Is late onset congenital hypoventilation with hypothalamic dysfunction associated with the PHOX2B (paired-like homeobox 2b) gene?

Late-Onset Congenital Hypoventilation with Hypothalamic Dysfunction Does NOT Have PHOX2B Gene Mutations

Late-onset central hypoventilation with hypothalamic dysfunction (now termed ROHHAD - Rapid-onset Obesity with Hypothalamic dysfunction, Hypoventilation, and Autonomic Dysregulation) is a distinctly different syndrome from congenital central hypoventilation syndrome (CCHS) and does NOT have PHOX2B gene mutations. 1

Critical Distinction Between Two Syndromes

The terminology "late-onset central hypoventilation with hypothalamic dysfunction" was historically used but has been renamed ROHHAD specifically to distinguish it from late-onset CCHS (LO-CCHS), which are two completely separate entities. 1

ROHHAD (Late-Onset with Hypothalamic Dysfunction):

• No PHOX2B mutations - this is the defining characteristic that separates it from CCHS 1, 2
• Presents between ages 1.5-7 years with rapid-onset obesity (20-40 pound gain over 4-6 months) 1
• Hypothalamic dysfunction includes water imbalance, elevated prolactin, altered puberty onset 1
• Hypoventilation appears after obesity and hypothalamic symptoms 1, 2
• Nearly 50% experience cardiorespiratory arrest after viral infection 1
• 40% develop neural crest tumors 1
• Diagnosis requires documented absence of PHOX2B mutations (both PARMs and NPARMs) 1
• No genetic testing available; diagnosis is clinical 1

Late-Onset CCHS (LO-CCHS):

• Always has PHOX2B mutations - typically 20/24 or 20/25 genotypes 1
• Can present in later infancy, childhood, or adulthood 1, 3, 4, 5
• Hypoventilation is the primary feature, not preceded by obesity 1
• No hypothalamic dysfunction as a defining feature 1
• Often triggered by anesthesia, sedation, or respiratory illness 1
• Distinguished from other mild hypoventilation syndromes by the presence of a PHOX2B mutation 1

Clinical Pitfall to Avoid

The most critical error is confusing these two entities based on the outdated terminology. If a patient presents with rapid-onset obesity followed by hypothalamic dysfunction and then hypoventilation, you must test for PHOX2B and document its absence to diagnose ROHHAD. 1 Conversely, if a patient has late-onset hypoventilation without the obesity-hypothalamic sequence, PHOX2B testing should be positive to confirm LO-CCHS. 1

Diagnostic Algorithm

For any patient with late-onset hypoventilation:

1. Obtain detailed history focusing on:

   • Timing of obesity onset relative to respiratory symptoms 1, 2
   • Presence of hypothalamic dysfunction (water imbalance, altered puberty, prolactin elevation) 1
   • Triggers: anesthesia, sedation, or severe respiratory illness 1
   • Past unexplained seizures or neurocognitive impairment 1

2. Order PHOX2B genetic testing (both PARMs and NPARMs) 1

3. If PHOX2B positive: Diagnosis is LO-CCHS 1, 3, 4, 5

4. If PHOX2B negative with obesity-hypothalamic-hypoventilation sequence: Diagnosis is ROHHAD 1, 2

The American Thoracic Society explicitly clarified in 2010 that practitioners must distinguish these syndromes through careful history and PHOX2B testing, as ROHHAD represents a distinctly different disorder with no identified genetic cause. 1