Rapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation
NORD is very grateful to the following experts for assistance in the preparation of this report: Pallavi P. Patwari, MD, Assistant Professor of Pediatrics, Northwestern University Feinberg School of Medicine and Assistant Director, Center for Autonomic Medicine in Pediatrics (C.A.M.P.), Children's Memorial Hospital; Diego Ize-Ludlow, MD, Assistant Professor of Pediatrics, University of Illinois at Chicago; and Debra E. Weese-Mayer, MD, Professor of Pediatrics at Northwestern University Feinberg School of Medicine and Director, Center for Autonomic Medicine in Pediatrics (C.A.M.P.), Children's Memorial Hospital.
Synonyms of Rapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation
- Hypoventilation, Autonomic Dysregulation with Neural Tumor
- Late Onset Central Hypoventilation Syndrome with Hypothalamic Dysfunction
- Rapid-onset Obesity,Hypothalamic Dysfunction,Hypoventilation,Autonomic Dys-
- regulation with Neural Tumor
- No subdivisions found.
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.
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.
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.
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.
Congenital Central Hypoventilation Syndrome (CCHS)
CCHS is a disorder of the ANS caused by a gene mutation in the PHOX2B gene that affects ANS development. Similar to ROHHAD, the "automatic" control of breathing, heart beat, digestion, and other features of ANSD are among the affected features. In people with CCHS, the hallmark is inadequate breathing (hypoventilation) while sleeping and if severe, hypoventilation while awake and asleep - despite anatomically normal heart, lung, and airways. This hypoventilation, also called a disorder of respiratory control, is also similar to ROHHAD. Hence, both CCHS and ROHHAD fall within the rubric of Respiratory and Autonomic Disorders of Infancy, Childhood, and Adulthood (RADICA). CCHS is a rare disorder for which reported cases increased from 170 to 1,000 in the past decade, likely because of increased awareness and a clinically available genetic test - allowing for early diagnosis and improved treatment. CCHS is often diagnosed in the newborn period because of breathing problems, but milder forms of CCHS may go undiagnosed through infancy, childhood, and even adulthood. A simple blood test can be done to look for a PHOX2B gene mutation. Different types of mutations can occur in this gene which will determine how severely an individual with CCHS is affected. Testing for PHOX2B mutations should be done with close involvement by a physician and genetic counselor.
Bougneres, et al. suggested the name of this disorder be ROHHADNET because of the findings of neural tumors, "NET" (all tumors in this study are ganglioneuromas). Because only a subset of patients (33-40%) with ROHHAD will develop these tumors, the name ROHHADNET is potentially misleading. Further, the development of neural crest tumors has been reported to be as late as 9 and even 16 years after the onset of obesity. Considering this, making the distinction that tumors of neural crest origin are required for this syndrome would lead to missed diagnosis of many of the ROHHAD children with subsequently devastating consequences because of the high incidence of cardiorespiratory arrest in this population.
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.
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.
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.
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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
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
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
web address: http://www.childrensmemorial.org/depts/autonomic-medicine/overview.aspx
Organizations related to Rapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation
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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.
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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.
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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
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