Monozygotic Twins Discordant for ROHHAD Phenotype

Abstract

Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) falls within a group of pediatric disorders with both respiratory control and autonomic nervous system dysregulation. Children with ROHHAD typically present after 1.5 years of age with rapid weight gain as the initial sign. Subsequently, they develop alveolar hypoventilation, autonomic nervous system dysregulation, and, if untreated, cardiorespiratory arrest. To our knowledge, this is the first report of discordant presentation of ROHHAD in monozygotic twins. Twin girls, born at term, had concordant growth and development until 8 years of age. From 8 to 12 years of age, the affected twin developed features characteristic of ROHHAD including obesity, alveolar hypoventilation, scoliosis, hypothalamic dysfunction (central diabetes insipidus, hypothyroidism, premature pubarche, and growth hormone deficiency), right paraspinal/thoracic ganglioneuroblastoma, seizures, and autonomic dysregulation including altered pain perception, large and sluggishly reactive pupils, hypothermia, and profound bradycardia that required a cardiac pacemaker. Results of genetic testing for PHOX2B (congenital central hypoventilation syndrome disease-defining gene) mutations were negative. With early recognition and conservative management, the affected twin had excellent neurocognitive outcome that matched that of the unaffected twin. The unaffected twin demonstrated rapid weight gain later in age but not development of signs/symptoms consistent with ROHHAD. This discordant twin pair demonstrates key features of ROHHAD including the importance of early recognition (especially hypoventilation), complexity of signs/symptoms and clinical course, and importance of initiating comprehensive, multispecialty care. These cases confound the hypothesis of a monogenic etiology for ROHHAD and indicate alternative etiologies including autoimmune or epigenetic phenomenon or a combination of genetic predisposition and acquired precipitant.

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

“…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

“…Hypoventilation develops few months later followed by hypothalamic dysfunction, diabetes insipidus, hyperprolactinemia, precocious/delayed puberty, growth hormone (GH) deficiency, adrenocorticotropic hormone (ACTH) deficiency, central hypothyroidism, autonomic dysfunction, light-nonresponsive pupils, constipation, temperature dysregulation, sweating disorders and reduced pain sensation. 4 Other features include developmental/behavioral disorders and seizures. 4 …”

Zespół ROHHAD u 9-letniego chłopca — opis przypadku

“…ROHHAD syndrome (Rapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation) is characterised by rapid-onset obesity in young children, hypoventilation, and hypothalamic and autonomic dysfunction [1][2][3][4][5][6]. The aetiology of the disease remains unknown.…”

“…The aetiology of the disease remains unknown. Genetic, epigenetic, autoimmune, and paraneoplastic factors are taken into account as possible causes of ROHHAD [1][2][3][4][5][6][7][8][9]. There have only been 76 reported cases of ROHHAD [2].…”