ROHHAD (Rapid-onset Obesity with Hypoventilation, Hypothalamic Dysfunction, Autonomic Dysregulation) Syndrome—What Every Pediatrician Should Know About the Etiopathogenesis, Diagnosis and Treatment: A Review

Figures & data

Table 1 Candidate Genes in ROHHAD Syndrome

Gene	Protein	Function	Associated Diseases	References
ASCL1	Human achaete-scute homolog 1	Regulation of neuroendocrine cell differentiation, development of specific neuronal lineages	Central hypoventilation syndrome, neuroblastoma	^Citation16,Citation18
BDNF	Brain-derived neurotrophic factor	Neuronal development, differentiation of selected neuronal populations, synaptic activity, regulation of energy balance, inflammation	Central hypoventilation syndrome, Wilms' tumor, aniridia, genitourinary anomalies, mental retardation	^Citation2
HCRT	Hypocretins	Sleep-wake cycle regulation, energy balance, regulation of food intake	Narcolepsy	^Citation14
HCRTR1	Hypocretin receptor type 1	Sleep-wake cycle regulation, energy balance, regulation of food intake	Narcolepsy	^Citation14
HCRTR2	Hypocretin receptor type 1	Sleep-wake cycle regulation, energy balance, regulation of food intake	Narcolepsy, cluster headache	^Citation14
HTR1A	5-hydroxytryptamine (serotonin) receptor 1A	Hypothalamic (appetite control and energy regulation), neural activity, behavior, mood	Periodic fever, generalized anxiety disorder	^Citation12
NECDIN	Necdin	Nervous system development, including peripheral autonomic neurons	Prader–Willi syndrome	^Citation16,Citation19
NTRK2	Tropomyosin receptor kinase B (TrkB)	Neuronal development, synaptic plasticity	Obesity, hyperphagia, developmental delay, epileptic encephalopathy	^Citation20,Citation21
OTP	Orthopedia homeobox	Hypothalamic neuroendocrine cells differentiation	Kwashiorkor, marasmus	^Citation12
PACAP	Pituitary adenylate cyclase activating polypeptide	Brain (respiratory, cardiovascular, visceral, thermoregulatory control, energy homeostasis)	Sudden infant death syndrome	^Citation12
PHOX2B	Paired-like homeobox protein 2B	Respiratory, development of the autonomic nervous system	Congenital central hypoventilation syndrome, neuroblastoma	^Citation2,Citation12
RAI1	Retinoic-acid induced 1	Craniofacial and nervous system development, neuronal differentiation, regulator of the circadian cycle	Smith–Magenis syndrome, alacrimia, achalasia, mental retardation	^Citation17

Table 2 Evaluation Workup in ROHHAD Syndrome

Clinical Manifestations		Investigations
Obesity		Morphometry Biological and imaging investigations for differential diagnosis
Hypothalamic dysfunction		Hormonal investigations: antidiuretic hormone secretion, IGF-1, thyroid function, prolactin secretion, gonadotropic function, corticotropic function Imaging investigations (ultrasound, MRI)
Hypoventilation		Overnight polysomnography Nocturnal blood gases Pulse oximetry
Autonomic dysregulation	Cardiovascular	Echocardiography 24-h Holter monitoring 24-h arterial blood pressure monitoring Tilt test
	Gastrointestinal	Transglutaminase autoantibodies Gastrointestinal motility studies
	Neuropsychological	Neurocognitive testing EEG
	Ophthalmological	Ophthalmological examination
Neural crest tumors		Abdominal ultrasound Chest and abdominal MRI MIGB I^123 scintigraphy
Metabolic disorders		Glucose, cholesterol, triglycerides, insulin

Note: Data from these studies.^4,5,32,35,38

Abbreviations: EEG, electroencephalography; IGF-1, insulin-like growth factor 1; MIGB I¹²³, metaiodobenzylguanidine iodine¹²³; MRI, magnetic resonance imaging.

Table 3 Clinic and Genetic Diagnostic Criteria in ROHHAD Syndrome, PWS and CCHS

Diagnostic Criteria		ROHHAD Syndrome	PWS	CCHS
Clinical features
Rapid-onset obesity		Yes	Yes	No
Hypoventilation		Yes	Sometimes	Yes
Hypothalamic dysfunction	Disturbance of maintenance of water balance	Yes	No	No
	Growth hormone deficiency	Sometimes	Sometimes	No
	Hypothyroidism	Sometimes	Sometimes	No
	Hyperprolactinemia	Yes	No	No
	Adrenal dysfunction	Sometimes	Sometimes	No
	Precocious puberty	Sometimes	Sometimes	No
	Hypogonadism	Sometimes	Sometimes	No
Autonomic dysregulation	Bradycardia	Sometimes	No	Sometimes
	Gastrointestinal dysmotility	Yes	No	Yes
	Thermal dysregulation	Yes	Yes	Yes
	Cold extremities	Yes	No
	Increased sweating	Yes	No	Yes
	Ophthalmologic abnormalities	Yes	Yes	Yes
	Altered pain perception	Yes	Yes	Yes
Behavioral disorders		Sometimes	Yes	Sometimes
Neurologic abnormalities	Seizures	Sometimes	Sometimes	Sometimes
	Sleep abnormalities	No	Yes	Sometimes
Neural crest tumors		Yes	No	Yes
Decreased fetal movement		No	Yes	No
Neonatal hypotonia		No	Yes	No
Delayed motor skills		No	Yes	Yes
Delayed cognitive development		Sometimes	Yes	Yes
Dysmorphic facial features		Sometimes	Yes	Sometimes
Small hands and feet		No	Yes	No
Scoliosis		Sometimes	Yes	No
Genetic testing		No candidate genes	Parent-specific DNA methylation	PHOX2B gene mutation

Note: Data from these studies.^6,40–42

Abbreviations: CCHS, congenital central hypoventilation syndrome; DNA, deoxyribonucleic acid; PHOX2B, paired-like homeobox protein 2B; PWS, Prader–Willi syndrome.

Table 4 Therapeutic Options in ROHHAD Syndrome

Clinical Manifestations		Treatment
Obesity		Diet Exercise
Hypothalamic dysfunction		Specific hormone replacement
Hypoventilation		Artificial ventilation during sleep or continuous ventilatory support mask ventilation continuous positive airway pressure mechanical ventilation tracheostomy
Autonomic dysregulation	Cardiovascular	Antihypertensive medication Cardiac pacemaker
	Gastrointestinal	Stool softeners Antidiarrhea drugs
	Neuropsychological	Antiepileptics Antipsychotics
	Thermal dysregulation	Regulation of ambient temperature
Neural crest tumors		Surgical removal Multimodal treatment
Metabolic disorders		Antidiabetic drugs Hypolipemiant drugs

Note: Data from these studies.^4,5

De Pontual L, Trochet D, Caillat-Zucman S, et al. Delineation of late onset hypoventilation associated with hypothalamic dysfunction syndrome. Pediatr Res. 2008;64(6):689–694. doi:10.1203/PDR.0b013e318187dd0e

 PubMed Web of Science ®Google Scholar

Larkin E, Patel S, Goodloe R, et al. A candidate gene study of obstructive sleep apnea in European Americans and African Americans. Am J Respir Crit Care Med. 2010;182(7):947–953. doi:10.1164/rccm.201002-0192OC

 PubMed Web of Science ®Google Scholar

Ize-Ludlow D, Gray JA, Sperling MA, et al. Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation presenting in childhood. Pediatrics. 2007;120(1):e179–e188. doi:10.1542/peds.2006-3324

 PubMed Web of Science ®Google Scholar

Barclay S, Rand C, Gray P, et al. Absence of mutations in HCRT, HCRTR1 and HCRTR2 in patients with ROHHAD. Resp Phys Neurobiol. 2015;221:59–63. doi:10.1016/j.resp.2015.11.002

 PubMed Web of Science ®Google Scholar

Rand CM, Patwari PP, Rodikova EA, et al. Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation: analysis of hypothalamic and autonomic candidate genes. Pediatr Res. 2011;70(4):375–378. doi:10.1203/PDR.0b013e318229474d

 PubMed Web of Science ®Google Scholar

Tennese A, Gee C, Wevrick R. Loss of the Prader-Willi syndrome protein necdin causes defective migration, axonal outgrowth, and survival of embryonic sympathetic neurons. Dev Dyn. 2008;237(7):1935–1943. doi:10.1002/dvdy.21615.

 PubMed Web of Science ®Google Scholar

Han JC. Rare Syndromes and Common Variants of the Brain-Derived Neurotrophic Factor Gene in Human Obesity. In: Tao Y-X, editor. Genetics of Monogenic and Syndromic Obesity. Vol. 140. Chennai: Academic Press; 2016:75–95.

 Google Scholar

Yeo G, Connie Hung -C-C, Rochford J, et al. A de novo mutation affecting human TrkB associated with severe obesity and developmental delay. Nat Neurosci. 2004;7(11):1187–1189. doi:10.1038/nn1336.

 PubMed Web of Science ®Google Scholar

Thaker V, Esteves K, Towne M, et al. Whole Exome Sequencing Identifies RAI1 Mutation in a Morbidly Obese Child Diagnosed With ROHHAD Syndrome. J Clin Endocrinol Metab. 2015;100(5):1723–1730. doi:10.1210/jc.2014-4215

 PubMed Web of Science ®Google Scholar

Lee J, Shin J, Kim S, et al. Rapid-onset obesity with hypoventilation, hypothalamic, autonomic dysregulation and neuroendocrine tumors (ROHHADNET) syndrome: a systematic review. Bio Med Res Int. 2018. doi:10.1155/2018/1250721.

 Web of Science ®Google Scholar

Harvengt J, Gernay C, Mastouri M, Farhat N, Lebrethon M-C, Seghaye M-C M-C. ROHHAD(NET) syndrome: systematic review of the clinical timeline and recommendations for diagnosis and prognosis. J Clin Endocrinol Metab. 2020;105(7):1–13. doi:10.1210/clinem/dgaa247.

 PubMed Web of Science ®Google Scholar

Kot K, Moszczynska E, Lecka-Ambroziak A, Migdal M, Szalecki M. Zespół ROHHAD u 9-letniego chłopca — opis przypadku. Endokrynologia Polska. 2016;67(2):226–231. doi:10.5603/EP.a2016.0037.

 PubMed Web of Science ®Google Scholar

Aljabban L, Kassab L, Bakoura NA, Alsalka MF, Maksoud I. Rapid-onset obesity, hypoventilation, hypothalamic dysfunction, autonomic dysregulation and neuroendocrine tumor syndrome with a homogenous enlargement of the pituitary gland: a case report. J Med Case Rep. 2016;10(1):328. doi:10.1186/s13256-016-1116-z.

 PubMedGoogle Scholar

Eldin JAW, Tombayoglu D, Butz L, et al. Natural history of ROHHAD syndrome: development of severe insulin resistance and fatty liver disease over time. Clinical Diabetes and Endocrinology. 2019;5(1):9. doi:10.1186/s40842-019-0082-y.

 PubMedGoogle Scholar

Cielo C, Marcus C. Central hypoventilation syndromes. Sleep Med Clin. 2014;9(1):105–118. doi:10.1016/j.jsmc.2013.10.005.

 PubMedGoogle Scholar

Barclay S, Rand C, Nguyen L, et al. ROHHAD and Prader-Willi syndrome (PWS): clinical and genetic comparison. Orphanet J Rare Dis. 2018;13(1):124. doi:10.1186/s13023-018-0860-0.

 PubMed Web of Science ®Google Scholar

Charnay A, Antisdel-Lomaglio J, Zelko FA. Congenital central hypoventilation syndrome: neurocognition already reduced in preschool-aged children. Chest. 2016;149(3):809–815. doi:10.1378/chest.15-0402.

 PubMed Web of Science ®Google Scholar