一例SOX10基因缺失所致的Waardenburg综合征2型合并低促性腺激素性性腺功能减退症的诊断和基因检测分析

doi:10.16288/j.yczz.22-161

遗传 ›› 2022, Vol. 44 ›› Issue (12): 1158-1166.doi: 10.16288/j.yczz.22-161

一例SOX10基因缺失所致的Waardenburg综合征2型合并低促性腺激素性性腺功能减退症的诊断和基因检测分析

王思琪(), 陈阳, 罗宽宏, 史宁杰, 肖康丽, 崔振海, 曾天舒, 黎慧清()

华中科技大学附属协和医院内分泌科，武汉 430000

收稿日期:2022-07-31 修回日期:2022-09-21 出版日期:2022-12-20 发布日期:2022-10-09
通讯作者: 黎慧清 E-mail:wangsiqi8958@163.com;lhqing5@126.com
作者简介:王思琪，在读硕士研究生，专业方向：内分泌和代谢病。E-mail: wangsiqi8958@163.com

Diagnosis and genetic analysis of a case of Waardenburg syndrome type 2 with hypogonadotropic hypogonadism caused by SOX10 gene deletion

Siqi Wang(), Yang Chen, Kuanhong Luo, Ningjie Shi, Kangli Xiao, Zhenhai Cui, Tianshu Zeng, Huiqing Li()

Department of Endocrinology, Union Hospital, Huazhong University of Science and Technology, Wuhan 430000, China

Received:2022-07-31 Revised:2022-09-21 Online:2022-12-20 Published:2022-10-09
Contact: Li Huiqing E-mail:wangsiqi8958@163.com;lhqing5@126.com

摘要/Abstract

摘要：

低促性腺激素性性腺功能减退症(hypogonadotropic hypogonadism, HH)是以下丘脑-垂体-性腺激素轴功能障碍为主要特征的一类疾病，可致性激素水平低和生育能力受损。伴随嗅觉丧失/减退的HH被称为Kallmann综合征(Kallmann syndrome, KS)。Waardenburg综合征(Waardenburg syndrome, WS)是一种罕见的常染色体显性遗传病，以感音神经性听力损失以及色素沉着异常为主要特征。本研究收集1例不明原因的低促性腺激素性性腺功能减退和先天性耳聋患者的临床资料，该患者进入青春期后无明显第二性征发育，在22q13.1区域(Chr.22:38106433-38525560)存在杂合缺失，至少419 kb，此区域覆盖了SOX10基因。患者父母、妹妹基因测序分析未见异常。通过总结分析该病例特点，分析探讨低促性腺激素性性腺功能减退症与Waardenburg综合征2型在分子生物学上的病因关联，丰富后续遗传学研究的临床资料，同时为此类疾病的诊疗措施提供参考。

关键词: Waardenburg综合征, 低促性腺激素性性腺功能减退症, Kallmann综合征, SOX10基因, 突变

Abstract:

Hypogonadotropic hypogonadism (HH) is a disease defined by dysfunction of the hypothalamic- pituitary-gonadal hormone axis, leading to low sex hormone levels and impaired fertility. HH with anosmia or hyposmia is known as Kallmann syndrome (KS). Waardenburg syndrome (WS) is a rare autosomal dominant genetic disorder characterized by sensorineural hearing loss and abnormal pigmentation. In this report, we collected the clinical data of a patient with hypogonadotropic hypogonadism and congenital hearing loss of unknown cause. The patient had no obvious secondary sexual characteristics development after puberty, and had a heterozygous deletion (at least 419 kb) in 22q13.1 region (Chr.22:38106433-38525560), which covered the SOX10 gene. The abnormalities were not found in gene sequencing analysis of both the parents and sister of the proband. By summarizing and analyzing the characteristics of this case, we further discussed the molecular biological etiological association between HH and WS type 2. This case also enriches the clinical data of subsequent genetic studies, and provides a reference for the diagnosis and treatment of such diseases.

Key words: Waardenburg syndrome, hypogonadotropic hypogonadism, Kallmann syndrome, SOX10 gene, mutation

王思琪, 陈阳, 罗宽宏, 史宁杰, 肖康丽, 崔振海, 曾天舒, 黎慧清. 一例SOX10基因缺失所致的Waardenburg综合征2型合并低促性腺激素性性腺功能减退症的诊断和基因检测分析[J]. 遗传, 2022, 44(12): 1158-1166.

Siqi Wang, Yang Chen, Kuanhong Luo, Ningjie Shi, Kangli Xiao, Zhenhai Cui, Tianshu Zeng, Huiqing Li. Diagnosis and genetic analysis of a case of Waardenburg syndrome type 2 with hypogonadotropic hypogonadism caused by SOX10 gene deletion[J]. Hereditas(Beijing), 2022, 44(12): 1158-1166.

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参考文献 30

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基本特征与实验室检查	结果				参考范围
性别	男				—
年龄	18				—
身高/cm	171				—
体重/kg	44				—
性激素
促黄体生成素(IU/L)	2.6				1.7~8.6
促卵泡生成素(IU/L)	2.45				1.5~12.4
泌乳素(ng/mL)	11.61				2.7~15.2
孕酮(ng/mL)	0.11				<0.149
雌二醇(pg/mL)	<5.00				11.3~43.2
睾酮(nmol/L)	0.81				Tanner 5期：6.5~30.6
戈那瑞林兴奋实验	基础值		峰值
促卵泡生成素(IU/L)	1.63		5.01		FSH增加0.5~2倍
促黄体生成素(IU/L)	1.40		12.67		LH峰值升高>5倍
睾酮(ng/mL)	0.62
人绒毛膜促性腺激素兴奋实验	实验前		注射HCG 3天后
睾酮(ng/mL)	0.51		8.26		注射HCG后，睾酮平均增加0.5~2倍
甲状腺激素
FT3(pmol/L)	4.5				3.47~10.43
FT4(pmol/L)	12.9				11.2~20.1
TSH(μIU/mL)	3.11				0.34~5.06
	8 am	4 pm		12 pm
皮质醇(μg/L)	57.35	41.0		9.65	—
促肾上腺皮质激素(pg/mL)	57.35	9.65		28.16	—
胰岛素样生长因子-1(ng/mL)	1210.52				12岁：143~693；成人：141~483
左手骨龄片	13				—

病例	年龄	性别	自发性青春期	嗅觉	听力损失	其他临床症状	核苷酸变异	氨基酸改变	参考文献
1	26	男	无	缺失	单侧	白发，隐睾症	c.2T>G	p.?	[4]
2	18	女	无	缺失	双侧	上睑下垂	c.331T>G	p.Phe111Val	[4]
3	39	女	无	缺失	双侧	肥胖	c.424T>C	p.Trp142Arg	[4]
4	25	女	延迟	缺失	双侧	—	c.698-1G>C	p.spl?	[4]
5	20	男	延迟	缺失	双侧	隐睾症	c.1290del	p.Ser431Argfs*71	[4]
6	20	男	未描述	缺失	正常	智力障碍，先天畸形	c.1298G>A	p.Arg433Gln	[4]
7	33	男	无	缺失	双侧	上睑下垂	c.323T>C	p.Met108Trh	[4]
8	19	女	无	缺失	正常	巨腿畸形	c.451C>T	p.Arg151Cys	[4]
9	25	男	延迟	缺失	双侧	上睑下垂,隐睾症	c.122G>T	p.Gly41Val	[11]
10	20	男	延迟	缺失	正常	—	c.131C>G	p.Ala44Gly	[11]
11	38	男	延迟	缺失	单侧	—	c.238C>G	p.Leu80Val	[11]
12	17	男	延迟	缺失	双侧	灰白发，鼻根宽大	c.184G>T	p.Glu62X	[12]
13	13	女	延迟	缺失	双侧	额前白发，虹膜色素缺失	c.506delC	p.Pro169fsX117	[13]
14	15	男	延迟	缺失	双侧	蓝色虹膜	c.434T>C	p.Leu145Pro	[7]
15	30	男	延迟	缺失	双侧	虹膜色素缺失，甲亢	c.565G>T	p.Phe189X	[14]
16	17	男	无	缺失	双侧	虹膜色素缺失	c.373C>T	p.Glu125X	[8]
17	15	女	无	缺失	双侧	虹膜色素缺失，先天性巨结肠	c.124delC	p.Leu42Cysfs*67	[6]
18	25	男	无	缺失	双侧	—	c.475C>T	p.Arg159Trp	[15]
19	18	男	无	减退	双侧	额前白发，虹膜色素缺失	22q13.1微缺失	—

一例SOX10基因缺失所致的Waardenburg综合征2型合并低促性腺激素性性腺功能减退症的诊断和基因检测分析

Diagnosis and genetic analysis of a case of Waardenburg syndrome type 2 with hypogonadotropic hypogonadism caused by SOX10 gene deletion

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