Rapid-Onset Obesity with Hypoventilation, Hypothalamic, Autonomic Dysregulation, and Neuroendocrine Tumors (ROHHADNET) Syndrome: A Systematic Review

Abstract

Background and Aim ROHHADNET (rapid-onset obesity with hypoventilation, hypothalamic, autonomic dysregulation, neuroendocrine tumor) syndrome is a rare disease with grave outcome. Although early recognition is essential, prompt diagnosis may be challenging due to its extreme rarity. This study aimed to systematically review its clinical manifestation and to identify genetic causes. Materials and Methods We firstly conducted a systematic review on ROHHAD/NET. Electronic databases were searched using related terms. We secondly performed whole exome sequencing (WES) and examined copy number variation (CNV) in two patients to identify genetic causes. Results In total, 46 eligible studies including 158 patients were included. There were 36 case reports available for individual patient data (IPD; 48 patients, 23 ROHHAD, and 25 ROHHADNET) and 10 case series available for aggregate patient data (APD; 110 patients, 71 ROHHAD, and 39 ROHHADNET). The median age at onset calculated from IPD was 4 years. Gender information was available in 100 patients (40 from IPD and 60 from APD) in which 65 females and 35 males were showing female preponderance. Earliest manifestation was rapid obesity, followed by hypothalamic symptoms. Most common types of neuroendocrine tumors were ganglioneuromas. Patients frequently had dysnatremia and hyperprolactinemia. Two patients were available for WES. Rare variants were identified in PIK3R3, SPTBN5, and PCF11 in one patient and SRMS, ZNF83, and KMT2B in another patient, respectively. However, there was no surviving variant shared by the two patients after filtering. Conclusions This study systematically reviewed the phenotype of ROHHAD/NET aiming to help early recognition and reducing morbidity. The link of variants identified in the present WES requires further investigation.

Natural history of ROHHAD syndrome: development of severe insulin resistance and fatty liver disease over time

“…Recently Lee et al reported a systematic review of the reported cases independent of our efforts, but this review did not focus on insulin resistance, dyslipidemia or fatty liver disease. In fact, the summary tables found in that review do not comment specifically on any of these novel features [10]. The syndrome is quite distinctive from Prader-Willi and other complex syndromes of obesity due to its sudden onset acquired nature, absence of symptoms at birth, predominance of autonomic features, and respiratory abnormalities as well as diabetes insipidus and hyperprolactinemia.…”

Three Cases of Hypoventilation in the First Decade with an Unusual Presentation and Rare Etiology: A Case Report

“…One important finding in these two patients was arterial and venous thrombosis without a known etiology, despite normal coagulation tests and absence of known genetic mutations. It should be noted that arterial or venous thrombosis has not been reported as one of the signs of ROHHAD syndrome (6). Considering the unknown etiology of the disease, variety of clinical symptoms, and course of ROHHAD syndrome (due to the low prevalence of this syndrome), it is suggested to consider this finding in other studies on ROHHAD syndrome in order to select the most appropriate treatment or prophylaxis.…”

Long-Term Non-invasive Ventilation in Children: Current Use, Indications, and Contraindications

“…Table 3 lists the potential indications for long-term non-invasive ventilation (39). Examples of alterations in central respiratory drive are congenital central hypoventilation syndrome (40,41), ROHHAD (rapid-onset obesity, hypothalamic dysfunction, hypoventilation, and autonomic dysregulation) (42,43) and various brainstem anomalies, such as Chiari type II malformation (44). Cerebral palsy can also lead to central hypoventilation, in addition to upper airway obstruction, spine and chest wall deformity, and/or chronic lung disease (45).…”