The term disorders of sex development (DSD) replaces the former terms intersex and hermaphroditism ( Table 23.1 ). The most common presenting symptom of DSD is atypical (ambiguous) genitalia at birth. Other presenting signs and symptoms include lack of some or all aspects of pubertal development, postnatal virilization of a phenotypic female, or infertility. The classification of DSD is based on broad categories related to blood sex chromosome composition and gonadal structure. These categories include 46,XX DSD, 46,XY DSD, ovotesticular DSD, and sex chromosome DSD ( Table 23.2 ).
| Previous | Currently Accepted |
|---|---|
| Intersex | Disorders of sex development (DSD) |
| Male pseudohermaphrodite | 46,XY DSD |
| Undervirilization of an XY male | 46,XY DSD |
| Undermasculinization of an XY male | 46,XY DSD |
| 46,XY intersex | 46,XY DSD |
| Female pseudohermaphrodite | 46,XX DSD |
| Overvirilization of an XX female | 46,XX DSD |
| Masculinization of an XX female | 46,XX DSD |
| 46,XX intersex | 46,XX DSD |
| True hermaphrodite | Ovotesticular DSD |
| Gonadal intersex | Ovotesticular DSD |
| XX male or XX sex reversal | 46,XX testicular DSD |
| XY sex reversal | 46,XY complete gonadal dysgenesis |
| 46,XX Disorders of Sex Development (DSD) |
| Androgen Exposure |
|
| Disorders of Ovarian Development |
|
| Undetermined Origin/Associated with Genitourinary and Gastrointestinal Tract Defects |
|
| 46,XY DSD |
| Defects in Testicular Development |
|
| Deficiency of Testicular Hormone Production |
|
| Persistent Müllerian Duct Syndrome Due to Antimüllerian Hormone Gene Mutations, or Receptor Defects for Antimüllerian Hormone |
| Defect in Androgen Action |
|
| Undetermined Causes, Including Those Associated with Other Congenital Defects |
| Ovotesticular DSD |
|
| Sex Chromosome DSD |
|
The terms atypical, or ambiguous genitalia, in a broad sense, refer to any case in which the external genitalia do not appear completely male or completely female. Although there are standards for genital size dimensions, variations in size of these structures do not always constitute ambiguity.
Development of the external genitalia begins with the potential to be either male or female ( Fig. 23.1 and Table 23.3 ). Virilization of a female, the most common form of DSD, results in varying phenotypes ( Fig. 23.2 ) that develop from the basic bipotential genital appearances of the embryo (see Fig. 23.1 ). Degrees of virilization at birth are often classified using the Prader stages ( Fig. 23.3 ).
| Precursor | Female | Male |
|---|---|---|
| Undifferentiated bipotential gonad | Ovary | Testis |
| Internal ducts | ||
| Wolffian (mesonephric) | Involution | Epididymis, vas deferens, seminal vesicles |
| Mullerian (paramesonephric) | Fallopian tubes, uterus, cervix, upper vagina | Involution, prostatic utricle |
| Urogenital sinus | Lower vagina, urethra | Urethra |
| External genitalia | ||
| Genital tubercle | Clitoris | Penile corpora cavernosa |
| Labioscrotal folds | Labia majora | Scrotum |
| Labiourethral folds | Labia minora | Penile urethra |
Overview of Sex Differentiation
(See Nelson Textbook of Pediatrics, p. 2750.)
In typical differentiation from the sexually undifferentiated early fetus, the final phenotype of the external and internal genitalia is consistent with a normal sex chromosome complement (either XX or XY). The process of sex differentiation and development follows a consistent timeline ( Fig. 23.4 ). The control of sex development is vast in its complexity and timing. A 46,XX complement of chromosomes as well as genetic factors, including DAX1, the signaling molecule WNT-4, CTNNB1 and R-spondin 1, are among the many factors needed for the development of normal ovaries and müllerian (paramesonephric) ducts (uterus, fallopian tubes, and upper vagina). Development of the male phenotype requires the product of a Y chromosome gene called SRY (Sex-determining Region on the Y chromosome), which, in concert with products of other genes such as SOX9, SF1, WT1, FGF9 and others, directs the undifferentiated gonad to become a testis. SRY acts as a transcriptional regulator to increase cellular proliferation, attract interstitial cells from adjacent mesonephros into the genital ridge, and stimulate testicular Sertoli cell differentiation. Sertoli cells act as an organizer of steroidogenic and germ cell lines and produce antimüllerian hormone (AMH) that causes the female (paramesonephric) duct system to regress. Aberrant genetic recombinations may result in X chromosomes carrying SRY, resulting in XX males (46,XX testicular DSD), or Y chromosomes that have lost SRY, resulting in XY females (46,XY DSD due to gonadal dysgenesis). Epigenetic causes of abnormal sex differentiation have been shown in plants, invertebrates, and vertebrates and will likely be shown to contribute to human DSD as well.
Antimüllerian hormone (AMH) from the ipsilateral fetal testis causes the müllerian (paramesonephric) ducts to regress. In its absence, they persist as the uterus, fallopian tubes, cervix, and upper vagina. By about 8 weeks of gestation, the Leydig cells of the testis begin to produce testosterone. During this critical period of male differentiation, testosterone secretion is stimulated by placental human chorionic gonadotropin (hCG), which peaks at 8-12 weeks. In the latter half of pregnancy, lower levels of testosterone are maintained by luteinizing hormone (LH) secreted by the fetal pituitary. Testosterone produced locally initiates development of the ipsilateral wolffian (mesonephric) duct into the epididymis, vas deferens, and seminal vesicle. Development of the external genitalia also requires dihydrotestosterone (DHT) , the more active metabolite of testosterone. DHT is produced largely from circulating testosterone and is necessary for fusion of the genital folds to form the penis and scrotum. DHT is also produced via an alternative biosynthetic pathway from androstanediol, and this pathway must also be intact for normal and complete prenatal virilization to occur. A functional androgen receptor , produced by an X-linked gene, is required for testosterone and DHT to produce the androgen effects.
In the XX fetus with normal long and short arms of the X chromosomes, the bipotential gonad develops into an ovary by about the 10th-11th week. This occurs only in the absence of SRY, testosterone, and AMH and requires a normal gene in the DSS (Dosage Sensitive Sex reversal) locus of DAX1 (DSS Adrenal hypoplasia congenital region on X, also known as NROB1), the WNT-4 molecule, and R-spondin 1. A female external phenotype will develop even in the absence of fetal gonads. Unlike development of the male external phenotype, which requires androgen production and its action, estrogen is unnecessary for normal female prenatal sex differentiation. This is demonstrated by 46,XX patients who lack estrogen due to a deficiency of aromatase, the enzyme required for conversion of androgen to estrogen. Development of the ovary was once thought to be a passive process in the absence of SRY. Although the morphologic changes in the developing ovary are less marked than in the testis, there are a number of sequentially expressed genes and pathways that are required for complete ovarian development as well as maintenance of ovarian integrity postnatally. One of these genes is R-spondin 1 which, if mutated, can result in testicular or ovotesticular development in 46,XX individuals. Once developed, the ovary requires FAX12 to preserve its differentiation and stability.
Several genes important to the pathoetiology of DSD are listed in Table 23.4 .
| Gene | Protein | OMIM # | Locus | Inheritance | Gonad | Müllerian Structures | External Genitalia | Associated Features/Variant Phenotypes |
|---|---|---|---|---|---|---|---|---|
| 46,XY DSD | ||||||||
| Disorders of Gonadal (Testicular) Development: Single Gene Disorders | ||||||||
| WT1 | TF | 607102 | 11p13 | AD | Testicular dysgenesis | ± | Female or ambiguous | Wilms tumor, renal abnormalities, gonadal tumors (WAGR, Denys-Drash, and Frasier syndromes) |
| SF1 (NR5A1) | Nuclear receptor TF | 184757 | 9q33 | AD/AR | Testicular dysgenesis | ± | Female or ambiguous | More severe phenotypes include primary adrenal failure; milder phenotypes have isolated partial gonadal dysgenesis; mothers who carry SF1 mutation have premature ovarian insufficiency |
| SRY | TF | 480000 | Yp11.3 | Y | Testicular dysgenesis or ovotestis | ± | Female or ambiguous | |
| SOX9 | TF | 608160 | 17q24-25 | AD | Testicular dysgenesis or ovotestis | ± | Female or ambiguous | Campomelic dysplasia (17q24 rearrangements; milder phenotype than point mutations) |
| DHH | Signaling molecule | 605423 | 12q13.1 | AR | Testicular dysgenesis | + | Female | The severe phenotype of 1 patient included minifascicular neuropathy; other patients have isolated gonadal dysgenesis |
| ATRX | Helicase (?chromatin remodeling) | 300032 | Xq13.3 | X | Testicular dysgenesis | – | Female, ambiguous or male | α-Thalassemia, developmental delay |
| ARX | TF | 300382 | Xp21.13 | X | Testicular dysgenesis | – | Ambiguous | X-linked lissencephaly, epilepsy, temperature instability |
| Disorders of Gonadal (Testicular) Development: Chromosomal Changes Involving Key Candidate Genes | ||||||||
| DMRT1 | TF | 602424 | 9p24.3 | Monosomic deletion | Testicular dysgenesis | ± | Female or ambiguous | Developmental delay |
| DAX1 (NR0B1) | Nuclear receptor TF | 300018 | Xp21.3 | dupXp21 | Testicular dysgenesis or ovary | ± | Female or ambiguous | |
| WNT4 | Signaling molecule | 603490 | 1p35 | dup1p35 | Testicular dysgenesis | + | Ambiguous | Developmental delay |
| Disorders in Hormone Synthesis or Action | ||||||||
| LHGCR | G-protein receptor | 152790 | 2p21 | AR | Testis | – | Female, ambiguous or micropenis | Leydig cell hypoplasia |
| DHCR7 | Enzyme | 602858 | 11q12-13 | AR | Testis | – | Variable | Smith-Lemli-Opitz syndrome: coarse facies, 2nd-3rd toe syndactyly, failure to thrive, developmental delay, cardiac and visceral abnormalities |
| StAR | Mitochondrial membrane protein | 600617 | 8p11.2 | AR | Testis | – | Female | Congenital lipoid adrenal hyperplasia (primary adrenal failure), pubertal failure |
| CYP11A1 | Enzyme | 118485 | 15q23-24 | AR | Testis | – | Female or ambiguous | Congenital adrenal hyperplasia (primary adrenal failure), pubertal failure |
| HSD3B2 | Enzyme | 201810 | 1p13.1 | AR | Testis | – | Ambiguous | CAH, primary adrenal failure, partial androgenization due to ↑ DHEA |
| CYP17 | Enzyme | 202110 | 10q24.3 | AR | Testis | – | Female ambiguous or micropenis | CAH, hypertension due to ↑ corticosterone and 11-deoxycorticosterone (except in isolated 17,20-lyase deficiency) |
| POR (P450 oxidoreductase) | CYP enzyme electron donor | 124015 | 7q11.2 | AR | Testis | – | Male or ambiguous | Mixed features of 21-hydroxylase deficiency, 17α-hydroxylase/17,20-lyase deficiency and aromatase deficiency; sometimes associated with Antley-Bixler skeletal dysplasia |
| HSD17B3 | Enzyme | 605573 | 9q22 | AR | Testis | – | Female or ambiguous | Partial androgenization at puberty, ↑ androstenedione : testosterone ratio |
| SRD5A2 | Enzyme | 607306 | 2p23 | AR | Testis | – | Ambiguous or micropenis | Partial androgenization at puberty, ↑ testosterone : DHT ratio |
| AKR1C4 | Enzyme | 600451 | 10p15.1 | Unclear | Testis | – | Ambiguous or micropenis | DHT deficiency in patients once thought to have 17,20-lyase deficiency; dose effect with AKR1C2 mutation is possible |
| AKR1C2 | Enzyme | 600450 | 10p15.1 | Unclear | Testis | – | Ambiguous or micropenis | DHT deficiency in patients once thought to have 17,20-lyase deficiency; dose effect with AKR1C2 mutation is possible |
| AMH | Signaling molecule | 600957 | 19p13.3-13.2 | AR | Testis | + | Normal male | Persistent müllerian duct syndrome (PMDS); male |
| AMH receptor | Serine–threonine kinase transmembrane receptor | 600956 | 12q13 | AR | Testis | – | Normal male | External genitalia, bilateral cryptorchidism |
| Androgen receptor | Nuclear receptor TF | 313700 | Xq12 | X | Testis | – | Female, ambiguous, micropenis, or normal male | Phenotypic spectrum from complete androgen insensitivity syndrome (female external genitalia) and partial androgen insensitivity (ambiguous) to normal male genitalia/infertility |
| 46,XX DSD | ||||||||
| Disorders of Gonadal (Ovarian) Development | ||||||||
| SRY | TF | 480000 | Yp11.3 | Translocation | Testis or ovotestis | – | Male or ambiguous | |
| SOX9 | TF | 608160 | 17q24 | dup17q24 | ND | – | Male or ambiguous | |
| R-spondin 1 | TF | 610644 | 1p34.3 | AR | Ovotestis | +/– | Male or ambiguous | Palmoplantar hyperkeratosis and certain malignancies |
| Androgen Excess | ||||||||
| HSD3B2 | Enzyme | 201810 | 1p13 | AR | Ovary | + | Clitoromegaly | CAH, primary adrenal failure, partial androgenization due to ↑ DHEA |
| CYP21A2 | Enzyme | 201910 | 6p21-23 | AR | Ovary | + | Ambiguous | CAH, phenotypic spectrum from severe salt-losing forms associated with adrenal failure to simple virilizing forms with compensated adrenal function, ↑ 17-hydroxyprogesterone |
| CYP11B1 | Enzyme | 20210 | 8q21-22 | AR | Ovary | + | Ambiguous | CAH, hypertension due to ↑ 11-deoxycortisol and 11-deoxycorticosterone |
| POR (P450 oxidoreductase) | CYP enzyme electron donor | 124015 | 7q11.2 | AR | Ovary | + | Ambiguous | Mixed features of 21-hydroxylase deficiency, 17α-hydroxylase/17,20-lyase deficiency and aromatase deficiency; associated with Antley-Bixler skeletal dysplasia |
| CYP19 | Enzyme | 107910 | 15q21 | AR | Ovary | + | Ambiguous | Maternal virilization during pregnancy, absent breast development at puberty, except in partial cases |
| Glucocorticoid receptor | Nuclear receptor TF | 138040 | 5q31 | AR | Ovary | + | Ambiguous | ↑ ACTH, 17-hydroxyprogesterone and cortisol; failure of dexamethasone suppression (patient heterozygous for a mutation in CYP21) |
Overview of Gonadal Function
Testes
Levels of placental hCG peak at 8-12 weeks of gestation and in males hCG stimulates the fetal Leydig cells to secrete testosterone, the main hormonal product of the testis. In the classical androgen biosynthetic pathway ( Fig. 23.5 ), testosterone is then converted by the enzyme 5α-reductase to its more potent metabolite, DHT. This early period is critical for virilization of the XY fetus including fusion of the midline to form the scrotum and extension of the urethral meatus to distal penile opening (see Fig. 23.1 ). Defects in this process lead to various deviations from typical male development. After virilization, fetal levels of testosterone decrease but are maintained at lower levels in the latter half of pregnancy by luteinizing hormone (LH) secreted by the fetal pituitary. This LH-mediated testosterone secretion is required for continued penile growth and to some degree, for testicular descent.
