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Disorders of sex development

Disorders of sex development (DSDs), also known as differences in sex development or variations in sex characteristics (VSC),[2] [3] are congenital conditions affecting the reproductive system, in which development of chromosomal, gonadal, or anatomical sex is atypical.[4]

Disorders of sex development

Disorders of sex differentiation, variations of sex characteristics[1]

Medical genetics

DSDs are subdivided into groups in which the labels generally emphasize the karyotype's role in diagnosis: 46,XX; 46,XY; sex chromosome; XX, sex reversal; ovotesticular disorder; and XY, sex reversal.[5]

46,XX DSD: Genetic Female Sex Chromosomes. Mainly females as a result of congenital adrenal hyperplasia (CAH) and girls with aberrant ovarian development.

virilized

46,XY DSD: Genetic Male Sex Chromosomes. Individuals with abnormal testicular differentiation, defects in testosterone biosynthesis, and impaired testosterone action.

DSD: patients with sex chromosome aneuploidy or mosaic sex karyotypes. This includes patients with Turner Syndrome (45,X or 45,X0) and Klinefelter Syndrome (47,XXY) even though they do not generally present with atypical genitals.

Sex chromosome

: consist of two groups of patients with male phenotypes, the first with translocated SRY and the second with no SRY gene.

XX, Sex reversal

: patients having both ovarian and testicular tissue. In some cases the ovarian tissue is functional.

Ovotesticular disorder

XY, Sex reversal: patients with female phenotypes where duplication in the Xp21.2 region of the X chromosome that contains the NR0B1 () gene is associated with XY sex reversal.

DAX1

(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.[18][19]

5α-reductase 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.[20][21]

17β-Hydroxysteroid dehydrogenase deficiency

- A chimeric condition where the person shows variable karyotype in the 23rd chromosome pair, resulting from the embryonic fusion.[22] It can vary in presentation from phenotypically normal, to ambiguous. [23]

46,XX/46,XY

(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.[24] 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.[25]

Androgen insensitivity syndrome

– A rare condition where a XY male is born without a penis. As of 2017, only 100 cases have been reported in literature.[26]

Aphallia

– A disorder 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.[27]

Aromatase deficiency

(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.[28]

Aromatase excess syndrome

– 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.[29]

Campomelic dysplasia

– 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.

Clitoromegaly

– A condition 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.[30]

Combined 17α-hydroxylase/17,20-lyase deficiency

(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.[31][32] 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.[33]

Complete androgen insensitivity syndrome

(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 funding of labia and an enlarged clitoris.[34][35] 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.[36]

Congenital adrenal hyperplasia

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).[37] The disorders are invariably fatal before the age of 15, causing kidney failure due to nephrotic syndrome.[38]

Denys–Drash 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.[39]

Estrogen insensitivity syndrome

- persistent Wolffian Ducts in XX females.

Gartner's duct cyst

– 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.

Gonadal dysgenesis

- A disorder where the Müllerian ducts fail to fuse during embryonic development. Leading to the presence of 2 vaginas, 2 uteruses, a single kidney. Can also affect the spleen, bladder and other urogenital structures.[40][41]

Herlyn-Werner-Wunderlich syndrome

– A condition that is characterized by either partial or complete inability to produce androgens and estrogens.[42] 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.[43]

Isolated 17,20-lyase deficiency

(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.[44] About 1 in 50,000 men are affected by variant 48,XXXY (Two extra X) and 1 in 100,000 men affected by variant 49,XXXXY (Three extra X).[45] 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.[46][4][47]

Klinefelter syndrome

- 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.[48][49]

Leydig cell hypoplasia

– 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.[50][51]

Lipoid congenital adrenal hyperplasia

(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.

Mild androgen insensitivity syndrome

– 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.[52]

Mixed gonadal dysgenesis

(also called true hermaphroditism) is rare a condition where an individual has both ovarian and testicular tissue.[53] It is the rarest DSD with at least 500 cases being reported in literature.[54]

Ovotesticular disorder

(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.[55] 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.[56]

Partial androgen insensitivity syndrome

Penoscrotal transposition

- A condition where fallopian tubes, uterus, or the upper part of the vagina are present in an otherwise normal male.[57]

Persistent Müllerian duct syndrome

(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.[58]

Pseudovaginal perineoscrotal hypospadias

(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.[59][60]

Swyer syndrome

(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,X0. It occurs in 1 in 2,000 to 5,000 females.[61] 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.[62]

Turner syndrome

(Mayer-Rokitansky-Küster-Hauser syndrome 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.[63][64]

Müllerian agenesis

is a condition where an individual with an XX karyotype has a male appearance. Genitalia can range from normal to ambiguous genitalia.[65] It is estimated to occur in 1 in 20,000 males.[66]

XX testicular DSD

Intersex South Africa

SIPD Uganda

Controversy[edit]

Terminology[edit]

The term disorders of sex development has generally been accepted by the medical community, as well as being a popular term in literature.[71] However, the term is not universal among patients or support groups.[72] One study stated that it can affect individuals covered by the description in a negative way, and that the terminology might impact choice and utilization of health care providers.[73] Another study found that most affected individuals did not find the term offensive.[74] The ICD-11, which is the World Health Organization's international guide to medical coding (effective as of January 1, 2022), references DSDs as intersex traits or conditions, as do some medical journals.[75] The Council of Europe[76] and Inter-American Commission on Human Rights[77] have called for a review of medical classifications that unnecessarily medicalize intersex traits.[76][77][78]


The DSD as a model was advocated for by intersex advocates to include all variation of atypical sexual development. Specifically the DSD exists as replacement for the "optimum gender rearing model," which was the standard model for individuals with atypical sexual development. This model stated goal was to assign a gender binary, usually female via non-consensual medicalization, often via the falsification of medical records. After the publication of individuals who had undergone the OGR model and had gone through serious physiological distress, (such as David Reimer), the model was discredited. The term "disorders of sexual development" was chosen to reflect the variation of sexual development over differences which effects all individuals, this however has been controversial, with many instead opting for "differentiation" or "variation."[79]


Sociological research in Australia on 272 "people born with atypical sex characteristics," published in 2016, found that 3% of respondents used 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.[80] U.S. research by the Lurie Children's Hospital, Chicago, and the AIS-DSD Support Group (now InterConnect Support Group) published in 2017 found that "disorders of sex development" terminology may negatively affect care, give offense, and result in lower attendance at medical clinics.[81][82]


A "dsd-LIFE" study in 2020 found that around 69% of 1,040 participants did not think the term disorders of sex development was offensive.[74]

. – Provides information regarding the causes, frequency and implications of DSD.

"Disorders of Sex Development Research"

. – Approaches to care for people that are affected by differences of sex development (DSD).

"Accord Alliance"

. YourChild. University of Michigan Health System.

"Disorders of Sex Development (DSD) Resources"

. Toronto: The Hospital for Sick Children. Archived from the original on 2010-07-04. An Overview Animation of prenatal genital development

"Sex Development"

. Consortium on the Management of Disorders of Sex Development.

"Handbook for Parents"

. Consortium on the Management of Disorders of Sex Development.

"Clinical Guidelines for the Management of Disorders of Sex Development in Childhood"