Disorders of sex development

Disorders of sex development (DSDs), also known as differences in sex development, diverse sex development and variations in sex characteristics (VSC),[2] are medical conditions involving the reproductive system. More specifically, these terms refer to "congenital conditions in which development of chromosomal, gonadal, or anatomical sex is atypical."[3]

Disorders of sex development
Other namesDisorders of sex differentiation, differences of sex development[1]
SpecialtyMedical genetics

The term has been controversial, and research has shown that affected people experience a negative impact, with the terminology impacting choice and utilization of health care providers.[4] The World Health Organization and many medical journals still reference DSDs as intersex traits or conditions.[5] The Council of Europe[6] and Inter-American Commission on Human Rights[7] have called for a review of medical classifications that unnecessarily medicalize intersex traits.[6][7][8]


DSDs are medical conditions involving the way the reproductive system develops from infancy (and before birth) through young adulthood. There are several types of DSDs and their effect on the external and internal reproductive organs varies greatly.

A frequently-used social and medical adjective for people with DSDs is "intersex".[9] Parents with DSD children and clinicians involved in DSD treatment usually try to make clear distinctions between biological sex, social gender, and sexual orientation. This helps reduce confusion about the differences between being intersex, being transgender, and being gay/lesbian.

The most common DSD is congenital adrenal hyperplasia (CAH), which results in a person with female (XX) chromosomes having genitals that look somewhat masculine. In mild cases, CAH results in a slightly enlarged clitoris, while in more severe cases it can be difficult to decide on observation whether a baby is male or female (ambiguous genitalia). CAH is caused by a problem with the adrenal glands and is usually treated by taking a daily medication to replace or supplement the missing adrenal hormones. (When this adrenal problem occurs in people with male (XY) chromosomes, the result is over-masculinization and premature puberty).

Another common DSD is androgen insensitivity syndrome (AIS), also known as "testicular feminising syndrome" in which a person with male (XY) chromosomes does not respond to testosterone in the usual way. This results in a body that to some degree has a feminine appearance. In complete androgen insensitivity syndrome (CAIS) the result is a totally feminine appearance, including typical female breast development. Consequently, most young women with CAIS are unaware of their condition until the early teen years when they fail to menstruate. In the milder form, called partial androgen insensitivity syndrome (PAIS), the genitals can vary from mostly female to almost completely male. Some people with PAIS think of themselves as women or girls, others regard themselves as men or boys, and some consider themselves nonbinary.

One of the more uncommon DSDs is 5-alpha-reductase deficiency (5ARD). It is caused by a shortage early in life of an enzyme that converts testosterone into DHT. DHT is required for the development of external male genitalia. Therefore, in this condition, a person with male (XY) chromosomes has a body that appears female before puberty. After puberty begins, other testosterone-activating enzymes become available and the body soon takes on a masculine appearance, with the scrotum and penis usually reaching typical or nearly-typical size. If 5ARD is diagnosed at a young age, the child is often raised as a boy (a 1996 Brazilian study suggested that the majority of adults with this condition consider themselves men[10] but this has been questioned in some more recent research).[citation needed]

In addition to CAH, AIS and 5ARD there are several rarer types of DSDs, and in some cases, it is not possible to make a clear diagnosis of the underlying condition.

Genital anatomyEdit

The Quigley scale is a method for describing genital development in AIS.

The penis (males) and clitoris (females) have a mutual origin, both arising from an embryonic structure called the primordial phallus. In typical males, the urethra is located at the tip of the penis, while in typical females the urethra is located below the base of the clitoris. It is also possible also to have a urethral opening located along the shaft; this condition is known as hypospadias.

Open-minded parenting, appropriate and conservative medical intervention, and age-appropriate child involvement in the treatment plan contribute greatly to successful outcomes for the entire range of DSDs.[11]


  • 47,XXY females - There are cases of 47,XXY females; in some cases SRY or androgen receptor abnormalities are detected.[12]
  • 5α-reductase deficiency (also known as 5-ARD) - An autosomal recessive condition caused by a mutation of the 5-alpha reductase type 2 gene. It only affects people with Y chromosomes, namely genetic males. People with this condition are fertile, with the ability to father children, but may be raised as females due to ambiguous or feminized genitalia.
  • 17β-Hydroxysteroid dehydrogenase deficiency – A condition characterized by impaired androgen and estrogen synthesis in males and females, respectively. Results in pseudohermaphroditism/undervirilization in males and in excessive virilization of adult females.
  • Androgen insensitivity syndrome (also known as AIS) – A condition which affects a genetic male's virilization. A person with androgen insensitivity syndrome produces androgens and testosterone but their body does not recognize it, either partially or completely. Mild androgen insensitivity syndrome generally causes no developmental issues and people with this form are raised as males. Partial androgen insensitivity syndrome results in ambiguous genitalia and there is no consensus regarding whether to raise a child with this form as male or female. Complete androgen insensitivity syndrome causes a genetic male to have a vagina (often incompletely developed, nearly always blind-ending), breasts, and a clitoris and people with this form are raised as females.
  • Aphallia – A rare occurrence where a male is born without a penis or where a female is born without a clitoris. As of 2005, only 75 cases of aphallia have been documented.[13] It should not be confused with intentional or accidental amputation of the genitalia.
  • Aromatase deficiency – A disorder in which, in females, is characterized by androgen excess and estrogen deficiency, and can result in inappropriate virilization, though without pseudohermaphroditism (i.e., genitals are phenotypically appropriate) (with the exception of the possible incidence of clitoromegaly). Aromatase deficiency can also be caused by mutations in P450 oxidoreductase gene.[14]
  • Aromatase excess syndrome (also known as familial hyperestrogenism) - A condition that causes excessive estrogen production, resulting in feminization without pseudohermaphroditism (i.e., male genitalia at birth and female secondary sexual characteristics at puberty) in males and hyperfeminization in females.
  • Campomelic dysplasia – a condition caused by de novo autosomal dominant mutations in the SOX9 gene, causing bowing of the limbs, sex reversal in around two thirds of 46,XY males (but not in 46,XX females), and respiratory insufficiency. While in roughly 95% of cases, death occurs in the neonatal period due to respiratory distress, those that live past infancy typically survive to become adults.
  • Clitoromegaly – A clitoris that is considered larger than average. While clitoromegaly may be a symptom of an intersex condition, it may also be considered a normal variation in clitoris size. Clitoromegaly causes no health issues. Surgical reduction of the clitoris or its complete removal may be performed to normalize the appearance of the genitalia. While female genital mutilation is outlawed in many countries, reduction or the removal of the clitoris in cases of clitoromegaly are generally exempt, despite the fact that it is a nontherapeutic and sexually damaging surgery. Clitoromegaly may also be caused by females using testosterone or anabolic steroids for purposes related to female to male gender transition or bodybuilding.
  • Combined 17α-hydroxylase/17,20-lyase deficiency – A condition in which presents as a combination of the symptoms of congenital adrenal hyperplasia and isolated 17,20-lyase deficiency. See those two conditions for more information.
  • Complete androgen insensitivity syndrome (also known as CAIS) – A condition which completely affects a genetic male's ability to recognize androgens. It is considered a form of androgen insensitivity syndrome and is the most severe form. People with complete androgen insensitivity are raised as females and usually do not discover they are genetic males until they experience amenorrhoea in their late teens or they need medical intervention due to a hernia caused by their undescended testes. Complete androgen insensitivity syndrome results in a genetic male having a vagina, clitoris, and breasts which are capable of breastfeeding. However, they will not have ovaries or a uterus. Because they do not have ovaries or sufficiently developed testicles, people with complete androgen insensitivity syndrome are infertile.
  • Congenital adrenal hyperplasia (also known as CAH) – A condition that causes excessive androgen production, which causes excessive virilization. It is most problematic in genetic females, where severe virilization can result in her having vaginal agenesis (absence of vagina) and a functional penis which is capable of penetrative intercourse. Females with this condition are usually fertile, with the ability to become pregnant and give birth. The salt-wasting variety of this condition is fatal in infants if left untreated.
  • De la Chapelle syndrome (also known as XX male syndrome) – a condition where a genetically female 46,XX individual is phenotypically male, usually caused by atypical chromosomal crossover of the Y chromosome's SRY gene. XX males are shorter and weigh less than XY males, may have genital ambiguities, usually have small testes, and are universally sterile.[15]
  • Denys–Drash syndrome and the related Frasier syndrome - similar rare conditions arising from de novo autosomal dominant mutations in the WT1 gene, causing symptoms ranging from undervirilization to complete sex reversal with persistent Müllerian ducts in affected 46,XY males (but not in 46,XX females). The disorders are invariably fatal before the age of 15, causing kidney failure due to nephrotic syndrome.
  • Estrogen insensitivity syndrome (EIS) – The estrogen counterpart to androgen insensitivity syndrome. Extremely rare, with only one verified case having been reported; a biological male presented with tall stature, a heightened risk of osteoporosis, and sterility.
  • Gonadal Dysgenesis – is any congenital developmental disorder of the reproductive system characterized by a progressive loss of primordial germ cells on the developing gonads of an embryo.
  • Isolated 17,20-lyase deficiency – A condition that is characterized by either partial or complete inability to produce androgens and estrogens.[16] Results in partial or complete feminization and undervirilization in males and in a delayed, reduced, or absent puberty in both sexes, in turn causing sexual infantilism and infertility, among other symptoms.
  • Klinefelter syndrome (also known as 47, XXY and XXY syndrome) – A condition that describes a male born with at least one extra X chromosome. Though the most common variation is 47, XXY, a man may also be 48, XXXY or 49, XXXXY. It is a common occurrence, affecting 1 in 500 to 1,000 men.[17] While some men may have no issues related to the syndrome, some may experience gynecomastia, micropenis, cognitive difficulties, hypogonadism, reduced fertility/infertility, and/or little or no facial hair. Testosterone therapy may be pursued by men who desire a more masculine appearance and those with gynecomastia may opt to undergo a reduction mammoplasty. Men who wish to father children may be able to do so with the help of IVF.[18][3][19]
  • Leydig cell hypoplasia - A condition solely affecting biological males which is characterized by partial or complete inactivation of the luteinizing hormone receptor, resulting in stymied androgen production. Patients may present at birth with a fully female phenotype, ambiguous genitalia, or only mild genital defects such as micropenis and hypospadias. Upon puberty, sexual development is either impaired or fully absent.
  • Lipoid congenital adrenal hyperplasia – An endocrine disorder that arises from defects in the earliest stages of steroid hormone synthesis: the transport of cholesterol into the mitochondria and the conversion of cholesterol to pregnenolone—the first step in the synthesis of all steroid hormones.
  • Mild androgen insensitivity syndrome (also known as MAIS) – A condition which mildly affects a genetic male's ability to recognize androgens. It is considered a form of androgen insensitivity syndrome and is considered the least severe form. While men generally do not need any specialized medical care related to this form, mild androgen insensitivity syndrome may result in gynecomastia and hypospadias. Neither gynecomastia nor hypospadias require surgical intervention or adversely affect a man's health though some men may opt to undergo surgery to remove their breasts and/or repair their hypospadias. Men with mild androgen insensitivity syndrome may have reduced fertility.
  • Mixed gonadal dysgenesis – is a condition of unusual and asymmetrical gonadal development leading to an unassigned sex differentiation. A number of differences have been reported in the karyotype, most commonly a mosaicism 45,X/ 46, XY.
  • Ovotesticular disorder (also called true hermaphroditism) – A condition where an individual has both testicular and ovary tissue.
  • Partial androgen insensitivity syndrome (also known as PAIS) – A condition which partially affects a genetic male's ability to recognize androgens. It is considered a form of androgen insensitivity syndrome and while it is not as severe as complete androgen insensitivity syndrome, it is more severe than mild androgen insensitivity syndrome. Partial androgen insensitivity syndrome causes major problems with gender assignment because it causes ambiguous genitalia such as a micropenis or clitoromegaly in addition to breast development. People with partial androgen insensitivity syndrome who are assigned as males may undergo testosterone therapy to virilize their body while those who are assigned as females may undergo a surgical reduction of the clitoris and/ or estrogen therapy.
  • Penoscrotal transposition
  • Persistent Müllerian duct syndrome A condition where Fallopian tubes, uterus, or the upper part of the vagina are present in an otherwise normal male.
  • Pseudovaginal perineoscrotal hypospadias (also known as PPSH) – A form of ambiguous genitalia which results in a phallic structure that is smaller than a penis but larger than a clitoris, a chordee, hypospadias, and a shallow vagina.
  • Swyer Syndrome (Also known as Pure Gonadal Dysgenesis or XY gonadal dysgenesis) is a type of hypogonadism in a person whose karyotype is 46,XY. The person is externally female with streak gonads, and left untreated, will not experience puberty. Such gonads are typically surgically removed (as they have a significant risk of developing tumors) and a typical medical treatment would include hormone replacement therapy with female hormones.
  • Turner syndrome (also known as Ullrich-Turner syndrome and gonadal dysgenesis) – A condition that describes a female born with only one X chromosome or with an abnormal X chromosome, making her karotype 45, XO. It occurs in 1 in 2,000 to 5,000 females. Turner syndrome causes numerous health and development problems, including but not limited to short stature, lymphedema, infertility, webbed neck, coarctation of the aorta, ADHD, amenorrhoea, and obesity.
  • Müllerian agenesis (also known as MRKH or Vaginal Agenesis) – A condition that causes the uterus and other reproductive organs in a 46,XX female to be small or absent, as well as the vaginal canal itself. It affects 1 out of 4,500 to 5,000 females and can also come with skeletal or endocrine system issues at conception.


Clinical networks and organizationsEdit


The Differences of Sex Development-Translational Research Network (DSD-TRN) is based in the United States and aims to improve DSD care across the United States. Founded by Dr. David Sandberg and Dr. Eric Vilain, the DSD-TRN is funded by the NIH and works to develop a registry that will ultimately gather evidence to produce evidence-based guidelines in DSD care.[20] The TRN comprises many children's hospitals across the country, with investigators at each site contributing to the TRN's research output.[21] It is currently in partnership with the Accord Alliance,[22] a DSD patient support and advocacy non-profit organization.

In 2015, key patient organizations and individuals left the Network, citing a "pattern of misrepresentation",[23] and network function that served "not to change medicine but to absolve clinicians of their responsibility.[24][25]


The International-Differences of Sex Development (I-DSD) is a research organization in Europe. This organization connects medical and research centers internationally in an effort to improve clinical practice, research, and general understanding of differences of sex development.[26] I-DSD regularly hosts a symposium in order to provides updates on current care in DSD internationally, facilitate networking for those in DSD Care, and promote high quality DSD research.[27]

Patient support and advocacy organizationsEdit

Notable patient support and advocacy organizations include:




Latin AmericaEdit

North AmericaEdit




Human rights and community concernsEdit

The term DSD (and particularly its association with medical disorders) has been controversial. The argument over terminology reflects a deeper disagreement over the extent to which intersex conditions require medical intervention, the appropriateness of certain interventions, and whether physicians and parents should make irreversible treatment decisions on behalf of young children if the condition is not life-threatening.

  • Use of the term disorder of sex development (DSD) is controversial among many activists and community organizations due to the label "disorders".[28][29][30][31] Many governments and international institutions use the term 'intersex' in preference to 'DSD', or have called for the review of medical classifications.[6][7] In May 2019, more than 50 intersex-led organizations signed a multilingual joint statement condemning the introduction of "disorders of sex development" language into the International Classification of Diseases, stating that this causes "harm" and facilitates human rights violations, calling on the World Health Organization to publish clear policy to ensure that intersex medical interventions are "fully compatible with human rights norms".[32][33][34][35][36]
  • Lee et al. in a 2006 Consensus statement on management of intersex disorders proposed a system of nomenclature based on "disorders of sex development" for clinical use, suggesting that "terms such as intersex, pseudohermaphroditism, hermaphroditism, sex reversal, and gender based diagnostic labels are particularly controversial," may be perceived as pejorative, and are confusing to practitioners and parents alike.[3] However, research by the Lurie Children's Hospital, Chicago, and the AIS-DSD Support Group published in 2017 found that affected persons, and care givers, object to the term, and that this may impact choice, access, and utilization of health care providers.[4] Australian sociological research on people born with atypical sex characteristics, published in 2016, found that 3% of respondents choose the term "disorders of sex development" or "DSD" to define their sex characteristics, while 21% use the term when accessing medical services. In contrast, 60% used the term "intersex" in some form to self-describe their sex characteristics.[37]
  • A committee of the Senate of Australia found that labelling intersex as "pejorative" appeared to be a post-hoc rationalisation in the 2006 Consensus statement. It recommended a review of clinical use of the term.[38]
  • Alternative terms have been offered: Milton Diamond has suggested the use of "variation"[39][40] or of "difference",[41] Elizabeth Reis has suggested "divergence";[42] Liao and Simmonds suggest "diverse sex development".[43] The latter suggestions would retain the initial D in DSD.
  • The 2006 Consensus statement on management of intersex disorders stated that evidence for early surgery for cosmetic reasons is lacking, outcomes include "decreased sexual sensitivity" and long term outcome data is absent.[3] A 2016 Global Disorders of Sex Development Update since 2006 states that there is "still no consensual attitude regarding indications, timing, procedure and evaluation of outcome of DSD surgery" and "no evidence regarding the impact of surgically treated or non-treated DSDs during childhood for the individual, the parents, society or the risk of stigmatization".[19]
  • In 2013, Juan E. Méndez, the United Nations Special Rapporteur on torture and other cruel, inhuman or degrading treatment or punishment, condemned "irreversible sex assignment, involuntary sterilization, involuntary genital normalizing surgery, performed without their informed consent, or that of their parents, 'in an attempt to fix their sex'" stating that "members of sexual minorities are disproportionately subjected to torture and other forms of ill-treatment because they fail to conform to socially constructed gender expectations".[44]
  • In May 2014, the World Health Organization issued a joint statement on Eliminating forced, coercive and otherwise involuntary sterilization, An interagency statement with the OHCHR, UN Women, UNAIDS, UNDP, UNFPA and UNICEF. Referencing the involuntary surgical "sex-normalising or other procedures" on "intersex persons", the report recommends a range of guiding principles for medical treatment, including ensuring patient autonomy in decision-making, ensuring non-discrimination, accountability and access to remedies.[45]

National and international medical classifications which pathologise variations in sex characteristics should be reviewed with a view to eliminating obstacles to the effective enjoyment, by intersex persons, of human rights, including the right to the highest attainable standard of health.[6]

Clinical disagreements about the termEdit

While the 2006 clinical consensus statement that introduced the term,[3] its 2016 update,[19] included some sex chromosome anomalies within the term DSD, the inclusion of those conditions is opposed by some clinicians.[citation needed] Medical historian David Griffiths has identified continued controversy about the relationship between sex chromosome variations and intersex/DSD classifications.[48]

Similarly, some clinicians have proposed that congenital adrenal hyperplasia be excluded.[49] Human rights advocate Morgan Carpenter has remarked that this proposal appears motivated by support for contentious medical interventions.[50]

See alsoEdit


  1. ^ Diamond M, Beh HG (January 2008). "Changes in the management of children with intersex conditions". Nature Clinical Practice. Endocrinology & Metabolism. 4 (1): 4–5. doi:10.1038/ncpendmet0694. hdl:10125/66380. PMID 17984980. S2CID 13382948.
  2. ^ "Differences in sex development". nhs.uk. 2017-10-18. Retrieved 2020-04-10.
  3. ^ a b c d e Lee PA, Houk CP, Ahmed SF, Hughes IA (August 2006). "Consensus statement on management of intersex disorders. International Consensus Conference on Intersex". Pediatrics. 118 (2): e488-500. doi:10.1542/peds.2006-0738. PMC 2082839. PMID 16882788.
  4. ^ a b Johnson EK, Rosoklija I, Finlayson C, Chen D, Yerkes EB, Madonna MB, et al. (December 2017). "Attitudes towards "disorders of sex development" nomenclature among affected individuals". Journal of Pediatric Urology. 13 (6): 608.e1–608.e8. doi:10.1016/j.jpurol.2017.03.035. PMID 28545802.
  5. ^ Jordan-Young RM, Sönksen PH, Karkazis K (April 2014). "Sex, health, and athletes". BMJ. 348: g2926. doi:10.1136/bmj.g2926. PMID 24776640. S2CID 2198650.
  6. ^ a b c d e f Council of Europe; Commissioner for Human Rights (April 2015), Human rights and intersex people, Issue Paper
  7. ^ a b c d e Comisión Interamericana de Derechos Humanos (November 12, 2015), Violencia contra Personas Lesbianas, Gays, Bisexuales, Trans e Intersex en América (PDF) (in Spanish)
  8. ^ a b c European Union Agency for Fundamental Rights (April 2015), The fundamental rights situation of intersex people (PDF)
  9. ^ UN Committee against Torture; UN Committee on the Rights of the Child; UN Committee on the Rights of People with Disabilities; UN Subcommittee on Prevention of Torture and other Cruel, Inhuman or Degrading Treatment or Punishment; Juan Méndez, Special Rapporteur on torture and other cruel inhuman or degrading treatment or punishment; Dainius Pῡras Special Rapporteur on the right of everyone to the enjoyment of the highest attainable standard of physical and mental health; Dubravka Šimonoviæ, Special Rapporteur on violence against women its causes and consequences; Marta Santos Pais, Special Representative of the UN Secretary-General on Violence against Children; African Commission on Human and Peoples' Rights; Council of Europe Commissioner for Human Rights; Inter-American Commission on Human Rights (October 24, 2016), "Intersex Awareness Day – Wednesday 26 October. End violence and harmful medical practices on intersex children and adults, UN and regional experts urge", Office of the High Commissioner for Human Rights
  10. ^ Peterson RE, Imperato-McGinley J, Gautier T, Sturla E (February 1977). "Male pseudohermaphroditism due to steroid 5-alpha-reductase deficiency". The American Journal of Medicine. 62 (2): 170–91. doi:10.1016/0002-9343(77)90313-8. PMID 835597.
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  14. ^ Parween S, Fernández-Cancio M, Benito-Sanz S, Camats N, Rojas Velazquez MN, López-Siguero JP, et al. (April 2020). "Molecular Basis of CYP19A1 Deficiency in a 46,XX Patient With R550W Mutation in POR: Expanding the PORD Phenotype". The Journal of Clinical Endocrinology and Metabolism. 105 (4): e1272–e1290. doi:10.1210/clinem/dgaa076. PMID 32060549.
  15. ^ Vorona, Elena; Zitzmann, Michael; Gromoll, Jörg; Schüring, Andreas N.; Nieschlag, Eberhard (2007-09-01). "Clinical, Endocrinological, and Epigenetic Features of the 46,XX Male Syndrome, Compared with 47,XXY Klinefelter Patients". The Journal of Clinical Endocrinology & Metabolism. 92 (9): 3458–3465. doi:10.1210/jc.2007-0447. ISSN 0021-972X. PMID 17579198.
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  17. ^ The Focus Foundation. X & Y Variations. thefocusfoundation.org Archived 2013-01-13 at Archive.today
  18. ^ Fullerton G, Hamilton M, Maheshwari A (March 2010). "Should non-mosaic Klinefelter syndrome men be labelled as infertile in 2009?". Human Reproduction. 25 (3): 588–97. doi:10.1093/humrep/dep431. PMID 20085911.
  19. ^ a b c Lee PA, Nordenström A, Houk CP, Ahmed SF, Auchus R, Baratz A, et al. (January 28, 2016). "Global Disorders of Sex Development Update since 2006: Perceptions, Approach and Care". Hormone Research in Paediatrics. 85 (3): 158–80. doi:10.1159/000442975. PMID 26820577.
  20. ^ "Project Information - NIH RePORTER - NIH Research Portfolio Online Reporting Tools Expenditures and Results". projectreporter.nih.gov. Retrieved 2021-01-18.
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  26. ^ "(no title)". home.i-dsd.org. Retrieved 2021-01-18. Cite uses generic title (help)
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Further readingEdit

External linksEdit