Department of Medical Genetics, University of Calgary, Calgary, Alberta, Canada.
Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada.
Am J Med Genet C Semin Med Genet. 2018 Dec;178(4):387-397. doi: 10.1002/ajmg.c.31661.
Dubowitz syndrome was described in 1965 as a recognizable syndrome characterized by microcephaly, short stature, eczema, mild developmental delays, and an increased risk of malignancy. Since its original description, there have been over 200 reported cases though no single gene has been identified to explain a significant proportion of affected individuals. Since the last definitive review of Dubowitz syndrome in 1996, there have been 63 individuals with a clinical, or suspected, diagnosis of Dubowitz syndrome reported in 51 publications. These individuals show a markedly wide spectrum with respect to growth, facial gestalt, psychomotor development, and risk of malignancy; genetic causes were identified in 33% (21/63). Seven individuals had deleterious copy number variants, in particular deletions at 14q32 and 17q24 were reported and showed overlap with the Dubowitz phenotype. Several cases were shown to have single gene disorders that included de novo or biallelic pathogenic variants in several genes including NSUN2 and LIG4 frequently identified by next-generation sequencing methods. It appears that the inability to identify a single gene responsible for Dubowitz syndrome reflects its extreme clinical and genetic heterogeneity. However, detailed phenotyping combined with careful grouping of subsets of unsolved cases and in conjunction with data-sharing will identify novel disease genes responsible for additional cases. In the interim, for those clinically diagnosed with a Dubowitz phenotype, we recommend assessment by a Medical Geneticist, a microarray and, if available, clinical or research based genome-wide sequencing. Management suggestions, including decisions regarding malignancy screening in select patients will be discussed.
杜氏综合征于 1965 年被描述为一种可识别的综合征，其特征为小头畸形、身材矮小、湿疹、轻度发育迟缓以及恶性肿瘤风险增加。自最初描述以来，已经有超过 200 例报告病例，但没有一个单一的基因被确定可以解释很大比例的受影响个体。自 1996 年最后一次对杜氏综合征进行明确审查以来，在 51 篇出版物中报告了 63 例具有杜氏综合征临床或疑似诊断的个体。这些个体在生长、面部整体外观、精神运动发育和恶性肿瘤风险方面表现出明显的广泛谱；在 33%（21/63）的个体中确定了遗传原因。有 7 名个体存在有害的拷贝数变异，特别是在 14q32 和 17q24 上的缺失被报道，并与杜氏表型重叠。几个病例显示存在单基因疾病，包括几个基因中的新生或双等位基因致病性变异，包括经常通过下一代测序方法鉴定的 NSUN2 和 LIG4。似乎无法确定导致杜氏综合征的单一基因反映了其极端的临床和遗传异质性。然而，详细的表型分析结合对未解决病例的亚组进行仔细分组，并结合数据共享，将确定负责额外病例的新疾病基因。在此期间，对于那些临床诊断为杜氏表型的患者，我们建议由医学遗传学家进行评估、微阵列分析，如果可行，还可以进行临床或研究性全基因组测序。将讨论管理建议，包括在某些患者中进行恶性肿瘤筛查的决策。
