NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH, Bethesda, Maryland, USA.
Section of the Human Biochemical Genetics, Medical Genetics Branch, NHGRI, National Institutes of Health, Bethesda, Maryland, USA.
Am J Med Genet A. 2020 Dec;182(12):3007-3013. doi: 10.1002/ajmg.a.61886. Epub 2020 Sep 29.
Chediak-Higashi disease is a rare disease caused by bi-allelic mutations in the lysosomal trafficking regulator gene, LYST. Individuals typically present in early childhood with partial oculocutaneous albinism, a bleeding diathesis, recurrent infections secondary to immune dysfunction, and risk of developing hemophagocytic lymphohistiocytosis (HLH). Without intervention, mortality is high in the first decade of life. However, some individuals with milder phenotypes have attenuated hematologic and immunologic presentations, and lower risk of HLH. Both classic and milder phenotypes develop progressive neurodegeneration in early adulthood. Here we present a remarkable patient diagnosed with Chediak-Higashi disease at age 67, many decades after the diagnosis is usually established. Diagnosis was suspected by observing the pathognomonic granules within leukocytes, and confirmed by identification of bi-allelic mutations in LYST, reduced LYST mRNA expression, enlarged lysosomes within fibroblasts, and decreased NK cell lytic activity. This case further expands the phenotype of Chediak-Higashi disease and highlights the need for increased awareness. Individuals with milder phenotypes may escape early diagnosis, but identification is important for close monitoring of potential complications, and to further our understanding of the function of LYST.
希-格二氏综合征是一种由溶酶体运输调节基因 LYST 的双等位基因突变引起的罕见疾病。患者通常在儿童早期出现部分眼皮肤白化病、出血倾向、免疫功能障碍引起的反复感染以及发生噬血细胞性淋巴组织细胞增生症（HLH）的风险。如果不干预，患者在生命的第一个十年死亡率很高。然而，一些具有较轻表型的患者具有减轻的血液学和免疫学表现，以及较低的 HLH 风险。经典表型和较轻表型在成年早期都会发生进行性神经退行性变。在这里，我们介绍了一位在 67 岁时被诊断为希-格二氏综合征的患者，其发病时间比通常的诊断时间晚了几十年。通过观察白细胞中的特征性颗粒怀疑诊断为希-格二氏综合征，并通过鉴定 LYST 中的双等位基因突变、降低 LYST mRNA 表达、成纤维细胞中溶酶体增大和 NK 细胞裂解活性降低来确诊。该病例进一步扩展了希-格二氏综合征的表型，并强调了提高认识的必要性。具有较轻表型的患者可能会逃避早期诊断，但识别对于密切监测潜在并发症以及进一步了解 LYST 的功能非常重要。
