AR基因突变雄激素不敏感综合征相关因素在性别分配中的作用分析
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摘要
目的分析与青春期后AR基因突变雄激素不敏感综合征患儿的临床结局及外生殖器发育相关因素在性别分配中的作用,探讨AR基因突变雄激素不敏感综合症的最佳性别分配方案。方法以2015年11月至2018年10月浙江大学医学院附属儿童医院收治的21例出现AR基因突变的雄激素不敏感综合征(androgen insensitivity syndrome,AIS)患儿为研究对象,年龄3个月至13岁5个月,中位数为49. 7个月。初诊性别女14例,男7例。外生殖器均表现为不同程度的雄性化不全,其中8例表型为完全女性化、10例为外生殖器模糊、3例为小阴茎。在分子诊断结果的基础上,将外生殖器雄性化评分(external masculinisation score,EMS)、性心理评估结果、外生殖器对雄激素刺激反应情况作为青春期后临床结局和外生殖器发育程度的预测因素,结合社会文化因素、性腺发育特点、患儿及其父母主观层面认知等因素,由本院多学科团队(multidisciplinary team,MDT)作出性别分配。结果 8例(38. 1%)诊断为完全性雄激素不敏感综合征(complete androgen insensitivity syndrome,CAIS)患儿的Prader评分均为0分,EMS评分为1～2分,性心理量表评估结果均表现为女性优势,雄激素治疗外生殖器无明显反应,性别分配均为女性。10例(42. 9%) Prader评分为1～3分的部分性雄激素不敏感综合征(partial androgen insensitivity syndrome,PAIS)患儿EMS评分为2～9分,性心理量表评估结果除1例表现为女性优势外,其余均表现为男性优势,雄激素治疗后阴茎增长明显,性别分配均为男性。3例(14%)小阴茎患儿性心理量表评估结果均表现为男性优势,雄激素治疗后阴茎明显增长,性别分配均为男性。男性性别分配者的Prader评分和EMS评分高于女性性别分配者,且差异有统计学意义(P <0. 05),雄激素治疗有效性、性心理评估结果与性别分配结果间均具有良好的关联性(P <0. 05)。结论分析AR基因突变情况、EMS评分、性心理评估结果和外生殖器雄激素治疗反应结局等因素对AIS患儿未来性别认同、外生殖器发育程度等青春期后临床结局进行预测具有一定的可行性,在充分考虑社会文化因素、患儿及其父母主观层面认知情况下,由MDT进行性别分配是目前较为适宜的AIS性别分配方法。
Objective To explore the gender assignments of androgen insensitivity syndrome( AIS) patients and analyze the role of predictors related to clinical outcomes after puberty and external genital development in gender assignments. Methods Methods From November 2015 to October 2018,a total of 21 AIS inpatients with androgen receptor( AR) gene mutation were retrospectively analyzed. The average age was 49. 7( 3-161) months. The primary diagnosis was female( n =14) and male( n =7). Their phenotypes varied with different severity of external undermasculinisation. There were complete feminization( n = 8),ambiguous external genitalia( n = 10) and micropenis( n = 3). Based on molecular diagnostics,external masculinisation score( EMS),psychological evaluations and reaction of external genitalia to androgen stimulation were used as the predictors for clinical outcomes after puberty and external genital development,considering sociocultural factors,gonadal characteristics and opinions from parents or children. Our multidisciplinary team( MDT) made final gender assignments. Results Eight cases( 38. 1%) were diagnosed as complete androgen insensitivity syndrome( CAIS) with Prader stage 0,EMS 1-2,female dominant and no response to androgen treatment of external genitalia. Ten cases( 42. 9%) were diagnosed as PAIS with Prader stageⅠ-Ⅲ and EMS 2-9 according to their sex role inventory. One case presented to be female dominant while another 8 cases were male dominant and their penises grew up significantly after androgen treatment,whose gender assignments came out to be male.All 3 micropenile cases( 14%) were evaluated as male dominant by psychosexual assessment. After androgen treatment,their penises expanded markedly and all gender assignments were male. Prader stage and EMS of patients assigned male were both higher than female's,the difference was statistically significant( P < 0. 05) and gender assignments are related with the efficacy of androgen therapy and psychosexual assessment. Conclusion Comprehensive analysis of AR gene mutations,EMS score,psychosexual assessments and response of genitals to androgen treatment may help to predict the clinical outcome,gender identity and external genital development after puberty. Meanwhile,fully considering the sociocultural factors and the viewpoint of children with parents or children,is a quite reliable method for MDT to make decision in gender assignment for AIS patients at present.
Objective To explore the gender assignments of androgen insensitivity syndrome( AIS) patients and analyze the role of predictors related to clinical outcomes after puberty and external genital development in gender assignments. Methods Methods From November 2015 to October 2018,a total of 21 AIS inpatients with androgen receptor( AR) gene mutation were retrospectively analyzed. The average age was 49. 7( 3-161) months. The primary diagnosis was female( n =14) and male( n =7). Their phenotypes varied with different severity of external undermasculinisation. There were complete feminization( n = 8),ambiguous external genitalia( n = 10) and micropenis( n = 3). Based on molecular diagnostics,external masculinisation score( EMS),psychological evaluations and reaction of external genitalia to androgen stimulation were used as the predictors for clinical outcomes after puberty and external genital development,considering sociocultural factors,gonadal characteristics and opinions from parents or children. Our multidisciplinary team( MDT) made final gender assignments. Results Eight cases( 38. 1%) were diagnosed as complete androgen insensitivity syndrome( CAIS) with Prader stage 0,EMS 1-2,female dominant and no response to androgen treatment of external genitalia. Ten cases( 42. 9%) were diagnosed as PAIS with Prader stageⅠ-Ⅲ and EMS 2-9 according to their sex role inventory. One case presented to be female dominant while another 8 cases were male dominant and their penises grew up significantly after androgen treatment,whose gender assignments came out to be male.All 3 micropenile cases( 14%) were evaluated as male dominant by psychosexual assessment. After androgen treatment,their penises expanded markedly and all gender assignments were male. Prader stage and EMS of patients assigned male were both higher than female's,the difference was statistically significant( P < 0. 05) and gender assignments are related with the efficacy of androgen therapy and psychosexual assessment. Conclusion Comprehensive analysis of AR gene mutations,EMS score,psychosexual assessments and response of genitals to androgen treatment may help to predict the clinical outcome,gender identity and external genital development after puberty. Meanwhile,fully considering the sociocultural factors and the viewpoint of children with parents or children,is a quite reliable method for MDT to make decision in gender assignment for AIS patients at present.
引文
1 Mendoza N,Motos MA.Androgen insensitivity syndrome[J].Gynecol Endocrinol.2013,29(1):1-5.DOI:10.3109/09513590.2012.705378.
2 Lee PA,Houk CP,Ahmed SF,et al.International consensus conference on intersex organized by the Lawson Wilkins Pediatric Endocrine Society and the European Society for Paediatric Endocrinology.Consensus statement on management of intersex disorders.International consensus conference on intersex[J].Pediatrics,2006,18(2):488-500.DOI:10.1542/peds.2006-0738.
3 Ercan O,Kutlug S,Uysal O,et al.Gender identity and gender role in DSD patients raised as females:a preliminary outcome study[J].Front Endocrinol(Lausanne),2013,4(1):86.DOI:10.3389/fendo.2013.00086.
4 Fliegner M,Krupp K,Brunner F,et al.Sexual life and sexual wellness in individuals with complete androgen insensitivity syndrome(CAIS)and Mayer-Rokitansky-Küster-Hauser Syndrome(MRKHS)[J].J Sex Med,2014,11(3):729-742.DOI:10.1111/jsm.12321.
5 Ahemed SF,Khwaja O,Hughes IA.Clinical features and gender assignment in cases of male undermasculinisation:the role for a masculinization score[J].BJ.Uro Int,2000,85(2):120-124.
6 Prader A,Gurtner HP.The syndrome of male pseudohermaphrodism in congenital adrenocortical hyperplasia without overproduction of androgens(adrenal male pseudohermaphrodism)[J].Helv Paediatr Acta,1955,10(4):397-412.
7 Golombok S,Rust J.The Pre-School Activities Inventory:Astandardized assessment of gender role in children[J].Psychological Assessment,1993,5(5):131-136.
8 Boldizar JP.Assessing sex typing and androgyny in children:The Children's Sex Role Inventory[J].Developmental Psychology,1991,27(3):505-515.
9 Mouriquand PD,Gorduza DB,Gay CL,et al.Surgery in disorders of sex development(DSD)with a gender issue:If(why),when,and how?[J].J Pediatr Urol,2016,12(3):139-149.DOI:10.1016/j.jpurol.2016.04.001.
10 Wolfe-Christensen C,Fedele DA,Kirk K,et al.Caregivers of children with a disorder of sex development:associations between parenting capacities and psychological distress[J].J Pediatr Urol,2014,10(3):538-543.DOI:10.1016/j.jpurol.2013.11.016.
11 Goodman SH,Rouse MH,Connell AM,et al.Maternal depression and child psychopathology:a meta-analytic review[J].Clin Child Fam Psychol Rev,2011,14(1):1-27.DOI:10.1007/s10567-010-0080-1.
12 Bakula DM,Mullins AJ,Sharkey CM,et al.Gender identity outcomes in children with disorders/differences of sex development:Predictive factors[J].Semin Perinatol,2017,41(4):214-217.DOI:10.1053/j.semperi.2017.03.010.
13 Joseph AA,Shabir I,Marumadi E,et al.Psychosexual outcomes in three siblings with partial androgen insensitivity syndrome:impact of nature versus nurture[J].J Pediatr Endocrinol Metab,2013,26(9):915-920.DOI:10.1515/jpem-2013-0154.
14 Mazur T.Gender dysphoria and gender changes in androgen insensitivity or micropenis[J].Arch Sex Behav,2005,34(4):411-421.DOI:10.1007/s10508-005-4341-x.
15 Audi L,Fernandez-Cancio M,Carrascosa A,et al.Novel(60%)and recurrent(40%)androgen receptor gene mutations in a series of 59 patients with a 46XY disorder of sex development[J].J Clin Endocrinol Metab,2010,95(4):1876-1888.DOI:10.1210/jc.2009-2146.
16 Hughes IA,Deeb A.Androgen resistance[J].Best Pract Res Clin Endocrinol Metab,2006,20(5):577-598.
17 Lucas-Herald A,Bertelloni S,Juul A,et al.The Long-Term Outcome of Boys With Partial Androgen Insensitivity Syndrome and a Mutation in the Androgen Receptor Gene[J].J Clin Endocrinol Metab,2016,101(11):3959-3967.
18 O'Hara L,Smith LB.Androgen receptor roles in spermatogenesis and infertility[J].Best Pract Res Clin Endocrinol Metab,2015,29(4):595-605.DOI:10.1016/j.beem.2015.04.006.
19 Lek N,Tadokoro-Cuccaro R,Whitchurch JB,et al.Predicting puberty in partial androgen insensitivity syndrome:Use of clinical and functional androgen receptor indices[J].EBio Medicine,2018,36(4):401-409.DOI:10.1016/j.ebiom.2018.09.047.
20 Wisniewski AB,Migeon CJ,Meyer-Bahlburg HFL,et al.Complete androgen insensitivity syndrome:long-term medical,surgical,and psychosexual outcome[J].J Clin Endocrinol Metab,2000,85(8):2664-2669.
21 Mongan NP,Tadokoro-Cuccaro R,Bunch T,et al.Androgen insensitivity syndrome[J].Best Pract Res Clin Endocrinol Metab,2015,29(4):569-580.DOI:10.1016/j.beem.2015.04.005.
22 Kolesinska Z,Ahmed SF,Niedziela M,et al.Changes over time in sex assignment for disorders of sex development[J].Pediatrics,2014,134(3):710-715.DOI:10.1542/peds.2014-1088.
23 Tordjman KM,Yaron M,Berkovitz A,et al.Fertility after high-dose testosterone and intracytoplasmic sperm injection in a patient with androgen insensitivity syndrome with a previously unreported androgen receptor mutation[J].Andrologia,2014,46(6):703-706.DOI:10.1111/and.12126.
24 Batista RL,Costa EMF,Rodrigues AS,et al.Androgen insensitivity syndrome:a review[J].Arch Endocrinol Metab,2018,62(2):227-235.DOI:10.20945/2359-3997000000031.
25 Rajpert-De Meyts E,Nielsen JE,Skakkebaek NE,et al.Diagnostic markers for germ cell neoplasms:from placentallike alkaline phosphatase to micro-RNAs[J].Folia Histochem Cytobiol,2015,53(3):177-188.DOI:10.5603/FHC.a2015.0020.
26 Becker D,Wain LM,Chong YH,et al.Topical dihydrotestosterone to treat micropenis secondary to partial androgen insensitivity syndrome(PAIS)before,during,and after puberty-a case series[J].J Pediatr Endocrinol Metab,2016,29(2):173-177.DOI:10.1515/jpem-2015-0175.
27 Fisher AD,Ristori J,Fanni E,et al.Gender identity,gender assignment and reassignment in individuals with disorders of sexdevelopment:a major of dilemma[J].J Endocrinol Invest,2016,39(11):1207-1224.DOI:10.1007/s40618-016-0482-0.
28 Chaudhry S,Tadokoro-Cuccaro R,Hannema SE,et al.Frequency of gonadal tumours in complete androgen insensitivity syndrome(CAIS):A retrospective case-series analysis[J].J Pediatr Urol,2017,13(5):498.e1-498.e6.DOI:10.1016/j.jpurol.2017.02.013.
29 Hurt WG,Bodurtha JN,McCall JB,et al.Seminoma in pubertal patient with androgen insensitivity syndrome[J].Am J Obstet Gynecol,1989,161(4):530-531.
30 Bermúdez de la Vega JA,Fernández-Cancio M,Bernal S,et al.Complete androgen insensitivity syndrome associated with male gender identity or female precocious puberty in the same family[J].Sex Dev,2015,9(2):75-79.DOI:10.1159/000371617.
31 Kohler B,Kleinemeier E,Lux A,et al.Satisfaction with genital surgery and sexual life of adults with XY disorders of sex development:results from the German clinical evaluation study[J].J Clin Endocrinol Metab,2012,97(2):577-588.DOI:10.1210/jc.2011-1441.
2 Lee PA,Houk CP,Ahmed SF,et al.International consensus conference on intersex organized by the Lawson Wilkins Pediatric Endocrine Society and the European Society for Paediatric Endocrinology.Consensus statement on management of intersex disorders.International consensus conference on intersex[J].Pediatrics,2006,18(2):488-500.DOI:10.1542/peds.2006-0738.
3 Ercan O,Kutlug S,Uysal O,et al.Gender identity and gender role in DSD patients raised as females:a preliminary outcome study[J].Front Endocrinol(Lausanne),2013,4(1):86.DOI:10.3389/fendo.2013.00086.
4 Fliegner M,Krupp K,Brunner F,et al.Sexual life and sexual wellness in individuals with complete androgen insensitivity syndrome(CAIS)and Mayer-Rokitansky-Küster-Hauser Syndrome(MRKHS)[J].J Sex Med,2014,11(3):729-742.DOI:10.1111/jsm.12321.
5 Ahemed SF,Khwaja O,Hughes IA.Clinical features and gender assignment in cases of male undermasculinisation:the role for a masculinization score[J].BJ.Uro Int,2000,85(2):120-124.
6 Prader A,Gurtner HP.The syndrome of male pseudohermaphrodism in congenital adrenocortical hyperplasia without overproduction of androgens(adrenal male pseudohermaphrodism)[J].Helv Paediatr Acta,1955,10(4):397-412.
7 Golombok S,Rust J.The Pre-School Activities Inventory:Astandardized assessment of gender role in children[J].Psychological Assessment,1993,5(5):131-136.
8 Boldizar JP.Assessing sex typing and androgyny in children:The Children's Sex Role Inventory[J].Developmental Psychology,1991,27(3):505-515.
9 Mouriquand PD,Gorduza DB,Gay CL,et al.Surgery in disorders of sex development(DSD)with a gender issue:If(why),when,and how?[J].J Pediatr Urol,2016,12(3):139-149.DOI:10.1016/j.jpurol.2016.04.001.
10 Wolfe-Christensen C,Fedele DA,Kirk K,et al.Caregivers of children with a disorder of sex development:associations between parenting capacities and psychological distress[J].J Pediatr Urol,2014,10(3):538-543.DOI:10.1016/j.jpurol.2013.11.016.
11 Goodman SH,Rouse MH,Connell AM,et al.Maternal depression and child psychopathology:a meta-analytic review[J].Clin Child Fam Psychol Rev,2011,14(1):1-27.DOI:10.1007/s10567-010-0080-1.
12 Bakula DM,Mullins AJ,Sharkey CM,et al.Gender identity outcomes in children with disorders/differences of sex development:Predictive factors[J].Semin Perinatol,2017,41(4):214-217.DOI:10.1053/j.semperi.2017.03.010.
13 Joseph AA,Shabir I,Marumadi E,et al.Psychosexual outcomes in three siblings with partial androgen insensitivity syndrome:impact of nature versus nurture[J].J Pediatr Endocrinol Metab,2013,26(9):915-920.DOI:10.1515/jpem-2013-0154.
14 Mazur T.Gender dysphoria and gender changes in androgen insensitivity or micropenis[J].Arch Sex Behav,2005,34(4):411-421.DOI:10.1007/s10508-005-4341-x.
15 Audi L,Fernandez-Cancio M,Carrascosa A,et al.Novel(60%)and recurrent(40%)androgen receptor gene mutations in a series of 59 patients with a 46XY disorder of sex development[J].J Clin Endocrinol Metab,2010,95(4):1876-1888.DOI:10.1210/jc.2009-2146.
16 Hughes IA,Deeb A.Androgen resistance[J].Best Pract Res Clin Endocrinol Metab,2006,20(5):577-598.
17 Lucas-Herald A,Bertelloni S,Juul A,et al.The Long-Term Outcome of Boys With Partial Androgen Insensitivity Syndrome and a Mutation in the Androgen Receptor Gene[J].J Clin Endocrinol Metab,2016,101(11):3959-3967.
18 O'Hara L,Smith LB.Androgen receptor roles in spermatogenesis and infertility[J].Best Pract Res Clin Endocrinol Metab,2015,29(4):595-605.DOI:10.1016/j.beem.2015.04.006.
19 Lek N,Tadokoro-Cuccaro R,Whitchurch JB,et al.Predicting puberty in partial androgen insensitivity syndrome:Use of clinical and functional androgen receptor indices[J].EBio Medicine,2018,36(4):401-409.DOI:10.1016/j.ebiom.2018.09.047.
20 Wisniewski AB,Migeon CJ,Meyer-Bahlburg HFL,et al.Complete androgen insensitivity syndrome:long-term medical,surgical,and psychosexual outcome[J].J Clin Endocrinol Metab,2000,85(8):2664-2669.
21 Mongan NP,Tadokoro-Cuccaro R,Bunch T,et al.Androgen insensitivity syndrome[J].Best Pract Res Clin Endocrinol Metab,2015,29(4):569-580.DOI:10.1016/j.beem.2015.04.005.
22 Kolesinska Z,Ahmed SF,Niedziela M,et al.Changes over time in sex assignment for disorders of sex development[J].Pediatrics,2014,134(3):710-715.DOI:10.1542/peds.2014-1088.
23 Tordjman KM,Yaron M,Berkovitz A,et al.Fertility after high-dose testosterone and intracytoplasmic sperm injection in a patient with androgen insensitivity syndrome with a previously unreported androgen receptor mutation[J].Andrologia,2014,46(6):703-706.DOI:10.1111/and.12126.
24 Batista RL,Costa EMF,Rodrigues AS,et al.Androgen insensitivity syndrome:a review[J].Arch Endocrinol Metab,2018,62(2):227-235.DOI:10.20945/2359-3997000000031.
25 Rajpert-De Meyts E,Nielsen JE,Skakkebaek NE,et al.Diagnostic markers for germ cell neoplasms:from placentallike alkaline phosphatase to micro-RNAs[J].Folia Histochem Cytobiol,2015,53(3):177-188.DOI:10.5603/FHC.a2015.0020.
26 Becker D,Wain LM,Chong YH,et al.Topical dihydrotestosterone to treat micropenis secondary to partial androgen insensitivity syndrome(PAIS)before,during,and after puberty-a case series[J].J Pediatr Endocrinol Metab,2016,29(2):173-177.DOI:10.1515/jpem-2015-0175.
27 Fisher AD,Ristori J,Fanni E,et al.Gender identity,gender assignment and reassignment in individuals with disorders of sexdevelopment:a major of dilemma[J].J Endocrinol Invest,2016,39(11):1207-1224.DOI:10.1007/s40618-016-0482-0.
28 Chaudhry S,Tadokoro-Cuccaro R,Hannema SE,et al.Frequency of gonadal tumours in complete androgen insensitivity syndrome(CAIS):A retrospective case-series analysis[J].J Pediatr Urol,2017,13(5):498.e1-498.e6.DOI:10.1016/j.jpurol.2017.02.013.
29 Hurt WG,Bodurtha JN,McCall JB,et al.Seminoma in pubertal patient with androgen insensitivity syndrome[J].Am J Obstet Gynecol,1989,161(4):530-531.
30 Bermúdez de la Vega JA,Fernández-Cancio M,Bernal S,et al.Complete androgen insensitivity syndrome associated with male gender identity or female precocious puberty in the same family[J].Sex Dev,2015,9(2):75-79.DOI:10.1159/000371617.
31 Kohler B,Kleinemeier E,Lux A,et al.Satisfaction with genital surgery and sexual life of adults with XY disorders of sex development:results from the German clinical evaluation study[J].J Clin Endocrinol Metab,2012,97(2):577-588.DOI:10.1210/jc.2011-1441.