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

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Last updated: 03/22/2023
Years published: 2009, 2010, 2013, 2023


Acknowledgment

NORD gratefully acknowledges Debra E. Weese-Mayer, MD, Beatrice Cummings Mayer Professor of Pediatric Autonomic Medicine at Northwestern University Feinberg School of Medicine and Chief, Division of Autonomic Medicine, Center for Autonomic Medicine in Pediatrics (CAMP), Ann & Robert H. Lurie Children’s Hospital of Chicago and Stanley Manne Children’s Research Institute, Casey M. Rand, BS, CAMP, Tracey M. Stewart, CRTT, CAMP, Kyle C Kurek, MD, PhD, Professor of Pathology, University of Calgary School of Medicine, Frank A Zelko, PhD, Professor of Psychology, Northwestern University Feinberg School of Medicine, Elizabeth A Sokol, MD, Assistant Professor of Pediatrics, Northwestern University Feinberg School of Medicine, Susan M. Slattery, MD, MS, Assistant Professor of Pediatrics, Northwestern University Feinberg School of Medicine and Ilya Khaytin, MD, Assistant Professor of Pediatrics, Northwestern University Feinberg School of Medicine, for assistance in the preparation of this report. Sally F. Vitez, BA, CAMP, Ann & Robert H. Lurie Children’s Hospital of Chicago and Diego Ize-Ludlow, MD, Assistant Professor of Pediatrics, University of Illinois at Chicago contributed to an earlier version of this report.


Disease Overview

Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) is an ultra-rare disorder of respiratory control and autonomic nervous system (ANS) regulation, with endocrine system abnormalities. Respiratory control is a function of the ANS that is responsible for changing breathing in response to varied activities of daily living (ex. exercise, sleep, eating) and in response to changes in oxygen and carbon dioxide. The ANS is the portion of the nervous system that controls or regulates many automatic involuntary body functions including breathing, heart rate, blood pressure, temperature regulation, bowel and bladder control, and more. The endocrine system is regulated by the hypothalamus, and through hormones it controls growth, energy and water balance, sexual maturation and fertility as well as response to stress.

ROHHAD presents after 1.5 years of age, in otherwise healthy children. The rapid-onset weight gain (often 20-30 pounds in 3-12 months) is typically the herald of the disease and the harbinger of the later features of the ROHHAD phenotype. The acronym ROHHAD describes the typical sequence of symptoms experienced by children with ROHHAD, in the order of their appearance. The clinical features of ROHHAD seem to “unfold” with advancing age in each child. ROHHAD was first described in 1965 (albeit under a different name) and since that time at least 200 children have been reported in the literature or identified with this disorder. Because of the high prevalence of cardiorespiratory arrest, early recognition and treatment of the symptoms associated with ROHHAD are essential and may be lifesaving.

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Synonyms

  • late onset central hypoventilation syndrome with hypothalamic dysfunction
  • LO-CCHS/HD
  • ROHHAD
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Signs & Symptoms

Children with ROHHAD are seemingly healthy before the rapid-onset weight gain, making the diagnosis even more challenging to parents and health care personnel. Between 1.5 and 7 years of age, these children begin to manifest abnormalities that will evolve into the features of ROHHAD. Most commonly, the first sign is dramatic (often 20-30 pounds) and rapid (over 3 to 12 months) weight gain without 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 not be detected at the time of the rapid weight gain but will be identified any time from months to years following the rapid-onset obesity. These other hypothalamic/endocrine abnormalities 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, growth hormone insufficiency, early or late puberty, and low cortisol among other abnormalities. Children with ROHHAD can have variable timing and number of these symptoms of hypothalamic dysfunction, but all will have some abnormalities, especially increased prolactin. After the rapid weight gain, children with ROHHAD will begin to show breathing abnormalities despite normal lungs. Some children may present with obstructive sleep apnea which means that airflow is intermittently blocked during sleep; they may have snoring and they may have pauses in breathing related to the air flow blockage (obstructive apnea). Because obstructive sleep apnea is not unusual in young obese children, health care personnel may not be alarmed at this stage, and a connection to the ROHHAD phenotype might be delayed. All children with ROHHAD, whether they had preceding OSA or not, develop alveolar hypoventilation with very shallow breathing during sleep (nap and night). In more severely affected patients with ROHHAD, the hypoventilation is apparent awake and asleep. As a result of altered control of breathing, low oxygen saturation and elevated carbon dioxide occur during wakefulness as well as sleep, without any shortness of breath (awake) or awakening (from sleep). This hypoventilation/control of breathing deficit is the most life-threatening feature of ROHHAD, yet it is often unnoticed until after a dramatic event such as a cardiorespiratory arrest. Therefore, all children with ROHHAD will require help with their breathing, relying on a ventilator to prevent low oxygen or increased carbon dioxide. Approximately half of the children with ROHHAD require ventilator support during sleep only and the other half require ventilator support awake and asleep (24-hours per day), though the ventilatory needs of a child with ROHHAD may vary with advancing age (and unfolding of the clinical features of ROHHAD). This ventilator support can be provided with bi-level positive airway pressure through a mask that fits tightly at the nose or with nasal pillows or a full-face mask or with a mechanical ventilator through a surgically made hole in the airway called a tracheostomy, or potentially with diaphragm pacing (still requiring a tracheostomy).

Also, after the rapid weight gain, the symptoms of ANS dysregulation (ANSD) become more apparent. As described above, 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, “lazy eye”(strabismus), intestinal abnormalities such as altered motility which causes chronic constipation or diarrhea, temperature dysregulation with episodes of very high body temperature (hyperthermia) or more typically very low body temperatures (hypothermia), icy cold hands and feet, decreased sensation of pain, low heart rate that may be so slow that a cardiac pacemaker is required, altered sweating, and many other symptoms reflecting dysregulation of automatic functions.

Some individuals (approximately 40%) with ROHHAD will 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 most commonly ganglioneuromas or ganglioneuroblastomas, but neuroblastomas have also been reported. These neural crest tumors are found in the chest or abdomen, or anywhere along the sympathetic nervous system chain (part of ANS), are present but likely very small in early infancy, and can be identified at any age (though characteristically in early childhood). Thus far, no children with ROHHAD have anatomic/structural malformations of the intestine such as Hirschsprung disease (absent ganglion cells of the distal intestine). This is in contrast to children with another ultra-rare disorder termed congenital central hypoventilation syndrome (CCHS), which co-occurs with Hirschsprung disease in ~30% of individuals with CCHS. Tumors of neural crest origin have been described in patients with CCHS, though rarely with polyalanine repeat expansion PHOX2B mutations (PARMs) (genotypes 20/29 and 20/33; if present typically ganglioneuromas and ganglioneuroblastomas) but more commonly with the non-PARMs (NPARMs) (~40% of cases; most will have a neuroblastoma but less commonly ganglioneuroma or ganglioneuroblastoma).

Bougneres, et al. suggested the suffix “NET” be added to the name designated by Ize-Ludlow et al in 2007, “ROHHAD”, because of the findings of associated neural crest tumors in a subset of patients with ROHHAD. Because only a subset of patients (~40%) with ROHHAD have been shown to develop these neuroendocrine tumors, and they may be ganglioneuromas or ganglioneuroblastomas but not typically neuroblastoma, the name ROHHADNET is potentially misleading. Currently, there is insufficient evidence that individuals presenting with tumors represent a distinct entity.  Further, the development of neural crest tumors has been reported to occur as late as 7 and even in one case 16 years after the onset of obesity. Consequently, making co-occurrence of tumors of neural crest origin requisite to the diagnosis of ROHHAD would lead to missed diagnosis of many of the children and may subsequently lead to devastating consequences due to the high incidence of cardiorespiratory arrest in this population.

A remarkably high percentage of children with ROHHAD have normal or high IQs, suggesting that IQ in children with ROHHAD likely has many related factors. A small subset of individuals with ROHHAD have behavioral, mood, and developmental disorders such that the intelligence quotient (IQ) score may be reduced. Preliminarily, those children with the behavioral and mood disorders have more typically had delayed diagnosis and/or suboptimal ventilatory support. Some children with ROHHAD may develop seizures, though this feature may be related to episodes of low oxygen (hypoxemia) levels due to inadequate ventilator support.

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Causes

The diagnosis of ROHHAD is currently based on clinical criteria and though investigation of genetic changes (pathogenic variants or mutations) is underway, no specific cause for ROHHAD has been found to date.

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Affected populations

ROHHAD is a very rare disorder with approximately 200 cases reported in the literature and clinically 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 (documented absence of CCHS-related PHOX2B mutations). 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. Because of the explosion of children with exogenous obesity worldwide, a very high level of vigilance in consideration of ROHHAD is essential.

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Diagnosis

The criteria for diagnosis of ROHHAD include the following: 1) rapid-onset obesity and alveolar hypoventilation during sleep starting after the age of 1.5 years, 2) evidence of hypothalamic dysfunction, as defined by at least 1 of the following findings: rapid-onset obesity, hyperprolactinemia, central hypothyroidism, disordered water balance, growth hormone deficiency, corticotrophin deficiency, or altered onset of puberty (delayed or precocious), and 3) absence of a CCHS-related PHOX2B variant (to genetically distinguish ROHHAD from CCHS). At present there is no genetic testing available to diagnose ROHHAD, so the diagnosis is based on the clinical presentation and clinical course which should include cooperative consultation by pediatric experts in the fields of pulmonology, endocrinology, autonomic medicine, oncology, psychology, nutrition, otolaryngology, surgery, cardiology and sleep medicine.

Clinical Testing and Work-Up

As the symptoms of ROHHAD can have variable presentation in severity and timing, it is essential that an initial comprehensive evaluation be performed to characterize the nature of the hypoventilation and ANSD and to address appropriate intervention—especially regarding the child’s breathing. Initial evaluation can include overnight polysomnography to evaluate for any signs of obstructive sleep apnea and, more importantly, evidence of central hypoventilation, imaging (chest x-ray of chest and ultrasound of abdomen) to screen for evidence of neural crest tumors, and comprehensive cardiac evaluation. As the prevalence of cardiorespiratory arrest is relatively high (up to 40% 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.

Sequential comprehensive evaluation is recommended, ideally at a center with expertise in respiratory and autonomic medicine–including expertise specifically with ROHHAD, and in keeping with the current recommendations in the 2010 ATS Statement on CCHS, as there is not an ATS Statement on ROHHAD at present. Broadly speaking, these  evaluations include detailed respiratory physiologic evaluation while awake in varied age-appropriate activities of daily living and while asleep, comprehensive cardiac evaluation including Holter recordings, exercise testing, 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 non-invasive evaluation of ANSD. The frequency of these comprehensive evaluations is dependent upon each patient’s clinical condition and may be as frequent as 3 months and as extended as 12 months, depending upon the rate of the phenotype “unfolding”.

Described more specifically, for children with ROHHAD, the physiologic evaluation should include annual comprehensive physiologic assessment during spontaneous breathing awake (in varying levels of concentration and activity) and during sleep in a pediatric respiratory physiology laboratory with extensive expertise in ROHHAD (often referred to as Centers of Excellence). Responses to endogenous (the result of the child’s own hypoventilation) and exogenous (ventilatory challenges from inhaled gas mixtures) hypercarbia, hypoxemia, and hyperoxia should be assessed, ideally awake and asleep. 72-hour Holter recording should be performed annually to evaluate for bradycardia that might (rarely) require a cardiac pacemaker. A head up tilt test should be performed annually to better understand the autonomic response to positional changes. An echocardiogram should be performed annually to rule out cor pulmonale or right ventricular hypertrophy (response to low oxygen from insufficient ventilator management). Neurocognitive testing should be performed annually to determine the effectiveness of the ventilatory management and compliance. In children under the age of three years, the above-described age-appropriate testing should be performed every 6 months. Gastrointestinal motility studies should be performed in the event of severe constipation. All of the above-described tests are part of routine standard of care for individuals with ROHHAD. Efforts are underway to create an expanded comprehensive testing profile for autonomic regulation in children which will also be considered standard of care for children with ROHHAD (testing of temperature regulation, vasomotor tone, integration of breathing, heart rate, and blood pressure, cerebrovascular regional blood flow, and pupillometry have already been integrated into care). These comprehensive evaluations are typically performed inpatient to optimize safety and assure the test results are representative of the patient’s condition.

A complete evaluation of endocrine function should be performed with particular attention to water balance regulation, obesity, and other signs of pituitary dysfunction. The lab work should include: complete blood count with differential, reticulocytes, blood comprehensive metabolic profile, urine osmolality, prolactin, leptin, thyroxine free (FT4), thyroid-stimulating hormone-sensitive (S-TSH), lipid panel, cortisol (urine and serum), vitamin B12, vitamin D (25-hydroxy vitamin D2 and D3 serum), insulin-like growth factor binding protein, insulin-like growth factor I.

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 considered 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, and recurrent screening performed for tumors of neural crest origin, especially with imaging performed upon recognition of scoliosis or an unidentified shadow on chest x-ray. A chest x-ray and abdominal ultrasound to view the sympathetic chain and both adrenals are an effective serial evaluation to monitor for neural crest tumors in children with ROHHAD.

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Standard Therapies

Treatment

The treatment of ROHHAD at present is based on the clinical features and their relative severity. The obesity is exceedingly difficult to control with diet and exercise. More effective is special emphasis to avoid further weight gain as the child grows vertically (with or without growth hormone supplement to treat growth hormone deficiency), but intervention requires consultation with a nutritionist and endocrinologist. Since patients with ROHHAD do not increase their breathing adequately during physical exertion, it is important to recommend only mild exertion until safe parameters have been established by a physician based on end tidal carbon dioxide and pulse oximetry monitoring during exercise.

The hypothalamic dysfunction seen in these patients must be evaluated and treated by a pediatric endocrinologist, with long-term evaluations and labwork every three months. Since patients with ROHHAD have variable hypothalamic abnormalities, it is important that their care be individualized to meet their needs. These treatments may include hormone replacement, a strict fluid intake regimen, and other measures designed to make up for a dysfunctional hypothalamus. Growth hormone supplementation has improved vertical growth though evaluation of change in body composition has not been reported.  Use of a dopamine agonist to normalize prolactin levels has not been systematically evaluated to determine effect on the clinical course.

One of the main challenges in ROHHAD is the control of breathing deficit that is typically unapparent at the time of the rapid-onset weight gain but seems to worsen with advancing age. Some children may initially need artificial ventilation during sleep only, then progress to need for continuous support (awake and asleep). From the beginning, the key goal is optimization of oxygenation and ventilation. Many patients with ROHHAD can be managed with mask ventilation and bi-level positive airway pressure at night only (but provided with an actual mechanical ventilator); those children requiring 24 hour/day mechanical ventilation will need a tracheostomy (surgically creating a temporary opening in the throat into which a small tracheostomy tube is inserted), 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 ideally 24 hours/day. Other assistive breathing techniques such as diaphragm pacing may have limited success due to the obesity associated with ROHHAD but may be considered in select patients.  Though gastric sleeve surgery has not been formally assessed in ROHHAD patients especially in terms of potential effect on control of breathing (gut-brain interaction), this is not an unreasonable consideration.

In terms of ANSD, individuals with ROHHAD are at risk for severely low heart rates (bradycardia). Their lack of temperature control requires careful regulation of ambient temperature and attention to reduced body temperatures. Ophthalmologic findings including pupillary or other ocular abnormalities (such as “lazy eye”) should be evaluated by a pediatric 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 a pediatric oncologist. To date, surgical removal of the neural crest tumors has not interrupted the unfolding of the ROHHAD phenotype nor induced recovery from the ROHHAD phenotype, but it averts local organ and vascular compression if the tumor grows large.

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 the diagnosis of ROHHAD is delayed and/or if the clinical symptoms are not anticipated and adequately treated, the affected child will likely suffer neurocognitive compromise and may be at heightened risk for sudden death. If identified promptly, 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, but the anecdotal observation of improved breathing while awake with advancing age (refolding of the phenotype) is remarkably heartening.

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Clinical Trials and Studies

An International ROHHAD Registry is available for all patients with a clinical diagnosis of ROHHAD. The purpose of the Registry is to collect data about the clinical development of ROHHAD with advancing age as the disease process unfolds (and ideally recedes or refolds). The Registry is achieved through a secure questionnaire via REDCap (Research Electronic Data Capture). The aim is to consent and enroll ALL patients worldwide with ROHHAD to have a central repository to advance understanding of this rare disease and improve early diagnosis, offer anticipatory management and decrease disease burden.

Physicians or parents interested in enrolling in the International ROHHAD REDCap Registry should contact the authors of this NORD report at the following e-mail addresses:

CRand@LurieChildrens.org

DWeese-Mayer@LurieChildrens.org

For more information on ROHHAD and clinical trials please contact:

Debra E. Weese-Mayer, MD
Beatrice Cummings Mayer Professor of Pediatric Autonomic Medicine at Northwestern University Feinberg School of Medicine
Chief, Division of Autonomic Medicine and Center for Autonomic Medicine in Pediatrics (CAMP)
Ann & Robert H. Lurie Children’s Hospital of Chicago
225 East Chicago Avenue–Mailstop #165
Chicago, IL 60611
phone: 312-227-3300
fax: 312-227-9606
e-mail: DWeese-Mayer@LurieChildrens.org or D-Weese-Mayer@Northwestern.edu
https://www.luriechildrens.org/en/specialties-conditions/autonomic-medicine/

International ROHHAD Registry

Publications

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

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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References

TEXTBOOKS

Barclay SF, Khaytin I, Zhou A, Rand CM, Weese-Mayer DE: Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD). In:  Nelson Textbook of Pediatrics 22nd edition (Kliegman RM, St. Geme III JW, Blum N, Wilson K, Tasker R, Deardorff M, Ralston S, and Schuh A, editors), Elsevier-Saunders, Philadelphia, PA. In press, 2022.

Ceccherini I, Kurek KC, Weese-Mayer DE. Developmental disorders affecting the respiratory system: CCHS and ROHHAD. In: R. Chen and P.G. Guyenet (Eds). In: Respiratory Neurobiology: Physiology and Clinical Disorders, Part II. Handbook of Clinical Neurology, Vol. 189, pp.  53–92, 2022. Elsevier, Amsterdam, the Netherlands.

JOURNAL ARTICLES

Khaytin I, Stewart TM, Zelko FA, Kee MAL, Osipoff JN, Slattery SM, Weese-Mayer DE.   Evolution of physiologic and autonomic phenotype in ROHHAD: Unfolding then refolding over a decade from age at diagnosis. J Clin Sleep Med (JCSM) 2022; 18(3):937–944.

Mandel-Brehm C, Benson LA, Tran B, Kung AF, Mann SA, Vazquez SE, Retallack H, Sample HA, Zorn KC, Khan LM, Kerr LM, McAlpine PL, Zhang L, McCarthy F, Elias JE, Katwa U, Astley CM, Tomko S, Dalmau J, Seeley WW, Pleasure SJ, Wilson MR, Gorman MP, DeRisi JL. ZSCAN1 autoantibodies are associated with pediatric paraneoplastic ROHHAD. Ann Neurol. 2022; 92(2):279-291.

Victor AK, Hedgecock T, Donaldson M, Johnson D, Rand CM, Weese-Mayer DE, Reiter LR. Analysis and comparisons of gene expression changes in patient derived neurons from ROHHAD, CCHS, and PWS. Frontiers in Genetics 2022. In revision.

Zelko FA, Welbel RZ, Rand CM, Stewart TM, Fadl-Alla A, Khaytin I, Slattery SM, Weese-Mayer DE. Neurocognition as a biomarker in the rare autonomic disorders of CCHS and ROHHAD. Clin Auton Res. (Special edition on Pediatric Autonomic Disorders). 2022 Oct 27. doi: 10.1007/s10286-022-00901-1. In press, 2022. Online ahead of print. PMID: 36289132.

Zhou A, Rand CM, Hockney SM, Niewijk G, Reineke P, Speare V, Berry-Kravis EM, Zhou L, Jennings LJ, Yu M, Ceccherini I, Bachetti, T, Pennock M, Yap KL, Weese-Mayer DE. Paired-like Homeobox Gene (PHOX2B) non-polyalanine repeat expansion mutations (NPARMs):  Genotype-phenotype correlation in congenital central hypoventilation syndrome (CCHS).  Genetics in Medicine 2021; 23(9):1656-1663.

Barclay SF, Wevrick R, Rand CM, Wilson RJ, Gibson WT, Wilson RJ, Bech-Hanson NT, Weese-Mayer DE.  ROHHAD and Prader-Willi syndrome (PWS): clinical and genetic comparison. Orphanet J Rare Dis. 2018; 13:124-132.

Barclay SF, Rand CM, Gray PA, Gibson WT, Wilson RJ, Berry-Kravis EM, Ize-Ludlow D, Bech-Hansen NT, Weese-Mayer DE. Absence of mutations in hypocretin (HCRT), hypocretin receptor-1 (HCRTR1) and hypocretin receptor-2 (HCRTR2) genes in patients with ROHHAD.  Respir Physiol & Neurobiol. 2015; 221:59-63.

Carroll MS, Patwari PP, Kenny AS, Brogadir CD, Stewart TM, Weese-Mayer DE.  Rapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD): Response to ventilatory challenges.  Pediatr Pulmonol. 2015; 50(12):1336-1345.

Patwari PP, Rand CM, Berry-Kravis EM, Jennings LJ, Yu M, Weese-Mayer DE. Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD): Report on identical twins discordant for ROHHAD phenotype. Pediatrics 2011; 128:3 and e711-e715. PMID: 21807698.

Rand CM, Patwari PP, Rodikova EA, Zhou L, Berry-Kravis EM, Wilson RJA, Bech-Hansen T, Weese-Mayer DE. Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD): Analysis of hypothalamic and autonomic candidate genes. Pediatr Res 2011; 70(4):375-378. PMID: 21691246.

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

Weese-Mayer DE, Berry-Kravis EM, Ceccherini I, et al. An official ATS clinical policy statement: congenital central hypoventilation syndrome, genetic basis, diagnosis, and management. Am J Respir Crit Care Med. 2010;181: 626-644.

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. 2009;179:A6337.

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. 2008; 93(10):3971-80.

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. 2008; 64(6):689-694.

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

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 2007; 120:e179-e188.

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 2003; 40:326-328.

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

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

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

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. 1981;10(1):18-27.

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

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

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

INTERNET

Weese-Mayer DE, Rand CM, Khaytin I, et al. Congenital Central Hypoventilation Syndrome. 2004 Jan 28 [Updated 2021 Jan 28]. In: Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1427/ Accessed March 14, 2023.

Kniffin CL, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore, MD: The Johns Hopkins University; Entry No. 209880; Last Update: 12/13/2022. Available at: https://omim.org/entry/209880  Accessed March 14, 2023.

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Rare Caregiver Respite Program

This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder.

Learn more https://rarediseases.org/patient-assistance-programs/caregiver-respite/

Patient Organizations


National Organization for Rare Disorders