Ambiguous Genitalia (Disorders of Sexual Development)
- Genital ambiguity occurs when it is not possible to categorize the gender of the child based on outward genital appearance.
- Can result from various disorders of sexual development (DSD), a generic term defined as a congenital condition in which development of chromosomal, gonadal, or phenotypic sex is atypical
- General DSD categories are sex chromosome DSD; 46,XX DSD; 46,XY DSD; ovotesticular DSD; 46,XX testicular DSD; and 46,XY complete gonadal dysgenesis. Specific diagnoses (when available) are preferable to these broad categories.
- Previous terms such as “intersex,” “pseudohermaphroditism,” or “sex reversal” should be avoided.
- Criteria that suggest that a child may have a DSD include the following:
- Bilateral nonpalpable testes
- Micropenis (stretched length <2.5 cm at full term)
- Severe hypospadias or mild hypospadias with a unilateral undescended testis
- Clitoromegaly (width >6 mm or length >9 mm), posterior labial fusion
- An inguinal/labial mass
- Family history of a DSD
- Discordance between genital appearance and prenatal karyotype
- Note: The term “DSD” also comprises sex chromosome disorders including Turner (45,X) and Klinefelter syndromes (47,XXY). However, these usually do not present as ambiguous genitalia.
- Genital anomalies at birth have a prevalence as high as 1 in 300.
- Genital ambiguity has a prevalence of approximately 1 in 5,000 births.
- Congenital adrenal hyperplasia (CAH) is the most common cause of DSD. CAH is discussed in detail in a separate chapter.
- Partial androgen insensitivity syndrome (PAIS) is the next most common cause of DSD (classified as a 46,XY DSD).
- Disorders causing genital ambiguity are congenital and usually present in the newborn period.
- Later presentations can occur in older children and young adults. Examples:
- 46,XY individuals with complete 17α-hydroxylase/17,20-lyase deficiency may present in adolescence with hypertension and delayed puberty.
- Women with complete androgen insensitivity syndrome (CAIS) may present during adolescence with primary amenorrhea.
- Children with 5α-reductase deficiency may become virilized during puberty.
- Several single-gene disorders causing gonadal dysgenesis have been described. However, only 15–20% of patients with DSDs are diagnosed at the molecular level.
- 46,XY DSD may be associated with mutations in the following genes:
- Genes involved in testicular development: sex-determining region on Y (SRY), SOX9, steroidogenic factor 1 (SF-1), Wilms tumor suppressor (WT1) gene, WNT4 duplication, and DAX1 duplication
- Genes involved in steroid hormone action or synthesis (autosomal recessive, except for the androgen receptor [AR])
- LH/choriogonadotropin receptor (LHCGR) gene, leading to Leydig cell hypoplasia and decreased testosterone (T) production
- Genes encoding adrenal steroidogenic enzymes, causing undervirilization: 17α-hydroxylase (CYP17A1), 3β-hydroxysteroid dehydrogenase (HSD3B2), P450 oxidoreductase, and StAR protein (lipoid hyperplasia)
- 5α-reductase gene (SRD5A2), leading to defective conversion of T to dihydrotestosterone (DHT). DHT is necessary for the development of male external genitalia in utero.
- AR gene located on the X chromosome (X-linked recessive), leading to impaired androgen action
- 46,XX DSD may be associated with mutations in the following genes:
- Genes involved in ovarian development and leading to gonadal dysgenesis: FSH receptor (FSHR), SF-1
- Genes involved in testicular development: presence of SRY, SOX9 duplication
- Genes encoding adrenal steroidogenic enzymes, leading to virilizing CAH: 21-hydroxylase (CYP21A), the most common form; 11β-hydroxylase (CYP11B1); 3β-hydroxysteroid dehydrogenase (HSD3B2)
- Aromatase gene (CYP19A1), leading to impaired placental conversion of fetal adrenal androgens to estrogens
- Sex chromosome DSDs (45,X; 47,XXY; 45,X/46,XY; and 46,XX/46,XY) are caused by meiotic or mitotic nondisjunction.
- 46,XY DSD
- Incomplete masculinization of the male fetus can be caused by disorders of T synthesis (e.g., CAH, 5α-reductase deficiency), unresponsiveness to T action (androgen insensitivity syndromes), or defects in testicular development (complete or partial gonadal dysgenesis).
- 46,XX DSD
- Masculinization of the female fetus is caused by exposure to androgens, either endogenous or exogenous. The most common cause is CAH in which the fetal adrenal glands overproduce androgens in an attempt to produce cortisol.
- The ovaries and müllerian derivatives are normal, and the sexual ambiguity is limited to masculinization of the external genitalia.
- Ovotesticular DSD
- Presence of both ovarian and testicular elements. Combinations may include one ovary and one testis, two ovotestes, or one ovotestis with either an ovary or a testis. Differentiation of internal and external genitalia often coincides with the gonad on the ipsilateral side.
- Karyotypes are 46,XX most commonly; the molecular basis of this disorder may not be known; 46,XX/46,XY and 46,XX/47,XXY reported.
- Gonadal dysgenesis
- Mixed gonadal dysgenesis (MGD) (classically 45,X/46,XY) involves a streak gonad on one side and a testis, often dysgenetic, on the other side. Phenotype is highly variable and ranges from female external genitalia through all stages of ambiguous genitalia to a normal male.
- Pure (complete) gonadal dysgenesis (46,XX, 46,XY, or a Turner syndrome karyotype) involves replacement of gonads by streak gonads. Neonates have female external genitalia and often present later in life with delayed puberty and primary amenorrhea.
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