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Clinical Features and Mutation Analysis of Gordon Holmes Syndrome Associated with RNF216 Gene Mutation and a Literature Review
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摘要:
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。 -
关键词:
- RNF216基因 /
- Gordon Holmes综合征 /
- 低促性腺性性腺功能减退症 /
- 小脑共济失调 /
- 神经系统退行性疾病
Abstract: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. -
图 1 Gordon Holmes综合征(GHS)患者头MRI结果
A.轴位T2加权像显示双脑半球广泛白质病变；B.轴位T2加权FLAIR像显示脑半球广泛白质病变；C.轴位T2加权FLAIR像显示脑干广泛白质病变；D.中矢状位T1加权切片显示小脑萎缩
Figure 1. The result of head MRI in patient with Gordon Holmes syndrome (GHS)
图 2 先证者及其父亲和母亲的Sanger测序结果
A.先证者RNF216基因存在纯合突变c.1549C＞T(p. R517*)；B、C.先证者父亲和母亲检出RNF216基因c.1549C＞T(p. R517*)杂合突变；椭圆示突变位点
Figure 2. Sanger sequencing of the proband and his parents
图 3 RNF216基因突变汇总
RNF216蛋白全长由866个氨基酸，两个RING域(RING1和RING2)和in-between-RING(IBR)域组成，图中标记目前文献中已报道的14种突变和本例突变(加粗表示)
Figure 3. Summary of all mutations of RNF216
图 4 RNF216基因突变患者神经系统临床(A)和影像学表现(B)
Figure 4. Neurological manifestations (A) and imaging findings (B) in the patients with RNF216 mutations
表 1 RNF216基因突变患者临床特征及基因突变情况总结
Table 1. Summary of clinical characteristics and gene mutations of patients with RNF216 mutations
年份，作者 编号 性别 访视
年龄
(岁)基因型 性腺轴
功能异常性激素水平 GnRH
治疗反应神经系统表现 起病
年龄
(岁)CT/MRI表现 其他 2013，Margolin等[2] 1*#$ 男 c.2251C＞T，homo. 无自发青春期，未育 ↓LH，垂体前叶其余激素正常 无反应 构音障碍+小脑共济失调+痴呆 22 CT：皮质萎缩+小脑萎缩+白质病变 2*#$ 女 38 c.2251C＞T，homo. 16岁初潮，继发性闭经，未育 ↓LH+E2 无反应 构音障碍+小脑共济失调+痴呆 30 CT：皮质萎缩+小脑萎缩+白质病变 41岁死于吸入性肺炎 3*#$ 男 c.2251C＞T，homo. 正常青春期，20岁勃起功能障碍，未育 ↓LH+FSH 构音障碍+小脑共济失调+痴呆 29 MRI：皮质萎缩+小脑萎缩+白质病变 47岁死亡(可能肺栓塞) 4 男 c.615_616delGA，c.1791T＞A，comhete. 无自发青春期，未育 NA 构音障碍+小脑共济失调+痴呆+舞蹈病 22 MRI：小脑萎缩+白质病变+丘脑病变 36岁死亡 5* 男 c.414delG，hete. 正常青春期，36岁性功能减退，未育 TSH正常 小脑共济失调+痴呆+舞蹈病 36 MRI：皮质萎缩+白质病变 6* 女 33 c.414delG，hete. 正常青春期，27岁月经量少，闭经，未育 ↓LH，PRL+TSH+F正常 ↑LH，FSH，E2，优势卵泡生长 小脑共济失调+痴呆+舞蹈病 31 MRI：小脑萎缩+白质病变 7 女 c.721C＞T，hete. 原发性闭经，未育 PRL+TSH+F正常 小脑共济失调+痴呆 27 MRI：小脑萎缩+白质病变 8 男 c.2149C＞T，hete. 无自发青春期，未育 ↓LH，其他垂体前叶激素正常 T水平正常，睾丸体积增大 构音障碍+小脑共济失调+认知功能障碍 21 MRI：皮质萎缩+小脑萎缩+白质病变 2015，Ganos等[4] 9# 男 35 c.2453-2A＞G，homo. 乳房发育，育有一名健康的孩子 ↓ LH+FSH+T 小脑共济失调+认知功能障碍 18 MRI：小脑萎缩+白质病变+丘脑病变+苍白球病变 缺2颗下门牙齿 2016，Alqwaifly等[5] 10*# 男 26 c.2061G＞A，homo. 第二性征发育不良，未育 ↓LH+T 小脑共济失调 20 MRI：小脑萎缩+白质病变+部分空鞍 面部毛发生长不良，男性乳房发育不良，骨骼延迟 11*# 男 31 c.2061G＞A，homo. 第二性征发育不良，未育 ↓LH+T 构音障碍+小脑共济失调+认知功能障碍+眼动异常+腱反射亢进 24 MRI：小脑萎缩+白质病变 骨骼延迟 2015，Santens等[6] 12*# 女 32 c.1367G＞A，homo. 未育 ↓LH+FSH+E2 构音障碍+小脑共济失调+痴呆+认知功能障碍+舞蹈病+腱反射亢进 32 CT：皮质萎缩+小脑萎缩+白质病变 45岁死亡(吸入性肺炎) 13*# 女 42 c.1367G＞A，homo. 生育3名孩子 ↓LH，FSH，E2，P 构音障碍+小脑共济失调+痴呆+认知功能障碍+舞蹈病+眼动异常+腱反射亢进 36 MRI：皮质萎缩+小脑萎缩+白质病变 尿失禁 14* 女 49 c.904C＞T，c.1616A＞G，comhete. 生育2名孩子 NA 构音障碍+痴呆+舞蹈病+认知功能障碍 49 MRI：小脑萎缩+白质病变+脑干萎缩 15* 男 49 c.904C＞T，c.1616A＞G，comhete. 未育 ↓T 痴呆+舞蹈病+认知功能障碍 49 MRI：白质病变+脑干白质病变 16 女 71 c.1616A＞G，hete. 生育2名孩子 LH+FSH正常 痴呆+帕金森病 71 NA 2019，Calandra等[7] 17*# 男 31 c.1988C＞T，homo. 第二性征发育不良，未育 ↓LH+FSH+T T替代治疗 构音障碍+小脑共济失调+痴呆+认知功能障碍+腱反射亢进 28 MRI：皮质萎缩+小脑萎缩+白质病变 低骨密度，弓形足 18*# 男 29 c.1988C＞T，homo. 第二性征发育不良，未育 ↓LH+FSH，T正常 构音障碍+小脑共济失调+痴呆+腱反射亢进 27 MRI：皮质萎缩+小脑萎缩+白质病变 身材矮小 2020，Chen等[8] 19 女 38 Exon2 del，homo.新生突变 绝经后子宫，未见卵巢，生育1名男孩 ↓LH+FSH+E2，PRL，F正常 构音障碍+痴呆+认知功能障碍+舞蹈病+眼动异常 28 MRI：小脑萎缩+白质病变 乳房萎缩，间断泌乳 2022，Chen等[9] 20# 男 34 c.1948G＞T，homo. 28岁无精症，不育 ↓LH+FSH+T 无反应 构音障碍+小脑共济失调+认知功能障碍 33 MRI：小脑萎缩+白质病变+脑干白质病变 本例 21# 男 26 c.1549C＞T，homo. 无自发青春期，未育 ↓LH+FSH+T T替代治疗，肌力改善 构音障碍+小脑共济失调+认知功能障碍 23 MRI：小脑萎缩+白质病变+脑干白质病变 身材矮小，生长激素缺乏，骨龄延迟 *表示家系病历报告，家系1，2，3；家系5，6；家系10，11；家系12，13；家系14，15；家系17，18；#表示近亲婚配；$同时携带OTUD4基因突变；homo.：纯合突变，hete.：杂合突变，comhete.：复合杂合突变；GnRH：促性腺激素释放激素；FSH：卵泡刺激素；LH：黄体生成素；T：睾酮；E2：雌激素；PRL：泌乳素；F：皮质醇；NA：数据未获得 
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