Clinical Description of Ten Pediatric Patients with Clinical Signs of ROHHAD-NET Syndrome and Review of the Literature

Introduction: Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) syndrome is a rare disorder characterized by respiratory failure, autonomic dysregulation, and endocrine abnormalities. Some of these patients may also develop neuroendocrine tumors (ROHHAD-NET). The aim of this study was to evaluate the clinical features, biochemical findings, treatments, and outcomes in a cohort of pediatric patients with ROHHAD-NET syndrome followed at a single tertiary center. Methods: A retrospective review of 10 medical records of patients with ROHHAD-NET syndrome followed between 2007 and 2024 was conducted. Data analyzed included clinical, biochemical, therapeutic interventions and outcomes. Results: Rapid-onset obesity, observed in all 10 patients, was the first clinical sign with a mean age at onset (MAO) of 5.1 ± 1.8 years. Neurobehavioral disorders were also an early manifestation, occurring in 5 cases with a MAO of 5 ± 1 years. All patients developed respiratory symptoms, with a MAO of 7.4 ± 3 years. Six patients were diagnosed with obstructive sleep apnea syndrome, including 2 with associated alveolar central hypoventilation. Seven patients required ventilatory support. All patients had hypothalamic dysfunction, MAO 6.6 ± 1.3 years. Disorders of water balance were the most frequent manifestation (n = 10), followed by hyperprolactinemia, central hypothyroidism, growth hormone deficiency, adrenal insufficiency, precocious puberty, and hypogonadotropic hypogonadism. Autonomic dysregulation was present in the entire cohort (MAO 6.7 ± 2.3 years), with strabismus as the most common clinical sign (n = 6). Neural crest tumors (ganglioneuromas) were identified in 5 patients, with a MAO of 5.4 ± 1.3 years. Tumor location included the adrenal gland (n = 2) and mediastinum (n = 3). Other clinical findings included thrombocytopenia, celiac disease, enuresis, type 1 and type 2 diabetes, seizures, hypo- and hypertension, and primary hypothyroidism. All patients received symptomatic treatment; 3 also received intravenous immunoglobulin as compassionate therapy, without significant benefit. Three patients died. Conclusion: High clinical suspicion and early recognition are essential for a prompt diagnosis, timely initiation of respiratory support, and reduction of morbidity and mortality. Larger cohorts are needed for better characterization of this syndrome and to further elucidate its etiology.