RESUMO
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.
Assuntos
Proteínas de Homeodomínio , Hipoventilação , Apneia do Sono Tipo Central , Fatores de Transcrição , Humanos , Apneia do Sono Tipo Central/diagnóstico , Apneia do Sono Tipo Central/terapia , Apneia do Sono Tipo Central/genética , Recém-Nascido , Hipoventilação/congênito , Hipoventilação/terapia , Hipoventilação/diagnóstico , Hipoventilação/genética , Feminino , Proteínas de Homeodomínio/genética , Fatores de Transcrição/genética , Ventilação não Invasiva , Pressão Positiva Contínua nas Vias Aéreas , Acidose Respiratória/diagnóstico , Acidose Respiratória/terapia , Acidose Respiratória/etiologia , Mutação , OxigenoterapiaRESUMO
Mutations in the transcription factor Phox2b cause congenital central hypoventilation syndrome (CCHS). The syndrome is characterized by hypoventilation and inability to regulate breathing to maintain adequate O2 and CO2 levels. The mechanism by which CCHS impact respiratory control is incompletely understood, and even less is known about the impact of the non-polyalanine repeat expansion mutations (NPARM) form. Our goal was to investigate the extent by which NPARM Phox2b mutation affect (a) respiratory rhythm; (b) ventilatory responses to hypercapnia (HCVR) and hypoxia (HVR); and (c) number of chemosensitive neurons in mice. We used a transgenic mouse line carrying a conditional Phox2bΔ8 mutation (same found in humans with NPARM CCHS). We crossed them with Atoh1cre mice to introduce mutation in regions involved with respiratory function and central chemoreflex control. Ventilation was measured by plethysmograph during neonatal and adult life. In room air, mutation in neonates and adult did not greatly impact basal ventilation. However, Phox2bΔ8, Atoh1cre increased breath irregularity in adults. The HVR and HCVR were impaired in neonates. The HVR, but not HCVR, was still partially compromised in adults. The mutation reduced the number of Phox2b+/TH--expressing neurons as well as the number of fos-activated cells within the ventral parafacial region (also named retrotrapezoid nucleus [RTN] region) induced by hypercapnia. Our data indicates that Phox2bΔ8 mutation in Atoh1-expressing cells impaired RTN neurons, as well as chemoreflex under hypoxia and hypercapnia specially early in life. This study provided new evidence for mechanisms related to NPARM form of CCHS neuropathology.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos , Proteínas de Homeodomínio , Hipercapnia , Apneia do Sono Tipo Central , Animais , Humanos , Camundongos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Hipercapnia/genética , Hipóxia/genética , Camundongos Transgênicos , Mutação , Apneia do Sono Tipo Central/genética , Proteínas de Homeodomínio/genéticaAssuntos
Análise Mutacional de DNA , Expansão das Repetições de DNA/genética , Proteínas de Homeodomínio/genética , Hipoventilação/congênito , Apneia do Sono Tipo Central/genética , Fatores de Transcrição/genética , Adolescente , Criança , Pré-Escolar , Pressão Positiva Contínua nas Vias Aéreas , Seguimentos , Humanos , Hipoventilação/diagnóstico , Hipoventilação/genética , Hipoventilação/terapia , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Cooperação do Paciente , Fenótipo , Polissonografia , Recidiva , Síndrome do Desconforto Respiratório do Recém-Nascido/diagnóstico , Síndrome do Desconforto Respiratório do Recém-Nascido/genética , Apneia do Sono Tipo Central/diagnóstico , Apneia do Sono Tipo Central/terapia , TraqueotomiaRESUMO
Most children with idiopathic central hypoventilation have symptoms at birth or shortly thereafter and have mutations of the PHOX2B gene. Those whose symptoms appear later usually have obesity and hypothalamic abnormalities. We describe a case of a boy who presented at 5 years of age with severe idiopathic central hypoventilation, but no obesity or hypothalamic abnormalities, and who tested negative for mutation of the PHOX2B gene. This case illustrates the heterogeneity of childhood idiopathic central hypoventilation syndromes and indicates the multifactorial etiology of these syndromes.