LHCGR基因突变致家族性男性性早熟2例报告及文献复习

doi:10.16150/j.1671-2870.2022.05.009

摘要/Abstract

摘要：

目的：报道2例家族性男性性早熟（familial male-limited precious puberty，FMPP）患者的临床特征、基因检测结果及治疗结果。方法：对2例FMPP患者进行详细的病史采集及体格检查，行促性腺激素释放激素（gonadotropin-releasing hormone, GnRH）激发试验、性激素、肾上腺皮质激素等检测以及相关影像学检查，同时采集相关家系成员的外周血进行基因检测，并在中文数据库及PubMed数据库中检索相关文献，进行综合探讨。结果：2例患者的初诊年龄分别为6岁1个月龄（病例1）和3岁7个月龄（病例2），均表现为阴茎、睾丸增大、生长加速、骨龄超前，病例2伴有攻击行为。实验室检查提示，2例患者的黄体生成素峰值分别为7.28 mIU/mL和4.96 mIU/mL，基础睾酮水平升高达2.49 ng/mL和3.58 ng/mL，而影像学检查未见异常。根据2例患者的病史及各项检查结果，临床诊断为中枢性性早熟。经基因检测显示，2例患儿的黄体生成素/人绒毛膜促性腺激素受体（luteinizing hormone/choriogonadotropin receptor，LHCGR）基因上均存在杂合变异[病例1存在c.1756TCTdel（p.Ser586del）变异来自其父亲；病例2存在c.1723A>C（p.Ile575Leu）变异，来自其母亲]，根据美国医学遗传学与基因组学学会（The American College of Medical Genetics and Genomics, ACMG）指南评定为可能的致病性变异，故明确2例患儿均为继发于LHCGR基因突变的中枢性性早熟。检索数据库，分析35例FMPP资料完整的患者，中位发病时间在4岁，加入例1的变异，计18种基因变异被报道。结论：本文报道2例罕见FMPP病例，均为LHCGR基因突变导致，其中病例1的突变类型为国内外首次报道，病例2的突变类型已有报道。临床对于年龄小、起病或治疗效果欠佳的中枢性性早熟男童，需进一步明确有无LHCGR基因突变。

关键词: 家族性男性性早熟, 黄体生成素/人绒毛膜促性腺激素受体基因, 功能获得性突变, 病因诊断

Abstract:

Objective: To report the clinical features, gene detection results and treatment results of two patients with familial male limited precocious puberty(FMPP). Methods: Detailed medical history collection and physical examination were carried out in 2 FMPP patients. LHRH challenge test, sex hormone, adrenal cortical hormone and other tests and relevant imaging examinations were performed. At the same time, peripheral blood of related family members was collected for gene detection, and relevant literature was retrieved in the Chinese database and PubMed database for comprehensive discussion. Results: The initial diagnosis age of the two patients was 6 years and 1 month (case 1) and 3 years and 7 months (case 2), respectively. The symptoms were penis and testis enlargement, accelerated growth, and advanced bone age. Case 2 was accompanied by aggressive behavior. Laboratory examination indicated that the peak value of luteinizing hormone was 7.28 mIU/mL and 4.96 mIU/mL respectively, and the basal testosterone level rose to 2.49 ng/mL and 3.58 ng/mL, while no abnormality was found in imaging examination. According to the medical history and various examination results of 2 patients, central precocious puberty was clinically diagnosed. Gene testing showed that there were heterozygous variations in the luteinizing hormone/chorionic gonadotropin receptor (LHCGR) gene boys including c.1756TCTdel (p.Ser586del) variation and c.1723A>C (p.Ile575Leu) variation were identified in case 1 and case 2). It revealed that genetic variation in case 1 resulted from his father, while in case 2 came from his mother. According to the guidelines of The American College of Medical Genetics and Genomics(ACMG), genovariation of LHCGR gene was assessed as possible pathogenic variation, so it was clear that central precocious puberty was caused by LHCGR gene mutation. Conclusions: Two male FMPP caused by LHCGR genetic variation are reported in this paper, and c.1756TCTdel(p.Ser586del) in case 1 which is first reported both in demastic and aboard. For boys with central precocious onseting in low age or with poor treatment effect, test on LHCGR genetic variation may be performed.

Key words: Familial male precocious puberty, Luteinizing hormone/choriogonadotropin receptor gene, Functional acquired mutation, Etiology diagnosis

中图分类号:

R725.8

何亲羽, 王伟, 陈立芬, 张雪蕾, 董治亚. LHCGR基因突变致家族性男性性早熟2例报告及文献复习[J]. 诊断学理论与实践, 2022, 21(05): 598-605.

HE Qinyu, WANG Wei, CHEN Lifen, ZHANG Xuelei, DONG Zhiya. Diagnosis and treatment of familial male precocious puberty caused by LHCGR gene mutation: two case reports and literature review[J]. Journal of Diagnostics Concepts & Practice, 2022, 21(05): 598-605.

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参考文献 41

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指标	病例1	病例2	参考范围
黄体生成素峰值（mIU/mL）	7.28	4.96	-
卵泡刺激素峰值（mIU/mL）	6.96	9.07	-
睾酮（ng/mL）	2.49	3.58	1.42~9.23
17羟孕酮（ng/mL）	0.99	0.42	0.5~2.4
促肾上腺皮质激素（pg/mL）	22.63	33.76	7.0~65.0
硫酸脱氢表雄酮（ug/dL）	94.60	20.20	-
β人绒毛膜促性激素（mIU/mL）	0.30	0.27	<5
骨龄	13岁	5岁	-
影像学检查	（-）	（-）	-

文献	氨基酸改变	病例数（n）	遗传方式	起病年龄（岁）	就诊年龄（岁）	BA-CA	睾酮水平（ng/mL）
[2]	S277I	1	D	0.5	1.4	2.6	10.1
[3]	L368P	2	M M	3.5 2.5	3.5 2.5	2.5 1.5	1.93 2.40
[2] [4]	A373V A373V	1 1	M M	1.5 5	1.5 8.0	2 5	4.79 2.5
[5] [6] [7] [8]	M398T M398T M398T M398T	1 1 2 2	M P P P D D	3 4.4 2 6 3 3	4.6 5.4 2.3 7.5 4.2 5.3	0.3 2.6 1 1 4.3 3.3	5.1 2.72 3.0 3.79 4.9 6.4
[9] [3]	L457R L457R	1 1	D D	2.5 2.8	2.5 2.8	3.5 3.2	3.92 6.2
[10]	I542L	2	M P	3.1 4.1	3.1 4.1	0.9 4.9	0.74 4.8
[11]	D564G	1	M	1.5	4.5	5.5	2.54
[12] [9]	A568V A568V	1 2	P D P	0.8 1.7 6.2	3.1 5.0 6.2	5.9 8 2.8	2.3 2.6 3.6
[3]	M571I	2	P P	4.0 4.7	- -	2 2.3	0.91 1.05
[13]	A572V	2	D D	5.5 4.5	5.5 6.8	- 5.9	1.92 2.21
[14] 本文	I575L I575L	1 1	M M	0.5 0.2	2.5 3.5	1.5 1.5	3.09 3.58
[15] [16]	T577I T577I	1 2	M M M	4.0 2.8 2.5	7.5 3.0 2.8	5.5 1.6 0.1	6.5 5.1 1.4
[17] [18]	D578H D578H	1 1	D D	3 0.5	4.0 0.8	4 2.2	2.68 11.2
[19]	D578V	2	D D	0.8 1.0	3.4 1.0	6.6 4.0	6.73 3.34
[20]	D578G	1	D	2	2.1	0.9	-
[21]	D578Y	1	D	0.9	1.3	3.7	8.9
[22]	D578A	1	D	1	1.5	0.5	2.89
[23]	C581R	1	-	-	-	-	-
[24]	C617Y	1	M	6	6.5	2	2.79
本文	S586X	1	P	5.5	6.1	6.9	2.49