Anti-Hypothalamus and Anti-Pituitary Auto-antibodies in ROHHAD Syndrome: Additional Evidence Supporting an Autoimmune Etiopathogenesis
Anti-Hypothalamus and Anti-Pituitary Auto-antibodies in ROHHAD Syndrome: Additional Evidence Supporting an Autoimmune Etiopathogenesis
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DOI：
10.1159/000499163
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发表时间：
2020-01-01
影响因子：
3.2
通讯作者：
Cutrera, Renato
中科院分区：
文献类型：
--
作者：
Giacomozzi, Claudio;Guaraldi, Federica;Cutrera, Renato
背景：快速发作性肥胖伴下丘脑功能障碍、通气不足和自主神经失调（ROHHAD）是一种非常罕见和复杂的儿科综合征，其特征是下丘脑热调节、痛阈和呼吸控制改变，嗜食伴快速体重增加，通常伴有下丘脑-垂体功能障碍。其发病机制尚未确定。我们研究了-ROHHAD综合征患者靶基因和下丘脑-垂体自身免疫改变的存在。方法：1例3岁女童，体重快速增加后出现肥胖，根据临床表现及生化、功能检查结果异常，诊断为ROHHAD综合征。由于症状迅速恶化，脑脊液（CSF）分析显示寡克隆带，她接受血浆分离、甲基强的松龙、抗cd20单克隆抗体和硫唑嘌呤治疗。尽管最初的部分临床改善，病人很快死于心肺骤停。对血液和脑脊液进行尸检、全外显子组测序、高分辨率比较基因组杂交阵列和优化间接免疫荧光（IIF）分析。结果：未检测到与显性或隐性遗传相容的推定致病基因组变异，也未检测到具有临床意义的结构重排。血清和脑脊液的IIF显示存在抗垂体和抗下丘脑自身抗体。结论：这些发现支持自身免疫参与ROHHAD综合征。然而，对免疫抑制治疗的反应只是短暂的，患者死亡。需要进一步的病例来确定复杂的疾病发病机制。
Background: Rapid-onset Obesity with Hypothalamic dysfunction, Hypoventilation and Autonomic Dysregulation (ROHHAD) is a very rare and complex pediatric syndrome characterized by altered hypothalamic thermal regulation, pain threshold, and respiratory control, hyperphagia with rapid weight gain and, often, hypothalamic-pituitary dysfunction. Its etiopathogenesis remains undetermined. We investigated the presence of alterations to target genes and hypothalamic-pituitary autoimmunity in a patient with -ROHHAD syndrome. Methods: A 3-year-old girl presenting with obesity after rapid weight gain was diagnosed with ROHHAD syndrome based on clinical features and abnormal biochemical and functional testing results. Because of worsening of rapid symptoms and demonstration of oligoclonal bands on cerebrospinal fluid (CSF) analysis, she was treated with plasmapheresis, methylprednisolone, anti-CD20 monoclonal antibodies, and azathioprine. Despite initial partial clinical improvement, the patient soon died of cardiorespiratory arrest. Post-mortem, whole exome sequencing, high-resolution comparative genomic hybridization array, and optimized indirect immunofluorescence (IIF) analysis were performed on blood and CSF. Results: No putative causative genomic variants compatible with dominant or recessive inheritance nor clinically significant structural rearrangement were detected. IIF on serum and CSF demonstrated the presence of anti-pituitary and anti-hypothalamus autoantibodies. Conclusions: These findings support the involvement of autoimmunity in ROHHAD syndrome. However, response to immunosuppressive treatment was only transient and the patient died. Further cases are required to define the complex disease pathogenesis.