BACKGROUND:Cardiorespiratory coupling (cardiovascular-respiratory interactions) is a marker of autonomic nervous system function and maturation. We hypothesize that differences in autonomic maturation are associated with disparate outcomes of premature infants. METHODS:We collected continuous bedside cardiorespiratory data from birth to 40 weeks post-menstrual age (PMA) for 191 preterm infants born between 23-0/7 weeks to 28-6/7 weeks of gestation. Using the respiratory and ECG wave forms, we calculated cardiorespiratory phase synchronization (CRPS) as a measure of cardiorespiratory coupling. Using linear mixed effects modeling, we studied the trajectory of CRPS as a function of PMA and chronological age (CA) and any difference between groups separated by discharge status, respiratory outcome and neurological outcomes at the 40th week PMA, and different gestational ages. RESULTS:CRPS showed a decline reaching a nadir at approximately 3 weeks of age followed by a gradual increase toward term. The infants born at later GA showed higher values and steeper increases than infants of lower GA. Contrary to our hypothesis, the trajectory of the increase was similar regardless of outcome assessed. CONCLUSION:Autonomic maturation following preterm birth shows a fixed predictable pattern that appears to be independent of respiratory or neurologic outcomes or clinicians' assessment of readiness for discharge. IMPACT:Cardiorespiratory phase synchronization (CRPS) trajectories, a marker of autonomic nervous system functio is provided for 175 extremely preterm infants across post-menstrual age (PMA) and chronological age (CA). CRPS initially declines but subsequently increases with advancing PMA and CA, irrespective of discharge status and respiratory and neurological outcomes at 40 weeks PMA. At all CAs after the initial decrease, CRPS was higher for infants born at 27-28 weeks compared to those born earlier.

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 analyzed completed initial surveys. Descriptive statistics were generated for all PRS, and by PHOX2B variant groups, with statistical comparison using the Wilcoxon Rank-Sum and Fisher's exact tests with Benjamini-Hochberg correction.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, respiratory, 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.

Pathogenic heterozygous variants in PHOX2B are associated with congenital central hypoventilation syndrome (CCHS), which is characterized by autonomic nervous system dysregulation severely affecting respiratory control. The interpretation of PHOX2B missense variation is challenging due to their rarity and the lack of available functional evidence. Consequently, most PHOX2B missense variants are classified as variants of uncertain significance (VUSs), complicating the timely diagnosis and clinical management of the condition. To generate an improved model for assessments of PHOX2B missense variants, a methodology was derived to evaluate all PHOX2B missense variants in the literature and public/private databases according to a consensus classification framework and assigned pathogenicity classifications. Pathogenicity prediction scores from the in silico prediction tools CADD, REVEL, BayesDel, and AlphaMissense were obtained for all variants. A weighted logistic regression in a multiple imputation framework was performed to assess the strength of evidence supporting application of ACMG/AMP guidelines ' PP3/BP4 criteria. CADD, REVEL, and BayesDel meet the predictive strengths for PP3/BP4 recommended by the Clinical Genome Resource (ClinGen). Based on their areas under the curve and low proportions of variants with indeterminate pathogenicity predictions, BayesDel and REVEL were the strongest predictive tools and should be utilized for routine PHOX2B missense variant assessment with this study ' s calculated score thresholds for PP3/BP4 strength levels. Furthermore, the positional distribution of pathogenic and benign variants was analyzed to assess potential hotspots or critical functional domains in PHOX2B, and pathogenic variants were found to cluster in the homeodomain. The enrichment of pathogenic variation was substantiated by the prediction tools, supporting the use of the PM1 criterion for variants in the homeodomain. This calibration of existing computational prediction tools for PHOX2B missense variant classification and recognition of the homeodomain variants will enable fewer VUS classifications in favor of conclusive results, aiding in these individuals ' care.

RATIONALE:Congenital central hypoventilation syndrome (CCHS) is caused by PHOX2B gene variants, resulting in highly variable cardiac autonomic dysregulation, including abrupt sinus pauses and risk of sudden unexpected death. The relationship between age, PHOX2B genotype, and cardiac autonomic dysfunction remains unknown, and CCHS-related physiomarkers are lacking. OBJECTIVE:To assess the impact of age and genotype severity on longitudinal heart rate variability (HRV), a noninvasive measure of cardiovascular autonomic function, in CCHS. METHODS:Longitudinal HRV measures were calculated from continuous overnight electrocardiography during polysomnography during clinical evaluation with provided artificial ventilation. PHOX2B variants were divided into moderate and severe groupings based on clinical, cellular, and in-silico PHOX2B data. Linear mixed-effects models were used to examine demographic and clinical differences in HRV by age and PHOX2B variant grouping. MEASUREMENTS AND MAIN RESULTS:A total of 226 overnight recordings from 52 unique individuals with CCHS were included. PHOX2B variant severity was associated with decreased vagal tone, baroreflex activity, and total HRV. Increasing age was associated with reduced parasympathetic and baroreflex activity with increased sympathetic dominance. CONCLUSIONS:Our findings suggest parasympathetic withdrawal with advancing age in CCHS and, potentially in response, increasing sympathetic contribution to cardiac autonomic control. Reduced baroreflex sensitivity with age, potentially due to cumulative physiologic stress, may contribute to this sympathetic dominance, offering insight into the heightened cardiovascular risk observed clinically with age. This novel relationship between PHOX2B variant severity, age, and HRV suggests that HRV may be a sensitive, easy-to-obtain physiomarker of CCHS phenotype severity and progression, providing an opportunity to predict and anticipate increasing cardioautonomic dysregulation and risk in CCHS.

Background: CCHS is a rare disorder characterized by autonomic dysregulation and impaired breathing control requiring artificial ventilatory support during sleep, and its severity is variable. Some patients breathe spontaneously (without support) when awake, but others require 24-hour/day ventilatory support. EEG studies show unique cortical respiratory network activation during spontaneous breathing in CCHS. Cognitive loading in adults with CCHS leads to increased breathing variability with altered oxygen saturation (SpO2), potentially due to cortical resource competition. The impact of cognitive load on breathing in school-aged individuals with CCHS is of particular importance but remains unknown. We investigated breathing during cognitive load in school-aged children and young adults with CCHS, both in those spontaneously breathing and those with daytime ventilatory support. Methods: SpO2 and ETCO2 were continuously recorded during 10-minute baseline and NIH Toolbox™ cognitive testing in 19 spontaneously breathing CCHS patients (ages 3-27y, mean=15.5y) (unsupported) and 17 daytime ventilatory supported CCHS patients (ages 4-35y, mean=12.8y). SpO2 and ETCO2 were averaged over 30-second epochs during baseline and Toolbox. Changes from baseline (% difference; ΔSpO2, ΔETCO2) were calculated for each epoch. Results: During Toolbox, unsupported CCHS patients exhibited decreased SpO₂ (-0.93% [range: -3.21-0.79] p<0.01) from baseline, with 53% experiencing intermittent hypoxemia (IH, 92-95% SpO₂) and 32% showing desaturation events (≤92% SpO₂). The decrease in SpO₂ was greater in the last two minutes (-1.11%) of Toolbox compared to the first two minutes (-0.49%) of Toolbox (p<0.01). There was a trend toward increased ETCO2 during Toolbox compared to baseline (mean +2.8% [range: -5.09 to 8.30]), and the ETCO2 increase was greater in the last two minutes (+0.89%) of Toolbox compared to the first two minutes of Toolbox (-2.10%; p<.01). In supported CCHS patients, while trends were similar to unsupported CCHS patients, no significant changes in SpO₂ or ETCO2 were identified during Toolbox (-0.71% SpO₂[range: -3.00-1.75]; +2.74% ETCO2 [range: -6.89-6.05]). However, 70% of the supported patients experienced IH and 41% experienced desaturations during Toolbox. Implications: These results support our hypothesis that cognitive load may interfere with spontaneous breathing in CCHS, leading to physiologic compromise, even with artificial ventilatory support. Though this cohort is small, our findings suggest that alternative or supplemental strategies may be necessary to manage respiratory function during periods of cognitive demand, particularly to address cumulative respiratory effects from sustained cognitive effort. Further research into optimizing ventilatory support for cognitive tasks could improve both safety and cognitive outcomes for individuals with CCHS.

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:Two hundred seventy-one 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.

Introduction: Congenital Central Hypoventilation Syndrome (CCHS) is a rare genetic disorder characterized by impaired chemosensitivity and autonomic regulation due to PHOX2B mutations, with resultant life-threatening hypercarbia and hypoxemia. Patients require lifelong artificial ventilatory life-support asleep (in more severe cases awake and asleep). Currently there are no known therapeutic targets for intervention to address their hypoventilation and impaired chemosensitivity. Anecdotal clinical observation suggests decreased sighing in CCHS. Sigh breaths are deep, long breaths occurring every ∼5 minutes in healthy adults, playing a critical role in maintaining alveolar patency. Sigh frequency increases during hypercarbia and hypoxia and is conserved across mammals. Most neurons in the retrotrapezoid nucleus that project to the sigh-producing preBötC, express PHOX2B (Li et al.). Consequently, we posit that CCHS-causing PHOX2B mutations disrupt the production of sighs, highlighting sighing as a potential biomarker and therapeutic target in CCHS. Like CCHS, Rapid-onset Obesity with Hypothalamic dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD) causes severe respiratory deficits requiring artificial ventilatory support. Unlike CCHS, ROHHAD is not linked to PHOX2B, and emerging evidence suggests an autoimmune mechanism. This study explored differences in sigh breathing between CCHS and ROHHAD to evaluate the impact of their distinct pathophysiology on sigh frequency. We hypothesized that sigh frequency would be diminished in CCHS but relatively normal in ROHHAD. Methods: Continuously recorded respiratory inductance plethysmography (RIP) and end-tidal CO₂ waveforms in awake spontaneously breathing, PHOX2B mutation-confirmed patients with CCHS and clinically-confirmed ROHHAD during clinical testing at Ann & Robert H. Lurie Children's Hospital, between January 2018 and December 2024, were included. A sigh breath was defined as a RIP sum channel amplitude ≥2× the 5 preceding stable tidal-breaths and followed by stable tidal-breathing or post-sigh apnea. Results: 116 hours of continuous recording from 10 CCHS (mean age 20.6yrs (range 9-35), 60% female) and 47 hours from 5 ROHHAD (mean age 16.5yrs (range 13-20), 40% female) patients were analyzed. Sigh frequency in CCHS was significantly reduced compared to ROHHAD patients (6.0 vs 12.4 sighs/hour; p<0.004). Conclusion: While sigh frequency appears to be conserved in ROHHAD, with frequency similar to published healthy controls (12/hour), CCHS patients have significantly diminished sigh frequency (6/hour). Findings of conserved sighing in ROHHAD and diminished sighing in CCHS support the role of PHOX2B-expressing retrotrapezoid nucleus neurons in sigh-generation and highlight their potential role in CCHS pathology. These findings underscore fundamental differences in respiratory control and provide insight into both potential biomarker and targeted therapeutic strategies.

Background: CCHS is a rare genetic disorder characterized by impaired autonomic function, especially breathing control. All patients require artificial ventilation asleep, but some breathe independently awake. A recent study showed that in adults with CCHS, cognitive loading leads to dysregulated breathing, exhibited by increased variability in breathing, or inter-breath-interval variability (IBI-v). It is posited that this is due to cortical resource competition during cognitive tasks. Because this phenomenon has not been investigated in affected children and young adults, we assessed the impact of cognitive loading on school-aged children and young adults with CCHS. Hypothesis: During NIH Toolbox cognitive assessment (Toolbox), spontaneously breathing CCHS patients will have increased IBI-v compared to baseline. CCHS patients on ventilatory support and healthy controls will not have increased IBI-v between baseline and Toolbox. Methods: End tidal waveform (ETW) was continuously recorded via nasal cannula during 10-minute baseline and during Toolbox in 15 spontaneously breathing CCHS patients (ages:6-29y, mean=15y), 14 CCHS patients on ventilatory support (ages:4-35.5, mean=14), and 8 healthy controls (ages 7-21y, mean=14y). Total breath time was calculated using a peak detection algorithm in MATLAB. The coefficient of variation in breath time (IBI-v) was calculated for each participant's baseline period and Toolbox period. Results: CCHS patients demonstrated significantly higher IBI-v than controls (p = 0.0002). This was seen in both supported (p=0.003) and unsupported (p=0.001) CCHS participants. No differences in IBI-v were identified between supported and unsupported CCHS participants. No differences between baseline and Toolbox IBI-v were identified in CCHS, supported or unsupported, or controls. There was a strong positive correlation between age and IBI-v during Toolbox (r = 0.7). Implications: Identification of increased breathing variability both at rest and during cognitive task in CCHS, both those supported and unsupported, is a novel finding that may have important implications for management of CCHS. While prior literature identified increased IBI-v during cognitive load in CCHS adults, our results in younger CCHS individuals (pediatric and young adult) did not support this finding. However, we did identify increasing IBI-v during cognitive task with age in CCHS, indicating the dysregulated breathing previously identified during concentration may be age-related. Further analysis in the form of a larger, longitudinal study is needed to better understand breathing during concentration in CCHS patients, especially as related to patient age and genotype.

Rationale: CCHS is a rare disorder caused by PHOX2B gene variants, leading to impaired autonomic nervous system development and function, with disease severity related to genotype. Individuals with CCHS are at risk of severe hypoventilation and hypercarbia, require artificial ventilation as life-support during sleep, with some requiring support 24-hours/day. Evaluating respiratory physiology during everyday activities in spontaneously breathing individuals with CCHS is paramount to guiding care and understanding disease severity and progression. This study evaluates a novel, standardized protocol (the COOKIES trial) for assessing CCHS respiratory physiology during common activities while spontaneously breathing. Methods: Oxygen saturation (SpO2) and end-tidal carbon dioxide (ETCO2) were recorded continuously during a 5-minute baseline and: watching nature video with peaceful music (15-minutes), concentrational task (13-minutes), eating (5-minutes), and exertion (ATS 6-minute walk test (6MWT)), with 5-minute breaks between each activity. Nine spontaneously breathing individuals with CCHS (age:6-28, average:15.0y) and seven controls (age:6-16, average:11.4y) completed COOKIES. Standard ventilatory support was utilized during baseline for individuals typically on daytime support. 4 individuals with CCHS had moderate genotypes (PARMS (24-26 alanines) and NPARMs (point mutations or frameshift causing protein contraction) and 5 had severe genotypes (PARMS (27-33 alanines) and NPARMs frameshift causing protein expansion). SpO2 and ETCO2 were averaged over 1-minute epochs and changes from baseline (%) were calculated. Results: Across the entire trial and each individual COOKIES activity, individuals with CCHS show a greater decrease in SpO2 levels and increase in ETCO2 levels from baseline compared to controls (p<0.01, Figure 1a, b). Across the entire trial and some individual COOKIES activity, severe PHOX2B genotypes show a greater decrease in SpO2 and increase in ETCO2 from baseline in comparison to moderate genotypes (p<0.05, Figure 1c, d). Conclusions: These pilot results demonstrate the ability of the COOKIES protocol to detect and evaluate the impact of everyday tasks on SpO2 and ETCO2 in individuals with CCHS. The differences identified by genotype supports the efficacy of this test to sensitively evaluate respiratory physiology. COOKIES has potential to advance understanding of respiratory physiology in CCHS and to shape future clinical management and therapeutic trials. Further work is needed in an expanded cohort of individuals with CCHS to assess COOKIES clinical validity, test-retest reliability, sensitivity, and specificity.

Rationale: CCHS is a rare genetic disorder associated with awide array of autonomic nervous system (ANS)-related abnormalities, including cardiovascular dysfunction. CCHS is caused by PHOX2B mutations including polyalanine repeat expansion mutations (PARMs) or non-PARMs (NPARMs). CCHS phenotype severity, including cardiovascular dysfunction, is related to PHOX2B genotype. Heart Rate Variability (HRV) is a well-established measurement of ANS cardiovascular function and a key biomarker in CCHS. Given the rarity and geographic dispersion of CCHS, methods of remote HRV monitoring in this population are critical. This study investigated HRV using thesmart wearable Hexoskin® system (Carre Technologies Inc., Montreal, Canada) in CCHS patients compared to healthy controls. Methods: 16 CCHS patients and 21 healthy controls were enrolled. Six CCHS patients had repeated measurements (annual visits, 22 total CCHS recordings). CCHS patients were divided into the following groups: 1) severe PHOX2B genotypes including 20/27 PARMs and severe NPARMs (N=13 recordings) and 2) moderate PHOX2B genotypes including 20/25, 20/26, and non-severe NPARMs (N=9 recordings). For each recording, between 1-34 hours of continuous electrocardiogram (ECG) was captured using Hexoskin® 3-lead ECG. ECG data were processed through Kubios® HRV Premium (Kubios, Kuopio, Finland). Time-domain-based HRV parameters (standard deviation of NN intervals (SDNN) andtheroot mean square of successive differences (RMSSD)), and frequency-domain-based HRV parameters (low-frequency/high-frequency ratio (LF/HF)) were calculated. Short-term (SD1)and long-term (SD2) variations in heart rate and their ratio were obtained using Poincaré plots. Results: Hexoskin®-based HRV assessment in CCHS patients versus healthy controls showed significant alterations in all domains. Comparing all CCHS patients to healthy controls revealed higher levels of time domain parameters SDNN (p=0.0001) and RMSSD (p=0.0136), frequency domain LF/HF (p=0.0237), and non-linear domain SD1/SD2 (p=0.0357). A significant increase in SDNN (p=0.0019) in the CCHS severe genotype group was detected compared to the healthy control group. Significant increases in the levels of SDNN (p=0.02), RMSSD (p=0.0002), andLF/HF ratio (p=0.03) were identified in theCCHS moderate genotype group compared to the healthy control group. Conclusion: This study highlights the feasibility of wearable technology to monitor HRV in CCHS patients. Validation of these results on alarge scale in the home, especially compared to hospital-based, gold-standard systems, would be the logical next step to move toward remote HRV monitoring in CCHS. Collectively this would allow clinical guidance based on in-home recordings in activities of daily living and serve as a reliable biomarker for future therapeutic trials.

RATIONALE:Congenital central hypoventilation syndrome (CCHS) is a rare disorder characterized by alveolar hypoventilation and variable autonomic nervous system (ANS) dysfunction (ANSD) due to mutations in PHOX2B, a gene crucial for ANS neural crest lineage differentiation. OBJECTIVES AND METHODS:Our prospective study aims were twofold: to (1) assess the relationships between the subjective Composite Autonomic Symptom Score (COMPASS)-31 and objective indices of ANSD obtained from heart rate variability analyses, ambulatory blood pressure (BP) monitoring, and CO2 chemosensitivities and (2) describe the organ system ANSD, its relationship to PHOX2B genotype, and its consequences on quality of life (PedsQL) in children with CCHS. RESULTS:Thirty-two PHOX2B mutation-confirmed subjects (median [range] age 9.2 years (4.4; 18.0), 15 girls) were enrolled. COMPASS-31 was assessed in 32 matched (sex and age, range: 4.3; 18.9 years) healthy controls. As compared to healthy controls, children with CCHS had increased vasomotor (p = 0.001), secretomotor (p = 0.021), gastrointestinal (p = 0.002) and pupillomotor (p = 0.028) scores and decreased orthostatic intolerance scores (p = 0.050). There was no difference in overall COMPASS-31 score between CCHS and controls (p = 0.083). However, in CCHS, overall COMPASS-31 scores correlated with high frequencies (HF) normalized (cardiac parasympathetic modulation: R = -0.53; p = 0.002), low frequencies (LF)/HF ratio (R = 0.56; p< 0.001), and both systolic and diastolic nighttime BP dipping (R = 0.45, p = 0.012 and R = 0.40, p = 0.028, respectively). No significant relationships between COMPASS-31 scores and chemosensitivity testing, PedsQL scores, or PHOX2B genotype were identified. CONCLUSIONS:COMPASS-31 identified some aspects of CCHS-related ANSD, and scores correlate with objective ANS function measures, supporting the potential utility of COMPASS-31 in CCHS.

Rationale: Congenital Central Hypoventilation Syndrome (CCHS) is a rare disorder characterized by global autonomic nervous system (ANS) dysregulation (ANSD) and dysfunctional control of breathing, necessitating artificial ventilation for life-support during sleep and up to 24h/day. CCHS is caused by PHOX2B gene variants. Recent in-silico data suggest grouping CCHS-causing PHOX2B variants into moderate and severe genotypes based on predicted protein dysfunction. Cardiovascular ANSD reported in cross-sectional CCHS studies includes altered heart rate variability (HRV), blood pressure variability, and prolonged sinus pauses with risk of sudden death. Clinically, we have observed progressive cardiovascular ANSD with age in CCHS, with a subset dying unexpectedly in early adulthood despite artificial ventilation and cardiac pacemakers. However, the relationship between cardiovascular ANSD and age has not been objectively assessed, and biomarkers of increased cardiovascular risk in CCHS are lacking. HRV represents a non-invasive measure of cardiovascular autonomic function, with specific HRV measures reflecting parasympathetic and sympathetic nervous system (PNS; SNS) and baroreflex activity. This study aimed to assess the impact of age and PHOX2B genotype severity groupings on longitudinal cardiac autonomic function in CCHS using HRV analyses. We hypothesized that patients with CCHS would demonstrate alterations in HRV parameters, correlated with age and PHOX2B genotype severity. Methods: 52 CCHS patients (3-36yrs) were tracked longitudinally (average: 4.5 visits; range: 1-12). Standard HRV measures (Table 1) were analyzed from continuous overnight ECG. Patient PHOX2B genotypes were divided into moderate and severe groupings. Linear mixed-effects models were used to examine demographic and clinical differences in HRV indices. Results: Genotype severity was associated with HRV measures reflecting a significant decrease in PNS and baroreceptor activity. Age was associated with a significant increase in SNS activity and decreased PNS and baroreceptor activity (Table 1). Conclusions: This novel relationship between genotype severity, age, and HRV in CCHS, suggests that HRV may be a sensitive marker of disease severity, progression, and potential risk of death. Significantly reduced HRV in severe vs. moderate PHOX2B variants supports these novel, in-silico groupings. Our findings suggest a parasympathetic withdrawal in aging CCHS patients and, potentially in response, increasing sympathetic contribution to cardiac autonomic control. A possible hypothesis for this sympathetic dominance is reduced baroreflex sensitivity with age due to hypoxic exposure, supported by significantly decreased LFnu with age. Blunting baroreflex response with hyperactive SNS and withdrawn PNS may explain the heightened cardiovascular risk observed clinically with aging CCHS patients.

OBJECTIVES:To report the association of zinc finger and SCAN domain containing 1 antibodies (ZSCAN1-abs) with rapid-onset obesity, hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) syndrome in patients without tumor. METHODS:Patients with symptoms compatible with ROHHAD syndrome but without an associated tumor were selected from our database. Serum and CSF samples were examined for the presence of ZSCAN1-abs by an in-house cell-based assay. In addition, samples from 149 patients with several inflammatory and noninflammatory disorders and 50 healthy participants served as controls. RESULTS:Thirteen patients with ROHHAD syndrome were identified. Of these, we had paired serum/CSF samples from 6 patients and only serum from the other 7. Five of 6 patients (83.3%) with paired serum/CSF (4 children, 1 adult) had ZSCAN-abs only in CSF and 1 had antibodies in serum and CSF. ZSCAN1-abs were not detected in the remaining 7 patients with ROHHAD with only serum available or in any of the 199 control samples. DISCUSSION:Patients with ROHHAD syndrome should be investigated for the presence of ZSCAN1-abs in CSF. The antibodies do not necessarily predict the presence of a tumor. The detection of ZSCAN1-abs in an adult patient suggests that this condition also occurs beyond the pediatric age.

Heterozygous pathogenic variants in PHOX2B are diagnostic for congenital central hypoventilation syndrome (CCHS), a rare autonomic disorder characterized by inadequate respiratory control necessitating artificial ventilation as life support. Comprehensive assessments of PHOX2B genotypes have enabled establishment of phenotypic predictors for the clinical management of patients affected with CCHS due to PHOX2B polyalanine repeat mutations (PARMs), truncating and frameshift non-PARMs (NPARMs), and full-gene deletions.

BACKGROUND:Congenital Central Hypoventilation Syndrome (CCHS) has devastating consequences if not diagnosed promptly. Despite identification of the disease-defining gene PHOX2B and a facial phenotype, CCHS remains underdiagnosed. This study aimed to incorporate automated techniques on facial photos to screen for CCHS in a diverse pediatric cohort to improve early case identification and assess a facial phenotype-PHOX2B genotype relationship. METHODS:Facial photos of children and young adults with CCHS were control-matched by age, sex, race/ethnicity. After validating landmarks, principal component analysis (PCA) was applied with logistic regression (LR) for feature attribution and machine learning models for subject classification and assessment by PHOX2B pathovariant. RESULTS:Gradient-based feature attribution confirmed a subtle facial phenotype and models were successful in classifying CCHS: neural network performed best (median sensitivity 90% (IQR 84%, 95%)) on 179 clinical photos (versus LR and XGBoost, both 85% (IQR 75-76%, 90%)). Outcomes were comparable stratified by PHOX2B genotype and with the addition of publicly available CCHS photos (n = 104) using PCA and LR (sensitivity 83-89% (IQR 67-76%, 92-100%). CONCLUSIONS:Utilizing facial features, findings suggest an automated, accessible classifier may be used to screen for CCHS in children with the phenotype and support providers to seek PHOX2B testing to improve the diagnostics. IMPACT:Facial landmarking and principal component analysis on a diverse pediatric and young adult cohort with PHOX2B pathovariants delineated a distinct, subtle CCHS facial phenotype. Automated, low-cost machine learning models can detect a CCHS facial phenotype with a high sensitivity in screening to ultimately refer for disease-defining PHOX2B testing, potentially addressing gaps in disease underdiagnosis and allow for critical, timely intervention.

To provide an overview of the discovery, presentation, and management of Rapid-onset Obesity with Hypothalamic dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD). To discuss a search for causative etiology spanning multiple disciplines and continents. The literature (1965–2022) on the diagnosis, management, pathophysiology, and potential etiology of ROHHAD was methodically reviewed. The experience of several academic centers with expertise in ROHHAD is presented, along with a detailed discussion of scientific discovery in the search for a cause. ROHHAD is an ultra-rare syndrome with fewer than 200 known cases. Although variations occur, the acronym ROHHAD is intended to alert physicians to the usual sequence or unfolding of the phenotypic presentation, including the full phenotype. Nearly 60 years after its first description, more is known about the pathophysiology of ROHHAD, but the etiology remains enigmatic. The search for a genetic mutation common to patients with ROHHAD has not, to date, demonstrated a disease-defining gene. Similarly, a search for the autoimmune basis of ROHHAD has not resulted in a definitive answer. This review summarizes current knowledge and potential future directions. ROHHAD is a poorly understood, complex, and potentially devastating disorder. The search for its cause intertwines with the search for causes of obesity and autonomic dysregulation. The care for the patient with ROHHAD necessitates collaborative international efforts to advance our knowledge and, thereby, treatment, to decrease the disease burden and eventually to stop, and/or reverse the unfolding of the phenotype.