Delineation of Late Onset Hypoventilation Associated with Hypothalamic Dysfunction Syndrome

Abstract

Late Onset Central Hypoventilation Syndrome associated with Hypothalamic Dysfunction (LO-CHS/HD) is a distinct entity among the clinical and genetic heterogeneous group of patients with late onset central hypoventilation. Here we report a series of 13 patients with LO-CHS/HD. Rapid onset obesity is the first symptom of HD followed by hypoventilation with a mean delay of 18 mos. The outcome remains poor for this group of patients and would benefit from early diagnosis to anticipate ventilation and possible metabolic disorders. Tumor predisposition is more frequent than initially suspected and as high as 40% in this series. These tumors of the sympathetic nervous system (TSNS) are usually differentiated and do not significantly worsen the prognosis. We report a familial case with recurrence in siblings. The cause underlying LO-CHS/HD remains poorly understood although recurrence in siblings argues for a monogenic disorder. We ruled out PHOX2B, ASCL1, and NECDIN as disease-causing genes by direct sequencing in our series of patients and discuss possible disease-causing mechanisms. A genetic basis for C-CHS was postulated because of, i) concordant monozygotic twins; ii) rare cases of recurrence in siblings and vertical transmission; and iii) the association with genetically determined neurocristopathies (i.e. Hirschsprung disease and tumors of the sympathetic nervous system). The screening of genes involved in the developmental cascade of the autonomic nervous system pointed to PHOX2B as the gene underlying C-CHS with an autosomal dominant mode of inheritance and de novo mutations in the first generation (4). We and others subsequently showed that PHOX2B mutations also account for a subset of CHS presenting later in life and named Late-Onset Central Hypoventilation Syndrome (LO-CHS) (5-7). LO-CHS is genetically and clinically heterogeneous and a subset of patients presenting hypothalamic dysfunction (HD) in association with LO-CHS is clearly recognized as a distinct entity (8).Single-case reports of LO-CHS/HD patients, one series and review of the literature have been reported and, thus, far (9 -22) for a total of 30 patients to date. Here we present a series of 13 additional patients with LO-CHS/HD, one being a familial case with recurrence in siblings. This observation strongly argues that LO-CHS/HD is a monogenic condition. In this series, PHOX2B, ASCL1, and NECDIN have been ruled out as disease-causing genes by direct sequencing. PATIENTS AND METHODSThirteen patients with LO-CHS/HD were referred to us between 2000 and 2007 and medical records were reviewed. Inclusion criteria were i) central hypoventilation confirmed by polysomnographic recordings with normal brain MRI and no lung or neuromuscular diseases and ii) at least one other sign of hypothamic dysfunction among the following: rapid-onset obesity due to hyperphagia, hyperprolactinemia, central hypothyroidism, water balance disorder, nonresponse to growth hormone stimulation test, corticotrophin deficiency, or abnormal puberty (precocious or dela...

Improved Behavior and Neuropsychological Function in Children With ROHHAD After High-Dose Cyclophosphamide

“…2, 7-9 The association with neural crest tumors suggests an immune-mediated process resembling opsoclonus myoclonus ataxia syndrome. 2,5,7,10 Lymphocytic infiltration of the brain, 11, 12 presence of oligoclonal bands in the cerebrospinal fluid, 13 and response to immunomodulary therapy 5, 14 support an autoimmune process.High-dose cyclophosphamide (Hi-Cy) results in near total ablation of active lymphocytes without myeloablation, thereby "rebooting" the immune system, making it an efficacious and safe approach for selected patients with severe refractory autoimmune diseases. 5,15 We previously reported on a child with ROHHAD whose symptoms improved after Hi-Cy.…”

“…1,2,[4][5][6] The etiology of ROHHAD is unknown and careful investigations have not revealed a genetic etiology. 2,[7][8][9] The association with neural crest tumors suggests an immune-mediated process resembling opsoclonus myoclonus ataxia syndrome. 2,5,7,10 Lymphocytic infiltration of the brain, 11,12 presence of oligoclonal bands in the cerebrospinal fluid, 13 and response to immunomodulary therapy 5,14 support an autoimmune process.…”

Rapid onset obesity and ondine’s curse: a deadly syndrome

“…In contrast to most cases of exogenous obesity. 2,9 where growth velocity and IGF-1 levels are high normal, in ROHHAD patients IGF-1 levels are depressed with sub-optimal GH response to stimulatory tests.…”

“…1,2,9 There has been a report of "Retinoic acid Induced-1" gene (RAI-1) receptor mutation in one case. 16 It was later confirmed that none of these 8 genes or RAI1 gene were major ROHHAD genes.…”

“…These children appear "normal" until its onset between 1.5 and 10 years of age. [1][2][3] The acronym ROHHAD describes the typical sequence of symptoms experienced by most children, in order of their appearance. Often, the first sign is hyperphagia with dramatic weight gain.…”