Variations in sex characteristics
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Disorders of sex development (DSDs), also known as differences in sex development, diverse sex development and variations in sex characteristics (VSC), are congenital conditions affecting the
reproductive system The reproductive system of an organism, also known as the genital system, is the biological system made up of all the anatomical organs involved in sexual reproduction. Many non-living substances such as fluids, hormones, and pheromones are als ...
, in which development of
chromosomal A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins are ...
, gonadal, or
anatomical sex Sex is the trait that determines whether a sexually reproducing animal or plant produces male or female gametes. Male plants and animals produce smaller mobile gametes (spermatozoa, sperm, pollen), while females produce larger ones ( ova, of ...
is atypical. 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.


Overview

DSDs are medical conditions encompassing any problem noted at birth where the genitalia are atypical in relation to the chromosomes or gonads. 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".
Urologists Urology (from Greek οὖρον ''ouron'' "urine" and ''-logia'' "study of"), also known as genitourinary surgery, is the branch of medicine that focuses on surgical and medical diseases of the urinary-tract system and the reproductive organ ...
were concerned that terms like intersex, hermaphrodite, and pseudohermaphrodite were confusing and pejorative. This led to the Chicago Consensus, recommending a new terminology based on the umbrella term ''disorders of sex differentiation.'' DSDs are divided into following categories, emphasizing the karyotype's role in diagnosis: * 46, XX DSD: mainly virilized females as a result of
congenital adrenal hyperplasia Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders characterized by impaired cortisol synthesis. It results from the deficiency of one of the five enzymes required for the synthesis of cortisol in the adrenal cort ...
(CAH) and girls with aberrant ovarian development. * 46, XY DSD: patients with abnormal testicular differentiation, defects in testosterone biosynthesis, and impaired testosterone action. *
Sex chromosome A sex chromosome (also referred to as an allosome, heterotypical chromosome, gonosome, heterochromosome, or idiochromosome) is a chromosome that differs from an ordinary autosome in form, size, and behavior. The human sex chromosomes, a typical ...
DSD: patients with sex chromosome
aneuploidy Aneuploidy is the presence of an abnormal number of chromosomes in a cell, for example a human cell having 45 or 47 chromosomes instead of the usual 46. It does not include a difference of one or more complete sets of chromosomes. A cell with any ...
or
mosaic A mosaic is a pattern or image made of small regular or irregular pieces of colored stone, glass or ceramic, held in place by plaster/mortar, and covering a surface. Mosaics are often used as floor and wall decoration, and were particularly pop ...
sex karyotypes. This includes patients with
Turner Syndrome Turner syndrome (TS), also known as 45,X, or 45,X0, is a genetic condition in which a female is partially or completely missing an X chromosome. Signs and symptoms vary among those affected. Often, a short and webbed neck, low-set ears, low hair ...
and
Klinefelter Syndrome Klinefelter syndrome (KS), also known as 47,XXY, is an aneuploid genetic condition where a male has an additional copy of the X chromosome. The primary features are infertility and small, poorly functioning testicles. Usually, symptoms are sub ...
even though they do not generally present with atypical genitals. * XX, Sex reversal: consist of two groups of patients with male phenotypes, the first with translocated '' SRY'' and the second with no ''SRY'' gene. * Ovotesticular disorder: patients having both
ovarian The ovary is an organ in the female reproductive system that produces an ovum. When released, this travels down the fallopian tube into the uterus, where it may become fertilized by a sperm. There is an ovary () found on each side of the body ...
and
testicular A testicle or testis (plural testes) is the male reproductive gland or gonad in all bilaterians, including humans. It is homologous to the female ovary. The functions of the testes are to produce both sperm and androgens, primarily testosteron ...
tissue. In some cases the ovarian tissue is functional. * XY, Sex reversal: patients with female phenotypes where duplication in the Xp21.2 region of the X chromosome that contains the ''NR0B1'' (''
DAX1 DAX1 (dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1) is a nuclear receptor protein that in humans is encoded by the ''NR0B1'' gene (nuclear receptor subfamily 0, group B, member 1). The ''NR0B1'' gene i ...
'') gene is associated with XY sex reversal.


Genital anatomy

The penis (males) and clitoris (females) have a common origin, both arising from an embryonic structure called the
primordial phallus In embryology, the primordial phallus refers to the clitoris of a female or the penis in the male, particularly during fetal development of the urinary and reproductive organs, before sexual differentiation is evident. This is also the case for ...
. 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 to have a urethral opening located along the shaft; this condition is known as
hypospadias Hypospadias is a common variation in fetal development of the penis in which the urethra does not open from its usual location in the head of the penis. It is the second-most common birth abnormality of the male reproductive system, affecting abou ...
.


Management of DSDs

Due to the significant and life-long impacts that DSDs can have on patients and their families, it is widely accepted that children with DSDs should be managed by an experienced
multidisciplinary Interdisciplinarity or interdisciplinary studies involves the combination of multiple academic disciplines into one activity (e.g., a research project). It draws knowledge from several other fields like sociology, anthropology, psychology, ec ...
team. Health care providers generally agree that children with DSDs should be notified early. 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.


Conditions

*
5α-reductase deficiency 5α-Reductases, also known as 3-oxo-5α-steroid 4-dehydrogenases, are enzymes involved in steroid metabolism. They participate in three metabolic pathways: bile acid biosynthesis, androgen and estrogen metabolism. There are three isozymes of ...
(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 hydroxysteroid is a molecule derived from a steroid with a hydrogen replaced with a hydroxy group. When the hydroxy group is specifically at the C3 position, hydroxysteroids are referred to as sterols, with an example being cholesterol. See a ...
– 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 Androgen insensitivity syndrome (AIS) is a difference in sex development involving hormonal resistance due to androgen receptor dysfunction. It affects 1 in 20,000 to 64,000 XY ( karyotypically male) births. The condition results in the partial ...
(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 Mild androgen insensitivity syndrome (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 sexu ...
generally causes no developmental issues and people with this form are raised as males.
Partial androgen insensitivity syndrome Partial androgen insensitivity syndrome (PAIS) is a condition that results in the partial inability of the cell to respond to androgens. It is an X linked recessive condition. The partial unresponsiveness of the cell to the presence of androgenic ...
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 Complete androgen insensitivity syndrome (CAIS) is an AIS condition that results in the complete inability of the cell to respond to androgens. As such, the insensitivity to androgens is only clinically significant when it occurs in individuals ...
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 condition where a XY male is born without a
penis A penis (plural ''penises'' or ''penes'' () is the primary sexual organ that male animals use to inseminate females (or hermaphrodites) during copulation. Such organs occur in many animals, both vertebrate and invertebrate, but males d ...
. As of 2017 only 100 cases have been reported in literature. * Aromatase deficiency – 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 Clitoromegaly (or macroclitoris) is an abnormal enlargement of the clitoris that is mostly congenital or acquired, though deliberately induced clitoris enlargement as a form of genital body modification is achieved through various uses of anabo ...
). Aromatase deficiency can also be caused by mutations in P450 oxidoreductase gene. *
Aromatase excess syndrome Aromatase excess syndrome (AES or AEXS) is a rare genetic and endocrine syndrome which is characterized by an overexpression of aromatase, the enzyme responsible for the biosynthesis of the estrogen sex hormones from the androgens, in turn resu ...
(also known as familial hyperestrogenism) - A condition that causes excessive
estrogen Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal ac ...
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 Respiratory failure results from inadequate gas exchange by the respiratory system, meaning that the arterial oxygen, carbon dioxide, or both cannot be kept at normal levels. A drop in the oxygen carried in the blood is known as hypoxemia; a rise ...
. While in roughly 95% of cases, death occurs in the
neonatal An infant or baby is the very young offspring of human beings. ''Infant'' (from the Latin word ''infans'', meaning 'unable to speak' or 'speechless') is a formal or specialised synonym for the common term ''baby''. The terms may also be used to ...
period due to respiratory distress, those that live past infancy typically survive to become adults. *
Clitoromegaly Clitoromegaly (or macroclitoris) is an abnormal enlargement of the clitoris that is mostly congenital or acquired, though deliberately induced clitoris enlargement as a form of genital body modification is achieved through various uses of anabo ...
– 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 Testosterone is the primary sex hormone and anabolic steroid in males. In humans, testosterone plays a key role in the development of male reproductive tissues such as testes and prostate, as well as promoting secondary sexual characteristi ...
or anabolic steroids for purposes related to female to male
gender transition Gender transition is the process of changing one's gender presentation or sex characteristics to accord with one's internal sense of gender identity – the idea of what it means to be a man or a woman,Brown, M. L. & Rounsley, C. A. (1996) ''True ...
or
bodybuilding Bodybuilding is the use of progressive resistance exercise to control and develop one's muscles (muscle building) by muscle hypertrophy for aesthetic purposes. It is distinct from similar activities such as powerlifting because it focuses ...
. * Combined 17α-hydroxylase/17,20-lyase deficiency – A condition in which presents as a combination of the symptoms of
congenital adrenal hyperplasia Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders characterized by impaired cortisol synthesis. It results from the deficiency of one of the five enzymes required for the synthesis of cortisol in the adrenal cort ...
and
isolated 17,20-lyase deficiency Isolated 17,20-lyase deficiency (ILD), also called isolated 17,20-desmolase deficiency, is a rare endocrine and autosomal recessive genetic disorder which is characterized by a complete or partial loss of 17,20-lyase activity and, in turn, impair ...
. See those two conditions for more information. *
Complete androgen insensitivity syndrome Complete androgen insensitivity syndrome (CAIS) is an AIS condition that results in the complete inability of the cell to respond to androgens. As such, the insensitivity to androgens is only clinically significant when it occurs in individuals ...
(also known as CAIS) – A condition which completely affects a genetic male's ability to recognize
androgens An androgen (from Greek ''andr-'', the stem of the word meaning "man") is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This in ...
. It is considered a form of
androgen insensitivity syndrome Androgen insensitivity syndrome (AIS) is a difference in sex development involving hormonal resistance due to androgen receptor dysfunction. It affects 1 in 20,000 to 64,000 XY ( karyotypically male) births. The condition results in the partial ...
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 Amenorrhea is the absence of a menstrual period in a woman of reproductive age. Physiological states of amenorrhoea are seen, most commonly, during pregnancy and lactation (breastfeeding). Outside the reproductive years, there is absence of mense ...
in their late teens or they need medical intervention due to a
hernia A hernia is the abnormal exit of tissue or an organ, such as the bowel, through the wall of the cavity in which it normally resides. Various types of hernias can occur, most commonly involving the abdomen, and specifically the groin. Groin herni ...
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 Breastfeeding, or nursing, is the process by which human breast milk is fed to a child. Breast milk may be from the breast, or may be expressed by hand or pumped and fed to the infant. The World Health Organization (WHO) recommends that br ...
. However, they will not have
ovaries The ovary is an organ in the female reproductive system that produces an ovum. When released, this travels down the fallopian tube into the uterus, where it may become fertilized by a sperm. There is an ovary () found on each side of the body. T ...
or a
uterus The uterus (from Latin ''uterus'', plural ''uteri'') or womb () is the organ in the reproductive system of most female mammals, including humans that accommodates the embryonic and fetal development of one or more embryos until birth. The ...
. Because they do not have ovaries or sufficiently developed testicles, people with complete androgen insensitivity syndrome are infertile. *
Congenital adrenal hyperplasia Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders characterized by impaired cortisol synthesis. It results from the deficiency of one of the five enzymes required for the synthesis of cortisol in the adrenal cort ...
(also known as CAH) – A condition that causes excessive
androgen An androgen (from Greek ''andr-'', the stem of the word meaning "man") is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This in ...
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. *
Denys–Drash syndrome Denys–Drash syndrome (DDS) or Drash syndrome is a rare disorder or syndrome characterized by gonadal dysgenesis, nephropathy, and Wilms' tumor. Signs and symptoms Clinically, Denys–Drash is characterized by the triad of pseudohermaphrodit ...
and the related Frasier syndrome - similar rare conditions arising from ''de novo'' autosomal dominant mutations in the
WT1 Wilms tumor protein (WT33) is a protein that in humans is encoded by the ''WT1'' gene on chromosome 11p. Function This gene encodes a transcription factor that contains four zinc finger motifs at the C-terminus and a proline / glutamine-ric ...
gene, causing symptoms ranging from undervirilization to complete sex reversal with persistent
Müllerian ducts Paramesonephric ducts (or Müllerian ducts) are paired ducts of the embryo that run down the lateral sides of the genital ridge and terminate at the sinus tubercle in the primitive urogenital sinus. In the female, they will develop to form the fal ...
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 Estrogen insensitivity syndrome (EIS), or estrogen resistance, is a form of congenital estrogen deficiency or hypoestrogenism which is caused by a defective estrogen receptor (ER) – specifically, the estrogen receptor alpha (ERα) – that res ...
(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 Gonadal dysgenesis is classified as any congenital developmental disorder of the reproductive system in the male or female. It is the atypical development of the gonads in an embryo, with reproductive tissue replaced with functionless, fibrous ti ...
– 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. * Herlyn-Werner-Wunderlich syndrome - A disorder where the Mullerian 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. *
Isolated 17,20-lyase deficiency Isolated 17,20-lyase deficiency (ILD), also called isolated 17,20-desmolase deficiency, is a rare endocrine and autosomal recessive genetic disorder which is characterized by a complete or partial loss of 17,20-lyase activity and, in turn, impair ...
– A condition that is characterized by either partial or complete inability to produce androgens and estrogens. 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 Klinefelter syndrome (KS), also known as 47,XXY, is an aneuploid genetic condition where a male has an additional copy of the X chromosome. The primary features are infertility and small, poorly functioning testicles. Usually, symptoms are sub ...
(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. While some men may have no issues related to the syndrome, some may experience
gynecomastia Gynecomastia (also spelled gynaecomastia) is the abnormal non-cancerous enlargement of one or both breasts in males due to the growth of breast tissue as a result of a hormone imbalance between estrogens and androgens. Updated by Brent Wisse ( ...
,
micropenis Micropenis is an unusually small penis. A common criterion is a dorsal (measured on top) penile length of at least 2.5 standard deviations smaller than the mean human penis size (stretched penile length less than 9.3 cm (3.67 in) in adults). ...
, cognitive difficulties,
hypogonadism Hypogonadism means diminished functional activity of the gonads—the testes or the ovaries—that may result in diminished production of sex hormones. Low androgen (e.g., testosterone) levels are referred to as hypoandrogenism and low estroge ...
, reduced fertility/ infertility, and/or little or no facial hair.
Testosterone Testosterone is the primary sex hormone and anabolic steroid in males. In humans, testosterone plays a key role in the development of male reproductive tissues such as testes and prostate, as well as promoting secondary sexual characteristi ...
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 In vitro fertilisation (IVF) is a process of fertilisation where an egg is combined with sperm in vitro ("in glass"). The process involves monitoring and stimulating an individual's ovulatory process, removing an ovum or ova (egg or eggs) f ...
. *
Leydig cell hypoplasia Leydig cell hypoplasia (or aplasia) (LCH), also known as Leydig cell agenesis, is a rare autosomal recessive genetic disorder, genetic and endocrine disease, endocrine syndrome affecting an estimated 1 in 1,000,000 genetic males. It is characteriz ...
- 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 Micropenis is an unusually small penis. A common criterion is a dorsal (measured on top) penile length of at least 2.5 standard deviations smaller than the mean human penis size (stretched penile length less than 9.3 cm (3.67 in) in adults). ...
and
hypospadias Hypospadias is a common variation in fetal development of the penis in which the urethra does not open from its usual location in the head of the penis. It is the second-most common birth abnormality of the male reproductive system, affecting abou ...
. Upon puberty, sexual development is either impaired or fully absent. *
Lipoid congenital adrenal hyperplasia Lipoid congenital adrenal hyperplasia is an endocrine disorder that is an uncommon and potentially lethal form of congenital adrenal hyperplasia (CAH). It arises from defects in the earliest stages of steroid hormone synthesis: the transport of ch ...
– An endocrine disorder that arises from defects in the earliest stages of
steroid hormone A steroid hormone is a steroid that acts as a hormone. Steroid hormones can be grouped into two classes: corticosteroids (typically made in the adrenal cortex, hence ''cortico-'') and sex steroids (typically made in the gonads or placenta). Withi ...
synthesis: the transport of
cholesterol Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell mem ...
into the mitochondria and the conversion of cholesterol to
pregnenolone Pregnenolone (P5), or pregn-5-en-3β-ol-20-one, is an endogenous steroid and precursor/ metabolic intermediate in the biosynthesis of most of the steroid hormones, including the progestogens, androgens, estrogens, glucocorticoids, and mineraloc ...
—the first step in the synthesis of all steroid hormones. *
Mild androgen insensitivity syndrome Mild androgen insensitivity syndrome (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 sexu ...
(also known as MAIS) – A condition which mildly affects a genetic male's ability to recognize
androgens An androgen (from Greek ''andr-'', the stem of the word meaning "man") is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This in ...
. It is considered a form of
androgen insensitivity syndrome Androgen insensitivity syndrome (AIS) is a difference in sex development involving hormonal resistance due to androgen receptor dysfunction. It affects 1 in 20,000 to 64,000 XY ( karyotypically male) births. The condition results in the partial ...
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 Gynecomastia (also spelled gynaecomastia) is the abnormal non-cancerous enlargement of one or both breasts in males due to the growth of breast tissue as a result of a hormone imbalance between estrogens and androgens. Updated by Brent Wisse ( ...
and
hypospadias Hypospadias is a common variation in fetal development of the penis in which the urethra does not open from its usual location in the head of the penis. It is the second-most common birth abnormality of the male reproductive system, affecting abou ...
. 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 Sexual differentiation is the process of development of the sex differences between males and females from an undifferentiated zygote. Sex determination is often distinct from sex differentiation; sex determination is the designation for the dev ...
. A number of differences have been reported in the karyotype, most commonly a
mosaicism Mosaicism or genetic mosaicism is a condition in multicellular organisms in which a single organism possesses more than one genetic line as the result of genetic mutation. This means that various genetic lines resulted from a single fertilized ...
45,X/ 46, XY. * Ovotesticular disorder (also called true hermaphroditism) is rare a condition where an individual has both ovarian and testicular tissue. It is the rarest DSD with at least 500 cases being reported in literature. *
Partial androgen insensitivity syndrome Partial androgen insensitivity syndrome (PAIS) is a condition that results in the partial inability of the cell to respond to androgens. It is an X linked recessive condition. The partial unresponsiveness of the cell to the presence of androgenic ...
(also known as PAIS) – A condition which partially affects a genetic male's ability to recognize
androgens An androgen (from Greek ''andr-'', the stem of the word meaning "man") is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This in ...
. It is considered a form of
androgen insensitivity syndrome Androgen insensitivity syndrome (AIS) is a difference in sex development involving hormonal resistance due to androgen receptor dysfunction. It affects 1 in 20,000 to 64,000 XY ( karyotypically male) births. The condition results in the partial ...
and while it is not as severe as
complete androgen insensitivity syndrome Complete androgen insensitivity syndrome (CAIS) is an AIS condition that results in the complete inability of the cell to respond to androgens. As such, the insensitivity to androgens is only clinically significant when it occurs in individuals ...
, it is more severe than
mild androgen insensitivity syndrome Mild androgen insensitivity syndrome (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 sexu ...
. Partial androgen insensitivity syndrome causes major problems with gender assignment because it causes ambiguous genitalia such as a
micropenis Micropenis is an unusually small penis. A common criterion is a dorsal (measured on top) penile length of at least 2.5 standard deviations smaller than the mean human penis size (stretched penile length less than 9.3 cm (3.67 in) in adults). ...
or
clitoromegaly Clitoromegaly (or macroclitoris) is an abnormal enlargement of the clitoris that is mostly congenital or acquired, though deliberately induced clitoris enlargement as a form of genital body modification is achieved through various uses of anabo ...
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 Persistent Müllerian duct syndrome (PMDS) is the presence of Müllerian duct derivatives ( fallopian tubes, uterus, and/or the upper part of the vagina) in what would be considered a genetically and otherwise physically normal male animal by typ ...
- 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 Chordee is a condition in which the head of the penis curves downward or upward, at the junction of the head and shaft of the penis. The curvature is usually most obvious during erection, but resistance to straightening is often apparent in the ...
,
hypospadias Hypospadias is a common variation in fetal development of the penis in which the urethra does not open from its usual location in the head of the penis. It is the second-most common birth abnormality of the male reproductive system, affecting abou ...
, and a shallow vagina. * Swyer Syndrome (Also known as Pure Gonadal Dysgenesis or XY gonadal dysgenesis) is a type of
hypogonadism Hypogonadism means diminished functional activity of the gonads—the testes or the ovaries—that may result in diminished production of sex hormones. Low androgen (e.g., testosterone) levels are referred to as hypoandrogenism and low estroge ...
in a person whose karyotype is 46,XY. The person is externally female with streak gonads, and left untreated, will not experience
puberty Puberty is the process of physical changes through which a child's body matures into an adult body capable of sexual reproduction. It is initiated by hormonal signals from the brain to the gonads: the ovaries in a girl, the testes in a bo ...
. 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 Hormone replacement therapy (HRT), also known as menopausal hormone therapy or postmenopausal hormone therapy, is a form of hormone therapy used to treat symptoms associated with female menopause. These symptoms can include hot flashes, vaginal ...
with female hormones. *
Turner syndrome Turner syndrome (TS), also known as 45,X, or 45,X0, is a genetic condition in which a female is partially or completely missing an X chromosome. Signs and symptoms vary among those affected. Often, a short and webbed neck, low-set ears, low hair ...
(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, X0. 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 Lymphedema, also known as lymphoedema and lymphatic edema, is a condition of localized swelling caused by a compromised lymphatic system. The lymphatic system functions as a critical portion of the body's immune system and returns interstitial fl ...
, infertility,
webbed neck A webbed neck, or pterygium colli, is a congenital skin fold that runs along the sides of the neck down to the shoulders. There are many variants. Signs and symptoms On babies, webbed neck may look like loose folds of skin on the neck. As the ch ...
,
coarctation of the aorta Coarctation of the aorta (CoA or CoAo), also called aortic narrowing, is a congenital condition whereby the aorta is narrow, usually in the area where the ductus arteriosus (ligamentum arteriosum after regression) inserts. The word ''coarctation' ...
, ADHD,
amenorrhoea Amenorrhea is the absence of a menstrual period in a woman of reproductive age. Physiological states of amenorrhoea are seen, most commonly, during pregnancy and lactation (breastfeeding). Outside the reproductive years, there is absence of mense ...
, and
obesity Obesity is a medical condition, sometimes considered a disease, in which excess body fat has accumulated to such an extent that it may negatively affect health. People are classified as obese when their body mass index (BMI)—a person's ...
. *
Müllerian agenesis Müllerian agenesis, also known as Müllerian aplasia, vaginal agenesis, or Mayer-Rokitansky-Küster-Hauser syndrome (MRKH syndrome), is a congenital malformation characterized by a failure of the Müllerian ducts to develop, resulting in a missi ...
(also known as 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. * XX Testicular DSD is a condition where an individual with an XX karyotype has a male appearance. Genitalia can range from normal to ambiguous genitalia. It is estimated to occur in 1 in 20,000 males.


Organizations


Clinical networks and organizations


DSD-TRN

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.


I-DSD

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. I-DSD regularly hosts a symposium to provide updates on current care in DSD internationally, facilitate networking for those in DSD Care, and promote high quality DSD research.


Patient support and advocacy organizations

Notable patient support and advocacy organizations include:


Controversy


Terminology

The term ''disorders of sex development'' has generally been accepted by the medical community, as well as being a popular term in literature. However, the term is not universal among patients or support groups. 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. Another study found that most affected individuals didn't find the term offensive. The
ICD-11 The ICD-11 is the eleventh revision of the International Classification of Diseases (ICD). It replaces the ICD-10 as the global standard for recording health information and causes of death. The ICD is developed and annually updated by the World H ...
, which is the
World Health Organization The World Health Organization (WHO) is a specialized agency of the United Nations responsible for international public health. The WHO Constitution states its main objective as "the attainment by all peoples of the highest possible level of ...
's international guide to medical coding (effective as of January 1, 2022), references DSDs as
intersex Intersex people are individuals born with any of several sex characteristics including chromosome patterns, gonads, or genitals that, according to the Office of the United Nations High Commissioner for Human Rights, "do not fit typical bin ...
traits or conditions, as do some medical journals. The Council of Europe and Inter-American Commission on Human Rights have called for a review of medical classifications that unnecessarily medicalize intersex traits. 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. 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. 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.


Human rights and community concerns

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". Many governments and international institutions use the term 'intersex' in preference to 'DSD', or have called for the review of medical classifications. 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 The International Classification of Diseases (ICD) is a globally used diagnostic tool for epidemiology, health management and clinical purposes. The ICD is maintained by the World Health Organization (WHO), which is the directing and coordinating ...
, stating that this causes "harm" and facilitates human rights violations, calling on the
World Health Organization The World Health Organization (WHO) is a specialized agency of the United Nations responsible for international public health. The WHO Constitution states its main objective as "the attainment by all peoples of the highest possible level of ...
to publish clear policy to ensure that
intersex medical interventions Intersex medical interventions, also known as intersex genital mutilations (IGM), are surgical, hormonal and other medical interventions performed to modify atypical or ambiguous genitalia and other sex characteristics, primarily for the purposes ...
are "fully compatible with human rights norms". * 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 Intersex people are individuals born with any of several sex characteristics including chromosome patterns, gonads, or genitals that, according to the Office of the United Nations High Commissioner for Human Rights, "do not fit typical bin ...
, pseudohermaphroditism,
hermaphroditism In reproductive biology, a hermaphrodite () is an organism that has both kinds of reproductive organs and can produce both gametes associated with male and female sexes. Many taxonomic groups of animals (mostly invertebrates) do not have s ...
, sex reversal, and gender based diagnostic labels are particularly controversial," may be perceived as pejorative, and are confusing to practitioners and parents alike. 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. Australian sociological research on people born with atypical
sex characteristics Sexual characteristics are physical traits of an organism (typically of a sexually dimorphic organism) which are indicative of its biological sex. These can include sex organs used for reproduction and secondary sex characteristics which disting ...
, 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. * 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. * Alternative terms have been offered:
Milton Diamond Milton Diamond (born March 6, 1934) is an American Professor Emeritus of anatomy and reproductive biology at the University of Hawaiʻi at Mānoa. After a career in the study of human sexuality, Diamond retired from the university in December 20 ...
has suggested the use of "variation" or of "difference", Elizabeth Reis has suggested "divergence"; Liao and Simmonds suggest "diverse sex development". 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. 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". * 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". * In May 2014, the
World Health Organization The World Health Organization (WHO) is a specialized agency of the United Nations responsible for international public health. The WHO Constitution states its main objective as "the attainment by all peoples of the highest possible level of ...
issued a joint statement on ''Eliminating forced, coercive and otherwise involuntary sterilization, An interagency statement'' with the
OHCHR The Office of the United Nations High Commissioner for Human Rights, commonly known as the Office of the High Commissioner for Human Rights (OHCHR) or the United Nations Human Rights Office, is a department of the Secretariat of the United Nat ...
,
UN Women The United Nations Entity for Gender Equality and the Empowerment of Women, also known as UN Women, is a United Nations entity working for gender equality and the empowerment of women. UN Women advocates for the rights of women and girls, and foc ...
,
UNAIDS The Joint United Nations Programme on HIV and AIDS (UNAIDS) (, ONUSIDA) is the main advocate for accelerated, comprehensive and coordinated global action on the HIV/AIDS pandemic. The mission of UNAIDS is to lead, strengthen and support an ...
,
UNDP The United Nations Development Programme (UNDP)french: Programme des Nations unies pour le développement, PNUD is a United Nations agency tasked with helping countries eliminate poverty and achieve sustainable economic growth and human dev ...
,
UNFPA The United Nations Population Fund (UNFPA), formerly the United Nations Fund for Population Activities, is a UN agency aimed at improving reproductive and maternal health worldwide. Its work includes developing national healthcare strategies ...
and
UNICEF UNICEF (), originally called the United Nations International Children's Emergency Fund in full, now officially United Nations Children's Fund, is an agency of the United Nations responsible for providing humanitarian and developmental aid to ...
. 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. * During 2015, the Council of Europe and Inter-American Commission on Human Rights called for a review of medical classifications that may unnecessarily medicalize intersex traits, an end to medical interventions without consent, and improved disclosure. The Council of Europe's Human Rights Commissioner recommended: * The
European Union Agency for Fundamental Rights The European Union Agency for Fundamental Rights, usually known in English as the Fundamental Rights Agency (FRA), is a Vienna-based agency of the European Union inaugurated on 1 March 2007. It was established by Council Regulation (EC) No 168/20 ...
and UN Treaty Bodies have called for informed consent by individuals subjected to medical treatment, improved disclosure, and access to redress.


Clinical disagreements about the term

While the 2006 clinical consensus statement that introduced the term, its 2016 update, included some sex chromosome anomalies within the term DSD, the inclusion of those conditions is opposed by some clinicians. Medical historian David Griffiths has identified continued controversy about the relationship between sex chromosome variations and intersex/DSD classifications. Similarly, some clinicians have proposed that
congenital adrenal hyperplasia Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders characterized by impaired cortisol synthesis. It results from the deficiency of one of the five enzymes required for the synthesis of cortisol in the adrenal cort ...
be excluded. Human rights advocate Morgan Carpenter has remarked that this proposal appears motivated by support for contentious medical interventions. A member of the legal committee for the World Professional Association for Transgender Health and co-founder of the Australian and New Zealand Professional Association for Transgender Health has described "transsexualism" as "an intersex condition and a disorder of sexual development therapeutically medically treated by hormonal therapy and Genital Reassignment Surgery". Such views are contested.


People with DSDs competing in sporting events

There is particular contention around female presenting athletes with DSDs (which can cause an elevated level of testosterone) competing in female-only sports events.


See also

*
Intersex Intersex people are individuals born with any of several sex characteristics including chromosome patterns, gonads, or genitals that, according to the Office of the United Nations High Commissioner for Human Rights, "do not fit typical bin ...
*
Intersex medical interventions Intersex medical interventions, also known as intersex genital mutilations (IGM), are surgical, hormonal and other medical interventions performed to modify atypical or ambiguous genitalia and other sex characteristics, primarily for the purposes ...
*
Intersex human rights Intersex people are born with sex characteristics, such as chromosomes, gonads, or genitals, that, according to the UN Office of the High Commissioner for Human Rights, "do not fit typical binary notions of male or female bodies." Intersex peo ...


References


Further reading

* *


External links

* – Provides information regarding the causes, frequency and implications of DSD. * – Approaches to care for people that are affected by differences of sex development (DSD). * * An Overview Animation of prenatal genital development * * {{DEFAULTSORT:Disorders Of Sex Development Intersex Congenital disorders of genital organs Intersex and medicine Sex differences in humans