Rapid-onset childhood obesity-hypothalamic dysfunction-hypoventilation-autonomic dysregulation syndrome (ORPHA:293987)
A rare syndromic endocrine disease characterized by childhood-onset hyperphagia and obesity, alveolar hypoventilation, dysautonomia, hypothalamic dysfunction and neurobehavioral disorders. Central hypothyroidism, endocrine anomalies, electrolyte imbalances and respiratory failure may also be associated.
Epidemiology
Fewer than 100 cases have been reported in the medical literature to date.
Clinical description
Disease onset is between 1.5 to 7 years of age with dramatic weight gain (approximately 9-13 kg over a 3-12 month period) associated with alveolar hypoventilation in a previously healthy child. This rapid-onset obesity is considered as the first sign of hypothalamic dysfunction. Other symptoms of hypothalamic dysfunction may include hyperprolactinemia, central hypothyroidism, water balance disorder, abnormal growth hormone response, adrenocortical insufficiency or puberty disorders. Autonomic dysfunction is principally characterized by an alveolar hypoventilation but may also manifest later with thermal dysregulation, excessive sweating, cardiovascular manifestations (arrhythmias or blood pressure dysregulation), strabismus, abnormal pupillary reaction to light, gastrointestinal or sensory disturbances. Some behavioral (such as aggressiveness) or mood disorders may also be present and seem to be linked with a suboptimal ventilation management. The risk of neuroendocrine tumors in patients is estimated at 50%. These tumors typically include ganglioneuromas and ganglioneuroblastoma and are essentially intra-abdominally located. Patients associating neuroendocrine tumors are described as ROHHADNET.
Etiology
Etiology is currently unknown. Genetic studies have investigated numerous genes involved in neuronal development as well as candidate genes of hypothalamic and autonomic dysfunction without identifying any specific mutation. Apart from genetic etiologies, other hypotheses include an epigenetic, autoimmune or even paraneoplastic process.
Diagnostic methods
Diagnosis is based on the clinical criteria of dramatic weight gain in a previously healthy child in association with alveolar hypoventilation and at least one other sign of hypothalamic dysfunction (e.g. hyperprolactinemia, central hypothyroidism, water balance disorder, abnormal growth hormone response, adrenocortical insufficiency or puberty disorder). Mutation in the PHOX2B gene must be excluded.
Differential diagnosis
The primary differential diagnosis is Ondine syndrome, which is defined by a congenital absence of central respiratory control, diffuse involvement of the autonomic nervous system and, in 90% of cases, presence of a PHOX2B mutation. Other diagnoses to be considered include Genetic non-syndromic obesity, Cushing syndrome, a hypothalamic tumor or other conditions with hypothalamic dysfunction, such as Narcolepsy type 1.
Management and treatment
Specific pediatric multidisciplinary approach is required, with regular follow-up by a cardiologist, pulmonologist, endocrinologist, surgeon, psychiatrist, neurologist and sleep medicine physician. Early recognition of the symptoms is essential as management is based on the rapid instauration of the appropriate therapeutic for each symptom. Hypoventilation, the most life-threatening feature, requires either ventilator support during sleep or 24 hour/day support with BPAP (bilevel positive airway pressure) ventilation through a facial mask or a tracheostomy. Cardiac pacemaker is required in cases of severe bradycardia. Specific hormonal therapies are established based on the endocrine disturbances. Oncologic and surgical management is required in cases of neuroendocrine tumors.
Prognosis
The long-term outlook is variable. Children who are diagnosed early and appropriately managed can have a relatively good quality of life. On the contrary, if the diagnosis is delayed or the symptoms are not anticipated, children present an increased risk for sudden death (typically due to respiratory failure or cardiorespiratory arrest) with demise occurring on average around 10 years of age.

                            Last update: 
                            April 2019


                            - Expert reviewer(s): 
                            Dr Julie HARVENGT