Disorders of sex development (DSDs), also known as differences in sex development, variations in sex characteristics (VSC), sexual anomalies, or sexual abnormalities, 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 al ...

, in which development of

chromosomal A chromosome is a package of DNA containing part or all of the genetic material of an organism. In most chromosomes, the very long thin DNA fibers are coated with nucleosome-forming packaging proteins; in eukaryotic cells, the most importa ...

gonad A gonad, sex gland, or reproductive gland is a Heterocrine gland, mixed gland and sex organ that produces the gametes and sex hormones of an organism. Female reproductive cells are egg cells, and male reproductive cells are sperm. The male gon ...

al, or anatomical sex is atypical. DSDs are subdivided into groups in which the labels generally emphasize the

karyotype A karyotype is the general appearance of the complete set of chromosomes in the cells of a species or in an individual organism, mainly including their sizes, numbers, and shapes. Karyotyping is the process by which a karyotype is discerned by de ...

's role in diagnosis: 46,XX; 46,XY; sex chromosome; XX, sex reversal; ovotesticular disorder; and XY, sex reversal. Infants born with atypical genitalia often cause confusion and distress for the family.

Psychosexual development In psychoanalysis, psychosexual development is a central element of the sexual drive theory. According to Freud, personality develops through a series of childhood stages in which pleasure-seeking energies from the child become focused on certa ...

is influenced by numerous factors that include, but are not limited to, gender differences in brain structure,

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

s associated with sexual development, prenatal androgen exposure, interactions with family, and cultural and societal factors. Because of the complex and multifaceted factors involved, communication and psychosexual support are all important. A team of experts, or patient support groups, are usually recommended for cases related to sexual anomalies. This team of experts are usually derived from a variety of disciplines including

pediatricians Pediatrics (American English) also spelled paediatrics (British English), is the branch of medicine that involves the medical care of infants, children, adolescents, and young adults. In the United Kingdom, pediatrics covers many of their yout ...

neonatologists Neonatology is a subspecialty of pediatrics that consists of the medical care of newborn infants, especially the ill or premature newborn. It is a hospital-based specialty and is usually practised in neonatal intensive care units (NICUs). The ...

, pediatric

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 system and the reproductive organs. Orga ...

, pediatric general surgeons,

endocrinologist Endocrinology (from ''endocrine'' + '' -ology'') is a branch of biology and medicine dealing with the endocrine system, its diseases, and its specific secretions known as hormones. It is also concerned with the integration of developmental events ...

geneticist A geneticist is a biologist or physician who studies genetics, the science of genes, heredity, and variation of organisms. A geneticist can be employed as a scientist or a lecturer. Geneticists may perform general research on genetic process ...

radiologists Radiology ( ) is the medical specialty that uses medical imaging to diagnose diseases and guide treatment within the bodies of humans and other animals. It began with radiography (which is why its name has a root referring to radiation), but tod ...

psychologist A psychologist is a professional who practices psychology and studies mental states, perceptual, cognitive, emotional, and social processes and behavior. Their work often involves the experimentation, observation, and explanation, interpretatio ...

s and

social work Social work is an academic discipline and practice-based profession concerned with meeting the basic needs of individuals, families, groups, communities, and society as a whole to enhance their individual and collective well-being. Social wo ...

ers. These professionals are capable of providing first line (prenatal) and second line diagnostic (postnatal) tests to examine and diagnose sexual anomalies.

Overview

DSDs are defined as "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, casual social adjective for people with DSDs is "

intersex Intersex people are those 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 binar ...

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 system and the reproductive organs. Orga ...

were concerned that terms like intersex,

hermaphrodite A hermaphrodite () is a sexually reproducing organism that produces both male and female gametes. Animal species in which individuals are either male or female are gonochoric, which is the opposite of hermaphroditic. The individuals of many ...

, and pseudohermaphrodite were confusing and pejorative with respect to humans. This led to the Chicago Consensus, recommending a new terminology based on the umbrella term ''disorders of sex development.'' Other than disorders of sex development, another term is congenital conditions of sex development (CCSD). Since 2006, people who were previously incorrectly categorized as hermaphrodites are now labelled as having

ovotesticular syndrome Ovotesticular syndrome (also known as ovotesticular disorder or OT-DSD) is a rare congenital condition where an individual is born with both ovarian and testicular tissue. It is one of the rarest disorders of sex development (DSDs), with only 50 ...

. DSDs are divided into the following categories, emphasizing the

's role in diagnosis: * 46,XX DSD: Genetic Female Sex Chromosomes. Mainly

virilized Virilization or masculinization is the biological development of adult male characteristics in young males or females. Most of the changes of virilization are produced by androgens. Virilization is a medical term commonly used in three medical a ...

females as a result of

congenital adrenal hyperplasia Congenital adrenal hyperplasia (CAH) is a group of Genetic disorder#Autosomal recessive, autosomal recessive disorders characterized by impaired cortisol synthesis. It results from the deficiency of one of the five enzymes required for the Biosy ...

(CAH) and girls with aberrant ovarian development. * 46,XY DSD: Genetic Male Sex Chromosomes. Individuals with abnormal testicular differentiation, defects in testosterone biosynthesis, and impaired testosterone action. *

Sex chromosome Sex chromosomes (also referred to as allosomes, heterotypical chromosome, gonosomes, heterochromosomes, or idiochromosomes) are chromosomes that carry the genes that determine the sex of an individual. The human sex chromosomes are a typical pair ...

DSD: patients with sex chromosome

aneuploidy Aneuploidy is the presence of an abnormal number of chromosomes in a cell (biology), cell, for example a human somatic (biology), somatic cell having 45 or 47 chromosomes instead of the usual 46. It does not include a difference of one or more plo ...

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 (masonry), mortar, and covering a surface. Mosaics are often used as floor and wall decoration, and ...

sex karyotypes. This includes patients with

Turner Syndrome Turner syndrome (TS), commonly known as 45,X, or 45,X0,Also written as 45,XO. is a chromosomal disorder in which cells of females have only one X chromosome instead of two, or are partially missing an X chromosome (sex chromosome monosomy) lea ...

(45,X or 45,X0) and

Klinefelter Syndrome Klinefelter syndrome (KS), also known as 47,XXY, is a chromosome anomaly where a male has an extra X chromosome. These complications commonly include infertility and small, poorly functioning testicles (if present). These symptoms are often n ...

(47,XXY) 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

Sex-determining region Y protein Sex-determining region Y protein (SRY), or testis-determining factor (TDF), is a DNA-binding protein (also known as gene-regulatory protein/transcription factor) encoded by the ''SRY'' gene that is responsible for the initiation of male sex ...

(SRY) and the second with no SRY gene. * Ovotesticular disorder: patients having both

ovarian The ovary () is a gonad in the female reproductive system that produces ova; when released, an ovum travels through the fallopian tube/oviduct into the uterus. There is an ovary on the left and the right side of the body. The ovaries are endoc ...

and

testicular A testicle or testis ( testes) is the gonad in all male bilaterians, including humans, and is homologous to the ovary in females. Its primary functions are the production of sperm and the secretion of androgens, primarily testosterone. The r ...

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'') gene is associated with XY sex reversal.

Genital anatomy

Quigley scale for androgen insensitivity syndrome

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 embryonic development of the urinary and reproductive organs, before sexual differentiation is evident. This is also the case ...

. 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 malformation in fetal development of the penis in which the urethra does not open from its usual location on the head of the penis. It is the second-most common birth defect of the male reproductive system, affecting about ...

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 An academic discipline or academic field is a subdivision of knowledge that is taught and researched at the college or university level. Disciplines are defined (in part) and recognized by the academic journals in which research is published, ...

team. Health care providers generally agree that children with DSDs should be notified early. Appropriate and conservative

medical intervention A therapy or medical treatment is the attempted remediation of a health problem, usually following a medical diagnosis. Both words, ''treatment'' and ''therapy'', are often abbreviated tx, Tx, or Tx. As a rule, each therapy has indications an ...

and age-appropriate child involvement in the treatment plan contribute greatly to successful outcomes for the entire range of DSDs.

Key hormones

In the normal prenatal stages of

fetal development Prenatal development () involves the development of the embryo and of the fetus during a viviparous animal's gestation. Prenatal development starts with fertilization, in the germinal stage of embryonic development, and continues in fetal deve ...

, the fetus is exposed to

testosterone Testosterone is the primary male sex hormone and androgen in Male, males. In humans, testosterone plays a key role in the development of Male reproductive system, male reproductive tissues such as testicles and prostate, as well as promoting se ...

- albeit more in male fetuses than female ones. Upon the presence of the 5α-reductase enzyme, testosterone is converted to

dihydrotestosterone Dihydrotestosterone (DHT, 5α-dihydrotestosterone, 5α-DHT, androstanolone or stanolone) is an endogenous androgen sex steroid and hormone primarily involved in the growth and repair of the prostate and the penis, as well as the production o ...

(i.e. DHT). If DHT is present, the male external genitalia will develop. Development of male external genitalia: *

Genital tubercle A genital tubercle, phallic tubercle, or clitorophallic structure is a body of tissue present in the development of the reproductive system of amniotes. It forms in the ventral, caudal region of mammalian embryos of both sexes, and eventually ...

forms the

penis A penis (; : penises or penes) is a sex organ through which male and hermaphrodite animals expel semen during copulation (zoology), copulation, and through which male placental mammals and marsupials also Urination, urinate. The term ''pen ...

* Urethral folds form the

penile raphe The penile raphe is a visible line or ridge of tissue that runs on the ventral (urethral) side of the human penis beginning from the base of the shaft and ending in the prepuce between the penile frenulum. The line is typically darker than the ...

* Genital swellings form the

scrotum In most terrestrial mammals, the scrotum (: scrotums or scrota; possibly from Latin ''scortum'', meaning "hide" or "skin") or scrotal sac is a part of the external male genitalia located at the base of the penis. It consists of a sac of skin ...

On the other hand, if maternal

placenta The placenta (: placentas or placentae) is a temporary embryonic and later fetal organ that begins developing from the blastocyst shortly after implantation. It plays critical roles in facilitating nutrient, gas, and waste exchange between ...

estrogen Estrogen (also spelled oestrogen in British English; see spelling differences) is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three ...

is present without DHT, then the development of female external genitalia occurs. Development of female external genitalia (the

vulva In mammals, the vulva (: vulvas or vulvae) comprises mostly external, visible structures of the female sex organ, genitalia leading into the interior of the female reproductive tract. For humans, it includes the mons pubis, labia majora, lab ...

): *

forms the

clitoris In amniotes, the clitoris ( or ; : clitorises or clitorides) is a female sex organ. In humans, it is the vulva's most erogenous zone, erogenous area and generally the primary anatomical source of female Human sexuality, sexual pleasure. Th ...

* Urethral folds form the

labia minora The labia minora (Latin for 'smaller lips', : labium minus), also known as the inner labia, inner lips, or nymphae, are two flaps of skin that are part of the primate vulva, extending outwards from the inner Vagina#Vaginal opening and hymen, vagi ...

* Genital swellings form the

labia majora In primates, and specifically in humans, the labia majora (: labium majus), also known as the outer lips or outer labia, are two prominent Anatomical terms of location, longitudinal skin folds that extend downward and backward from the mons pubis ...

However, in abnormal cases, sexual anomalies occur due to a variety of factors that lead to an excess of

androgen An androgen (from Greek ''andr-'', the stem of the word meaning ) is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This includes ...

s in the fetus. The effects of excessive androgens differ in fetuses with XX chromosome (female) and XY chromosomes (male). In XX chromosome fetuses, excess androgens result in

ambiguous genitalia Intersex people are those born with any of several Sexual characteristics, sex characteristics, including chromosome patterns, gonads, or sex organ, genitals that, according to the Office of the United Nations High Commissioner for Human ...

. This makes identification of external genitalia as male or female difficult. Additionally, the individual may have

clitoromegaly Clitoromegaly (or macroclitoris) is an abnormal enlargement of the clitoris that is mostly congenital; it is otherwise acquired through deliberately induced clitoral enlargement, a form of body modification, by use of anabolic steroids, in parti ...

, a shallow

vagina In mammals and other animals, the vagina (: vaginas or vaginae) is the elastic, muscular sex organ, reproductive organ of the female genital tract. In humans, it extends from the vulval vestibule to the cervix (neck of the uterus). The #Vag ...

, early and rapid growth of pubic hair in childhood,

delayed puberty Delayed puberty is when a person lacks or has incomplete development of specific sexual characteristics past the usual age of onset of puberty. The person may have no physical or hormone, hormonal signs that puberty has begun. In the United States ...

hirsutism Hirsutism is excessive body hair on parts of the body where hair is normally absent or minimal. The word is from early 17th century: from Latin ''hirsutus'' meaning "hairy". It usually refers to a male pattern of hair growth in a female that ma ...

, virilisation,

irregular menstrual cycle Irregular menstruation is a menstrual disorder whose manifestations include irregular cycle lengths as well as metrorrhagia (vaginal bleeding between expected periods). The possible causes of irregular menstruation may vary. The common factors of ...

in adolescence and infertility due to

anovulation Anovulation is when the ovaries do not release an oocyte during a menstrual cycle. Therefore, ovulation does not take place. However, a woman who does not ovulate at each menstrual cycle is not necessarily going through menopause. Chronic anovulat ...

. In XY chromosome fetuses, excess androgens result in a functional and average-sized penis with extreme virilisation, but the inability for sperm production. Additionally, the individual will also experience early and rapid growth of pubic hair during childhood and precocious puberty stages.

Causes

Sexual anomalies often generate from genetic abnormalities caused by many factors, leading to different sexual development. These genetic abnormalities occur during the prenatal stage of an individual's fetal development. During this stage, genetic mutations can result from endocrine disrupters in the mother's diet or environmental factors. The general causes of sexual anomalies can not be outlined due to the high variability of each individual's situations. Thus, the cause of each specific anomaly has to be studied independently. Sexual differentiation occurs through various processes during the prenatal development period of the fetus. These processes are initiated and regulated by biological metabolites such as

DNA Deoxyribonucleic acid (; DNA) is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic instructions for the development, functioning, growth and reproduction of al ...

hormone A hormone (from the Ancient Greek, Greek participle , "setting in motion") is a class of cell signaling, signaling molecules in multicellular organisms that are sent to distant organs or tissues by complex biological processes to regulate physio ...

s and

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

s. The initial steps of sexual differentiation begin with the development of the gonads and genitals. This process is consistent with both genders spanning over the course of the first 6 weeks following conception, during which the embryo remains

pluripotent Cell potency is a cell's ability to differentiate into other cell types. The more cell types a cell can differentiate into, the greater its potency. Potency is also described as the gene activation potential within a cell, which like a continuum ...

. Differentiation of the gonads begins after the 6th week, which is determined by the sex-determining region Y (SRY) gene in the Y chromosome. The SRY gene plays an important role in developing the testes of a male individual. Following the development of the testes, hormones synthesized within the testes regulate the differentiation of both internal and external parts of the genitals. The absence of the testicles or the hormones synthesized may lead to irregular differentiation of the genitals. Genetic abnormalities or environmental factors that influence these procedures may lead to the incomplete development of the gonads and the genitals. These malformations can occur any time during the development or the birth of the embryo, manifesting as ambiguous genitals or dissonance within the genotypic and phenotypic sex of the individual, leading to a late onset of puberty, amenorrhea, a lack of or excess virilization, or later in life, infertility or early occurrence of

menopause Menopause, also known as the climacteric, is the time when Menstruation, menstrual periods permanently stop, marking the end of the Human reproduction, reproductive stage for the female human. It typically occurs between the ages of 45 and 5 ...

Chromosomal variation

DSDs caused by chromosomal variation generally do not present with genital ambiguity. This includes sex chromosome DSDs such as

Klinefelter syndrome Klinefelter syndrome (KS), also known as 47,XXY, is a chromosome anomaly where a male has an extra X chromosome. These complications commonly include infertility and small, poorly functioning testicles (if present). These symptoms are often n ...

Turner syndrome Turner syndrome (TS), commonly known as 45,X, or 45,X0,Also written as 45,XO. is a chromosomal disorder in which cells of females have only one X chromosome instead of two, or are partially missing an X chromosome (sex chromosome monosomy) lea ...

and 45,X or 46,XY

gonadal dysgenesis Gonadal dysgenesis is classified as any congenital developmental disorder of the reproductive system characterized by a progressive loss of primordial germ cells on the developing gonads of an embryo. One type of gonadal dysgenesis is the devel ...

. Males with Klinefelter syndrome usually have a

of 47,XXY as a result of having two or more X

chromosome A chromosome is a package of DNA containing part or all of the genetic material of an organism. In most chromosomes, the very long thin DNA fibers are coated with nucleosome-forming packaging proteins; in eukaryotic cells, the most import ...

s. Affected patients generally have normal genital development, yet are infertile and have small, poor functioning

testes A testicle or testis ( testes) is the gonad in all male bilaterians, including humans, and is homologous to the ovary in females. Its primary functions are the production of sperm and the secretion of androgens, primarily testosterone. The ...

, breast growth and delayed puberty. The incidence for 47,XXY is 1 in 500 males, but severe and rare cases of Klinefelter syndrome presents as three or more X chromosomes. Turner syndrome is classified as

or structural rearrangement of the X chromosome. Signs and symptoms of affected females vary among them, such as low birth weight, low-set ears, short stature, short neck and delayed puberty. The incidence is 1 in 2500 live-born females, while most patients do not survive for more than one year after birth.

Gonadal development disorders

Gonadal development disorders form a wide spectrum, classified by their

cytogenetic Cytogenetics is essentially a branch of genetics, but is also a part of cell biology/cytology (a subdivision of human anatomy), that is concerned with how the chromosomes relate to cell behaviour, particularly to their behaviour during mitosis an ...

and

histopathological Histopathology (compound of three Greek language, Greek words: 'tissue', 'suffering', and ''-logy, -logia'' 'study of') is the light microscope, microscopic examination of Tissue (biology), tissue in order to study the manifestations of dis ...

features. However, unsolved diagnosis and

malignancy Malignancy () is the tendency of a medical condition to become progressively worse; the term is most familiar as a characterization of cancer. A ''malignant'' tumor contrasts with a non-cancerous ''benign'' tumor in that a malignancy is not ...

still represent difficulties in the sex determination of these patients. Such disorders include partial or complete gonadal dysgenesis, ovotesticular DSD,

DSD and sex reversal.

Abnormal genital development

Genital abnormality can occur in the penis, scrotum or testes in males; and vagina and labia in females. Sometimes, ambiguous genitalia could occur, where the clear distinction of external genitalia is absent in both male and female. Hence, examination (typically at birth) is carried out where the sex of the patient will be determined through

imaging Imaging is the representation or reproduction of an object's form; especially a visual representation (i.e., the formation of an image). Imaging technology is the application of materials and methods to create, preserve, or duplicate images. ...

and

blood test A blood test is a medical laboratory, laboratory analysis performed on a blood sample that is usually extracted from a vein in the arm using a hypodermic needle, or via fingerprick. Multiple tests for specific blood components, such as a glucose ...

s. Abnormal genital development includes disorders of fetal origin, disorders in androgen synthesis or action, disorders in

anti-Müllerian hormone Anti-Müllerian hormone (AMH), also known as Müllerian-inhibiting hormone (MIH), is a glycoprotein hormone structurally related to Activin and inhibin, inhibin and activin from the transforming growth factor beta superfamily, whose key roles a ...

synthesis or action.

Others

In addition to the aforementioned sexual anomalies, there are other unclassified sexual anomalies. In males, this includes severe early-onset

intrauterine growth restriction Intrauterine growth restriction (IUGR), or fetal growth restriction, is the poor growth of a fetus while in the womb during pregnancy. IUGR is defined by clinical features of malnutrition and evidence of reduced growth regardless of an infant's ...

, isolated

, congenital hypogonadotropic hypogonadism,

hypogonadism Hypogonadism means diminished functional activity of the human gonad, gonads—the testicles or the ovary, ovaries—that may result in diminished biosynthesis, production of sex hormones. Low androgen (e.g., testosterone) levels are referred t ...

and

cryptorchidism Cryptorchidism, also known as undescended testis, is the failure of one or both testes to descend into the scrotum. The word is . It is the most common birth defect of the male genital tract. About 3% of full-term and 30% of premature infant boy ...

. In females, this includes Malformation syndromes,

Müllerian agenesis Müllerian may refer to: * Müllerian mimicry, a type of mimicry or convergence named after Fritz Müller * Müllerian ducts, which enter the cloaca of an embryo (named after Johannes Peter Müller) * Mullerian anomalies are structural anomalies c ...

hypoplasia Hypoplasia (; adjective form ''hypoplastic'') is underdevelopment or incomplete development of a tissue or organ.uterine anomalies,

vaginal atresia Vaginal atresia is a condition in which the vagina is abnormally closed or absent. The main causes can either be complete vaginal hypoplasia, or a vaginal obstruction, often caused by an imperforate hymen or, less commonly, a transverse vaginal sep ...

and labial adhesions.

Conditions

* 5α-reductase deficiency (5-ARD) – an

autosomal recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...

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 ...

– a condition characterized by impaired androgen and estrogen synthesis in males and females, respectively. Results in pseudohermaphroditism/undervirilization in males. *

46,XX/46,XY 46,XX/46,XY is either a chimeric or mosaic genetic condition characterized by the presence of some cells that express a 46,XX karyotype and some cells that express a 46,XY karyotype in a single human being. Individuals with these conditions are c ...

– a chimeric condition where the person shows variable karyotype in the 23rd chromosome pair, resulting from embryonic merging. It can vary in presentation from phenotypically normal, to ambiguous. *

Androgen insensitivity syndrome Androgen insensitivity syndrome (AIS) is a condition involving the inability to respond to androgens, typically due to androgen receptor dysfunction. It affects 1 in 20,000 to 64,000 XY (karyotype, karyotypically male) births. The condition result ...

(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 Eukaryote#Animal cell, cell to respond to androgens. It is an X linked recessive condition. The partial unresponsiveness of the cell to the ...

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 individual ...

causes a genetic male to have a vagina (often incompletely developed, nearly always blind-ending), breasts, and a clitoris; people with this form are raised as females. *

Aphallia Aphallia is a congenital malformation in which the phallus (penis or clitoris) is absent. It is also known as penile agenesis in the case of males. The word is derived . It is classified as a disorder of sex development. Causes Aphallia has no k ...

– a rare condition where a XY male is born without a

. As of 2017, only 100 cases have been reported in literature. *

Aromatase deficiency Aromatase deficiency is a rare condition characterized by extremely low levels or complete absence of the enzyme aromatase activity in the body. It is an autosomal recessive disease resulting from various mutations of gene CYP19 (P450arom) which ...

– 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

). Aromatase deficiency can also be caused by mutations in P450 oxidoreductase gene. *

Aromatase excess syndrome Aromatase excess syndrome (AES or AEXS) is a rarely diagnosed genetic disorder, genetic and endocrine disease, endocrine syndrome which is characterized by an gene expression, overexpression of aromatase, the enzyme responsible for the biosynthesi ...

(familial hyperestrogenism) - a condition that causes excessive

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 Campomelic dysplasia (CMD) is a genetic disorder characterized by bowing of the long bones and many other skeletal and extraskeletal features. It can be lethal in the neonatal period due to respiratory insufficiency, but the severity of the diseas ...

– a condition caused by ''de novo'' autosomal dominant mutations in the

SOX9 Transcription factor SOX-9 is a protein that in humans is encoded by the ''SOX9'' gene. Function SOX-9 recognizes the sequence CCTTGAG along with other members of the HMG-box class DNA-binding domain, DNA-binding proteins. It is expressed by ...

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 r ...

. While in roughly 95% of cases, death occurs in the

neonatal In common terminology, a baby is the very young offspring of adult human beings, while infant (from the Latin word ''infans'', meaning 'baby' or 'child') is a formal or specialised synonym. The terms may also be used to refer to Juvenile (orga ...

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; it is otherwise acquired through deliberately induced clitoral enlargement, a form of body modification, by use of anabolic steroids, in parti ...

– a

that is considered larger than average. While clitoromegaly may be a symptom of an

intersex condition Intersex people are those born with any of several Sexual characteristics, sex characteristics, including chromosome patterns, gonads, or sex organ, genitals that, according to the Office of the United Nations High Commissioner for Human ...

, 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 Female genital mutilation (FGM) (also known as female genital cutting, female genital mutilation/cutting (FGM/C) and female circumcision) is the cutting or removal of some or all of the vulva for non-medical reasons. Prevalence of female ge ...

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

anabolic steroids Anabolic steroids, also known as anabolic-androgenic steroids (AAS), are a class of drugs that are structurally related to testosterone, the main male sex hormone, and produce effects by binding to the androgen receptor (AR). Anabolic steroids ...

for purposes related to

female to male A trans man or transgender man is a man who was assigned female at birth. Trans men have a male gender identity, and many trans men undergo medical and social transition to alter their appearance in a way that aligns with their gender identit ...

gender transition Gender transition is the process of affirming and expressing one's internal sense of gender, rather than the sex assigned to them at birth. It is a recommended course of treatment for individuals experiencing gender dysphoria, providing impro ...

bodybuilding Bodybuilding is the practice of Resistance training, progressive resistance exercise to build, control, and develop one's skeletal muscle, muscles via muscle hypertrophy, hypertrophy. An individual who engages in this activity is referred to a ...

. * Combined 17α-hydroxylase/17,20-lyase deficiency – a condition which presents as a combination of the symptoms of

and isolated 17,20-lyase deficiency. See those two conditions for more information. *

(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 ) is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This includes ...

. It is considered a form of

androgen insensitivity syndrome Androgen insensitivity syndrome (AIS) is a condition involving the inability to respond to androgens, typically due to androgen receptor dysfunction. It affects 1 in 20,000 to 64,000 XY (karyotype, karyotypically male) births. The condition result ...

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 or amenorrhoea is the absence of a menstrual period in a female organism who has reached reproductive age. Physiological states of amenorrhoea are most commonly seen during pregnancy and lactation (breastfeeding). In humans, it is wher ...

in their late teens or they need medical intervention due to a

hernia A hernia (: hernias or herniae, from Latin, meaning 'rupture') is the abnormal exit of tissue or an organ (anatomy), organ, such as the bowel, through the wall of the cavity in which it normally resides. The term is also used for the normal Devel ...

caused by their

undescended testes Cryptorchidism, also known as undescended testis, is the failure of one or both testes to descend into the scrotum. The word is . It is the most common birth defect of the male genital tract. About 3% of full-term and 30% of premature infant boy ...

. Complete androgen insensitivity syndrome results in a genetic male having a vagina, clitoris, and breasts which are capable of

breastfeeding Breastfeeding, also known as nursing, is the process where breast milk is fed to a child. Infants may suck the milk directly from the breast, or milk may be extracted with a Breast pump, pump and then fed to the infant. The World Health Orga ...

. However, they will not have

ovaries The ovary () is a gonad in the female reproductive system that produces ova; when released, an ovum travels through the fallopian tube/oviduct into the uterus. There is an ovary on the left and the right side of the body. The ovaries are endocr ...

or a

uterus The uterus (from Latin ''uterus'', : uteri or uteruses) or womb () is the hollow organ, organ in the reproductive system of most female mammals, including humans, that accommodates the embryonic development, embryonic and prenatal development, f ...

. Because they do not have ovaries or sufficiently developed testicles, people with complete androgen insensitivity syndrome are

infertile In biology, infertility is the inability of a male and female organism to reproduce. It is usually not the natural state of a healthy organism that has reached sexual maturity, so children who have not undergone puberty, which is the body's sta ...

. *

Congenital adrenal hyperplasia Congenital adrenal hyperplasia (CAH) is a group of Genetic disorder#Autosomal recessive, autosomal recessive disorders characterized by impaired cortisol synthesis. It results from the deficiency of one of the five enzymes required for the Biosy ...

(CAH) – a condition that causes excessive

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. 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 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-rich ...

gene, causing symptoms ranging from undervirilization to complete sex reversal with persistent

Müllerian ducts The paramesonephric ducts (or Müllerian ducts) are paired ducts of the embryo in the reproductive system of humans and other mammals that run down the lateral sides of the genital ridge and terminate at the sinus tubercle in the primitive urogen ...

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 Nephrotic syndrome is a collection of symptoms due to kidney damage. This includes proteinuria, protein in the urine, hypoalbuminemia, low blood albumin levels, hyperlipidemia, high blood lipids, and significant edema, swelling. Other symptoms ...

. *

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 r ...

(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. *

Gartner's duct cyst A Gartner's duct cyst (sometimes incorrectly referred to as ''vaginal inclusion cyst'') is a benign vaginal cyst that originates from the Gartner's duct, which is a vestigial remnant of the mesonephric duct (Wolffian duct) in females. They are typ ...

– persistent Wolffian Ducts in XX females. *

Gonadal dysgenesis Gonadal dysgenesis is classified as any congenital developmental disorder of the reproductive system characterized by a progressive loss of primordial germ cells on the developing gonads of an embryo. One type of gonadal dysgenesis is the devel ...

– any congenital developmental disorder of the reproductive system characterized by a progressive loss of

primordial germ cells A germ cell is any cell that gives rise to the gametes of an organism that reproduces sexually. In many animals, the germ cells originate in the primitive streak and migrate via the gut of an embryo to the developing gonads. There, they undergo ...

on the developing gonads of an embryo. * Herlyn-Werner-Wunderlich syndrome – a disorder where the Müllerian ducts fail to fuse during embryonic development, leading to the presence of 2 vaginas, 2 uteruses, and a single kidney. Can also affect the spleen, bladder and other urogenital structures. * Isolated 17,20-lyase deficiency – 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. *

(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. 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). While some men may have no issues related to the syndrome, some may experience

gynecomastia Gynecomastia (also spelled gynaecomastia) is the non-cancerous enlargement of one or both breasts in men due to the growth of breast tissue as a result of a hormone imbalance between estrogens and androgens. Updated by Brent Wisse (10 Novemb ...

micropenis A micropenis or microphallus is an unusually small Human penis, penis. A common criterion is a dorsal (measured on top) Human penis size, penile length of at least 2.5 standard deviations smaller than the mean human penis size for age. A micr ...

, cognitive difficulties,

, reduced fertility/

infertility In biology, infertility is the inability of a male and female organism to Sexual reproduction, reproduce. It is usually not the natural state of a healthy organism that has reached sexual maturity, so children who have not undergone puberty, whi ...

, and/or little or no

facial hair Facial hair is hair grown on the face, usually on the chin, cheeks, bottom lip and upper lip region. It is typically a secondary sex characteristic of human males. Men typically start developing facial hair in the later stages of puberty or adol ...

Testosterone Testosterone is the primary male sex hormone and androgen in Male, males. In humans, testosterone plays a key role in the development of Male reproductive system, male reproductive tissues such as testicles and prostate, as well as promoting se ...

therapy may be pursued by men who desire a more masculine appearance and those with gynecomastia may opt to undergo a

reduction mammoplasty Reduction mammoplasty (also breast reduction and reduction mammaplasty) is the plastic surgery procedure for reducing the size of large breasts. In a breast reduction surgery for re-establishing a functional Cleavage (breasts), bust that is propo ...

. 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 in which an egg is combined with sperm in vitro ("in glass"). The process involves monitoring and stimulating the ovulatory process, then removing an ovum or ova (egg or eggs) from t ...

. *

Leydig cell hypoplasia Leydig cell hypoplasia (or aplasia) (LCH), also known as Leydig cell agenesis, is a rare autosomal recessive genetic and endocrine syndrome affecting an estimated 1 in 1,000,000 individuals with XY chromosomes. It is characterized by an inability ...

– 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

and

. 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 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). Wit ...

synthesis: the transport of

cholesterol Cholesterol is the principal sterol of all higher animals, distributed in body Tissue (biology), tissues, especially the brain and spinal cord, and in Animal fat, animal fats and oils. Cholesterol is biosynthesis, biosynthesized by all anima ...

into the

mitochondria A mitochondrion () is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is us ...

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. *

(MAIS) – a condition which mildly affects a genetic male's ability to recognize

. It is considered a form of

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

and

. 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 45,X/46,XY mosaicism, also known as X0/XY mosaicism and mixed gonadal dysgenesis, is a mutation of sex development in humans associated with sex chromosome aneuploidy and mosaicism of the Y chromosome. It is a fairly rare chromosomal disorder a ...

– 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 differentiation is usually distinct from sex determination; sex determination is the designation of the de ...

. A number of differences have been reported in the

, most commonly a

mosaicism Mosaicism or genetic mosaicism is a condition in which a multicellular organism possesses more than one genetic line as the result of genetic mutation. This means that various genetic lines resulted from a single fertilized egg. Mosaicism is o ...

45,X/ 46,XY. * Ovotesticular disorder (also called true hermaphroditism) – a rare condition where an individual has both ovarian and testicular tissue. It is the rarest DSD with at least 500 cases being reported in literature. *

(PAIS) – a condition which partially affects a genetic male's ability to recognize

. It is considered a form of

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 individual ...

, 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 Sex assignment (also known as gender assignment) is the discernment of an infant's sex, typically made at birth based on an examination of the baby's external genitalia by a healthcare provider such as a midwife, nurse, or physician. In the v ...

because it causes ambiguous genitalia such as a

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 Penoscrotal transposition (PST) is a group of congenital defects involving an abnormal spatial arrangement of penis and scrotum In most terrestrial mammals, the scrotum (: scrotums or scrota; possibly from Latin ''scortum'', meaning "hide" ...

(PST) – a group of congenital defects involving an abnormal spatial arrangement of penis and scrotum. *

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. In humans, ...

– a condition where fallopian tubes, uterus, or the upper part of the vagina are present in an otherwise normal male. * Pseudovaginal perineoscrotal hypospadias (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 Glans penis, head of the Human penis, penis curves downward or upward, at the junction of the head and Body of penis, shaft of the penis. The curvature is usually most obvious during erection, but resistance to ...

, and a shallow vagina. *

Swyer syndrome XY complete gonadal dysgenesis, also known as Swyer syndrome, is a type of defect hypogonadism in a person whose karyotype is 46,XY. Though they typically have normal vulvas, the person has underdeveloped gonads, fibrous tissue termed " streak go ...

(Pure Gonadal Dysgenesis or XY gonadal dysgenesis) – a type of

in a person whose

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 female, the testicles i ...

. 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. Effects of menopause can include symptoms such ...

with female hormones. *

(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 can cause 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 edema, swelling caused by a compromised lymphatic system. The lymphatic system functions as a critical portion of the body's immune system and returns inters ...

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) 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'' means "pressing or drawing toget ...

ADHD Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by symptoms of inattention, hyperactivity, impulsivity, and emotional dysregulation that are excessive and pervasive, impairing in multiple ...

, and

obesity Obesity is a medical condition, considered by multiple organizations to be a disease, in which excess Adipose tissue, body fat has accumulated to such an extent that it can potentially have negative effects on health. People are classifi ...

. *

( 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 – 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.

Diagnosis and symptoms

First line diagnostic tests (prenatal)

Family history

* Symptoms such as infertility, early menopause,

amenorrhea Amenorrhea or amenorrhoea is the absence of a menstrual period in a female organism who has reached reproductive age. Physiological states of amenorrhoea are most commonly seen during pregnancy and lactation (breastfeeding). In humans, it is wher ...

or sudden infant death syndrome (SIDS) could be a sign. Hence, an early check-up should be conducted.

Analysis of karyotype

* Peripheral blood is collected for karyotyping. This helps classify the patient in one of the three main categories of DSD: chromosomal variation, gonadal development disorders and abnormal genital development.

Abdominal ultrasounds

* The presence of gonads, uterus and vagina should be monitored. This can be done through abdominal ultrasounds. However, the absence of these sex organs will lead to difficulties in gender identification.

Second line diagnostic tests (postnatal)

Physical Examination

# Inspection of the genitalia with care and palpation must be conducted with the following points in mind. #* Determining the degree of

virilization Virilization or masculinization is the biological development of adult male characteristics in young males or females. Most of the changes of virilization are produced by androgens. Virilization is a medical term commonly used in three medical a ...

or masculinisation: #** In a female fetus, the Prader scale should be used to assess the extent of the virilisation if the karyotyping results are not out yet. #** In males, the external masculinization score should be used. # Palpation of gonads from the labioscrotal fold to the

abdomen The abdomen (colloquially called the gut, belly, tummy, midriff, tucky, or stomach) is the front part of the torso between the thorax (chest) and pelvis in humans and in other vertebrates. The area occupied by the abdomen is called the abdominal ...

(

inguinal canal The inguinal canal is a passage in the anterior abdominal wall on each side of the body (one on each side of the midline), which in males, convey the spermatic cords and in females, the round ligament of the uterus. The inguinal canals are lar ...

). # Hydration and blood pressure assessment should be conducted. # Additional dysmorphic features should be ruled out because genitalia malformations would occur if the patient has multiple malformation syndromes.

Evaluation of hormones 48 hours after birth

* 17-Hydroxyprogesterone can be used to screen for congenital adrenal hyperplasia (CAH). This is commonly found in patients with 46, XX DSD. * Dehydroepiandrosterone (DHEA) in addition to progesterone allows for the diagnosis of more uncommon forms of CAH and other inherited disorders. * Base

follicle stimulating hormone Follicle-stimulating hormone (FSH) is a gonadotropin, a glycoprotein polypeptide hormone. FSH is synthesized and secreted by the gonadotropic cells of the anterior pituitary gland and regulates the development, growth, pubertal maturation, ...

(FSH) and

luteinising hormone Luteinizing hormone (LH, also known as luteinising hormone, lutropin and sometimes lutrophin) is a hormone produced by gonadotropic cells in the anterior pituitary gland. The production of LH is regulated by gonadotropin-releasing hormone (GnR ...

(LH) levels are precursors in individuals with 46,XX DSD. These tests are conducted within the timeframe of thirty hours post-birth to anywhere between fifteen and ninety days post-birth. This data collected within time frame can be used to gauge the growth of the fetus when it reaches six months of age. * Basal

cortisol Cortisol is a steroid hormone in the glucocorticoid class of hormones and a stress hormone. When used as medication, it is known as hydrocortisone. Cortisol is produced in many animals, mainly by the ''zona fasciculata'' of the adrenal corte ...

levels and

adrenocorticotropic hormone Adrenocorticotropic hormone (ACTH; also adrenocorticotropin, corticotropin) is a polypeptide tropic hormone produced by and secreted by the anterior pituitary gland. It is also used as a medication and diagnostic agent. ACTH is an important ...

(ACTH) is essential in diagnosing

panhypopituitarism Hypopituitarism is the decreased (''hypo'') secretion of one or more of the eight hormones normally produced by the pituitary gland at the base of the brain. If there is decreased secretion of one specific pituitary hormone, the condition is know ...

and

enzymatic An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as produc ...

disorders affecting adrenal steroidogenesis. * The

is used for evaluating the function of Sertoli cells. * A urinary steroid profile shows the ratio of precursor metabolites within measured urine concentrations and the resultant products produced indicates the enzyme is the cause of a sexual defect. This is a more specific procedure in the detection of the defect in comparison to analysing blood.

Treatment and management

The treatment and/or management of DSDs with atypical genitalia will vary from person to person. This may include gender affirmation surgery, medical treatment and surgical treatment.

Gender affirmation surgery

Gender affirmation plays a critical role in the management of sexual anomaly cases. Ultimately, the parents and a multidisciplinary team are responsible for assigning the sex that is affirmative the gender of the concerned person. The current guidelines of gender affirmation include the psychosocial effects in adults with etiological diagnosis, the potential for fertility, surgical opportunities and hormone replacement therapy in the course of puberty. There are other factors considered during this process. This may include cultural and religious factors as well as the implications it has on the individual in later life. It is regulated by reference centers with groups specialised in managing cases of sexual anomalies.

Medical treatment

Hormonal treatment is an accepted and standardised approach to treat different congenital sexual anomalies. Patients that are deficient in hormones produced by the

adrenal gland The adrenal glands (also known as suprarenal glands) are endocrine glands that produce a variety of hormones including adrenaline and the steroids aldosterone and cortisol. They are found above the kidneys. Each gland has an outer adrenal corte ...

s require immediate medical attention. They are given a hormone called

hydrocortisone Hydrocortisone is the name for the hormone cortisol when supplied as a medication. It is a corticosteroid and works as an anti-inflammatory and by immune suppression. Uses include conditions such as adrenocortical insufficiency, adrenogenit ...

, a form of hormone replacement therapy, with the objective to induce puberty. Utilizing

sex steroids Sex hormones, also known as sex steroids, gonadocorticoids and gonadal steroids, are steroid hormones that interact with vertebrate steroid hormone receptors. The sex hormones include the androgens, estrogens, and progestogens. Their effects a ...

as hormonal therapy is deemed controversial with concerns of its duration of initiation, dosage and regimen. However, it is agreed amongst most clinicians that low doses of hormonal treatment should begin around the age of 11 to 12 years old and should be increased progressively.

Surgical treatment

Surgical procedures are an alternative to hormonal treatment available for patients to address genital anomalies and improve the body's sexual functions. However, a common dilemma in these procedures is that they are often derived from the patient's expectation of 'normal' genitals from an aesthetic and functional standpoint. Oftentimes, this leads to extensive surgical interventions. In most cases, surgical procedures result in permanent changes to the appearance and function of the patient's body. Therefore, the decision to proceed with this arrangement must be a joint agreement between the family and the multidisciplinary team. The most ideal situation would be to include the patient as part of the decision-making process. However, cases where surgical treatments were performed at an early age are recognised as

mutilation Mutilation or maiming (from the ) is Bodily harm, severe damage to the body that has a subsequent harmful effect on an individual's quality of life. In the modern era, the term has an overwhelmingly negative connotation, referring to alteratio ...

of the body. Subsequently, it has become increasingly common to defer surgical treatments until the patient is of appropriate age to be involved in the decision-making process.

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

Even though the term disorder of sex development (DSD) is widely accepted by the medical community, its suitability and adequacy to represent these individuals are criticised by many support and

advocacy group Advocacy groups, also known as lobby groups, interest groups, special interest groups, pressure groups, or public associations, use various forms of advocacy or lobbying to influence public opinion and ultimately public policy. They play an impor ...

s. Firstly, the word 'disorder' carries negative connotations. Secondly, with current

nomenclature Nomenclature (, ) is a system of names or terms, or the rules for forming these terms in a particular field of arts or sciences. (The theoretical field studying nomenclature is sometimes referred to as ''onymology'' or ''taxonymy'' ). The principl ...

, DSD is an overly generalised term for conditions that do not have differences in genital appearance or gender identity (e.g.

and

). Thirdly, the term 'DSD' lacks specificity and clarity; and therefore unhelpful in the diagnosis process. Hence, many support groups and advocates believe that the medical community should discontinue the use of 'DSD' as a designation tool. Furthermore, people who live with conditions regarding sexual abnormalities may encounter various mental and physical health problems. This may include traumatic experience with their own bodies, dissatisfaction with

body image Body image is a person's thoughts, feelings and perception of the aesthetics or sexual attractiveness of their own body. The concept of body image is used in several disciplines, including neuroscience, psychology, medicine, psychiatry, psycho ...

, low-self esteem,

anxiety Anxiety is an emotion characterised by an unpleasant state of inner wikt:turmoil, turmoil and includes feelings of dread over Anticipation, anticipated events. Anxiety is different from fear in that fear is defined as the emotional response ...

, depression,

bipolar disorder Bipolar disorder (BD), previously known as manic depression, is a mental disorder characterized by periods of Depression (mood), depression and periods of abnormally elevated Mood (psychology), mood that each last from days to weeks, and in ...

eating disorder An eating disorder is a mental disorder defined by abnormal eating behaviors that adversely affect a person's health, physical or mental health, mental health. These behaviors may include eating too much food or too little food. Types of eatin ...

personality disorder Personality disorders (PD) are a class of mental health conditions characterized by enduring maladaptive patterns of behavior, cognition, and inner experience, exhibited across many contexts and deviating from those accepted by the culture. ...

schizophrenia Schizophrenia () is a mental disorder characterized variously by hallucinations (typically, Auditory hallucination#Schizophrenia, hearing voices), delusions, thought disorder, disorganized thinking and behavior, and Reduced affect display, f ...

disorders, trauma and stress-related disorders, etc. Many

people are engaged in activism to stop hormonal treatments, citing the extreme and harmful nature of many of the treatments, further arguing that many of the treatments serve no medical purpose.

Terminology

The term ''disorders of sex development'' has generally been accepted by the medical community, as well as being a popular term in academic 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 did not 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 list of specialized agencies of the United Nations, specialized agency of the United Nations which coordinates responses to international public health issues and emergencies. It is headquartered in Gen ...

's international guide to medical coding (effective as of January 1, 2022), references DSDs as

traits or conditions, as do some

medical journal A medical journal is a peer-reviewed scientific journal that communicates medical information to physicians, other health professionals. Journals that cover many medical specialties are sometimes called general medical journals. History The first ...

s. The

Council of Europe The Council of Europe (CoE; , CdE) is an international organisation with the goal of upholding human rights, democracy and the Law in Europe, rule of law in Europe. Founded in 1949, it is Europe's oldest intergovernmental organisation, represe ...

and

Inter-American Commission on Human Rights The Inter-American Commission on Human Rights (the IACHR or, in the three other official languages Spanish, French, and Portuguese language, Portuguese CIDH, ''Comisión Interamericana de los Derechos Humanos'', ''Commission Interaméricaine des ...

have called for a review of medical classifications that unnecessarily medicalize intersex traits. 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 Various criteria have been offered for the definition of intersex, including ambiguous genitalia, atypical genitalia, and differential sexual development. Ambiguous genitalia occurs in roughly 0.05% of all births, usually caused by masculiniza ...

," which was the

standard model The Standard Model of particle physics is the Scientific theory, theory describing three of the four known fundamental forces (electromagnetism, electromagnetic, weak interaction, weak and strong interactions – excluding gravity) in the unive ...

for individuals with atypical sexual development. This model stated goal was to assign a

gender binary The gender binary (also known as gender binarism) is the classification of gender into two distinct forms of masculine and feminine, whether by social system, Culture, cultural belief, or both simultaneously. Most cultures use a gender binary, ...

, usually female via non-consensual

medicalization Medicalization is the process by which human conditions and problems come to be defined and treated as medical conditions, and thus become the subject of medical study, diagnosis, prevention, or treatment. Medicalization can be driven by new evi ...

, often via the falsification of

medical records The terms medical record, health record and medical chart are used somewhat interchangeably to describe the systematic documentation of a single patient's medical history and care across time within one particular health care provider's jurisdict ...

. After the publication of individuals who had undergone the OGR model and had gone through serious physiological distress, (such as

David Reimer David Reimer (born Bruce Peter Reimer; 22 August 1965 – 4 May 2004) was a Canadian man raised as a girl following medical advice and intervention after his penis was severely injured during a botched circumcision in infancy. The psychologis ...

), the model was discredited. The term "disorders of sexual development" was chosen to reflect the variation of

sexual development Puberty is the process of physical changes through which a child's Human body, body matures into an adult body capable of sexual reproduction. It is initiated by hormone, hormonal signals from the Human brain, brain to the gonads: the ovary ...

over differences which effects all individuals, this however has been controversial, with many instead opting for "differentiation" or "variation." 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 Ann & Robert H. Lurie Children's Hospital of Chicago, formerly Children's Memorial Hospital and commonly known as Lurie Children's, is a nationally ranked pediatric acute care children's hospital located in Chicago, Illinois. The hospital has ...

, 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 reported that DSD applied to their condition or that they felt neutral about the term, with most participants preferring terms that were specific to their somatic condition.

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 A community is a social unit (a group of people) with a shared socially-significant characteristic, such as place, set of norms, culture, religion, values, customs, or identity. Communities may share a sense of place situated in a given g ...

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 medical classification that is used in epidemiology, health management and clinical diagnosis. The ICD is maintained by the World Health Organization (WHO), which is the dir ...

, stating that this causes "harm" and facilitates human rights violations, calling on the

to publish clear policy to ensure that

intersex medical interventions Intersex medical interventions (IMI), sometimes known as intersex genital mutilations (IGM), are surgery, surgical, hormonal and other medical interventions performed to modify atypical or ambiguous genitalia and other sex characteristics, primar ...

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

pseudohermaphroditism Pseudohermaphroditism is an outdated term for when an individual's gonads were mismatched with their internal reproductive system and/or external genitalia. The term was contrasted with "true hermaphroditism" (now known as ovotesticular syndrome), ...

hermaphroditism A hermaphrodite () is a sexually reproducing organism that produces both male and female gametes. Animal species in which individuals are either male or female are gonochoric, which is the opposite of hermaphroditic. The individuals of many ...

, 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

, 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 or resultant from biological sexual factors. These include both primary sex characteristics, such as gonads, and sec ...

, 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 The Senate is the upper house of the bicameral Parliament of Australia, the lower house being the House of Representatives. The powers, role and composition of the Senate are set out in Chapter I of the federal constitution as well as feder ...

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 (March 6, 1934 – March 20, 2024) was an American professor 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 Decem ...

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 Special rapporteur (or independent expert) is the title given to independent human rights experts whose expertise is called upon by the United Nations (UN) to report or advise on human rights from a thematic or country-specific perspective. De ...

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

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 (OHCHR) is a department of the United Nations Secretariat that works to promote and protect human rights that are guaranteed under international law and stipulated in the Univers ...

UN Women The United Nations Entity for Gender Equality and the Empowerment of Women, also known as UN Women, is a United Nations entity charged with working for gender equality and the empowerment of women. UN Women is charged with advocating for the righ ...

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 ex ...

UNDP The United Nations Development Programme (UNDP) is a United Nations agency tasked with helping countries eliminate poverty and achieve sustainable economic growth and human development. The UNDP emphasizes on developing local capacity towar ...

UNFPA The United Nations Population Fund (UNFPA) is a UN agency aimed at improving reproductive and maternal health worldwide. Its work includes developing national healthcare strategies and protocols, increasing access to birth control, and leadin ...

and

UNICEF UNICEF ( ), originally the United Nations International Children's Emergency Fund, officially United Nations Children's Fund since 1953, is an agency of the United Nations responsible for providing Humanitarianism, humanitarian and Development a ...

. 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

and

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/ ...

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

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 The World Professional Association for Transgender Health (WPATH), formerly the Harry Benjamin International Gender Dysphoria Association (HBIGDA), is a professional organization devoted to the understanding and treatment of gender identity and ...

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.

World Athletics World Athletics, formerly known as the International Amateur Athletic Federation and International Association of Athletics Federations and formerly abbreviated as the IAAF, is the international sports governing body, governing body for the sport ...

claimed that while 46 XY DSD occurs in roughly 1 in 20,000 people in the general population, it is found in about 7 in 1,000 elite female athletes (with a prevalence 140 times higher) arguing that this offers significant performance advantage. Within the scientific community there is ongoing debate over whether any physiological advantage, in fact, exists.

References

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 topics Congenital disorders of genital organs Intersex healthcare Sex differences in humans

Overview

Genital anatomy

Management of DSDs

Key hormones

Causes

Chromosomal variation

Gonadal development disorders

Abnormal genital development

Others

Conditions

Diagnosis and symptoms

First line diagnostic tests (prenatal)

Family history

Analysis of karyotype

Abdominal ultrasounds

Second line diagnostic tests (postnatal)

Physical Examination

Evaluation of hormones 48 hours after birth

Treatment and management

Gender affirmation surgery

Medical treatment

Surgical treatment

Organizations

Clinical networks and organizations

DSD-TRN

I-DSD

Patient support and advocacy organizations

Controversy

Terminology

Human rights and community concerns

Clinical disagreements about the term

People with DSDs competing in sporting events

See also

References

Further reading

External links