Background: rapid onset of obesity with hypothalamic dysfunction, hypoventilation and autonomic dysregulation (ROHHAD), which was previously known as late-onset central hypoventilation with hypothalamic dysfunction, is a rare and complex syndrome that has been described in several case reports and series worldwide. Patients with ROHHAD are usually reported to be healthy prior to a characteristic rapid weight gain associated with autonomic and hypothalamic dysfunction and fatal central hypoventilation in the absence of mutations in the paired-like homeobox 2B (PHOX2B) gene. Case study: despite increased advancing knowledge of the disease course, the variable onset often results in delaying or missed diagnosis of ROHHAD syndrome which resulted in fatal cardiopulmonary arrest, central hypoventilation or impaired neurocognitive function. Here, we reported the first case series of ROHAAD syndrome from Saudi Arabia comprising four patients with different clinical manifestations. In this article we reported 4 cases of ROHHAD as a first serial cases from Arab area according to our Knowledge, with variable manifestations, but all sharing the rapid onset of obesity and hypoventilation, but case 1 her main striking feature was altered pain sensation and thirsty as autonomic dysregulation, while the second patient was twin 2 had pseudotumor cerebri and behavioral changes and her second twin was healthy, the third case also had behavioral changes and case 4 had obstructive sleep apnea. Conclusion: due to the overlap in symptoms and signs between ROHHAD and other well-characterized disease entities, multidisciplinary care with input from a center with expertise in ROHHAD was crucial to the successful management of patients with suspected ROHHAD syndrome. Furthermore, mortality associated with the high incidence of cardiopulmonary arrest may be prevented by early ventilatory support.