PHOX2B Tyr14Ter Mutation Might Be Associated with Sustained Diurnal Hypertension: Case Report and Review of the Literature

TL;DR

A rare PHOX2B mutation in a child with CCHS is linked to mild symptoms and high blood pressure, showing how genetic changes can affect disease severity.

Contribution

The p.Tyr14Ter mutation may produce a partially functional protein, leading to a milder CCHS phenotype with sustained hypertension.

Findings

Non-polyalanine repeat mutations like p.Tyr14Ter may result in a truncated but partially functional PHOX2B protein.

Blood pressure abnormalities can occur in CCHS patients with non-PARM genotypes, indicating broader cardiovascular dysregulation.

The p.Tyr14Ter mutation is associated with milder clinical presentation compared to severe polyalanine repeat mutations.

Abstract

What are the main findings?
Non-polyalanine repeat mutations (NPARMs), including nonsense variants, are rare and generally associated with severe clinical phenotypes; however, the p.Tyr14Ter mutation may allow the production of a partially functional truncated protein, resulting in a relatively mild presentation.Baroreflex dysfunction in CCHS can manifest as orthostatic hypotension due to an inadequate blood pressure response to orthostatic stress and as impaired nocturnal vagal control leading to nocturnal hypertension.

Non-polyalanine repeat mutations (NPARMs), including nonsense variants, are rare and generally associated with severe clinical phenotypes; however, the p.Tyr14Ter mutation may allow the production of a partially functional truncated protein, resulting in a relatively mild presentation.

Baroreflex dysfunction in CCHS can manifest as orthostatic hypotension due to an inadequate blood pressure response to orthostatic stress and as impaired nocturnal vagal control leading to nocturnal hypertension.

What are the implications of the main findings?
The genotype influences the prevalence of hypertension in children with CCHS, with a higher prevalence in patients carrying severe polyalanine repeat mutations (PARMs) compared with non-PARM genotypes.The presence of blood pressure abnormalities in a patient with an NPARM genotype, unlike previous reports, suggests that cardiovascular dysregulation may also occur in non-PARM CCHS.

The genotype influences the prevalence of hypertension in children with CCHS, with a higher prevalence in patients carrying severe polyalanine repeat mutations (PARMs) compared with non-PARM genotypes.

The presence of blood pressure abnormalities in a patient with an NPARM genotype, unlike previous reports, suggests that cardiovascular dysregulation may also occur in non-PARM CCHS.

Introduction: Congenital central hypoventilation syndrome (CCHS) is a rare disorder characterized by an impaired ventilatory response to hypercapnia and hypoxia, particularly during sleep, and frequently associated with autonomic dysfunction. It is caused by pathogenic variants in the PHOX2B gene. Although CCHS is typically diagnosed in the neonatal period, milder forms may present later in infancy or childhood, often triggered by respiratory infections. Case presentation: We report the case of 16-month-old male diagnosed with CCHS following an episode of hypoxemic–hypercapnic respiratory failure during respiratory syncytial virus (RSV) infection. His medical history included neonatal respiratory distress requiring oxygen therapy and recurrent wheezing. At 15 months, he developed acute respiratory distress with severe hypercapnia (PaCO2 70 mmHg), requiring admission to the Pediatric Intensive Care Unit and invasive mechanical ventilation. Persistent sleep-related hypercapnia and hypoxemia prompted evaluation for central hypoventilation, confirmed by means of transcutaneous capnography and nocturnal pulse oximetry. Genetic testing revealed a de novo nonsense mutation in exon 1 of PHOX2B (p.Tyr14Ter). Brain magnetic resonance imaging showed diffuse white matter changes suggestive of gliosis. Further investigations identified early-onset systemic hypertension, requiring antihypertensive therapy. The patient was discharged on nocturnal non-invasive ventilation and enrolled in a neurodevelopmental rehabilitation program. Conclusions: This case highlights the phenotypic variability of CCHS and the importance of considering this diagnosis in children presenting with unexplained hypercapnia and sleep-related hypoxemia. It underscores the need for comprehensive autonomic evaluation, including blood pressure monitoring. The p.Tyr14Ter variant may allow partial protein function, potentially accounting for the relatively mild phenotype.

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