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Review
. 2024 Apr 24:15:1385901.
doi: 10.3389/fendo.2024.1385901. eCollection 2024.

Testicular differentiation in 46,XX DSD: an overview of genetic causes

Maria Tereza Martins Ferrari  1 , Elinaelma Suelane do Nascimento Silva  1 , Mirian Yumie Nishi  1 , Rafael Loch Batista  1 , Berenice Bilharinho Mendonca #  1   2 , Sorahia Domenice #  1
Affiliations
Review

Testicular differentiation in 46,XX DSD: an overview of genetic causes

Maria Tereza Martins Ferrari et al. Front Endocrinol (Lausanne). .

Abstract

In mammals, the development of male or female gonads from fetal bipotential gonads depends on intricate genetic networks. Changes in dosage or temporal expression of sex-determining genes can lead to differences of gonadal development. Two rare conditions are associated with disruptions in ovarian determination, including 46,XX testicular differences in sex development (DSD), in which the 46,XX gonads differentiate into testes, and 46,XX ovotesticular DSD, characterized by the coexistence of ovarian and testicular tissue in the same individual. Several mechanisms have been identified that may contribute to the development of testicular tissue in XX gonads. This includes translocation of SRY to the X chromosome or an autosome. In the absence of SRY, other genes associated with testis development may be overexpressed or there may be a reduction in the activity of pro-ovarian/antitesticular factors. However, it is important to note that a significant number of patients with these DSD conditions have not yet recognized a genetic diagnosis. This finding suggests that there are additional genetic pathways or epigenetic mechanisms that have yet to be identified. The text will provide an overview of the current understanding of the genetic factors contributing to 46,XX DSD, specifically focusing on testicular and ovotesticular DSD conditions. It will summarize the existing knowledge regarding the genetic causes of these differences. Furthermore, it will explore the potential involvement of other factors, such as epigenetic mechanisms, in developing these conditions.

Keywords: 46; XX ovotesticular DSD; XX testicular DSD; differences of sex development (DSD); gonadal development; ovary.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Genes and mechanisms of sex determination. The proliferation of cells from the mesonephros and coelomic epithelium leads to the formation of an undifferentiated and bipotential gonad. This process is regulated by several factors, including GATA4, EMX2, CBX2, LHX9, and WT1. These factors, in turn, regulate NR5A1, SIX1, SIX4, TCF21, and members of the IGF family, leading to the formation of an undifferentiated gonad. The process continues until the fate of the gonad is established, resulting in the formation of either an ovary or a testis. Ovarian differentiation. In the XX fetuses (absence of SRY), the expression of SOX9 remains low and other factors such as NR0B1, FOXL2, WNT4, and RSPO1 become dominant. The upregulation of WNT4 and RSPO1 leads to the activation of the canonical WNT signaling pathway, which in turn upregulates and stabilizes β-catenin. The activation of the WNT/β-catenin pathway plays a crucial role in the differentiation of the female gonad. NR2F2 has a role in maintaining a multipotent state in early supporting gonadal cells, which seems to be necessary for commitment to ovarian development. After birth, FOXL2 continues to suppress male-specific factors, including SOX9 and DMRT1. Testicular differentiation. In XY fetuses, the expression of SRY is triggered by MAP3K4, GATA4, WT1, and NR5A1. The presence of SRY and NR5A1 initiates the expression of SOX9, which leads to the differentiation of pre-Sertoli cells and subsequent Sertoli cells. Other members of the SOX family are also upregulated. SOX9 expression is maintained through positive feedback loops involving FGF9 and PGD2, as well as the regulation from WT1 and NR5A1. The increased expression of SOX9 prevails over NR0B1, FOXL2, WNT4, and RSPO1, promoting testicular differentiation. After birth, DMRT1 suppresses the female-specific factor FOXL2. These interactions between the male and female pathways remain essential throughout adulthood to maintain the gonadal identity.
Figure 2
Figure 2
46,XX Testicular and ovotesticular DSD. Loss of the antagonistic balance of the RSPO1/WNT4/β-catenin pathway and the SRY/SOX9/FGF9 pathway can lead to the development of an abnormal gonad. (A) In XX individuals with Yp translocations and the presence of SRY, testicular differentiation can occur. In 46,XX SRY-negative individuals, testicular development may result from different conditions: overexpression of “pro-testicular” factors such as SOX9, SOX3, SOX10, FGF9, DMRT1, and (B) reduced expression of “pro-ovarian” factors such as RSPO1, WNT4, NR2F2. These changes in gene expression can be caused by an increase in the number of gene copies or their regulatory sequences. Additionally, in particular conditions, factors like WT1 and NR5A1 can also promote testicular development in 46,XX individuals. *Indicates genes associated with 46,XX testicular and ovotesticular DSD in humans.
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The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Grants No. 312543/2021-2 (to SD) and 307571/2021-1 (to BM), and by the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Grants No. 2019/26780-9 (to BM), and by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) (to MF).

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