Genetic control of typical and atypical sex development - Nature Reviews Urology
- ️Harley, Vincent R.
- ️Wed Apr 05 2023
Duranteau, L. et al. Participant- and clinician-reported long-term outcomes after surgery in individuals with complete androgen insensitivity syndrome. J. Pediatr. Adolesc. Gynecol. 34, 168–175 (2021).
Hughes, I. A., Houk, C., Ahmed, S. F. & Lee, P. A., Lawson Wilkins Pediatric Endocrine Society/European Society for Paediatric Endocrinology Consensus Group. Consensus statement on management of intersex disorders. J. Pediatr. Urol. 2, 148–162 (2006).
Lee, P. A. et al. Consensus statement on management of intersex disorders. International Consensus Conference on Intersex. Pediatrics 118, e488–e500 (2006).
Ahmed, S. F. et al. Society for endocrinology UK Guidance on the initial evaluation of a suspected difference or disorder of sex development (revised 2021). Clin. Endocrinol. 95, 818–840 (2021).
Audi, L. et al. Genetics in endocrinology: approaches to molecular genetic diagnosis in the management of differences/disorders of sex development (DSD): position paper of EU COST Action BM 1303 ‘DSDnet’. Eur. J. Endocrinol. 179, R197–R206 (2018).
Camats, N., Fernandez-Cancio, M., Audi, L., Schaller, A. & Fluck, C. E. Broad phenotypes in heterozygous NR5A1 46,XY patients with a disorder of sex development: an oligogenic origin? Eur. J. Hum. Genet. 26, 1329–1338 (2018).
Leon, N. Y., Reyes, A. P. & Harley, V. R. A clinical algorithm to diagnose differences of sex development. Lancet Diabetes Endocrinol. 7, 560–574 (2019).
Kavanaugh, G. L. et al. “Good practices” in pediatric clinical care for disorders/differences of sex development. Endocrine 73, 723–733 (2021).
Stevant, I. & Nef, S. Genetic control of gonadal sex determination and development. Trends Genet. 35, 346–358 (2019).
Lecluze, E. et al. Dynamics of the transcriptional landscape during human fetal testis and ovary development. Hum. Reprod. 35, 1099–1119 (2020).
Wilhelm, D. & Englert, C. The Wilms tumor suppressor WT1 regulates early gonad development by activation of Sf1. Genes Dev. 16, 1839–1851 (2002).
Swain, A. & Lovell-Badge, R. Mammalian sex determination: a molecular drama. Genes Dev. 13, 755–767 (1999).
Bunce, C., McKey, J. & Capel, B. Concerted morphogenesis of genital ridges and nephric ducts in the mouse captured through whole-embryo imaging. Development https://doi.org/10.1242/dev.199208 (2021).
Albrecht, K. H. & Eicher, E. M. Evidence that Sry is expressed in Pre-Sertoli cells and Sertoli and granulosa cells have a common precursor. Dev. Biol. 240, 92–107 (2001).
Hanley, N. A. et al. SRY, SOX9, and DAX1 expression patterns during human sex determination and gonadal development. Mech. Dev. 91, 403–407 (2000).
Garcia-Alonso, L. et al. Single-cell roadmap of human gonadal development. Nature 607, 540–547 (2022).
Hu, Y.-C., Okumura, L. M. & Page, D. C. Gata4 is required for formation of the genital ridge in mice. PLoS Genet. 9, e1003629 (2013).
Richardson, B. E. & Lehmann, R. Mechanisms guiding primordial germ cell migration: strategies from different organisms. Nat. Rev. Mol. Cell Biol. 11, 37–49 (2010).
Miyamoto, N., Yoshida, M., Kuratani, S., Matsuo, I. & Aizawa, S. Defects of urogenital development in mice lacking Emx2. Development 124, 1653–1664 (1997).
Kusaka, M. et al. Abnormal epithelial cell polarity and ectopic epidermal growth factor receptor (EGFR) expression induced in Emx2 KO embryonic gonads. Endocrinology 151, 5893–5904 (2010).
Jameson, S. A. et al. Temporal transcriptional profiling of somatic and germ cells reveals biased lineage priming of sexual fate in the fetal mouse gonad. PLoS Genet. 8, e1002575 (2012).
Ostrer, H., Huang, H. Y., Masch, R. J. & Shapiro, E. A cellular study of human testis development. Sex. Dev. 1, 286–292 (2007).
Schnabel, C. A., Selleri, L. & Cleary, M. L. Pbx1 is essential for adrenal development and urogenital differentiation. Genesis 37, 123–130 (2003).
Capellini, T. D. et al. Scapula development is governed by genetic interactions of Pbx1 with its family members and with Emx2 via their cooperative control of Alx1. Development 137, 2559–2569 (2010).
Eozenou, C. et al. The TALE homeodomain of PBX1 is involved in human primary testis-determination. Hum. Mutat. 40, 1071–1076 (2019).
Biason-Lauber, A., Konrad, D., Meyer, M., DeBeaufort, C. & Schoenle, E. J. Ovaries and female phenotype in a girl with 46,XY karyotype and mutations in the CBX2 gene. Am. J. Hum. Genet. 84, 658–663 (2009).
Hart, D., Rodríguez Gutiérrez, D. & Biason-Lauber, A. CBX2 in DSD: the quirky kid on the block. Sex. Dev. 16, 162–170 (2022).
Birk, O. S. et al. The LIM homeobox gene Lhx9 is essential for mouse gonad formation. Nature 403, 909–913 (2000).
Ono, M. & Harley, V. R. Disorders of sex development: new genes, new concepts. Nat. Rev. Endocrinol. 9, 79–91 (2013).
Rey, R. A. & Grinspon, R. P. Normal male sexual differentiation and aetiology of disorders of sex development. Best. Pract. Res. Clin. Endocrinol. Metab. 25, 221–238 (2011).
Sekido, R. & Lovell-Badge, R. Sex determination and SRY: down to a wink and a nudge? Trends Genet. 25, 19–29 (2009).
Bhattacharya, I. & Dey, S. Emerging concepts on Leydig cell development in fetal and adult testis. Front. Endocrinol. 13, 1086276 (2022).
Tingen, C., Kim, A. & Woodruff, T. K. The primordial pool of follicles and nest breakdown in mammalian ovaries. Mol. Hum. Reprod. 15, 795–803 (2009).
Kerr, J. B., Myers, M. & Anderson, R. A. The dynamics of the primordial follicle reserve. Reproduction 146, R205–R215 (2013).
Young, J. M. & McNeilly, A. S. Theca: the forgotten cell of the ovarian follicle. Reproduction 140, 489–504 (2010).
Liu, C., Peng, J., Matzuk, M. M. & Yao, H. H. Lineage specification of ovarian theca cells requires multicellular interactions via oocyte and granulosa cells. Nat. Commun. 6, 6934 (2015).
Hatzirodos, N., Hummitzsch, K., Irving-Rodgers, H. F. & Rodgers, R. J. Transcriptome comparisons identify new cell markers for theca interna and granulosa cells from small and large antral ovarian follicles. PLoS ONE 10, e0119800 (2015).
Haber, D. A. et al. Alternative splicing and genomic structure of the Wilms tumor gene WT1. Proc. Natl Acad. Sci. USA 88, 9618–9622 (1991).
Hammes, A. et al. Two splice variants of the Wilms’ tumor 1 gene have distinct functions during sex determination and nephron formation. Cell 106, 319–329 (2001).
Sirokha, D. et al. A novel WT1 mutation identified in a 46,XX testicular/ovotesticular DSD patient results in the retention of Intron 9. Biology https://doi.org/10.3390/biology10121248 (2021).
She, Z. Y. & Yang, W. X. Sry and SoxE genes: how they participate in mammalian sex determination and gonadal development? Semin. Cell Dev. Biol. 63, 13–22 (2017).
Bashamboo, A. & McElreavey, K. Mechanism of sex determination in humans: insights from disorders of sex development. Sex. Dev. 10, 313–325 (2016).
van der Zwan, Y. G., Biermann, K., Wolffenbuttel, K. P., Cools, M. & Looijenga, L. H. Gonadal maldevelopment as risk factor for germ cell cancer: towards a clinical decision model. Eur. Urol. 67, 692–701 (2015).
Bagheri-Fam, S. et al. Testis determination requires a specific FGFR2 isoform to repress FOXL2. Endocrinology 158, 3832–3843 (2017).
Barseghyan, H. et al. Identification of novel candidate genes for 46,XY disorders of sex development (DSD) using a C57BL/6J-Y (POS) mouse model. Biol. Sex. Differ. 9, 8 (2018).
Fabbri-Scallet, H. et al. Functional characterization of five NR5A1 gene mutations found in patients with 46,XY disorders of sex development. Hum. Mutat. 39, 114–123 (2018).
Granados, A. et al. MAP3K1-related gonadal dysgenesis: six new cases and review of the literature. Am. J. Med. Genet. C. Semin. Med. Genet. 175, 253–259 (2017).
Hagan, A. & Amarillo, I. E. Small copy-number variations involving genes of the FGF pathway in differences in sex development. Hum. Genome Var. 4, 17011 (2017).
Kuroki, S. et al. Rescuing the aberrant sex development of H3K9 demethylase Jmjd1a-deficient mice by modulating H3K9 methylation balance. PLoS Genet. 13, e1007034 (2017).
Zhao, F. et al. Elimination of the male reproductive tract in the female embryo is promoted by COUP-TFII in mice. Science 357, 717–720 (2017).
Ottolenghi, C. et al. Foxl2 is required for commitment to ovary differentiation. Hum. Mol. Genet. 14, 2053–2062 (2005).
Chassot, A. A. et al. Activation of β-catenin signaling by Rspo1 controls differentiation of the mammalian ovary. Hum. Mol. Genet. 17, 1264–1277 (2008).
Chassot, A. A., Gillot, I. & Chaboissier, M. C. R-spondin1, WNT4, and the CTNNB1 signaling pathway: strict control over ovarian differentiation. Reproduction 148, R97–R110 (2014).
Ohnesorg, T., Vilain, E. & Sinclair, A. H. The genetics of disorders of sex development in humans. Sex. Dev. 8, 262–272 (2014).
Arboleda, V. A., Sandberg, D. E. & Vilain, E. DSDs: genetics, underlying pathologies and psychosexual differentiation. Nat. Rev. Endocrinol. 10, 603–615 (2014).
Pannetier, M., Chassot, A. A., Chaboissier, M. C. & Pailhoux, E. Involvement of FOXL2 and RSPO1 in ovarian determination, development, and maintenance in mammals. Sex. Dev. 10, 167–184 (2016).
Pannetier, M. et al. FOXL2 activates P450 aromatase gene transcription: towards a better characterization of the early steps of mammalian ovarian development. J. Mol. Endocrinol. 36, 399–413 (2006).
Uhlenhaut, N. H. et al. Somatic sex reprogramming of adult ovaries to testes by FOXL2 ablation. Cell 139, 1130–1142 (2009).
Tucker, E. J. The genetics and biology of FOXL2. Sex. Dev. 16, 184–193 (2022).
Pierson Smela, M. D. et al. Directed differentiation of human iPSCs to functional ovarian granulosa-like cells via transcription factor overexpression. Elife 12, e83291 (2023).
Edelsztein, N. Y., Valeri, C., Lovaisa, M. M., Schteingart, H. F. & Rey, R. A. AMH regulation by steroids in the mammalian testis: underlying mechanisms and clinical implications. Front. Endocrinol. 13, 906381 (2022).
Jost, A. Problems of fetal endocrinology: the gonadal and hypophyseal hormones. Recent. Progr Horm. Res. 8, 379–413 (1953).
Roly, Z. Y. et al. The cell biology and molecular genetics of Mullerian duct development. Wiley Interdiscip. Rev. Dev. Biol. 7, e310 (2018).
Rabinovici, J. & Jaffe, R. B. Development and regulation of growth and differentiated function in human and subhuman primate fetal gonads. Endocr. Rev. 11, 532–557 (1990).
Biason-Lauber, A. The battle of the sexes: human sex development and its disorders. Results Probl. Cell Differ. 58, 337–382 (2016).
Mendonca, B. B. et al. Steroid 5α-reductase 2 deficiency. J. Steroid Biochem. Mol. Biol. 163, 206–211 (2016).
Thankamony, A., Pasterski, V., Ong, K. K., Acerini, C. L. & Hughes, I. A. Anogenital distance as a marker of androgen exposure in humans. Andrology 4, 616–625 (2016).
Tremblay, J. J. What signals testis descent? Biol. Reprod. 83, 687–689 (2010).
Miller, W. L. & Auchus, R. J. The “backdoor pathway” of androgen synthesis in human male sexual development. PLoS Biol. 17, e3000198 (2019).
O’Shaughnessy, P. J. et al. Alternative (backdoor) androgen production and masculinization in the human fetus. PLoS Biol. 17, e3000002 (2019).
Bay, K., Main, K. M., Toppari, J. & Skakkebaek, N. E. Testicular descent: INSL3, testosterone, genes and the intrauterine milieu. Nat. Rev. Urol. 8, 187–196 (2011).
Hutson, J. M. A biphasic model for the hormonal control of testicular descent. Lancet 2, 419–421 (1985).
Heyns, C. F. The gubernaculum during testicular descent in the human fetus. J. Anat. 153, 93–112 (1987).
Barteczko, K. J. & Jacob, M. I. The testicular descent in human. Origin, development and fate of the gubernaculum Hunteri, processus vaginalis peritonei, and gonadal ligaments. Adv. Anat. Embryol. Cell Biol. 156, 1–98 (2000).
Hutson, J. M. et al. The regulation of testicular descent and the effects of cryptorchidism. Endocr. Rev. 34, 725–752 (2013).
Josso, N. & Picard, J. Y. Genetics of anti-Mullerian hormone and its signaling pathway. Best. Pract. Res. Clin. Endocrinol. Metab. 36, 101634 (2022).
Rajpert-De Meyts, E. et al. Expression of anti-Mullerian hormone during normal and pathological gonadal development: association with differentiation of Sertoli and granulosa cells. J. Clin. Endocrinol. Metab. 84, 3836–3844 (1999).
di Clemente, N., Racine, C., Pierre, A. & Taieb, J. Anti-mullerian hormone in female reproduction. Endocr. Rev. 42, 753–782 (2021).
Du, H. & Taylor, H. S. The role of hox genes in female reproductive tract development, adult function, and fertility. Cold Spring Harb. Perspect. Med. 6, a023002 (2015).
Blackless, M. et al. How sexually dimorphic are we? Review and synthesis. Am. J. Hum. Biol. 12, 151–166 (2000).
Sax, L. How common is intersex? A response to Anne Fausto-Sterling. J. Sex. Res. 39, 174–178 (2002).
Eggers, S. et al. Disorders of sex development: insights from targeted gene sequencing of a large international patient cohort. Genome Biol. 17, 243 (2016).
Conway, G. S. Differences in sex development (DSD) and related conditions: mechanisms, prevalences and changing practice. Int. J. Impot. Res. 35, 46–50 (2023).
Thyen, U., Lanz, K., Holterhus, P. M. & Hiort, O. Epidemiology and initial management of ambiguous genitalia at birth in Germany. Horm. Res. 66, 195–203 (2006).
Abdullah, M. A. et al. Ambiguous genitalia: medical, socio-cultural and religious factors affecting management in Saudi Arabia. Ann. Trop. Paediatr. 11, 343–348 (1991).
Aydin, B. K. et al. Frequency of ambiguous genitalia in 14,177 newborns in Turkey. J. Endocr. Soc. 3, 1185–1195 (2019).
Mazen, I., Hiort, O., Bassiouny, R. & El Gammal, M. Differential diagnosis of disorders of sex development in Egypt. Horm. Res. 70, 118–123 (2008).
Nassau, D. E. et al. Androgenization in Klinefelter syndrome: clinical spectrum from infancy through young adulthood. J. Pediatr. Urol. 17, 346–352 (2021).
Syryn, H., Van De Vijver, K. & Cools, M. Ovotesticular difference of sex development: genetic background, histological features, and clinical management. Horm. Res. Paediatr. https://doi.org/10.1159/000519323 (2021).
Berglund, A., Stochholm, K. & Gravholt, C. H. The epidemiology of sex chromosome abnormalities. Am. J. Med. Genet. C. Semin. Med. Genet. 184, 202–215 (2020).
Gravholt, C. H., Viuff, M. H., Brun, S., Stochholm, K. & Andersen, N. H. Turner syndrome: mechanisms and management. Nat. Rev. Endocrinol. 15, 601–614 (2019).
Huang, A. C., Olson, S. B. & Maslen, C. L. A review of recent developments in turner syndrome research. J. Cardiovasc. Dev. Dis. https://doi.org/10.3390/jcdd8110138 (2021).
Zitzmann, M. & Rohayem, J. Gonadal dysfunction and beyond: clinical challenges in children, adolescents, and adults with 47,XXY Klinefelter syndrome. Am. J. Med. Genet. C. Semin. Med. Genet. 184, 302–312 (2020).
Cools, M. et al. Caring for individuals with a difference of sex development (DSD): a Consensus Statement. Nat. Rev. Endocrinol. 14, 415–429 (2018).
Akcan, N. et al. Mutations in AR or SRD5A2 Genes: clinical findings, endocrine pitfalls, and genetic features of children with 46,XY DSD. J. Clin. Res. Pediatr. Endocrinol. https://doi.org/10.4274/jcrpe.galenos.2021.2021-9-19 (2022).
Berglund, A. et al. Incidence, prevalence, diagnostic delay, and clinical presentation of female 46,XY disorders of sex development. J. Clin. Endocrinol. Metab. 101, 4532–4540 (2016).
Peng, Y. et al. Identification of potential genes in pathogenesis and diagnostic value analysis of partial androgen insensitivity syndrome using bioinformatics analysis. Front. Endocrinol. 12, 731107 (2021).
Ulloa-Aguirre, A. et al. Incomplete regression of mullerian ducts in the androgen insensitivity syndrome. Fertil. Steril. 53, 1024–1028 (1990).
Van, Y. H. et al. Novel point mutations in complete androgen insensitivity syndrome with incomplete mullerian regression: two Taiwanese patients. Eur. J. Pediatr. 162, 781–784 (2003).
Damiani, D. et al. Persistence of Mullerian remnants in complete androgen insensitivity syndrome. J. Pediatr. Endocrinol. Metab. 15, 1553–1556 (2002).
Nichols, J. L., Bieber, E. J. & Gell, J. S. Case of sisters with complete androgen insensitivity syndrome and discordant Mullerian remnants. Fertil. Steril. 91, 932 e915–932 e938 (2009).
Audi, L. et al. Novel (60%) and recurrent (40%) androgen receptor gene mutations in a series of 59 patients with a 46,XY disorder of sex development. J. Clin. Endocrinol. Metab. 95, 1876–1888 (2010).
Philibert, P. et al. Complete androgen insensitivity syndrome is frequently due to premature stop codons in exon 1 of the androgen receptor gene: an international collaborative report of 13 new mutations. Fertil. Steril. 94, 472–476 (2010).
Guven, A., Dursun, F., Ozkanli, S., Gucluer, B. & Kuru, L. I. Complete androgen insensitivity syndrome and discordant Mullerian remnants: two cases with novel mutation in the androgen receptor. J. Pediatr. Endocrinol. Metab. 26, 909–914 (2013).
Dodge, S. T., Finkelston, M. S. & Miyazawa, K. Testicular feminization with incomplete Mullerian regression. Fertil. Steril. 43, 937–938 (1985).
Gottlieb, B., Beitel, L. K., Nadarajah, A., Paliouras, M. & Trifiro, M. The androgen receptor gene mutations database: 2012 update. Hum. Mutat. 33, 887–894 (2012).
Kumar, A. et al. Clinical, biochemical, and molecular characterization of Indian children with clinically suspected androgen insensitivity syndrome. Sex. Dev. 16, 34–45 (2022).
Hughes, I. A. et al. Androgen insensitivity syndrome. Lancet 380, 1419–1428 (2012).
Pizzo, A., Lagana, A. S., Borrielli, I. & Dugo, N. Complete androgen insensitivity syndrome: a rare case of disorder of sex development. Case Rep. Obstet. Gynecol. 2013, 232696 (2013).
Wang, K. N., Chen, Q. Q., Zhu, Y. L. & Wang, C. L. Complete androgen insensitivity syndrome caused by the c.2678C>T mutation in the androgen receptor gene: a case report. World J. Clin. Cases 9, 11036–11042 (2021).
Han, B. et al. Differences of adrenal-derived androgens in 5α-reductase deficiency versus androgen insensitivity syndrome. Clin. Transl. Sci. 15, 658–666 (2022).
Ilaslan, E. et al. The FKBP4 gene, encoding a regulator of the androgen receptor signaling pathway, is a novel candidate gene for androgen insensitivity syndrome. Int. J. Mol. Sci. https://doi.org/10.3390/ijms21218403 (2020).
Hornig, N. C. et al. Identification of an AR mutation-negative class of androgen insensitivity by determining endogenous AR activity. J. Clin. Endocrinol. Metab. 101, 4468–4477 (2016).
Hornig, N. C. & Holterhus, P. M. Molecular basis of androgen insensitivity syndromes. Mol. Cell. Endocrinol. 523, 111146 (2021).
Cools, M. & Looijenga, L. Update on the pathophysiology and risk factors for the development of malignant testicular germ cell tumors in complete androgen insensitivity syndrome. Sex. Dev. 11, 175–181 (2017).
Barros, B. A. et al. Complete androgen insensitivity syndrome and risk of gonadal malignancy: systematic review. Ann. Pediatr. Endocrinol. Metab. 26, 19–23 (2021).
Cools, M., Drop, S. L., Wolffenbuttel, K. P., Oosterhuis, J. W. & Looijenga, L. H. Germ cell tumors in the intersex gonad: old paths, new directions, moving frontiers. Endocr. Rev. 27, 468–484 (2006).
Dohnert, U., Wunsch, L. & Hiort, O. Gonadectomy in complete androgen insensitivity syndrome: why and when? Sex. Dev. 11, 171–174 (2017).
Michala, L., Goswami, D., Creighton, S. M. & Conway, G. S. Swyer syndrome: presentation and outcomes. BJOG 115, 737–741 (2008).
Gabriel Ribeiro de Andrade, J. et al. Long-term follow-up of patients with 46,XY partial gonadal dysgenesis reared as males. Int. J. Endocrinol. 2014, 480724 (2014).
Ocal, G. et al. The clinical and genetic heterogeneity of mixed gonadal dysgenesis: does “disorders of sexual development (DSD)” classification based on new Chicago consensus cover all sex chromosome DSD? Eur. J. Pediatr. 171, 1497–1502 (2012).
Das, D. V. & Jabbar, P. K. Clinical and reproductive characteristics of patients with mixed gonadal dysgenesis (45,X/46, XY). J. Obstet. Gynaecol. India 71, 399–405 (2021).
Fine, S. et al. Mixed gonadal dysgenesis with an ovotestis on imaging mimicking ovotesticular disorder of sexual differentiation. Proc 34, 739–741 (2021).
Weidler, E. M., Pearson, M., van Leeuwen, K. & Garvey, E. Clinical management in mixed gonadal dysgenesis with chromosomal mosaicism: considerations in newborns and adolescents. Semin. Pediatr. Surg. 28, 150841 (2019).
Ljubicic, M. L. et al. Clinical but not histological outcomes in males with 45,X/46,XY mosaicism vary depending on reason for diagnosis. J. Clin. Endocrinol. Metab. 104, 4366–4381 (2019).
Vasundhera, C., Jyotsna, V. P., Kandasamy, D. & Gupta, N. Clinical, hormonal and radiological profile of 46XY disorders of sexual development. Indian. J. Endocrinol. Metab. 20, 300–307 (2016).
Elzaiat, M., McElreavey, K. & Bashamboo, A. Genetics of 46,XY gonadal dysgenesis. Best. Pract. Res. Clin. Endocrinol. Metab. 36, 101633 (2022).
Altunoglu, U. et al. Expanding the spectrum of syndromic PPP2R3C-related XY gonadal dysgenesis to XX gonadal dysgenesis. Clin. Genet. 101, 221–232 (2022).
Mazen, I. et al. A homozygous missense variant in hedgehog acyltransferase (HHAT) gene associated with 46,XY gonadal dysgenesis. Sex. Dev. https://doi.org/10.1159/000520366 (2022).
White, S. et al. A multi-exon deletion within WWOX is associated with a 46,XY disorder of sex development. Eur. J. Hum. Genet. 20, 348–351 (2012).
Baetens, D. et al. Biallelic and monoallelic ESR2 variants associated with 46,XY disorders of sex development. Genet. Med. 20, 717–727 (2018).
Fabbri-Scallet, H. et al. Can non-coding NR5A1 gene variants explain phenotypes of disorders of sex development? Sex. Dev. https://doi.org/10.1159/000524956 (2022).
Sreenivasan, R. et al. Mutant NR5A1/SF-1 in patients with disorders of sex development shows defective activation of the SOX9 TESCO enhancer. Hum. Mutat. 39, 1861–1874 (2018).
McElreavey, K., Pailhoux, E. & Bashamboo, A. DHX37 and 46,XY DSD: a new ribosomopathy? Sex. Dev. 16, 194–206 (2022).
da Silva, T. E. et al. Genetic evidence of the association of DEAH-box helicase 37 defects with 46,XY gonadal dysgenesis spectrum. J. Clin. Endocrinol. Metab. 104, 5923–5934 (2019).
Bagheri-Fam, S. et al. Defective survival of proliferating Sertoli cells and androgen receptor function in a mouse model of the ATR-X syndrome. Hum. Mol. Genet. 20, 2213–2224 (2011).
Harley, V. R. & Goodfellow, P. N. The biochemical role of SRY in sex determination. Mol. Reprod. Dev. 39, 184–193 (1994).
Zhao, L. & Koopman, P. SRY protein function in sex determination: thinking outside the box. Chromosome Res. 20, 153–162 (2012).
Phillips, N. B. et al. SRY and human sex determination: the basic tail of the HMG box functions as a kinetic clamp to augment DNA bending. J. Mol. Biol. 358, 172–192 (2006).
Chamberlin, A. et al. Mutations in MAP3K1 that cause 46,XY disorders of sex development disrupt distinct structural domains in the protein. Hum. Mol. Genet. 28, 1620–1628 (2019).
Warr, N. et al. Gadd45γ and Map3k4 interactions regulate mouse testis determination via p38 MAPK-mediated control of Sry expression. Dev. Cell 23, 1020–1031 (2012).
Cools, M. et al. Gonadal pathology and tumor risk in relation to clinical characteristics in patients with 45,X/46,XY mosaicism. J. Clin. Endocrinol. Metab. 96, E1171–E1180 (2011).
Lu, L., Luo, F. & Wang, X. Gonadal tumor risk in pediatric and adolescent phenotypic females with disorders of sex development and Y chromosomal constitution with different genetic etiologies. Front. Pediatr. 10, 856128 (2022).
Huang, H., Wang, C. & Tian, Q. Gonadal tumour risk in 292 phenotypic female patients with disorders of sex development containing Y chromosome or Y-derived sequence. Clin. Endocrinol. 86, 621–627 (2017).
Batista, R. L. & Mendonca, B. B. Integrative and analytical review of the 5-alpha-reductase type 2 deficiency worldwide. Appl. Clin. Genet. 13, 83–96 (2020).
Akcay, T. et al. AR and SRD5A2 gene mutations in a series of 51 Turkish 46,XY DSD children with a clinical diagnosis of androgen insensitivity. Andrology 2, 572–578 (2014).
Boudon, C. et al. A new deletion of the 5α-reductase type 2 gene in a Turkish family with 5 α-reductase deficiency. Clin. Endocrinol. 43, 183–188 (1995).
Ocal, G. et al. Mutations of the 5α-steroid reductase type 2 gene in six Turkish patients from unrelated families and a large pedigree of an isolated Turkish village. J. Pediatr. Endocrinol. Metab. 15, 411–421 (2002).
Nie, M., Zhou, Q., Mao, J., Lu, S. & Wu, X. Five novel mutations of SRD5A2 found in eight Chinese patients with 46,XY disorders of sex development. Mol. Hum. Reprod. 17, 57–62 (2011).
Zhu, H. et al. Phenotypic and molecular characteristics in eleven Chinese patients with 5α-reductase type 2 deficiency. Clin. Endocrinol. 81, 711–720 (2014).
Bertelloni, S. et al. 5α-reductase-2 deficiency: clinical findings, endocrine pitfalls, and genetic features in a large Italian cohort. Sex. Dev. 10, 28–36 (2016).
Imperato-McGinley, J., Guerrero, L., Gautier, T. & Peterson, R. E. Steroid 5α-reductase deficiency in man: an inherited form of male pseudohermaphroditism. Science 186, 1213–1215 (1974).
Ko, J. M. et al. Clinical characterization and analysis of the SRD5A2 gene in six Korean patients with 5α-reductase type 2 deficiency. Horm. Res. Paediatr. 73, 41–48 (2010).
Mendonca, B. B. et al. Male pseudohermaphroditism due to steroid 5α-reductase 2 deficiency. Diagnosis, psychological evaluation, and management. Medicine 75, 64–76 (1996).
Sahakitrungruang, T. et al. Identification of mutations in the SRD5A2 gene in Thai patients with male pseudohermaphroditism. Fertil. Steril. 90, 2015.e11–2015.e15 (2008).
Canto, P. et al. Mutations of the 5α-reductase type 2 gene in eight Mexican patients from six different pedigrees with 5α-reductase-2 deficiency. Clin. Endocrinol. 46, 155–160 (1997).
Maria Guadalupe, O. L., Katy, S. P., Charmina, A. A., Vihko, P. & Marta, M. Molecular characterization of two known SRD5A2 gene variants in Mexican patients with disorder of sexual development. Front. Genet. 12, 794476 (2021).
Vilchis, F. et al. Molecular analysis of the SRD5A2 in 46,XY subjects with incomplete virilization: the P212R substitution of the steroid 5α-reductase 2 may constitute an ancestral founder mutation in Mexican patients. J. Androl. 31, 358–364 (2010).
Andonova, S. et al. New territory for an old disease: 5-α-reductase type 2 deficiency in Bulgaria. Sex. Dev. 11, 21–28 (2017).
Avendano, A. et al. 5α-Reductase type 2 deficiency in families from an isolated Andean population in Venezuela. Ann. Hum. Genet. 84, 151–160 (2020).
Cheon, C. K. Practical approach to steroid 5α-reductase type 2 deficiency. Eur. J. Pediatr. 170, 1–8 (2011).
Imperato-McGinley, J. & Zhu, Y. S. Androgens and male physiology the syndrome of 5α-reductase-2 deficiency. Mol. Cell Endocrinol. 198, 51–59 (2002).
Wilson, J. D., Griffin, J. E. & Russell, D. W. Steroid 5 α-reductase 2 deficiency. Endocr. Rev. 14, 577–593 (1993).
Maimoun, L. et al. Phenotypical, biological, and molecular heterogeneity of 5α-reductase deficiency: an extensive international experience of 55 patients. J. Clin. Endocrinol. Metab. 96, 296–307 (2011).
Pang, S. et al. Dihydrotestosterone and its relationship to testosterone in infancy and childhood. J. Clin. Endocrinol. Metab. 48, 821–826 (1979).
Costa, E. M., Domenice, S., Sircili, M. H., Inacio, M. & Mendonca, B. B. DSD due to 5α-reductase 2 deficiency — from diagnosis to long term outcome. Semin. Reprod. Med. 30, 427–431 (2012).
Walsh, P. C. et al. Familial incomplete male pseudohermaphroditism, type 2. Decreased dihydrotestosterone formation in pseudovaginal perineoscrotal hypospadias. N. Engl. J. Med. 291, 944–949 (1974).
Mendonca, B. B. et al. Male pseudohermaphroditism due to 5 α reductase deficiency associated with gynecomastia. Rev. Hosp. Clin. Fac. Med. Sao Paulo 42, 66–68 (1987).
Kanakis, G. A. et al. EAA clinical practice guidelines — gynecomastia evaluation and management. Andrology 7, 778–793 (2019).
Imperato-McGinley, J., Peterson, R. E., Gautier, T. & Sturla, E. Androgens and the evolution of male-gender identity among male pseudohermaphrodites with 5α-reductase deficiency. N. Engl. J. Med. 300, 1233–1237 (1979).
Bertelloni, S., Russo, G. & Baroncelli, G. I. Human chorionic gonadotropin test: old uncertainties, new perspectives, and value in 46,XY disorders of sex development. Sex. Dev. 12, 41–49 (2018).
Fernandez-Cancio, M. et al. SRD5A2 gene mutations and polymorphisms in Spanish 46,XY patients with a disorder of sex differentiation. Int. J. Androl. 34, e526–e535 (2011).
Mendonca, B. B. Gender assignment in patients with disorder of sex development. Curr. Opin. Endocrinol. Diabetes Obes. 21, 511–514 (2014).
Samtani, R., Bajpai, M., Ghosh, P. K. & Saraswathy, K. N. SRD5A2 gene mutations — a population-based review. Pediatr. Endocrinol. Rev. 8, 34–40 (2010).
Vija, L. et al. Testicular histological and immunohistochemical aspects in a post-pubertal patient with 5α-reductase type 2 deficiency: case report and review of the literature in a perspective of evaluation of potential fertility of these patients. BMC Endocr. Disord. 14, 43 (2014).
Claahsen-van der Grinten, H. L. et al. Congenital adrenal hyperplasia — current insights in pathophysiology, diagnostics, and management. Endocr. Rev. 43, 91–159 (2022).
Terribile, M. et al. 46,XX Testicular disorder of sex development (DSD): a case report and systematic review. Medicina 55, 371 (2019).
Auchus, R. J. The uncommon forms of congenital adrenal hyperplasia. Curr. Opin. Endocrinol. Diabetes Obes. 29, 263–270 (2022).
Khalid, J. M. et al. Incidence and clinical features of congenital adrenal hyperplasia in Great Britain. Arch. Dis. Child. 97, 101–106 (2012).
Gidlöf, S., Wedell, A., Guthenberg, C., von Döbeln, U. & Nordenström, A. Nationwide neonatal screening for congenital adrenal hyperplasia in Sweden: a 26-year longitudinal prospective population-based study. JAMA Pediatr. 168, 567–574 (2014).
Li, Z. et al. Analysis of the screening results for congenital adrenal hyperplasia involving 7.85 million newborns in China: a systematic review and meta-analysis. Front. Endocrinol. 12, 624507 (2021).
El-Maouche, D., Arlt, W. & Merke, D. P. Congenital adrenal hyperplasia. Lancet 390, 2194–2210 (2017).
Gidlof, S. et al. One hundred years of congenital adrenal hyperplasia in Sweden: a retrospective, population-based cohort study. Lancet Diabetes Endocrinol. 1, 35–42 (2013).
Merke, D. P. & Auchus, R. J. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. N. Engl. J. Med. 383, 1248–1261 (2020).
Neeman, B., Bello, R., Lazar, L., Phillip, M. & de Vries, L. Central precocious puberty as a presenting sign of nonclassical congenital adrenal hyperplasia: clinical characteristics. J. Clin. Endocrinol. Metab. 104, 2695–2700 (2019).
Eugster, E. A. et al. Height outcome in congenital adrenal hyperplasia caused by 21-hydroxylase deficiency: a meta-analysis. J. Pediatr. 138, 26–32 (2001).
New, M. I. Extensive clinical experience: nonclassical 21-hydroxylase deficiency. J. Clin. Endocrinol. Metab. 91, 4205–4214 (2006).
Al Wattar, B. H. et al. Clinical practice guidelines on the diagnosis and management of polycystic ovary syndrome: a systematic review and quality assessment study. J. Clin. Endocrinol. Metab. 106, 2436–2446 (2021).
Azziz, R. et al. Positions statement: criteria for defining polycystic ovary syndrome as a predominantly hyperandrogenic syndrome: an Androgen Excess Society guideline. J. Clin. Endocrinol. Metab. 91, 4237–4245 (2006).
Papadakis, G., Kandaraki, E. A., Tseniklidi, E., Papalou, O. & Diamanti-Kandarakis, E. Polycystic ovary syndrome and NC-CAH: distinct characteristics and common findings. A systematic review. Front. Endocrinol. 10, 388 (2019).
Mallappa, A. & Merke, D. P. Management challenges and therapeutic advances in congenital adrenal hyperplasia. Nat. Rev. Endocrinol. 18, 337–352 (2022).
Merke, D. P. et al. Modified-release hydrocortisone in congenital adrenal hyperplasia. J. Clin. Endocrinol. Metab. 106, e2063–e2077 (2021).
Whitaker, M. et al. An oral multiparticulate, modified-release, hydrocortisone replacement therapy that provides physiological cortisol exposure. Clin. Endocrinol. 80, 554–561 (2014).
Ruiz-Babot, G. et al. Modeling congenital adrenal hyperplasia and testing interventions for adrenal insufficiency using donor-specific reprogrammed cells. Cell Rep. 22, 1236–1249 (2018).
Markmann, S. et al. Biology of the adrenal gland cortex obviates effective use of adeno-associated virus vectors to treat hereditary adrenal disorders. Hum. Gene Ther. 29, 403–412 (2018).
US National Library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT04783181 (2023).
Bharucha, K. et al. ODP046 Initial lessons from a prescreening protocol to identify participants with classic CAH potentially eligible for gene therapy treatment with BBP-631, an adeno-associated virus (AAV) serotype 5-Based Recombinant Vector Encoding the Human CYP21A2 Gene. J. Endocr. Soc. 6, A60–A61 (2022).
Yildiz, M. et al. Ovarian and paraovarian adrenal rest tumors are not uncommon in gonadectomy materials of historical congenital adrenal hyperplasia cases in childhood. Eur. J. Endocrinol. 187, K13–K18 (2022).
Nermoen, I. & Falhammar, H. Prevalence and characteristics of adrenal tumors and myelolipomas in congenital adrenal hyperplasia: a systematic review and meta-analysis. Endocr. Pract. 26, 1351–1365 (2020).
Kim, M. S. et al. Testicular adrenal rest tumors in boys and young adults with congenital adrenal hyperplasia. J. Urol. 197, 931–936 (2017).
Maciel-Guerra, A. T. et al. XX Maleness and XX true hermaphroditism in SRY-negative monozygotic twins: additional evidence for a common origin. J. Clin. Endocrinol. Metab. 93, 339–343 (2008).
Naasse, Y. et al. A novel homozygous missense mutation in the FU-CRD2 domain of the R-spondin1 gene associated with familial 46,XX DSD. Sex. Dev. 11, 269–274 (2017).
Grinspon, R. P. & Rey, R. A. Disorders of sex development with testicular differentiation in SRY-negative 46,XX individuals: clinical and genetic aspects. Sex. Dev. 10, 1–11 (2016).
Berglund, A. et al. Incidence, prevalence, diagnostic delay, morbidity, mortality and socioeconomic status in males with 46,XX disorders of sex development: a nationwide study. Hum. Reprod. 32, 1751–1760 (2017).
Eozenou, C. et al. Testis formation in XX individuals resulting from novel pathogenic variants in Wilms’ tumor 1 (WT1) gene. Proc. Natl Acad. Sci. USA 117, 13680–13688 (2020).
Wei, J. et al. Duplication of SOX3 in an SRY-negative 46,XX male with prostatic utricle: case report and literature review. BMC Med. Genomics 15, 188 (2022).
Gomes, N. L. et al. A 46,XX testicular disorder of sex development caused by a Wilms’ tumour Factor-1 (WT1) pathogenic variant. Clin. Genet. 95, 172–176 (2019).
Tallapaka, K., Venugopal, V., Dalal, A. & Aggarwal, S. Novel RSPO1 mutation causing 46,XX testicular disorder of sex development with palmoplantar keratoderma: a review of literature and expansion of clinical phenotype. Am. J. Med. Genet. A 176, 1006–1010 (2018).
Parma, P. et al. R-spondin1 is essential in sex determination, skin differentiation and malignancy. Nat. Genet. 38, 1304–1309 (2006).
Mandel, H. et al. SERKAL syndrome: an autosomal-recessive disorder caused by a loss-of-function mutation in WNT4. Am. J. Hum. Genet. 82, 39–47 (2008).
Baetens, D. et al. NR5A1 is a novel disease gene for 46,XX testicular and ovotesticular disorders of sex development. Genet. Med. 19, 367–376 (2017).
Bashamboo, A. et al. A recurrent p.Arg92Trp variant in steroidogenic factor-1 (NR5A1) can act as a molecular switch in human sex development. Hum. Mol. Genet. 25, 3446–3453 (2016).
Knarston, I. M. et al. NR5A1 gene variants repress the ovarian-specific WNT signaling pathway in 46,XX disorders of sex development patients. Hum. Mutat. 40, 207–216 (2019).
Bashamboo, A. et al. Loss of function of the nuclear receptor NR2F2, encoding COUP-TF2, causes testis development and cardiac defects in 46,XX children. Am. J. Hum. Genet. 102, 487–493 (2018).
Carvalheira, G. et al. The natural history of a man with ovotesticular 46,XX DSD caused by a novel 3-Mb 15q26.2 deletion containing NR2F2 gene. J. Endocr. Soc. 3, 2107–2113 (2019).
Sutton, E. et al. Identification of SOX3 as an XX male sex reversal gene in mice and humans. J. Clin. Invest. 121, 328–341 (2011).
Vetro, A. et al. Testis development in the absence of SRY: chromosomal rearrangements at SOX9 and SOX3. Eur. J. Hum. Genet. 23, 1025–1032 (2015).
Cox, J. J., Willatt, L., Homfray, T. & Woods, C. G. A SOX9 duplication and familial 46,XX developmental testicular disorder. N. Engl. J. Med. 364, 91–93 (2011).
Qian, Z. et al. Whole genome sequencing identifies a cryptic SOX9 regulatory element duplication underlying a case of 46,XX ovotesticular difference of sexual development. Am. J. Med. Genet. A 185, 2782–2788 (2021).
Falah, N. et al. 22q11.2q13 duplication including SOX10 causes sex-reversal and peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome, and Hirschsprung disease. Am. J. Med. Genet. A 173, 1066–1070 (2017).
Seeherunvong, T. et al. 46,XX sex reversal with partial duplication of chromosome arm 22q. Am. J. Med. Genet. A 127a, 149–151 (2004).
Croft, B. et al. Human sex reversal is caused by duplication or deletion of core enhancers upstream of SOX9. Nat. Commun. 9, 5319 (2018).
Gonen, N. et al. Sex reversal following deletion of a single distal enhancer of Sox9. Science 360, 1469–1473 (2018).
Kobayashi, M. et al. Expanding homogeneous culture of human primordial germ cell-like cells maintaining germline features without serum or feeder layers. Stem Cell Rep. 17, 507–521 (2022).
Ge, W. et al. Dissecting the initiation of female meiosis in the mouse at single-cell resolution. Cell. Mol. Life Sci. 78, 695–713 (2021).
Sproll, P. et al. Assembling the jigsaw puzzle: CBX2 isoform 2 and its targets in disorders/differences of sex development. Mol. Genet. Genom. Med. 6, 785–795 (2018).
Croft, B. et al. FGF9 variant in 46,XY DSD patient suggests a role for dimerization in sex determination. Clin. Genet. https://doi.org/10.1111/cge.14261 (2022).
Bagheri-Fam, S. et al. FGFR2 mutation in 46,XY sex reversal with craniosynostosis. Hum. Mol. Genet. 24, 6699–6710 (2015).