What is the diagnosis for a patient with PHOX2B (Paired Homeobox 2B) mutation not meeting developmental milestones and experiencing weight loss?

From the Guidelines

For a child with PHOX2B mutations who is not meeting developmental milestones and experiencing weight loss, immediate medical evaluation by a pediatric neurologist and pulmonologist is essential, and comprehensive respiratory support, nutritional intervention, and early intervention services should be considered to address weight loss and developmental delays. The child likely needs comprehensive respiratory support, which may include mechanical ventilation during sleep or continuous monitoring, as CCHS affects multiple body systems due to autonomic nervous system dysfunction, and the PHOX2B gene's role in neural crest development explains why affected children have both breathing regulation problems and often gastrointestinal issues that contribute to poor growth and development 1.

Key Considerations

• Comprehensive respiratory support, including mechanical ventilation during sleep or continuous monitoring, should be considered to address breathing regulation problems.
• Nutritional intervention with high-calorie formulas (such as Pediasure 1.5 or Nutren Junior) and possibly feeding tube placement (NG or G-tube) should be considered to address weight loss.
• Early intervention services, including physical, occupational, and speech therapy, are crucial for addressing developmental delays.
• Parents should maintain a daily log of respiratory patterns, feeding volumes, and developmental progress to monitor the child's condition and adjust management as needed.

Management and Monitoring

• Annual in-hospital comprehensive evaluation with physiologic studies during awake and asleep states, 72-hour Holter monitoring, echocardiogram, and evaluation of ANS dysregulation across all organ systems affected by the ANS should be performed to monitor the child's condition and adjust management as needed 1.
• Imaging for neural crest tumors in individuals at greatest risk based on PHOX2B mutation should be performed to monitor for potential complications.
• Comprehensive autonomic testing as clinically indicated to assess syncope and to assess autonomic nervous system function may include tilt testing, deep breathing, Valsalva maneuver, thermal stressors, pupillometry, and more, as new measures of autonomic testing are developed for infants and children.

From the Research

PHOX2B and Congenital Central Hypoventilation Syndrome

• Congenital central hypoventilation syndrome (CCHS) is a rare disorder characterized by decreased response to hypercarbia, often presenting with alveolar hypoventilation during sleep and wakefulness, and autonomic nervous system (ANS) dysregulation 2, 3.
• The PHOX2B gene is the disease-defining gene for CCHS, with mutations in this gene associated with the disorder in over 90% of cases 4.
• Individuals with CCHS may experience weight loss, altered respiratory control, and thermoregulation, as well as an absence of perception of shortness of breath 2.

Clinical Features and Genotype-Phenotype Relationships

• The severity of CCHS can vary depending on the PHOX2B genotype, with nonpolyalanine repeat mutations producing more severe disruption of PHOX2B function 4.
• Patients with nonpolyalanine repeat mutations are more likely to experience continuous ventilatory dependence, Hirschsprung disease, and neural crest tumors 4.
• The PHOX2B genotype can also determine the risk for sudden death, with certain genotypes associated with longer r-r intervals and QTc intervals 5.

Respiratory Control and PHOX2B

• The PHOX2B transcription factor plays a crucial role in the control of respiration, with restricted neuronal types expressing and depending on PHOX2B essential for adequate breathing 6.
• The retrotrapezoid nucleus (RTN) in the rostral medulla is a key region involved in the control of respiration, with RTN neurons depending on PHOX2B for their development and function 6.