Section of Human Biochemical Genetics, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.
Section of Human Biochemical Genetics, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland; Department of Genetics and Pediatrics, Johns Hopkins University School of Medicine, Bloomberg Children's Center, Baltimore, Maryland.
Transl Res. 2020 Jan;215:31-40. doi: 10.1016/j.trsl.2019.08.008. Epub 2019 Aug 28.
Precision medicine has generated diagnoses for many patients with challenging undiagnosed disorders. Some individuals remain without a diagnosis despite comprehensive testing, and this impedes their treatment. This report addresses the role of personalized medicine in identifying effective therapy for an undiagnosed disease. A 22-year-old woman presented with chronic severe recurrent trismus, facial pain, progressive multicentric inflammatory and fibrotic masses, and high C-reactive protein. Sites of disease included the pterygomaxillary region, masseter muscles, mandible, lung, pericardium, intrabdominal cavity, and retroperitoneum. A diagnosis was not established after an extensive assessment, including multiple biopsies. The patient was subsequently evaluated under the Undiagnosed Diseases Program at the National Institutes of Health. Large scale genotyping, proteomic studies, and in vitro and gene expression analyses of fibroblasts obtained from a major disease locus were performed. Germline genetic testing did not identify strong candidate genes; proteomic studies of the patient's serum and bronchoalveolar lavage fluid and gene expression analyses of her cells were consistent with dysregulation of the tumor necrosis factor-alpha pathway. The patient's cultured fibroblasts were incubated with selected drugs, and cell proliferation was inhibited by hydroxychloroquine. Treatment of the patient with hydroxychloroquine conferred prolonged beneficial clinical effects, including stabilization of trismus and reduction of corticosteroid dose, C-reactive protein, and size of masses. This case represents an example of precision medicine applied to discover effective treatments for individuals with enigmatic undiagnosed disorders.
精准医学为许多患有疑难未确诊疾病的患者提供了诊断。尽管进行了全面的检查，仍有一些患者没有得到诊断，这阻碍了他们的治疗。本报告探讨了个性化医学在确定未确诊疾病有效治疗方法中的作用。一名 22 岁女性出现慢性严重复发性牙关紧闭、面部疼痛、进行性多中心炎症性和纤维性肿块以及高 C 反应蛋白。病变部位包括翼上颌区、咬肌、下颌骨、肺、心包、腹腔和腹膜后腔。经过广泛评估，包括多次活检后仍未确诊。随后，该患者在国立卫生研究院未确诊疾病计划下进行了评估。对来自主要疾病部位的成纤维细胞进行了大规模基因分型、蛋白质组学研究以及体外和基因表达分析。种系基因检测未发现强候选基因；对患者血清和支气管肺泡灌洗液的蛋白质组学研究以及对其细胞的基因表达分析表明，肿瘤坏死因子-α 通路失调。将患者的成纤维细胞在选定的药物中孵育，羟氯喹抑制细胞增殖。羟氯喹治疗该患者带来了长期有益的临床效果，包括牙关紧闭的稳定和皮质类固醇剂量、C 反应蛋白和肿块大小的减少。该病例代表了将精准医学应用于发现具有神秘未确诊疾病的个体的有效治疗方法的一个例子。
