ROHHAD Syndrome Research Articles

The Enigma That Is ROHHAD Syndrome: Challenges and Future Strategies

Rapid-onset obesity with hypoventilation, hypothalamic dysfunction, and autonomic dysregulation (ROHHAD) is a rare syndrome presenting in early childhood associated with a high risk of mortality between 50 and 60%. It is characterised by rapid, early onset of obesity between 1.5–7 years, along with central hypoventilation and hypothalamic dysfunction, such as central hypothyroidism, hyperprolactinemia, disorders of sodium and water balance, growth hormone deficiency, adrenocortical insufficiency, or disorders of puberty and features of autonomic dysregulation. Up to half of cases have neural crest tumours, most commonly ganglioneuromas or ganglioneuroblastomas. The incidence of ROHHAD syndrome in any population is unknown. Currently, there is no specific diagnostic or genetic biomarker for ROHHAD, and diagnosis is based on clinical signs and symptoms, which is often challenging, and consequently may be delayed or unrecognised. Early diagnosis is important, as without intervention, ROHHAD is associated with high morbidity and mortality. Aetiology remains unclear; an autoimmune origin has been postulated, with immunosuppressive agents being used with variable benefit. With no cure, multidisciplinary management is largely supportive. Therefore, there are many unanswered questions in ROHHAD syndrome. In this review article, we outline the challenges posed by ROHHAD syndrome, including aetiology, genetics, diagnosis, screening, management, and prognosis. We present research priorities to tackle these issues to improve outcomes.

6610 Emphasizing the evaluation of autonomic dysfunctioncontributes to the diagnosis of ROHHAD Syndrome -- Based on a comparative analysis of two center ROHHAD Syndrome case reports and reported literature

Abstract Disclosure: Y. Wang: None. L. Chen: None. C. Gong: None. Background: ROHHAD is the acronym of rapid-onset obesity with hypothalamic dysfunction, hypoventilation and autonomic dysfunction, it is an extremely rare and potentially fatal disease.The purpose of this study is to describe the clinical symptoms and timelines of ROHHAD syndrome. Methods: All patients with ROHHAD syndrome were included. Patients from 2007 to2019 published previously was regarded as group 1. We searched for the keyword "ROHHAD" in the PUMBED database, and included all literature describing theclinical symptoms of ROHHAD patients (group 2, from October 2019 to August 2023).We compared and analyzed the above two sets of data with our data (group 3). Results: In the past 2 years, we diagnosed 16 cases of ROHHAD syndrome totally, with a male to female ratio of 8:8. Mean BMI z score was 4.23 ± 1.70, and the age of rapid obesity was 3.17 (1.67, 7.92) years old, ranging from 3 to 22.5 kg/year. The age at which hypoventilation, hypothalamic dysfunction, and autonomic dysfunction occurred was 5.55 (3.61, 8.25) years old, 4.46 (1.83, 9.25) years old, 3.42 (1.83, 8.00) years old, respectively. The most common autonomic dysfunction were cardiovascular manifestations (13 cases), thermal dysregulation and excessive sweating (each with 11 cases). Totally 13 cases had emotional, cognitive and behavioral abnormalities, 7 cases had neurogenic tumors. Case 2 had neurogenic tumors more than 5 years before rapid obesity, cognitive and behavioral abnormalities more than 2 years ago. Case 10 had abnormal pain sensation shortly after birth, and following polyuria in 2 years before rapid obesity. A total of 116 patients including 100 cases previously reported and 16 cases in this study were analyzed. Compared with the incidence rates of rapid obesity, central hypoventilation and hypothalamic dysfunction in patients in this study, there was no statistically significant difference between three groups. Among patients who had autonomic dysfunction (group 1 vs group 2 vs group 3), thermal dysregulation was 65.7% vs 17.0% vs 68.8%, cardiovascular manifestations was NA vs 12.8% vs 81.2%, excessive sweating was 28.6% vs 10.6% vs 68.8%, gastrointestinal disturbances was 11.4% vs 8.5% vs 62.5%, strabismus was 25.7% vs 12.8% vs 62.5%, and sleep disturbance was NA vs 6.4% vs 50.0%, all p< 0.05. The incidence of abnormal emotion, cognition and behavior was NA vs 29.8% vs 81.2% (p<0.05). Conclusion: The incidence of autonomic dysfunction in 16 patients of this study is100%, with multiple manifestations of autonomic dysfunction coexisting. The incidenceof autonomic dysfunction and abnormal emotion, cognition and behavior in reportedcases from different eras were significantly lower than those of our study, indicating theimportance of fully evaluating the autonomic dysfunction and limbic system. Fewpatients may occur tumors or autonomic dysfunction before rapid obesity. Presentation: 6/3/2024

Antibodies Against ZSCAN1 in Pediatric and Adult Patients With Non-Paraneoplastic ROHHAD Syndrome.

To report the association of zinc finger and SCAN domain containing 1 antibodies (ZSCAN1-abs) with rapid-onset obesity, hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) syndrome in patients without tumor. Patients with symptoms compatible with ROHHAD syndrome but without an associated tumor were selected from our database. Serum and CSF samples were examined for the presence of ZSCAN1-abs by an in-house cell-based assay. In addition, samples from 149 patients with several inflammatory and noninflammatory disorders and 50 healthy participants served as controls. Thirteen patients with ROHHAD syndrome were identified. Of these, we had paired serum/CSF samples from 6 patients and only serum from the other 7. Five of 6 patients (83.3%) with paired serum/CSF (4 children, 1 adult) had ZSCAN-abs only in CSF and 1 had antibodies in serum and CSF. ZSCAN1-abs were not detected in the remaining 7 patients with ROHHAD with only serum available or in any of the 199 control samples. Patients with ROHHAD syndrome should be investigated for the presence of ZSCAN1-abs in CSF. The antibodies do not necessarily predict the presence of a tumor. The detection of ZSCAN1-abs in an adult patient suggests that this condition also occurs beyond the pediatric age.

An autopsy case of an adult woman with Rapid-Onset Obesity with Hypoventilation, Hypothalamic, Autonomic Dysregulation, and Neuroendocrine Tumors (ROHHAD(NET)) syndrome developing nonalcoholic steatohepatitis and hepatocellular carcinoma: A case report.

Nonalcoholic steatohepatitis (NASH) is an important etiology of hepatocellular carcinoma (HCC), and there is no established therapy for this syndrome. Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, autonomic dysregulation, and neural crest tumor (ROHHAD(NET)) is an extremely rare syndrome considered to be life-threatening, with death occurring around 10 years of age. We present the oldest known autopsy case of this syndrome that developed HCC. This case provided important information on not only improving the course of this syndrome, but also understanding the natural history and therapeutic modalities of NASH and HCC. The patient was diagnosed with ROHHAD(NET) syndrome in childhood, and liver cirrhosis due to NASH was diagnosed at age 17. HCC was detected at age 20, and embolization and irradiation were performed. At age 21, she died from accidental acute pancreatitis and subsequent liver failure and pulmonary hemorrhage. Rapid onset of obesity, hypoventilation, and hypothalamic disturbance appeared in childhood and was diagnosed as this syndrome. At age 17, liver cirrhosis due to NASH was diagnosed by liver biopsy, and at age 20, HCC was diagnosed by imaging. Transarterial chemoembolization and irradiation were performed, and the HCC was well controlled for a year. At age 21, she died from accidental acute pancreatitis, subsequent liver failure and pulmonary hemorrhage. Autopsy revealed that the HCC was mostly necrotized. This case was valuable not only for other ROHHAD(NET) syndrome cases, but also in improving our understanding of the natural history of NASH and HCC.

ROHHAD syndrome spectrum in an adult: a possible new variant.

This case report describes for the first time the evolution of a mature patient with all the diagnostic criteria for ROHHAD syndrome. It shows a rare case of central alveolar hypoventilation with hypothalamic impairment, dysautonomia and rapid weight gain. https://bit.ly/49AN3Vv.

66 Neuropsychological Profile of ROHHAD Syndrome: A Case Study

Objective:Rapid Onset Obesity with Hypoventilation, Hypothalamic Dysfunction, Autonomic Dysregulation (ROHHAD) is a rare and often progressive syndrome with unknown etiology and only 100 cases reported to date. The syndrome is characterized by generally normal development followed by rapid onset of pain, muscle weakness, personality changes, and developmental regression. Associated chronic pain and fatigue result in difficulty concentrating, slow information processing, and executive function challenges. Only one study has examined the neuropsychological profile of pediatric patients with this syndrome.Participants and Methods:Our patient was a 10-year-old, right-handed male with a history of ROHHAD syndrome, focal epilepsy, mild neurocognitive disorder, autism spectrum disorder (ASD), and attention-deficit/hyperactivity disorder (ADHD) who underwent two comprehensive neuropsychological evaluations at our medical center.Results:Findings across multiple evaluations showed solid verbal skills and difficulty processing visual-spatial and nonverbal information, as well as problems with attention, executive functioning, and adaptive skills, and psychosocial functioning consistent with his diagnoses of ADHD and ASD. He exhibited fine-and gross-motor challenges associated with hypotonia. Chronic fatigue contributed to his challenges with attention and information processing. These findings are generally consistent with previous research examining the neuropsychological profile associated with ROHHAD syndrome.Conclusions:Results from our case study highlight the complexity and challenges associated with ROHHAD syndrome. Consistent with available information, etiology of our patients’ neuropsychological weakness and functional decline is unclear. Yearly neuropsychological evaluations are recommended for these patients to update interventions based on their variable abilities. More research is needed to firmly establish the neuropsychological profile in youth of varying ages afflicted with this syndrome.

Immune modulatory response to rituximab in ROHHAD syndrome

Immune modulatory response to rituximab in ROHHAD syndrome

Blood Lymphocyte Subsets and Proinflammatory Cytokine Profile in ROHHAD(NET) and non-ROHHAD(NET) Obese Individuals.

Rapid-onset obesity with central hypoventilation, hypothalamic dysfunction, and autonomic dysregulation with neural crest tumors (ROHHAD-NET) syndrome pathophysiology remains elusive. Acquired neuroimmunological dysfunction has been proposed as a possible pathogenetic pathway. The aim of our study was to characterize lymphocyte subpopulations subsets in peripheral blood (PB) and to evaluate a panel of proinflammatory cytokines/chemokines in ROHHAD(NET) patients vs controls. We included 11 ROHHAD(NET) patients, 7 ROHHAD and 4 ROHHAD-NET, selected by clinical criteria. Controls were 11 simple obese children, matched for age and sex. Flow cytometric analysis and enzyme-linked immunosorbent assay were performed on PB and serum samples of the 2 groups. Analysis revealed that T lymphocytes are significantly increased in ROHHAD(NET) patients (P = .04) with a prevalence of CD4-T cells (P = .03) and a lower number of activated CD8-T cells (P = .02). With regard to regulatory subset, patients displayed increased regulatory B cells (P = .05) and type-1 regulatory T cells (P = .03). With regard to CD8-T cells, a lower number of T effector memory was observed (P = .02). In contrast, among CD4-T cells, we found a higher number of T naive (P = .04) and T effector (P = .0008). Interleukin-8 (IL-8) levels and monocyte chemotactic protein-1 were increased in patients vs controls (P = .008 and P = .01, respectively). Furthermore, IL-8 levels were higher in the subgroup with neural tumor (P = .0058) (ROHHAD-NET) than in patients without neural tumor (ROHHAD). Soluble HLA-G was significantly lower in patients vs controls (P = .03). Our findings contribute to support the hypothesis of immune dysregulation, which may underlie this complex, often fatal disease. Because ROHHAD(NET) syndrome is an ultra-rare disease, multicentric studies are needed to improve the effect of our data in the management of this condition.

1015 Chasing after Sleep in ROHHAD syndrome

Abstract Introduction Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, autonomic dysregulation, (ROHHAD) syndrome is a childhood disorder consisting of rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation. Sleep disordered breathing, obesity hypoventilation, and daytime hypersomnia are common sleep conditions found in this syndrome. The purpose of this case report is to review the polysomnography findings and propose a multidisciplinary approach in treating a patient with ROHHAD syndrome. Report of case(s) This is a case of a 5-year-old female with a clinical presentation consistent with ROHHAD who experienced daytime hypersomnia and worsening obesity hypoventilation due to the progressive nature of her disease. We report the use of several wake-promoting pharmacological agents, in conjunction with positive airway pressure (PAP) therapy to improve quality of life and reduce burden of disease. Conclusion Early detection and treatment of sleep disorders in patients with ROHHAD syndrome are essential to improve health outcomes. Given the complex, evolving clinical course of this disease, these patients are best served by coordinated, multi-specialty care. Support (if any)

1034 A Rare Case of ROHHAD Syndrome

Abstract Introduction Early diagnosis of pediatric syndromes that are rare and involve multiple systems can be challenging. Rapid onset obesity, hypoventilation, hypothalamic dysfunction, and autonomic dysregulation characterizes ROHHAD syndrome which, if undiagnosed, can lead to potentially harmful outcomes including deferring radiological workup for a neural crest tumor (which has an over 50% association) and cardiopulmonary arrest. Report of case(s) A 10-year-old female with a history of obesity, precocious puberty, recurrent hypothermia, recurrent sodium derangements, bilateral ptosis, seizure disorder, and GERD initially presented to sleep clinic as a 4-year-old in 2017 when she recently began snoring with excessive daytime sleepiness as a result of rapid onset of weight gain. BMI at that time was 99th percentile and Epworth was 11. An in-lab polysomnography revealed severe OSA with AHI 26.4 events/hour; nocturnal hypoxemia with TS90 27% and O2 nadir 70%; and sleep related hypoventilation based on elevated pCO2 on end-tidal capnometry. Patient underwent adenotonsillectomy, revision adenoidectomy, and was started on CPAP before transitioning to BiPAP over the span of the next several years with serial polysomnographies ultimately showing significant improvement of sleep apnea with AHI 5.4 events/hour. Sleep-related hypoventilation, however, remained persistent with blood gases showing pCO2 as high as 89. PHOX2B gene testing was negative and secondary causes of hypoventilation were ruled out. During this time, she was also followed by Endocrinology for suspected hypothalamic dysfunction resulting in precocious puberty, deceleration of growth rate, sodium derangements. Autonomic dysfunction was also suspected due to recurrent hypothermia including a recent admission for Temperature < 95F and ophthalmologic abnormalities including bilateral ptosis. At a multidisciplinary care conference, a working diagnosis of ROHHAD syndrome was made based on the rapid onset of obesity, hypoventilation on sleep studies and CBGs, hypothalamic dysfunction, and autonomic degeneration. Workup for neural crest tumor with MRI chest and abdomen unremarkable. Outside academic consultation was sought for management which recommended shared decision-making regarding steroids, immunosuppressive therapy (eg rituximab, cyclophosphamide), and IVIG. Conclusion For ROHHAD syndrome, there are very few documented cases in the United States and there is no known laboratory marker; diagnosis remains clinical and takes multidisciplinary collaboration, education, and a high degree of suspicion. Support (if any)

1021 An 8-year-old child with ROHAAD syndrome and its comorbid association with narcolepsy, cardiomyopathy, and malignant catatonia

Abstract Introduction Rapid-onset obesity with hypothalamic dysregulation, hypoventilation, and autonomic dysregulation (ROHHAD) is a rare disease with an unknown etiology. It manifests with varying clinical signs making the diagnosis challenging. We present a case of ROHHAD syndrome with narcolepsy, heart failure with cardiomyopathy, and malignant catatonia. Report of case(s) An 8-year-old boy with speech and developmental delay presents to sleep clinic at 4 years of age, with snoring, witnessed apneas during sleep, daytime somnolence and obesity for evaluation of obstructive sleep apnea. At three years of age, he started to gain weight rapidly; with an increase in BMI from 26 to 30 over a period of few months. His weight gain was initially attributed to a high caloric diet and sedentary lifestyle. A baseline polysomnogram revealed mild obstructive sleep apnea without hypoxemia or hypoventilation (oRDI of 4.2, oxygen nadir 90%, CAI 1). Over time, he was admitted multiple times for hypernatremia, respiratory failure with hypoxemia and hypercapnia, psychosis, and fever of unknown origin. After a thorough evaluation, the diagnosis of ROHHAD was made based upon his history of rapid weight gain, hyperthermia, respiratory failure with hypercapnia, hypopituitarism, and hypothyroidism. During one of his admissions for altered mental status the patient manifested agitation, auditory and visual hallucinations, and excessive daytime sleepiness. Due to these behavioral changes, cerebral spinal fluid was obtained showing a hypocretin of < 50pg/ml. Based on the low hypocretin levels, daytime sleepiness, and hallucinations; a diagnosis of narcolepsy type 1 was made. He subsequently developed heart failure with severely dilated cardiomyopathy and depressed contractility. The patient was deemed not a candidate for heart transplant due to his underlying comorbidities. He unfortunately died at the age of 8 years due to complications from advanced heart failure. Conclusion ROHHAD is a rare and fatal disease that can manifest in several ways. ROHHAD with coexistent narcolepsy, malignant catatonia and cardiomyopathy is extremely rare presentation. Providers need to be aware of the varying clinical presentations and have a high index of suspicion in diagnosing this condition. Early diagnosis might improve the morbidity and mortality. Support (if any)

Anesthetic management of a child with ROHHAD syndrome for major abdominal surgery.

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

Abstract #1408090: A Case of Rapid-Onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation in a 5-Year-Old Boy

With an estimated prevalence of less than 1000 in the U.S, rapid onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) is an exceedingly rare but fatal syndrome that surfaces abruptly in previously healthy infants or children aged 1 month-11 years. Due to the wide range of symptom variability, onset, and obscure documentation, it is often overlooked and misdiagnosed by clinicians, leading to inadequate treatment and consequent early mortality secondary to cardio-pulmonary arrest. The etiology is currently unknown, though some sources and clinical trials have postulated an underlying autoimmune mechanism directed at the brain. We aim to present a potential inciting event in addition to a promising treatment response for ROHHAD syndrome in this case study. This case describes a 5-year-old male who presents to the pediatrician with a chief complaint of 2 years rapid, incessant weight gain and fatigue following an adenoviral infection at 3 years of age. He had previously been evaluated at numerous specialists with preliminary diagnoses of hypothyroidism and diabetes insipidus, despite inconsistent response to dietary restrictions, exercise and levothyroxine therapy. Diagnosis of ROHHAD syndrome was finally confirmed with a sleep study that revealed severe obstructive sleep apnea (OSA). After continuous positive airway pressure (CPAP) intervention, the patient has reported stable weight maintenance as well as significant improvement in energy levels. The diagnosis of ROHHAD syndrome is often missed due to the many physiological processes affected. Subsequent involvement of many specialists creates focus on the individual endocrine abnormalities and often results in nominal clinical improvement. The presentation of rapid onset obesity in a child between the ages of 1 month to 11 years with concurrent widespread endocrine abnormalities such as hypothyroidism, short stature, puberty delay, hyperprolactinemia and overlying sleep apnea should raise suspicion and place ROHHAD syndrome in the differential. Positive sleep study results complete the clinical picture and indicate the need for CPAP, which in this case has shown to significantly slow weight gain and improve energy levels. Early intervention with CPAP may even help slow the onset of cardiopulmonary abnormalities and increase patient survival. It is critical to establish a multidisciplinary team only after the syndrome is clinically confirmed that may include a primary care physician, endocrinologist, pulmonologist, and many more, working coherently to optimize care and patient quality of life. Patients with a confirmed diagnosis may also benefit from referral to a center with expertise in ROHHAD syndrome, such as Ann and Robert H. Lurie Children’s Hospital of Chicago. More research is needed to determine whether adenovirus may contribute to a potential autoimmune mechanism that triggers the onset of ROHHAD syndrome in susceptible individuals.

Rapid-Onset Obesity with Hypoventilation, Hypothalamic Dysfunction, and Autonomic Dysregulation Neuroendocrine Tumor Syndrome

Background: Rapid-onset obesity with hypoventilation, hypothalamic dysfunction, and autonomic dysregulation (ROHHAD) syndrome is a rare cause of obesity, characterized by early and rapid onset of obesity, hypoventilation, hypothalamic dysfunction, and autonomic dysfunction. When there is an associated neuroendocrine tumor, (NET) it becomes ROHHAD NET. Hypothalamic dysfunction causes endocrine problems, respiratory dysfunction, and autonomic alterations. It is difficult to distinguish this clinically from other obesity syndromes of genetic origin unless an individualized strategic approach is used. Clinical Description: We present a case of a 5-year-old developmentally normal girl with excessive weight gain starting in early childhood and the development of a squint. The clinical phenotype of central hypoventilation and autonomic dysfunction, central hypothyroidism, and central precocious puberty satisfied the criteria for ROHHAD syndrome. Management: A right-sided paraspinal supradiaphragmatic mass was identified that was excised and diagnosed as neuroblastoma on histopathology. Since there was no evidence of metastases, chemotherapy was not indicated. Alpha and beta-blockers were started for autonomic dysfunction and high catecholamine levels. Lack of improvement in behavioral manifestations prompted a trial of immunosuppressive therapy, but yielded no results. She ultimately succumbed to a probable cardiorespiratory arrest during sleep. Conclusions: ROHHAD syndrome should be considered a differential diagnosis in rapid-onset monogenic obesity and should be managed with a multidisciplinary approach. Prognosis is guarded due to sudden life-threatening events secondary to autonomic dysfunction.

The impact of the intensive immunosuppressive treatment, a case report of ROHHAD syndrome in two siblings

Introduction: ROHHAD is an acronym for rapid-onset obesity with hypoventilation, hypothalamic, and autonomic dysregulation. It is a rare disorder that presents with rapidly onset obesity with multiorgan disorders during early childhood. There are less than 100 cases reported. In this paper, we aimed to present a case of ROHHAD syndrome with rare neurologic symptoms. We also discuss our treatment regimen for this specific patient.

RF14 | P984 Early Onset of Insulin Resistance In a Patient with ROHHAD(NET) Syndrome

Abstract Background ROHHAD(NET) is a rare syndrome with a constellation of rapid-onset obesity, hypothalamic dysfunction, hypoventilation, autonomic dysregulation, and neural crest tumors. The endocrine disruptions can include obesity, growth hormone dysregulation, hyperprolactinemia, sodium/water imbalances, central hypothyroidism, adrenal insufficiency and puberty disorders. There have been just over 100 cases described thus far and only one adult patient described with severe insulin resistance. We present a pediatric patient diagnosed with ROHHAD(NET) with overgrowth and extremely elevated insulin concentrations Case Our patient initially presented with severe obesity, rapid linear growth, abnormal lipids, and elevated fasting insulin at the age of 2.5 years. He progressively developed breathing abnormalities, hypothalamic dysfunction, autonomic dysregulation, and a neural crest tumor. With this group of symptoms, criteria for ROHHAD (NET) was met. He progressed to develop insulin resistance, hyperprolactinemia, diabetes insipidus, central hypothyroidism and central adrenal insufficiency. He also required right adrenalectomy for a poorly differentiated neuroblastoma and ganglioneuroblastoma. Results Evaluation of his obesity included a negative monogenic obesity genetic panel (>30 genes tested), normal leptin levels (11.6 ng/ml) and borderline elevated IGF-1 levels 166 ng/ml (z-score 2.5). Glucose levels were usually in the normal range but increased into the diabetes range when he was stressed or sick. HbA1c ranged from 5.6-6.2% (Ref. range <6%) between age 2.5 and 4.5 years. A standard oral glucose tolerance test with blood draws performed at 0, 30, 60 and 120 minutes showed glucose levels of 78,118,123 and 122 mg/dl, insulin of 36,302, 338 and 449 mIU/L and c-peptide levels of 2.9,13.2,14.5 and 16.3 ng/ml respectively. Age at this time was 3.0 years and height, weight and BMI were on the 100% (Z-score 4.28,6.95 and 4.28 respectively) and HbA1c was 5.7% Management: Although glucose tolerance was normal, insulin and C-peptide concentrations were extremely elevated for age and prepubertal status, suggestive of marked insulin resistance. Subsequently, he was started on liquid Metformin 250 mg BID as an adjunct to a calorie-restricted diet. He tolerated this well. His response to therapy has been hard to assess given frequent illnesses and hospitalizations for his various comorbidities; however, he has shown no progression to hyperglycemia, except during acute sickness. Conclusion To the best of our knowledge, this is the youngest patient with ROHADD(NET) reported to have very elevated insulin levels. In addition to rapidly progressing obesity, he had impressive linear overgrowth. Hyperglycemia and insulin resistance could be secondary to severe associated obesity and/or speculatively related to his underlying condition. This case expands the reported morbidities associated with this often-fatal disease Presentation: Sunday, June 12, 2022 1:00 p.m. - 1:05 p.m., Sunday, June 12, 2022 1:00 p.m. - 1:05 p.m., Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

ROHHAD syndrome without rapid-onset obesity: A diagnosis challenge.

BackgroundROHHAD syndrome (Rapid-onset Obesity with Hypothalamic dysfunction, Hypoventilation and Autonomic Dysregulation) is rare. Rapid-onset morbid obesity is usually the first recognizable sign of this syndrome, however a subset of patients develop ROHHAD syndrome without obesity. The prevalence of this entity is currently unknown. Alteration of respiratory control as well as dysautonomic disorders often have a fatal outcome, thus early recognition of this syndrome is essential.Material and methodsA retrospective, observational, multicenter study including all cases of ROHHAD without rapid-onset obesity diagnosed in France from 2000 to 2020.ResultsFour patients were identified. Median age at diagnosis was 8 years 10 months. Median body mass index was 17.4 kg/m2. Signs of autonomic dysfunction presented first, followed by hypothalamic disorders. All four patients had sleep apnea syndrome. Hypoventilation led to the diagnosis. Three of the four children received ventilatory support, all four received hormone replacement therapy, and two received psychotropic treatment. One child in our cohort died at 2 years 10 months old. For the three surviving patients, median duration of follow-up was 7.4 years.ConclusionROHHAD syndrome without rapid-onset obesity is a particular entity, appearing later than ROHHAD with obesity. This entity should be considered in the presence of dysautonomia disorders without brain damage. Likewise, the occurrence of a hypothalamic syndrome with no identified etiology requires a sleep study to search for apnea and hypoventilation. The identification of ROHHAD syndrome without rapid-onset obesity is a clinical challenge, with major implications for patient prognosis.

Case Report: Considerations of nocturnal ventilator support in ROHHAD syndrome in chronic care of childhood central hypoventilation with hypothalamus dysfunction

Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) is a rare life-threatening disorder that can occur during childhood. All children with ROHHAD develop alveolar hypoventilation during wakefulness and sleep. The key treatment for these patients is the optimization of oxygenation and ventilation. Here, we report the case of a 5-year-old girl with suspected ROHHAD, with rapid weight gain, breathing cessation, decreased height, hypoventilation, central hypothyroidism, hyperprolactinemia, and absolute deficiency of growth hormone, and negative PHOX2B sequencing results. The presentation met the diagnostic criteria for ROHHAD syndrome. During the 5-year follow-up, she presented with progressive deterioration of the function of the hypothalamus and respiratory center, hypoxemia (PO2 < 60 mmHg), and hypercapnia [transcutaneous carbon dioxide (TcPCO2) > 70 mmHg] during the first two cycles of N3 sleep with a poor response to ventilatory support. Early diagnosis and application of non-invasive positive pressure ventilation during sleep can improve the quality of life and outcomes of patients with ROHHAD, and polysomnography and TcPCO2 should be repeated every 3–6 months to follow the progress and regulate ventilator support. Multidisciplinary care is crucial for the successful management of these patients.

Autoimmunity Related to Adipsic Hypernatremia and ROHHAD Syndrome.

Specific antibody responses to subfornical organs, including Nax antibody, have been reported in patients with adipsic hypernatremia of unknown etiology who do not have structural lesions in the hypothalamic–pituitary gland. The subfornical organ, also referred to as the window of the brain, is a sensing site that monitors sodium and osmotic pressure levels. On the other hand, ROHHAD syndrome is a rare disease for which the etiology of the hypothalamic disorder is unknown, and there have been some reports in recent years describing its association with autoimmune mechanisms. In addition, abnormal Na levels, including hypernatremia, are likely to occur in this syndrome. When comparing the clinical features of adipsic hypernatremia due to autoimmune mechanisms and ROHHAD syndrome, there are similar hypothalamic–pituitary dysfunction symptoms in addition to abnormal Na levels. Since clinical diagnoses of autoimmunological adipsic hypernatremia and ROHAD syndrome might overlap, we need to understand the essential etiology and carry out precise assessments to accurately diagnose patients and provide effective treatment. In this review, I review the literature on the autoimmune mechanism reported in recent years and describe the findings obtained so far and future directions.

Adrenal ganglioneuroma: Prognostic factors (Review).

Ganglioneuroma, a rare neural crest-derived tumor, exhibits a benign profile in contrast to other neuroblastic tumors (neuroblastoma/ganglioneuroblastoma). Ganglioneuromas can be found anywhere autonomic ganglia are located, mostly abdominal/pelvic sites followed by the adrenal glands (one-third of cases), mediastinum/thorax and cervical area. Affecting especially children more than 10 years of age, Ganglioneuroma is either asymptomatic or may cause local compressive effects; rarely inducing nonspecific abdominal complains or arterial hypertension related to oversecretion of epinephrine/norepinephrine/dopamine. Despite a good prognosis, adrenalectomy is necessary in order to rule out a malignancy. Open procedure represents the standard therapeutic option; alternatively, centers with large laparoscopic pediatric experience and good stratification protocols have reported successful procedures. High uptake of I123-MIBG is associated with a more severe outcome in cases with increased mitotic index. In neuroblastic tumors, neuron-specific enolase >33 ng/ml, age at diagnosis <49 months, and blood vessel invasion indicate a poor prognosis. Concurrent extra-adrenal/adrenal ganglioneuroma is associated with a more severe prognosis; post-surgical complications are more frequent in non-adrenal vs. adrenal ganglioneuroma. Exceptionally, immune-mediated paraneoplastic neurologic syndromes have been reported: anti-N-methyl-D-aspartate receptor encephalitis and opsoclonus-myoclonus-ataxia syndrome. ROHHAD syndrome is the underlying cause in 40-56% of cases of neuroendocrine tumors including ganglioneuroma; 70% of tumors are diagnosed within the first 24 months after hypothalamic obesity onset, associated with a severe prognosis due to hypoventilation, sleep apnea, and dysautonomia. Recently, the PKB/AKT/mTOR/S6 pathway was identified as a tumorigenic pathway in pediatric ganglioneuroma, not in neuroblastoma; mTOR inhibitors are a potential option for pre-operatory tumor shrinkage. Pediatric adrenal ganglioneuroma has a good prognosis if adequately treated; its recognition requires adrenalectomy. Further development of specific biomarkers is needed. In the present article, we aimed to introduce a review of the literature involving adrenal ganglioneuroma based on a practical, multidisciplinary perspective of prognostic factors.