THE GENETICS OF SEXUAL DEVELOPMENT DISORDERS

Malik Ejder Yıldırım

doi:10.7197/cmj.1605185

Derleme

CİNSEL GELİŞİM BOZUKLUKLARININ GENETİĞİ

Yıl 2025, Cilt: 47 Sayı: 1, 2 - 9, 29.03.2025

Malik Ejder Yıldırım

Öz

Cinsel gelişim embriyogenezin önemli aşamalarından biridir. Bu süreçte, genetik temelde (seks kromozomları) gerçekleşen gonadal farklılaşma bireyin cinsel kimliğini belirler. Başlangıçta gonadlar bipotansiyel olarak kabul edilir çünkü gonadal primordium sonraki dönemde belirli genetik unsurların aktivasyonu ile testis veya overe dönüşebilir. Bu dönemin herhangi bir aşamasında bir aksama olduğunda, cinsel gelişim bozuklukları (DSD) adı verilen çeşitli klinik durumlar ortaya çıkar. Genellikle çeşitli mutasyonlar veya cinsiyet kromozomu anormalliklerinin eşlik ettiği bu koşullara, gonadal disgenezi dahil olabilir ve erkek (46, XY) veya dişi (46, XX) cinsiyet dönüşümü ile sonuçlanabilir. 46,XY DSD genellikle belirsiz bir durumu veya dişi dış ve/veya Müllerian dokuların mevcut olup olmamasına bağlı olarak iç genital organların varlığını içerir. Öte yanda, yine genetik bazda farklı enzim defektleri, hem erkeklerde (örn. 5α-redüktaz) hem de dişilerde (örn. aromataz) cinsiyet gelişimi bozukluklarına yol açabilmektedir. Konjenital adrenal hiperplazi, özellikle 46,XX DSD olgularında, nispeten sık görülen, otozomal resesif bir enzim defektidir. Bir dizi sendrom, erkeklerde belirli ölçüde yetersiz cinsel gelişime veya dişilerde erkekleşmeye yol açar. Hastalar da, ayrıca mental problemlerin eşliğinde bazı karakteristik fiziksel semptomlar bulunur. Gonadal disgeneziye, başta SRY geni olmak üzere, çeşitli mutasyonlar (örneğin Swyer sendromu) veya cinsiyet kromozom bozuklukluğu (Turner sendromu) neden olabilir. Netice itibarıyla, 46,XY DSD, karma gonadal disgenezi ve diğer bazı durumlarda, malignite riski nedeniyle profilaktik gonadektomi düşünülebilir.

Anahtar Kelimeler

Cinsel gelişim, mutasyon, kromozomal anormallik, gonadal disgenezi, cinsiyet dönüşümü

Kaynakça

1. Lamothe S, Bernard V, Christin-Maitre S. Gonad differentiation toward ovary. Ann Endocrinol (Paris). 2020;81(2-3):83-88.
2. Vivanco E, Goles E, Montalva-Medel M, Poupin MJ. Dynamical robustness of a Boolean model for the human gonadal sex determination. Comput Biol Chem. 2024;113:108225.
3. Acién P, Acién M. Disorders of Sex Development: Classification, Review, and Impact on Fertility. J Clin Med. 2020;9(11):3555.
4. Kim KR, Kwon Y, Joung JY, Kim KS, Ayala AG, Ro JY. True hermaphroditism and mixed gonadal dysgenesis in young children: a clinicopathologic study of 10 cases. Mod Pathol. 2002;15(10):1013-9.
5. Allen L. Disorders of sexual development. Obstet Gynecol Clin North Am. 2009;36(1):25-45.
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7. Davies K. The XY Female: Exploring Care for Adolescent Girls with Complete Androgen Insensitivity Syndrome. Compr Child Adolesc Nurs. 2020;43(4):378-88.
8. Massanyi EZ, Dicarlo HN, Migeon CJ, Gearhart JP. Review and management of 46,XY disorders of sex development. J Pediatr Urol. 2013;9(3):368-79.
9. Basri NI, Soon CH, Ali A, Abdul Ghani NA, Zainuddin AA. Prophylactic gonadectomy in 46 XY females; why, where and when? Horm Mol Biol Clin Investig. 2021;42(3):325-8.
10. Luppino G, Wasniewska M, Coco R, Pepe G, Morabito LA, Li Pomi A, et al. Role of NR5A1 Gene Mutations in Disorders of Sex Development: Molecular and Clinical Features. Curr Issues Mol Biol. 2024;46(5):4519-32.
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12. Sreenivasan R, Gonen N, Sinclair A. SOX Genes and Their Role in Disorders of Sex Development. Sex Dev. 2022;16(2-3):80-91.
13. Racca JD, Chen YS, Brabender AR, Battistin U, Weiss MA, Georgiadis MM. Role of nucleobase-specific interactions in binding and bending of DNA by human male sex-determination factor SRY. J Biol Chem. 2024:107683. doi: 10.1016/j.jbc.2024.107683.
14. Witchel SF. Disorders of sex development. Best Pract Res Clin Obstet Gynaecol. 2018;48:90-102. 15. Harpelunde Poulsen K, Nielsen JE, Frederiksen H, Melau C, Juul Hare K, Langhoff Thuesen L, et al. Dysregulation of FGFR signalling by a selective inhibitor reduces germ cell survival in human fetal gonads of both sexes and alters the somatic niche in fetal testes. Hum Reprod. 2019;34(11):2228-43.
16. Schmahl J, Kim Y, Colvin JS, Ornitz DM, Capel B. Fgf9 induces proliferation and nuclear localization of FGFR2 in Sertoli precursors during male sex determination. Development. 2004;131(15):3627-36.
17. Alhamoudi KM, Alghamdi B, Aljomaiah A, Alswailem M, Al-Hindi H, Alzahrani AS. Case Report: Severe Gonadal Dysgenesis Causing 46,XY Disorder of Sex Development Due to a Novel NR5A1 Variant. Front Genet. 2022;13:885589.
18. Tang F, Richardson N, Albina A, Chaboissier M-C, Perea-Gomez A. Mouse Gonad Development in the Absence of the Pro-Ovary Factor WNT4 and the Pro-Testis Factor SOX9 Cells. 2020;9(5):1103.
19. Lundgaard Riis M, Delpouve G, Nielsen JE, Melau C, Langhoff Thuesen L, Juul Hare K, et al. Inhibition of WNT/beta-catenin signalling during sex-specific gonadal differentiation is essential for normal human fetal testis development. Cell Commun Signal. 2024;22(1):330.
20. Sowińska-Przepiera E, Krzyścin M, Przepiera A, Brodowska A, Malanowska E, Kozłowski M, et al. Late Diagnosis of Swyer Syndrome in a Patient with Bilateral Germ Cell Tumor Treated with a Contraceptive Due to Primary Amenorrhea. Int J Environ Res Public Health. 2023;20(3):2139.
21. Tarenia SS, Chattopadhyay S, Das N, Hathi D, Baidya A, Chakrabarty P, et al. Swyer Syndrome Presenting as Dysgerminoma: A Case Report. J ASEAN Fed Endocr Soc. 2023;38(1):108-13.
22. Winkler I, Jaszczuk I, Gogacz M, Szkodziak P, Paszkowski T, Skorupska K, et al. A Successful New Case of Twin Pregnancy in a Patient with Swyer Syndrome-An Up-to-Date Review on the Incidence and Outcome of Twin/Multiple Gestations in the Pure 46,XY Gonadal Dysgenesis. Int J Environ Res Public Health. 2022;19(9):5027.
23. Biason-Lauber A.WNT4, RSPO1, and FOXL2 in sex development. Semin Reprod Med. 2012;30(5):387-95.
24. Ragitha TS, Sunish KS, Gilvaz S, Daniel S, Varghese PR, Raj S, et al. Mutation analysis of WNT4 gene in SRY negative 46,XX DSD patients with Mullerian agenesis and/or gonadal dysgenesis- An Indian study. Gene. 2023;861:147236.
25. Chiang HS, Wu YN, Wu CC, Hwang JL. Cytogenic and molecular analyses of 46,XX male syndrome with clinical comparison to other groups with testicular azoospermia of genetic origin. J Formos Med Assoc. 2013;112(2):72-8.
26. Zhou L, Charkraborty T, Zhou Q, Mohapatra S, Nagahama Y, Zhang Y. Rspo1-activated signalling molecules are sufficient to induce ovarian differentiation in XY medaka (Oryzias latipes). Sci Rep. 2016;6:19543.
27. Abalı ZY, Guran T. Diagnosis and management of non-CAH 46,XX disorders/differences in sex development. Front Endocrinol (Lausanne). 2024;15:1354759.
28. Xie Y, Wu C, Li Z, Wu Z, Hong L. Early Gonadal Development and Sex Determination in Mammal. Int J Mol Sci. 2022;23(14):7500.
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THE GENETICS OF SEXUAL DEVELOPMENT DISORDERS

Yıl 2025, Cilt: 47 Sayı: 1, 2 - 9, 29.03.2025

Malik Ejder Yıldırım

Öz

Sexual development is one of the significant stages of the embryogenesis. In this process, the gonadal differentiation taking place on a genetic basis (sex chromosomes) determines the sexual identity of the individual. Initially, the gonads are considered bipotential because the gonadal primordium can turn into a testicle or ovary through the activation of certain genetic elements in the subsequent period. When there is a disruption at any phase of this period, various clinical conditions called disorders of sexual development (DSD) arise. These conditions, often accompanied by various mutations or sex chromosome abnormalities, may include gonadal dysgenesis and result in a male (46, XY) or female (46, XX) sex reversal. DSD with 46,XY usually contains ambiguous condition, or the presence of female external and/or internal genitalia depending on whether Müllerian tissues are present. On the other hand, different enzyme defects, again, on a genetic basis can lead to disorders of sex development in both males (e.g. 5α-reductase) and females (e.g. aromatase). Congenital adrenal hyperplasia is a relatively common, autosomal recessive enzyme defect, especially in 46,XX DSD cases. A number of syndromes lead to a certain degree of inadequate sexual development in males or masculinization in females. Patients also have some characteristic physical symptoms accompanied by mental problems. Gonadal dysgenesis can be caused by various mutations, mainly in the SRY gene (e.g. Swyer syndrome) or sex chromosome disorder (Turner syndrome). In cases of 46,XY DSD, mixed gonadal dysgenesis, and some other conditions, prophylactic gonadectomy may be considered because of the malignancy risk.

Anahtar Kelimeler

sexual development, mutation, chromosomal abnormality, gonadal dysgenesis, sex reversal

Kaynakça

1. Lamothe S, Bernard V, Christin-Maitre S. Gonad differentiation toward ovary. Ann Endocrinol (Paris). 2020;81(2-3):83-88.
2. Vivanco E, Goles E, Montalva-Medel M, Poupin MJ. Dynamical robustness of a Boolean model for the human gonadal sex determination. Comput Biol Chem. 2024;113:108225.
3. Acién P, Acién M. Disorders of Sex Development: Classification, Review, and Impact on Fertility. J Clin Med. 2020;9(11):3555.
4. Kim KR, Kwon Y, Joung JY, Kim KS, Ayala AG, Ro JY. True hermaphroditism and mixed gonadal dysgenesis in young children: a clinicopathologic study of 10 cases. Mod Pathol. 2002;15(10):1013-9.
5. Allen L. Disorders of sexual development. Obstet Gynecol Clin North Am. 2009;36(1):25-45.
6. García-Acero M, Moreno O, Suárez F, Rojas A. Disorders of Sexual Development: Current Status and Progress in the Diagnostic Approach. Curr Urol. 2020;13(4):169-178.
7. Davies K. The XY Female: Exploring Care for Adolescent Girls with Complete Androgen Insensitivity Syndrome. Compr Child Adolesc Nurs. 2020;43(4):378-88.
8. Massanyi EZ, Dicarlo HN, Migeon CJ, Gearhart JP. Review and management of 46,XY disorders of sex development. J Pediatr Urol. 2013;9(3):368-79.
9. Basri NI, Soon CH, Ali A, Abdul Ghani NA, Zainuddin AA. Prophylactic gonadectomy in 46 XY females; why, where and when? Horm Mol Biol Clin Investig. 2021;42(3):325-8.
10. Luppino G, Wasniewska M, Coco R, Pepe G, Morabito LA, Li Pomi A, et al. Role of NR5A1 Gene Mutations in Disorders of Sex Development: Molecular and Clinical Features. Curr Issues Mol Biol. 2024;46(5):4519-32.
11. Alkhzouz C, Bucerzan S, Miclaus M, Mirea AM, Miclea D. 46,XX DSD: Developmental, Clinical and Genetic Aspects. Diagnostics (Basel). 2021;11(8):1379.
12. Sreenivasan R, Gonen N, Sinclair A. SOX Genes and Their Role in Disorders of Sex Development. Sex Dev. 2022;16(2-3):80-91.
13. Racca JD, Chen YS, Brabender AR, Battistin U, Weiss MA, Georgiadis MM. Role of nucleobase-specific interactions in binding and bending of DNA by human male sex-determination factor SRY. J Biol Chem. 2024:107683. doi: 10.1016/j.jbc.2024.107683.
14. Witchel SF. Disorders of sex development. Best Pract Res Clin Obstet Gynaecol. 2018;48:90-102. 15. Harpelunde Poulsen K, Nielsen JE, Frederiksen H, Melau C, Juul Hare K, Langhoff Thuesen L, et al. Dysregulation of FGFR signalling by a selective inhibitor reduces germ cell survival in human fetal gonads of both sexes and alters the somatic niche in fetal testes. Hum Reprod. 2019;34(11):2228-43.
16. Schmahl J, Kim Y, Colvin JS, Ornitz DM, Capel B. Fgf9 induces proliferation and nuclear localization of FGFR2 in Sertoli precursors during male sex determination. Development. 2004;131(15):3627-36.
17. Alhamoudi KM, Alghamdi B, Aljomaiah A, Alswailem M, Al-Hindi H, Alzahrani AS. Case Report: Severe Gonadal Dysgenesis Causing 46,XY Disorder of Sex Development Due to a Novel NR5A1 Variant. Front Genet. 2022;13:885589.
18. Tang F, Richardson N, Albina A, Chaboissier M-C, Perea-Gomez A. Mouse Gonad Development in the Absence of the Pro-Ovary Factor WNT4 and the Pro-Testis Factor SOX9 Cells. 2020;9(5):1103.
19. Lundgaard Riis M, Delpouve G, Nielsen JE, Melau C, Langhoff Thuesen L, Juul Hare K, et al. Inhibition of WNT/beta-catenin signalling during sex-specific gonadal differentiation is essential for normal human fetal testis development. Cell Commun Signal. 2024;22(1):330.
20. Sowińska-Przepiera E, Krzyścin M, Przepiera A, Brodowska A, Malanowska E, Kozłowski M, et al. Late Diagnosis of Swyer Syndrome in a Patient with Bilateral Germ Cell Tumor Treated with a Contraceptive Due to Primary Amenorrhea. Int J Environ Res Public Health. 2023;20(3):2139.
21. Tarenia SS, Chattopadhyay S, Das N, Hathi D, Baidya A, Chakrabarty P, et al. Swyer Syndrome Presenting as Dysgerminoma: A Case Report. J ASEAN Fed Endocr Soc. 2023;38(1):108-13.
22. Winkler I, Jaszczuk I, Gogacz M, Szkodziak P, Paszkowski T, Skorupska K, et al. A Successful New Case of Twin Pregnancy in a Patient with Swyer Syndrome-An Up-to-Date Review on the Incidence and Outcome of Twin/Multiple Gestations in the Pure 46,XY Gonadal Dysgenesis. Int J Environ Res Public Health. 2022;19(9):5027.
23. Biason-Lauber A.WNT4, RSPO1, and FOXL2 in sex development. Semin Reprod Med. 2012;30(5):387-95.
24. Ragitha TS, Sunish KS, Gilvaz S, Daniel S, Varghese PR, Raj S, et al. Mutation analysis of WNT4 gene in SRY negative 46,XX DSD patients with Mullerian agenesis and/or gonadal dysgenesis- An Indian study. Gene. 2023;861:147236.
25. Chiang HS, Wu YN, Wu CC, Hwang JL. Cytogenic and molecular analyses of 46,XX male syndrome with clinical comparison to other groups with testicular azoospermia of genetic origin. J Formos Med Assoc. 2013;112(2):72-8.
26. Zhou L, Charkraborty T, Zhou Q, Mohapatra S, Nagahama Y, Zhang Y. Rspo1-activated signalling molecules are sufficient to induce ovarian differentiation in XY medaka (Oryzias latipes). Sci Rep. 2016;6:19543.
27. Abalı ZY, Guran T. Diagnosis and management of non-CAH 46,XX disorders/differences in sex development. Front Endocrinol (Lausanne). 2024;15:1354759.
28. Xie Y, Wu C, Li Z, Wu Z, Hong L. Early Gonadal Development and Sex Determination in Mammal. Int J Mol Sci. 2022;23(14):7500.
29. Holterhus PM, Kulle A, Busch H, Spielmann M. Classic genetic and hormonal switches during fetal sex development and beyond. Med Genet. 2023;35(3):163-71.
30. Huang YC, Tsai MC, Tsai CR, Fu LS. Frasier Syndrome: A Rare Cause of Refractory Steroid-Resistant Nephrotic Syndrome. Children (Basel). 2021;8(8):617.
31. Gomes NL, de Paula LCP, Silva JM, Silva TE, Lerário AM, Nishi MY, et al. A 46,XX testicular disorder of sex development caused by a Wilms' tumour Factor-1 (WT1) pathogenic variant. Clin Genet. 2019;95(1):172-6.
32. Lopez-Gonzalez M, Ariceta G. WT1-related disorders: more than Denys-Drash syndrome. Pediatr Nephrol. 2024;39(9):2601-9.
33. Li T, Zhou J, Wu H, Gao X, Shen Q, Cheng R, et al. Single-cell transcriptomes of kidneys in a 6-month-old boy with Denys-Drash syndrome reveal stromal cell heterogeneity in the tumor microenvironment. Clin Kidney J. 2023;17(1):sfad277.
34. Shao Q, Xie X, Geng J, Yang X, Li W, Zhang Y. Frasier Syndrome: A 15-Year-Old Phenotypically Female Adolescent Presenting with Delayed Puberty and Nephropathy. Children (Basel). 2023;10(3):577.
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Toplam 74 adet kaynakça vardır.

Ayrıntılar

Birincil Dil	İngilizce
Konular	Multimorbidite
Bölüm	Derlemeler
Yazarlar	Malik Ejder Yıldırım 0000-0003-4386-1583
Erken Görünüm Tarihi	29 Mart 2025
Yayımlanma Tarihi	29 Mart 2025
Gönderilme Tarihi	21 Aralık 2024
Kabul Tarihi	8 Mart 2025
Yayımlandığı Sayı	Yıl 2025Cilt: 47 Sayı: 1

Kaynak Göster

AMA	Yıldırım ME. THE GENETICS OF SEXUAL DEVELOPMENT DISORDERS. CMJ. Mart 2025;47(1):2-9. doi:10.7197/cmj.1605185

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