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PubMed This is a summary of 16 peer-reviewed journal articles Updated
Genetics

The Biology and Diagnosis of 46,XX Ovotesticular DSD

At a Glance

46,XX ovotesticular DSD occurs when specific genetic switches, like SRY or SOX9, cause both ovarian and testicular tissue (an ovotestis) to develop. Diagnosis involves genetic testing like chromosomal microarrays and gonadal biopsies to evaluate the tissue and guide medical care.

The biological development of sex is often compared to a series of genetic switches. While most embryos with 46,XX chromosomes (typically female) follow a pathway toward developing ovaries, sometimes a biological “flip” occurs that directs the body to develop testicular tissue as well [1][2].

The Genetic Switches

In early development, all embryos have the potential to develop either way. Specific genes act as signals to choose a path:

  • The SRY Switch: The SRY gene (Sex-determining Region Y) is normally found on the Y chromosome and acts as the primary “on” switch for making testes [3].
    • SRY-Positive: In some cases, a small piece of the Y chromosome containing the SRY gene accidentally “jumps” or translocates onto an X chromosome. While this usually leads to typical male development (46,XX testicular DSD), in rare cases—often involving mosaicism (a mix of different cell types)—it can lead to ovotesticular DSD [3][4].
    • SRY-Negative: This is the vast majority of 46,XX ovotesticular DSD cases. Here, the SRY gene is missing, but other “downstream” switches like SOX9 or SOX3 get stuck in the “on” position—often due to a genetic duplication—tricking the body into developing testicular tissue without the SRY gene [1][2][5].
  • The Ovarian Protectors: Genes like RSPO1 and WNT4 normally act as “guards” for the ovarian pathway, blocking the male switches. If these guards are mutated or missing, the male pathway can proceed even in a 46,XX embryo [6][7].

The Diagnostic Roadmap

To understand exactly how the body is developing, doctors use a specific set of tools to identify which “switches” are involved:

  1. Karyotype: A high-level map of the chromosomes to confirm the 46,XX pattern and check for any large missing or extra pieces [8][9].
  2. Chromosomal Microarray (CMA): A much more detailed “zoom-in” on the DNA. This test can find tiny duplications (like extra copies of SOX9) that a regular karyotype would miss [8][10].
  3. Gonadal Biopsy: If the diagnosis is unclear, a surgeon may take a tiny sample of the gonads to examine under a microscope. This is how the presence of an ovotestis is confirmed [11][12].

Understanding the Pathology Report

If a biopsy is performed, the results will come in a pathology report. The key term you will see is ovotestis. This is not a “third type” of organ, but rather a single gonad that contains both:

  • Ovarian Tissue: Indicated by the presence of follicles (which contain eggs) [11][12].
  • Testicular Tissue: Indicated by seminiferous tubules (which would normally produce sperm) and Sertoli/Leydig cells [11][12].

When reviewing your results, ask your medical team whether these tissues are “well-organized” or “dysgenetic” (poorly formed). Dysgenetic tissue often does not produce useful hormones and carries a different risk profile for malignancy, meaning it may need to be surgically removed rather than preserved [13][14]. It is important to note that SRY-negative cases often have a lower risk of germ cell tumors (cancer), but the pathology report helps the team create a specific, individualized monitoring plan [15][16].

Common questions in this guide

What does it mean if my 46,XX ovotesticular DSD is SRY-negative?
Being SRY-negative means the SRY gene is missing, but other genetic pathways like SOX9 or SOX3 were activated during embryonic development. This is the most common cause of 46,XX ovotesticular DSD and is often associated with a lower risk of germ cell tumors.
What does 'ovotestis' mean on my pathology report?
An ovotestis is a single gonad that contains both ovarian tissue with egg-containing follicles and testicular tissue with seminiferous tubules. A biopsy is typically used to confirm the presence of this specific tissue structure.
Why does dysgenetic tissue sometimes need to be surgically removed?
Dysgenetic, or poorly formed, gonadal tissue often does not produce useful hormones and can carry an increased risk for developing cancer over time. Your medical team may recommend surgical removal of this tissue to manage long-term health risks.
How is 46,XX ovotesticular DSD diagnosed?
Doctors use a combination of tools to diagnose this condition. This usually includes a karyotype to check overall chromosomes, a chromosomal microarray to find tiny genetic duplications, and sometimes a gonadal biopsy to examine the tissue under a microscope.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.Was the genetic testing SRY-positive or SRY-negative?
  2. 2.Did the microarray identify a duplication of the SOX9 gene or another 'switch'?
  3. 3.Are there terms in the reports I don't understand that I should ask the genetic counselor to explain?
  4. 4.Are the tissues described as 'well-organized' or 'dysgenetic', and how does that impact function?
  5. 5.Does the presence of both tissue types change the way we monitor for cancer risks?

Questions For You

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References

References (16)
  1. 1

    SRY-negative 46,XX testicular/ovotesticular DSD: Long-term outcomes and early blockade of gonadotropic axis.

    Lambert S, Peycelon M, Samara-Boustani D, et al.

    Clinical endocrinology 2021; (94(4)):667-676 doi:10.1111/cen.14389.

    PMID: 33296530
  2. 2

    The 46, XX Ovotesticular Disorder of Sex Development With Xq27.1q27.2 Duplication Involving the SOX3 Gene: A Rare Case Report and Literature Review.

    Zhuang J, Chen C, Li J, et al.

    Frontiers in pediatrics 2021; (9()):682846 doi:10.3389/fped.2021.682846.

    PMID: 34178900
  3. 3

    Sex-determining Region of Y-gene Translocation and 46,XX Testicular Disorders of Sex Development: Cytogenetic and Molecular Insights into Male Infertility.

    Priya PK, Patel H, Dalal D, Shah A

    Journal of human reproductive sciences 2025; (18(4)):254-258 doi:10.4103/jhrs.jhrs_167_25.

    PMID: 41560884
  4. 4

    46, XX Male Disorder of Sexual Development.

    Flannery C, Agha A

    Irish medical journal 2021; (114(1)):243.

    PMID: 37556122
  5. 5

    Duplication of SOX9 associated with 46,XX ovotesticular disorder of sex development.

    López-Hernández B, Méndez JP, Coral-Vázquez RM, et al.

    Reproductive biomedicine online 2018; (37(1)):107-112 doi:10.1016/j.rbmo.2018.03.017.

    PMID: 29673731
  6. 6

    The genetic make-up of ovarian development and function: the focus on the transcription factor FOXL2.

    Elzaiat M, Todeschini AL, Caburet S, Veitia RA

    Clinical genetics 2017; (91(2)):173-182 doi:10.1111/cge.12862.

    PMID: 27604691
  7. 7

    Novel RSPO1 mutation causing 46,XX testicular disorder of sex development with palmoplantar keratoderma: A review of literature and expansion of clinical phenotype.

    Tallapaka K, Venugopal V, Dalal A, Aggarwal S

    American journal of medical genetics. Part A 2018; (176(4)):1006-1010 doi:10.1002/ajmg.a.38646.

    PMID: 29575617
  8. 8

    Phenotypes Linked to Duplication Upstream of SOX9: New Insights Into Presentation and Diagnosis.

    Unal E, Tekmenuray-Unal A, Cayir A, et al.

    The Journal of clinical endocrinology and metabolism 2025; (110(10)):e3482-e3488 doi:10.1210/clinem/dgaf020.

    PMID: 39812180
  9. 9

    45,X/46,XX at amniocentesis associated with cytogenetic discrepancy between cultured amniocytes and uncultured amniocytes and in different amniocenteses and a favorable fetal outcome with a normal karyotype at birth.

    Chen CP, Wu FT, Pan YT, et al.

    Taiwanese journal of obstetrics & gynecology 2023; (62(4)):586-587 doi:10.1016/j.tjog.2023.05.005.

    PMID: 37407200
  10. 10

    A Duplication Upstream of SOX9 Associated with SRY Negative 46,XX Ovotesticular Disorder of Sex Development: A Case Report

    Mengen E, Kayhan G, Kocaay P, Uçaktürk SA

    Journal of clinical research in pediatric endocrinology 2020; (12(3)):308-314 doi:10.4274/jcrpe.galenos.2019.2019.0101.

    PMID: 31476840
  11. 11

    Ambiguous genitalia: A rare case report.

    Agarwal PK, Ali M, Ranjan R, Pandey A

    Indian journal of pathology & microbiology 2016; (59(1)):72-4 doi:10.4103/0377-4929.178229.

    PMID: 26960641
  12. 12

    46 XY Ovotesticular Disorder: A Rare Case Report with Review of Literature.

    Meenal B, Meenakshi G, Pratibha S, et al.

    Gynecology and minimally invasive therapy 2021; (10(3)):171-173 doi:10.4103/GMIT.GMIT_107_19.

    PMID: 34485063
  13. 13

    Disorders of sexual differentiation: Report of two rare cases.

    Correya MA, Babu R, Archana B, Ravirajendiran S

    Indian journal of pathology & microbiology 2021; (64(2)):390-393 doi:10.4103/IJPM.IJPM_358_20.

    PMID: 33851643
  14. 14

    45,X/46,XY ovotesticular disorder of sex development revisited: undifferentiated gonadal tissue may be mistaken as ovarian tissue.

    Andrade JGR, Andrade LALA, Guerra-Junior G, Maciel-Guerra AT

    Journal of pediatric endocrinology & metabolism : JPEM 2017; (30(8)):899-904.

    PMID: 28742519
  15. 15

    Gonadal Genetics and Germ Cell Tumor Risk in SRY-Negative 46,XX Testicular/Ovotesticular Disorders of Sex Development.

    Yang H, Tian H, Wu D, et al.

    Hormone research in paediatrics 2025; 1-9 doi:10.1159/000548934.

    PMID: 41108712
  16. 16

    An Unusual and Late Presentation of 46, XY Ovotesticular Difference of Sex Development.

    Elsa Mathew U, Arun CS, George V, et al.

    JCEM case reports 2025; (3(8)):luaf115 doi:10.1210/jcemcr/luaf115.

    PMID: 40520042

This information about the genetics and pathology of 46,XX ovotesticular DSD is for educational purposes only. Always consult your genetic counselor or medical team to interpret your specific diagnostic reports.

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