46,XY-DSD - Endo-ERN

Disorders (or differences) of Sex Development (DSD) is an umbrella term for a group of rare conditions affecting the reproductive system, in which development of chromosomal, gonadal or anatomical sex is atypical. There are many different types of DSD. They are categorized into three main categories: 46 XY DSD, 46 XX DSD and chromosomal DSD, based on the person’s sex chromosomes. This nomenclature was chosen to allow for a biological pathway driven approach to the underlying diagnosis.

46 XY DSD conditions are caused by reduced testosterone production, decreased conversion of testosterone to dihydrotestosterone or impaired peripheral testosterone or dihydrotestosterone action. Intrauterine virilization is often incomplete which can result in ambiguous or ‘female’ appearing external genitalia.

Some individuals with 46, XY DSD have a complete absence of testosterone and AMH production resulting in female appearing external genitalia and reproductive organs (e.g., uterus and fallopian tubes), while others do not.[1] People with 46, XY DSD may be raised as males or females or in a non-binary fashion. Treatment involves surgery and hormone replacement therapy, but here – as in all forms of DSD – a psychosocial management and counselling is equally important.[1] In some 46, XY DSD conditions there is an increased risk for gonadal tumors and benefit from regular surveillance or surgery to remove atypically developed gonads.

There are numerous causes of 46, XY DSD. One frequent possible cause is androgen insensitivity syndrome (AIS).

AIS is a condition that affects sex development before birth and during puberty. Individuals with this condition have a 46, XY karyotype and the testes development is apparently typical. They produce testosterone and AMH but due to a functional deficit in the androgen receptor the produced testosterone cannot act properly. Androgen insensitivity syndrome is caused by mutations in the AR gene and is inherited in an X-linked recessive pattern.

There are different types:

complete androgen insensitivity syndrome (CAIS)
partial androgen insensitivity syndrome (PAIS)
mild androgen insensitivity syndrome (MAIS)

CAIS: In complete AIS there is no virilisation of the external genitalia and affected persons have complete female appearing external genitalia, but in contrast have no uterus due to unhindered action of AMH, and have testes mostly located in the abdomen or the groin. CAIS is not usually obvious at birth because affected babies are unequivocally appearing female, including a vagina and labial folds on either side of the vaginal opening. They may have undescended testicles, and this will usually go unnoticed unless they cause an inguinal hernia (where they push through a weakness in the surrounding tissue). The first signs usually begin at puberty, which starts at around the age of 11 or 12. When a girl with CAIS reaches puberty, she will develop breasts and have growth spurts as normal although she may end up slightly taller than usual for a girl. However, she will not start having periods and will develop little or no pubic and underarm hair. Girls with CAIS do not have a womb or ovaries, so are unable to get pregnant. Their vagina will also be shorter than normal, which may make some sexual acts difficult.

When some residual activity of testosterone as in partial AIS (PAIS) is present, individuals ware born with variable degree of ambiguous genitalia. The development of children with PAIS can vary. In many cases, the ambiguous genitalia at birth are the first sign and affected babies may have an enlarged clitoris (the sexual organ that allows women to have an orgasm), partially undescended testicles or hypospadias – where the hole through which urine passes out of the body is on the underside of the penis, rather than at the end.

In children with PAIS raised as boys, the penis may be small throughout life and they may develop some breast tissue at puberty. Some children with PAIS are raised as girls. Like those with CAIS, people with PAIS do not have a womb or ovaries and will be infertile. If these people with PAIS will stay in the female sex, sometimes they will require a vaginal construction if they want to have penetrative sex.

MAIS is a condition that results in a mild impairment of the cell’s ability to respond to androgens. The degree of impairment is sufficient to impair spermatogenesis and / or the development of secondary sexual characteristics at puberty in males but does not affect genital differentiation or development. Female genital and sexual development are not significantly affected by the insensitivity to androgens; as such, MAIS is only diagnosed in males. The clinical phenotype associated with MAIS is a normal male habitus with mild spermatogenic defect and / or reduced secondary terminal hair.

Other conditions, which fall also within the spectrum of 46, XY DSD, include 5 alpha-reductase type 2 deficiency, Denys-Drash syndrome, T biosynthesis defects, Ovotesticular DSD, Persistent Müllerian duct syndrome, Leydig cell aplaisa/hypoplasia.

Individuals with 46, XY disorders of sex development (DSD) should be evaluated and followed by multidisciplinary team of healthcare providers including mental health professionals who are experienced in the field of DSD. 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 include hormone measurements (e.g., LH, FSH, inhibin B, T, DHT, AMH, A, and DHEAS), imaging (e.g., ultrasound), and genetic testing.

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(Source references: NIH GARD, NHS, Orphanet, NORD, DSD-Life, website patient organisations)

Information on the rare disease

Further links:

https://www.radboudumc.nl/expertisecentra/dsd

https://www.dsd-life.eu/about-dsd-life

https://rarediseases.info.nih.gov/diseases/8538/46-xy-disorders-of-sexual-development

Recommendations/information for school, travel, peer consulting etc.

Literature recommendations in German:
Ulla Fröhling, „Leben zwischen den Geschlechtern – Intersexualität: Erfahrungen in einem Tabu-Bereich“, Ch. Links Verlag 2003.
Claudia Lang, „Intersexualität – Menschen zwischen den Geschlechtern“, Campus Verlag 2006.
„Jill ist anders“– Ein Kinderbuch zur Intergeschlechtlichkeit von Ursula Rosen.

Literature recommendations in English:
Be Who You Are by Todd Parr
My Body is Me! By Rachel Rooney
Pipo and Pepo_GB.pdf (CAIS_PAIS)

Literature recommendations in Spanish:
El cuento de Pipo y Pepo (CAIS_PAIS)

Cuento_pipoypepo_ca.pdf (CAIS_PAIS)

Literature recommendations in French:
Cuento_pipoypepo_fr.pdf (CAIS_PAIS)

Booklist:

Medienkiste | Intergeschlechtliche Menschen e.V. (im-ev.de)_DE

Children’s books: DSD Families_GB

VIM Literaturliste (proserver1.at)

Libros – GrApSIA

AIS e DSD nei media – AISIA OdV_IT

Peer consulting:

Germany, Intergeschlechtliche Menschen e.V.