Variable phenotypes in congenital central hypoventilation syndrome with PHOX2B nonpolyalanine repeat mutations.

STUDY OBJECTIVES: Congenital central hypoventilation syndrome (CCHS) is a rare disorder affecting the autonomic nervous system that is caused by variants in the paired-like homeobox 2B (PHOX2B) gene. About 10% of patients with CCHS have nonpolyalanine repeat mutations (NPARM) that are associated with severe phenotypes requiring continuous assisted ventilation, Hirschsprung's disease, and increased neural crest tumor risk. However, some patients with NPARM have milder phenotypes. Our objective was to describe the phenotypes in patients with CCHS PHOX2B NPARM. METHODS: Retrospective case series of patients with CCHS PHOX2B NPARM was conducted at 2 children's hospitals to evaluate their phenotypes. RESULTS: We identified 8 patients with CCHS PHOX2B NPARM aged 3-31 years. Seven patients were diagnosed in infancy and 1 patient at 2 years of age. All patients presented with respiratory depression in the first 2 months of life. Only 1 patient was identified with a severe phenotype requiring continuous assisted ventilation, Hirschsprung's disease, and a neural crest tumor, which was resected. Five patients required positive pressure ventilation via tracheostomy only during sleep and 2 patients required oxygen only during sleep. Four patients had Hirschsprung's disease and 1 patient had a cardiac pacemaker due to a bradyarrhythmia. None of the patients had echocardiographic abnormalities. CONCLUSIONS: Patients with CCHS PHOX2B NPARM can have variable phenotypes, emphasizing the importance of implementing a plan of care that is individualized for each patient. The type of NPARM and their respective location on the PHOX2B gene may play a critical role in the severity of phenotypes displayed by each patient. CITATION: Kasi AS, Li H, Jurgensen TJ, Guglani L, Keens TG, Perez IA. Variable phenotypes in congenital central hypoventilation syndrome with PHOX2B nonpolyalanine repeat mutations. J Clin Sleep Med. 2021;17(10):2049-2055.

Severe Positional Central Sleep Apnea in an Asymptomatic Adult With a PHOX2B Frameshift Mutation.

ABSTRACT: We report an unusual case of an adult patient carrying a germline PHOX2B frameshift mutation and hence was diagnosed with congenital central hypoventilation syndrome. He came to medical attention after the mutation was identified in his daughter who presented with hypoventilation and a neuroblastoma. Although PHOX2B mutations are usually associated with a phenotype of congenital hypoventilation, severe autonomic dysfunction and neural crest tumors, our patient had no complaints at the time of presentation. At polysomnography we found severe positional hypercapnic central sleep apnea, partly responsive to positional therapy. Eventually, he was titrated to noninvasive ventilation with resolution of the central breathing events and, in hindsight, a more refreshing sleep than before. Clinicians working in sleep medicine need to be aware of the variable expression of this rare condition to prevent late cardiorespiratory and neurocognitive complications.

Three-Generation Family With Congenital Central Hypoventilation Syndrome and Novel PHOX2B Gene Non-Polyalanine Repeat Mutation.

ABSTRACT: PHOX2B non-polyalanine repeat mutation (NPARM) in patients with congenital central hypoventilation syndrome (CCHS) is generally considered to be associated with full-time ventilator dependence and severe autonomic nervous system dysfunction. We report a three-generation family with four individuals possessing a novel PHOX2B NPARM (c.245C > T) with variable phenotypes. This mutation was inherited in an autosomal dominant pattern with variable penetrance. The affected family members with CCHS have a milder phenotype than is typically expected with a NPARM. Two family members are ventilator dependent only during sleep and do not have Hirschsprung disease or neural crest tumors. One family member was asymptomatic until systemic hypertension developed during adulthood and another family member remains asymptomatic as an adult. Our findings emphasize the importance of monitoring adults with a PHOX2B NPARM who are considered asymptomatic in childhood.