Congenital central hypoventilation syndrome (CCHS) is a rare cause of apnea and hypoventilation requiring long-term multidisciplinary care. In this article, we report the case of a two-month-old female child who presented with recurrent apnea and cyanosis, requiring long-term ventilation. After ruling out other common causes of apnea like sepsis, metabolic disorders, and neuromuscular disorders, a genetic study was done, which confirmed the diagnosis of CCHS. The child was discharged on home oxygen therapy, and the parents were counseled about genetic testing and informed about the prognosis and requirement for home ventilation therapy, as well as parental testing.

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.

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.

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.

Congenital central hypoventilation syndrome is a rare genetic disorder that affects control of breathing caused by variants in the paired-like homeobox 2B (PHOX2B) gene. During pregnancy, women with congenital central hypoventilation syndrome are at risk for hypoventilation and require frequent assessments of oxygenation and ventilation during wakefulness and sleep on their ventilator. This could potentially lead to adjustments in the ventilator settings or a change in the assisted ventilation modality. We report the case of a 31-year-old pregnant woman with congenital central hypoventilation syndrome and an implanted cardiac pacemaker who underwent prenatal genetic testing for congenital central hypoventilation syndrome and who delivered a healthy newborn by cesarean delivery. She received collaborative multidisciplinary care from a team that included specialists in obstetrics, maternal and fetal medicine, medical genetics, sleep and pulmonary medicine, cardiology, and anesthesiology. She used bilevel positive airway pressure therapy throughout pregnancy and after cesarean delivery without requiring adjustments in the bilevel positive airway pressure settings. Our case highlights the importance of multidisciplinary care in women with congenital central hypoventilation syndrome during pregnancy to optimize pregnancy and fetal outcomes.

Retrotrapezoid nucleus (RTN) neurons in the brainstem regulate the ventilatory response to hypercarbia. It is unclear how PHOX2B-polyalanine repeat mutations (PHOX2B-PARMs) alter the function of PHOX2B and perturb the formation of RTN neurons. Here, we generated human brainstem organoids (HBSOs) with RTN-like neurons from human pluripotent stem cells. Single-cell transcriptomics revealed that expression of PHOX2B+7Ala PARM alters the differentiation trajectories of the hindbrain neurons and hampers the formation of the RTN-like neurons in HBSOs. With the unguided cerebral organoids (HCOs), PHOX2B+7Ala PARM interrupted the patterning of PHOX2B+ neurons with dysregulation of Hedgehog pathway and HOX genes. With complementary use of HBSOs and HCOs with a patient and two mutant induced pluripotent stem cell lines carrying different polyalanine repetition in PHOX2B, we further defined the association between the length of polyalanine repetition and malformation of RTN-respiratory center and demonstrated the potential toxic gain of function of PHOX2B-PARMs, highlighting the uniqueness of these organoid models for disease modeling.

UNASSIGNED: Congenital central hypoventilation syndrome (CCHS), a rare disease caused by variants in the paired-like homeobox 2B (PHOX2B) gene, affects regulation of respiration necessitating lifelong assisted ventilation (AV). Most patients require full-time AV during infancy and some patients may sustain adequate spontaneous ventilation during wakefulness and change AV modalities at a later age. The aims of this study were to assess the changes in duration and modalities of AV, long-term respiratory outcomes, and to correlate them with PHOX2B genotypes.
UNASSIGNED: We conducted a retrospective study of patients with CCHS treated at our institution between January 1997 and May 2022. Results analyzed included: clinical presentation, PHOX2B genotype, modality and duration of AV at diagnosis and follow-up, survival, and transition to adult care.
UNASSIGNED: We identified 30 patients with CCHS-8 with PHOX2B nonpolyalanine repeat mutations (NPARMs), 21 with polyalanine repeat mutations (PARMs), and 1 with unknown PHOX2B genotype. The median age at presentation was 0.25 months (IQR 0.1-0.7 months). At diagnosis of CCHS, 24 (80%) patients required continuous AV and 28 (93%) received AV via tracheostomy. Twenty-six patients required sleep-only AV at a median age of 9 months (IQR 6-14 months). Nine patients requiring sleep-only AV underwent tracheostomy decannulation at a median age of 11.2 years (IQR 5.9-15.7 years) and used noninvasive positive pressure ventilation or diaphragm pacing. There was insufficient evidence to conclude that patients with PARMs and NPARMs differed by age at presentation (P = .39), tracheostomy (P = .06), and transition to sleep-only AV (P = .9). Six patients transitioned to adult care, 23 continued receiving pediatric care, and 1 patient died due to complications from Hirschsprung\'s disease.
UNASSIGNED: Our study demonstrates prolonged survival and good long-term respiratory outcomes possibly related to the early diagnosis of CCHS, optimizing AV strategies, and multidisciplinary care. The increasing number of patients attaining adulthood highlights the necessity for multidisciplinary care for adults with CCHS.

Congenital central hypoventilation syndrome is a rare disorder due to a mutation in the PHOX2B gene, characterized by a failure in autonomic control of breathing with diminished or absent response to hypoxia and hypercapnia, which is most pronounced during sleep. Most patients present from birth with central apneas and hypoventilation, or later in the setting of a physiologic stress. Recent literature in mice with a Phox2b27Ala/+ mutation suggests a predisposition to obstructive apneas likely due to hypoglossal dysgenesis. We report on three patients with obstructive sleep apneas with absent or mild hypoventilation. Our cases propose that obstructive apneas can be the primary presentation in patients who subsequently develop the classic phenotype of congenital central hypoventilation syndrome and emphasize their close monitoring and surveillance.
Kagan O, Zhang C, McElyea C, Keens TG, Davidson Ward SL, Perez IA. Obstructive sleep apnea as a presentation of congenital central hypoventilation syndrome. J Clin Sleep Med. 2023;19(9):1697-1700.