Rapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation

Rapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation

National Organization for Rare Disorders, Inc.

Important

It is possible that the main title of the report Rapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation is not the name you expected. Please check the synonyms listing to find the alternate name(s) and disorder subdivision(s) covered by this report.

Synonyms

  • Late Onset Central Hypoventilation Syndrome with Hypothalamic Dysfunction
  • Hypoventilation, Autonomic Dysregulation with Neural Tumor
  • LO-CCHS/HD
  • Rapid-onset Obesity,Hypothalamic Dysfunction,Hypoventilation,Autonomic Dys-
  • ROHHADNET
  • regulation with Neural Tumor

Disorder Subdivisions

  • None

General Discussion

Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) is a rare disorder with abnormalities in breathing (hypoventilation), the endocrine system, and the autonomic nervous system (ANS). The ANS is part of the nervous system that controls the involuntary body functions. Hence, it works "automatically" to control breathing, heart beat, digestion, among many other things. ROHHAD was first described in 1965 and since that time only 75 children have been reported in the literature with this disorder. Because of the high prevalence of cardiorespiratory arrest, early recognition and treatment of the symptoms associated with ROHHAD is essential.

Symptoms

Most remarkable about ROHHAD is that these children appear to be normal early in life. Between 1.5 and 7 years of life, these children start to show abnormalities that will evolve into the features of ROHHAD. Most commonly, the first sign is rapid (within 6 to 12 months) and dramatic (often over 20 pounds) weight gain with associated abnormal increase in hunger (hyperphagia). This rapid-onset obesity is considered a sign of hypothalamic dysfunction (abnormality of the endocrine system). Other hypothalamic abnormalities may be detected at any time from months to years following the rapid-onset obesity; these may include inability to maintain normal water balance in the body (leading to abnormally high or low sodium levels), high prolactin levels, low thyroid hormone, early or late puberty, low cortisol, and growth hormone deficiency, among other abnormalities. Children with ROHHAD can have variable timing and number of these symptoms of hypothalamic dysfunction.



After rapid-onset obesity, some children with ROHHAD will begin to show breathing abnormalities. Some children will have obstructive sleep apnea which means that the airway is intermittently blocking air flow during sleep; they may have snoring and they may have pauses in breathing related to the air flow blockage (obstructive apnea). All children with ROHHAD develop alveolar hypoventilation which means that they have inadequate breathing (very shallow breathing) and inability to increase breathing in response to abnormal oxygen or carbon dioxide levels. This is the most dangerous feature of ROHHAD which may take a dramatic event such as a respiratory arrest before being recognized. Therefore, all children with ROHHAD will require help with their breathing with a machine at some time; once the hypoventilation is recognized, it does not go away. Half of the children with ROHHAD require help breathing during sleep only and the other half require help with breathing awake and asleep (24-hours per day). This breathing help can be provided with bi-level positive airway pressure (BiPAP) through a mask that fits tightly at the nose or with nasal pillows, or with a mechanical ventilator through a surgically made hole in the airway called a tracheostomy.



Also after the rapid weight gain, ANS dysregulation (ANSD) becomes more apparent. ANSD means that there are abnormalities with the "automatic" regulation of different organ systems of the body. At some point, all patients with ROHHAD have signs of ANSD. These include eye abnormalities such as altered pupil response to light or strabismus, gut abnormalities such as altered motility (ability of the gut to push food through) which causes chronic constipation or diarrhea, temperature dysregulation with episodes of very high body temperature (hyperthermia) or very low body temperatures (hypothermia), decreased sensation of pain, low heart rhythm that may be so slow that a cardiac pacemaker is required, altered sweating, and many other symptoms.



Some individuals (40%) with ROHHAD develop anatomic malformations of the ANS which include tumors of neural crest origin (meaning, they originate from a specific type of cell that is seen very early in development of the body). These neural crest tumors found in children with ROHHAD are ganglioneuromas or ganglioneuroblastomas; they are found in the chest or abdomen and can develop at any age. To date, no cases of Hirschsprung disease have been reported in ROHHAD. Hirschsprung disease is a rare gastrointestinal disorder characterized by absence at birth of certain cells (autonomic ganglia) in the lower segment of the large bowel; it is another example of anatomic ANSD and reported in many cases of Congenital Central Hypoventilation Syndrome (CCHS).



Other features in a subset of individuals with ROHHAD include behavioral disorders, developmental disorders with very low Intelligence Quotient (IQ) on presentation or a subset that develop neurocognitive (intellectual) impairment later, and seizures which need to be closely evaluated to be sure that episodes are not related to low oxygen (hypoxemia) levels.

Causes

The diagnosis of ROHHAD is currently based on clinical criteria and though investigation of genetic mutations is underway, no specific cause for ROHHAD has been found.

Affected Populations

ROHHAD is a very rare disorder with only 75 cases reported in the literature to date. Though first described under a different name in 1965, it was not re-named until 2007 nor shown to be distinct from CCHS until 2000. Therefore, as ROHHAD is a relatively "new" disorder without many cases identified thus far, it is not yet clear if any certain population is at greater risk for developing ROHHAD.

Standard Therapies

Diagnosis

The criteria for diagnosis of ROHHAD are 1) Rapid-onset obesity and alveolar hypoventilation starting after the age of 1.5 years, 2) Evidence of hypothalamic dysfunction, as defined by =1 of the following findings: rapid-onset obesity, hyperprolactinemia, central hypothyroidism, disordered water balance, failed growth hormone stimulation test, corticotrophin deficiency, or altered onset of puberty (delayed or precocious), and 3) Absence of PHOX2B mutation (to genetically distinguish ROHHAD from CCHS). As there is no genetic testing available for ROHHAD, the diagnosis of ROHHAD is based on the clinical presentation and clinical course which should include cooperative consultation by experts in the fields of respiratory, endocrine, and autonomic medicine.



Clinical Testing

As the symptoms of ROHHAD can have variable presentation in severity and timing, it is essential that an initial comprehensive evaluation be performed to identify the nature of the ANSD and to address appropriate intervention. Initial evaluation can include an overnight polysomnography to evaluate for any signs of obstructive sleep apnea and, more importantly, evidence of central hypoventilation, computed tomography (CT) of chest and abdomen to screen for evidence of neural crest tumors, and comprehensive cardiac evaluation. As the prevalence of cardiorespiratory arrest is relatively high (50-60%) as reported in the literature, it is essential that a comprehensive respiratory, cardiac, endocrine, and oncology evaluation be performed as soon as the diagnosis of ROHHAD is considered.



Yearly comprehensive evaluation is recommended, ideally at a center with expertise in respiratory and autonomic medicine--including expertise specifically with ROHHAD. This evaluation includes detailed respiratory physiologic evaluation while awake and while asleep, comprehensive cardiac evaluation including 72-hour Holter, cycle ergometry (exercise test), and echocardiogram, neurocognitive testing for tracking intellectual function as a marker for neurologic stability vs. decline, endocrine evaluation for development of new symptoms of hypothalamic dysfunction, and age-appropriate evaluation of ANSD.



Respiratory evaluation includes assessment of spontaneous breathing in varying levels of concentration and activity, including typical activities of daily living for children (playing, running, eating, among others), assessment of the child's response to endogenous and exogenous hypercarbia, hypoxemia, and hyperoxia challenges while awake, and assessment of response to endogenous challenges while asleep in various conditions (sitting up, supine, at sleep onset, and within sleep).



The cardiac evaluation is focused on detection of any signs of cor pulmonale or right ventricular hypertrophy as may develop with chronic hypoventilation and detection of prolonged sinus pause or asystole that might require a cardiac pacemaker. Neurocognitive testing should be performed annually to determine the effectiveness of the ventilatory management, as an objective measure of intellectual function, with aim to address early signs of neurologic decline as may occur in a subset of children with ROHHAD; confounding mood and behavior problems may obscure true intellectual function in ROHHAD.



Comprehensive ANS testing is limited in children, but efforts are underway to create a comprehensive testing profile to assess autonomic regulation for children of all ages. Depending on the child's ability to cooperate, the ANS testing may include pupillometry, heart-rate-deep-breathing test, Valsalva maneuver, tilt test, comprehensive review of ANS symptoms, orthostatic response, and more. A complete evaluation of endocrine function should be performed with particular attention to water balance regulation, obesity, and other signs of pituitary dsyfunction. If hypernatremic dehydration is found, formal testing of antidiuretic hormone secretion should be done before assuming the patient has diabetes insipidus. Patients with ROHHAD can become dehydrated due to lack of thirst with normal or partial antidiuretic hormone function. Obesity can alter growth hormone secretion and levels of insulin like growth factor-1 (IGF-1) which should be taken into account when assessing growth hormone function.



Complications of obesity including fatty liver, elevated lipids, or diabetes mellitus should be considered. A high suspicion should be maintained for tumors of neural crest origin, with imaging performed upon recognition of scoliosis or an unidentified shadow on chest x-ray.



Treatment

The treatment of ROHHAD is based on the affected systems involved. The obesity can be controlled with diet and exercise with special emphasis in avoiding further weight gain as the child grows vertically, but should be done in consultation with a nutritionist. Since patients with ROHHAD do not increase their breathing adequately during physical exertion, it is important to recommend only modest exertion until safe parameters have been established by a physician based on end tidal carbon dioxide and pulse oximetry values recorded during exercise.



The hypothalamic dysfunction seen in these patients must be evaluated and treated by a pediatric endocrinologist. Since patients with ROHHAD have variable hypothalamic abnormalities it is important that their care be individualized to meet their particular needs. These treatments may include hormone replacement, a strict fluid intake regimen, and other measures designed to make up for a dysfunctional hypothalamus.



One of the main challenges in ROHHAD is the control of breathing deficit, with the goal of optimization of oxygenation and ventilation. At some point all children with ROHHAD require artificial ventilation during sleep, though signs of hypoventilation may not occur immediately after onset of the rapid weight gain. Awake ventilatory needs will vary. Many patients with ROHHAD can be managed with mask ventilation and bi-level positive airway pressure (BiPAP) at night only, but a subset requires 24 hour/day mechanical ventilation. These patients are treated by surgically creating a temporary opening in the throat (tracheostomy) into which a small tube (tracheostomy tube) is inserted, and through which the patient is then mechanically ventilated. These children require a mechanical ventilator at home (with a back-up ventilator, pulse oximeter, end tidal carbon dioxide monitor, and power generator) as well as experienced registered nursing care 24 hours/day. Other assistive breathing techniques such as diaphragm pacing may have limited success due to the obesity associated with ROHHAD.



In terms of ANSD, individuals with ROHHAD are at risk for severely low heart rates (bradycardia). If long pauses in the heart beat (asystole) are found to be longer than 3 seconds, then a cardiac pacemaker implantation would be necessary. Their lack of temperature control requires careful regulation of ambient temperature. Ophthalmologic findings including pupillary or other ocular abnormalities should be evaluated by an ophthalmologist. Often, chronic constipation due to gastrointestinal motility dysfunction can be symptomatically treated with stool softeners. Lastly, tumors of neural crest origin, thought to be a form of anatomic (as opposed to physiologic) ANSD, require surgical removal and should be treated in consultation with an oncologist.



Multidisciplinary care with input from a center with expertise in ROHHAD is crucial to the successful management of these patients. This team may include primary care physicians, pulmonologists, endocrinologists, cardiologists, intensivists, otolaryngologists, surgeons, gastroenterologists, neurologists, ophthalmologists, psychologists, psychiatrists, respiratory therapists, nurses, social workers, speech and language therapists, special education teachers, and more, all working together with the child and the family to optimize care and quality of life.



A high index of suspicion, early detection, and aggressive conservative intervention are critical to optimizing neurocognitive outcome. If inadequately treated, the affected individuals will likely suffer neurocognitive compromise and sudden death. If treated conservatively and followed comprehensively, individuals with ROHHAD can have a good quality of life. It remains unknown if optimally managed children with ROHHAD will have a normal life span.

Investigational Therapies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.



For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:



Tollfree: (800) 411-1222

TTY: (866) 411-1010

Email: prpl@cc.nih.gov



For information about clinical trials sponsored by private sources, contact:

www.centerwatch.com



For more information on rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation and/or PHOX2B Testing, please contact:



Pallavi P. Patwari, M.D.

Assistant Professor of Pediatrics at Northwestern University Feinberg School of Medicine

Assistant Director, Center for Autonomic Medicine in Pediatrics (C.A.M.P.)

Children's Memorial Hospital

2300 Children's Plaza--Mailstop #165

Chicago, IL 60614

phone: 773-880-8188

fax: 773-880-8100

e-mail: PPatwari@ChildrensMemorial.org

web address: www.ChildrensMemorial.org/depts/autonomic-medicine/overview.aspx



Diego Ize-Ludlow MD

Assistant Professor of Clinical Pediatrics at University of Illinois at Chicago

Division of Pediatric Endocrinology

840 S. Wood St, M/C 856

Chicago, IL, 60612

Phone: 312-996-1795

e-mail: diegoize@uic.edu



Debra E. Weese-Mayer, M.D.

Professor of Pediatrics at Northwestern University Feinberg School of Medicine

Director, Center for Autonomic Medicine in Pediatrics (C.A.M.P.)

Children's Memorial Hospital

2300 Children's Plaza--Mailstop #165

Chicago, IL 60614

phone: 773-880-8188

fax: 773-880-8100

e-mail: DWeese-Mayer@ChildrensMemorial.org

web address: http://www.childrensmemorial.org/depts/autonomic-medicine/overview.aspx

References

JOURNAL ARTICLES

Bougneres P, Pantalone L, Linglart A, Rothenbuhler A, Le Stunff C. Endocrine manifestations of the rapid-onset obesity with hypoventilation, hypothalamic, autonomic dysregulation, and neural tumor syndrome in childhood. J Clin Endocrinol Metabol 93(10):3971-80, 2008.



Carroll MS, Patwari PP, Weese-Mayer DE. Carbon dioxide chemoreception and hypoventilation syndrome with autonomic dysregulation, J Appl Physiol 108:979-988, 2010.



Del Carmen Sanchez M, Lopez-Herce J, Carrillo A, Moral R, Arias B, Rodriguez A, Sancho L. Late onset central hypoventilation syndrome. Pediatr Pulmonol 21:189-91, 1996.



De Pontual L, Trochet.D., Caillat-Zucman S, Abou Shenab OA, Bougneres P, Crow Y, Cunningham S, Esteva B, Heberle LC, Leger J, Pinto G, Polak M, Shafik MH, Straus C, Trang H, Munnich A, Lyonnet S, Desguerre I, Amiel J., Delineation of late onset hypoventilation associated with hypothalamic dysfunction syndrome. Pediatr Res 64(6):689-694, 2008.



Dunger DB, Leonard JV, Wolff OH, Preece MA. Effect of naloxone in a previously undescribed hypothalamic syndrome. A disorder of the endogenous opioid peptide system? Lancet 1(8181):1277-81, 1980.



duRivage SK, Winter RJ, Brouillette RT, Hunt CE, Noah Z. Idiopathic hypothalamic dysfunction and impaired control of breathing. Pediatrics 75(5):896-8, 1985.



Fishman LS, Samson JH, Sperling DR. Primary alveolar hypoventilation syndrome (Ondine's Curse). Am J Dis Child 110:155-61, 1965.



Frank Y, Kravath RE, Inoue K, Hirano A, Pollak CP, Rosenberg RN, Weitzman ED. Sleep apnea and hypoventilation syndrome associated with acquired nonprogressive dysautonomia: clinical and pathological studies in a child. Ann Neurol 10(1):18-27, 1981.



Gothi D, Joshi JM. Late onset hypoventilation syndrome: is there a spectrum of idiopathic hypoventilation syndromes? Indian J Chest Dis Allied Sci 47(4):293-7, 2005.



Gurewitz R, Blum I, Lavie P, Pertzelan A, Stivel M, Weinstein R, Galatzer A, Laron Z. Recurrent hypothermia, hypersomnolence, central sleep apnea, hypodipsia, hypernatremia, hypothyroidism, hyperprolactinemia, and growth hormone deficiency in a boy - treatment with clomopramine. Acta Endocrinol Suppl (Copenh) 279:468-72, 1986.



Ize-Ludlow D, Gray J, Sperling MA, Berry-Kravis EM, Milunsky JM, Farooqi IS, Rand CM, Weese-Mayer DE. Rapid onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation presenting in childhood. Pediatrics 120:e179-e188, 2007.



Ize-Ludlow D, Weese-Mayer DE, Facilitating the Diagnosis of ROHHAD syndrome. JCEM Online, 19 Sep 2008.



Katz, ES, McGrath S, Marcus CL. Late-onset central hypoventilation with hypothalamic dysfunction: a distinct clinical syndrome. Pediatr Pulmonol 29(1):62-8, 2000.



Moskowitz MA, Fisher JN, Simpser MD, Strieder DJ. Periodic apnea, exercise hypoventilation, and hypothalamic dysfunction. Ann Int Med 84:171-173, 1976.



Nattie EE, Bartlett D, Rozycki AA. Central alveolar hypoventilation in a child: an evaluation using a whole body plethysmograph. Am Rev Respir Dis 112(2):259-66, 1975.



North KN, Ouvrier RA, McLean CA, Hopkins IJ. Idiopathic hypothalamic dysfunction with dilated unresponsive pupils: report of two cases. J Child Neurol 9(3):320-5, 1994.



Ouvrier R, Nunn K, Sprague T, McLean C, Arbuckle S, Hopkins I, North K. Idiopathic hypothalamic dysfunction: a paraneoplastic syndrome? Lancet 346(8985):1298, 1995.



Patwari PP, Zelko FA, Phillips AJ, Nelson MN, Berry-Kravis EM, Koliboski CM, Peters P, Kenny AS, Rand CM, Weese-Mayer DE. Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD): Neurocognitive functioning in school-aged children. Am J Respir Crit Care Med 181:A2435, 2010.



Proulx F, Weber ML, Collu R, Lelievre M, Larbrisseau A, Delisle M. Hypothalamic dysfunction in a child: a distinct syndrome? Report of a case and review of the literature. Eur J Pediatr 152(6):526-9, 1993.



Rand CM, Berry-Kravis EM, Weese-Mayer DE. Rapid onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD): HTR1A and OTP as candidate genes. Am J Respir Crit Care Med 179:A6337, 2009.



Sirvent N, Berard E, Chastagner P, Feillet F, Wagner K, Sommelet D. Hypothalamic dysfunction associated with neuroblastoma: Evidence for a new paraneoplastic syndrome? Med Pediatr Oncol 40:326-328, 2003.



FROM THE INTERNET

Weese-Mayer DE, Berry-Kravis EM, Ceccherini I, Keens TG, Loghmanee DA, Trang H. American Thoracic Society Statement, Congenital central hypoventilation syndrome: Genetic basis, diagnosis, and management. Am J Respir Crit Care Med 181:626-644, 2010. http://www.thoracic.org/newsroom/press-releases/resources/cchs-statement.pdf

Resources

NIH/National Institute of Neurological Disorders and Stroke

P.O. Box 5801

Bethesda, MD 20824

Tel: (301)496-5751

Fax: (301)402-2186

Tel: (800)352-9424

TDD: (301)468-5981

Internet: http://www.ninds.nih.gov/



Genetic and Rare Diseases (GARD) Information Center

PO Box 8126

Gaithersburg, MD 20898-8126

Tel: (301)251-4925

Fax: (301)251-4911

Tel: (888)205-2311

TDD: (888)205-3223

Internet: http://rarediseases.info.nih.gov/GARD/



ROHHAD Fight Inc.

3 Surrey Lane

Hempstead, NY 11550

Tel: (516)459-6960

Fax: (516)483-0566

Email: rohhadfight@aol.com

Internet: www.rohhadfight.org



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