Greene Sunny, Soldatos Ariane, Toro Camilo, Zein Wadih M, Snow Joseph, Lehky Tanya J, Malicdan May Christine V, Introne Wendy J
Department of Medical Education, University of Miami, Miller School of Medicine, Miami, FL, USA.
National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
Semin Pediatr Neurol. 2024 Dec;52:101168. doi: 10.1016/j.spen.2024.101168. Epub 2024 Nov 8.
Chedíak-Higashi Syndrome (CHS) is a rare autosomal recessive disorder caused by mutations in the Lysosomal Trafficking Regulator (LYST) gene, leading to defective lysosomal function in immune cells, melanocytes, and neurons. Clinically, CHS is characterized by a spectrum of symptoms, including immunodeficiency, partial oculocutaneous albinism, bleeding tendencies, neurodevelopmental deficits and progressive neurodegenerative symptoms. The severity of CHS correlates with the type of LYST mutation: the classic form, linked to nonsense or frameshift mutations, presents early in childhood with severe immune dysfunction, recurrent infections, and a high risk of hemophagocytic lymphohistiocytosis (HLH), a life-threatening hyperinflammatory state. Without timely treatment, including hematopoietic stem cell transplantation (HSCT), prognosis is poor, with high mortality in early life. Atypical forms, associated with missense mutations, manifest later with milder immunologic symptoms but inevitably progress to neurological impairment, including cognitive decline and motor dysfunction. Diagnosing CHS is complex due to its rarity, phenotypic variability, and overlap with other disorders. A thorough approach, incorporating clinical evaluation, peripheral blood smear for giant granules in leukocytes, and genetic testing for LYST mutations, is crucial for accurate diagnosis. Management of CHS requires a multidisciplinary approach, focusing on HSCT for immunologic and hematologic stabilization and symptomatic and supportive care for neurological symptoms. Even those patients who undergo stabilizing HSCT eventually develop neurological difficulties. This review provides an in-depth exploration of CHS, covering its epidemiology, clinical presentation, molecular genetics, diagnostic challenges, and current management strategies, while emphasizing the necessity of a comprehensive, multidisciplinary approach to improve patient outcomes.
切迪阿克-希加什综合征（CHS）是一种罕见的常染色体隐性疾病，由溶酶体运输调节因子（LYST）基因突变引起，导致免疫细胞、黑素细胞和神经元中的溶酶体功能缺陷。临床上，CHS的特征是一系列症状，包括免疫缺陷、部分眼皮肤白化病、出血倾向、神经发育缺陷和进行性神经退行性症状。CHS的严重程度与LYST突变的类型相关：经典形式与无义或移码突变有关，在儿童早期出现严重的免疫功能障碍、反复感染以及噬血细胞性淋巴组织细胞增生症（HLH）的高风险，HLH是一种危及生命的高炎症状态。如果不及时治疗，包括造血干细胞移植（HSCT），预后很差，早年死亡率很高。与错义突变相关的非典型形式，后期表现为较轻的免疫症状，但不可避免地会发展为神经功能障碍，包括认知能力下降和运动功能障碍。由于CHS罕见、表型变异且与其他疾病重叠，其诊断很复杂。采用全面的方法，包括临床评估、白细胞巨大颗粒的外周血涂片检查以及LYST突变的基因检测，对于准确诊断至关重要。CHS的管理需要多学科方法，重点是进行HSCT以稳定免疫和血液系统，并对神经症状进行对症和支持治疗。即使是那些接受了稳定病情的HSCT的患者最终也会出现神经方面的问题。本综述对CHS进行了深入探讨，涵盖其流行病学、临床表现、分子遗传学、诊断挑战和当前的管理策略，同时强调了采用全面、多学科方法改善患者预后的必要性。
