Male Azoospermia Caused by Compound Heterozygous Mutation in CYP21A2 Gene and Multi-Gene Mutations: A Case Report and Literature Review

doi:10.12280/gjszjk.20220207

Abstract

Abstract:

CYP21A2 mutation causes 21-hydroxylase deficiency (21-OHD), leading to congenital adrenal hyperplasia and gonadal dysplasia. There is heterogeneity in clinical phenotype due to the different gene mutation sites. Infertility appears to be the leading cause for adult 21-OHD outpatients. The complicated cases of the CYP21A2 mutation combined with multiple gene mutations were rarely reported in the worldwide. We reported a case of male azoospermia with the compound heterozygous mutation of c.518T>A/c.293-13A>G coding CYP21A2. Interestingly, this case was complicated with DNAJB13/DNAI1/QRICH2J/FSIP2/HYDIN multi-gene mutations. The clinical phenotype was male infertility, and spermatogenesis was established by the treatment with glucocorticoid for three months. This case report enriched the genotypes of male infertility, and provided us with experience in the clinical diagnosis and treatment of these diseases.

Key words: CYP21A2 gene, 21-hydroxylase deficiency, Azoospermia, Mutation, Case reports

GONG Yi-xin, DING Yu, LUO Si-hui, ZHENG Xue-ying. Male Azoospermia Caused by Compound Heterozygous Mutation in CYP21A2 Gene and Multi-Gene Mutations: A Case Report and Literature Review[J]. Journal of International Reproductive Health/Family Planning, 2022, 41(4): 284-288.

Figures/Tables 3

References 25

[1]	Speiser PW, Arlt W, Auchus RJ, et al. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency an endocrine society clinical practice guideline[J]. J Clin Endocrinol Metab, 2018, 103(11):4043-4088. doi: 10.1210/jc.2018-01865. doi: 10.1210/jc.2018-01865 URL
[2]	Wang X, Wang Y, Ma D, et al. Neonatal Screening and Genotype-Phenotype Correlation of 21-Hydroxylase Deficiency in the Chinese Population[J]. Front Genet, 2020, 11:623125. doi: 10.3389/fgene.2020.623125. doi: 10.3389/fgene.2020.623125 URL
[3]	Carmina E, Dewailly D, Escobar-Morreale HF, et al. Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women[J]. Hum Reprod Update, 2017, 23(5):580-599. doi: 10.1093/humupd/dmx014. doi: 10.1093/humupd/dmx014 pmid: 28582566
[4]	Knowles MR, Leigh MW, Carson JL, et al. Mutations of DNAH11 in patients with primary ciliary dyskinesia with normal ciliary ultrastructure[J]. Thorax, 2012, 67(5):433-441. doi: 10.1136/thoraxjnl-2011-200301. doi: 10.1136/thoraxjnl-2011-200301 URL
[5]	Shen Y, Zhang F, Li F, et al. Loss-of-function mutations in QRICH2 cause male infertility with multiple morphological abnormalities of the sperm flagella[J]. Nat Commun, 2019, 10(1):433. doi: 10.1038/s41467-018-08182-x. doi: 10.1038/s41467-018-08182-x
[6]	Martinez G, Kherraf ZE, Zouari R, et al. Whole-exome sequencing identifies mutations in FSIP2 as a recurrent cause of multiple morphological abnormalities of the sperm flagella[J]. Hum Reprod, 2018, 33(10):1973-1984. doi: 10.1093/humrep/dey264. doi: 10.1093/humrep/dey264 URL
[7]	WHO. WHO Laboratory Manual for the Examination and Processing of Human Semen[M]. 5th ed. World Health Organization,Geneva,Switzerland, 2010.
[8]	New MI, Abraham M, Gonzalez B, et al. Genotype-phenotype correlation in 1,507 families with congenital adrenal hyperplasia owing to 21-hydroxylase deficiency[J]. Proc Natl Acad Sci U S A, 2013, 110(7):2611-2616. doi: 10.1073/pnas.1300057110. doi: 10.1073/pnas.1300057110 URL
[9]	Umino S, Kitamura M, Katoh-Fukui Y, et al. A case of combined 21-hydroxylase deficiency and CHARGE syndrome featuring micropenis and cryptorchidism[J]. Mol Genet Genomic Med, 2019, 7(6):e730. doi: 10.1002/mgg3.730. doi: 10.1002/mgg3.730
[10]	Sharaf S, Hafez M, ElAbd D, et al. High frequency of splice site mutation in 21-hydroxylase deficiency children[J]. J Endocrinol Invest, 2015, 38(5):505-511. doi: 10.1007/s40618-014-0207-1. doi: 10.1007/s40618-014-0207-1 pmid: 25501839
[11]	Scaroni C, Favia G, Lumachi F, et al. Unilateral adrenal tumor, erectile dysfunction and infertility in a patient with 21-hydroxylase deficiency: effects of glucocorticoid treatment and surgery[J]. Exp Clin Endocrinol Diabetes, 2003, 111(1):41-43. doi: 10.1055/s-2003-37499. doi: 10.1055/s-2003-37499 URL
[12]	Claahsen-van der Grinten HL, Otten BJ, Sweep FC, et al. Repeated successful induction of fertility after replacing hydrocortisone with dexamethasone in a patient with congenital adrenal hyperplasia and testicular adrenal rest tumors[J]. Fertil Steril, 2007, 88(3):705.e5-e8. doi: 10.1016/j.fertnstert.2006.11.148. doi: 10.1016/j.fertnstert.2006.11.148
[13]	Collet TH, Pralong FP. Reversal of primary male infertility and testicular adrenal rest tumors in salt-wasting congenital adrenal hyperplasia[J]. J Clin Endocrinol Metab, 2010, 95(5):2013-2014. doi: 10.1210/jc.2009-2691. doi: 10.1210/jc.2009-2691 URL
[14]	Rohayem J, Tüttelmann F, Mallidis C, et al. Restoration of fertility by gonadotropin replacement in a man with hypogonadotropic azoospermia and testicular adrenal rest tumors due to untreated simple virilizing congenital adrenal hyperplasia[J]. Eur J Endocrinol, 2014, 170(4):K11-K17. doi: 10.1530/EJE-13-0449. doi: 10.1530/EJE-13-0449 URL
[15]	Tanaka M, Enatsu N, Chiba K, et al. Two cases of reversible male infertility due to congenital adrenal hyperplasia combined with testicular adrenal rest tumor[J]. Reprod Med Biol, 2017, 17(1):93-97. doi: 10.1002/rmb2.12068. doi: 10.1002/rmb2.12068 URL
[16]	Jha S, El-Maouche D, Marko J, et al. Individualizing Management of Infertility in Classic Congenital Adrenal Hyperplasia and Testicular Adrenal Rest Tumors[J]. J Endocr Soc, 2019, 3(12):2290-2294. doi: 10.1210/js.2019-00227. doi: 10.1210/js.2019-00227 URL
[17]	Fouques C, Fatfouta I, Hieronimus S, et al. Two cases of male patients followed for a classical form of congenital adrenal hyperplasia (CAH), presenting an azoospermia: analysis and review of the literature[J]. Basic Clin Androl, 2019, 29:10. doi: 10.1186/s12610-019-0084-8. doi: 10.1186/s12610-019-0084-8 pmid: 31143447
[18]	梁凯, 卿立, 刘福强, 等. 21-羟化酶缺陷症合并睾丸肾上腺残基瘤致男性不育一例报道[J]. 中华内分泌代谢杂志, 2018, 34(12):1048-1051. doi: 10.3760/cma.j.issn.1000-6699.2018.12.012. doi: 10.3760/cma.j.issn.1000-6699.2018.12.012
[19]	Bry-Gauillard H, Cartes A, Young J. Mitotane for 21-hydroxylase deficiency in an infertile man[J]. N Engl J Med, 2014, 371(21):2042-2044. doi: 10.1056/NEJMc1410041. doi: 10.1056/NEJMc1410041
[20]	Bachelot A, Lapoirie M, Dulon J, et al. Effects of mitotane on testicular adrenal rest tumors in congenital adrenal hyperplasia due to 21-hydroxylase deficiency: a retrospective series of five patients[J]. Eur J Endocrinol, 2021, 184(3):365-371. doi: 10.1530/EJE-20-0787. doi: 10.1530/EJE-20-0787 pmid: 33444225
[21]	FALLS JL. Accessory adrenal cortex in the broad ligament: incidence and functional significance[J]. Cancer, 1955, 8(1):143-150. doi: 10.1002/1097-0142(1955)8:1<143::aid-cncr2820080120>3.0.co;2-p. doi: 10.1002/1097-0142(1955)8:1<143::aid-cncr2820080120>3.0.co;2-p pmid: 13231045
[22]	Symonds DA, Driscoll SG. An adrenal cortical rest within the fetal ovary: report of a case[J]. Am J Clin Pathol, 1973, 60(4):562-564. doi: 10.1093/ajcp/60.4.562. doi: 10.1093/ajcp/60.4.562 pmid: 4743798
[23]	Dumic M, Duspara V, Grubic Z, et al. Testicular adrenal rest tumors in congenital adrenal hyperplasia-cross-sectional study of 51 Croatian male patients[J]. Eur J Pediatr, 2017, 176(10):1393-1404. doi: 10.1007/s00431-017-3008-7. doi: 10.1007/s00431-017-3008-7 URL
[24]	Engels M, Span PN, van Herwaarden AE, et al. Testicular Adrenal Rest Tumors: Current Insights on Prevalence, Characteristics, Origin, and Treatment[J]. Endocr Rev, 2019, 40(4):973-987. doi: 10.1210/er.2018-00258. doi: 10.1210/er.2018-00258 pmid: 30882882
[25]	Claahsen-van der Grinten HL, Otten BJ, Takahashi S, et al. Testicular adrenal rest tumors in adult males with congenital adrenal hyperplasia: evaluation of pituitary-gonadal function before and after successful testis-sparing surgery in eight patients[J]. J Clin Endocrinol Metab, 2007, 92(2):612-615. doi: 10.1210/jc.2006-1311. doi: 10.1210/jc.2006-1311 URL

文献来源	临床分型	突变形式	治疗方案	干预结果
Scaroni等（2003）^[11]	SW型	/	口服DXM 1 mg/d（给药时间不详）	第7个月出现不活动精子
Claahsen-van der Grinten等（2007）^[12]	SV型	I1del/I12N	口服DXM 0.75 mg/d（分早中晚各1次给药）	第3个月精子数量增加,第7个月其妻妊娠
Collet等（2010）^[13]	SW型	/	口服DXM 0.5 mg bid,MC 0.05 mg bid	第12个月其妻分娩一男婴
Rohayem 等（2014）^[14]	SV型	g.655A/C>G	注射人绒毛膜促性腺激素1 500 IU biw,人绝经期促性腺激素150 IU tiw	第21个月精子数量增加,其妻自然妊娠,分娩一健康女婴
Tanaka 等（2017）^[15]	SV型	c.518T>A	口服DXM 0.5 mg/d（给药时间不详）	第2个月精子浓度34×10⁶/mL,2年后其妻体外受精妊娠,后分娩一健康婴儿
Jha 等（2019）^[16]	SW型	c.293-13A/C>G	口服泼尼松 5 mg qm,MC 50 μg bid,出现增重、失眠、腹部紫纹,更换泼尼松为DXM 0.25 mg qn	第9个月其妻自然妊娠,后分娩一女婴,女婴CYP21A2等位基因30 kb缺失
Fouques等（2019）^[17]	SW型	c.1160A>T	口服HC 25 mg qm,DXM 0.5 mg qn	第4个月精子数量增加,第6个月其妻自然妊娠,分娩健康女婴
	SW型	c.293-13A/C>G	口服HC 20 mg qm,HC 10 mg q12n,DXM 0.5 mg qn	第12个月精子数量仍为0
梁凯等（2018）^[18]	SV型	c.518T>A/c.955c>T	初始口服DXM 0.75 mg qd,自第4个月调整DXM用量为0.375 mg qd	第12个月精子数量仍为0
Bry-Gauillard等（2014）^[19]	SV型	/	口服米托坦3 g/d,维持7个月后减量为2 g/d	第8个月精子数量开始升高,第25个月时精子浓度4.5×10⁶/mL
Bachelot等（2021）^[20]	SW型	c.293-13A/C>G	口服米托坦 0.5 g/d	第12个月精子数量增加,12×10⁶/mL,2年后其妻分娩一健康婴儿

文献来源	临床分型	突变形式	治疗方案	干预结果
Scaroni等（2003）^[11]	SW型	/	口服DXM 1 mg/d（给药时间不详）	第7个月出现不活动精子
Claahsen-van der Grinten等（2007）^[12]	SV型	I1del/I12N	口服DXM 0.75 mg/d（分早中晚各1次给药）	第3个月精子数量增加,第7个月其妻妊娠
Collet等（2010）^[13]	SW型	/	口服DXM 0.5 mg bid,MC 0.05 mg bid	第12个月其妻分娩一男婴
Rohayem 等（2014）^[14]	SV型	g.655A/C>G	注射人绒毛膜促性腺激素1 500 IU biw,人绝经期促性腺激素150 IU tiw	第21个月精子数量增加,其妻自然妊娠,分娩一健康女婴
Tanaka 等（2017）^[15]	SV型	c.518T>A	口服DXM 0.5 mg/d（给药时间不详）	第2个月精子浓度34×10⁶/mL,2年后其妻体外受精妊娠,后分娩一健康婴儿
Jha 等（2019）^[16]	SW型	c.293-13A/C>G	口服泼尼松 5 mg qm,MC 50 μg bid,出现增重、失眠、腹部紫纹,更换泼尼松为DXM 0.25 mg qn	第9个月其妻自然妊娠,后分娩一女婴,女婴CYP21A2等位基因30 kb缺失
Fouques等（2019）^[17]	SW型	c.1160A>T	口服HC 25 mg qm,DXM 0.5 mg qn	第4个月精子数量增加,第6个月其妻自然妊娠,分娩健康女婴
	SW型	c.293-13A/C>G	口服HC 20 mg qm,HC 10 mg q12n,DXM 0.5 mg qn	第12个月精子数量仍为0
梁凯等（2018）^[18]	SV型	c.518T>A/c.955c>T	初始口服DXM 0.75 mg qd,自第4个月调整DXM用量为0.375 mg qd	第12个月精子数量仍为0
Bry-Gauillard等（2014）^[19]	SV型	/	口服米托坦3 g/d,维持7个月后减量为2 g/d	第8个月精子数量开始升高,第25个月时精子浓度4.5×10⁶/mL
Bachelot等（2021）^[20]	SW型	c.293-13A/C>G	口服米托坦 0.5 g/d	第12个月精子数量增加,12×10⁶/mL,2年后其妻分娩一健康婴儿