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Causes of differences of sex development

Causes of differences of sex development
Literature review current through: Jan 2024.
This topic last updated: Dec 19, 2022.

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 variation 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 genital appearance 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

Partial and complete 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

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

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

5-alpha reductase deficiency

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 androgens, 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 the other types of virilizing CAH (3-beta-hydroxysteroid dehydrogenase [3-beta-HSD] deficiency and 11-beta-hydroxylase deficiency). Concentrations of 17-hydroxypregnenolone, 11-deoxycortisol, and cortisol 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 and is the most frequent cause of atypical genital appearance 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 (dehydroepiandrosterone [DHEA], androstenedione, and 11-ketotestosterone). Affected infants with 21-hydroxylase deficiency often have salt wasting, which causes hyponatremia with hyperkalemia, dehydration, 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 variants 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 condition 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 variants 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-OHP are often moderately elevated as well; 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 largely female-appearing 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 variants 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 genital appearance, and there can be maternal virilization during pregnancy due to decreased placental aromatase activity [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 variants in the NR3C1 gene that encodes the glucocorticoid receptor can cause features similar to those of virilizing forms of CAH, although it is not classified as a form of CAH, because 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 and XX 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 largely 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 levels of AMH above the female reference range 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 inability to produce sperm. If there is intact ovarian tissue, oocyte maturation 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.

Variants 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 variants in NR5A1 have been described in approximately 10 to 20 percent of cases of XX testicular or ovotesticular DSD [7-10]. Almost all of these variants affect a single amino acid residue, so it is possible that these are gain-of-function variants that cause inappropriate activation of testicular pathways in an 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 variants in the SOX3 regulatory region).

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

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

RSPO1 gene variants are an autosomal recessive cause of palmoplantar hyperkeratosis in combination with testicular or ovotesticular DSD [11,12]

Aromatase deficiency — Aromatase deficiency (due to variants 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 typical ovarian and adrenal function can result from exposure to maternal androgens or synthetic androgenic progestins. 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 causes are suggested by a history of maternal virilization during pregnancy and/or exogenous exposure to androgens or an androgenic progestin [14,15]. (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 androgen 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) and inhibin B. Serum concentrations of AMH and inhibin B can be undetectable, detectable but below the male reference range, or within the male reference range, depending on the degree of the defect.

Because AMH secretion by the testes causes müllerian duct regression, decreased AMH secretion can result in fully or partially developed müllerian duct structures [16,17]. Low AMH concentration and/or persistence of müllerian structures in an XY individual suggests one of the following conditions, 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 [18]. 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 genital appearance 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:

Variants 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 variants in NR5A1 are rare and result in gonadal dysgenesis and adrenocortical insufficiency. Heterozygous loss-of-function variants 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 variants ranges from minimal to complete, and other genes may contribute to this heterogeneity [19]. Some specific NR5A1 variants may also cause testicular or ovotesticular DSD in an XX individual. (See 'Gonadal overproduction of androgens' above.)

Variants in SRY – Decreased SRY (sex-determining region on the Y chromosome) function can result in complete or partial testicular dysgenesis, XY ovarian DSD, or XY ovotesticular DSD [20,21].

Variants in WT1 – The WT1 gene is involved in both renal development and gonadal development, and WT1 variants 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 lifetime incidence).

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

Gain-of-function variants 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 variants in NR0B1 do not have a gonadal phenotype, although they do cause X-linked 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 variants in SRY [21], CBX2 [22], and NR5A1 [23] have been described as causes. Because cells have only one X chromosome, ovarian function in these cases would be expected to be reduced, similar to that of a girl with Turner syndrome (45,X karyotype).

Testicular dysfunction without atypical genital appearance — Other conditions that affect testicular function but do not usually present with atypical genital appearance include:

Persistent müllerian duct syndrome – Persistent müllerian duct syndrome is caused by variants in the AMH gene, with low serum levels of AMH, or in the AMH receptor gene (AMHR2), with lack of response to AMH in an XY individual. The condition is characterized by a typical male external genital appearance, variable testicular descent, and presence of müllerian structures (such as a uterus) that may be discovered only incidentally [24-26].

Testicular regression syndrome (also called congenital anorchia and previously referred to as vanishing testes syndrome) – Loss of testicular function later 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 often unclear but is thought to be due to bilateral fetal/infant testicular torsion in some cases. Variants in the DHX37 gene have also been described as a cause of testicular regression syndrome as well as of XY gonadal dysgenesis, suggesting that some cases of testicular regression syndrome lie along a spectrum with XY gonadal dysgenesis [27].

Conditions affecting androgen synthesis or response — XY infants with reduced androgen synthesis or androgen sensitivity may demonstrate undervirilization but have typical AMH production (serum AMH in the typical male range and 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 [28]. (See "Evaluation of the infant with atypical genital appearance (difference of sex development)", section on 'Human chorionic gonadotropin stimulation test'.)

Reduced androgen synthesis — Reduced 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 conditions affecting signaling through the LH/CG receptor, synthesis of cholesterol (the substrate for steroid hormone synthesis), 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]), or the conversion of testosterone to dihydrotestosterone.

These conditions, 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 [29,30]. XY patients with variants in LHCGR characteristically have a typical female external genital appearance, though partial virilization is sometimes present, and lack a uterus and fallopian tubes; the epididymis and vas deferens may be present [31,32]. Laboratory evaluation reveals low testosterone concentrations despite an elevated concentration of LH (if assessed when the hypothalamic-pituitary-gonadal axis is active, ie, during the minipuberty of infancy or after puberty has started), and these children have absent or reduced responsiveness to exogenous hCG.

Smith-Lemli-Opitz syndrome — This autosomal recessive condition arises from a defect in the enzyme, sterol delta-7-reductase (encoded by the DHCR7 gene), that catalyzes the last step in cholesterol synthesis. 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 an elevated serum level of 7-dehydrocholesterol and/or by genetic testing. The mechanism by which Smith-Lemli-Opitz syndrome causes these myriad phenotypes is unclear; possibilities include decreased production of steroid hormones (which all derive from cholesterol), impaired signal transduction through pathways that require cholesterol, and accumulation of toxic cholesterol-related metabolites.

17-beta-hydroxysteroid dehydrogenase type 3 deficiency — 17-beta-hydroxysteroid dehydrogenase (17-beta-HSD) type 3 deficiency is caused by variants in the HSD17B3 gene, which encodes an enzyme required for conversion of androstenedione to testosterone in the testes [33]. 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) [34,35]. The ratio of testosterone to androstenedione (when expressed in the same units) is usually less than 0.8, which distinguishes this condition from other forms of undervirilization, but, in some cases, there are no detectable hormonal abnormalities and the diagnosis is made only through genetic testing [36]. (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 5-alpha-reductase type 2 deficiency (due to variants in the SRD5A2 gene), XY individuals with bilateral testes and normal testosterone synthesis have reduced external virilization during embryogenesis due to impaired conversion of testosterone to dihydrotestosterone [37-39]. In this condition, the ratio of testosterone:dihydrotestosterone (when expressed in the same units) is usually >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 condition is caused by variants in the HSD3B2 gene; it causes variable undervirilization in XY individuals due to impaired 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 can 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 condition is caused by variants 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. Variants in CYP17A1 that affect only 17,20-lyase activity are extremely rare and produce undervirilization without cortisol deficiency. (See "Uncommon congenital adrenal hyperplasias", section on 'CYP17A1 deficiencies'.)

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

Lipoid CAH – This condition 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 enzyme deficiency – This condition is caused by variants in the CYP11A1 gene [40]. 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 'Cholesterol side-chain cleavage enzyme (CYP11A1) 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 conditions must be considered and diagnosed early. CAH caused by 21-hydroxylase deficiency does not result in atypical genital development 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 variants in the androgen receptor (AR) gene. Patients with complete AIS (CAIS) have a typical female external genital appearance. 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. (See "Diagnosis and treatment of disorders of the androgen receptor".)

The diagnosis of AIS (CAIS or PAIS) can be definitively established with AR gene sequencing (whether through single-gene sequencing or as part of a gene panel or exome/genome sequencing) or fibroblast AR kinetics (not widely available). Gene panels and exome/genome sequencing have the advantage of potentially detecting other causes of XY undervirilization such as gonadal dysgenesis due to an NR5A1/SF-1 gene variant or impaired testosterone biosynthesis due to 17-beta-HSD deficiency, which may have clinical presentations similar to that of PAIS. Of note, responses to hCG may be attenuated in patients with androgen insensitivity for reasons that are unclear [41].

Management of this condition 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 a more atypical genital appearance 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 an atypical genital appearance.

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 dysgenetic 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. Most individuals with a 45,X/46,XY karyotype have sufficient bilateral testicular development and function to lead to a typical male appearance of the external genitalia. For those who have mixed gonadal dysgenesis, a typical phenotype involves having a dysgenetic testicle, Wolffian structures, and a hemiscrotum on one side (usually the right) and a gonadal streak, müllerian structures (often incompletely developed), and an empty and underdeveloped labioscrotal fold on the other, producing asymmetric genital anatomy (picture 1 and image 1). Individuals with mixed gonadal dysgenesis have variable degrees of atypical genital appearance. The presence of any external genital asymmetry should raise suspicion of this condition. 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

Terminology – Infants born with a genital appearance that is neither typically male nor female or that have an appearance discordant with the chromosomal sex are classified as having a difference (or variation) 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). (See "Evaluation of the infant with atypical genital appearance (difference of sex development)", section on 'Terminology'.)

Causes in 46,XX individuals – Causes of atypical genital appearance in 46,XX individuals include (table 2):

Classic congenital adrenal hyperplasia (CAH) – The most common cause of an atypical genital appearance is classic 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 condition is diagnosed by detecting marked elevations in 17-hydroxyprogesterone (17-OHP). (See 'Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency' above.)

Other:

-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 androgenic progestins (see 'Gestational hyperandrogenism' above)

Causes in XY individuals – Causes of an atypical genital appearance 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)

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

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

Sex chromosome DSD – 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 varying degrees of dysgenesis), normal or dysgenetic testes or ovaries, streak gonads, or ovotestes. (See 'Sex chromosome differences of sex development' above.)

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

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Topic 118045 Version 9.0

References

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