Further description of two individuals with de novo p.(Glu127Lys) missense variant in the ASCL1 gene.

Achaete-Scute Family basic-helix-loop-helix (bHLH) Transcription Factor 1 (ASCL1) is a proneural transcription factor involved in neuron development in the central and peripheral nervous system. While initially suspected to contribute to congenital central hypoventilation syndrome-1 (CCHS) with or without Hirschsprung disease (HSCR) in three individuals, its implication was ruled out by the presence, in one of the individuals, of a Paired-like homeobox 2B (PHOX2B) heterozygous polyalanine expansion variant, known to cause CCHS. We report two additional unrelated individuals sharing the same sporadic ASCL1 p.(Glu127Lys) missense variant in the bHLH domain and a common phenotype with short-segment HSCR, signs of dysautonomia, and developmental delay. One has also mild CCHS without polyalanine expansion in PHOX2B, compatible with the diagnosis of Haddad syndrome. Furthermore, missense variants with homologous position in the same bHLH domain in other genes are known to cause human diseases. The description of additional individuals carrying the same variant and similar phenotype, as well as targeted functional studies, would be interesting to further evaluate the role of ASCL1 in neurocristopathies.

Dyspnea in young subjects with congenital central hypoventilation syndrome.

BACKGROUND: It has been stated that patients with congenital central hypoventilation syndrome (CCHS) do not perceive dyspnea, which could be related to defective CO2 chemosensitivity. METHODS: We retrospectively selected the data of six-minute walk tests (6-MWT, n = 30), cardiopulmonary exercise test (CPET, n = 5) of 30 subjects with CCHS (median age, 9.3 years, 17 females) who had both peripheral (controller loop gain, CG0) and central CO2 chemosensitivity (hyperoxic, hypercapnic response test [HHRT]) measurement. MAIN RESULTS: Ten subjects had no symptom during the HHRT, as compared to the 20 subjects exhibiting symptoms, their median ages were 14.7 versus 8.8 years (p = 0.006), their maximal PETCO2 were 71.6 versus 66.7 mmHg (p = 0.007), their median CO2 response slopes were 0.28 versus 0.30 L/min/mmHg (p = 0.533) and their CG0 values were 0.75 versus 0.50 L/min/mmHg (p = 0.567). Median dyspnea Borg score at the end of the 6-MWT was 1/10 (17/30 subjects >0), while at the end of the CPET it was 3/10 (sensation: effort). This Borg score positively correlated with arterial desaturation at walk (R = 0.43; p = 0.016) and did not independently correlate with CO2 chemosensitivities. CONCLUSION: About half of young subjects with CCHS do exhibit mild dyspnea at walk, which is not related to hypercapnia or residual CO2 chemosensitivity. IMPACT: Young subjects with CCHS exhibit some degree of dyspnea under CO2 exposure and on exercise that is not related to residual CO2 chemosensitivity. It has been stated that patients with CCHS do not perceive sensations of dyspnea, which must be tempered. The mild degree of exertional dyspnea can serve as an indicator for the necessity of breaks.

The role of atypical deglutition in children and adolescents with moderate to severe obstructive sleep apnea syndrome.

This cross-sectional study aimed to assess the prevalence of atypical deglutition (tongue thrust) in children diagnosed with moderate to severe obstructive sleep apnea syndrome (OSAS) and to explore its associations, particularly in relation to the type of dentition (mixed or permanent). The study was conducted over a 5 year period at a paediatric hospital in Paris, France. Children aged 6-18 years with moderate to severe OSAS (apnea-hypopnea index ≥5/h) underwent a comprehensive evaluation, including the recording of demographic data, symptoms of snoring and breathing issues, and otolaryngology examination. The swallowing pattern was assessed and orthodontic evaluations were performed. Cephalometric radiography and pharyngometry tests (pharyngeal collapsibility was computed) were conducted. The study found a high prevalence of atypical deglutition in children with mixed 74% [56-87] or permanent 38% [25-51] dentition. In children with mixed dentition and atypical deglutition, the pharyngeal compliance and lower facial dimensions were increased. In children with permanent dentition, atypical deglutition was associated with more severe OSAS and a lower hyoid bone position. Independent of the type of dentition, atypical deglutition was associated with an increase in the apnea-hypopnea index, an increase in the lower facial dimension, increased pharyngeal compliance, and a more caudal hyoid bone position. Atypical deglutition was strongly associated with increased pharyngeal collapsibility, more severe OSAS and altered facial measurements in children. The findings suggest that identifying atypical deglutition in children with OSAS could help to guide a personalised therapeutic approach, including myofunctional therapy.

Case-control study of heart rate variability and sleep apnea in childhood sickle cell disease.

Obstructive sleep apnea (OSA) is common in sickle cell disease (SCD) despite the absence of overweight, suggesting a specific pathophysiology. We previously showed that otherwise healthy children with increased pharyngeal compliance, a main endotype of OSA, exhibited decreased sympathetic modulation. Our objective was to assess whether modifications of heart rate variability (HRV) and compliance are associated in SCD. Cases (children with SCD, African or Caribbean ethnicity) and controls (otherwise healthy children, same ethnicity), aged 4-18 years, were selected from our database of children referred for OSA and matched for sex, age, and obstructive apnea-hypopnoea index (OAHI) score. The children underwent polysomnography and acoustic pharyngometry (to compute compliance). HRV analyses were performed from 5 min ECG recordings in wakeful, NREM, and REM sleep states and from the whole night. Twenty-one pairs were analysed (median age 10.5 years, 24 girls). Children with SCD had lower BMI z-scores and more tonsil hypertrophy than control children. Children with SCD and OSA (OAHI ≥2/hour) were characterised by lower compliance than children with SCD without OSA. An inverse relationship between compliance and SD2 (HRV from whole night, inversely related to sympathetic modulation) was evidenced (negative relationship in SCD: R = -0.63, p = 0.002 vs. positive relationship in controls R = 0.59, p = 0.006). In conclusion, while the decrease in sympathetic modulation in control children may contribute to increasing pharyngeal compliance, its decrease seems protective in children with sickle cell disease, which underlines the specificity of OSAS pathophysiology in SCD that could be due to sickle cell disease related smooth muscle dystonia.

Nap polysomnography in infants with laryngomalacia as a tool to predict treatment strategy.

PURPOSE: This study aimed to investigate the role of nap polysomnography (NPSG) in predicting treatment strategies for infants with moderate to severe laryngomalacia and to explore the association between obstructive sleep apnea (OSA) severity, weight gain, and laryngomalacia severity. METHODS: A retrospective analysis was conducted on infants diagnosed with moderate to severe laryngomalacia who underwent NPSG between January 2019 and June 2023. Clinical variables, NPSG parameters, and treatment decisions were collected. Weight gain rate and its correlation with NPSG indices were assessed. Logistic regression analyses were performed to predict treatment strategies based on NPSG findings. RESULTS: Of the 39 infants included (median age: 3.3 months), 77% exhibited OSA, with 69% having moderate to severe OSA [apnea-hypopnea index (AHI) > 5/h]. Weight gain rate correlated negatively with indices of OSA severity, including the hypopnea index (HI) and the AHI. In a multiple logistic regression analysis incorporating the severity of OSA (AHI), weight gain rate, and laryngomalacia severity, only AHI predicted the decision for surgical or non-invasive ventilation treatment (OR = 2.1, CI95 [1.6; 2.8], p ≤ 10-4). The weight gain rate was predicted (r2 = 0.28) by the AHI and the presence of retractions of auxiliary inspiratory muscles. CONCLUSION: This study underscores the importance of NPSG in assessing infants with moderate to severe laryngomalacia. The AHI from NPSG emerged as a potential predictor for treatment decisions and weight gain rate, emphasizing its clinical relevance. These findings advocate incorporating NPSG into the diagnostic and management process for infants with laryngomalacia.

Obstructive sleep apnea in children with Down syndrome: contribution of upper airway and chemosensitivity.

BACKGROUND: The high prevalence of obstructive sleep apnea syndrome (OSAS) in children with Down syndrome (DS) has been attributed to a reduced upper airway size, while the role of ventilatory control is unclear. The objectives of our case-control study were to evaluate the upper airway reduction in children with DS and moderate to severe OSAS as compared to typically developing (TD) children with similar OSAS severity and to evaluate the degree of chemical loop gain modifications including its components: controller and plant gains (CG, PG). METHODS: Thirteen children with DS were matched for age, sex, OSAS severity and ethnicity with 26 TD children. They had undergone acoustic rhinometry and pharyngometry, chemical LG obtained during awake tidal breathing measurement and hypercapnic-hyperoxic ventilatory response testing. RESULTS: As compared to TD, children with DS depicted reduced oropharyngeal dimensions, significantly lower CG and LG and no different PG. Their hypercapnic ventilatory response slopes were not different. CONCLUSIONS: We concluded that the decreased CG in DS was related to decreased peripheral chemoreceptor sensitivity, and while central chemosensitivity was normal, the former explained the increased end-tidal PCO2 observed in children with DS as compared to TD. Pharyngeal dimensions are reduced in children with DS and OSAS. IMPACT: Reduced upper airway size and nocturnal alveolar hypoventilation in children with Down syndrome (DS) have been previously reported. We confirmed that children with DS and moderate-to-severe OSA have reduced oropharyngeal size as compared to typically developing children with similar OSAS severity and demonstrated decreased peripheral chemosensitivity explaining the alveolar hypoventilation observed in children with DS. Central chemosensitivity appears to be intact in children with DS and moderate to severe OSAS Our results support growing evidence that Down syndrome is associated with autonomic nervous system dysfunction.

Heart rate variability in congenital central hypoventilation syndrome: relationships with hypertension and sinus pauses.

BACKGROUND: Autonomic nervous system (ANS) dysregulation has been described in congenital central hypoventilation syndrome (CCHS). The objectives were to describe heart rate variability (HRV) analyses in children suffering from CCHS both while awake and asleep and their relationships with both ambulatory blood pressure (BP) and ECG monitoring results. METHODS: This retrospective study enrolled children with CCHS (n = 33, median age 8.4 years, 18 girls) who had BP and ECG monitored during the same 24 h. From the latter, HRV analyses were obtained during daytime and nighttime. RESULTS: The prevalences of hypertension and sinus pauses were 33% (95% confidence interval [CI]: 18-52) and 18% (95% CI: 7-35), respectively. The decrease in systolic BP at night negatively correlated with an increase in very low frequency (VLF) and LF powers at night, and the longest RR interval positively correlated with daytime VLF and LF powers. Among the three groups of children (polyalanine repeat expansion mutation [PARM], moderate [20/25 and 20/26], severe [20/27 and 20/33], and non-PARMs), the prevalence of elevated BP or hypertension was different: in PARM subjects: 6/18 moderate, 7/9 severe versus 0/6 in non-PARM (p = 0.002). CONCLUSION: Modifications of cardiac ANS are associated with systemic hypertension and the occurrence of sinus pauses in CCHS. IMPACT: Children with congenital central hypoventilation syndrome (CCHS) exhibit an increased prevalence of hypertension and sinus pauses that are linked to cardiac autonomic nervous system dysfunction. Sinus pauses are the main manifestation of sinus nodal dysfunction in children with CCHS. The increased prevalence of hypertension, especially at nighttime, is a new finding in CCHS. Sinus nodal dysfunction can be due to the sole impairment of the cardiac autonomic nervous system. Ambulatory blood pressure and ECG monitoring are mandatory in patients with CCHS.

Determinants of awake oropharyngeal volume reduction between sitting and supine positions in children evaluated for snoring.

Pharyngeal collapsibility is a major determinant of obstructive sleep apnea (OSA) pathophysiology, but its anatomical predictors in children are largely unknown. We hypothesised that anatomical (tonsillar hypertrophy, narrow palate, nasal obstruction, dental/skeletal malocclusion, obesity) and OSA-related (apnea-hypopnea index, AHI) parameters could be related to a measure of awake pharyngeal collapsibility. We performed acoustic pharyngometry in children evaluated for suspected OSA, allowing us to measure the reduction of oropharyngeal volume in supine versus sitting position normalised for the volume in supine position (ΔV%), a measure of pharyngeal collapsibility. In addition to polysomnography and a clinical examination (anatomical parameters), acoustic rhinometry was used to assess nasal obstruction. A total of 188 snoring children were included, 118 (63%) of whom were obese and 74 (39%) of whom had moderate to severe OSA (AHI ≥5/h). The median (25th-75th percentiles) ΔV% in the whole population was 20.1% (4.7; 43.3). ΔV% was independently and positively associated with AHI (p = 0.023), z-score of BMI (p = 0.001), tonsillar hypertrophy (p = 0.007), narrow palate (p = 0.035), and African (p < 0.001) ancestry. By contrast, ΔV% was not modified by dental or skeletal malocclusion, Friedman palate position class or nasopharyngeal obstruction. Tonsillar hypertrophy, obesity, narrow palate and African ancestry are independently associated with an increase in pharyngeal collapsibility in snoring children, thus increasing the risk of OSA. Increased pharyngeal compliance in African children may explain the increased risk of residual OSA after adenotonsillectomy observed in this population.

Reliability of parental reporting of child snoring in children referred for obstructive sleep apnea.

Despite the high number of studies based on subjective reports of snoring, self-reported snoring has hardly been validated at all. As there is no "gold-standard" for objective snoring measurements, studies must evaluate whether the presence of snoring based on parental judgement is linked to objective measurements of nasal and/or pharyngeal obstruction in children referred for obstructive sleep apnea. A total of 146 children (median age 11 years) underwent polysomnography (with snoring recording using nasal cannula signal), acoustic rhinometry and pharyngometry, while their parents filled out the Spruyt-Gozal questionnaire assessing both frequency and loudness of subjective snoring. Three categories were further differentiated (null, low and high) for both frequency and loudness. The apnea-hypopnea index was significantly different in the three groups for both frequency (p = 0.04) and loudness (p = 0.01) of subjective snoring. Children in the low or high groups (frequency or loudness), compared with those in the null group, experienced a decline in both pharyngeal (sitting and supine positions) and nasopharyngeal (supine position) volumes (frequency, pharynx sitting: p = 0.03; supine: 0.005 and nasopharynx: p = 0.002; loudness, p = 0.03; p = 0.007 and p = 0.03; three group comparisons). Objective snoring frequency during the night obtained with cannula was weakly related to loudness of subjective snoring but not to subjective snoring frequency during the week, and was biased by nasal obstruction. In conclusion, our study showed that parental assessment of snoring is related to a reduction in both pharyngeal and nasopharyngeal volumes in snorers, arguing for the adequacy of their evaluation of both snoring frequency and loudness.

Effect of Facemask in Congenital Central Hypoventilation Syndrome.

INTRODUCTION: Congenital central hypoventilation syndrome (CCHS) is a rare genetic disorder with a mutation in the PHOX2B gene. Patients need ventilatory support by noninvasive ventilation or tracheostomy to treat alveolar hypoventilation. Patients with CCHS have a defect in chemosensitivity signal integration. Recently, due to the COVID-19 pandemic, the entire world has had to get used to wearing medical masks (MM). OBJECTIVES: The aim of the study was to evaluate the effect of an MM on gas exchange and to determine the role of central and peripheral chemoresponsiveness on the partial pressure of transcutaneous carbon dioxide (PtcCO2) in patients with CCHS wearing an MM. METHODS: This study was based on the analysis of recordings obtained without and with an MM during hospitalization and was conducted to assess the impact of MM on PtcCO2 and SpO2 recordings with the SenTec Digital Monitor and their relationships with peripheral CO2 chemosensitivity obtained during tidal breathing measurement and with the hypercapnic hyperoxic ventilatory response. RESULTS: Sixteen patients were included (13 boys) and were 10.2 (7.5; 18.5) years old. The use of an MM had a negative impact on gas exchange in patients with CCHS. The median PtcCO2 increased significantly. Peripheral chemosensitivity correlated with MM-induced PtcCO2 changes (R = -0.72, p = 0.005), but central chemosensitivity (the hypercapnic ventilator response slope) did not (R = -0.22, p = 0.510). CONCLUSION: The use of an MM had a negative impact on gas exchange in patients with CCHS.

Expanding the phenotype in Adams-Oliver syndrome correlating with the genotype.

RATIONALE: Adams-Oliver syndrome (AOS) is a genetic disorder characterized by the association of aplasia cutis congenita (ACC), terminal transverse limb defect (TTLD), congenital cardiac malformation (CCM), and minor features, such as cutaneous, neurological, and hepatic abnormalities (HAs). The aim of the study is to emphasize phenotype-genotype correlations in AOS. METHODS: We studied 29 AOS patients. We recorded retrospectively detailed phenotype data, including clinical examination, biological analyses, and imaging. The molecular analysis was performed through whole exome sequencing (WES). RESULTS: Twenty-nine patients (100%) presented with ACC, the principal inclusion criteria in the study. Seventeen of twenty-one (81%) had cutis marmorata telangiectasia congenita, 16/26 (62%) had TTLD, 14/23 (61%) had CCM, 7/20 (35%) had HAs, and 9/27 (33%) had neurological findings. WES was performed in 25 patients. Fourteen of twenty-five (56%) had alterations in the genes already described in AOS. CCM and HAs are particularly associated with the NOTCH1 genotype. TTLD is present in patients with DOCK6 and EOGT alterations. Neurological findings of variable degree were associated sometimes with DOCK6 and NOTCH1 rarely with EOGT. CONCLUSION: AOS is characterized by a clinical and molecular variability. It appears that degrees of genotype-phenotype correlations exist for patients with identified pathogenic mutations, underlining the need to undertake a systematic but adjusted multidisciplinary assessment.

Awakening efficacy of a vibrotactile device in patients on home nocturnal ventilatory assistance and healthy subjects as family caregiver proxies.

The objective of this study was to test the capacity of vibrotactile stimulation transmitted to the wrist bones by a vibrating wristband to awaken healthy individuals and patients requiring home mechanical ventilation during sleep. Healthy subjects (n = 20) and patients with central hypoventilation (CH) (Congenital Central Hypoventilation syndrome n = 7; non-genetic form of CH n = 1) or chronic obstructive pulmonary disease (COPD) (n = 9), underwent a full-night polysomnography while wearing the wristband. Vibrotactile alarms were triggered five times during the night at random intervals. Electroencephalographic (EEG), clinical (trunk lift) and cognitive (record the time on a sheet of paper) arousals were recorded. Cognitive arousals were observed for 94% of the alarms in the healthy group and for 66% and 63% of subjects in the CH and COPD groups, respectively (p < 0.01). The percentage of participants experiencing cognitive arousals for all alarms, was 72% for healthy subjects, 37.5% for CH patients and 33% for COPD patients (ns) (94%, 50% and 44% for clinical arousals (p < 0.01) and 100%, 63% and 44% for EEG arousals (p < 0.01)). Device acceptance was good in the majority of cases, with the exception of one CH patient and eight healthy participants. In summary this study shows that a vibrotactile stimulus is effective to induce awakenings in healthy subjects, but is less effective in patients, supporting the notion that a vibrotactile stimulus could be an effective backup to a home mechanical ventilator audio alarm for healthy family caregivers.

Obstructive sleep apnea in Down syndrome: Benefits of surgery and noninvasive respiratory support.

Children with Down syndrome are at increased risk of obstructive sleep apnea (OSA). The aim of the study was to describe the management of OSA in a large cohort of children with Down syndrome. A retrospective analysis of sleep studies and consequent management was performed for all consecutive Down syndrome patients evaluated between September 2013 and April 2016. The data of 57 patients were analyzed: 51/53 had an interpretable overnight polygraphy and 4 the recording of nocturnal gas exchange. Mean age at baseline sleep study was 6.2 ± 5.9 years. Eighteen patients (32%) had prior upper airway surgery. Mean apnea-hypopnea index (AHI) was 14 ± 16 events/hr with 41 of the 51 (80%) patients having OSA with an AHI >1 event/hr and 20 patients (39%) having an AHI ≥10 events/hr. Consequently, eight patients (14%) had upper airway surgery. OSA improved in all patients except two who needed noninvasive respiratory support. Nineteen (33%) patients required noninvasive respiratory support. Mean age at noninvasive respiratory support initiation was 7 ± 7 years. On 11 patients with objective adherence data available, mean compliance at 2 ± 1 years of treatment was excellent with an average use per night of 8 hr46 ± 3 hr59 and 9 patients using the noninvasive respiratory support >4 hr/night. Noninvasive respiratory support was associated with an improvement of nocturnal gas exchange. The prevalence of OSA is high in Down syndrome. Upper airway surgery is not always able to correct OSA. Noninvasive respiratory support represents then an effective treatment for OSA and good compliance may be achieved in a majority of patients.

Autism spectrum disorder in young patients with congenital central hypoventilation syndrome: role of the autonomic nervous system dysfunction.

BACKGROUND: Congenital central hypoventilation syndrome (CCHS) is a rare condition characterized by alveolar hypoventilation and autonomic nervous system (ANS) dysfunction requiring long-term ventilation. CCHS could constitute a risk factor of autism spectrum disorder (ASD) due to birth injury related to respiratory failure, which remains to be determined. ANS dysfunction has also been described in ASD and there are indications for altered contribution of ANS-central nervous system interaction in processing of social information; thus, CCHS could be a risk factor for ASD based on pathophysiological background also. Our study aimed to determine the prevalence of ASD among CCHS patients, identify risk factors, and explore the relationship between the ANS, evaluated by heart rate variability indices, and adaptative functioning. RESULTS: Our retrospective study, based on the analysis of records of a French national center of patients with CCHS under 20 years of age, determined that the prevalence of ASD (diagnosed by a psychiatrist, following the criteria of DSM-4 or DSM-5) was 6/69 patients, 8.7% (95% confidence interval: 3.3-18.0%). In a case (CCHS with ASD, n = 6) - control (CCHS without ASD, n = 12) study with matching on sex, longer neonatal hospitalization stay and glycemic dysfunction were associated with ASD. Adaptative functioning was assessed using Vineland Adaptative behavioral scales (VABS) and heart rate variability indices (including daytime RMSSD as an index of parasympathetic modulation) were obtained from ECG Holter performed the same day. In 19 young subjects with CCHS who had both ECG Holter and VABS, significant positive correlations were observed between RMSSD and three of four sub-domains of the VABS (communication: R = 0.50, p = 0.028; daily living skills: R = 0.60, p = 0.006; socialization: R = 0.52, p = 0.021). CONCLUSION: Our study suggests a high prevalence of ASD in patients with CCHS. Glycemic dysfunction and longer initial hospitalization stays were associated with ASD development. A defect in parasympathetic modulation was associated with worse adaptative functioning.

Airway obstruction in two children with congenital central hypoventilation syndrome and review of the literature.

Congenital central hypoventilation syndrome (CCHS) is an autosomal dominant disease that is caused by heterozygous mutations in the paired-like homeobox 2B gene (PHOX2B). Madani et al. described an abnormally high degree of not only central apnea but also obstructive and mixed apnea in Phox2b27Ala/+newborn mice. Newborns with CCHS must undergo polysomnography for obstructive respiratory events in order to guide the optimal ventilation strategy if oxygen desaturation, bradycardia, and malaise persist under noninvasive ventilation. Newborns and infants with CCHS must be systematically tested for obstructive apnea, especially in cases of inefficient noninvasive ventilation.

Pediatric long-term noninvasive respiratory support in children with central nervous system disorders.

RATIONALE: The use of long-term noninvasive respiratory support is increasing in children along with an extension of indications, in particular in children with central nervous system (CNS) disorders. OBJECTIVE: The aim of this study was to describe the characteristics of children with CNS disorders treated with long-term noninvasive respiratory support in France. METHODS: Data were collected from 27 French pediatric university centers through an anonymous questionnaire filled for every child treated with noninvasive ventilatory support ≥3 months on 1st June 2019. MAIN RESULTS: The data of 182 patients (55% boys, median age: 10.2 [5.4;14.8] years old [range: 0.3-25]) were collected: 35 (19%) patients had nontumoral spinal cord injury, 22 (12%) CNS tumors, 63 (35%) multiple disabilities, 26 (14%) central alveolar hypoventilation and 36 (20%) other CNS disorders. Seventy five percent of the patients were treated with noninvasive ventilation (NIV) and 25% with continuous positive airway pressure (CPAP). The main investigations performed before CPAP/NIV initiation were nocturnal gas exchange recordings, alone or coupled with poly(somno)graphy (in 29% and 34% of the patients, respectively). CPAP/NIV was started in an acute setting in 10% of the patients. Median adherence was 8 [6;10] hours/night, with 12% of patients using treatment <4 h/day. Nasal mask was the most common interface (70%). Airway clearance techniques were used by 31% of patients. CONCLUSION: CPAP/NIV may be a therapeutic option in children with CNS disorders. Future studies should assess treatment efficacy and patient reported outcome measures.

Development and validation of moderate to severe obstructive sleep apnea screening test (ColTon) in a pediatric population.

OBJECTIVE: Development and validation of a machine learning algorithm to predict moderate to severe obstructive sleep apnea syndrome (OSAS) in otherwise healthy children. DESIGN: Multivariable logistic regression and cforest algorithm of a large cross-sectional data set of children with sleep-disordered breathing. SETTING: An university pediatric sleep centre. PARTICIPANTS: Children underwent clinical examination, acoustic rhinometry and pharyngometry, and surveying through parental sleep questionnaires, allowing the recording of 14 predictors that have been associated with OSAS. The dataset was nonrandomly split into a training (development) versus test (external validation) set (2:1 ratio) based on the time of the polysomnography. We followed the TRIPOD checklist. RESULTS: We included 336 children in the analysis: 220 in the training set (median age [25th-75th percentile]: 10.6 years [7.4; 13.5], z-score of BMI: 1.96 [0.73; 2.50], 89 girls) and 116 in the test set (10.3 years [7.8; 13.0], z-score of BMI: 1.89 [0.61; 2.46], 51 girls). The prevalence of moderate to severe OSAS was 106/336 (32%). A machine learning algorithm using the cforest with pharyngeal collapsibility (pharyngeal volume reduction from sitting to supine position measured by pharyngometry) and tonsillar hypertrophy (Brodsky scale), constituting the ColTon index, as predictors yielded an area under the curve of 0.89, 95% confidence interval [0.85-0.93]. The ColTon index had an accuracy of 76%, sensitivity of 63%, specificity of 81%, negative predictive value of 84%, and positive predictive value of 59% on the validation set. CONCLUSION: A cforest classifier allows valid predictions for moderate to severe OSAS in mostly obese, otherwise healthy children.

Central CO2 chemosensitivity and CO2 controller gain independently contribute to daytime Pco2 in young subjects with congenital central hypoventilation syndrome.

Whether peripheral chemoreceptor response is altered in congenital central hypoventilation syndrome (CCHS) remains debated. Our aim was to prospectively evaluate both peripheral and central CO2 chemosensitivity and to evaluate their correlations with daytime Pco2 and arterial desaturation during exercise in CCHS. To this end, tidal breathing was recorded in patients with CCHS allowing the calculation of loop gain and its components {steady-state controller (assumed to mainly be peripheral chemosensitivity) and plant gains using a bivariate [end-tidal Pco2 ([Formula: see text]) and ventilation] constrained model}, a hyperoxic, hypercapnic ventilatory response test (central chemosensitivity), and a 6-min walk test (arterial desaturation). The results of loop gain were compared with those previously obtained in a healthy group of similar age. The study prospectively included 23 subjects with CCHS, without daytime ventilatory support; the subjects had a median age of 10 (5.6 to 27.4) yr (15 females) with moderate polyalanine repeat mutation (PARM: 20/25, 20/26, n = 11), severe PARM (20/27, 20/33, n = 8), or non-PARM (n = 4). As compared with 23 healthy subjects (4.9-27.0 yr), the subjects with CCHS had a decreased controller gain and an increased plant gain. Mean daytime [Formula: see text] level of subjects with CCHS correlated negatively to both Log(controller gain) and the slope of CO2 response. Genotype was not related to chemosensitivity. Arterial desaturation on exercise correlated negatively with Log(controller) gain but not with the slope of the CO2 response. In conclusion, we demonstrate that peripheral CO2 chemosensitivity is altered in some patients with CCHS and that the daytime [Formula: see text] depends on central and peripheral chemoreceptor responses.NEW & NOTEWORTHY Altered central CO2 chemosensitivity is a hallmark of congenital central hypoventilation syndrome (CCHS). Peripheral CO2 chemosensitivity can be partly assessed by controller gain measurement obtained from tidal breathing recording. In young subjects with CCHS, this study shows that both central and peripheral CO2 sensitivities independently contribute to daytime Pco2. Hypocapnia during nighttime-assisted ventilation is associated with higher peripheral chemosensitivity that is further associated with lesser arterial desaturation at walk.

Neurogenic hypertension characterizes children with congenital central hypoventilation syndrome and is aggravated by alveolar hypoventilation during sleep.

OBJECTIVES: Autonomic nervous system (ANS) dysfunction characterizes congenital central hypoventilation syndrome (CCHS). The objectives were to describe ambulatory blood pressure monitoring (ABPM) of children with CCHS, to assess cardiac ANS dysfunction as compared with control participants and to search for relationships between ANS dysfunction and blood pressure (BP) or night-time PCO 2 measurements. METHODS: Retrospective study of ABPM of children with CCHS and case (CCHS)-control (healthy children) study of heart rate variability (HRV) indices obtained during polysomnography (wakefulness, nonrapid eye movement sleep, rapid eye movement sleep, and whole night). The HRV indices analyzed were low, high-frequency powers, low frequency/high frequency, and for the whole night, SD1/SD2. RESULTS: Twenty-four children with CCHS (14 girls) who underwent 81 ABPM (2-6/patient, 74 after 4 years) were included in the longitudinal study. Hypertension was evidenced in 29 of 45 (64%) ABPM made between 5 and 9 years of age as compared with 12 of 36 (33%) ABPM made between 10 and 17 years of age ( P  = 0.005). In the case-control study (12 pairs), as compared with control children, children with CCHS were characterized by a decreased HRV while awake, which was aggravated at night. In children with CCHS, at daytime, SBP percentiles positively correlated with low-frequency power ( R  = -0.82; P  = 0.001), while at night-time, SBP percentiles negatively correlated with SD1/SD2 ( R  = -0.79; P  = 0.010). The SD1/SD2 ratio also negatively correlated with median PCO 2 under mechanical ventilation ( R  = -0.69; P  = 0.013). CONCLUSION: Neurogenic hypertension is frequent in CCHS and correlates with ANS dysfunction, which also correlates with alveolar ventilation during mechanical ventilation.