Gonadal and Androgenic DSDs
Typical genotype-phenotype relationships:
46 XX, female-typical phenotype
- Primordial germ cells in the gonadal ridge induce ovarian differentiation, in approximately week 8.
- Genes from the Wnt family and others transform the paramesonephric ducts to produce the uterine tubes, uterus, and the vagina.
- Estrogen from the fetal ovaries and placenta guide formation of the vulva, aka, the female external genitalia.
- The SRY gene in the somatic cells of the gonadal ridge induces testes differentiation.
- Subsequently, the testes produce androgens and anti-Mullerian hormone (AMH), which facilitate transformation of the mesonephric ducts to produce the tubules of the testes, the epididymis, and the ductus deferens.
- Androgens also guide formation of the male external genitalia, the penis and scrotum.
Atypical Genotype-Phenotype Relationships: Gonadal Development
46 XX, DSD
- Female-atypical genotype; the "DSD" informs us that the phenotype and genotype will not share the typical relationship.
- Most cases of 46 XX DSD are caused by translocation of the SRY gene, which induces testes formation.
- Gonadal development is typically incomplete, and the gonads take the form of the following:
- Streak gonads, which are fibrous, non-functional gonads
- Dysgenic testes, which are non-functional testes (lacking in seminiferous tubules)
- Ovotestes, in which both testicular and ovarian tissues are present (either symmetrically or asymmetrically)
- The anatomy of the genitalia depends on the amount and functionality of testicular tissue
- The more testosterone-producing testicular tissue present, the more masculine the genitalia are likely to be.
- Male-atypical genotype
- Testes are absent or incompletely developed:
- Complete testicular dysgenesis and the presence of streak gonads; Swyer's Syndrome is an example of this, in which there are no definitive gonads, but, in the absence of the testes and AMH, a uterus is present.
- Partial dysgenesis; anatomical features vary according to the degree of testicular presence.
- Ovotestes are also possible.
- Anatomy of the genitalia depends on androgen concentrations.
Atypical Genotype-Phenotype Relationships: Androgen Disorders
46 XX DSD
- Exposure to high androgen concentrations in fetal period results in ambiguous or masculine genitalia.
- The degree of masculinization (aka, virilization) depends on the timing of exposure: if exposure occurs later during development, a large clitoris (hypertrophy, aka, clitoromegalia) may be the only sign of excess exposure.
- A key clinical association is that 46 XX DSD is associated with congenital adrenal hyperplasia (CAH).
- The salt-wasting form of CAH is life-threatening; the adrenal glands do not produce aldosterone, the hormone responsible for retaining sodium in the urine to maintain homeostatic body water volume. Thus, these individuals experience severe dehydration, which leads to hyperkalemia and other ion imbalances.
- Androgen receptor failure
- Characterized by the absence or insensitivity of androgen receptors.
- The testes exist, but are often undescended (cryptorchidism) with impaired function.
- Additionally, a small vagina may be present, since the androgen receptors on the paramesonephric ducts fail to trigger their regression.
- External genitalia will be ambiguous or feminine.
- Complete Androgen Insensitivity Disorder (CAIS) is the most common cause of this disorder.
- Testosterone biosynthesis disorders
- Individuals may have testes, but, because necessary elements of testosterone production and/or conversion are not available, the genitalia are ambiguous or female.
- For example, 46 XY individuals with 5-alpha reductase deficiency cannot convert testosterone to dihydrotestosterone, which is necessary for male genital differentiation during the fetal period.
- 17-beta hydroxysteroid dehydrogenase 3 deficiency, which impairs conversion of androstenedione to testosterone, is another example of an androgenic DSD.