329 results on '"Hypoventilation congenital"'
Search Results
2. Congenital Central Hypoventilation Syndrome and Disorders of Control of Ventilation.
- Author
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Kasi AS and Perez IA
- Subjects
- Humans, Prader-Willi Syndrome physiopathology, Prader-Willi Syndrome therapy, Prader-Willi Syndrome complications, Prader-Willi Syndrome diagnosis, Infant, Newborn, Sleep Apnea, Central therapy, Sleep Apnea, Central physiopathology, Sleep Apnea, Central diagnosis, Hypoventilation congenital, Hypoventilation therapy, Hypoventilation physiopathology, Hypoventilation diagnosis
- Abstract
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., Competing Interests: Disclosure The authors report no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)
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- 2024
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3. Congenital central hypoventilation syndrome in korea: 20 years of clinical observation and evaluation of the ventilation strategy in a single center.
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Lee MJ, Park JS, Kim K, Ko JM, Park JD, and Suh DI
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- Humans, Female, Male, Retrospective Studies, Infant, Republic of Korea epidemiology, Child, Preschool, Transcription Factors genetics, Respiration, Artificial statistics & numerical data, Infant, Newborn, Child, Phenotype, Genotype, Mutation, Tracheostomy, Sleep Apnea, Central genetics, Sleep Apnea, Central therapy, Sleep Apnea, Central diagnosis, Hypoventilation congenital, Hypoventilation therapy, Hypoventilation genetics, Hypoventilation diagnosis, Homeodomain Proteins genetics
- Abstract
Congenital central hypoventilation syndrome (CCHS) is a rare genetic disorder characterized by hypoventilation due to impaired breathing control by the central nervous system and other symptoms of autonomic dysfunction. Mutations in paired-like homeobox 2 B (PHOX2B) are responsible for most cases of CCHS. Patients with CCHS have various phenotypes and severities, making the diagnosis difficult. This study aimed to present a comprehensive single-center experience of patients with CCHS, including key clinical features, treatment strategies, and outcomes. A retrospective chart review was performed for patients diagnosed with CCHS between January 2001 and July 2023 at Seoul National University Children's Hospital. Finally, we selected 24 patients and collected their demographic data, genotypes, ventilation methods, and clinical features related to autonomic dysfunction. The relationship between the clinical manifestations and genotypes was also examined. All patients used home ventilators, and tracheostomy was performed in 87.5% of patients. Fifteen (62.5%) patients had constipation and nine (37.5%) were diagnosed with Hirschsprung disease. Arrhythmia, endocrine dysfunction, and subclinical hypothyroidism were present in nine (37.5%), six patients (25.0%), and two patients (16.7%), respectively. A significant number of patients exhibited neurodevelopmental delays (19 patients, 79.2%). There was a correlation between the phenotype and genotype of PHOX2B in patients with CCHS. (r = 0.71, p < 0.001). Conclusion: There was a positive correlation between paired-like homeobox 2 B mutations (especially the number of GCN repeats in the polyalanine repeat mutations sequence) and clinical manifestations. This study also demonstrated how initial treatment for hypoventilation affects neurodevelopmental outcomes in patients with CCHS. What is Known: • Congenital central hypoventilation syndrome is a rare genetic disorder characterized by hypoventilation and dysfunction of autonomic nervous system. • The disease-defining gene of CCHS is PHOX2B gene - most of the cases have heterozygous PARMs and the number of GCN triplets varies among the patients(20/24 - 20/33). What is New: • We have noted in the Korean patients with CCHS that there is a correlation between genotype (number of GCN repeats) and severity of phenotype. • National support for rare diseases allowed for a prompter diagnosis of patients with CCHS in Korean population., (© 2024. The Author(s).)
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- 2024
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4. Autism spectrum disorder in young patients with congenital central hypoventilation syndrome: role of the autonomic nervous system dysfunction.
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Dudoignon B, Maruani A, Delorme R, Patout M, Fefeu M, Ellul P, Bokov P, and Delclaux C
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- Humans, Female, Male, Retrospective Studies, Adolescent, Child, Young Adult, Autonomic Nervous System Diseases physiopathology, Child, Preschool, Risk Factors, Autism Spectrum Disorder physiopathology, Hypoventilation congenital, Hypoventilation physiopathology, Sleep Apnea, Central physiopathology, Sleep Apnea, Central epidemiology, Autonomic Nervous System physiopathology
- Abstract
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., (© 2024. The Author(s).)
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- 2024
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5. Tracheostomy and inpatient outcomes among children with congenital central hypoventilation syndrome: A kids' inpatient database study.
- Author
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Tsou PY and Tapia IE
- Subjects
- Humans, Female, Male, Infant, Child, Child, Preschool, Adolescent, Risk Factors, Infant, Newborn, Hospitalization statistics & numerical data, Retrospective Studies, United States epidemiology, Tracheostomy statistics & numerical data, Sleep Apnea, Central epidemiology, Sleep Apnea, Central therapy, Sleep Apnea, Central complications, Hypoventilation congenital, Hypoventilation epidemiology, Hypoventilation therapy, Databases, Factual
- Abstract
Study Objectives: 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., (© 2024 Wiley Periodicals LLC.)
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- 2024
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6. Genetic identification of medullary neurons underlying congenital hypoventilation.
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Cui K, Xia Y, Patnaik A, Salivara A, Lowenstein ED, Isik EG, Knorz AL, Airaghi L, Crotti M, Garratt AN, Meng F, Schmitz D, Studer M, Rijli FM, Nothwang HG, Rost BR, Strauß U, and Hernandez-Miranda LR
- Subjects
- Animals, Mice, Sleep Apnea, Central genetics, Phenotype, Humans, Hypoventilation congenital, Hypoventilation genetics, Neurons metabolism, Homeodomain Proteins genetics, Homeodomain Proteins metabolism, Transcription Factors genetics, Transcription Factors metabolism, Medulla Oblongata metabolism
- Abstract
Mutations in the transcription factors encoded by PHOX2B or LBX1 correlate with congenital central hypoventilation disorders. These conditions are typically characterized by pronounced hypoventilation, central apnea, and diminished chemoreflexes, particularly to abnormally high levels of arterial PCO
2 . The dysfunctional neurons causing these respiratory disorders are largely unknown. Here, we show that distinct, and previously undescribed, sets of medullary neurons coexpressing both transcription factors (dB2 neurons) account for specific respiratory functions and phenotypes seen in congenital hypoventilation. By combining intersectional chemogenetics, intersectional labeling, lineage tracing, and conditional mutagenesis, we uncovered subgroups of dB2 neurons with key functions in (i) respiratory tidal volumes, (ii) the hypercarbic reflex, (iii) neonatal respiratory stability, and (iv) neonatal survival. These data provide functional evidence for the critical role of distinct medullary dB2 neurons in neonatal respiratory physiology. In summary, our work identifies distinct subgroups of dB2 neurons regulating breathing homeostasis, dysfunction of which causes respiratory phenotypes associated with congenital hypoventilation.- Published
- 2024
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7. Recurrence of CCHS-associated PHOX2B Poly-Alanine expansion variant due to paternal mosaicism.
- Author
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Jiang H, Ping Z, Li S, and Zhu J
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- Humans, Male, Female, Pregnancy, Mosaicism, Mutation, Alanine, Transcription Factors genetics, Fathers, Hypoventilation genetics, Hypoventilation congenital, Homeodomain Proteins genetics, Sleep Apnea, Central
- Abstract
Background: Paired-like Homeobox 2B (PHOX2B) is considered the causative gene of Congenital Central Hypoventilation Syndrome (CCHS), a dominant genetic disorder characterized by impaired central respiratory control and subsequent hypoventilation during sleep., Methods: Herein, we present a family with recurrent severe CCHS. The potential causative genetic variant was confirmed through Whole-Exome Sequencing (WES), Sanger sequencing, and droplet digital PCR (ddPCR). Furthermore, prenatal diagnosis was performed on the proband's mother at 20 weeks of her fourth pregnancy upon request., Results: The proband and her brother were both carriers of the PHOX2B polyalanine expansion variant: c.744_758dupCGCGGCAGCGGCGGCGGCGGC. Sanger sequencing revealed that the proband's father had a small variant peak in the gene position, implying potential somatic mosaicism. In addition, ddPCR results showed that the proband's father had germline mosaicism, with a mosaicism proportion of 14.3%. Notably, the detect p.(Ala241[26]) variant was not detected in the fetus., Conclusions: These findings have important implications for improving genetic counseling of CCHS families as they suggest that even parents without CCHS symptoms may have somatic chimerism, necessitating careful genetic counseling and consideration of prenatal testing for subsequent pregnancies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)
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- 2024
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8. Computer-aided diagnostic screen for Congenital Central Hypoventilation Syndrome with facial phenotype.
- Author
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Slattery SM, Wilkinson J, Mittal A, Zheng C, Easton N, Singh S, Baker JJ, Rand CM, Khaytin I, Stewart TM, Demeter D, and Weese-Mayer DE
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- Humans, Female, Male, Child, Child, Preschool, Diagnosis, Computer-Assisted methods, Principal Component Analysis, Adolescent, Machine Learning, Young Adult, Infant, Genotype, Photography, Case-Control Studies, Logistic Models, Homeodomain Proteins genetics, Phenotype, Transcription Factors genetics, Hypoventilation congenital, Hypoventilation diagnosis, Hypoventilation genetics, Face abnormalities, Sleep Apnea, Central diagnosis, Sleep Apnea, Central genetics
- Abstract
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., (© 2024. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)
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- 2024
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9. [Congenital Central Hypoventilation Syndrome: neonatal diagnosis and management].
- Author
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Valdés Carrillo M, Diaz Caamaño M, Prado Atlagic F, Huerta Armijo A, García Mora M, Hernandez Gómez A, and D Alessandri Demelchiore R
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- Humans, Infant, Newborn, Female, Noninvasive Ventilation, Continuous Positive Airway Pressure, Acidosis, Respiratory diagnosis, Acidosis, Respiratory therapy, Acidosis, Respiratory etiology, Mutation, Oxygen Inhalation Therapy, Sleep Apnea, Central diagnosis, Sleep Apnea, Central therapy, Sleep Apnea, Central genetics, Hypoventilation congenital, Hypoventilation therapy, Hypoventilation diagnosis, Hypoventilation genetics, Homeodomain Proteins genetics, Transcription Factors genetics
- Abstract
Congenital Central Hypoventilation Syndrome (CCHS) is a rare genetic condition affecting the autonomic nervous system and respiratory center due to mutations in the PHOX2B gene, and it is associated with alveolar hypoventilation during sleep and sudden death. It requires early invasive mechanical ventilation (IMV)., Objective: To report a neonatal case successfully treated with non-invasive ventilatory support (NVS), avoiding tracheostomy., Clinical Case: Full-term newborn, whose mother uses nocturnal NVS due to CCHS. During the transition period, she presented desaturations associated with hypercapnia and respiratory acidosis, without pulmonary involvement. She developed severe hypoventilation during sleep, with no respiratory effort, peripheral oxygen saturation (SpO2) < 80%, plus respiratory acidosis. While awake, she had good respiratory effort and normal SpO2 without assistance. Noninvasive continuous positive airway pressure and oxygen therapy worsened her condition while sleeping. Complete NVS with nasal interface and bi-level airway positive pressure, inspiratory/expiratory pressure 14-16/4 cm H2O, normalized SpO2 during sleep, and arterial blood gases while awake. Sequencing of the PHOX2B gene confirmed the presence of a heterozygous pathogenic variant with the 20/26 genotype. At 2 months of age, she was discharged maintaining NVS with nasal interface and 0 PEEP, achieving adequate neurodevelopment., Conclusion: We highlight the importance of genetic diagnosis of CCHS in neonates with clinical presentation of early alveolar hypoventilation, especially if there is a family history. We are not aware of other reports of neonatal onset in which NVS prevents IMV, in this potentially lethal pathology.
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- 2024
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10. Revolutionizing congenital central hypoventilation syndrome screening: the potential of machine learning approaches.
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Chen Q and Wang S
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- Humans, Infant, Newborn, Neonatal Screening methods, Machine Learning, Sleep Apnea, Central diagnosis, Hypoventilation congenital, Hypoventilation diagnosis
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- 2024
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11. PHOX2B: a diagnostic cornerstone in neurocristopathies and neuroblastomas.
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Windels ML, Cordier F, Van Dorpe J, Ferdinande L, and Creytens D
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- Humans, Sleep Apnea, Central diagnosis, Sleep Apnea, Central genetics, Biomarkers, Tumor genetics, Biomarkers, Tumor analysis, Hirschsprung Disease diagnosis, Hirschsprung Disease genetics, Hirschsprung Disease pathology, Mutation, Adrenal Gland Neoplasms genetics, Adrenal Gland Neoplasms diagnosis, Adrenal Gland Neoplasms pathology, Genetic Predisposition to Disease, Homeodomain Proteins genetics, Transcription Factors genetics, Hypoventilation congenital, Hypoventilation diagnosis, Hypoventilation genetics, Neuroblastoma diagnosis, Neuroblastoma genetics, Neuroblastoma pathology, Immunohistochemistry
- Abstract
Paired-like homeobox 2B ( PHOX2B ) is a gene essential in the development of the autonomic nervous system. PHOX2B mutations are associated with neurocristopathies-Hirschsprung disease (HSCR) and congenital central hypoventilation syndrome (CCHS)-and peripheral neuroblastic tumours. PHOXB2 plays an important role in the diagnostics of these conditions.Genotyping of a PHOX2B pathogenic variant is required to establish a diagnosis of CCHS. In HSCR patients, PHOX2B immunohistochemical staining has proven to be a valuable tool in identifying this disease. Furthermore, PHOXB2 is a predisposition gene for neuroblastoma, in which PHOX2B immunohistochemical staining can be used as a highly sensitive and specific diagnostic marker. The utility of PHOX2B immunohistochemistry in pheochromocytoma and paraganglioma has also been studied but yields conflicting results.In this review, an overview is given of PHOX2B , its associated diseases and the usefulness of PHOX2B immunohistochemistry as a diagnostic tool., Competing Interests: Competing interests: One of the coauthors (DC) is an editor for the Journal of Clinical Pathology. The other authors declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2024
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12. Knockdown of PHOX2B in the retrotrapezoid nucleus reduces the central CO 2 chemoreflex in rats.
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Cardani S, Janes TA, Betzner W, and Pagliardini S
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- Animals, Male, Rats, Chemoreceptor Cells metabolism, Gene Knockdown Techniques, Neurons metabolism, Neurons physiology, Sleep Apnea, Central genetics, Sleep Apnea, Central metabolism, Carbon Dioxide metabolism, Homeodomain Proteins genetics, Homeodomain Proteins metabolism, Hypoventilation genetics, Hypoventilation congenital, Hypoventilation metabolism, Transcription Factors genetics, Transcription Factors metabolism
- Abstract
PHOX2B is a transcription factor essential for the development of different classes of neurons in the central and peripheral nervous system. Heterozygous mutations in the PHOX2B coding region are responsible for the occurrence of Congenital Central Hypoventilation Syndrome (CCHS), a rare neurological disorder characterised by inadequate chemosensitivity and life-threatening sleep-related hypoventilation. Animal studies suggest that chemoreflex defects are caused in part by the improper development or function of PHOX2B expressing neurons in the retrotrapezoid nucleus (RTN), a central hub for CO
2 chemosensitivity. Although the function of PHOX2B in rodents during development is well established, its role in the adult respiratory network remains unknown. In this study, we investigated whether reduction in PHOX2B expression in chemosensitive neuromedin-B (NMB) expressing neurons in the RTN altered respiratory function. Four weeks following local RTN injection of a lentiviral vector expressing the short hairpin RNA (shRNA) targeting Phox2b mRNA, a reduction of PHOX2B expression was observed in Nmb neurons compared to both naive rats and rats injected with the non-target shRNA. PHOX2B knockdown did not affect breathing in room air or under hypoxia, but ventilation was significantly impaired during hypercapnia. PHOX2B knockdown did not alter Nmb expression but it was associated with reduced expression of both Task2 and Gpr4 , two CO2 /pH sensors in the RTN. We conclude that PHOX2B in the adult brain has an important role in CO2 chemoreception and reduced PHOX2B expression in CCHS beyond the developmental period may contribute to the impaired central chemoreflex function., Competing Interests: SC, TJ, WB, SP No competing interests declared, (© 2024, Cardani, Janes et al.)- Published
- 2024
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13. An unusual ophthalmologic finding in a patient with congenital central hypoventilation syndrome.
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Aguado-Casanova V, Pérez-García D, Orejudo-Rivas M, Ramiro-Millán P, Ibañez-Alperte J, Calvo-Simon C, and Remón L
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- Humans, Male, Homeodomain Proteins genetics, Infant, Newborn, Transcription Factors genetics, Strabismus diagnosis, Strabismus physiopathology, Hypoventilation congenital, Hypoventilation diagnosis, Hypoventilation genetics, Hypoventilation physiopathology, Blepharoptosis diagnosis, Blepharoptosis congenital, Blepharoptosis physiopathology, Sleep Apnea, Central diagnosis, Sleep Apnea, Central physiopathology, Sleep Apnea, Central genetics
- Abstract
Introduction: Congenital Central Hypoventilation Syndrome (CCHS) is a rare disease due to a severely impaired central control of breathing and dysfunction of the autonomic nervous system. Ophthalmologic abnormalities are common in patients with CCHS and include horizontal strabismus, pupil and iris abnormalities and ptosis. We report a unique case of CCHS in association with monocular elevation deficit (MED) in a boy diagnosed with CCHS at birth., Case Description: We report a case of a boy with a confirmed diagnosis of CCHS (complete sequencing of the paired-like homeobox 2b (PHOX2B) gene) after presenting little respiratory effort and cyanosis at birth. The ophthalmological examination shows an impaired elevation of the left eye, both in adduction and abduction, associated with mild and variable left ptosis. His mother has observed that the left eyelid elevates when the child feeds. A deviation in the primary gaze position or a chin-up position are not present. The funduscopic examination is normal. Given that deviation is limited to upgaze, the ptosis is mild and the patient's age, observation is decided., Conclusions: Ophthalmologic abnormalities are common in patients with CCHS and include horizontal strabismus, pupil and iris abnormalities and ptosis. To the best of our knowledge, this is the first report of MED in association with CCHS. Further studies are needed to determine if an association between MED and CCHS exists or is just a casual finding in this case., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
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- 2024
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14. Airway obstruction in two children with congenital central hypoventilation syndrome and review of the literature.
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Wolff R, Dudoignon B, Naudin J, Madani A, Delclaux C, Bokov P, and Dauger S
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- Animals, Child, Humans, Infant, Infant, Newborn, Mice, Homeodomain Proteins genetics, Mutation, Transcription Factors genetics, Airway Obstruction etiology, Hypoventilation congenital, Sleep Apnea, Central diagnosis, Sleep Apnea, Central genetics, Sleep Apnea, Central therapy, Sleep Apnea, Obstructive
- Abstract
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 Phox2b
27Ala/+ 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., Competing Interests: Declaration of competing interest The authors have no conflict of interest to disclose., (Copyright © 2024 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.)- Published
- 2024
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15. Congenital Central Hypoventilation Syndrome: The Singularity of A Successful Case.
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Barreto I, Fernandes Pedro I, Alves D, Pereira ML, and Moreira S
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- Humans, Mutation, Sleep Apnea, Central, Hypoventilation congenital
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- 2024
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16. Alternative low-populated conformations prompt phase transitions in polyalanine repeat expansions.
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Antón R, Treviño MÁ, Pantoja-Uceda D, Félix S, Babu M, Cabrita EJ, Zweckstetter M, Tinnefeld P, Vera AM, and Oroz J
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- Animals, Humans, Peptides genetics, Peptides chemistry, Hypoventilation genetics, Hypoventilation congenital, Mutation, Mammals metabolism, Homeodomain Proteins metabolism, Transcription Factors metabolism
- Abstract
Abnormal trinucleotide repeat expansions alter protein conformation causing malfunction and contribute to a significant number of incurable human diseases. Scarce structural insights available on disease-related homorepeat expansions hinder the design of effective therapeutics. Here, we present the dynamic structure of human PHOX2B C-terminal fragment, which contains the longest polyalanine segment known in mammals. The major α-helical conformation of the polyalanine tract is solely extended by polyalanine expansions in PHOX2B, which are responsible for most congenital central hypoventilation syndrome cases. However, polyalanine expansions in PHOX2B additionally promote nascent homorepeat conformations that trigger length-dependent phase transitions into solid condensates that capture wild-type PHOX2B. Remarkably, HSP70 and HSP90 chaperones specifically seize PHOX2B alternative conformations preventing phase transitions. The precise observation of emerging polymorphs in expanded PHOX2B postulates unbalanced phase transitions as distinct pathophysiological mechanisms in homorepeat expansion diseases, paving the way towards the search of therapeutics modulating biomolecular condensates in central hypoventilation syndrome., (© 2024. The Author(s).)
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- 2024
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17. Images: Atypical presentation of congenital central hypoventilation syndrome in an infant with central and obstructive sleep apnea.
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Fain ME, Raghunandan S, Pencheva B, Leu RM, and Kasi AS
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- Male, Infant, Humans, Hypoventilation complications, Hypoventilation genetics, Hypoventilation therapy, Sleep, Hypoventilation congenital, Sleep Apnea, Central complications, Sleep Apnea, Central genetics, Sleep Apnea, Central therapy, Sleep Apnea, Obstructive complications, Sleep Apnea, Obstructive therapy
- Abstract
Congenital central hypoventilation syndrome (CCHS), a rare disease caused by paired-like homeobox 2B variants, affects control of breathing. We report on a 21-month-old boy with CCHS caused by a novel nonpolyalanine repeat mutation, neuroblastoma, severe obstructive and central sleep apnea, and sleep-related hypoxemia without hypoventilation. At 10 months, due to persistent central sleep apnea during serial polysomnography, bilevel positive airway pressure therapy was initiated despite the absence of hypoventilation. Nonpolyalanine repeat mutations are associated with severe phenotypes requiring continuous assisted ventilation, Hirschsprung's disease, and neural crest tumors; however, our patient had a relatively milder respiratory phenotype requiring sleep-only assisted ventilation without tracheostomy. Although alveolar hypoventilation is the hallmark of CCHS, our patient lacked hypoventilation. Bilevel positive airway pressure could be considered in some infants with CCHS requiring sleep-only assisted ventilation for tracheostomy avoidance. Our case demonstrates the expanding phenotypic spectrum in CCHS and the importance of formulating an individualized care plan., Citation: Fain ME, Raghunandan S, Pencheva B, Leu RM, Kasi AS. Images: atypical presentation of congenital central hypoventilation syndrome in an infant with central and obstructive sleep apnea. J Clin Sleep Med . 2024;20(3):478-481., (© 2024 American Academy of Sleep Medicine.)
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- 2024
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18. Higher baseline heart rate variability in CCHS patients with progestin-associated recovery of hypercapnic ventilatory response.
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Sevoz-Couche C, Patout M, Charbit B, Similowski T, and Straus C
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- Humans, Female, Hypercapnia diagnosis, Hypercapnia drug therapy, Desogestrel therapeutic use, Heart Rate, Homeodomain Proteins therapeutic use, Progestins therapeutic use, Sleep Apnea, Central, Hypoventilation congenital
- Abstract
After a fortuitous observation of two cases of chemosensitivity recovery in women with congenital central hypoventilation syndrome (CCHS) who took desogestrel, we aimed to evaluate the ventilatory response to hypercapnia of five CCHS patients with or without treatment consisting of desogestrel (DESO) or levonorgestrel (LEVO). Only two patients became responsive to hypercapnia under treatment, according to their basal vagal heart rate variability. These results suggest that heart rate variability may be promising tool to discriminate patients susceptible to become responsive to hypercapnia under DESO-LEVO treatment.Clinical Trials Identifier NCT01243697., (© 2024. The Author(s).)
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- 2024
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19. Characteristics and outcomes in children with congenital central hypoventilation syndrome on long-term mechanical ventilation in the Netherlands.
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Evers-Bikker EE, de Weerd W, Wijkstra PJ, Corel L, Verweij LP, and Vosse BAH
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- Child, Infant, Newborn, Humans, Homeodomain Proteins genetics, Respiration, Artificial, Retrospective Studies, Netherlands, Transcription Factors genetics, Mutation, Hypoventilation genetics, Hypoventilation therapy, Hypoventilation congenital, Sleep Apnea, Central genetics, Sleep Apnea, Central therapy
- Abstract
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., Conclusion: 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., What Is Known: • The majority of CCHS patients are dependent on ventilatory support. • Variants in the PHOX2B gene are responsible for the characteristics of CCHS., What Is New: • 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., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
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- 2024
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20. [Study of GCN repeats of PHOX2B gene among individuals from southwest China and diagnosis of two patients with Congenital central hypoventilation syndrome].
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Qin S, Ye M, Yin Y, Wang J, Wang X, Zhang Z, Chen X, Yan M, He Y, Yi D, and Deng Q
- Subjects
- Humans, Infant, Newborn, Homeodomain Proteins genetics, Hypoventilation diagnosis, Hypoventilation genetics, Hypoventilation congenital, Mutation, Sleep Apnea, Central diagnosis, Sleep Apnea, Central genetics, Transcription Factors genetics
- Abstract
Objective: To study the trinucleotide repeats of GCN (GCA, GCT, GCC, GCG) encoding Alanine in exon 3 of the PHOX2B gene among healthy individuals from southwest China and two patients with Congenital central hypoventilation syndrome (CCHS)., Methods: The number and sequence of the GCN repeats of the PHOX2B gene were analyzed by capillary electrophoresis, Sanger sequencing and cloning sequencing of 518 healthy individuals and two newborns with CCHS, respectively., Results: Among the 1036 alleles of the 518 healthy individuals, five alleles were identified, including (GCN)
7 , (GCN)13 , (GCN)14 , (GCN)15 and (GCN)20 . The frequency of the (GCN)20 allele was the highest (94.79%). And five genotypes were identified, which included (GCN)7 /(GCN)20 , (GCN)13/ (GCN)20 , (GCN)14 /(GCN)20 , (GCN)15 /(GCN)20 , (GCN)20 /(GCN)20 . The homozygous genotypes were all (GCN)20 /(GCN)20 , and the carrier rate was 89.58%. Four GCN sequences of the (GCN)20 homozygous genotypes were identified among the 464 healthy individuals. The GCN repeat numbers in the exon 3 of the PHOX2B gene showed no significant difference between the expected and observed values, and had fulfilled the,Hardy-Weinberg equilibrium. The genotypes of the two CCHS patients were (GCN)20 /(GCN)25 and (GCN)20 /(GCN)30 , respectively., Conclusion: It is important to determine the GCN repeats and genotypic data of the exon 3 of the PHOX2B gene among the healthy individuals. The number of GCN repeats in 518 healthy individuals was all below 20. The selection of appropriate methods can accurately detect the polyalanine repeat mutations (PARMs) of the PHOX2B gene, which is conducive to the early diagnosis, intervention and treatment of CCHS.- Published
- 2024
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21. [Research advances on late-onset congenital central hypoventilation syndrome].
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Yang Q and Zheng YJ
- Subjects
- Humans, Hypoventilation genetics, Hypoventilation therapy, Hypoventilation congenital, Homeodomain Proteins, Sleep Apnea, Central diagnosis, Sleep Apnea, Central genetics, Sleep Apnea, Central therapy
- Published
- 2024
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22. Early diagnosis of congenital central hypoventilation syndrome.
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Miyosawa Y, Nakamura C, Fujimori M, and Kamiya M
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- Humans, Infant, Newborn, Male, Female, Hypoventilation congenital, Hypoventilation diagnosis, Sleep Apnea, Central diagnosis, Early Diagnosis
- Published
- 2024
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23. Volume assured pressure support mode use for non-invasive ventilation in pediatrics.
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Cithiravel N, Xiao L, Shi J, Chiang J, and Amin R
- Subjects
- Adult, Humans, Child, Respiration, Artificial, Positive-Pressure Respiration, Hypoventilation congenital, Noninvasive Ventilation, Sleep Apnea, Central
- Abstract
There has been increasing interest in utilizing volume assured pressure support (VAPS) modes of ventilation for children, which historically had only been favored in adult populations. In addition to patients with obesity hypoventilation syndrome, newer pediatric populations for which it has recently been prescribed include congenital central hypoventilation syndrome and children with neuromuscular disease such as Duchenne muscular dystrophy and spinal muscular atrophy. Given its expanding use in pediatrics, greater familiarity with VAPS is essential for pediatric pulmonologists and sleep physicians. This review article will highlight methods of initiation for this mode, specific ventilator settings, discussion of suitable pediatric patient populations, ventilator titrations via formal polysomnograms and detailed ventilator data downloads specific interpretation. Finally, common challenges to be aware of and how to troubleshoot relevant machine alarms will be reviewed., (© 2023 Wiley Periodicals LLC.)
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- 2024
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24. Obstructive sleep apnea as a presentation of congenital central hypoventilation syndrome.
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Kagan O, Zhang C, McElyea C, Keens TG, Davidson Ward SL, and Perez IA
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- Humans, Male, Female, Polysomnography, Infant, Homeodomain Proteins genetics, Transcription Factors, Sleep Apnea, Central genetics, Sleep Apnea, Central diagnosis, Sleep Apnea, Central complications, Sleep Apnea, Central physiopathology, Hypoventilation congenital, Hypoventilation genetics, Hypoventilation complications, Hypoventilation diagnosis, Sleep Apnea, Obstructive diagnosis, Sleep Apnea, Obstructive genetics
- Abstract
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., Citation: 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., (© 2023 American Academy of Sleep Medicine.)
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- 2023
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25. [Two children with late-onset congenital central hypoventilation syndrome].
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Qiu S, Yang L, Zhong J, Luo X, and Liu D
- Subjects
- Humans, Child, Male, Female, Infant, Respiration, Artificial, Hypoventilation therapy, Hypoventilation congenital, Oxygen, Sleep Apnea, Central therapy
- Abstract
Two children with late-onset congenital central hypoventilation syndrome were reported, one of whom was male and had no abnormal manifestations after birth, respiratory failure occurs at the age of 1 year and 6 months. After being hospitalized, he was treated with oxygen inhalation and non-invasive ventilation, but carbon dioxide retention could not be corrected. After one month of tracheal intubation, he was failure to wean from ventilator, so tracheostomy was performed. He needs a ventilator to help breath while sleeping, and can breath autonomously during the day without ventilator. The other case was a female, with no abnormalities after birth. At the age of 11 months, she developed respiratory failure. During sleep, the child needs non-invasive assisted ventilation through a nasal mask, and during the day, she breathed autonomously.Two patients were followed up forever 2 years and their growth and development were normal., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Editorial Department of Journal of Clinical Otorhinolaryngology Head and Neck Surgery.)
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- 2023
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26. Central CO 2 chemosensitivity and CO 2 controller gain independently contribute to daytime Pco 2 in young subjects with congenital central hypoventilation syndrome.
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Bokov P, Dudoignon B, Patout M, Matrot B, Gallego J, and Delclaux C
- Subjects
- Female, Humans, Hypoventilation congenital, Hypoventilation genetics, Respiration, Carbon Dioxide, Sleep Apnea, Central
- Abstract
Whether peripheral chemoreceptor response is altered in congenital central hypoventilation syndrome (CCHS) remains debated. Our aim was to prospectively evaluate both peripheral and central CO
2 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.- Published
- 2023
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27. Neurogenic hypertension characterizes children with congenital central hypoventilation syndrome and is aggravated by alveolar hypoventilation during sleep.
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Dudoignon B, Bokov P, Couque N, Denjoy I, Matrot B, and Delclaux C
- Subjects
- Child, Female, Humans, Blood Pressure Monitoring, Ambulatory, Case-Control Studies, Longitudinal Studies, Retrospective Studies, Sleep physiology, Male, Child, Preschool, Adolescent, Hypertension complications, Hypoventilation congenital
- Abstract
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., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)
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- 2023
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28. Neurocognition as a biomarker in the rare autonomic disorders of CCHS and ROHHAD.
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Zelko FA, Welbel RZ, Rand CM, Stewart T, Fadl-Alla A, Khaytin I, Slattery SM, and Weese-Mayer DE
- Subjects
- Humans, Child, Child, Preschool, Hypoventilation diagnosis, Hypoventilation congenital, Hypoventilation genetics, Obesity, Biomarkers, Sleep Apnea, Central genetics, Sleep Apnea, Central psychology, Autonomic Nervous System Diseases
- Abstract
Purpose: Congenital central hypoventilation syndrome (CCHS) and rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) are rare disorders of autonomic regulation with risk for disrupted neurocognitive development. Our aim is to summarize research on neurocognitive outcomes in these conditions, advance understanding of how to best support these individuals throughout development, and facilitate future research., Methods: We conducted a narrative review of literature on neurocognitive outcomes in CCHS and ROHHAD, supplemented with previously unpublished data from patients with CCHS and ROHHAD at our Center for Autonomic Medicine in Pediatrics (CAMP)., Results: Individuals with CCHS and ROHHAD experience a wide range of neurocognitive functioning ranging from above average to below average, but are at particular risk for difficulties with working memory, processing speed, perceptual reasoning, and visuographic skills. An assessment framework emphasizing fluid cognition seems especially appropriate for these conditions. Owing to small cohorts and varied methods of data collection, it has been difficult to identify associations between disease factors (including CCHS PHOX2B genotypes) and cognitive outcomes. However, results suggest that early childhood is a period of particular vulnerability, perhaps due to the disruptive impact of recurrent intermittent hypoxic episodes on brain and cognitive development., Conclusion: Neurocognitive monitoring is recommended as a component of routine clinical care in CCHS and ROHHAD as a marker of disease status and to ensure that educational support and disability accommodations are provided as early as possible. Collaborative efforts will be essential to obtain samples needed to enhance our understanding of neurocognitive outcomes in CCHS and ROHHAD., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)
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- 2023
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29. Decannulation in congenital central hypoventilation syndrome.
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Ghelab Z, Bokov P, Teissier N, Micaelli D, Patout M, Hayotte A, Dauger S, Delclaux C, and Dudoignon B
- Subjects
- Child, Humans, Hypoventilation therapy, Hypoventilation congenital, Positive-Pressure Respiration methods, Tracheostomy, Retrospective Studies, Respiration, Artificial methods, Sleep Apnea, Central therapy
- Abstract
Rationale: Patients with congenital central hypoventilation syndrome (CCHS) require long-term ventilation to ensure gas exchange and to prevent deleterious consequences for neurocognitive development. Two ventilation modes may be used for these patients depending on their tolerance, one invasive by tracheostomy and the other noninvasive (NIV). For patients who have undergone a tracheostomy, transition to NIV is possible when they meet predefined criteria. Identifying the conditions favorable for weaning from a tracheostomy is critical for the success of the process., Objective: The aim of the study was to share our experience of decannulation in a reference center; we hereby describe the modality of ventilation and its effect on nocturnal gas exchange before and after tracheostomy removal., Methods: Retrospective observational study at Robert Debré Hospital over the past 10 years. The modalities of decannulation and transcutaneous carbon dioxide recordings or polysomnographies before and after decannulation were collected., Results: Sixteen patients underwent decannulation following a specific procedure for transition from invasive to NIV. All decannulations were successful. The median age at decannulation was 12.6 [9.4; 14.1] years. Nocturnal gas exchange was not significantly different before and after decannulation, while expiratory positive airway pressure and inspiratory time increased significantly. An oronasal interface was chosen in two out of three patients. The median duration of hospital stay for decannulation was 4.0 [3.8; 6.0] days., Conclusion: Our study underlines that decannulation and transition to NIV are achievable in CCHS children using a well-defined procedure. Patient preparation is crucial to the success of the process., (© 2023 Wiley Periodicals LLC.)
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- 2023
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30. phox2ba: The Potential Genetic Link behind the Overlap in the Symptomatology between CHARGE and Central Congenital Hypoventilation Syndromes.
- Author
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MacLean JE, Wertman JN, Prykhozhij SV, Chedrawe E, Langley S, Steele SL, Ban K, Blake K, and Berman JN
- Subjects
- Animals, Hypoventilation genetics, Hypoventilation congenital, Transcription Factors genetics, Transcription Factors metabolism, CHARGE Syndrome genetics, Zebrafish genetics, Zebrafish metabolism, Zebrafish Proteins genetics, Zebrafish Proteins metabolism
- Abstract
CHARGE syndrome typically results from mutations in the gene encoding chromodomain helicase DNA-binding protein 7 ( CHD7 ). CHD7 is involved in regulating neural crest development, which gives rise to tissues of the skull/face and the autonomic nervous system (ANS). Individuals with CHARGE syndrome are frequently born with anomalies requiring multiple surgeries and often experience adverse events post-anesthesia, including oxygen desaturations, decreased respiratory rates, and heart rate abnormalities. Central congenital hypoventilation syndrome (CCHS) affects ANS components that regulate breathing. Its hallmark feature is hypoventilation during sleep, clinically resembling observations in anesthetized CHARGE patients. Loss of PHOX2B (paired-like homeobox 2b) underlies CCHS. Employing a chd7 -null zebrafish model, we investigated physiologic responses to anesthesia and compared these to loss of phox2b . Heart rates were lower in chd7 mutants compared to the wild-type. Exposure to tricaine, a zebrafish anesthetic/muscle relaxant, revealed that chd7 mutants took longer to become anesthetized, with higher respiratory rates during recovery. chd7 mutant larvae demonstrated unique phox2ba expression patterns. The knockdown of phox2ba reduced larval heart rates similar to chd7 mutants. chd7 mutant fish are a valuable preclinical model to investigate anesthesia in CHARGE syndrome and reveal a novel functional link between CHARGE syndrome and CCHS.
- Published
- 2023
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31. Perioperative outcomes and the effects of anesthesia in congenital central hypoventilation patients.
- Author
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Chang GY, Salazar T, Karnwal A, Kun SS, Ellashek J, Shin CE, McComb JG, Keens TG, and Perez IA
- Subjects
- Humans, Female, Child, Preschool, Child, Adolescent, Male, Retrospective Studies, Hypoxia complications, Anesthesia, General, Homeodomain Proteins genetics, Hypoventilation congenital, Sleep Apnea, Central
- Abstract
Purpose: Patients with congenital central hypoventilation syndrome (CCHS) have autonomic dysfunction and lack ventilatory responses to hypoxemia and hypercarbia and thus are prone to adverse events during general anesthesia. The objective of this study was to describe the perioperative outcomes of patients with CCHS who were undergoing diaphragm pacer (DP) implantation surgeries under general anesthesia., Methods: A retrospective cohort study was conducted on patients with CCHS who underwent DP implantation surgeries at CHLA between January 2000 and May 2016. Charts were reviewed for demographics, PHOX2B genotype, ventilatory support, comorbidities, anesthesia administered, and perioperative courses., Results: Of 19 patients with CCHS (58% female) mean age at surgeries was 8.6 ± 5.8 years. Seventeen patients were ventilator-dependent during sleep only; two were ventilator dependent 24 h per day. Mean surgery duration was 3.1 ± 0.5 h. Seventeen patients were extubated to PPV via tracheostomy in the OR. Two patients were extubated to NPPV on postoperative day (POD) 1. Mean transition time to home ventilator or NPPV was 3.0 ± 2.2 days, and mean hospital stay was 5.0 ± 2.1 days. One patient premedicated without ventilatory support developed hypoxemia and hypoventilation. Ten patients (52%) had intraoperative events such as bradycardia, hypotension, significant hypoxemia, and bronchospasm. Fifteen patients had postoperative events. Hypoxemia, pneumonia, and atelectasis accounted for most of perioperative complications. One patient experienced seizure on POD 2 due to hypercarbia., Conclusion: Patients with CCHS are vulnerable to the cardiorespiratory effects of sedative and anesthetic agents. Therefore, they require vigilant monitoring and optimal ventilatory support in the perioperative period., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)
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- 2023
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32. Sleep disturbances in parental caregivers and patients with congenital central hypoventilation syndrome.
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Finch CE, Leu RM, Harford KL, Westbrook AL, and Kasi AS
- Subjects
- Child, Humans, Caregivers, Hypoventilation congenital, Transcription Factors genetics, Parents, Sleep, Homeodomain Proteins genetics, Mutation, Sleep Apnea, Central genetics, Sleep Wake Disorders
- Abstract
Study Objectives: Congenital central hypoventilation syndrome (CCHS) is a rare disease characterized by impaired control of breathing caused by paired-like homeobox 2B ( PHOX2B ) gene variants, necessitating lifelong assisted ventilation (AV). This study aimed to assess sleep quality in patients with CCHS and their parents using sleep questionnaires., Methods: Parents of patients with CCHS completed the Pittsburgh Sleep Quality Index (PSQI) regarding their sleep and the Sleep Disturbance Scale for Children (SDSC) regarding their child's sleep., Results: Twenty participants completed the questionnaires. The median (interquartile range) ages of the parents and patients were 41.5 (38.5-51.5) and 11.5 (7.4-16.7) years, respectively. The median (interquartile range) PSQI and SDSC scores were elevated at 6.5 (4-10) and 41.5 (34-51.5), respectively, suggesting that parents and patients with CCHS can experience sleep disturbances and poor sleep quality. There were no significant differences in SDSC ( P = 1.0) and PSQI ( P = .76) scores for AV with or without tracheostomy. Similarly, there were no significant differences in SDSC ( P = .22) and PSQI ( P = .34) scores based on PHOX2B genotypes. There was a moderately strong, significant, and positive correlation between the CCHS SDSC scores and parental PSQI scores ( r = .48, P = .03), suggesting that sleep disturbances in patients with CCHS were associated with poor parental sleep quality. There was no difference in the median parental sleep duration between those with and without nighttime home nursing ( P = .09)., Conclusions: Patients with CCHS and their parents are at risk for sleep disturbances regardless of their AV modality and PHOX2B genotype. In addition to AV management, patients with CCHS and their parents should be assessed for sleep disturbances., Citation: Finch CE, Leu RM, Harford K-L, Westbrook AL, Kasi AS. Sleep disturbances in parental caregivers and patients with congenital central hypoventilation syndrome. J Clin Sleep Med . 2023;19(3):549-554., (© 2023 American Academy of Sleep Medicine.)
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- 2023
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33. Effect of Facemask in Congenital Central Hypoventilation Syndrome.
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Dudoignon B, Patout M, Couque N, Delclaux C, and Bokov P
- Subjects
- Male, Humans, Adolescent, Masks, Pandemics, Hypercapnia therapy, Homeodomain Proteins genetics, Hypoventilation therapy, Hypoventilation congenital, Sleep Apnea, Central therapy
- Abstract
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., (© 2023 S. Karger AG, Basel.)
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- 2023
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34. Long-term home mechanical ventilation using a noninvasive ventilator via tracheotomy in patients with myasthenia gravis: a case report and literature review.
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Liu Y, Li T, and Shi L
- Subjects
- Male, Humans, Aged, 80 and over, Respiration, Artificial, Tracheostomy adverse effects, Tracheotomy, Apnea, Ventilators, Mechanical, Hypoventilation congenital, Cyanosis, Noninvasive Ventilation adverse effects, Pulmonary Disease, Chronic Obstructive, Myasthenia Gravis diagnosis, Myasthenia Gravis therapy
- Abstract
Neuromuscular diseases (NMD) are indications for long-term home mechanical ventilation (HMV). Noninvasive ventilation is preferred to HMV. However, invasive mechanical ventilation (IMV) is more appropriate if the patient has uncontrollable airway secretions, the possibility of aspiration, failure to wean, or severe weakness of the respiratory muscles. But if the patient undergoes multiple intubation or tracheotomy, it will be more painful and unbearable. For some end-stage NMD patients who need long-term tracheostomy, HMV using noninvasive ventilator via tracheotomy may be a conservative care option. An 87-year-old male with myasthenia gravis underwent repeated IMV and failed to wean. We used a noninvasive ventilator connected to a tracheostomy tube for mechanical ventilation. One and a half years later, the patient weaned successfully. However, there was a lack of evidence-based medicine and standardized guidelines in such areas as indications, contraindications, and ventilator parameter setting. For the systematic review, a literature search was performed in PubMed, Embase, Cochrane, and CNKI (China National Knowledge Infrastructure) to identify reported cases of using noninvasive ventilator in patients undergoing tracheostomy. A total of 72 cases who performed ventilation via tracheotomy tube were identified. The main diagnoses included NMD, chronic obstructive pulmonary disease (COPD), pneumonia, and congenital central hypoventilation syndrome (CCHS). Indications included dysfunctional ventilatory weaning response (DVWR), apnea and cyanosis. Clinical outcome was as follows: 33 patients were weaned, and 24 patients underwent HMV. A total of 288 cases who performed ventilation through the mask after blocking the tracheostomy tube were identified. The primary diagnoses included COPD, NMD, thoracic restriction, spinal cord injured (SCI), and CCHS. Indications included DVWR, apnea and cyanosis, routine weaning. Clinical outcome was as follows: successful tracheostomy tube decannulations were performed in 254 patients and failed in 33 patients. So, in patients requiring HMV, selection of noninvasive ventilation (NIV) or IMV should be individualized. Tracheostomy preservation should be considered in some patients with advanced NMD if there is respiratory muscle weakness or the risk of aspiration. And attempts can be made to use a noninvasive ventilator because of its advantages of portability, ease of operation, and low cost. Noninvasive ventilators can be used in patients with tracheotomy, whether direct connection tracheotomy or mask ventilation after the tube is capped, especially in weaning and tracheostomy tube decannulation.
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- 2023
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35. Neurocognitive monitoring in congenital central hypoventilation syndrome with the NIH Toolbox®.
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Welbel RZ, Rand CM, Zhou A, Fadl-Alla A, Chen ML, Weese-Mayer DE, and Zelko FA
- Subjects
- Homeodomain Proteins genetics, Humans, Mutation, Transcription Factors genetics, Hypoventilation congenital, Hypoventilation diagnosis, Hypoventilation psychology, Mental Status and Dementia Tests, Sleep Apnea, Central diagnosis, Sleep Apnea, Central psychology
- Abstract
Congenital central hypoventilation syndrome (CCHS) is a rare neurocristopathy, caused by mutations in the paired-like homeobox gene PHOX2B, which alters control of breathing and autonomic nervous system regulation, necessitating artificial ventilation as life-support. A broad range of neurocognitive performance has been reported in CCHS, including an array of cognitive deficits. We administered the NIH Toolbox® Cognition Battery (NTCB), a novel technology comprised of seven tasks presented via an interactive computer tablet application, to a CCHS cohort and studied its convergent and divergent validity relative to traditional clinical neurocognitive measures. The NTCB was administered to 51 CCHS participants, including a subcohort of 24 who also received traditional clinical neurocognitive testing (Wechsler Intelligence Scales). Age-corrected NTCB scores from the overall sample and subcohort were compared to population norms. Associations between NTCB indices and Wechsler Intelligence scores were studied to determine the convergent and divergent validity of the NTCB. NTCB test results indicated reduced Fluid Cognition, which measures new learning and speeded information processing (p < 0.001), but intact Crystallized Cognition, which measures past learning, in CCHS relative to population norms. Moderate to strong associations (r > 0.60) were found between age-corrected NTCB Fluid and Crystallized indices and comparable Wechsler indices, supporting the convergent and discriminant validity of the NTCB. Results reveal deficits of Fluid Cognition in individuals with CCHS and indicate that the NTCB is a valid and sensitive measure of cognitive outcomes in this population. Our findings suggest that the NTCB may play a useful role in tracking neurocognition in CCHS., (© 2022 The Authors. Pediatric Pulmonology published by Wiley Periodicals LLC.)
- Published
- 2022
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36. Children with Congenital Central Hypoventilation Syndrome Do Not Wake up to Ventilator Alarms.
- Author
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Mathur S, Laifman E, Keens TG, Kun S, Ward SLD, and Perez IA
- Subjects
- Adolescent, Child, Child, Preschool, Female, Homeodomain Proteins, Humans, Male, Respiration, Artificial, Transcription Factors, Ventilators, Mechanical, Hypoventilation congenital, Sleep Apnea, Central
- Abstract
Purpose: Congenital Central Hypoventilation Syndrome (CCHS) requires lifelong ventilatory support during sleep. Subjects with CCHS are vulnerable to sleep disturbances associated with treatments, monitoring alarms, and care they receive. We hypothesized that sleep would be disrupted in patients with CCHS due to ventilatory support and other treatments at night., Methods: An anonymous survey of patients with CCHS, age up to 17 years was conducted through REDCAP. Subjects were recruited in person, by flyer, email, and social media. Data collected included demographics, PHOX2B genotype, ventilatory support, treatments, nursing, and sleep parameters., Results: We received 23 responses (35% female, 8.1 years ± 5.6). PHOX2B genotypes were 20/24 PARM (2), 20/25 PARM (4), 20/26 PARM (2), 20/27 PARM (9), ≥ 20/28 PARM (2), and NPARM (2). Two subjects did not indicate the PHOX2B genotype. 13/23 were ventilated by PPV via tracheostomy, 7 by NIPPV, 2 by diaphragm pacing, and 1 did not indicate. Additional treatments received at night included suctioning (9), aerosol (1), G-tube feeding (2), and none (11). Only 9 received nursing at night. 13 used pulse oximetry for monitoring, and 9 used both pulse oximetry and end tidal CO
2 monitor. 17/23 rarely woke up due to ventilator or monitor alarms. 11/23 usually or sometimes woke up at least once a night; only 2/11 woke up due to alarms. 5/17 who rarely woke up to the alarms had night nursing., Conclusion: Most subjects with CCHS did not awaken to ventilator or monitoring alarms and a majority of these patients did not have nighttime nursing. (Mathur et al. in Sleep 43(Supplement_1):A333, 2020)., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)- Published
- 2022
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37. A novel case of central hypoventilation syndrome or just heavy breathing?
- Author
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McCoy J, Karp N, Brar J, Amin R, and St-Laurent A
- Subjects
- Child, Humans, Hypoventilation congenital, Hypoventilation diagnosis, Hypoventilation genetics, Respiration, Obesity Hypoventilation Syndrome diagnosis, Obesity Hypoventilation Syndrome genetics, Obesity Hypoventilation Syndrome therapy, Sleep Apnea Syndromes, Sleep Apnea, Central diagnosis, Sleep Apnea, Central genetics
- Abstract
With the growing prevalence of obesity in the pediatric population, reports of its severe complications are increasing. Obesity hypoventilation syndrome is an uncommon disorder in children with altered respiratory mechanics, sleep-disordered breathing, and impaired ventilatory responses leading to persistent hypercapnia. Presentation is varied, and children may remain relatively asymptomatic until challenged with a respiratory infection, when they may present with acute respiratory failure. With increasing use of genetic testing in pediatric patients, our knowledge of potential contributors to hypoventilation syndromes is growing. Although mutations in the paired-like homeobox 2B gene are known to be causative of congenital central hypoventilation syndrome, other genes may also contribute to hypoventilation phenotypes. We report one of the youngest reported patients with obesity hypoventilation syndrome in pediatrics, with a proposed congenital predisposition for central hypoventilation derived from a deletion in the brain-derived neurotrophic factor gene., Citation: McCoy J, Karp N, Brar J, Amin R, St-Laurent A. A novel case of central hypoventilation syndrome or just heavy breathing? J Clin Sleep Med. 2022;18(9):2321-2325., (© 2022 American Academy of Sleep Medicine.)
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- 2022
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38. Sonographic findings of total colonic aganglionosis in a neonate with Haddad syndrome: A case report.
- Author
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Lim YJ and Jung HK
- Subjects
- Humans, Hypoventilation congenital, Hypoventilation diagnosis, Infant, Newborn, Meconium, Hirschsprung Disease complications, Hirschsprung Disease diagnostic imaging, Sleep Apnea, Central diagnosis
- Abstract
Haddad syndrome is a rare congenital disorder characterized by congenital central hypoventilation syndrome and Hirschsprung disease. Total colonic aganglionosis is a rare and long-segment form of Hirschsprung disease, which is primarily diagnosed using contrast enemas. However, the diagnostic performance of contrast enemas is relatively low, making the diagnosis of total colonic aganglionosis challenging. In neonates, ultrasound may be used as an additional imaging modality for the diagnosis of Hirschsprung disease. We describe the unique sonographic findings of total colonic aganglionosis in a term neonate with failure to pass meconium and respiratory distress, who was subsequently diagnosed with Haddad syndrome., (© 2022 Wiley Periodicals LLC.)
- Published
- 2022
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39. Impaired ventilation during 6-min walk test in congenital central hypoventilation syndrome.
- Author
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Ghosh RN, Guglani L, Westbrook AL, Mao CY, Bai S, Keens TG, and Kasi AS
- Subjects
- Adolescent, Child, Cross-Sectional Studies, Homeodomain Proteins genetics, Humans, Hypercapnia, Hypoxia, Mutation, Transcription Factors genetics, Walk Test, Hypoventilation congenital, Sleep Apnea, Central diagnosis, Sleep Apnea, Central genetics
- Abstract
Background: Patients with congenital central hypoventilation syndrome (CCHS) can develop hypoxemia and hypercapnia during exercise. However, there is limited literature on cardiorespiratory responses during submaximal exercise and their correlation with paired-like homeobox 2B (PHOX2B) genotype., Objectives: To assess oxygen saturation (SpO
2 ), end-tidal carbon dioxide (ETCO2 ), heart rate (HR), and 6-min walk distance (6MWD) during a 6-min walk test (6MWT) in CCHS subjects and to correlate them with PHOX2B genotypes and assisted ventilation (AV) via tracheostomy., Methods: In this cross-sectional study, subjects with CCHS performed 6MWT with continuous pulse oximetry, HR, and capnography recorded before and during the 6MWT. Medical records were reviewed for PHOX2B genotype and phenotype data. Patients were categorized based on PHOX2B genotype and AV via tracheostomy., Results: Fifteen subjects aged 10.5 (interquartile range 7.9-16.2) years completed the 6MWT. Nine subjects used AV via tracheostomy. Seven (47%) subjects developed hypoxemia (SpO2 ≤ 90%, n = 7) and hypoventilation (ETCO2 ≥ 50 mmHg, n = 3) during the 6MWT. There was a significant decline from baseline SpO2 , increase from baseline ETCO2 , and increase in HR during the 6MWT (all p < 0.05). Subjects had decreased median percent predicted 6MWD (59.7% [50.6%-62.5%]). Nadir SpO2 (p = 0.029) and peak ETCO2 (p = 0.046) differed significantly between PHOX2B genotype groups but 6MWD did not (p = 0.8)., Conclusion: Despite normal oxygenation and ventilation at rest and during sleep on AV, patients with CCHS can develop hypoxemia and hypercapnia during submaximal exercise. Our study highlights the importance of assessing ventilatory responses during submaximal exercise in patients with CCHS regardless of their PHOX2B genotype., (© 2022 Wiley Periodicals LLC.)- Published
- 2022
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40. Diaphragm pacing in congenital central hypoventilation syndrome: A safe and final tool.
- Author
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Alibrahim O and Esquinas AM
- Subjects
- Humans, Hypoventilation congenital, Hypoventilation therapy, Diaphragm, Sleep Apnea, Central therapy
- Published
- 2022
- Full Text
- View/download PDF
41. Strategy of changing from tracheostomy and non-invasive mechanical ventilation to diaphragm pacing in children with congenital central hypoventilation syndrome.
- Author
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Tsolakis N, Sindelar R, Markström A, Nilsson P, and Jonzon A
- Subjects
- Child, Humans, Hypoventilation congenital, Hypoventilation therapy, Respiration, Artificial, Tracheostomy, Diaphragm, Sleep Apnea, Central therapy
- Published
- 2022
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42. Applying diaphragm pacing in previously tracheostomised children with congenital central hypoventilation syndrome is a safe tool.
- Author
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Tsolakis N, Sindelar R, Markström A, Nilsson P, and Jonzon A
- Subjects
- Child, Humans, Hypoventilation congenital, Hypoventilation therapy, Diaphragm, Sleep Apnea, Central congenital, Sleep Apnea, Central therapy
- Published
- 2022
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- View/download PDF
43. Generation of two hiPSC lines (UMILi027-A and UMILi028-A) from early and late-onset Congenital Central hypoventilation Syndrome (CCHS) patients carrying a polyalanine expansion mutation in the PHOX2B gene.
- Author
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Cuadros Gamboa AL, Benfante R, Nizzardo M, Bachetti T, Pelucchi P, Melzi V, Arzilli C, Peruzzi M, Reinbold RA, Cardani S, Morrone A, Guerrini R, Zucchi I, Corti S, Ceccherini I, Piumelli R, Nassi N, Di Lascio S, and Fornasari D
- Subjects
- Female, Homeodomain Proteins genetics, Humans, Hypoventilation congenital, Mutation genetics, Peptides, Sleep Apnea, Central, Transcription Factors genetics, Induced Pluripotent Stem Cells
- Abstract
Congenital Central Hypoventilation Syndrome (CCHS) is a rare disorder of the autonomic nervous system (ANS), characterized by inadequate control of autonomic ventilation and global autonomic dysfunction. Heterozygous polyalanine repeat expansion mutations in exon 3 of the transcription factor Paired-like homeobox 2B (PHOX2B) gene occur in 90% of CCHS cases. In this study, we describe the generation and characterization of two human induced pluripotent stem cell (hiPSC) lines from female CCHS patients carrying a heterozygous + 5 alanine expansion mutation. The generated iPSC lines show a normal karyotype, express pluripotency markers and are able to differentiate into the three germ layers., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2022
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44. Non-polyalanine repeat mutation in PHOX2B is detected in autopsy cases of sudden unexpected infant death.
- Author
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Ueda A, Osawa M, Naito H, Ochiai E, and Kakimoto Y
- Subjects
- Adult, Autopsy, Homeodomain Proteins genetics, Humans, Hypoventilation congenital, Infant, Male, Mutation, Sleep Apnea, Central, Transcription Factors genetics, Sudden Infant Death genetics
- Abstract
Background: Congenital central hypoventilation syndrome (CCHS), which is caused by PHOX2B with phenotypic variations, has a point of controversy: CCHS is putatively involved in autopsy cases of sudden unexpected infant death (SUID) including sudden infant death syndrome., Objective: The relation of CCHS to SUID cases was investigated by extensive genotyping of PHOX2B., Methods: We analyzed 93 DNA samples of less than one-year-old SUID cases that were autopsied in our department. Unrelated adult volunteers (n = 942) were used as the control., Results: No polyalanine tract expansion was detected in the SUID cases. The allelic frequencies of repeat contractions and SNP (rs28647582) in intron 2 were not significantly different from that in those control group. Further extensive sequencing revealed a non-polyalanine repeat mutation (NPARM) of c.905A>C in a sudden death case of a one-month-old male infant. This missense mutation (p.Asn302Thr), registered as rs779068107, was annotated to 'Affected status is unknown', but it might be associated with the sudden death., Conclusion: NPARM was more plausibly related to sudden unexpected death than expansions because of severe clinical complications. This finding indicates possible CCHS involvement in forensic autopsy cases without ante-mortem diagnosis., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2022
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45. Etonogestrel Administration Reduces the Expression of PHOX2B and Its Target Genes in the Solitary Tract Nucleus.
- Author
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Cardani S, Janes TA, Saini JK, Di Lascio S, Benfante R, Fornasari D, and Pagliardini S
- Subjects
- Animals, Desogestrel, Female, Homeodomain Proteins metabolism, Hypoventilation congenital, Hypoventilation genetics, Mutation, Progestins pharmacology, Rats, Sleep Apnea, Central genetics, Solitary Nucleus metabolism
- Abstract
Heterozygous mutations of the transcription factor PHOX2B are responsible for Congenital Central Hypoventilation Syndrome, a neurological disorder characterized by inadequate respiratory response to hypercapnia and life-threatening hypoventilation during sleep. Although no cure is currently available, it was suggested that a potent progestin drug provides partial recovery of chemoreflex response. Previous in vitro data show a direct molecular link between progestins and PHOX2B expression. However, the mechanism through which these drugs ameliorate breathing in vivo remains unknown. Here, we investigated the effects of chronic administration of the potent progestin drug Etonogestrel (ETO) on respiratory function and transcriptional activity in adult female rats. We assessed respiratory function with whole-body plethysmography and measured genomic changes in brain regions important for respiratory control. Our results show that ETO reduced metabolic activity, leading to an enhanced chemoreflex response and concurrent increased breathing cycle variability at rest. Furthermore, ETO-treated brains showed reduced mRNA and protein expression of PHOX2B and its target genes selectively in the dorsal vagal complex, while other areas were unaffected. Histological analysis suggests that changes occurred in the solitary tract nucleus (NTS). Thus, we propose that the NTS, rich in both progesterone receptors and PHOX2B, is a good candidate for ETO-induced respiratory modulation.
- Published
- 2022
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- View/download PDF
46. An unusual cause of diaphragm pacer failure in congenital central hypoventilation syndrome.
- Author
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Kwon A, Lodge M, McComb JG, Durham S, Shin CE, Keens TG, and Perez IA
- Subjects
- Adult, Diaphragm, Female, Humans, Hypoventilation complications, Hypoventilation congenital, Hypoventilation diagnosis, Hypoventilation therapy, Electric Stimulation Therapy, Sleep Apnea, Central complications, Sleep Apnea, Central therapy
- Abstract
Congenital central hypoventilation syndrome is a rare genetic disorder affecting ventilatory response to hypercapnia and/or hypoxemia. We describe a case of diaphragm pacing (DP) failure in a 38-year-old woman with congenital central hypoventilation syndrome who used DP as ventilatory support only during sleep for 24 years. Diagnostic evaluation began with examination of external DP equipment, but adjustment did not elicit adequate diaphragm contractions. Clinical evaluation and transtelephonic monitoring showed absent function of the right pacer and diminished function of the left pacer. The patient had surgical exploration of her internal DP components. The operation revealed that the right pacer receiver had significant circumferential calcium accumulation. After replacement of the receivers in subcutaneous pockets closer to the skin surface, robust diaphragm contractions bilaterally occurred with stimulation. This case suggests DP failure can result from development of calcification and increased distance from the skin surface to the receivers due to weight gain., Citation: Kwon A, Lodge M, McComb JG, et al. An unusual cause of diaphragm pacer failure in congenital central hypoventilation syndrome. J Clin Sleep Med . 2022;18(3):949-952., (© 2022 American Academy of Sleep Medicine.)
- Published
- 2022
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47. Tracheostomy decannulation to noninvasive positive pressure ventilation in congenital central hypoventilation syndrome.
- Author
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Kasi AS, Anand N, Harford KL, Landry AM, Alfonso KP, Taylor M, Keens TG, and Leu RM
- Subjects
- Adolescent, Child, Humans, Hypoventilation therapy, Male, Positive-Pressure Respiration methods, Retrospective Studies, Treatment Outcome, Device Removal, Hypoventilation congenital, Sleep Apnea, Central therapy, Tracheostomy methods
- Abstract
Purpose: Noninvasive positive pressure ventilation (NPPV) may permit tracheostomy decannulation (TD) in patients with congenital central hypoventilation syndrome (CCHS) requiring nocturnal positive pressure ventilation via tracheostomy (PPV-T). There is limited evidence on optimal strategies for transitioning patients from PPV-T to NPPV. This study aimed to describe the clinical course and outcome of children with CCHS who underwent TD and transitioned from PPV-T to NPPV., Methods: Retrospective review was conducted on patients with CCHS using nocturnal PPV-T who underwent TD to NPPV. The results of clinical evaluations, airway endoscopy, polysomnography, and clinical course leading to TD were analyzed., Results: We identified 3 patients with CCHS aged 8-17 years who required PPV-T only during sleep. Patients underwent systematic multidisciplinary evaluations with a pediatric psychologist, pulmonologist, sleep physician, and otolaryngologist utilizing a TD algorithm. These included evaluation in the sleep clinic, NPPV mask fitting and desensitization, endoscopic airway evaluation, daytime tracheostomy capping, acclimatization to low-pressure NPPV, polysomnography with capped tracheostomy and NPPV titration, and if successful, TD. All patients underwent successful TD following optimal titration of NPPV during polysomnography. The duration to TD from decision to pursue NPPV was between 2.4 and 10.6 months, and the duration of hospitalization for TD was between 4 and 5 days. There were no NPPV-related complications; however, all patients required surgical closure of tracheocutaneous fistula., Conclusion: NPPV may be an effective and feasible option for patients with CCHS requiring PPV-T during sleep and permits TD. In patients with CCHS, a systematic multidisciplinary algorithm may optimize successful transition to NPPV and TD., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)
- Published
- 2022
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48. Rare cause of neonatal apnea from congenital central hypoventilation syndrome.
- Author
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Tovichien P, Rattananont K, Kulthamrongsri N, Chanvanichtrakool M, and Yangthara B
- Subjects
- Adult, Apnea, Female, Homeodomain Proteins genetics, Humans, Hypoventilation congenital, Hypoventilation diagnosis, Hypoventilation genetics, Hypoventilation therapy, Infant, Newborn, Mutation, Infant, Newborn, Diseases, Sleep Apnea, Central diagnosis, Sleep Apnea, Central genetics, Sleep Apnea, Central therapy
- Abstract
Background: Congenital central hypoventilation syndrome (CCHS) is a rare condition caused by mutations in the Paired-Like Homeobox 2B (PHOX2B) gene. It causes alveolar hypoventilation and autonomic dysregulation. This report aimed to raise awareness of this rare cause of neonatal apnea and hypoventilation as well as described the diagnostic work up to confirm the diagnosis in resource-limited setting where polysomnography for neonate is unavailable., Case Presentation: A late preterm female newborn born from a non-consanguineous primigravida 31-year-old mother had desaturation soon after birth followed by apnea and bradycardia. After becoming clinically stable, she still had extubation failure from apnea without hypercapnic ventilatory response which worsened during non-rapid eye movement (NREM) sleep. After exclusion of other etiologies, we suspected congenital central hypoventilation syndrome and sent genetic testing. The result showed a PHOX2B gene mutation which confirmed the diagnosis of CCHS. We gave the patient's caregivers multidisciplinary home respiratory care training including tracheostomy care, basic life support, and simulation training for respiratory problem solving. Then, the patient was discharged and scheduled for follow-up surveillance for associated conditions., Conclusion: Diagnosis of CCHS in neonates includes the main clue of the absence of hypercapnic ventilatory response which worsens during non-rapid eye movement (NREM) sleep after exclusion of other causes. Molecular testing for PHOX2B gene mutation was used to confirm the diagnosis., (© 2022. The Author(s).)
- Published
- 2022
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49. Cerebral Autoregulation during Orthostatic Challenge in Congenital Central Hypoventilation Syndrome.
- Author
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Vu EL, Dunne EC, Bradley A, Zhou A, Carroll MS, Rand CM, Brady KM, Stewart TM, and Weese-Mayer DE
- Subjects
- Adolescent, Biomarkers metabolism, Brain metabolism, Case-Control Studies, Child, Female, Humans, Hypotension, Orthostatic physiopathology, Hypoventilation metabolism, Hypoventilation physiopathology, Male, Oximetry, Sleep Apnea, Central metabolism, Tilt-Table Test, Young Adult, Brain physiopathology, Homeostasis physiology, Hypotension, Orthostatic etiology, Hypoventilation congenital, Oxygen metabolism, Posture physiology, Sleep Apnea, Central physiopathology
- Abstract
Rationale: Congenital central hypoventilation syndrome (CCHS) is a rare autonomic disorder with altered regulation of breathing, heart rate (HR), and blood pressure (BP). Aberrant cerebral oxygenation in response to hypercapnia/hypoxia in CCHS raises the concern that altered cerebral autoregulation may contribute to CCHS-related, variably impaired neurodevelopment. Objectives: To evaluate cerebral autoregulation in response to orthostatic challenge in CCHS cases versus controls. Methods: CCHS and age- and sex-matched control subjects were studied with head-up tilt (HUT) testing to induce orthostatic stress. Fifty CCHS and 100 control HUT recordings were included. HR, BP, and cerebral oxygen saturation (regional oxygen saturation) were continuously monitored. The cerebral oximetry index (COx), a real-time measure of cerebral autoregulation based on these measures, was calculated. Measurements and Main Results: HUT resulted in a greater mean BP decrease from baseline in CCHS versus controls (11% vs. 6%; P < 0.05) and a diminished increase in HR in CCHS versus controls (11% vs. 18%; P < 0.01) in the 5 minutes after tilt-up. Despite a similar COx at baseline, orthostatic provocation within 5 minutes of tilt-up caused a 50% greater increase in COx ( P < 0.01) and a 29% increase in minutes of impaired autoregulation ( P < 0.02) in CCHS versus controls (4.0 vs. 3.1 min). Conclusions: Cerebral autoregulatory mechanisms appear to be intact in CCHS, but the greater hypotension observed in CCHS consequent to orthostatic provocation is associated with greater values of COx/impaired autoregulation when BP is below the lower limits of autoregulation. Effects of repeated orthostatic challenges in everyday living in CCHS necessitate further study to determine their influence on neurodevelopmental disease burden.
- Published
- 2022
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- View/download PDF
50. Beyond the Retrotrapezoid Nucleus in Congenital Central Hypoventilation Syndrome.
- Author
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Amin R
- Subjects
- Humans, Hypoventilation congenital, Sleep Apnea, Central
- Published
- 2022
- Full Text
- View/download PDF
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