confirmed broad, multi-system ANS dysfunction in CCHS. Those with severe PHOX2B variants were more likely to report cardiovascular, gastrointestinal, neurological, and ophthalmological system dysfunction compared to individuals with moderate variants. Individuals with severe PHOX2B variants reported significantly more symptoms in 6/7 organ systems than those with moderate variants. Conclusions. The individual-reported impact of CCHS varies by both PHOX2B variant severity and the ANS organ system/symptom manifestations. Beyond the traditional clinical focus on cardiorespiratory dysfunction, these results highlight other ANS-related systems that are critical for comprehensive clinical management and future therapeutic trial design.

Background: Congenital central hypoventilation syndrome (CCHS) is a rare genetic disorder characterized by autonomic dysregulation and abnormal control of breathing, necessitating lifelong artificial ventilation. The impact of CCHS on patient quality of life (QoL) and caregiver burden remains unquantified. Methods: A cross-sectional study of QoL in CCHS patients (≥12 years; WHOQOL–BREF) and burden in CCHS caregivers (Zarit Burden Interview) was conducted. Participants were recruited from CCHS support organizations. Participant age group, sex, primary language, and country of residence were collected. Results: 271 individuals (78 CCHS, 193 caregivers) from 15 countries participated. CCHS patients reported significantly reduced physical, psychological, and social relationships domain scores compared to healthy controls (p<0.01), yet >70% reported good overall QoL. Over half reported moderate or worse impact on QoL items including medical treatment dependence and cognitive function. Young CCHS patients (<25 years) reported better overall QoL and general health than those ≥25 years. CCHS caregiver burden was increased compared to that reported in other chronic diseases, with >50% reporting frequent caregiving-induced stress. Caregivers who reported financial issues also reported higher total burden (p<0.05). Conclusions: CCHS QoL scores are depressed compared to healthy individuals. This study identified specific domains of QoL and caregiver burden most impacted by CCHS, revealed a relationship between age and QoL in CCHS, and finances and burden in caregivers. Results offer targets for future interventions to enhance QoL in CCHS and reduce caregiver burden. Further work is needed to elucidate the relationship between CCHS impact and disease- and treatment-specific factors.