ROHHAD Syndrome

Lee JM, et al. Rapid-Onset Obesity with Hypoventilation, Hypothalamic, Autonomic Dysregulation, and Neuroendocrine Tumors (ROHHADNET) Syndrome: A Systematic Review. Biomed Res Int. 2018 Nov 21;2018:1250721.

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.

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Recent articles published about ROHHAD (2017-2018):

Benvenga S, et al. Less known aspects of central  hypothyroidism: Part 2 – Congenital etiologies. J Clin Transl Endocrinol. 2018 Sep 27;14:5-11.

Barclay SF, et al. ROHHAD and Prader-Willi syndrome (PWS): clinical and genetic
comparison. Orphanet J Rare Dis. 2018 Jul 20;13(1):124.

Lim SH, et  al. Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation associated with neuroblastoma. Pediatr Blood Cancer. 2018 Jun;65(6):e26983.

Esparza Isasa E, et al. Anesthesia in a pediatric patient with ROHADD syndrome. Rev Esp Anestesiol Reanim. 2018 May 1. [Epub ahead of print]

Şiraz ÜG, et al. A Rare Cause of Hypothalamic Obesity, Rohhad Syndrome: 2 Cases. J Clin Res Pediatr Endocrinol. 2018 Mar 19.

Ibáñez-Micó S, et al. Rapid-onset obesity with hypothalamic dysregulation, hypoventilation, and autonomic dysregulation (ROHHAD syndrome): A case report and literature review. Neurologia. 2017 Nov – Dec;32(9):616-622.


Aljabban L, et al. 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 Nov 22;10(1):328.

The findings of this case could increase our understanding of the pathogenetic mechanisms of rapid-onset obesity with hypoventilation, hypothalamic dysfunction, and autonomic dysregulation, and place more emphases on pediatricians to consider rapid-onset obesity with hypoventilation, hypothalamic dysfunction, and autonomic dysregulation syndrome whenever early rapid onset of obesity, associated with any malfunction, is observed in children. This knowledge could be lifesaving for children with rapid-onset obesity with hypoventilation, hypothalamic dysfunction, and autonomic dysregulation syndrome.

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Al-Harbi AS, et al. Rapid-onset obesity, hypothalamic dysfunction, hypoventilation, and autonomic dysregulation in Saudi Arabia. Saudi Med J. 2016 Nov;37(11):1258-1260.

Rapid-onset obesity, hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) is a rare disease, but could be fatal if not diagnosed early. It mimics many other diseases and it may take few years after the onset of rapid obesity to have the other clinical features. Therefore, any patient with rapid-onset obesity after the age of 2 years should have high index of suspicion and long term follow up. We report a case of ROHHAD in Saudi Arabia and we highlight the clinical features and the importance of early diagnosis and management.

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Erensoy H, Ceylan ME, Evrensel A. Psychiatric Symptoms in Rapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation Syndrome and its Treatment: A Case Report. Chin Med J (Engl). 2016 Jan 20;129(2):242-3.

Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) syndrome is a rare disease. It is diagnosed in childhood (usually at 3–4 years of age). It affects endocrine, respiratory, and autonomic nervous systems. It shows different symptoms at different ages. Rapid weight gain, obesity, alveolar hypoventilation, hypernatremia, cardiopulmonary arrest, hyperprolactinemia, diabetes insipidus, excessive sweating, increase pain perception, obstructive sleep apnea, cold hands/feet, and digestive dysmotility can be seen. Alveolar hypoventilation is essential for the diagnosis.[1] Behavioral problems, mental retardation, personality changes, and mood disorders may accompany. There is no any special diagnostic test. Its treatment is symptomatic.[2] This study is intended to inform clinicians about psychiatric symptoms of a girl with ROHHAD syndrome.

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Carroll MS, et al. Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD): Response to ventilatory challenges. Pediatr Pulmonol. 2015 Dec;50(12):1336-45.

Hypoventilation is a defining feature of Rapid-onset Obesity with Hypothalamic dysfunction, Hypoventilation and Autonomic Dysregulation (ROHHAD), a rare respiratory and autonomic disorder. This chronic hypoventilation has been explained as the result of dysfunctional chemosensory control circuits, possibly affecting peripheral afferent input, central integration, or efferent motor control. However, chemosensory function has never been quantified in a cohort of ROHHAD patients. Therefore, the purpose of this study was to assess the response to awake ventilatory challenge testing in children and adolescents with ROHHAD. The ventilatory, cardiovascular and cerebrovascular responses in 25 distinct comprehensive physiological recordings from seven unique ROHHAD patients to three different gas mixtures were analyzed at breath-to-breath and beat-to-beat resolution as absolute measures, as change from baseline, or with derived metrics. Physiologic measures were recorded during a 3-min baseline period of room air, a 3-min gas exposure (of 100% O2; 95% O2, 5% CO2; or 14% O2, 7% CO2 balanced with N2), and a 3-min recovery period. An additional hypoxic challenge was conducted which consisted of either five or seven tidal breaths of 100% N2. While ROHHAD cases showed a diminished VT and inspiratory drive response to hypoxic hypercapnia and absent behavioral awareness of the physiologic compromise, most ventilatory, cardiovascular, and cerebrovascular measures were similar to those of previously published controls using an identical protocol, suggesting a mild chemosensory deficit. Nonetheless, the high mortality rate, comorbidity and physiological fragility of patients with ROHHAD demand continued clinical vigilance.


Reppucci D, et al. ROHHAD syndrome and evolution of sleep disordered breathing. Orphanet J Rare Dis. 2016 Jul 30;11(1):106.

Children with ROHHAD may initially present with OSA and only develop NH later as well as dysregulation of breathing during wakefulness. The recognition of the spectrum of respiratory abnormalities at presentation and over time may be important in raising the index of suspicion of ROHHAD. Early recognition and targeted therapeutic interventions may limit morbidity and mortality associated with ROHHAD.

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Ibáñez-Micó S, et al. Rapid-onset obesity with hypothalamic dysregulation, hypoventilation, and autonomic dysregulation (ROHHAD syndrome): A case report and literature review. Neurologia. 2016 Jun 20. [Epub ahead of print]

ROHHAD syndrome is a rare and little-known disease which requires a multidisciplinary approach because it involves complex symptoms and multiple organ system involvement. Alveolar hypoventilation should be identified early and appropriate treatment should be started promptly for the best possible outcome. Immunomodulatory treatment with immunoglobulins, cyclophosphamide, or rituximab has previously resulted in symptom improvement in some cases. Because of the low incidence of the syndrome, multi-centre studies must be carried out in order to gather more accurate information about ROHHAD pathophysiology and design an appropriate therapeutic approach.

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Jacobson LA, et al. Improved Behavior and Neuropsychological Function in Children With ROHHAD After High-Dose Cyclophosphamide. Pediatrics. 2016 Jul;138(1). pii: e20151080.

Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) is a rare, generally progressive, and potentially fatal syndrome of unclear etiology. The syndrome is characterized by normal development followed by a sudden, rapid hyperphagic weight gain beginning during the preschool period, hypothalamic dysfunction, and central hypoventilation, and is often accompanied by personality changes and developmental regression, leading to substantial morbidity and mortality. We describe 2 children who had symptomatic and neuropsychological improvement after high-dose cyclophosphamide treatment. Our experience supports an autoimmune pathogenesis and provides the first neuropsychological profile of patients with rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation.

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Sanklecha M, et al. ROHHAD Syndrome: The Girl who Forgets to Breathe. Indian Pediatr. 2016 Apr 8;53(4):343-4.

BACKGROUND: ROHHAD syndrome is an exceedingly rare cause of central
hypoventilation.

CASE CHARACTERISTICS: A 7-year-old girl with ROHHAD syndrome who had central
hypoventilation, rapid weight gain, multiple cardiac arrests and
hyperprolactinemia.

OUTCOME: She required prolonged and repeated ventilation, and finally died due to
complications of ventilation.

MESSAGE: ROHHAD Syndrome should be suspected in any child who presents with
obesity, behavioral changes or autonomic instability following a neural crest
tumor.

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Kot K, et al. ROHHAD in 9-year-old boy – clinical case. Endokrynol Pol. 2016 Feb 17. [Epub ahead of print]

ROHHAD syndrome (Rapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation and Autonomic Dysregulation) is characterized by rapid-onset obesity in young children, hypoventilation, hypothalamic and autonomic dysfunction. The exact etiology of the disease remains unknown and the number of reported cases seems to be underestimated. We present the case of a 9-year-old male patient suspected of ROHHAD due to weight gain since early childhood, decreased height velocity, hypoventilation, hypodipsia, excessive perspiration and pyrexial episodes. Presented symptoms, laboratory and imaging findings meet the criteria of ROHHAD syndrome. ROHHAD should be considered in differential diagnosis for obesity in children. Early identification of the disease prevents potential complications specific for the syndrome, in particular a life-threatening cardio-pulmonary arrest. Patients with ROHHAD require regular follow-up by a multidisciplinary team.

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Cemeroglu AP, et al. Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation syndrome and celiac disease in a 13-year-old girl: further evidence for autoimmunity? J Pediatr Endocrinol Metab. 2016 Jan 1;29(1):97-101.

Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) syndrome is a rare and potentially lethal disorder. The etiology is unclear but paraneoplastic syndrome and autoimmunity secondary to neural crest tumors have been considered, even in patients without any detectable tumor due to their tendency for spontaneous remission. We are presenting a 13-year-old girl with ROHHAD syndrome and celiac disease, which may suggest further evidence for immune-mediated etiology in the pathogenesis of ROHHAD syndrome.

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Maksoud I, Kassab L. Rapid-onset obesity, hypoventilation, hypothalamic dysfunction, autonomic dysregulation syndrome. Avicenna J Med. 2015 Jul-Sep;5(3):89-94.

Rapid-onset obesity with hypoventilation, hypothalamic dysfunction and autonomic dysregulation syndrome is a rare disorder that presents with rapidly evolving obesity with several endocrine disorders during early childhood. We present here a documented case of a 6-year-old Syrian girl with the characteristic symptoms of rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation, associated with an abdominal mass (mature ganglioneuroma).

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Barclay SF, et al. Rapid-Onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD): exome sequencing of trios, monozygotic twins and tumours. Orphanet J Rare Dis. 2015 Aug 25;10:103.

Clinical 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.

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Carroll MS, et al. Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD): Response to ventilatory challenges. Pediatr Pulmonol. 2015 Mar 16.

Hypoventilation is a defining feature of Rapid-onset Obesity with Hypothalamic dysfunction, Hypoventilation and Autonomic Dysregulation (ROHHAD), a rare respiratory and autonomic disorder. This chronic hypoventilation has been explained as the result of dysfunctional chemosensory control circuits, possibly affecting peripheral afferent input, central integration, or efferent motor control. However, chemosensory function has never been quantified in a cohort of ROHHAD patients. Therefore, the purpose of this study was to assess the response to awake ventilatory challenge testing in children and adolescents with ROHHAD. The ventilatory, cardiovascular and cerebrovascular responses in 25 distinct comprehensive physiological recordings from seven unique ROHHAD patients to three different gas mixtures were analyzed at breath-to-breath and beat-to-beat resolution as absolute measures, as change from baseline, or with derived metrics. Physiologic measures were recorded during a 3-min baseline period of room air, a 3-min gas exposure (of 100% O2 ; 95% O2 , 5% CO2 ; or 14% O2 , 7% CO2 balanced with N2 ), and a 3-min recovery period. An additional hypoxic challenge was conducted which consisted of either five or seven tidal breaths of 100% N2 . While ROHHAD cases showed a diminished VT and inspiratory drive response to hypoxic hypercapnia and absent behavioral awareness of the physiologic compromise, most ventilatory, cardiovascular, and cerebrovascular measures were similar to those of previously published controls using an identical protocol, suggesting a mild chemosensory deficit. Nonetheless, the high mortality rate, comorbidity and physiological fragility of patients with ROHHAD demand continued clinical vigilance.

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Kocaay P, et al. ROHHAD syndrome: reasons for diagnostic difficulties in obesity. J Clin Res Pediatr Endocrinol. 2014 Dec 5;6(4):254-7.

A very rare syndrome of rapid-onset obesity with hypoventilation, hypothalamic dysfunction and autonomic dysregulation (ROHHAD) has been recently described as causing morbidity due to hypothalamic dysfunction and respiratory arrest. Its prognosis is poor and often cardiac arrest occurs due to alveolar hypoventilation. This disorder can mimic genetic obesity syndromes and several endocrine disorders. We present a 13-year-old female patient who was reported to be healthy until the age of 3 years. She was admitted to our emergency department, presenting with respiratory distress. Features matching ROHHAD syndrome such as rapid-onset obesity, alveolar hypoventilation, central hypothyroidism, hyperprolactinemia, Raynaud phenomenon and hypothalamic hypernatremia were detected in the patient. In addition to these features, the patient was found to have hypergonadotropic hypogonadism and megaloblastic anemia. Because of its high mortality and morbidity, the possibility of ROHHAD syndrome needs to be considered in all pediatric cases of early- and rapid-onset obesity associated with hypothalamic-pituitary endocrine dysfunction.

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Sethi K, et al. ROHHADNET syndrome presenting as major behavioral changes in a 5-year-old obese girl. Pediatrics. 2014 Aug;134(2):e586-9.

Behavioral issues are a frequent problem in the pediatric population. Often, these are evaluated and considered to be psychiatric in origin. We report on a pediatric patient who presented with severe behavioral disturbance and developed organic symptoms including hypoventilation and dysautonomia and who was ultimately diagnosed with ROHHADNET syndrome, a syndrome of rapid-onset obesity, hypothalamic dysfunction, hypoventilation, and autonomic dysregulation associated with a neuroendocrine tumor. Autopsy findings revealed novel findings of the syndrome, including hypothalamic encephalitis.

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Patwari PP, Wolfe LF. Rapid-onset obesity with hypothalamic dysfunction,
hypoventilation, and autonomic dysregulation: review and update. Curr Opin Pediatr. 2014 Aug;26(4):487-92.

Key Points

  • ROHHAD can be diagnosed in children older than 18 months, based on development of both rapid weight gain and central hypoventilation with additional associated features of hypothalamic dysfunction.
  • CCHS is diagnosed by the presence of hypoventilation in the absence of brainstem lesion, neuromuscular weakness, or a primary respiratory or cardiac disease and is characterized by PHOX2B gene mutation.
  • Repeated evaluations are necessary in children with either ROHHAD or CCHS because of the evolving clinical course and potential for devastating outcome of inadequate support for hypoventilation. 
  • Management of children affected by ROHHAD is based on careful monitoring and therapeutic interventions that are supportive and symptom targeted, often requiring coordinated multisubspecialty care.

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Sartori S, et al. Intrathecal synthesis of oligoclonal bands in rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulationsyndrome: new evidence supporting immunological pathogenesis. J Child Neurol. 2014 Mar;29(3):421-5.

Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation syndrome (ROHHADS) is a rare, but potentially lethal, pediatric disorder. To date, nearly 80 patients have been reported in the literature; however, the etiopathogenesis is still unclear and debated. Both genetic and paraneoplastic or immune-mediated causes have been supposed to be involved in this syndrome. Nonetheless, at this time, a diagnostic biomarker is not available and diagnosis is based exclusively on clinical criteria. Aiming to establish the immune-mediated pathogenesis, we report 2 children with a clinical picture consistent with ROHHADS and whose cerebrospinal fluid analysis disclosed an intrathecal synthesis of oligoclonal bands. Even if many aspects remain to be explained, this finding suggests that ROHHADS could share similar pathogenetic mechanisms with other immune-mediated central nervous system disorders, and even more important, it might pave the way to a therapeutic chance for these patients by means of immunotherapy.

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Rossetti E, et al. Severe phenotype of rapid-onset obesity, hypoventilation, hypothalamic dysfunction, and autonomic dysfunction syndrome. Minerva Anestesiol. 2014 Jun;80(6):744-5.

ROHHAD is a rare and complex pediatric disorder that often evades timely diagnosis and can remain undetected until the onset of hypoventilation. Although the number of
children who have this syndrome is not known to be increasing, the number diagnosed correctly with ROHHAD certainly is. Consequently, the pediatric anesthesiologist will encounter an increasing number of children affected with ROHHAD. The major implications for the pediatric anesthesiologist are hypoventilation, obesity, and autonomic dysautonomia.

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Dhondt K, et al. Hypocretin-1 deficiency in a girl with ROHHAD syndrome. Pediatrics. 2013 Sep;132(3):e788-92.

“Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) is a rare and complex pediatric syndrome, essentially caused by dysfunction of 3 vital systems regulating endocrine, respiratory, and autonomic nervous system functioning. The clinical spectrum of ROHHAD is broad, but sleep/wake disorders have received relatively little attention so far, although the central hypothalamic dysfunction would make the occurrence of sleep symptoms likely. In this case report, we expand the phenotype of ROHHAD with a number of striking sleep symptoms that together can be classified as a secondary form of narcolepsy. We present a 7-year-old girl with ROHHAD who displayed the classic features of narcolepsy with cataplexy: excessive daytime sleepiness with daytime naps, visual hallucinations, and partial cataplexy reflected in intermittent loss of facial muscle tone. Nocturnal polysomnography revealed sleep fragmentation and a sleep-onset REM period characteristic for narcolepsy. The diagnosis was confirmed by showing an absence of hypocretin-1 in the cerebrospinal fluid. We discuss potential pathophysiological implications as well as symptomatic treatment options.”

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Grudnikoff E, et al. Nocturnal Anxiety in a Youth with Rapid-onset Obesity, Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD). J Can Acad Child Adolesc Psychiatry. 2013 Aug;22(3):235-7.

Results: A 14-year-old female began rapidly gaining weight as a preschooler, developed hormonal imbalance, and mixed sleep apnea. Consultation was requested after a month of ROHHAD exacerbation, with severe anxiety, insomnia, and auditory hallucinations. Olanzapine and citalopram were helpful in controlling the symptoms. Following discharge, the patient gained weight and olanzapine was discontinued. Lorazepam was started in coordination with pulmonary service. Relevant pharmacologic considerations included risk of respiratory suppression, history of paradoxical reaction to hypnotics, hepatic isoenzyme interactions and side effects of antipsychotics.

Conclusions: Core symptoms of ROHHAD may precipitate psychiatric disorders. A systematic evidence-based approach to psychopharmacology is necessary in the setting of psychiatric consultation.

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Weese-Mayer DE, et al. Commentary: Rapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD): Remember Your ABCs (Airway, Breathing, Circulation). J Can Acad Child Adolesc Psychiatry. 2013 Aug;22(3):238-9.

“Extensive experience with ROHHAD patients in the Center for Autonomic Medicine in Pediatrics (CAMP) at Ann & Robert H. Lurie Children’s Hospital of Chicago and the International ROHHAD Research Consortium informs us that children without early and adequate support of their hypoventilation (providing an adequate airway and breathing support) and anticipatory management of the ROHHAD phenotype (with particular attention to fluid balance and circulation) are most likely to have significant behavioral issues, deterioration, and heightened risk for sudden death.”

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 Abaci A, et al. A case of rapid-onset obesity with hypothalamic dysfunction, hypoventilation, autonomic dysregulation, and neural crest tumor: ROHHADNET syndrome. Endocr Pract. 2013 Jan-Feb;19(1):e12-6.

“Rapid-onset obesity with hypoventilation, hypothalamic dysfunction, and autonomic dysregulation (ROHHAD) is a rare disorder that mimics both common obesity and genetic obesity syndromes along with several endocrine disorders during early childhood. We aim to present the clinical features, laboratory and imaging results, and treatment outcomes of a patient with ROHHAD syndrome.Methods: In this case report, we describe a 26-month-old boy who was admitted to our emergency department with dyspnea and cyanosis and was suspected to have ROHHAD syndrome due to his rapid-onset obesity and alveolar hypoventilation.Results: A thoracal and abdominal magnetic resonance imaging was performed to demonstrate a possible accompanying neural crest tumor and it provided a yet asymptomatic retroperitoneal ganglioneuroblastoma. Based on these findings, the patient was diagnosed as ROHHADNET syndrome.Conclusion: Because of the high prevalence of cardiorespiratory arrest and probability of accompanying tumors, early recognition of ROHHAD syndrome is important. To prevent presumptive mortality and morbidity, ROHHAD syndrome should be considered in all cases of rapid and early-onset obesity associated with hypothalamic-pituitary endocrine dysfunctions.”

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Chandrakantan A, Poulton TJ. Anesthetic considerations for rapid-onset obesity, hypoventilation, hypothalamic dysfunction, and autonomic dysfunction (ROHHAD) syndrome in children. Paediatr Anaesth. 2013 Jan;23(1):28-32.

Rapid-onset obesity, hypoventilation, hypothalamic dysfunction, and autonomic dysfunction is an increasingly common diagnosis in patients who are being seen at tertiary care children’s hospitals. We present two cases of anesthetics from the authors’ own experience in addition to a comprehensive review of the disorder and anesthetic implications.

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Rand CM, et al. Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation: analysis of hypothalamic and autonomic candidate genes. Pediatr Res. 2011 Oct;70(4):375-8.

“Rapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD) is a rare and complex pediatric disorder. Despite increased identification and advancing knowledge of the disease course, the variable onset and timing of phenotypic features in ROHHAD often result in delayed or missed diagnosis, potentially leading to fatal central hypoventilation, cardiorespiratory arrest, and impaired neurocognitive development. The 5-hydroxytryptamine receptor 1A (HTR1A), orthopedia (OTP), and pituitary adenylate cyclase activating polypeptide (PACAP) genes were targeted in the etiology of ROHHAD based on their roles in the embryologic development of the hypothalamus and autonomic nervous system. We hypothesized that variations of HTR1A, OTP, and/or PACAP would be associated with ROHHAD. All coding regions and intron-exon boundaries of the HTR1A, OTP, and PACAP genes, in addition to the promoter region of the HTR1A gene, were analyzed by standard sequencing in 25 ROHHAD cases and 25 matched controls. Thirteen variations, including six protein-changing mutations, were identified. None of these variations were significantly correlated with ROHHAD. This report provides evidence that variation of the HTR1A, OTP, and PACAP genes are not responsible for ROHHAD. These results represent a further step in the investigation of the genetic determinants of ROHHAD.”

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Patwari PP, et al. Monozygotic twins discordant for ROHHAD phenotype. Pediatrics. 2011 Sep;128(3):e711-5.

“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.”

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Chew HB, et al. Rapid-onset obesity with hypothalamic dysfunction, hypoventilation and autonomic dysregulation (ROHHAD): a case with additional features and review of the literature. BMJ Case Rep. 2011 Mar 1;2011.

“A rare syndrome of rapid-onset obesity with hypothalamic dysfunction, hypoventilation and autonomic dysregulation (ROHHAD) has been recently described. We report the first patient with this syndrome in Southeast Asia and review reported cases to date. Our patient was good health with normal development until the age of 2. He then developed hyperphagic obesity, hypersomnolence, seizures, alveolar hypoventilation, central hypothyroidism, sodium and water dysregulation, gastrointestinal dysmotility, strabismus, disordered temperature and irregular heart rate, altered sweating, delayed puberty, mental retardation and recurrent respiratory tract infections. The cardiomyopathy with heart failure and abnormal cerebral spinal fluid (CSF) neurotransmitter analysis present in our patient have not been reported previously. Tumours of the sympathetic nervous system are known to be associated with this syndrome but had not been found in our patient at the time of reporting. We highlight the difficulty of achieving the diagnosis of ROHHAD syndrome and its overlap with other well-established disease entities. The mortality and morbidity resulting from the high incidence of cardiorespiratory arrest may be prevented by early ventilatory support.”

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Paz-Priel I, et al. Cyclophosphamide for rapid-onset obesity, hypothalamic dysfunction, hypoventilation, and autonomic dysregulation syndrome. J Pediatr. 2011 Feb; 158(2) :337-9.

“Patients with rapid-onset obesity, hypothalamic dysfunction, hypoventilation, autonomic dysregulation, and neural crest tumor syndrome have poor long-term outcomes. We report a patient who was treated successfully with high-dose cyclophosphamide immunoablation. This experience offers a novel therapeutic approach and an indirect insight into the underlying pathogenesis of this syndrome.”

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Lemaire M, et al. Index of suspicion. Pediatr Rev. 2008 Nov;29(11):399-406. doi: 10.1542/pir.29-11-399. Erratum in: Pediatr Rev. 2009 Jan;30(1):21.

“This patient exhibited rapid-onset obesity, fevers, hyperprolactinemia, hypernatremia, and a borderline low thyroxine concentration. The expert consultant, a pediatric endocrinologist, diagnosed rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD). (1) This recently described disorder of unknown cause presents in the first decade of life with rapid weight gain as the initial feature. Hypothalamic dysfunction follows, but can occur simultaneously and may manifest as hypernatremia, growth hormone deficiency, hyperprolactinemia, hypothyroidism, adrenal insufficiency, or pubertal irregularity. Other features of autonomic dysregulation that may manifest are ophthalmologic dysfunction, GI dysmotility, thermal dysregulation, and neural crest tumor formation. Hypoventilation is the last feature of the disorder to appear and may lead to death. The underlying pathophysiology involved in ROHHAD is unclear. The wide spectrum of involved organ systems suggests a genetic defect in the development of the autonomic nervous system. However, a specific mutation has yet to be identified, and imaging studies have been unsuccessful in detecting a structural abnormality.”

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Bougnères P, et al. Endocrine manifestations of the rapid-onset obesity with hypoventilation, hypothalamic, autonomic dysregulation, and neural tumor syndrome in childhood. J Clin Endocrinol Metab. 2008 Oct;93(10):3971-80.

“Various hypothalamic-pituitary endocrine dysfunctions are associated with ROHHADNET, carrying a risk of misdiagnosis until other elements of the syndrome make it more easily recognizable. Given its severity, ROHHADNET syndrome should be considered in all cases of isolated, rapid, and early obesity.”

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Ize-Ludlow D, et al. Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation presenting in childhood. Pediatrics. 2007 Jul;120(1):e179-88.

“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.”

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Created 08/22/2013; updated 12/11/13, 02/06/14, 06/16/14, 10/09/14, 06/12/15, 09/25/15, 11/12/15, 02/22/16, 05/16/16, 06/28/16, 08/01/16, 09/06/16, 11/29/16, 02/09/17, 07/25/17, 10/18/18, 12/31/18.

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