ROHHAD syndrome is extremely rare with fewer than 200 cases documented worldwide. Due to an absence of a specific diagnostic biomarker, it is likely that many individuals with this condition may remain undiagnosed.

The exact cause of ROHHAD is unknown. Theories include genetic, epigenetic (changes in gene expression from environmental factors), autoimmune, or paraneoplastic (production of chemical signaling molecules resulting from the presence of a tumor) mechanisms.

ROHHAD manifests as a constellation of clinical features that typically emerge over time:

1. Rapid-onset obesity: Often the first visible sign, with sudden weight gain of 20–30 pounds over 3–12 months, usually between ages 2–7 years.

2. Hypothalamic dysfunction: May include hormonal dysregulation like:

   • Abnormal sodium balance (hyponatremia from low sodium or hypernatremia from high sodium)

   • Growth hormone deficiency

   • Hypothyroidism, adrenal insufficiency, hyperprolactinemia

   • Early or delayed puberty

3. Hypoventilation (insufficient breathing):  Hypoventilation tends to follow obesity onset and can lead to life-threatening cardiorespiratory arrest if unrecognized. 

4. Autonomic nervous system dysregulation resulting in irregularities in:

   • Temperature control (hot/cold intolerance)

   • Gastrointestinal motility (constipation or diarrhea)

   • Cardiac rhythm (e.g., bradycardia)

   • Ophthalmic signs (pupillary dysfunction, strabismus)

   • Pain perception abnormalities

5. Neuroendocrine tumors: Around 40% of patients develop ganglioneuromas or ganglioneuroblastomas (neural crest-derived tumors).

6. Behavioral and cognitive issues: Some children show behavioral disorders or intellectual impairments—often thought to result from hypoxic damage due to untreated hypoventilation.

The list of symptoms demonstrates that ROHHAD exerts far-reaching effects across multiple organ systems, including the cardiovascular, gastrointestinal, neurological and metabolic systems. The progressive and chronic nature of the disease necessitates continuous, comprehensive, adaptive, multidisciplinary care.

Diagnosis of ROHHAD syndrome is primarily based on a specific set of clinical criteria, as there is currently no single definitive diagnostic test or genetic biomarker available. 

Major Criteria for Diagnosis:

• Dramatic weight gain (rapid-onset obesity) in a previously healthy child, typically occurring between 2 and 7 years of age. This rapid-onset obesity is considered the initial manifestation of hypothalamic dysfunction.

• Alveolar hypoventilation (lack of oxygen to the lungs), which typically appears after 1.5 years of age.

Additional Criterion:

• At least one other sign of hypothalamic dysfunction must be present. These include:

• Hyperprolactinemia - high levels of prolactin protein in the blood (often associated with milk production) pointing to dysregulation of the pituitary gland

• Central hypothyroidism - deficiency in thyroid function, associated with pituitary gland  problems

• Water balance disorder (e.g., dysnatremia, diabetes insipidus, syndrome of inappropriate antidiuretic hormone secretion - SIADH) 

• Abnormal growth hormone response or deficiency 

• Adrenocortical insufficiency 

• Puberty disorders (either early or delayed onset) 

Autonomic dysfunction may also manifest later in the disease course.

To differentiate ROHHAD from a similar syndrome, an important step in the diagnostic process can be the exclusion of mutations in the PHOX2B gene, involved in the development of Congenital Central Hypoventilation Syndrome (CCHS).

There is no cure for ROHHAD. Treatment is supportive, multidisciplinary and tailored for each patient:

• Ventilatory support:  As hypoventilation is the most life-threatening feature of ROHHAD, noninvasive or invasive respiratory support (e.g., CPAP, BiPAP, or tracheostomy) is often needed, especially during sleep.

• Endocrine/hormone replacement therapies for growth hormone, thyroid, adrenal, and other deficiencies.

• Tumor surveillance and surgical removal if neural crest tumors are detected.

• Nutritional management: Emphasis on avoiding further weight gain rather than weight loss, as obesity is difficult to control by conventional means.

• Experimental therapies: Immunosuppressive agents like cyclophosphamide and rituximab have shown anecdotal benefit in some cases but lack robust clinical trial support.

• Supportive therapies for autonomic symptoms, psychiatric care, and physical therapy as needed.

The prognosis for ROHHAD is guarded. Cardiopulmonary arrest is a leading cause of mortality. Up to 50-60% of patients may die due to sudden arrest before adolescence if untreated or if diagnosis is delayed. Historically, survival beyond the third decade of life is uncommon, with the average age of death being around 10 years.

1. Hawton K, Giri D, Crowne E, Greenwood R, Hamilton-Shield J. (2024). “The Enigma That Is ROHHAD Syndrome: Challenges and Future Strategies.” Brain Sci. 14(11):1046. doi: 10.3390/brainsci14111046. PMID: 39595809; PMCID: PMC11591771.

2. National Organization for Rare Disorders:  Rapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation.

3. Cleveland Clinic - Hyperprolactinemia