Abstract
Background: Congenital central hypoventilation syndrome (CCHS) is a rare disorder whose clinical phenotype is closely related to genotype.Methods: A retrospective analysis has been conducted on 22 patients with CCHS, who were referred to the Pediatric Pulmonology and Respiratory Intermediate Care Unit of Bambino Gesù Children's Hospital (Italy) for a multidisciplinary follow-up program between 2000 and 2020.Results: Apnea and cyanosis were the most frequent symptoms at onset (91%). Overall, 59% of patients required tracheostomy and invasive mechanical ventilation (IMV) in the first months of life. Thirty-two percent of patients had Hirschsprung disease (HSCR) that was associated with longer polyalanine repetitions or non-polyalanine repeat expansion mutations (NPARMs). Polyalanine repeat expansion mutations (PARMs) were more frequent and two novel NPARMs (c.780dupT and C.225–256delCT) were described in 14% of patients. Focal epilepsy was first described in 14% of patients and neurocognitive and neuromotor impairment involved 27% and 23% of children, respectively. Symptoms due to autonomic nervous system dysfunction/dysregulation (ANSD)—including strabismus (27%), dysphagia (27%), abnormal heart rhythm (10%), breath-holding spells (9%), and recurrent seizures due to hypoglycemia (9%)—were associated with an increased number of polyalanine repetitions of exon 3 or NPARMs of PHOX2B gene. Overall, the number of patients with moderate to severe phenotype initially treated with non-invasive ventilation (NIV) increased over time, and the decannulation program was concluded with 3 patients who started with IMV.Conclusions: Our study confirms that more severe phenotypes of CCHS are related to the number of polyalanine repetitions or to NPARMs. Although invasive ventilation is often required by patients with severe genotype/phenotype, gradual acquisition of specific skills in the management of patients with CCHS and technological improvements in mechanical ventilation allowed us to improve our therapeutic approach in this population.
Highlights
Congenital central hypoventilation syndrome (CCHS) is a rare life-threatening disorder characterized by autonomic dysregulation and alveolar hypoventilation, requiring lifelong ventilatory assistance
The aims of our study are: [1] to describe the genotypes and the clinical findings of patients affected with CCHS followed by a Abbreviations: CCHS, central congenital hypoventilation syndrome; PARMs, polyalanine repeat expansion mutations; NPARMs, non-polyalanine repeat expansion mutations; HSCR, Hirschsprung’s disease; ANSD, autonomic nervous system dysfunction/dysregulation; LO–CCHS, late-onset central congenital hypoventilation syndrome; ICU, Intensive Care Unit; PICU, Pediatric Intermediate Care Unit; IMV, invasive mechanical ventilation; NIV, non-invasive ventilation; CNS, central nervous system; MRI, magnetic resonance imaging
Physiotherapists, and doctors of our team obtained the necessary expertise on CCHS, 14 patients have been followed in our Pediatric Intermediate Care Unit (PICU) since the onset of symptoms
Summary
Congenital central hypoventilation syndrome (CCHS) is a rare life-threatening disorder characterized by autonomic dysregulation and alveolar hypoventilation, requiring lifelong ventilatory assistance. Even though hypoventilation is accentuated during sleep, especially during the non-rapid eye movement (NREM) phase [2], more severely affected individuals exhibit it even when they are awake [3]. PHOX2B gene, encoding a transcription factor involved in autonomic system development, has a 20-polyalanine sequence in exon 3 [4]. Over 90% of CCHS cases are heterozygous for polyalanine repeat expansion mutations (PARMs) in the exon 3 of PHOX2B gene producing genotypes of 20/24 to 20/33, that often arise de novo [5]. Congenital central hypoventilation syndrome (CCHS) is a rare disorder whose clinical phenotype is closely related to genotype
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