Atypical presentations associated with non-polyalanine repeat PHOX2B mutations.

Area of Science:

• Genetics
• Pediatrics
• Neurology

Background:

• Congenital central hypoventilation syndrome (CCHS) is a rare genetic disorder affecting autonomic nervous system control of breathing.
• Mutations in the PHOX2B gene are the primary cause of CCHS, with polyalanine repeat mutations (PARMs) being most common.

Observation:

• This report describes two pediatric patients presenting with CCHS phenotypes.
• Patient 1 exhibited mild, nocturnal hypoventilation and a novel PHOX2B missense variant (p.R102S).
• Patient 2 presented with a severe, atypical CCHS phenotype including obstructive sleep apnea and a PHOX2B nonsense variant (p.Y78*).

Findings:

• Both patients carried non-polyalanine repeat mutations (NPARMs) in the PHOX2B gene, expanding the known mutation spectrum for CCHS.
• The identified NPARMs resulted in distinct clinical presentations, ranging from mild nocturnal hypoventilation to severe hypercarbia and the need for tracheostomy.
• Genetic analysis revealed a novel de novo missense variant in Patient 1 and a recently identified nonsense variant in Patient 2.

Implications:

• These findings underscore the genetic heterogeneity of CCHS and the diverse clinical manifestations associated with PHOX2B NPARMs.
• The study emphasizes the critical role of PHOX2B genetic sequencing in diagnosing CCHS, particularly in cases with atypical or severe phenotypes.
• Understanding the spectrum of PHOX2B mutations improves diagnostic accuracy and informs clinical management strategies for CCHS patients.