RNF216基因突变相关Gordon Holmes综合征的临床特征、基因分析及文献回顾

Clinical Features and Mutation Analysis of Gordon Holmes Syndrome Associated with RNF216 Gene Mutation and a Literature Review

目的总结1例Gordon Holmes综合征(GHS)患者的临床特点和RNF216基因检测结果,并通过文献复习,以期提高对本病的基因特点和临床表现的认识。方法收集1例GHS患者的临床资料,抽取患者及其父母外周静脉血2 mL,提取DNA进行全外显子组基因检测,并回顾分析既往报道所有RNF216基因突变患者的基因变异和临床表现。结果青年男性患者,6岁时发现身材矮小,诊断为生长激素缺乏,至15岁仍无第二性征发育,诊断为低促性腺激素性性腺功能减退症,22岁后逐渐出现步态异常,言语、运动和认知功能进行性减退。全外显子组基因检测结果显示RNF216基因c.1549C>T(p.R517*),纯合,无义突变。父母为近亲婚配,表型正常,基因型均为该突变杂合携带者。结合文献回顾和本例报道结果显示,目前全球共发现RNF216基因突变患者21例,包含15种致病变异类型,其中7种截短突变,5种错义突变,以及同义突变、剪接突变和缺失突变各1种。该基因突变可见于GHS、亨廷顿样疾病、4H综合征多种症状重叠的神经系统退行性疾病,主要临床表现为青春期或成年早期低促性腺性性腺功能减退症和早发进行性神经功能障碍,神经系统症状中位起病年龄为28岁,以小脑共济失调、构音障碍和认知障碍,以及广泛脑白质病变和小脑萎缩的影像学表现为特征。结论RNF216基因突变导致GHS发病,基因检测有助于罕见病明确诊断和治疗指导。

Objective To summarize the clinical characteristics and RNF216 gene mutation of a patient with Gordon Holmes syndrome(GHS),and to improve the understanding of the genetic and clinica characteristics of this disease through literature review.Methods We collected the clinical data of the patient with GHS,extracted the DNA from 2 mL peripheral venous blood of the patient and his parents for whole exome gene detection,and then we analyzed the clinical and genetic characteristics of all previously reported patients with RNF216 gene mutation.Results The young male patient was short in stature at sixyearsold and was diagnosed growth hormone deficiency.He had no secondary sexual characteristics by the age of 15 and was diagnosed hypogonadal hypogonadism.After the age of 22,he gradually developed abnormal gait and had progressive decline in speech,motor,and cognitive functions.Whole exome sequencing revealed a homozygous,nonsense mutation c.1549C>T(p.R517*)in the RNF216 gene.His parents were consanguineous and were heterozygous carriers of the mutations with phenotypic normality.Combined with literature review and this case report results showed that a total of 21 patients of the disease in the world and among them 15 had pathogenic variants of RNF216 gene mutation.7 of the 15 had truncated mutations,5 had missense mutations,and 1 synonym mutation,1 splice mutation,and 1 deletion mutation respectively.RNF216 gene mutation can be seen in neurodegenerative diseases with multiple overlapping symptoms of GHS,Huntington-like disease,and 4H syndrome.The main clinical manifestations are hypogonadotropic hypogonadism and early-onset progressive neurological dysfunction in adolescence or early adulthood.The median age of onset of neurological symptoms is 28 years old,featuring cerebellar ataxia,dysarthria,and cognitive impairment,as well as imaging manifestations of extensive white matter lesions and cerebellar atrophy.Conclusions The mutation of RNF216 gene can cause GHS.Genetic testing is helpful to the diagnosis and treatment of rare diseases.