Diagnosis and treatment of familial male precocious puberty caused by LHCGR gene mutation: two case reports and literature review

doi:10.16150/j.1671-2870.2022.05.009

Abstract

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

CLC Number:

R725.8

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.

Figures/Tables 8

References 41

[1]	Egli CA, Rosenthal SM, Grumbach MM, et al. Pituitary gonadotropin-independent male-limited autosomal dominant sexual precocity in nine generations: familial testotoxicosis[J]. J Pediatr, 1985, 106(1):33-40. doi: 10.1016/S0022-3476(85)80460-1 URL
[2]	Özcabı B, Tahmiscioğlu Bucak F, Ceylaner S, et al. Testotoxicosis: Report of Two Cases, One with a Novel Mutation in LHCGR Gene[J]. J Clin Res Pediatr Endocrinol, 2015, 7(3):242-248. doi: 10.4274/jcrpe.2067 pmid: 26831561
[3]	Almeida MQ, Brito VN, Lins TS, et al. Long-term treatment of familial male-limited precocious puberty (testotoxicosis) with cyproterone acetate or ketoconazole[J]. Clin Endocrinol (Oxf), 2008, 69(1):93-98. doi: 10.1111/j.1365-2265.2007.03160.x URL
[4]	Gromoll J, Partsch CJ, Simoni M, et al. A mutation in the first transmembrane domain of the lutropin receptor causes male precocious puberty[J]. J Clin Endocrinol Metab, 1998, 83(2):476-80. doi: 10.1210/jcem.83.2.4579 URL
[5]	茅江峰, 伍学焱, 聂敏, 等. 生殖细胞系黄体生成素受体基因杂合突变(M398T)导致家族性男性性早熟[J]. 中华内科杂志, 2010, 49(12):1024-1027.
	Mao JF, Wu XY, Nie M, et al. A report of familial male-limited precocious puberty caused by a germ-line heterozygous mutation (M398T) in luteinizing hormone receptor gene[J]. Chin J Inter Med, 2010, 49(12):1024-1027.
[6]	Ignacak M, Hilczer M, Zarzycki J, et al. Substitution of M398T in the second transmembrane helix of the LH receptor in a patient with familial male-limited precocious puberty[J]. Endocr J, 2000, 47(5):595-599. pmid: 11200941
[7]	Shinagawa T, Katsumata N, Sato N, et al. Japanese familial patients with male-limited precocious puberty[J]. Endocr J, 2000, 47(6):777-782. pmid: 11228053
[8]	Bertelloni S, Baroncelli GI, Lala R, et al. Long-term outcome of male-limited gonadotropin-independent precocious puberty[J]. Horm Res, 1997, 48(5):235-239. pmid: 9362394
[9]	Latronico AC, Abell AN, Arnhold IJ, et al. A unique constitutively activating mutation in third transmembrane helix of luteinizing hormone receptor causes sporadic male gonadotropin-independent precocious puberty[J]. J Clin Endocrinol Metab, 1998, 83(7):2435-2440.
[10]	Lenz AM, Shulman D, Eugster EA, et al. Bicalutamide and third-generation aromatase inhibitors in testotoxicosis[J]. Pediatrics, 2010, 126(3):e728-e733. doi: 10.1542/peds.2010-0596 URL
[11]	Jeha GS, Lowenthal ED, Chan WY, et al. Variable presentation of precocious puberty associated with the D564G mutation of the LHCGR gene in children with testotoxicosis[J]. J Pediatr, 2006, 149(2):271-274. doi: 10.1016/j.jpeds.2006.03.017 URL
[12]	陈瑞敏, 张莹, 杨晓红, 等. 家族性男性性早熟一家系LHCGR基因突变分析[J]. 中华医学遗传学杂志, 2012, 29(6):631-634.
	Chen RM, Zhang Y, Yang XH, et al. Analysis of a family affected with familial male-limited precocious puberty due to a Ala568Val mutation in LHCGR gene[J]. Chin J Med Genet, 2012, 29(6):631-634.
[13]	Yano K, Saji M, Hidaka A, et al. A new constitutively activating point mutation in the luteinizing hormone/choriogonadotropin receptor gene in cases of male-limited precocious puberty[J]. J Clin Endocrinol Metab, 1995, 80(4):1162-1168.
[14]	杨海花, 陈永兴, 卫海燕. LHCGR基因突变所致家族性男性性早熟家系分析[J]. 中国临床医学, 2020, 27(1):102-105.
	Yang HH, Chen YX, Wei HY. Analysis of a family affected with familial male-limited precocious puberty due to a mutation in LHCGR gene[J]. Chin J Clin Med, 2020, 27(1):102-105.
[15]	Kor Y. Central precocious puberty in a case of late-diagnosed familial testotoxicosis and long-term treatment monitoring[J]. Hormones (Athens), 2018, 17(2):275-278. doi: 10.1007/s42000-018-0029-1 pmid: 29858851
[16]	Eyssette-Guerreau S, Pinto G, Sultan A, et al. Effectiveness of anastrozole and cyproterone acetate in two brothers with familial male precocious puberty[J]. J Pediatr Endocrinol Metab, 2008, 21(10):995-1002. pmid: 19209621
[17]	Daussac A, Barat P, Servant N, et al. Testotoxicosis without testicular mass: revealed by peripheral precocious puberty and confirmed by somatic LHCGR gene mutation[J]. Endocr Res, 2020, 45(1):32-40. doi: 10.1080/07435800.2019.1645163 pmid: 31394950
[18]	王敏, 李敏, 刘悦笙, 等. LHCGR基因突变(Asp578His)致家族性男性性早熟1例临床特点及基因分析[J]. 中国当代儿科杂志, 2017, 19(11):1159-1164. pmid: 29132462
	Wang M, Li M, Liu YS, et al. Familial male-limited precocious puberty due to Asp578His mutations in the LHCGR gene: clinical characteristics and gene analysis in an infant[J]. Chin J Contemp Pediatr, 2017, 19(11):1159-1164. pmid: 29132462
[19]	Siviero-Miachon AA, Kizys MM, Ribeiro MM, et al. Cosegregation of a novel mutation in the sixth transmembrane segment of the luteinizing/choriogonadotropin hormone receptor with two Brazilian siblings with severe testotoxicosis[J]. Endocr Res, 2017, 42(2):117-124. doi: 10.1080/07435800.2016.1217005 pmid: 27532428
[20]	Martin MM, Wu SM, Martin AL, et al. Testicular seminoma in a patient with a constitutively activating mutation of the luteinizing hormone/chorionic gonadotropin receptor[J]. Eur J Endocrinol, 1998, 139(1):101-106. pmid: 9703386
[21]	Müller J, Gondos B, Kosugi S, et al. Severe testotoxicosis phenotype associated with Asp578-->Tyr mutation of the lutrophin/choriogonadotrophin receptor gene[J]. J Med Genet, 1998, 35(4):340-341. pmid: 9598734
[22]	Gurnurkar S, DiLillo E, Carakushansky M. A case of familial male-limited precocious puberty with a novel mutation[J]. J Clin Res Pediatr Endocrinol, 2021, 13(2):239-244. doi: 10.4274/jcrpe.galenos.2020.2020.0067 URL
[23]	Laue L, Wu SM, Kudo M, et al. Heterogeneity of activating mutations of the human luteinizing hormone receptor in male-limited precocious puberty[J]. Biochem Mol Med, 1996, 58(2):192-198. doi: 10.1006/bmme.1996.0048 pmid: 8812739
[24]	Nagasaki K, Katsumata N, Ogawa Y, et al. Novel C617Y mutation in the 7th transmembrane segment of luteinizing hormone/choriogonadotropin receptor in a Japanese boy with peripheral precocious puberty[J]. Endocr J, 2010, 57(12):1055-1060. pmid: 21060208
[25]	Schedewie HK, Reiter EO, Beitins IZ, et al. Testicular leydig cell hyperplasia as a cause of familial sexual precocity[J]. J Clin Endocrinol Metab, 1981, 52(2):271-278. doi: 10.1210/jcem-52-2-271 URL
[26]	Shenker A, Laue L, Kosugi S, et al. A constitutively activating mutation of the luteinizing hormone receptor in familial male precocious puberty[J]. Nature, 1993, 365(6447):652-654. doi: 10.1038/365652a0 URL
[27]	Roy N, Mascolo E, Lazzaretti C, et al. Endocrine disruption of the follicle-stimulating hormone receptor signaling during the human antral follicle growth[J]. Front Endocrinol (Lausanne), 2021, 12:791763. doi: 10.3389/fendo.2021.791763 URL
[28]	Qiao J, Han B. Diseases caused by mutations in luteini-zing hormone/chorionic gonadotropin receptor[J]. Prog Mol Biol Transl Sci, 2019, 161:69-89.
[29]	Kremer H, Martens JW, van Reen M, et al. A limited repertoire of mutations of the luteinizing hormone (LH) receptor gene in familial and sporadic patients with male LH-independent precocious puberty[J]. J Clin Endocrinol Metab, 1999, 84(3):1136-1140.
[30]	Kosugi S, Van Dop C, Geffner ME, et al. Characterization of heterogeneous mutations causing constitutive activation of the luteinizing hormone receptor in familial male precocious puberty[J]. Hum Mol Genet, 1995, 4(2):183-188. doi: 10.1093/hmg/4.2.183 pmid: 7757065
[31]	Boot AM, Lumbroso S, Verhoef-Post M, et al. Mutation analysis of the LH receptor gene in Leydig cell adenoma and hyperplasia and functional and biochemical studies of activating mutations of the LH receptor gene[J]. J Clin Endocrinol Metab, 2011, 96(7):E1197-E1205. doi: 10.1210/jc.2010-3031 URL
[32]	Juel Mortensen L, Blomberg Jensen M, Christiansen P, et al. Germ cell neoplasia in situ and preserved fertility despite suppressed gonadotropins in a patient with testotoxicosis[J]. J Clin Endocrinol Metab, 2017, 102(12):4411-4416. doi: 10.1210/jc.2017-01761 pmid: 29029242
[33]	Soriano-Guillén L, Lahlou N, Chauvet G, et al. Adult height after ketoconazole treatment in patients with familial male-limited precocious puberty[J]. J Clin Endocrinol Metab, 2005, 90(1):147-151. doi: 10.1210/jc.2004-1438 URL
[34]	Lane LC, Flowers J, Johnstone H, et al. Adult height in patients with familial male-limited precocious puberty and the role of an aromatase inhibitor in patient management[J]. J Pediatr Endocrinol Metab, 2018, 31(5):551-560. doi: 10.1515/jpem-2017-0363 pmid: 29654692
[35]	Fanelli F, Verhoef-Post M, Timmerman M, et al. Insight into mutation-induced activation of the luteinizing hormone receptor: molecular simulations predict the functional behavior of engineered mutants at M398[J]. Mol Endocrinol, 2004, 18(6):1499-1508. doi: 10.1210/me.2003-0050 pmid: 15016840
[36]	Latronico AC, Brito VN, Carel JC. Causes, diagnosis, and treatment of central precocious puberty[J]. Lancet Diabetes Endocrinol, 2016, 4(3):265-274. doi: 10.1016/S2213-8587(15)00380-0 URL
[37]	中华医学会儿科学分会内分泌遗传代谢学组,《中华儿科杂志》编辑委员会. 中枢性性早熟诊断与治疗共识(2015)[J]. 中华儿科杂志, 2015, 53(6):412-418.
	Endocrine Genetic Metabolism Group of Pediatric Branch of Chinese Medical Association, Editorial Committee of Chinese Journal of Pediatrics. Consensus on diagnosis and treatment of central precocious puberty(2015)[J]. Chin J Pediatr, 2015, 53(6):412-418.
[38]	Laue L, Jones J, Barnes KM, et al. Treatment of familial male precocious puberty with spironolactone, testolactone, and deslorelin[J]. J Clin Endocrinol Metab, 1993, 76(1):151-155.
[39]	Mitre N, Lteif A. Treatment of familial male-limited precocious puberty (testotoxicosis) with anastrozole and bicalutamide in a boy with a novel mutation in the luteinizing hormone receptor[J]. J Pediatr Endocrinol Metab, 2009, 22(12):1163-1167. pmid: 20333877
[40]	Leschek EW, Flor AC, Bryant JC, et al. Effect of antiandrogen, aromatase inhibitor, and gonadotropin-releasing hormone analog on adult height in familial male precocious puberty[J]. J Pediatr, 2017, 190:229-235. doi: 10.1016/j.jpeds.2017.07.047 URL
[41]	Wit JM, Hero M, Nunez SB. Aromatase inhibitors in pediatrics[J]. Nat Rev Endocrinol, 2011, 8(3):135-147. doi: 10.1038/nrendo.2011.161 pmid: 22024975

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