DSDs: Genetics, Underlying Pathologies and Psychosexual Differentiation

Overview

Journal Nat Rev Endocrinol

Specialty Endocrinology

Date 2014 Aug 6

PMID 25091731

Citations 53

Authors

Valerie A Arboleda

David E Sandberg

Eric Vilain

Affiliations

Soon will be listed here.

Abstract

Mammalian sex determination is the unique process whereby a single organ, the bipotential gonad, undergoes a developmental switch that promotes its differentiation into either a testis or an ovary. Disruptions of this complex genetic process during human development can manifest as disorders of sex development (DSDs). Sex development can be divided into two distinct processes: sex determination, in which the bipotential gonads form either testes or ovaries, and sex differentiation, in which the fully formed testes or ovaries secrete local and hormonal factors to drive differentiation of internal and external genitals, as well as extragonadal tissues such as the brain. DSDs can arise from a number of genetic lesions, which manifest as a spectrum of gonadal (gonadal dysgenesis to ovotestis) and genital (mild hypospadias or clitoromegaly to ambiguous genitalia) phenotypes. The physical attributes and medical implications associated with DSDs confront families of affected newborns with decisions, such as gender of rearing or genital surgery, and additional concerns, such as uncertainty over the child's psychosexual development and personal wishes later in life. In this Review, we discuss the underlying genetics of human sex determination and focus on emerging data, genetic classification of DSDs and other considerations that surround gender development and identity in individuals with DSDs.

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References

Bashamboo A, Brauner R, Bignon-Topalovic J, Lortat-Jacob S, Karageorgou V, Lourenco D . Mutations in the FOG2/ZFPM2 gene are associated with anomalies of human testis determination. Hum Mol Genet. 2014; 23(14):3657-65. DOI: 10.1093/hmg/ddu074. View

Yang Y, Muzny D, Reid J, Bainbridge M, Willis A, Ward P . Clinical whole-exome sequencing for the diagnosis of mendelian disorders. N Engl J Med. 2013; 369(16):1502-11. PMC: 4211433. DOI: 10.1056/NEJMoa1306555. View

Bagheri-Fam S, Sim H, Bernard P, Jayakody I, Taketo M, Scherer G . Loss of Fgfr2 leads to partial XY sex reversal. Dev Biol. 2007; 314(1):71-83. DOI: 10.1016/j.ydbio.2007.11.010. View

Jager R, Anvret M, Hall K, Scherer G . A human XY female with a frame shift mutation in the candidate testis-determining gene SRY. Nature. 1990; 348(6300):452-4. DOI: 10.1038/348452a0. View

Smith-Bouvier D, Divekar A, Sasidhar M, Du S, Tiwari-Woodruff S, King J . A role for sex chromosome complement in the female bias in autoimmune disease. J Exp Med. 2008; 205(5):1099-108. PMC: 2373842. DOI: 10.1084/jem.20070850. View

Sinclair A, Berta P, Palmer M, Hawkins J, GRIFFITHS B, Smith M . A gene from the human sex-determining region encodes a protein with homology to a conserved DNA-binding motif. Nature. 1990; 346(6281):240-4. DOI: 10.1038/346240a0. View

Calvari V, Bertini V, De Grandi A, Peverali G, Zuffardi O, Ferguson-Smith M . A new submicroscopic deletion that refines the 9p region for sex reversal. Genomics. 2000; 65(3):203-12. DOI: 10.1006/geno.2000.6160. View

Jordan B, Mohammed M, Ching S, Delot E, Chen X, Dewing P . Up-regulation of WNT-4 signaling and dosage-sensitive sex reversal in humans. Am J Hum Genet. 2001; 68(5):1102-9. PMC: 1226091. DOI: 10.1086/320125. View

Krentz A, Murphy M, Kim S, Cook M, Capel B, Zhu R . The DM domain protein DMRT1 is a dose-sensitive regulator of fetal germ cell proliferation and pluripotency. Proc Natl Acad Sci U S A. 2009; 106(52):22323-8. PMC: 2799724. DOI: 10.1073/pnas.0905431106. View

10.

Courtens W, Wuyts W, Rooms L, Pera S, Wauters J . A subterminal deletion of the long arm of chromosome 10: a clinical report and review. Am J Med Genet A. 2006; 140(4):402-9. DOI: 10.1002/ajmg.a.31053. View

11.

Shirai M, Osugi T, Koga H, Kaji Y, Takimoto E, Komuro I . The Polycomb-group gene Rae28 sustains Nkx2.5/Csx expression and is essential for cardiac morphogenesis. J Clin Invest. 2002; 110(2):177-84. PMC: 151044. DOI: 10.1172/JCI14839. View

12.

Stochholm K, Juul S, Juel K, Naeraa R, Gravholt C . Prevalence, incidence, diagnostic delay, and mortality in Turner syndrome. J Clin Endocrinol Metab. 2006; 91(10):3897-902. DOI: 10.1210/jc.2006-0558. View

13.

Canto P, Soderlund D, Reyes E, Mendez J . Mutations in the desert hedgehog (DHH) gene in patients with 46,XY complete pure gonadal dysgenesis. J Clin Endocrinol Metab. 2004; 89(9):4480-3. DOI: 10.1210/jc.2004-0863. View

14.

Fatica A, Bozzoni I . Long non-coding RNAs: new players in cell differentiation and development. Nat Rev Genet. 2013; 15(1):7-21. DOI: 10.1038/nrg3606. View

15.

Spiller C, Bowles J, Koopman P . Regulation of germ cell meiosis in the fetal ovary. Int J Dev Biol. 2013; 56(10-12):779-87. DOI: 10.1387/ijdb.120142pk. View

16.

Coulam C . Premature gonadal failure. Fertil Steril. 1982; 38(6):645-55. DOI: 10.1016/s0015-0282(16)46688-4. View

17.

Miyamoto Y, Taniguchi H, Hamel F, Silversides D, Viger R . A GATA4/WT1 cooperation regulates transcription of genes required for mammalian sex determination and differentiation. BMC Mol Biol. 2008; 9:44. PMC: 2387164. DOI: 10.1186/1471-2199-9-44. View

18.

Das D, Rahate S, Mehta B, Gawde H, Tamhankar P . Mutation analysis of mitogen activated protein kinase 1 gene in Indian cases of 46,XY disorder of sex development. Indian J Hum Genet. 2014; 19(4):437-42. PMC: 3897139. DOI: 10.4103/0971-6866.124372. View

19.

Mueller S, Temple V, Oh E, Vanryzin C, Williams A, Cornwell B . Early androgen exposure modulates spatial cognition in congenital adrenal hyperplasia (CAH). Psychoneuroendocrinology. 2008; 33(7):973-80. PMC: 2566857. DOI: 10.1016/j.psyneuen.2008.04.005. View

20.

Schmahl J, Kim Y, Colvin J, Ornitz D, Capel B . Fgf9 induces proliferation and nuclear localization of FGFR2 in Sertoli precursors during male sex determination. Development. 2004; 131(15):3627-36. DOI: 10.1242/dev.01239. View