INTRODUCTION — Infants born with genitals that do not appear typically male or female or that have an appearance discordant with the chromosomal sex are classified as having a difference or disorder of sex development (DSD). This term is not universally accepted by patients and is sometimes used to refer to a broad range of conditions including sex chromosome aneuploidies. In this topic review, we will use it to describe only those patients with a genital appearance that is atypical and/or discordant with chromosomal sex. (See "Evaluation of the infant with atypical genital appearance (difference of sex development)", section on 'Terminology'.)

The vocabulary used to describe features of DSD can also be confusing and is sometimes inconsistently applied. A glossary of terms is provided (table 1).

The causes of DSDs that present with atypical genitalia are presented here, grouped by karyotype and mechanism. The evaluation and management of such infants are discussed separately. (See "Evaluation of the infant with atypical genital appearance (difference of sex development)" and "Management of the infant with atypical genital appearance (difference of sex development)".)

EPIDEMIOLOGY — DSDs with genital abnormalities sufficient to prompt evaluation occur in approximately 1 in 1000 to 4500 live births [1-3]. The more common causes are:

●Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency in an XX individual

●Sex chromosome DSD with X/XY mosaicism

●Androgen insensitivity syndrome (AIS) in an XY individual

Rarer causes include:

●In individuals with an XX karyotype:

•CAH due to 11-beta-hydroxylase deficiency

•CAH due to 3-beta-hydroxysteroid dehydrogenase (3-beta-HSD) deficiency

•CAH due to P450 oxidoreductase (POR) deficiency

•XX testicular/ovotesticular DSD due to SRY (sex-determining region on the Y chromosome) translocation or NR5A1 gene mutation

●In individuals with an XY karyotype:

•XY gonadal dysgenesis (due to mutations in genes such as NR5A1, SRY, or WT1)

•CAH due to 3-beta-HSD deficiency or POR deficiency

•17-beta-hydroxysteroid dehydrogenase (17-beta-HSD) deficiency

•5-alpha reductase deficiency

•Smith-Lemli-Opitz syndrome

These and some even rarer causes of DSDs are described below and outlined in the tables (table 2 and table 3).

CAUSES OF XX DIFFERENCES OF SEX DEVELOPMENT — DSD in an individual with an XX complement of sex chromosomes is caused by atypically high levels of androgen, which can be due to overproduction of androgens by the adrenal cortex, overproduction by the gonads, or an ectopic or exogenous source of androgens. The genes implicated in XX DSD are summarized in the table (table 2).

Adrenal overproduction of androgens — Certain types of congenital adrenal hyperplasia (CAH) can cause overproduction of adrenal androgens and therefore lead to virilization in XX infants.

Measurement of serum 17-hydroxyprogesterone (17-OHP) identifies most XX infants with virilizing CAH because this metabolite is elevated in the most common type of CAH (21-hydroxylase deficiency), with lesser elevations in some other types of CAH (3-beta-hydroxysteroid dehydrogenase [3-beta-HSD] deficiency and 11-beta-hydroxylase deficiency). Concentrations of 17-hydroxypregnenolone, 11-deoxycortisol, cortisol, and dehydroepiandrosterone (DHEA) serve to distinguish among these various types of CAH (table 4). (See "Evaluation of the infant with atypical genital appearance (difference of sex development)", section on 'Initial laboratory testing' and "Uncommon congenital adrenal hyperplasias".)

Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency — 21-hydroxylase deficiency accounts for approximately 95 percent of CAH cases and is the most frequent enzymatic defect causing atypical genitalia in general because the gene that encodes 21-hydroxylase (CYP21A2) is prone to mutation. 21-hydroxylase deficiency can be diagnosed based on elevated serum 17-OHP, one of the substrates for the enzyme (table 4). In borderline cases, an adrenocorticotropic hormone (ACTH) stimulation test or genetic testing may be needed to establish the diagnosis. (See "Evaluation of the infant with atypical genital appearance (difference of sex development)", section on '17-hydroxyprogesterone' and "Clinical manifestations and diagnosis of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children", section on 'Additional testing for infants with equivocal results'.)

Decreased activity of 21-hydroxylase results in decreased production of cortisol and aldosterone and overproduction of adrenal androgens (DHEA, androstenedione, and 11-ketotestosterone). Affected infants with 21-hydroxylase deficiency often have salt wasting, which causes hyponatremia with hyperkalemia and hypotension, and they are at risk for the life-threatening complication of adrenal crisis.

Other types of congenital adrenal hyperplasia

●11-beta-hydroxylase deficiency (due to mutations in the CYP11B1 gene) is the second most common cause of CAH in the United States and Western Europe and is associated with significant elevation in 11-deoxycortisol and mild elevation in 17-OHP. As with 21-hydroxylase deficiency, there is overproduction of DHEA and androstenedione, and XX infants tend to have mildly to moderately virilized genitalia (clitoral enlargement, labial fusion). Salt wasting and adrenal crisis are rare. Both hypotension and hypertension have been reported in affected infants. Older children often manifest hypertension and hypokalemia because of mineralocorticoid effects of elevated 11-deoxycortisol, which distinguish this disorder from the hypotension and hyperkalemia that characterize 21-hydroxylase deficiency. (See "Uncommon congenital adrenal hyperplasias", section on '11-beta-hydroxylase deficiency'.)

●3-beta-HSD type 2 deficiency (due to mutations in the HSD3B2 gene) is characterized by elevated 17-hydroxypregnenolone (not to be confused with 17-OHP) and an elevated ratio of 17-hydroxypregnenolone to cortisol [4]. Levels of 17-hydroxypregnenolone are often moderately elevated; this apparently paradoxical elevation is due to the activity of another isoform of 3-beta-HSD that is encoded by a different gene (HSD3B1) and expressed in the liver, which can convert 17-hydroxypregnenolone to 17-OHP and DHEA to androstenedione, a relatively weak androgen.

Affected XX individuals tend to have female external genitalia with relatively mild virilization (clitoromegaly). They tend to present as neonates or in early infancy with clinical manifestations of both cortisol and aldosterone deficiency, including vomiting, volume depletion, hyponatremia, and hyperkalemia. Of note, affected XY infants often show undervirilization due to a block in testosterone synthesis, as noted below. (See 'Forms of congenital adrenal hyperplasia' below and "Uncommon congenital adrenal hyperplasias", section on '3-beta-hydroxysteroid dehydrogenase type 2 deficiency'.)

●P450 oxidoreductase (POR) deficiency (also known as apparent combined CYP21A2 and CYP17A1 deficiency due to mutations in the POR gene) is a very rare cause of CAH. POR deficiency causes abnormal electron transport leading to decreased action of both 21-hydroxylase and 17-alpha hydroxylase, as well as aromatase.

The phenotype is quite variable; XX individuals may be born with atypical genitalia, and there can be maternal virilization during pregnancy [5,6]. Some infants have craniofacial and limb abnormalities (also known as Antley-Bixler syndrome). Elevations in 17-OHP may be mild. Glucocorticoid deficiency is present to a variable degree, and patients are at risk for salt wasting and adrenal crisis. This condition can cause virilization in XX infants and undervirilization in XY infants (similar to 3-beta-HSD deficiency). (See "Uncommon congenital adrenal hyperplasias", section on 'P450 oxidoreductase deficiency (apparent combined CYP17A1 and CYP21A2 deficiency)'.)

Glucocorticoid resistance — Glucocorticoid resistance due to mutations in the NR3C1 gene that encodes the glucocorticoid receptor can cause features similar to those of virilizing forms of CAH, although it is not a cause of CAH, as cortisol synthesis is not disrupted. The impaired response to cortisol results in loss of negative feedback and high levels of ACTH, resulting in adrenal overproduction of mineralocorticoids (which can cause hypertension, hypokalemia, and alkalosis) and androgens (which can cause atypical genital appearance at birth or hyperandrogenism later in life in affected XX individuals). (See "Causes of primary adrenal insufficiency in children", section on 'End-organ unresponsiveness'.)

Gonadal overproduction of androgens

XX testicular or ovotesticular differences of sex development — XX testicular DSD is a term for conditions in which the gonads develop along the testicular rather than the ovarian pathway. The resulting gonad may be either a normal or a dysgenetic testis. The consequent phenotype depends on the degree of production of testosterone and anti-müllerian hormone (AMH; also known as müllerian-inhibiting substance [MIS] and müllerian regression factor). Most causes of XX testicular DSD can also cause XX ovotesticular DSD, in which both ovarian follicular and testicular tubular tissue are present; the diagnosis is made based on histology, although the diagnosis can sometimes be suggested based on imaging and/or hormonal evaluation.

XX testicular or ovotesticular DSD is suggested by detection of testosterone (at baseline or after human chorionic gonadotropin [hCG] stimulation) and/or higher-than-expected levels of AMH/MIS in an XX individual. (See "Evaluation of the infant with atypical genital appearance (difference of sex development)", section on 'Testosterone and other measures of gonadal function'.)

Because an intact Y chromosome is required for spermatogenesis, XX testicular DSD is associated with infertility. If there is intact ovarian tissue, fertility may be possible in some cases of XX ovotesticular DSD.

Causes of XX testicular or ovotesticular DSD include:

●Presence of SRY – This is due to translocation of SRY (sex-determining region on the Y chromosome) to the X chromosome or an autosome and accounts for roughly one-half of cases of XX testicular DSD. The presence of SRY results in activation of testicular pathways in the developing gonad.

●Mutations in NR5A1 – The NR5A1 (SF1) gene has long been known to play essential roles in initial gonadal development and in testicular differentiation; it is a well-known cause of XY DSD (see 'XY gonadal dysgenesis' below). In addition, heterozygous mutations in NR5A1 have been described in approximately 10 to 20 percent of cases of XX testicular or ovotesticular DSD [7-10]. These mutations all affect a single amino acid residue, so it is possible that these are gain-of-function mutations that cause inappropriate activation of testicular pathways in the XX gonad. Alternatively, NR5A1 may play a role in suppressing testicular pathways during ovarian development (in addition to playing a role in promoting testicular pathways during testicular development).

●Duplication of SOX9 – The SOX9 gene encodes a transcription factor that functions downstream of SRY and is both necessary and sufficient for testicular development. Duplications of the entire SOX9 locus as well as of its upstream regulatory region have been described in individuals with XX testicular DSD.

●Inappropriate expression of SOX3 – The SOX3 gene encodes a transcription factor similar to SOX9. SOX3 does not appear to have a role in normal gonadal development but appears to activate testicular pathways when inappropriately expressed (as can occur with duplications or mutations in the SOX3 regulatory region).

●Loss-of-function mutations in genes that repress testicular pathways – Mutations in these genes can cause XX testicular or ovotesticular DSD and are often associated with clinical abnormalities in nonreproductive organs:

•WNT4 gene mutations are associated with the autosomal recessive SERKAL syndrome (sex reversal with dysgenesis of kidneys, adrenals, and lungs)

•RSPO1 gene mutations appear to be an autosomal recessive cause of palmoplantar hyperkeratosis in combination with testicular or ovotesticular DSD [11,12]

Aromatase deficiency — Aromatase deficiency (due to mutations in the CYP19A1 gene) can result in overproduction of testosterone by an otherwise normal ovary as the aromatase enzyme catalyzes the conversion of androgens to estrogens (eg, testosterone to estradiol) [13]. Because placental expression of aromatase is deficient, androgens from the fetus can cross the placenta and also cause maternal virilization. (See "Gestational hyperandrogenism", section on 'Placental aromatase deficiency'.)

Gestational hyperandrogenism — Virilization in an XX individual with normal female internal anatomy can result from exposure to maternal androgen or synthetic progestational agents. Because the placenta produces the aromatase enzyme, which converts androgens to estrogens, only very high levels of maternal androgens can overcome placental aromatase to cause virilization of the fetus. Causes include maternal luteoma or theca lutein cysts. These disorders are suggested by a history of maternal virilization during pregnancy and/or exogenous progestin or androgen exposure [14]. (See "Gestational hyperandrogenism".)

CAUSES OF XY DIFFERENCES OF SEX DEVELOPMENT — XY DSDs occur because of atypically low levels of dihydrotestosterone action. This can be caused by a global defect in testicular function due to gonadal dysgenesis, a specific defect in dihydrotestosterone production, or an inability to respond to dihydrotestosterone and other androgens (androgen insensitivity). The genes implicated in XY DSD are summarized in the table (table 3).

Global defects in testicular function — In these conditions, there are defects in both Leydig cell function, resulting in underproduction of testosterone, and Sertoli cell function, resulting in underproduction of anti-müllerian hormone (AMH; also known as müllerian-inhibiting substance [MIS]) and inhibin B. Serum concentrations of AMH/MIS or inhibin B can range from absent to intermediate to normal, depending on the degree of the defect.

Because AMH/MIS secretion by the testes causes müllerian duct regression, decreased AMH/MIS secretion can result in fully or partially developed müllerian duct structures [15,16]. Low AMH/MIS concentration and/or persistence of müllerian structures in an XY individual suggests one of the following disorders, each of which is characterized by diminished testicular activity.

XY gonadal dysgenesis — Gonadal dysgenesis may be complete or partial. Complete XY gonadal dysgenesis (ie, complete failure of testicular development, also called Swyer syndrome) is associated with a typical female external genital appearance, intact müllerian structures, and streak gonads [17]. Partial gonadal dysgenesis can result in a wide range of testicular function and can in turn produce a similarly wide range of phenotypes, from isolated infertility without undervirilization, to hypospadias, to a frankly atypical genital appearance, to near-complete undervirilization with clitoromegaly. The müllerian structures may be normal, hypoplastic, or absent. By contrast, in XX individuals, gonadal dysgenesis does not interfere with genital development and therefore does not typically present with atypical genitalia but may present with failure to enter puberty, primary amenorrhea, or secondary amenorrhea. (See "Causes of primary amenorrhea".)

Gonadal dysgenesis and the presence of a Y chromosome creates a risk for gonadoblastoma. The risk varies depending on the condition and the degree of dysgenesis (with a lesser degree of dysgenesis associated with a lower risk). (See "Management of the infant with atypical genital appearance (difference of sex development)", section on 'Surgical decisions'.)

Specific causes of XY gonadal dysgenesis include:

●Mutations in NR5A1 – The NR5A1 gene encodes steroidogenic factor 1, a transcription factor essential for development of the gonads and the adrenal cortex. Homozygous loss-of-function mutations in NR5A1 are rare and result in gonadal dysgenesis and adrenocortical insufficiency. Heterozygous loss-of-function mutations in NR5A1 account for approximately 10 to 15 percent of cases of testicular dysgenesis and are not usually associated with adrenal insufficiency. The degree of dysgenesis associated with heterozygous NR5A1 mutations ranges from minimal to complete. Some specific NR5A1 mutations may also cause testicular or ovotesticular DSD in an XX individual. (See 'Gonadal overproduction of androgens' above.)

●Mutations in SRY – Loss of SRY (sex-determining region on the Y chromosome) function can result in complete or partial testicular dysgenesis, XY ovarian DSD, or XY ovotesticular DSD [18,19].

●Mutations in WT1 – The WT1 gene is involved in both renal development and gonadal development, and WT1 mutations are associated with a variety of conditions, some of which include partial or complete gonadal dysgenesis as a feature. Denys-Drash syndrome is associated with renal failure and high risk for Wilms tumor. Frasier syndrome is associated with nephrotic syndrome, usually due to focal segmental glomerulosclerosis, and particularly high risk for gonadoblastoma (around 50 percent).

●Loss-of-function mutations in genes essential for testicular development – These rare causes of XY gonadal dysgenesis are inherited in an autosomal recessive manner and include mutations in the MAP3K1, CBX2, DHH, DHX37, DMRT1, FGF9, FOG, GATA4, SOX9, and ZFPM2 genes. Some of these mutations are associated with clinical abnormalities in nonreproductive organs (eg, campomelic dysplasia with mutations in SOX9).

●Gain-of-function mutations in NR0B1 – Duplications of the NR0B1 (DAX1) gene can cause gonadal dysgenesis, possibly by inhibiting activity of NR5A1 (SF1). NR0B1 does not appear to have a direct role in normal human gonadal development, because loss-of-function mutations in NR0B1 do not have a gonadal phenotype, although they do cause adrenal insufficiency and hypogonadotropic hypogonadism.

Y chromosome mosaicism can also cause gonadal dysgenesis. (See 'Sex chromosome differences of sex development' below.)

XY ovarian differences of sex development — In rare cases, the gonads in an XY individual may develop as ovaries. Loss-of-function mutations in SRY [19], CBX2 [20], and NR5A1 [21] have been described as causes. Because cells have only one X chromosome, ovarian function in these cases would be expected to be impaired, similar to that of a girl with Turner syndrome (45,X karyotype).

Testicular dysfunction without atypical genitalia — Other conditions that affect testicular function but do not typically present with atypical genitalia include:

●Persistent müllerian duct syndrome – Persistent müllerian duct syndrome is caused by mutations in the AMH gene, with low serum levels of AMH/MIS, or in the AMH receptor gene (AMHR2), with lack of response to AMH/MIS in an XY individual. The disorder is characterized by normal external male genitalia, variable testicular descent, and presence of müllerian structures (such as a uterus) that may be discovered only incidentally [22-24].

●Testicular regression syndrome (also called congenital anorchia or vanishing testes syndrome) – Loss of testicular function late in fetal life results in anorchia but otherwise typical male genital appearance and absence of müllerian ducts (because of intact testicular function and production of dihydrotestosterone and AMH in early fetal development). The cause is unclear but is thought to be due to bilateral fetal/infant testicular torsion in some cases. Mutations in the DHX37 gene have been described as a cause of testicular regression syndrome [25].

Disorders with abnormal androgen synthesis or response — XY infants with abnormal androgen synthesis or abnormal androgen sensitivity may demonstrate undervirilization but have evidence of normal AMH/MIS production (serum AMH/MIS in the typical male range, absence of müllerian structures). Testosterone measured at baseline or in response to human chorionic gonadotropin (hCG) may help to distinguish androgen underproduction from androgen insensitivity [26]. (See "Evaluation of the infant with atypical genital appearance (difference of sex development)", section on 'Human chorionic gonadotropin stimulation test'.)

Abnormal androgen synthesis — Abnormal androgen synthesis is suggested by low serum testosterone and/or dihydrotestosterone despite adequate stimulation by endogenous luteinizing hormone (LH; which is often elevated because of loss of negative feedback from sex steroids) or in response to exogenous hCG. This can occur due to defects in the LH/CG receptor, defects in synthesis of cholesterol (the substrate for steroid hormone synthesis), defects in one of the many enzymatic steps for converting cholesterol to testosterone (some of which are also involved in adrenal hormone synthesis and can cause congenital adrenal hyperplasia [CAH]), and defects in the conversion of testosterone to dihydrotestosterone.

These disorders, which are all autosomal recessive and rare, are:

Leydig cell hypoplasia (LH/CG receptor defects) — Luteinizing hormone (LH) and human chorionic gonadotropin (hCG) share a common receptor, the LH/CG receptor, which is encoded by the LHCGR gene on chromosome 2p21 [27-29]. XY patients with mutations in LHCGR characteristically have female external genital appearance but lack a uterus and fallopian tubes; the epididymis and vas deferens may be present [30,31]. Laboratory evaluation reveals low testosterone concentrations despite elevated concentration of LH, and patients are unresponsive to exogenous hCG.

Smith-Lemli-Opitz syndrome — This autosomal recessive disorder arises from a defect in the enzyme that catalyzes the last step in cholesterol synthesis, sterol delta-7-reductase (encoded by the DHCR7 gene). Affected individuals can exhibit growth and developmental delays, microcephaly, characteristic facial features, cleft palate, syndactyly and/or polydactyly, and other features, in addition to varying degrees of undervirilization. Diagnosis is made by finding elevated serum 7-dehydrocholesterol and/or by genetic testing.

17-beta-hydroxysteroid dehydrogenase type 3 deficiency — 17-beta-hydroxysteroid dehydrogenase (17-beta-HSD) type 3 deficiency can be caused by at least 15 different mutations in the HSD17B3 gene, which encodes an enzyme required for conversion of androstenedione to testosterone [32]. In this condition, serum testosterone concentrations are often in the lower normal range, whereas serum concentrations of androstenedione, the intermediate before the enzymatic block, are elevated several-fold (figure 1) [33,34]. The ratio of testosterone to androstenedione (when expressed in the same units) is usually less than 0.8, which distinguishes this disorder from other forms of undervirilization, but, in some cases, there are no detectable hormonal abnormalities and the diagnosis is made only through genetic testing [35]. (See "Evaluation of the infant with atypical genital appearance (difference of sex development)", section on 'Genetic testing' and "Steroid 5-alpha-reductase 2 deficiency", section on 'Differential diagnosis'.)

5-alpha-reductase type 2 deficiency — In steroid 5-alpha-reductase type 2 deficiency (due to mutations in the SRD5A2 gene), XY individuals with bilateral testes and normal testosterone formation have impaired external virilization during embryogenesis due to defective conversion of testosterone to dihydrotestosterone [36-38]. In this disorder, the ratio of testosterone:dihydrotestosterone (when expressed in the same units) is typically >10:1. (See "Steroid 5-alpha-reductase 2 deficiency".)

Forms of congenital adrenal hyperplasia — Because many of the enzymes involved in cortisol synthesis are also involved in testosterone synthesis, several types of CAH can cause underproduction of testosterone and, in turn, undervirilization in an XY infant (table 4 and figure 2).

●3-beta-hydroxysteroid dehydrogenase type 2 deficiency (3-beta-HSD) – This disorder is caused by mutations in the HSD3B2 gene; it causes variable undervirilization in XY individuals due to defective conversion of dehydroepiandrosterone (DHEA) to androstenedione, the precursor to testosterone. Paradoxically, it can also cause mild virilization in XX individuals (as noted above) because of overproduction of DHEA, a weak androgen (see 'Other types of congenital adrenal hyperplasia' above). Affected individuals have both cortisol and aldosterone deficiency, which may be life-threatening. (See "Uncommon congenital adrenal hyperplasias", section on '3-beta-hydroxysteroid dehydrogenase type 2 deficiency'.)

●17-alpha-hydroxylase deficiency – This disorder is caused by mutations in the CYP17A1 gene, which encodes a protein with both 17-alpha-hydroxylase and 17,20-lyase activities; it is characterized by undervirilization in XY individuals and may result in typical female external genital appearance. Most affected individuals have hypertension and hypokalemia because of overproduction of mineralocorticoids; symptomatic adrenal insufficiency is rare. Partial deficiencies also occur and have milder phenotypes. Mutations in CYP17A1 that affect only 17,20-lyase activity are rare and produce undervirilization without cortisol deficiency. (See "Uncommon congenital adrenal hyperplasias", section on 'CYP17A1 deficiencies'.)

●P450 oxidoreductase (POR) deficiency – This disorder has features of 21-hydroxylase, 17-alpha hydroxylase, and aromatase deficiencies, and both XY and XX infants may be born with atypical genitalia. (See "Uncommon congenital adrenal hyperplasias", section on 'P450 oxidoreductase deficiency (apparent combined CYP17A1 and CYP21A2 deficiency)'.)

●Lipoid CAH – This disorder is caused by deficiency of steroidogenic acute regulatory (StAR) protein; it is characterized by severe adrenal insufficiency very soon after birth, presenting with vomiting, diarrhea, volume depletion, hyponatremia, and hyperkalemia, often with hyperpigmentation. XY individuals have typical female external genital appearance. (See "Uncommon congenital adrenal hyperplasias", section on 'Lipoid congenital adrenal hyperplasia'.)

●P450 side-chain cleavage (SCC) enzyme deficiency – This disorder is caused by mutations in the CYP11A1 gene [39]. Similar to lipoid CAH, it is characterized by adrenal insufficiency and hyperpigmentation presenting in infancy or childhood, with typical female external genital appearance in XY individuals. (See "Uncommon congenital adrenal hyperplasias", section on 'P450 11A1, cholesterol side-chain cleavage enzyme deficiency'.)

All of these forms of CAH except 17-alpha hydroxylase deficiency are usually associated with salt loss and may result in life-threatening adrenal crisis, so these disorders must be considered and diagnosed early. CAH caused by 21-hydroxylase deficiency does not result in atypical genitalia in XY children but can result in adrenal crisis. This is a strong argument for neonatal CAH screening. (See "Clinical manifestations and diagnosis of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children" and "Uncommon congenital adrenal hyperplasias", section on 'Lipoid congenital adrenal hyperplasia'.)

If a form of CAH is identified, the infant may be at risk for adrenal crisis. It is sometimes necessary to evaluate adrenal function by performing an adrenocorticotropic hormone (ACTH) stimulation test to assess for glucocorticoid deficiency and excessive precursor accumulation. (See "Evaluation of the infant with atypical genital appearance (difference of sex development)", section on 'Adrenocorticotropic hormone stimulation test'.)

Androgen insensitivity — In an individual with XY DSD, normal or elevated serum testosterone production at baseline or after hCG stimulation suggests androgen insensitivity syndrome (AIS), which is caused by mutations in the androgen receptor (AR) gene. Patients with partial AIS (PAIS) present with a range of phenotypes, from predominantly female genital appearance (with mild virilization), to more atypical genital appearance, to typical male genital appearance with infertility. Patients with complete AIS (CAIS) have typical female external genital appearance. (See "Diagnosis and treatment of disorders of the androgen receptor".)

The diagnosis of AIS can be definitively established with AR gene sequencing or fibroblast AR kinetics. XY DSD patients with phenotypic and biochemical evidence of AIS should undergo sequencing of the AR gene, although fewer than one-half of patients with the clinical diagnosis of PAIS show a definable mutation in the AR and clear-cut genotype-phenotype correlations in patients with AR mutations are lacking [40]. If no AR mutation is found, a provisional diagnosis of AIS may still be made on the basis of the clinical findings, but other causes should be considered (eg, NR5A1/SF-1 gene mutation or 17-beta-HSD deficiency). Of note, responses to hCG may be attenuated in patients with androgen insensitivity for reasons that are unclear [41].

Management of this disorder is discussed separately. (See "Management of the infant with atypical genital appearance (difference of sex development)", section on 'Partial androgen insensitivity syndrome' and "Diagnosis and treatment of disorders of the androgen receptor".)

Other causes of XY differences of sex development — Occasionally, boys with hypospadias or even more severely atypical genitalia may have histories of in utero exposure to "endocrine disrupters." Phenytoin and phenobarbital, as well as environmental exposures, have been implicated, but the relationship of putative endocrine disruptors to hypospadias is still unclear [42,43]. Children whose DSD was caused by in utero exposure to endocrine disrupters should have normal physiologic and anatomic responses to sex steroids as well as to gonadotropin stimuli after birth. (See "Hypospadias: Pathogenesis, diagnosis, and evaluation", section on 'Pathogenesis'.)

SEX CHROMOSOME DIFFERENCES OF SEX DEVELOPMENT — This subtype of DSD is defined by presence of a sex chromosome complement other than XX or XY. It includes conditions with mosaicism or chimerism resulting in the presence of the Y chromosome in some cells but not others, which may (or may not) result in atypical genitalia.

The term "sex chromosome DSD" is sometimes used to include karyotypes that do not result in atypical genital development, such as 45,X (Turner syndrome) and 47,XXY (Klinefelter syndrome). (See "Clinical manifestations and diagnosis of Turner syndrome" and "Clinical features, diagnosis, and management of Klinefelter syndrome".)

Mosaicism arises postzygotically due to the improper segregation of chromosomes during mitosis. The most common karyotype with mosaicism of the Y chromosome is 45,X/46,XY, but other combinations are possible (eg, 45,X/47,XXY; 46,XX/47,XXY). Chimerism results from the fusion of two zygotes; if the zygotes have different chromosomal sexes, the resulting chimera has a 46,XX/46,XY karyotype.

Y chromosome mosaicism/chimerism can result in a broad range of reproductive phenotypes. Each gonad can develop as:

●A normal or dysgenetic testis

●A normal or dysgenetic ovary

●A streak gonad (a gonad that is so dysgenetic that it is not readily recognizable as a testis or ovary)

●An ovotestis (very rare)

Also, the two gonads may develop differently. "Mixed gonadal dysgenesis" refers to asymmetric gonadal development with one gonad being dysgenetic. For unknown reasons, the right gonad is more likely to develop into a testis and the left gonad is more likely to be a streak gonad or an ovary. While the term "mixed gonadal dysgenesis" technically describes a gonadal phenotype, many use the term synonymously with a 45,X/46,XY karyotype resulting in atypical gonadal development. The identity of each gonad in turn influences the development of the ipsilateral internal and external reproductive structures. A typical phenotype with mixed gonadal dysgenesis and a 45,X/46,XY karyotype involves having a poorly developed testicle and Wolffian structures on one side (usually the right) and a gonadal streak and müllerian structures (often incompletely developed) on the other, potentially producing asymmetric genital anatomy (picture 1 and image 1). Individuals with mixed gonadal dysgenesis have variable degrees of genital atypia. The presence of any external genital asymmetry should raise suspicion of this disorder. However, both the degree of mosaicism and phenotype can be quite variable, with the phenotype ranging from typical male to typical female external genital appearance, potentially associated with somatic features of Turner syndrome. (See "Clinical manifestations and diagnosis of Turner syndrome".)

Patients with any of the above forms of Y chromosome mosaicism/chimerism and a dysgenetic gonad have an increased risk for gonadoblastoma, similar to patients with complete XY gonadal dysgenesis (Swyer syndrome). The risk is lower if the gonads are in the scrotum and higher if they are in the abdomen. Management of this risk, including consideration of gonadectomy, is discussed separately. (See "Management of the infant with atypical genital appearance (difference of sex development)", section on 'Gonads'.)

The underlying karyotype can cause other associated features. For instance, individuals with a 45,X/46,XY karyotype may have features of Turner syndrome and individuals with a 46,XX/47,XXY karyotype may have features of Klinefelter syndrome. Male fertility requires testicular tissue and an intact Y chromosome, and female fertility generally requires two X chromosomes in addition to ovarian tissue.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Classic and nonclassic congenital adrenal hyperplasia due to 21-hydroxylase deficiency" and "Society guideline links: Differences of sex development".)

SUMMARY — Infants born with genitals that do not appear typically male or female or that have an appearance discordant with the chromosomal sex are classified as having a difference or disorder of sex development (DSD). The vocabulary used to describe features of DSD can also be confusing and is sometimes inconsistently applied. A glossary of terms is provided (table 1).

●The most common cause of atypical genitalia is classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, which causes virilization in individuals with an XX karyotype. Prompt recognition (through newborn screening in all of the United States and in many Western countries) and treatment are important to avoid the possibility of early adrenal crisis; the disorder is diagnosed by detecting marked elevations in 17-hydroxyprogesterone (17-OHP). (See 'Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency' above.)

●Other disorders causing atypical genitalia in XX individuals include (table 2):

•Less common causes of CAH (eg, 11-beta-hydroxylase deficiency and 3-beta-hydroxysteroid dehydrogenase deficiency [3-beta-HSD]) (see 'Other types of congenital adrenal hyperplasia' above)

•Testicular DSD and ovotesticular DSD (resulting in gonadal production of androgens) (see 'Gonadal overproduction of androgens' above)

•Rarely, gestational hyperandrogenism due to exposure to maternal androgen or synthetic progestational agents (see 'Gestational hyperandrogenism' above)

●Causes of atypical genitalia in XY individuals include (table 3):

•Gonadal dysgenesis leading to global defects in testicular function, with underproduction of testosterone, anti-müllerian hormone (AMH; also known as müllerian-inhibiting substance [MIS] and müllerian regression factor) and inhibin B (see 'Global defects in testicular function' above)

•Disorders with abnormal androgen synthesis, including defects in the luteinizing hormone/human chorionic gonadotropin (LH/hCG) receptor and defects in several enzymes required for testosterone synthesis and metabolism (figure 1); these include several uncommon forms of CAH (table 4) (see 'Abnormal androgen synthesis' above)

•Androgen insensitivity syndrome (AIS) due to impairment of function of the androgen receptor (AR) (see 'Androgen insensitivity' above)

●Mosaicism or chimerism affecting the Y chromosome can result in a wide range of gonadal phenotypes, including mixed gonadal dysgenesis (gonads that develop differently from each other, with one being dysgenetic), normal or dysgenetic testes or ovaries, streak gonads, or ovotestes. (See 'Sex chromosome differences of sex development' above.)

●Patients with a Y chromosome and a dysgenetic gonad have an increased risk for gonadoblastoma. (See 'Sex chromosome differences of sex development' above.)