What is the difference in management between ROHHAD (Rapid-Onset Obesity with Hypothalamic dysfunction, Hypoventilation, and Autonomic Dysregulation) syndrome and Congenital Central Hypoventilation Syndrome (CCHS)?

Differences Between ROHHAD Syndrome and Congenital Central Hypoventilation Syndrome (CCHS)

ROHHAD syndrome and CCHS are distinct disorders with different genetic bases, clinical presentations, diagnostic approaches, and management strategies, with CCHS requiring genetic testing for PHOX2B mutations while ROHHAD has no identified genetic marker and requires a clinical diagnosis based on its characteristic presentation pattern. 1

Etiology and Diagnosis

CCHS

• Genetic basis: Caused by mutations in the PHOX2B gene, with most cases involving polyalanine repeat mutations (PARMs) or non-polyalanine repeat mutations (NPARMs) 1
• Diagnosis: Confirmed through PHOX2B genetic testing, which is considered definitive 1, 2
• Presentation: Typically presents in the newborn period, though later-onset CCHS (LO-CCHS) can occur 1
• Inheritance: Most mutations occur de novo, but 5-10% are inherited from mosaic parents 1

ROHHAD

• Genetic basis: No specific genetic marker identified; not associated with PHOX2B mutations 1, 3
• Diagnosis: Based on clinical presentation and exclusion of other disorders (including negative PHOX2B testing) 1, 3
• Presentation: Typically presents between 1.5-7 years of age with rapid-onset obesity as the initial sign 1, 4
• Inheritance: No clear inheritance pattern established 3

Clinical Presentation Differences

CCHS

• Presents with hypoventilation from birth or after specific triggers in LO-CCHS 1, 2
• No rapid-onset obesity component 1
• Characteristic facial features ("CCHS facies") may be present 1
• May have Hirschsprung disease or neural crest tumors 1

ROHHAD

• Presents with dramatic weight gain (20-40 pounds over 4-6 months) as the first symptom 1, 4
• Sequential development of symptoms: obesity → hypothalamic dysfunction → hypoventilation → autonomic dysregulation 1, 4
• Associated with hypothalamic disorders (water imbalance, elevated prolactin, altered puberty) 1, 5, 6
• Neural crest tumors present in approximately 40% of cases 1, 5, 3
• May present with behavioral disorders, strabismus, and abnormal pupillary responses 1, 6

Management Differences

CCHS

• Ventilatory support: American Thoracic Society recommends initial management with positive pressure ventilation via tracheostomy, especially in infancy 2
• Long-term management: Lifelong ventilatory support required 2
• Monitoring: Continuous monitoring of oxygen saturation, end-tidal CO₂, ECG, and respiratory plethysmography 2
• Precautions: Avoidance of sedatives and CNS depressants; prohibition of unsupervised swimming 2

ROHHAD

• Ventilatory support: Often begins with non-invasive ventilation (mask ventilation at night), though some patients progress to requiring 24-hour ventilation via tracheostomy 1, 5, 6
• Additional management: Treatment of hypothalamic dysfunction (hormone replacement) and autonomic dysregulation 6, 4
• Experimental treatments: Some cases have been treated with immunomodulatory therapies (immunoglobulins, cyclophosphamide, rituximab) based on autoimmune hypothesis 5, 3
• Multidisciplinary approach: Required due to multiple organ system involvement 5, 6, 4

Prognosis

CCHS

• Permanent condition requiring lifelong ventilatory support 2
• With proper management, patients can have good quality of life 2

ROHHAD

• Associated with high mortality (50-60%) without intervention 3
• Cardiorespiratory arrest may occur after intercurrent viral infections 1
• Early diagnosis and intervention improve prognosis 4

Clinical Pitfalls to Avoid

1. Misdiagnosis: Failing to distinguish between ROHHAD and LO-CCHS can lead to inappropriate management 1
2. Delayed diagnosis: For ROHHAD, waiting for all symptoms to develop before diagnosis can be fatal; consider ROHHAD in any child with rapid early obesity 4
3. Inadequate monitoring: Both conditions require vigilant monitoring to prevent respiratory compromise 1, 2
4. Relying solely on oxygen: Using supplemental oxygen without ventilatory support is dangerous in both conditions 2
5. Missing atypical presentations: Some cases of ROHHAD may present without obesity, making diagnosis challenging 7

Diagnostic Algorithm

1. For suspected CCHS:

   • Perform PHOX2B genetic testing
   • If positive: Diagnose CCHS and initiate ventilatory support
   • If negative: Consider ROHHAD or other causes of hypoventilation

2. For suspected ROHHAD:

   • Evaluate for rapid-onset obesity between ages 1.5-7 years
   • Screen for hypothalamic dysfunction (water imbalance, endocrine abnormalities)
   • Perform sleep study to assess for hypoventilation
   • Evaluate for autonomic dysregulation
   • Screen for neural crest tumors
   • Exclude CCHS with PHOX2B testing
   • Initiate appropriate ventilatory support and treat associated conditions