ROHHAD

Overview

ROHHAD (Rapid-onset Obesity with Hypothalamic dysfunction, Hypoventilation, and Autonomic Dysregulation) is a rare and life-threatening pediatric syndrome characterized by dramatic weight gain, followed by dysfunction of the hypothalamus, breathing abnormalities, and disturbances in the autonomic nervous system. Symptoms typically begin between the ages of 1.5 and 10 years, often after an apparently normal early development.

The syndrome is frequently misdiagnosed or diagnosed late due to its rarity and symptom overlap with other disorders such as Prader-Willi syndrome or simple obesity. Early recognition is critical, as delayed diagnosis can result in serious complications, including sudden respiratory failure and cardiac arrest. ROHHAD is distinct from Congenital Central Hypoventilation Syndrome (CCHS), although both involve hypoventilation.

Causes

The exact cause of ROHHAD is unknown. Unlike CCHS, which is caused by PHOX2B gene mutations, no consistent genetic mutation has been identified in ROHHAD patients. The condition is thought to have a complex origin, possibly involving:

Potential Mechanisms:

• Hypothalamic dysfunction: Disruption in the hypothalamus, which regulates hunger, temperature, thirst, and hormonal balance

• Immune or autoimmune component: Some cases show an association with neural crest tumors or autoantibodies

• Epigenetic or environmental triggers: These may influence gene expression in susceptible individuals

Genetic Considerations:

• No known familial inheritance pattern

• Most cases appear sporadic

Symptoms

Symptoms of ROHHAD appear in stages and progressively worsen over time. The initial sign is often rapid and unexplained weight gain, followed by multiple endocrine, respiratory, and autonomic disturbances.

Stage 1 – Rapid-Onset Obesity:

• Sudden and extreme weight gain over weeks to months

• Usually begins between ages 1.5 and 7 years

Stage 2 – Hypothalamic Dysfunction:

• Growth hormone deficiency or growth deceleration

• Disordered temperature regulation (hypothermia or hyperthermia)

• Hyperprolactinemia (elevated prolactin levels)

• Disordered water balance (diabetes insipidus or SIADH)

• Early or delayed puberty

Stage 3 – Hypoventilation and Respiratory Dysfunction:

• Alveolar hypoventilation, especially during sleep

• Central sleep apnea or obstructive sleep apnea

• Fatigue, cyanosis (bluish skin), morning headaches

• Possible sudden respiratory arrest without warning

Stage 4 – Autonomic Dysregulation:

• Altered heart rate or blood pressure

• Digestive issues (severe constipation, reflux, or diarrhea)

• Pupillary abnormalities

• Excessive sweating or cold intolerance

• Behavioral issues, mood swings, or cognitive changes

Associated Features:

• Neural crest tumors: Such as ganglioneuroma or ganglioneuroblastoma in ~40% of cases

• Seizures: Occasionally reported

• Anxiety or autistic-like behavior

Diagnosis

Diagnosis of ROHHAD is clinical and made by recognizing the characteristic constellation of symptoms, particularly after ruling out other disorders such as Prader-Willi syndrome, CCHS, and hypothalamic tumors.

Diagnostic Criteria:

• Rapid-onset obesity in early childhood

• Hypoventilation documented by sleep study or blood gases

• Evidence of hypothalamic and autonomic dysfunction

Recommended Investigations:

• Polysomnography (sleep study): To detect hypoventilation and sleep apnea

• Endocrine testing: Growth hormone, cortisol, prolactin, TSH, water balance hormones

• MRI of brain and spine: To rule out tumors or structural anomalies

• CT or MRI of the chest and abdomen: To look for neural crest tumors

• Genetic testing: To rule out PHOX2B mutations and Prader-Willi syndrome

Treatment

There is no cure for ROHHAD. Treatment is supportive, multidisciplinary, and focused on managing individual symptoms. Lifelong care is typically required.

1. Respiratory Support:

• Non-invasive ventilation (BiPAP) during sleep or 24/7 depending on severity

• Tracheostomy with mechanical ventilation in severe hypoventilation

• Oxygen therapy (with caution to avoid suppressing respiratory drive)

2. Endocrine and Hypothalamic Management:

• Hormone replacement therapy as needed (e.g., growth hormone, thyroid hormone, desmopressin)

• Fluid and electrolyte management for SIADH or diabetes insipidus

• Temperature regulation through environmental and medical means

3. Autonomic and Behavioral Management:

• Gastrointestinal care (e.g., laxatives, reflux treatment)

• Behavioral therapy and educational support

• Monitoring for anxiety, mood swings, or attention issues

4. Tumor Surveillance and Treatment:

• Regular imaging for neural crest tumors

• Surgical removal or oncologic treatment if tumors are found

5. Multidisciplinary Follow-up:

• Involvement of pulmonologists, endocrinologists, neurologists, gastroenterologists, psychologists, and sleep specialists

• Routine monitoring for emerging complications

Prognosis

ROHHAD is a chronic, progressive, and potentially fatal condition. The prognosis depends largely on the severity of hypoventilation and how early respiratory support is initiated. Sudden unexpected death, often during sleep, is a serious risk, particularly if hypoventilation is not adequately treated.

With aggressive and continuous medical support, many children can survive into adolescence or adulthood. However, quality of life is often significantly impacted by the need for ventilatory support and the burden of multisystemic care. Research is ongoing to better understand the underlying causes and develop targeted therapies, but early recognition and proactive management remain the cornerstone of care today.