Rapid-onset obesity with hypothalamic dysregulation, hypoventilation, and autonomic dysregulation (ROHHAD syndrome): A case report and literature review. / Síndrome ROHHAD (obesidad de rápida progresión, disfunción hipotalámica, hipoventilación y disregulación autonómica). Presentación de un caso y revisión de la literatura.

INTRODUCTION: ROHHAD syndrome (rapid-onset obesity with hypothalamic dysregulation, hypoventilation, and autonomic dysregulation) is a rare and complex disease, presenting in previously healthy children at the age of 2-4 years. Up to 40% of cases are associated with neural crest tumours. DEVELOPMENT: We present the case of a 2-year-old girl with symptoms of rapidly progressing obesity, who a few months later developed hypothalamic dysfunction with severe electrolyte imbalance, behaviour disorder, hypoventilation, and severe autonomic dysregulation, among other symptoms. Although the pathophysiology of this syndrome remains unclear, an autoimmune hypothesis has been proposed for ROHHAD. Therefore, after obtaining a limited response to intravenous immunoglobulins, we decided to test the response to a high dose cyclophosphamide (low dose was not effective either). Unfortunately our patient experienced many severe complications (among them central pontine myelinolysis, from which the patient recovered, and failure to wean from the ventilator requiring tracheostomy and long term ventilation) that required a prolonged ICU stay. Although her behaviour improved, our patient unfortunately died suddenly at home at the age of 5 due to respiratory pathology. CONCLUSIONS: ROHHAD syndrome is a rare and little-known disease which requires a multidisciplinary approach because it involves complex symptoms and multiple organ system involvement. Alveolar hypoventilation should be identified early and appropriate treatment should be started promptly for the best possible outcome. Immunomodulatory treatment with immunoglobulins, cyclophosphamide, or rituximab has previously resulted in symptom improvement in some cases. Because of the low incidence of the syndrome, multi-centre studies must be carried out in order to gather more accurate information about ROHHAD pathophysiology and design an appropriate therapeutic approach.

Rapid-onset obesity, hypoventilation, hypothalamic dysfunction, autonomic dysregulation and neuroendocrine tumor syndrome with a homogenous enlargement of the pituitary gland: a case report.

BACKGROUND: Rapid-onset obesity with hypoventilation, hypothalamic dysfunction, and autonomic dysregulation syndrome is a rare pediatric disorder with a variable sequence of clinical presentations, undefined etiology, and high risk of mortality. Our patient presented an unusual course of the disease accompanied by a homogenous mild enlargement of her pituitary gland with an intact pituitary-endocrine axis which, to the best of our knowledge, represents a new finding in rapid-onset obesity with hypoventilation, hypothalamic dysfunction, and autonomic dysregulation syndrome. CASE PRESENTATION: We present a documented case of a 4 years and 8-month-old Syrian Arabic girl with a distinctive course of signs and symptoms of rapid-onset obesity with hypoventilation, hypothalamic dysfunction, and autonomic dysregulation syndrome accompanied by mature ganglioneuroma in her chest, a homogenous mild enlargement of her pituitary gland, generalized cortical brain atrophy, and seizures. Three months after her first marked symptoms were noted she had a sudden progression of severe respiratory distress that ended with her death. CONCLUSIONS: The findings of this case could increase our understanding of the pathogenetic mechanisms of rapid-onset obesity with hypoventilation, hypothalamic dysfunction, and autonomic dysregulation, and place more emphases on pediatricians to consider rapid-onset obesity with hypoventilation, hypothalamic dysfunction, and autonomic dysregulation syndrome whenever early rapid onset of obesity, associated with any malfunction, is observed in children. This knowledge could be lifesaving for children with rapid-onset obesity with hypoventilation, hypothalamic dysfunction, and autonomic dysregulation syndrome.

Treatment of neuroblastoma in congenital central hypoventilation syndrome with a PHOX2B polyalanine repeat expansion mutation: New twist on a neurocristopathy syndrome.

Neuroblastoma in patients with congenital central hypoventilation syndrome (CCHS) as part of a neurocristopathy syndrome is a rare finding and has only been associated with paired-like homeobox 2b (PHOX2B) non-polyalanine-repeat-expansion mutations. To the best of our knowledge, we report the first case of a child with CCHS and Hirschsprung disease who had a PHOX2B polyalanine-repeat-expansion mutation (PARM) (genotype 20/33) and developed high-risk neuroblastoma. We further describe his treatment including chemotherapy and therapeutic I(131) -metaiodobenzylguanidine. This case highlights the need to consider neuroblastoma in patients with CCHS and the longest PHOX2B PARMs and to individualize treatment based on co-morbidities.

Prevalence, clinical characteristics, and predictors of obesity hypoventilation syndrome in a large sample of Saudi patients with obstructive sleep apnea.

OBJECTIVES: To assess the prevalence, clinical characteristics, and predictors of obesity hypoventilation syndrome (OHS) in a large sample of Saudi patients with obstructive sleep apnea (OSA). METHODS: This prospective observational study consisted of 1693 patients who were diagnosed to have sleep-disordered breathing using type I attended polysomnography (PSG) between January 2002 and December 2012 in the University Sleep Disorders Center (USDC) at King Saud University Hospital, Riyadh, Kingdom of Saudi Arabia. RESULTS: Out of 1693 OSA patients, OHS was identified in 144 (8.5%) (women 66.7%). Compared with the pure OSA patients, the OHS patients were significantly older (57.4±13.4 years versus 46.8±13.7 years), had a higher body mass index (44.6±10.8 versus 35.7±9.2 kg/m²), a higher daytime partial pressure of carbon dioxide (PaCO2) (56.5±12.7 versus 41.6±6.7 mmHg), a longer duration of nocturnal oxygen saturation (nSaO2) <90% (71.0±34.3 versus 10.5±20.5 minutes), and a higher apnea hypopnea index (68.2±47.1 versus 46.5±34.1 events/hour). A multivariate logistic regression analysis showed that serum bicarbonate (odds ratio [OR]=1.17, p=0.0001, confidence interval [CI]=1.10-1.25), and duration of nSaO2 <90% (OR=1.05, p=0.0001, CI=1.04-1.06) were predictors of OHS. CONCLUSION: Obesity hypoventilation syndrome is common among Saudi OSA patients referred to the Sleep Disorders Center. Serum bicarbonate and duration of nSaO2 <90% are independent predictors of OHS among patients with OSA.

La neurología en un personaje de Dickens: síndrome pickwickiano, apneas hipopneas del sueño e hipertensión intracraneal

En muchos casos, la literatura de ficción se ha adelantado a la ciencia. Charles Dickens (1812-1870) pobló su obra con un tropel de notables personajes. Como la mayoría de los grandes novelistas, le adornaban finos dotes de observación y una extraordinaria capacidad descriptiva. Uno de sus protagonistas secundarios se ganó un puesto en los anales de la medicina. El logro de esta empresa se da al presentarnos la figura de un sirviente gordo y somnoliento llamado Joe, que a pesar de tener un pequeño y breve rol en el capítulo 54 de sus “Pickwick Papers” (1836), ha trascendido al lenguaje médico diario. La cómica caricatura que caracteriza al individuo obeso, sobrevivió en el ámbito de la medicina como un caso clásico de apneas del sueño: el síndrome de Pickwick o más precisamente, el síndrome Pickwickiano. Debieron transcurrir más de 120 años para que Burwell y sus colaboradores, hallaran una explicación fisiopatológicaal fenotipo de Joe, ese “niño gordinflón, rosado y roncador con la respiración entrecortada, eternamente somnoliento”,describiendo así, la presencia del síndrome apneashipopneas del sueño e hipoventilación alveolar en el sujeto obeso. La presencia de hipertensión intracraneal es otro de sus infrecuentes componentes. Describimos una serie de cuatro pacientes

In many cases, fictional literature has preceded science. Charles Dickens (1812-1870) filled his novels with anumber of noteworthy characters. As most great novelists, he possessed fine observation skills and an extraordinary capacity for description. In fact, one of his secondary characters gained a place in the world of medicine. From the “Pickwick Papers” (1836), Joe, the overweight and lazy servant, in spite of his brief appearance in chapter 54, has transcended to become part of the physician’s every day lingo. The amusing depiction that characterizes the overweight individual, survived in the medical world as the classic case of sleep apneas, the Pickwick syndrome or more precisely, the Pickwickian syndrome. After 120 years Burwell and his collaborators found a physiopathological explanation to the phenotype of Joe, ¨that fat and red-faced, chubby, plump and wheeze boy, in a state of somnolence”, so describing the presence of sleep apneas hypopneas and alveolar hypoventilation in obese individuals. The presence of intracranial hypertension is another of its infrequent components. We described a series of 4 of such cases.

Dyslipidemia and atherosclerosis induced by chronic intermittent hypoxia are attenuated by deficiency of stearoyl coenzyme A desaturase.

Obstructive sleep apnea leads to chronic intermittent hypoxia (CIH) and is associated with atherosclerosis. We have previously shown that C57BL/6J mice exposed to CIH and a high-cholesterol diet develop dyslipidemia, atherosclerosis of the aorta, and upregulation of a hepatic enzyme of lipoprotein secretion, stearoyl coenzyme A desaturase 1 (SCD-1). We hypothesized that (1) SCD-1 deficiency will prevent dyslipidemia and atherosclerosis during CIH; and (2) human OSA is associated with dyslipidemia and upregulation of hepatic SCD. C57BL/6J mice were exposed to CIH or normoxia for 10 weeks while being treated with either SCD-1 or control antisense oligonucleotides. Obese human subjects underwent sleep study and bariatric surgery with intraoperative liver biopsy. In mice, hypoxia increased hepatic SCD-1 and plasma very-low-density lipoprotein cholesterol levels and induced atherosclerosis lesions in the ascending aorta (the cross-section area of 156514+/-57408 microm(2)), and descending aorta (7.0+/-1.2% of the total aortic surface). In mice exposed to CIH and treated with SCD-1 antisense oligonucleotides, dyslipidemia and atherosclerosis in the ascending aorta were abolished, whereas lesions in the descending aorta showed 56% reduction. None of the mice exposed to normoxia developed atherosclerosis. In human subjects, hepatic SCD mRNA levels correlated with the degree of nocturnal hypoxemia (r=0.68, P=0.001). Patients exhibiting oxyhemoglobin desaturations at night showed higher plasma triglyceride and low-density lipoprotein cholesterol levels, compared to subjects without hypoxemia. In conclusion, CIH is associated with dyslipidemia and overexpression of hepatic SCD in both humans and mice alike; SCD-1 deficiency attenuates CIH-induced dyslipidemia and atherosclerosis in mice.

Clinical characteristics of obesity-hypoventilation syndrome in Japan: a multi-center study.

OBJECTIVE: To clarify the prevalence and clinical characteristics of obesity-hypoventilation syndrome (OHS) in a large number of patients with moderate to severe obstructive sleep apnea syndrome (OSAS). METHODS: Subjects comprised 611 patients with OSAS registered from 7 sleep centers and clinics and analyzed according to the definitions of the Respiratory Failure Research Group of the Japanese Ministry of Health and Welfare. Baseline characteristics, polysomnographic data during sleep, laboratory blood examinations, excessive daytime sleepiness, pulmonary functions, and arterial blood gases were compared between OHS and non-OHS patients. Determinants of daytime hypercapnia were also examined in OHS patients. RESULTS: OHS was identified in 55 of the 611 patients with OSAS (9%). OHS patients were younger, heavier, and more somnolent than non-OHS patients and displayed more severe OSAS, liver dysfunctions, higher total cholesterol, and impaired pulmonary function. However, these differences were resolved except for pulmonary function after correction for obesity. Daytime hypercapnia was associated with impaired pulmonary function. Percent vital capacity (%VC) was most closely correlated with PaCO2 in OHS. CONCLUSION: OHS patients display numerous abnormalities due to obesity compared with non-OHS patients. Impaired pulmonary function, particularly %VC, may play an important role in the development of daytime hypercapnia independent of obesity in OHS patients.

[Clinical characteristics and morphology of Pickwickian syndrome]. / O klinike i morfologii sindroma Pikvika.

Clinical and morphological evidence obtained for 23 patients with Pickwickian syndrome has been analysed. 18 patients had no other symptoms, 12 patients died of the disease. Standard signs of the syndrome (drowsiness, respiratory distress, diffuse cyanosis, etc.) were not universal, whereas mixed-type respiratory disorders occurred in all the patients as well as right heart hypertrophy, sclerosis and hyalinosis of the lesser circulatory bed found morphologically and histologically.