What is the significance of PHOX2B (Paired Like Homeobox 2B)?

From the Guidelines

PHOX2B mutations are the primary cause of Congenital Central Hypoventilation Syndrome (CCHS), and PHOX2B testing is essential for diagnosing CCHS and identifying individuals at risk for related conditions like neuroblastoma and Hirschsprung's disease. The PHOX2B gene encodes a transcription factor crucial for the development of the autonomic nervous system, and mutations in this gene can lead to inadequate breathing during sleep, characterized by diminutive tidal volumes and monotonous respiratory rates awake and asleep 1. The most common mutations involve polyalanine repeat expansions in the gene, and children with PHOX2B mutations typically require lifelong ventilatory support during sleep, and in severe cases, while awake 1.

Key Points:

• PHOX2B mutations are associated with an autosomal dominant inheritance pattern, meaning affected individuals have a 50% chance of passing the mutation to their offspring 1.
• Genetic counseling is recommended for families with PHOX2B mutations to assess recurrence risk and provide prenatal testing options 1.
• Individuals with CCHS characteristically have diminished pupillary light response, esophageal dysmotility, breath-holding spells, reduced basal body temperature, sporadic profuse sweating, lack of perception to dyspnea, altered perception of anxiety, and lack of physiologic responsiveness to the challenges of exercise and environmental stressors 1.
• Conditions associated with CCHS reflecting anatomic ANSD include Hirschsprung disease (HSCR) and tumors of neural crest origin 1.

Management:

• Biannual then annual in-hospital comprehensive evaluation with physiologic studies during awake and asleep states to assess ventilatory needs and ventilatory responsiveness to physiologic challenges is recommended for individuals with CCHS 1.
• Positive pressure ventilation via tracheostomy in the first several years of life is recommended to ensure optimal oxygenation and ventilation beginning in the first days of life, and to provide for optimal neurocognitive outcome 1.
• Noninvasive ventilation is not a consideration in conservative management until 6 to 8 years of age at the earliest in stable patients with CCHS requiring ventilatory support only during sleep 1.

Future Directions:

• Further studies are needed to understand the relationship between PHOX2B genotype and CCHS phenotype, and to develop more effective management strategies for individuals with CCHS 1.
• Comprehensive clinical physiologic studies of patients with CCHS that explore the consequences of ANSD should be pursued to better understand the disease and develop more effective treatments 1.

From the Research

PHOX2B Gene and Congenital Central Hypoventilation Syndrome (CCHS)

• The PHOX2B gene is associated with Congenital Central Hypoventilation Syndrome (CCHS), a rare genetic disorder characterized by failure of central control of breathing and autonomic nervous system function 2.
• Mutations in the PHOX2B gene, including polyalanine repeat expansion mutations (PARM) and non-polyalanine repeat mutations (NPARM), can lead to CCHS 3, 4.
• The length of the polyalanine expansion in PARM correlates with clinical disease severity, with longer expansions associated with more severe symptoms 4.

Clinical Manifestations of CCHS

• Patients with CCHS often present with absent or negligible ventilatory sensitivity to hypercapnia and hypoxemia, and may not exhibit signs of respiratory distress when challenged with hypercarbia or hypoxia 2.
• CCHS can be associated with other conditions, including Hirschsprung disease, neural crest tumors, and cardiac arrhythmias 2, 3, 4.
• Patients with NPARM may have more severe symptoms and frequent complications, including hypoventilation in the neonatal period, Hirschsprung disease, and tumors of neural crest origin 3, 4.

Diagnosis and Management of CCHS

• Diagnosis of CCHS must be confirmed with PHOX2B gene mutation analysis 2.
• Management of CCHS requires ventilatory support, which can be provided through various methods, including positive pressure ventilation via tracheostomy, noninvasive positive pressure ventilation, and diaphragm pacing via phrenic nerve stimulation 2.
• Early diagnosis and advances in home mechanical ventilation and monitoring strategies have improved outcomes for CCHS patients, allowing many to survive into adulthood 2.

Genetic Counseling and Prenatal Testing

• Genetic counseling is important for families with a history of CCHS, as the risk of recurrence can be significant even if parental mosaicism is not detected 5.
• Prenatal testing can be considered for families with a history of CCHS, particularly if a parental carrier state or mosaicism is suspected 5.