We provide a comprehensive description of the clinical spectrum of rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation in terms of timing and scope of symptoms, study of candidate genes, and screening for chromosomal deletions and duplications. Negative PHOX2B sequencing results demonstrate that this entity is distinct from congenital central hypoventilation syndrome.

OBJECTIVEA progressive decline in insulin responses to glucose was noted in individuals before the onset of type 1 diabetes. We determined whether such abnormalities occurred in prediabetic NOD mice—the prototypic model for human type 1 diabetes.RESEARCH DESIGN AND METHODSMorning blood glucose was measured every other day in a cohort of NOD females. Glucose tolerance and insulin secretion were measured longitudinally by intraperitoneal glucose tolerance tests in NOD/ShiLtJ and BALB/cJ mice 6 to 14 weeks of age. Arginine-stimulated insulin secretion and insulin sensitivity were assessed during intraperitoneal arginine or intraperitoneal insulin tolerance tests.RESULTSDuring prediabetes, NOD females displayed a progressive increase in glucose levels followed by an acute onset of hyperglycemia. First-phase insulin responses (FPIRs) during the intraperitoneal glucose tolerance test (IPGTT) declined before loss of glucose tolerance in NOD. The failure of FPIR could be detected, with a decline in peak insulin secretion during IPGTT. Arginine-stimulated insulin secretion remained unchanged during the study period. The decline in insulin secretion in NOD mice could not be explained by changes in insulin sensitivity.CONCLUSIONSThere was an impressive decline in FPIR before changes in glucose tolerance, suggesting that impairment of FPIR is an early in vivo marker of progressive β-cell failure in NOD mice and human type 1 diabetes. We portend that these phenotypes in NOD mice follow a similar pattern to those seen in humans with type 1 diabetes and validate, in a novel way, the importance of this animal model for studies of this disease.

Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) falls within a group of pediatric disorders with both respiratory control and autonomic nervous system dysregulation. Children with ROHHAD typically present after 1.5 years of age with rapid weight gain as the initial sign. Subsequently, they develop alveolar hypoventilation, autonomic nervous system dysregulation, and, if untreated, cardiorespiratory arrest. To our knowledge, this is the first report of discordant presentation of ROHHAD in monozygotic twins. Twin girls, born at term, had concordant growth and development until 8 years of age. From 8 to 12 years of age, the affected twin developed features characteristic of ROHHAD including obesity, alveolar hypoventilation, scoliosis, hypothalamic dysfunction (central diabetes insipidus, hypothyroidism, premature pubarche, and growth hormone deficiency), right paraspinal/thoracic ganglioneuroblastoma, seizures, and autonomic dysregulation including altered pain perception, large and sluggishly reactive pupils, hypothermia, and profound bradycardia that required a cardiac pacemaker. Results of genetic testing for PHOX2B (congenital central hypoventilation syndrome disease-defining gene) mutations were negative. With early recognition and conservative management, the affected twin had excellent neurocognitive outcome that matched that of the unaffected twin. The unaffected twin demonstrated rapid weight gain later in age but not development of signs/symptoms consistent with ROHHAD. This discordant twin pair demonstrates key features of ROHHAD including the importance of early recognition (especially hypoventilation), complexity of signs/symptoms and clinical course, and importance of initiating comprehensive, multispecialty care. These cases confound the hypothesis of a monogenic etiology for ROHHAD and indicate alternative etiologies including autoimmune or epigenetic phenomenon or a combination of genetic predisposition and acquired precipitant.

BackgroundRapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD) is thought to be a genetic disease caused by de novo mutations, though causative mutations have yet to be identified. We searched for de novo coding mutations among a carefully-diagnosed and clinically homogeneous cohort of 35 ROHHAD patients.MethodsWe sequenced the exomes of seven ROHHAD trios, plus tumours from four of these patients and the unaffected monozygotic (MZ) twin of one (discovery cohort), to identify constitutional and somatic de novo sequence variants. We further analyzed this exome data to search for candidate genes under autosomal dominant and recessive models, and to identify structural variations. Candidate genes were tested by exome or Sanger sequencing in a replication cohort of 28 ROHHAD singletons.ResultsThe analysis of the trio-based exomes found 13 de novo variants. However, no two patients had de novo variants in the same gene, and additional patient exomes and mutation analysis in the replication cohort did not provide strong genetic evidence to implicate any of these sequence variants in ROHHAD. Somatic comparisons revealed no coding differences between any blood and tumour samples, or between the two discordant MZ twins. Neither autosomal dominant nor recessive analysis yielded candidate genes for ROHHAD, and we did not identify any potentially causative structural variations.ConclusionsClinical exome sequencing is highly unlikely to be a useful diagnostic test in patients with true ROHHAD. As ROHHAD has a high risk for fatality if not properly managed, it remains imperative to expand the search for non-exomic genetic risk factors, as well as to investigate other possible mechanisms of disease. In so doing, we will be able to confirm objectively the ROHHAD diagnosis and to contribute to our understanding of obesity, respiratory control, hypothalamic function, and autonomic regulation.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-015-0314-x) contains supplementary material, which is available to authorized users.