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Disease Profile

46, XY disorders of sexual development

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.

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Europe Estimated

Age of onset

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ICD-10

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Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease.

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Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype.

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X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

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X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder.

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Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

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Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

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Not applicable

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Other names (AKA)

46, XY DSD; 46, XY female; XY female

Summary

A 46, XY disorder of sex development (DSD) is a condition in which an individual with one X chromosome and one Y chromosome in each cell, the pattern normally found in males, have genitalia that is not clearly male or female. Infants with this condition tend to have penoscrotal hypospadias, abnormal development of the testes, and reduced to no sperm production. Some individuals with 46, XY DSD have fully to underdeveloped female reproductive organs (e.g., uterus and fallopian tubes), while others do not.[1] People with with 46, XY DSD may be raised as males or females. Treatment involves surgery and hormone replacement therapy.[1] People with 46, XY DSD are at an increased risk for gonadal tumors and benefit from regular surveillance or surgery to remove abnormally developed gonads.[1]

Cause

Typical sex development requires multiple genes, hormones, and hormone receptors to work in concert. 46, XY disorders of sex development (DSD) are caused by either disorders of testicular development or disorders involving the male hormone, androgen. Conditions which fall within the spectrum of 46, XY DSD, include:[2]

Diagnosis

People with 46, XY disorders of sex development (DSD) benefit from having a multidisciplinary team of healthcare providers. Initial work-up involves taking a family history, pregnancy history, and a physical exam. This information, combined with chromosome test results, guides additional testing. Additional tests may include hormone measurements (e.g., LH, FSH, inhibin B, T, DHT, AMH, A, and DHEAS), imaging (e.g., ultrasound), biopsy, and genetic testing.[2]

Treatment

As you can read in our GARD webpages, the 46, XY disorders are a group of different conditions including 46, XY complete gonadal dysgenesis (Swyer syndrome), 46 XY, partial gonadal dysgenesis (Denys-Drash syndrome, Frasier syndrome), ovotesticular DSD, testicular regression syndrome (vanishing testes syndrome) , Leydig cell aplaisa/hypoplasia, testosterone biosynthesis defects, POR gene abnormality, persistent Mullerian duct syndrome, 5 alpha-reductase type 2 deficiency and complete and partial androgen insensitivity syndromes.

Therefore, several biologic factors such as genetic and hormonal influences contribute to gender identity, gender role behavior, and sexual orientation in humans, but this relationship is also modified by psychological, social, and cultural factors. Sex assignment of children with ambiguous genitalia remains a difficult decision for the families involved and subject to controversial discussion among professionals and self-help groups. Every case is unique and it is suggested that gender assignment should be based on clinical experience, study of the literature, and interviews with affected individuals.[3]

In a large study recently published about women with complete androgen insensitivity syndrome (CAIS) it was found that they perceive themselves as highly feminine throughout development. Additionally, CAIS women largely report their sexual attraction, fantasies, and experiences were best described as female heterosexual. CAIS women unanimously reported satisfaction with being a woman (100%).[4] Another study with 46, XY individuals with androgen secreting testicular tissue and 46, XX individuals with congenital adrenal hyperplasia concluded that androgen exposure may have some effect in higher brain function and the perception of the gender. The authors suggested that gender counseling should be part of the routine management for these patients to make sure that they are happy with being females.[5]

The World Health Organization provides relevant information about gender and genetics in the following links: Genetic Components of Sex and Gender
Gender Assignment of Intersex Infants and Children
Legal Definitions of Gender

Organizations

Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

Organizations Supporting this Disease

    Learn more

    These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

    Where to Start

    • MedlinePlus was designed by the National Library of Medicine to help you research your health questions, and it provides more information about this topic.

      In-Depth Information

      • GeneReviews provides current, expert-authored, peer-reviewed, full-text articles describing the application of genetic testing to the diagnosis, management, and genetic counseling of patients with specific inherited conditions.
      • Medscape Reference provides information on this topic. You may need to register to view the medical textbook, but registration is free.
      • MeSH® (Medical Subject Headings) is a terminology tool used by the National Library of Medicine. Click on the link to view information on this topic.
      • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
      • The Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine. 
      • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
      • PubMed is a searchable database of medical literature and lists journal articles that discuss 46, XY disorders of sexual development. Click on the link to view a sample search on this topic.

        Selected Full-Text Journal Articles

          References

          1. Ostrer H. 46,XY Disorder of Sex Development and 46,XY Complete Gonadal Dysgenesis. In: Pagon RA, Bird TD, Dolan CR, Stephens K, Adam MP, editors. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle: 1993-2008 May 21 [updated 2009 Sep 15]. ;
          2. Gönül Öçal . Current Concepts in Disorders of Sexual Development. Clin Res Pediatr Endocrinol. 2011 September; 3(3):105–114; https://www.ncbi.nlm.nih.gov/pubmed?term=PMC3184510. Accessed 10/22/2012.
          3. Thyen U, Richter-Appelt H, Wiesemann C, Holterhus PM & Hiort O. Deciding on gender in children with intersex conditions: considerations and controversies. Treat Endocrinol. 2005; 4(1):1-8. https://www.ncbi.nlm.nih.gov/pubmed/15649096. Accessed 7/7/2015.
          4. Wisniewski AB & cols. Complete Androgen Insensitivity Syndrome: Long-Term Medical, Surgical, and Psychosexual Outcome. JCEM. July 2, 2013; 85:8. https://www.ncbi.nlm.nih.gov/pubmed/10946863. Accessed 7/7/2015.
          5. Ercan O, Kutlug S, Uysal O, Alikasifoglu M & Inceoglu D. Gender identity and gender role in DSD patients raised as females: a preliminary outcome study. Front Endocrinol. July 15, 2013; 4:86. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3711069/. Accessed 7/7/2015.

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