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PubMed This is a summary of 17 peer-reviewed journal articles Updated
Endocrinology

Signs, Symptoms, and Getting an Accurate Diagnosis

At a Glance

46,XX testicular DSD is diagnosed through karyotype and hormone testing. Symptoms vary by age and SRY gene status. Infants may have atypical genitalia, while adults are often diagnosed during evaluations for infertility (azoospermia) or low testosterone.

The journey to an accurate diagnosis of 46,XX Testicular DSD often begins at one of two very different life stages: shortly after birth or during the transition to adulthood. Because the condition is rare and its signs can be subtle, understanding what to look for and how the diagnosis is confirmed is the first step toward effective management. [1][2]

Common Paths to Diagnosis

1. Childhood Presentation (Common in SRY-Negative)

In many cases, particularly those where the SRY gene is absent (SRY-negative), the condition is discovered in infancy due to atypical genitalia. This might include:

  • Hypospadias: A condition where the opening of the urethra is on the underside of the penis rather than at the tip. [3][4]
  • Cryptorchidism: One or both testicles have not moved down into the scrotum (undescended testicles). [3]
  • Ambiguous Genitalia: The external appearance may not be clearly male or female, leading doctors to perform immediate genetic testing. [3][5]

2. Adulthood Presentation (Common in SRY-Positive)

For individuals who are SRY-positive, the external appearance is typically male, and the condition often goes unnoticed until puberty or later. [6] Discovery often happens during:

  • Infertility Evaluations: This is the most common time for diagnosis in adults. A semen analysis will show azoospermia (a complete absence of sperm). [7][8]
  • Pubertal Concerns: Some adolescents may experience gynecomastia (enlargement of breast tissue) or a delay in reaching pubertal milestones. [9]
  • Small Testicular Volume: During a physical exam, a doctor may notice that the testicles are smaller and firmer than average. [7]

The Hormonal Profile: Understanding the “Signal”

In 46,XX Testicular DSD, the body exhibits a pattern called hypergonadotropic hypogonadism. This is a medical term that describes a communication issue between the brain and the testicles. [7][10]

Hormone Typical Result Why?
Testosterone Low or Low-Normal The testicles (gonads) may struggle to produce enough male hormone for the body’s needs. [7][11]
LH & FSH Elevated (High) The brain senses low testosterone and sends out “loud” signals (Luteinizing Hormone and Follicle-Stimulating Hormone) to try to get the testicles to work harder. [7][12]

In adults, this hormonal profile is a hallmark of primary testicular failure. Because the Y chromosome is missing, the body lacks the AZF (Azoospermia Factor) regions—the “blueprints” required to produce sperm. [12][13]

Differentiating from Klinefelter Syndrome

It is common for 46,XX Testicular DSD to be confused with Klinefelter syndrome, as both can involve small testicles, infertility, and low testosterone. However, they are fundamentally different genetic conditions: [7][14]

  • Klinefelter Syndrome (47,XXY): These individuals have 47 chromosomes, including two X chromosomes and one Y chromosome. The presence of the Y chromosome is typical. [12]
  • 46,XX Testicular DSD: These individuals have 46 chromosomes, with two X chromosomes and no Y chromosome. Instead, the “male switch” (SRY gene) has moved to an X chromosome or a different gene has mistakenly turned on. [15][16]

A simple karyotype (chromosome map) is the definitive tool doctors use to tell these two conditions apart. [17][5] Once the 46,XX karyotype is confirmed, additional genetic tests are used to determine if the cause is SRY-positive or SRY-negative. [15][13]

Common questions in this guide

How is 46,XX testicular DSD diagnosed?
Diagnosis typically involves a karyotype test to map the chromosomes, along with blood tests to check hormone levels like testosterone, LH, and FSH. Doctors will also perform genetic testing to check for the presence or absence of the SRY gene.
What are the common signs of 46,XX DSD in infants?
Infants with SRY-negative 46,XX DSD often present with atypical genitalia. Common signs include undescended testicles, a urethral opening on the underside of the penis (hypospadias), or genitalia that are not clearly male or female.
Why is 46,XX DSD often diagnosed during adulthood instead of childhood?
Individuals who are SRY-positive typically have a standard male appearance, meaning the condition often goes unnoticed in childhood. It is most frequently discovered during adulthood when a patient undergoes evaluation for infertility or low testosterone.
How is 46,XX DSD different from Klinefelter syndrome?
While both conditions can cause small testicles, low testosterone, and infertility, they have different genetic causes. People with Klinefelter syndrome have 47 chromosomes (47,XXY), whereas individuals with 46,XX DSD have 46 chromosomes (two X chromosomes and no Y chromosome).

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.How do my (or my child’s) hormone levels compare to typical ranges for their age?
  2. 2.Can you explain the difference between our karyotype and the karyotype of someone with Klinefelter syndrome?
  3. 3.If we are SRY-negative, what specific childhood signs should we have addressed, and what should we monitor now?
  4. 4.What is the current size and health of the testicular tissue, and does it require a baseline ultrasound?
  5. 5.Are there any internal structures, like a persistent Müllerian duct, that we need to be aware of?

Questions For You

Tap a prompt to share your answer — we'll use it plus this page's context to start a tailored conversation.

References

References (17)
  1. 1

    Society for Endocrinology UK Guidance on the initial evaluation of a suspected difference or disorder of sex development (Revised 2021).

    Ahmed SF, Achermann J, Alderson J, et al.

    Clinical endocrinology 2021; (95(6)):818-840 doi:10.1111/cen.14528.

    PMID: 34031907
  2. 2

    Differences of Sex Development: Current Issues and Controversies.

    Johnson EK, Whitehead J, Cheng EY

    The Urologic clinics of North America 2023; (50(3)):433-446 doi:10.1016/j.ucl.2023.04.010.

    PMID: 37385705
  3. 3

    Retrospective analysis of children with 46,XX testicular/ovotesticular DSD: a 10-year single-center experience.

    Gong Y, Yin X, Xu J, et al.

    Frontiers in endocrinology 2025; (16()):1571467 doi:10.3389/fendo.2025.1571467.

    PMID: 40487758
  4. 4

    Endocrine Management of Ovotesticular DSD, an Index Case and Review of the Literature.

    Kilberg MJ, McLoughlin M, Pyle LC, Vogiatzi MG

    Pediatric endocrinology reviews : PER 2019; (17(2)):110-116 doi:10.17458/per.vol17.2019.kmv.endocrineovotesticulardsd.

    PMID: 31763803
  5. 5

    Molecular cytogenetic analysis and genetic counseling: a case report of eight 46,XX males and a literature review.

    Yue F, Zhang H, Xi Q, et al.

    Molecular cytogenetics 2019; (12()):44 doi:10.1186/s13039-019-0456-y.

    PMID: 31700544
  6. 6

    The importance of genetic research in cases of severe male factor infertility: A case of 46,XX testicular disorder of sex development.

    Faleiro D, Iser B, Silva AAD, Höher MA

    JBRA assisted reproduction 2022; (26(3)):559-562 doi:10.5935/1518-0557.20210092.

    PMID: 34978171
  7. 7

    46,XX Testicular Disorder of Sex Development (DSD) Presenting With Male Hypogonadism.

    Chin RT, Mok SF

    JCEM case reports 2025; (3(2)):luae237 doi:10.1210/jcemcr/luae237.

    PMID: 39906899
  8. 8

    SRY-Positive 46, XX Testicular Disorder of Sexual Development With Leydig Cell Tumor.

    Osaka A, Ide H, Matsuoka K, et al.

    American journal of men's health 2020; (14(5)):1557988320970071 doi:10.1177/1557988320970071.

    PMID: 33131361
  9. 9

    Ovotesticular disorder of sex development presenting as gynecomastia in a phenotypic male adolescent: a case report and literature insights.

    Gaur BK, Gupta S

    Hormone molecular biology and clinical investigation 2025; (46(4)):183-187 doi:10.1515/hmbci-2025-0061.

    PMID: 41312604
  10. 10

    Ten cases with 46,XX testicular disorder of sex development: single center experience.

    Akinsal EC, Baydilli N, Demirtas A, et al.

    International braz j urol : official journal of the Brazilian Society of Urology 2017; (43(4)):770-775 doi:10.1590/S1677-5538.IBJU.2016.0505.

    PMID: 28379671
  11. 11

    A Case Reported With 46, XX Testicular Disorders Of Sexual Development And Its Possible Association With Dysembryoplastic Neuroepithelial Tumour.

    Furqan S, Waleed M, Maan SA, et al.

    JPMA. The Journal of the Pakistan Medical Association 2023; (73(8)):1712-1715 doi:10.47391/JPMA.6451.

    PMID: 37697768
  12. 12

    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
  13. 13

    A 46,XX Karyotype in Men with Infertility: Two New Cases and Review of the Literature.

    Kouvidi E, Tsimela H, Lazaros L, et al.

    Journal of human reproductive sciences 2022; (15(3)):307-317 doi:10.4103/jhrs.jhrs_100_22.

    PMID: 36341017
  14. 14

    [Analysis of clinical features and related genes variation in five patients with 46, XX male syndrome].

    Qin XY, Dong WK, Wang W, et al.

    Zhonghua er ke za zhi = Chinese journal of pediatrics 2016; (54(11)):840-843 doi:10.3760/cma.j.issn.0578-1310.2016.11.010.

    PMID: 27806792
  15. 15

    [Genetic and clinical characteristics of 46,XX testicular disorders of sex development].

    Ye QL, Fang JZ, Yang XY

    Zhonghua nan ke xue = National journal of andrology 2024; (30(2)):118-122.

    PMID: 39177343
  16. 16

    A Follow-Up from Infancy to Puberty in a Japanese Male with SRY-Negative 46,XX Testicular Disorder of Sex Development Carrying a p.Arg92Trp Mutation in NR5A1.

    Saito-Hakoda A, Kanno J, Suzuki D, et al.

    Sexual development : genetics, molecular biology, evolution, endocrinology, embryology, and pathology of sex determination and differentiation 2019; (13(2)):60-66 doi:10.1159/000496777.

    PMID: 30739115
  17. 17

    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

This page explains signs, symptoms, and diagnostic testing for 46,XX testicular DSD for educational purposes only. Always consult a pediatric endocrinologist, urologist, or geneticist for an accurate diagnosis and treatment plan.

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