International Congenital Central Hypoventilation Syndrome (CCHS) Registry: Analysis of Patient-Reported Symptoms by PHOX2B Variant

International Congenital Central Hypoventilation Syndrome (CCHS) Registry: Analysis of Patient-Reported Symptoms by PHOX2B Variant | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 13 November 2025 V1 Latest version Share on International Congenital Central Hypoventilation Syndrome (CCHS) Registry: Analysis of Patient-Reported Symptoms by PHOX2B Variant Authors : Delaney Vandemore R 0009-0004-1383-3156 , Erin Lonergan K , Casey Rand 0000-0003-1077-8978 , and Debra Weese-Mayer 0000-0001-6061-220X [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.176306411.14920070/v1 376 views 197 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract 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. Title: International Congenital Central Hypoventilation Syndrome (CCHS) Registry: Analysis of Patient-Reported Symptoms by PHOX2B Variant Delaney R Vandemore, BS 1 ( [email protected] ), Erin K Lonergan, MS-RRT 1 ( [email protected] ), Casey M Rand, MSDS 1 ( [email protected] ), Debra E Weese-Mayer, MD 1,2 ( [email protected] ) 1 Center for Autonomic Medicine in Pediatrics (CAMP), Department of Pediatrics, Ann & Robert H. Lurie Children’s Hospital of Chicago and Stanley Manne Children’s Research Institute; Chicago, IL 2 Department of Pediatrics, Northwestern University Feinberg School of Medicine; Chicago, IL Corresponding Author: Debra E Weese-Mayer, MD Beatrice Cummings Mayer Professor in Pediatric Autonomic Medicine Northwestern University Feinberg School of Medicine Center for Autonomic Medicine in Pediatrics (CAMP) Ann & Robert H. Lurie Children’s Hospital of Chicago and Stanley Manne Children’s Research Institute 225 E Chicago Avenue, Box 165, Chicago, Illinois 60611-2605 T (312) 227-3300 | F (312) 227-9606 | [email protected] Funding: This research was funded in part by NHLBI R03TR003869 (DEW-M) and the Chicago Community Trust PHOX2B Patent Fund (CMR). Ethics Statement: This study followed all applicable US federal policies for protection of human subjects and was reviewed and approved by the Institutional Review Board at Ann & Robert H. Lurie Children’s Hospital of Chicago (project number 2013-15230). All participants provided informed consent and assent prior to beginning the research questionnaires. Conflicts of Interest: None to disclose. Keywords: autonomic dysregulation, mechanical ventilation, genotype-phenotype correlation, Hirschsprung Disease Author Contributions : DV : conceptualization, data acquisition, formal analysis, data interpretation, writing- original draft, writing- review and editing. EL : data acquisition, data interpretation, writing- review and editing. CR : conceptualization, formal analysis, data interpretation, writing- review and editing, supervision. DW-M : conceptualization, data interpretation, writing- review and editing, supervision. Presentations: These data were presented in part as a poster at the American Thoracic Society conference (San Francisco, CA; 2025). Running Title: CCHS Registry: Patient-Reported Symptom Analysis ABSTRACT 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. Abstract word count: 246 INTRODUCTION What is CCHS? Congenital Central Hypoventilation Syndrome (CCHS) is a rare disorder of the autonomic nervous system (ANS) primarily hallmarked by profound hypoventilation, especially during sleep, and respiratory control dysfunction 1 . However, the CCHS phenotype also includes variably diffuse ANS dysregulation (ANSD), resulting in a variety of symptoms such as altered pupillary response to light, reduced basal and peripheral body temperature, and altered sweating 1-3 . Genetic Basis. In 2003, the paired-like homeobox 2B ( PHOX2B) gene was confirmed as the disease-defining gene for CCHS, which arises via a heterozygous, autosomal dominant or de novo inheritance pattern 1; 4 . In approximately 90% of CCHS cases, PHOX2B variants occur in the polyalanine repeat region in exon 3 1; 5 . The wild-type of this region is 20 consecutive alanines, but in CCHS, the wild-type is expanded in-frame by an additional 4 to 13 alanines (referred to as 20/24 to 20/33) 1 . These polyalanine repeat expansion mutations are called PARMs. A genotype-phenotype relationship exists in PARMs for some symptoms of CCHS, with a correlation between longer expansions and more severe outcomes, including ventilatory needs, cardiac sinus pauses, Hirschsprung Disease (HSCR), and neural crest tumors 5-9 . The remaining approximately 10% of CCHS cases result from missense, nonsense, and frameshift variants that occur anywhere in the PHOX2B gene, called non-PARMs (NPARMs) 1 . To better understand the relationship between NPARM variant and phenotype, Zhou et al recently categorized NPARMs into the following groups based on cellular and in-silico data predicting: (1) missense and in-frame indels, (2) nonsense-mediated decay (NMD) variants, (3) non-NMD variants 10 . This study identified a novel relationship between NPARM group and clinical disease severity, with group 3 generally reporting more severe respiratory phenotypes and higher risk of HSCR and neural crest tumors 10 . However, the relationship between PHOX2B variant severity and patient-reported outcomes, including broader ANSD, remains unexplored. Introduction to the CCHS Registry. A foundational study by Weese-Mayer et al (2001) provided early insight and evidence into the impact of CCHS on the ANS. This case/control family study utilized a broad questionnaire that asked about symptoms in nine organ systems served by the ANS: cardiovascular, gastrointestinal, neurological, ophthalmologic, psychological, respiratory, renal, sudomotor, and reproductive 11 . Individuals with CCHS reported significantly more symptoms than age/race/gender matched controls for all systems except renal and reproductive 11 . However, this study was conducted prior to identification of PHOX2B as causative of CCHS in 2003, after which identification and treatment of CCHS has dramatically evolved. To expand upon these original findings and using the original ANS questionnaire as a starting point, the International CCHS Registry was developed and established in 2013; it is a secure, online REDCap entity that utilizes a branching logic ANS-questionnaire (ANSQ) to capture longitudinal data from PHOX2B variant-confirmed individuals with CCHS. The comprehensive ANSQ asks individuals and parent-proxies about ANS symptoms for seven organ systems: cardiovascular, gastrointestinal, respiratory, neurological, urinary, sudomotor, and ophthalmological. Utilizing these data, we sought to establish the multi-system impact of CCHS on individuals with a PHOX2B mutation-confirmed diagnosis and to investigate the genotype-phenotype relationship across all ANS-regulated systems, with the aim to better inform anticipatory clinical care. Hypothesis. We hypothesized that individuals with PHOX2B variants predicted to cause more severe dysfunction, including longer PARMs (20/27-20/33) and group 3 NPARMs, would report more system-level dysfunction and more autonomic symptoms than individuals with variants predicted to cause more moderate protein dysfunction (20/24-20/26 PARMs and group 1-2 NPARMs). METHODS Study Participants. Participants were recruited internationally, both in-person and online. Individuals who were patients at Ann & Robert H. Lurie Children’s Hospital of Chicago were recruited to participate while inpatients in the Center for Autonomic Medicine in Pediatrics (CAMP). International and out-of-state participants were recruited via our online Patient Registry and Referral Form and via physician email. This study followed all applicable US federal policies for protection of human subjects and was reviewed and approved by the Institutional Review Board at Ann & Robert H. Lurie Children’s Hospital of Chicago (project number 2013-15230). The study was registered at clinicaltrials.gov (NCT03088020). All participants provided informed consent and assent, as applicable, before the initial questionnaires began. Data Collection. The data collection period began in July 2013 and ended on April 1, 2025. Participants completed the initial CCHS Registry questionnaire and any annual updates online via the REDCap platform (version 14.5.7), a secure application designed for building and collecting survey data. For each possible symptom, participants were asked to select ‘yes’, ‘no’, or ‘unknown’. PHOX2B Categorization. Using guidelines published by Zhou et al, NPARMs were categorized based on the expected impact on protein function. Moderate variants include PARMs 20/24-20/26 and category 1/2 NPARMs, and severe variants consist of PARMs 20/27-20/33 and category 3 NPARMs 10 . Data Analysis. JMP Statistical software (version 18.2.1; Nashville, TN) was used for all data analysis and figure generation. General descriptive characteristics include sex at birth, variant group (PARMs vs NPARMs), race, and ethnicity. The right-side Fisher’s Exact Test was utilized for the analysis of system-level dysfunction and individual symptom comparison, testing the hypothesis that severe variants would cause increased patient-reported symptoms compared to moderate variants. ‘Unknown’ survey responses were excluded. The Wilcoxon Rank-Sum test was utilized to compare symptom counts between moderate and severe groups for each organ system, due to the ordinal nature of the data and the non-normal data distributions; one-sided t-tests and p-values were employed to understand if individuals with severe variants reported more symptoms than individuals with moderate variants. For comparison between common PARMs (20/25, 20/26, 20/27) and between the NPARM groups, the chi-square test for independence was used for group comparison and the Fisher’s exact test for further pairwise comparison of the significant variables (E-table 1). Statistical significance for all analysis was set at p<0.05. RESULTS Patient Cohort. 188 PHOX2B -confirmed individuals participated in an initial CCHS Registry patient-reported survey. Of these recorded surveys, 40 were incomplete and removed from the dataset, with 148 remaining for data analysis. The median age at the initial survey was 6.9 years old (range: 0.1-54.6 years). For moderate PHOX2B variants, the median age was 7.1 years old and for severe variants it was 5.6 years old. 69 participants (46.6%) were female. Among the cohort, 19 identified as Hispanic or Latino (12.8%), 101 were not Hispanic or Latino (68.2%), 4 were Ashkenazi Jewish (2.7%), and 24 were not reported/unknown (16.2%). For race, 120 individuals reported being White (81.1%), 6 were Asian (4.1%), 5 were Black or African American (3.4%), 1 was American Indian or Alaska Native (0.7%), 8 were multiracial (6 Asian and White, 1 White and unknown, 1 Asian and unknown, 1 Black/African American and White) (5.4%), and 7 were unknown or refused to answer (4.7%). Moderate variants included 101 (68.2%) participants, and the remaining 47 (31.8%) made up the severe variant cohort. Additional PHOX2B variant information is provided in Table 1. No differences were observed between the moderate and severe variants for any assessed demographic characteristics. Age and Sex Analysis. There were no significant differences in reported autonomic symptoms based on age at survey or sex. Cardiovascular System. The International CCHS Registry (Registry) contains 16 questions regarding cardiovascular system symptoms. 68% of individuals in the entire cohort (n=148) reported at least one symptom. Of individuals grouped into moderate variants, 59% reported at least 1 cardiovascular symptom compared to 85% of those with severe variants [p=0.0013] (Figure 1). Notably, dizziness affected 35% of respondents (n=110), representing the highest frequency among reported symptoms. The number of symptoms reported for individuals with severe PHOX2B variants (median=2, IQR=3) was significantly more than in individuals with moderate PHOX2B variants (median=1, IQR=3) [S=4028, p=0.01]. Gastrointestinal System. The Registry contains 10 questions regarding gastrointestinal symptoms. 61% of individuals with CCHS experienced at least one symptom. 51% of the moderate variant group experienced system-level dysfunction, compared to 81% of the severe variant group [p=0.0005] (Figure 1). Individuals with severe variants reported significantly more symptoms (median=2, IQR=1) than those with moderate variants (median=1, IQR=1) [S=4388.5; p<0.0001]. HSCR was the most prevalent symptom, reported by 28% (n=139) of individuals with CCHS. 53% of individuals (n=139) had either been diagnosed with HSCR or experienced other digestive symptoms such as persistent sense of bloating, severe constipation, or diarrhea unrelated to a viral illness. Neurological System. The Registry contains 8 questions regarding neurological symptoms. 66% of individuals in the entire cohort (n=148) experienced at least one symptom in this system. Of individuals grouped as moderate variants, 60% experienced system-level dysfunction versus 77% of those grouped as severe variants [p=0.0388] (Figure 1). The average number of symptoms reported for severe variants (median=1, IQR=2) was greater than those with moderate variants (median=1, IQR=2) [S=3940.5, p=0.0308]. Learning disability was the most prevalent symptom, reported by 44% (n=116) of respondents. There was no difference by PHOX2B variant category. 42% of individuals (n=100) reported an altered perception of anxiety. Of these, 67% reported heightened levels of anxiety and 33% reported a lower level or no anxiety response. There was no difference between moderate (43%; n=77) and severe (46%; n=39) variant groups. Ophthalmological System. The Registry contains 14 questions regarding ophthalmological system symptoms. 58% of individuals in the entire cohort (n=148) experienced at least one symptom. Of individuals with moderate variants, 46% experienced system-level dysfunction compared to 85% of those with severe variants [p<0.0001] (Figure 1). Individuals with severe variants reported significantly more symptoms (median=2, IQR=2) than individuals with moderate variants (median= 0, IQR=2) [S=4633.5, p<0.0001]. Diminished pupillary response to light emerged as the most prevalent symptom, reported by 42% (n=112) of individuals. Renal/Urinary System. The Registry contains 4 questions regarding renal/urinary symptoms. 15% of individuals in the entire cohort experienced urinary symptoms, and there was no difference between individuals grouped into moderate and severe variant cohorts or by sex at birth. Urgency to urinate emerged as the most prevalent symptom, reported by 11% (n=118) of individuals. There was no difference between the number of symptoms reported for severe variants (median=0, IQR=0) versus moderate variants (median=0, IQR=0). There was no difference in number of symptoms by sex at birth. Respiratory System. The Registry contains 5 questions regarding respiratory system symptoms. 96% of individuals in the entire cohort reported at least one symptom. There was no reported difference between the percent of the moderate variant group experiencing system-level dysfunction, 95%, compared to 98% of the severe variant group (Figure 1). Alveolar hypoventilation asleep was the most prevalent symptom, reported by 94% (n=145) of respondents. The number of symptoms reported for severe variants (median=2, IQR=1) was significantly more than the symptoms for moderate variants (median=2, IQR=1) [S=4249.5, p=0.0007]. Sudomotor System. The Registry contained 3 questions regarding sudomotor symptoms. 55% of individuals in the entire cohort experienced at least one symptom. There was no significant difference between system-level dysfunction: 50% of the moderate group versus 66% of the severe group (Figure 1). The average number of symptoms reported by severe variants (median=1, IQR=2) was significantly more than those with moderate variants (median=1, IQR=1) [S=3877.5, p=0.0479]. Altered sweating emerged as the most prevalent symptom, reported by 52% (n=125) of respondents. Number of Organ Systems Impacted. Individuals with severe variants reported on average 5 organ systems impacted (median=5, IQR=2), significantly more than in individuals with moderate variants (median=4, IQR=3) [S=4484, p<0.0001] (Figure 2). 20/25, 20/26, 20/27 Comparison . Data from the 20/25, 20/26, and 20/27 PARM variants, the most common CCHS-causing variants, each differing by just one additional alanine, were compared. Significant differences between the percent of individuals with organ-system dysfunction were noted in the cardiovascular, gastrointestinal, and ophthalmological systems (E-table 1). The frequency of patient-reported symptoms by organ system across all CCHS-variant groupings is presented in E-table 1. NPARM Comparison. Data from the NPARM Group 1, Group 2 and Group 3 individuals were used to analyze the difference between the NPARM groups. Significant differences between the percent of individuals with organ-system dysfunction were noted in the cardiovascular and ophthalmological systems (E-table 1). E-table 1 presents the percent of individuals affected by symptoms and systems in the Registry for these variants. DISCUSSION The study represents the largest CCHS cohort for patient/parent-reported symptom data. It is also the largest study to date that captures data across all systems served by the ANS. Our findings suggest that the patient-reported impact of CCHS varies both by PHOX2B variant and organ system. A significantly higher proportion of individuals in the severe variant cohort reported cardiovascular, gastrointestinal, neurological, and ophthalmological level dysfunction when compared to the moderate variant cohort (Figure 1). The lack of a significant difference between the proportion of the two groups experiencing respiratory system dysfunction reflects the hallmark respiratory dysfunction that characterizes CCHS. However, the severe variant cohort reporting significantly more respiratory symptoms than the moderate cohort is consistent with the established genotype-phenotype relationship for ventilatory needs, including the need for 24-hour ventilation as life-support 8; 12; 13 . When comparing the average number of symptoms between the variant groups, the severe cohort reported significantly more symptoms in all systems except for the renal/urinary system. These data support the characterization and distribution of PHOX2B variants into moderate and severe variants groups, extending the work of Zhou et al. and other studies that have established a PHOX2B genotype-phenotype relationship 2; 4; 6-10; 14 . In this study, 44% of individuals reported having a learning disability. Previous studies utilizing standardized neurocognitive testing have shown a wide range of neurocognitive outcomes in individuals with CCHS. However, areas of fluid intelligence, such as working memory and speeded information processing, appear to be markedly impacted 15; 16 . In this study, there was no relationship between PHOX2B variant and reported learning disability. While previous literature has identified a relationship between genotype and cognitive performance in preschool age children, our findings are aligned with other literature assessing cognitive performance in CCHS, which have failed to find a genotype-phenotype relationship in CCHS 17; 18 . Altogether, these data suggest that individuals with CCHS, regardless of PHOX2B variant, remain at a greater risk for adverse cognitive functioning, potentially as a secondary effect of alveolar hypoventilation and the subsequent hypoxemia and hypercarbia 16 . Consequently, and as recommended by the 2010 ATS Statement, children with CCHS should receive annual neurocognitive testing to track their cognitive development 1 . If indicated, children would be enrolled in supplemental educational and disability interventions. Longitudinal collection of neurocognitive functioning will aid in early detection and personalized intervention. HSCR is a known comorbidity, previously reported in 13-20% of individuals with CCHS 12; 14 . In this analysis, 28% of individuals overall reported HSCR, indicating the potential for greater risk of HSCR than previously described. Additionally, over half of respondents had been diagnosed with HSCR or experienced other GI/digestive symptoms. Thus, even without HSCR, individuals with CCHS still experience gastrointestinal complications and should be evaluated by GI (especially motility experts) and nutrition specialists as part of their routine clinical care. This is especially true in those with severe group PHOX2B variants, as over 80% of individuals in this cohort reported gastrointestinal dysfunction. In the neurological system, a high percentage of individuals reported an altered perception of anxiety, at both heightened levels and lower levels. The mental health concern for individuals with CCHS has been largely unexplored, with only a handful of articles published since PHOX2B was first identified as the disease-causing gene for CCHS. In 2006, Chen et al explored alcohol use in individuals with CCHS, specifically from three young adults with CCHS, all of whom had experienced serious adverse events after consumption of alcohol 19 . They concluded that individuals with CCHS may not be able to properly perceive the risk of CCHS in conjunction with known respiratory depressants like alcohol and postulated that the observed lack of anxiety could be due to abnormalities in the amygdala and limbic system 19-21 . However, in our CCHS Registry, about 67% of those that reported altered levels of anxiety experienced a heightened level of anxiety, not lower. Another study found that on the Beck Depression Inventory II (BDI-II), individuals with CCHS from ages 15-33 rarely reported depression, but frequently reported state and trait anxiety 22 . More recently, individuals with CCHS reported significantly depressed scores in the psychological and social relationship domains on the World Health Organization QOL-BREF despite, on average, reporting overall quality of life of good or very good 23 . Due to the limited amount of published data regarding mental health in individuals with CCHS and variability between published reports, additional comprehensive, diagnostic evaluations should be considered in CCHS. This is an especially important consideration as the percentage of young adults with CCHS continues to increase with proper ventilatory management and care. A limitation of this study is the sample size, including the distribution between moderate and severe variant categories. Specifically, the most common PHOX2B variants in CCHS are 20/25, 20/26, and 20/27, but two (20/25 and 20/26) are noted as moderate variants in this analysis. Our cohort breakdown roughly follows this 2:1 trend between the three most common variants, impacting the lower count of severe variants overall. Additionally, individuals with more severe PHOX2B variants require more consistent ventilatory support and have been noted to be at a higher disposition for cardiac sinus pauses, HSCR, and tumors of neural crest origin, ultimately putting them at higher risk for complications and potentially sudden death 1; 8 . Moving forward, it will remain essential to collect information from patients with all PHOX2B variants, especially those with category 3 NPARMs and PARMs 20/27 and above; this will allow for a better understanding of how these variants impact the CCHS phenotype throughout one’s lifetime. Another limitation of the study cohort is the age distribution. Due to the lack of confirmatory PHOX2B testing until 2003, many older individuals with CCHS have either gone undiagnosed or unfortunately, suffered from sudden and unexpected death. Therefore, the number of individuals over the age of 21 in this cohorts drops in comparison to age groups below age 21 years. With improved ventilatory management and care, data collection in teenagers and young adults should be prioritized. Likewise, adult pulmonologists should be trained in optimized transitional care of patients diagnosed with CCHS in childhood. Analysis of all systems served by the ANS revealed that CCHS often impacts more than the respiratory control system. Here, PRS indicated a median of over three additional organ systems impacted, highlighting the multi-system nature of the disorder. Taken together, patients with CCHS would benefit from proactive involvement of many sub-specialists, and routine and age-specific clinical care personalized to properly monitor and provide anticipatory management for the individual. Because burden of care varies by individual, continued, longitudinal analysis of PRS data by PHOX2B variant should be standard of care to better predict the progression of CCHS by variant over a lifetime and to personalize needed care for every patient affected by CCHS. Because CCHS presentation is widely variable both between organ systems and within variants, data collection should include all organ systems served by the ANS and consideration of the data should be specific to the patient as well as the PHOX2B cohort subgroups. Acknowledgements. Thank you to all the patients and families who participated in this study, and to the physicians and CCHS family groups, both nationally and internationally, that referred individuals to the International CCHS Registry. A cohort of this size was made possible by this support. The authors would like to thank Dr. Greg Redding, MD for his valuable input on data analysis. This study was presented as an abstract at the American Thoracic Society International Conference, San Francisco, CA, May 2025. FIGURES/TABLES Table 1. PHOX2B Variant Breakdown for the Patient Cohort. The PHOX2B variants involving polyalanine repeat mutations (PARMs) are heterozygous and shown with standard nomenclature with the normal 20 alanine allele/the expanded allele (e.g., 20/24-20/33). *Variants categorized as severe including the 20/27-20/33 PARMs and the Category 3 non-PARMS (NPARMs). 20/24 2 (1.4) 20/25 36 (24.3) 20/26 31 (20.9) 20/27* 33 (22.3) 20/28* 1 (0.7) 20/30* 1 (0.7) 20/31* 1 (0.7) 20/32* 1 (0.7) 20/33* 4 (2.7) Category 1 NPARMs 11 (7.4) Category 2 NPARMs 21 (14.2) Category 3 NPARMs* 6 (4.1) Total NPARMs 38 (25.7) Total PARMs 110 (74.3) Figure 1. ANS System-Level Dysfunction by PHOX2B Variant Category. Results for patient-reported organ-system dysfunction between moderate and severe PHOX2B variant cohorts. Each organ system reports the percent of respondents who experienced at least one symptom. Figure 2. Percent of Respondents with Autonomic Nervous System Dysfunction by Number of Organ Systems Impacted and PHOX2B Variant Category. 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Rand CM, Pelissou J, Krishnamurthi N, Chapelle XP, Samuels M, Riccitelli M, Dokas L, Kasi A, Massenavette B, Lampin ME et al. 2025. Congenital central hypoventilation syndrome (CCHS): Patient quality of life and caregiver burden. Pediatr Pulmonol. 60(3):e71012. Information & Authors Information Version history V1 Version 1 13 November 2025 Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords autonomic dysregulation genotype-phenotype correlation hirschsprung disease mechanical ventilation Authors Affiliations Delaney Vandemore R 0009-0004-1383-3156 Ann & Robert H Lurie Children's Hospital of Chicago View all articles by this author Erin Lonergan K Ann & Robert H Lurie Children's Hospital of Chicago View all articles by this author Casey Rand 0000-0003-1077-8978 Ann & Robert H Lurie Children's Hospital of Chicago View all articles by this author Debra Weese-Mayer 0000-0001-6061-220X [email protected] Ann & Robert H Lurie Children's Hospital of Chicago View all articles by this author Metrics & Citations Metrics Article Usage 376 views 197 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Delaney Vandemore R, Erin Lonergan K, Casey Rand, et al. International Congenital Central Hypoventilation Syndrome (CCHS) Registry: Analysis of Patient-Reported Symptoms by PHOX2B Variant. Authorea . 13 November 2025. 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