Haven Fowler was born a healthy baby. She remained so until the age of two and a half when she began to gain weight very rapidly, gaining 40 pounds over eight months. She also started having unusual neurological symptoms, including hallucinations, sleep-eating and sleepwalking, irritability and profuse sweating.
Month after month, Haven’s parents took her from doctor to doctor, each one increasingly bewildered by her mysterious symptoms and unable to find an answer. Finally, the Fowlers — then living in California — were told that if they wanted answers, they needed to go to Johns Hopkins. And so they did. About three weeks after her cross-country trip to Baltimore, Haven suffered a serious seizure, which landed her at Hopkins Children’s, where the mystery of her condition eventually would be solved.
Haven arrived at Hopkins Children’s in the middle of the night with elevated blood pressure and heart rate and what one resident described as a “striking presentation.” The girl’s weight suddenly shot up – 25 pounds in one month – and she had been sleep walking and experiencing night terrors and a seizure....
When blood tests showed elevated levels of the hormone metanephrine, Cooke started thinking neuroblastoma, an early childhood cancer that typically forms in the adrenal gland. Indeed, a CT scan and an MRI test indicated there was a tumor near the spine. Haven underwent surgery to remove the tumor, which marked the beginning of a very long treatment.
Despite expectations to the contrary, Haven’s symptoms did not improve after the surgery...
Then serendipity played a hand when senior pediatric resident Hema Dave reviewed the literature and found an association between neuroblastomas and paraneoplastic syndrome – a rare degenerative disorder of unknown origins, though one hypothesis is that it may be an autoimmune reaction to a tumor. The syndrome’s symptoms include loss of muscle tone, sleep disturbances, and seizures, all of which the child had experienced.
This was the Eureka moment for the clinical team: Haven had ROHHAD, or Rapid-Onset Obesity, Hypothalamic Dysfunction, Hypoventilation and Autonomic Dysregulation. Haven’s tumor was just one of many problems requiring treatment. Thus, Cooke and his colleagues from oncology devised a special immune-suppressive cocktail to “reboot” Haven’s overactive immune system. Doing so, they believed, would also reduce or completely eliminate her seizures, sleep problems and the weight gain. So far, it’s been working, so much so that the novel treatment was described in the medical Journal of Pediatrics in 2010 (editor's note: actually 2011).
From Paz-Priel I, Cooke DW, Chen AR. Cyclophosphamide for rapid-onset obesity,
hypothalamic dysfunction, hypoventilation, and autonomic dysregulation syndrome.
J Pediatr. 2011 Feb;158(2):337-9:
A syndrome characterized by rapid onset of obesity, hypothalamic dysfunction, hypoventilation, autonomic dysregulation (ROHHAD), and neural crest tumors has been recently identified. Although the spectrum of this syndrome's manifestations has been described, the underlying pathogenesis is not clear, and an extensive effort to sequence candidate genes, including PHOX2B, was unrevealing. The association with neural crest tumors suggests a paraneoplastic, autoimmune etiology; this has not yet been confirmed, however. Many patients with ROHHAD succumb to respiratory failure or sudden death, and survivors experience debilitating sociocognitive deficits. Better therapeutic approaches are needed...
A 3-year, 10-month-old girl presented with hyperphagia and rapid weight gain. After growth at the 50th percentile up to age 2 years, her body mass index increased from 16.8 kg/m2 (standard deviation [SD], 0.0) to 20.7 kg/m2 (SD, 2.45) at age 30 months, and then to 25.4 kg/m2 (SD, 6.18) at age 36 months. This was associated with aggressive food-seeking behavior, abnormal sleep patterns, hypertension, decreased pain sensitivity, irritability, aggressive behavior, loss of toilet training, diffuse sweating without temperature instability, and left eye exotropia. Her serum prolactin level was 76.5 ng/mL, and her thyroid and adrenal gland function were normal. Computed tomography revealed a retroperitoneal tumor, which was resected and identified as a ganglioneuroblastoma with favorable biological features. No further therapy for this neoplasm was indicated.
Because of the associated ganglioneuroblastoma, an immune-mediated process, akin to opsoclonus myoclonus ataxia (OMA) syndrome, was presumed. The patient was treated with cyclophosphamide, 750 mg/m2/dose every 28 days for 6 doses; intravenous immunoglobulin, 1g/kg/dose every 28 days for 8 doses and then every 56 days for 2 additional doses; and prednisone, 2 mg/kg/day for 28 days, followed by a 20-week-long taper. Five weekly doses of rituximab, 375 mg/m2/dose, were added based on previous reports of failure of conventional dose immunosuppression and the utility of this agent in OMA...
Our patient failed conventional-dose immunosupression, as previously reported, and experienced only short-lived relief from rituximab. High-dose cyclophosphamide “reboots” the immune system by ablating the mature immune elements and has been found to be efficacious in patients who fail conventional immunosuppression. The acute toxicity of this regimen is well tolerated, and quality-of-life measures compare favorably with those associated with conventional-dose cyclophosphamide. However, potential risks, including infection, infertility, and secondary neoplasm, must be considered. Our patient markedly improved after high-dose cyclophosphamide, albeit with limited follow-up. Given the progressive deterioration of most patients with ROHHAD, our experience is encouraging, and in carefully selected patients, this therapy may balance the potential risks of intensive immunosuppression.
Inspired by a patient here with ROHHAD.
Barclay SF, Rand CM, Borch LA, Nguyen L, Gray PA, Gibson WT, Wilson RJ, Gordon PM, Aung Z, Berry-Kravis EM, Ize-Ludlow D, Weese-Mayer DE, Bech-Hansen NT. Rapid-Onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD): exome sequencing of trios, monozygotic twins and tumours. Orphanet J Rare Dis. 2015 Aug 25;10:103.ReplyDelete
Rapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD) is thought to be a genetic disease caused by de novo mutations, though causative mutations have yet to be identified. We searched for de novo coding mutations among a carefully-diagnosed and clinically homogeneous cohort of 35 ROHHAD patients.
We sequenced the exomes of seven ROHHAD trios, plus tumours from four of these patients and the unaffected monozygotic (MZ) twin of one (discovery cohort), to identify constitutional and somatic de novo sequence variants. We further analyzed this exome data to search for candidate genes under autosomal dominant and recessive models, and to identify structural variations. Candidate genes were tested by exome or Sanger sequencing in a replication cohort of 28 ROHHAD singletons.
The analysis of the trio-based exomes found 13 de novo variants. However, no two patients had de novo variants in the same gene, and additional patient exomes and mutation analysis in the replication cohort did not provide strong genetic evidence to implicate any of these sequence variants in ROHHAD. Somatic comparisons revealed no coding differences between any blood and tumour samples, or between the two discordant MZ twins. Neither autosomal dominant nor recessive analysis yielded candidate genes for ROHHAD, and we did not identify any potentially causative structural variations.
Clinical exome sequencing is highly unlikely to be a useful diagnostic test in patients with true ROHHAD. As ROHHAD has a high risk for fatality if not properly managed, it remains imperative to expand the search for non-exomic genetic risk factors, as well as to investigate other possible mechanisms of disease. In so doing, we will be able to confirm objectively the ROHHAD diagnosis and to contribute to our understanding of obesity, respiratory control, hypothalamic function, and autonomic regulation.
Patwari PP, Wolfe LF. Rapid-onset obesity with hypothalamic dysfunction,ReplyDelete
hypoventilation, and autonomic dysregulation: review and update. Curr Opin
Pediatr. 2014 Aug;26(4):487-92.
PURPOSE OF REVIEW:
The focus of this review is to compare and contrast two orphan disorders of late-onset hypoventilation. Specifically, rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) and congenital central hypoventilation syndrome (CCHS) are distinct in presentation, pathophysiology, and etiology.
While limited new information is available, appreciation and understanding of rare disorders can be attained through case reports. Recent literature in ROHHAD has included case reports with new findings that may provide insight into pathophysiology involving possible aberrant immune process and dysregulation at the level of the orexinergic system.
The etiology of ROHHAD continues to be elusive. The hope is that, with growing recognition, discussion, and investigation into the overlap of ROHHAD with disorders outside congenital central hypoventilation syndrome, further advancement will be made.
ROHHAD is a horrible disease. I hope that a lifesaving cure could be found, or at least effective treatment that could give ROHHAD sufferers somewhat normal lives and a normal lifespan.ReplyDelete