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Congenital disorders of ventilatory control typically manifest as central apneas, periodic breathing, and hypoventilation in the neonatal period, but some may present at a later age. Obstructive apneas may be the initial presentation, and some may have associated autonomic nervous system dysfunction. Individuals with these disorders can have absent or impaired ventilatory and arousal responses to hypoxemia and hypercapnia. This article discusses the presentation, pathophysiology, evaluation, and management of congenital central hypoventilation syndrome, rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) syndrome, Prader-Willi syndrome, and myelomeningocele.

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).
CONCLUSIONS: 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.

OBJECTIVE: Congenital central hypoventilation syndrome (CCHS) is a rare disease predisposing children to respiratory failure due to abnormal ventilatory drive. Variability in hypoventilation and respiratory support need have been reported. We aim to identify clinical variables associated with incident tracheostomy and common etiologies of hospitalization among children with CCHS.
METHODS: Hospital discharge records were obtained for children (<21 years) with CCHS hospitalized between 2006 and 2019 from the Kid\'s Inpatient Database. Primary diagnostic categories for hospitalizations with CCHS were summarized. Multivariable logistic regression models were used to explore risk factors associated with incident tracheostomy.
RESULTS: Among 2404 hospitalizations with CCHS, 133 (5.5%) had incident tracheostomy, 1230 (51.2%) had established tracheostomy, and 1041 (43.3%) had no tracheostomy. Compared with children without tracheostomy, those with incident tracheostomy were younger, had a history of prematurity, congenital heart disease, laryngeal, glottic, and subglottic stenosis (LGSS), congenital airway anomalies, neuromuscular weakness, gastroesophageal reflux disease. Children without tracheostomy had higher mortality than those with tracheostomy status (2.19% vs. 0.66%). Multivariable-adjusted analyses showed that incident tracheostomy was associated with infancy (0-1 years), neuromuscular weakness, and congenital heart disease. Most common diagnostic categories include (1) diseases of the respiratory system (30.23%), (2) injury and poisoning (9.35%), and (3) diseases of the nervous system and sense organs (6.71%).
CONCLUSIONS: Children with CCHS who received incident tracheostomy are more likely to be younger and with LGSS, neuromuscular weakness and congenital heart disease. Clinicians should be aware of these risk factors representing more severe CCHS with earlier manifestation needing tracheostomy. Higher mortality among nontracheostomy group highlights the need for considering tracheostomy in caring for children with CCHS.

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.

UNASSIGNED: Congenital central hypoventilation syndrome (CCHS) is a life-threatening disorder of autonomic respiratory control. Mutations in the paired-like homeobox 2B (PHOX2B) gene impair respiratory drive, causing hypercarbia and hypoxaemia. Most patients with CCHS are diagnosed in the neonatal period; however, a few are diagnosed in adulthood.
UNASSIGNED: We report a 32-year-old man with a history of unexplained cyanosis 14 days after birth. He presented to our hospital with breathlessness and abnormal electrocardiogram findings discovered in a health check-up. Pulmonary hypertension (PH) was suspected based on electrocardiographic and echocardiographic evidence of right ventricular (RV) overload. Results of pulmonary function tests and chest computed tomography were normal. Arterial blood gas analysis revealed type 2 respiratory failure without a significant alveolar-arterial oxygen gradient, indicating alveolar hypoventilation. Right heart catheterization (RHC) showed pre-capillary PH [pulmonary artery pressure 47/24 (35) mmHg], and a hyperventilation challenge test and a non-invasive positive pressure ventilation (NPPV) treatment during RHC provided drastic improvement in PH [pulmonary artery pressure 28/12 (18) mmHg]. Congenital central hypoventilation syndrome was diagnosed based on genetic testing (20/25 polyalanine repeat expansion mutations in PHOX2B). After NPPV therapy initiation, the RV overload was slightly improved.
UNASSIGNED: Some patients with CCHS develop mild hypoventilation without overt clinical signs, and PH can be the first clinical manifestation. In our case, the hyperventilation challenge test improved PH. Although CCHS causes chronic alveolar hypoxia and hypoxic pulmonary vasoconstriction with subsequent PH, optimal ventilation therapy can improve pulmonary circulation even in affected adults.

Expansion mutations in polyalanine stretches are associated with a growing number of diseases sharing a high degree of genotypic and phenotypic commonality. These similarities prompted us to query the normal function of physiological polyalanine stretches and to investigate whether a common molecular mechanism is involved in these diseases. Here, we show that UBA6, an E1 ubiquitin-activating enzyme, recognizes a polyalanine stretch within its cognate E2 ubiquitin-conjugating enzyme USE1. Aberrations in this polyalanine stretch reduce ubiquitin transfer to USE1 and, subsequently, polyubiquitination and degradation of its target, the ubiquitin ligase E6AP. Furthermore, we identify competition for the UBA6-USE1 interaction by various proteins with polyalanine expansion mutations in the disease state. The deleterious interactions of expanded polyalanine tract proteins with UBA6 in mouse primary neurons alter the levels and ubiquitination-dependent degradation of E6AP, which in turn affects the levels of the synaptic protein Arc. These effects are also observed in induced pluripotent stem cell-derived autonomic neurons from patients with polyalanine expansion mutations, where UBA6 overexpression increases neuronal resilience to cell death. Our results suggest a shared mechanism for such mutations that may contribute to the congenital malformations seen in polyalanine tract diseases.

BACKGROUND: 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).
OBJECTIVE: 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).
CONCLUSIONS: The use of an MM had a negative impact on gas exchange in patients with CCHS.

Congenital central hypoventilation syndrome (CCHS) is a rare condition characterized by central hypoventilation, leading to the majority of patients being dependent on ventilatory support during sleep. This condition is often accompanied by various associated symptoms, due to a PHOX2B gene variant involved in neuronal crest cell migration. This study is the first to review the characteristics and outcomes in children with CCHS on long-term mechanical ventilation in the Netherlands. We performed a retrospective study of all CCHS patients treated in the 4 Centers of Home Mechanical Ventilation of the University Medical Centers in the Netherlands from 2000 till 2022 by collecting information from the electronic medical records, documented during follow-up. We included 31 patients, out of which 27 exhibited a known genetic profile associated with CCHS, while no PHOX2B variant was identified in the remaining patients. Among the 27 patients with known genetic profiles, 10 patients had a non-polyalanine repeat expansion mutation (NPARM), followed by 20/27, 20/25, and 20/26 polyalanine repeat expansion mutations (PARMs) in descending order. The most common presentation involved respiratory failure or apneas during the neonatal period with an inability to wean off ventilation. The majority of patients required ventilatory support during sleep, with four patients experiencing life-threatening events related to this dependency. Daily use of ventilatory support varied among different genetic profiles. All genotypes reported comorbidities, with Hirschsprung\'s disease and cardiac arrhythmias being the most reported comorbidities. Notably, Hirschprung\'s disease was exclusively observed in patients with a 20/27 PHOX2B variant.
CONCLUSIONS: Our study results suggest that in our cohort, the genotype is not easily associated to the phenotype in CCHS. Consistent with these findings and international literature, we recommend a thorough annual evaluation for all patients with CCHS to ensure optimal management and follow-up.
BACKGROUND: • The majority of CCHS patients are dependent on ventilatory support. • Variants in the PHOX2B gene are responsible for the characteristics of CCHS.
BACKGROUND: • This study provides insight into the clinical course and long-term outcomes of CCHS patients in the Netherlands. • In CCHS, the genotype is not easily associated with the phenotype, requiring a thorough life-long follow-up for all patients.

BACKGROUND: Congenital central hypoventilation syndrome (CCHS) is a rare autosomal dominant disease that is mainly caused by PHOX2B mutations. The purpose of this study is to analyze and summarize the clinical and genetic characteristics of CCHS patients in the Chinese population from our study and previous literature.
METHODS: The potential pathogenic gene mutations of CCHS were identified and verified by next generation sequencing combined with Sanger sequencing, fluorescent probe PCR and capillary electrophoresis. The clinical characteristics and gene mutations of CCHS cases in Chinese population were summarized from our study and previous literature to explore the genotype-phenotype correlations.
RESULTS: We identified 48 CCHS cases including three new cases from our report in China. Overall, 77.1% of the patients had PHOX2B polyalanine repeat expansion mutations (PARMs), and the remaining 22.9% had 10 distinct PHOX2B non-polyalanine repeat expansion mutations (NPARMs). Compared to those with PARMs, patients with NPARMs were more likely to have premature birth (54.5% vs. 2.8%, p < 0.001) and lower birth weight (33.3% vs. 3.2%, p = 0.030), with statistical significance. The patients with PARMs were more likely to have cardiovascular defects (64.9% vs. 27.3%, p = 0.063), cerebral hemorrhage (29.7% vs. 9.1%, p = 0.322) and seizures (37.8% vs. 9.1%, p = 0.151) than those with NPARMs, with no statistical significance.
CONCLUSIONS: CCHS patients with PHOX2B NPARMs were more likely to have premature birth and low birth weight, while PHOX2B PARMs tended to be positively associated with the risk of cardiovascular defects, cerebral hemorrhage and seizures in Chinese population.