Key Points
Disease summary:
Genetic sex is determined by the paternally inherited X or Y chromosome. Once established sexual determination, the commitment of the primordial gonads to becoming testes or ovaries, will follow and lead to the final phase of sexual differentiation which is the subsequent development of the internal and external genitalia. Sexual differentiation under normal circumstances is under the control of a 35 kb region of the Y chromosome known as the SRY gene. A defect anywhere in this process can cause disorders of sexual differentiation and can be classified as one of the following:
46,XY disorders of gonadal determination
46,XX disorders of gonadal determination
46,XY disorders of androgen biosynthesis and action
Luteinizing hormone (LH) receptor defects
Disorders of antimüllerian hormone (AMH) or antimüllerian hormone receptor
Androgen excess
Monogenic forms:
All enzymatic defects associated with the adrenals are monogenic.
Family history:
A pedigree of at least three generations should be obtained to evaluate consanguinity.
Environmental factors:
Fetal exposure to compounds with estrogenic effects (xenoestrogens) such as herbicides, pesticides, polychlorinated biphenyls (PCBs), polystyrenes, as well as antiandrogens such as the polyaromatic hydrocarbons, linuron, vinclozolin. Androgen exposure includes inadvertent contact by the mother with testosterone creams used by a family member or the mother taking progestin-containing oral contraceptives.
Diagnostic Criteria and Clinical Characteristics
Diagnostic criteria should include
All those being evaluated for a disorder of sexual differentiation will need a rapid and complete evaluation including
Serum hormone concentrations
Genotype
Extensive pedigree searching for abnormalities of sex development in family members including infertility
See Table 63-1.
| XY | ||||||||
|---|---|---|---|---|---|---|---|---|
| 46, XY DSD | Inheritance | External Genitalia | Internal Genitalia | Presentation | Hormone profile | Risk of gonadal tumor | Treatment | Chromosome |
| Complete Gonadal Dysgenesis | AR, X-linked, Y-linked | Female | Female | Present with pubertal delay, no secondary sex characteristics, primary amenorrhea | ↑FSH, LH no ↑ in T with hCG. Compete GD: ↓↓ T, DHT, E2 | Present | Estrogen replacement beginning at puberty Prophylactic/therapeutic gonadectomy | Multiple: Yp11.3 9p24.3 9q33 12q13.1 |
| Mixed/Partial GD | AR, X-linked, Y-linked | variable | variable | Ambiguous genitalia, pubertal delay, amenorrhea (depends on the amount of functional testicular tissue) | Mixed/Partial GD: ↓ T, DHT, E2, nml to ↓AMH | Present | Estrogen if reared as female, Testosterone if reared as a male. | Multiple:Yp11.39p24.39q3312q13.1 |
| Testicular Regression Syndrome | AR limited to Males | variable | M | Lack of secondary male characteristics | ↑FSH, LH ↓↓ T, DHT, E2 ↓↓ AMH No response to hCG | None | Testosterone if reared as a male | unknown |
| 5α-reductase type 2 deficiency | AR | Ambiguous or F | M | Virilization during puberty, | Nml FSH, LH Nml T,E2, ↓DHT, ↑ Ratio T/DHT (>30) | ? | Depends on which gender role the patient decides during adolescence or puberty | 2p23 |
| P450 Oxoreductase deficiency | AR | variable | M | variable | ↑ 17-OHProg ↑ Prog ↓ F, DHEA ↓ Δ4 steroid, T | none | Ad hoc | 7q11.2 |
| 17 β-hydroxysteroid dehydrogenase type 3 deficiency | AR | F | M | Virilization during puberty | Nml to ↑ Δ4 steroid ↑ratio Δ4/T (>15) ↓ T, DHT | none | Testosterone at puberty | 9q22 |
| Complete androgen insensitivity | X linked recessive | F | M or rudimentary mullerian | Infertile, amenorrhea + breast development | ↓ FSH, LH Nml to ↑ AMH Nml Δ4 steroid Nml T, DHT ↑↑ hCG response | None | Estrogen if castrated | Xq11-q12 |
| Partial Androgen insensitivity | X linked recessive | variable | M | variable | Nml FSH, LH Nml to ↑ AMH Nml Δ4 steroid Nml T, DHT ↑↑ hCG response | None | Dependent on sex assignment | Xq11-q12 |
| Leydig cell hypoplasia | AR | Type I: F Type II: ambiguous | M | variable | ↑ LH, nml FSH\↑ AMH ↓ T, DHT, E2 ↓hCG response Nml ratio Δ4steroid/T | ? | Type I: Estrogen Type II: Estrogen if raised as a female, T if raised as male | 2p21 |
| Persistent Müllerian duct syndrome | AR | M | M + F | Müllerian derivatives discovered incidentally | Nml hormonal profile | none | none | Type I: 19p13.3 Type II: 12q13 |
| XX | ||||||||
| 46, XX DSD | Inheritance | External Genitalia | Internal Genitalia | Presentation | Hormone profile | Risk of gonadal tumor | Treatment | Chromosome |
| Ovotesticular DSD | Unknown | variable | M + F (variable) | variable | ↑ LH, FSH ↓ T, DHT No ↑ with hCG Nml AMH | ? | Varies with the degree of ambiguity | X |
| Testicular DSD | Unknown | M | M | Small testicles (if descended), gynecomastia, azoospermia | ↑ LH, FSH ↓ T, DHT No ↑ with hCG Nml AMH | none | Testosterone | SRY translocation to X |
| XX gonadal dysgenesis | Unknown | F | F | Amenorrhea, no secondary sexual characteristics (Turner’s syndrome is most common) | ↑↑ LH, FSH ↓ E2, | none | Estrogen | 2p16 |
| P450 aromatase deficiency | AD | Ambiguous/M | F | Virilization stops after delivery Mother virilization during pregnancy | ↑ FSH, LH, Δ4steroid, T ↓ E2, Estrone ↑ 16-OHAn (maternal) | none | Estrogen | 15q21.1 |
The SRY gene, a 35-kb region located on Yp11.3, is a key genetic component of sex determination. A mutation or deletion in this region will cause maldevelopment of testicular tissue which affects both internal and external genitalia. Approximately 1:20,000 live births are affected with one of the following conditions:
Complete gonadal dysgenesis (CGD): Also known as Swyer syndrome or 46,XY pure gonadal dysgenesis. Only 15% to 20% with CGD have been identified to have a defect in the SRY gene. Patients are born without normal testicular tissue (streak gonads) bilaterally and express phenotypic female external and internal genitalia. Subjects are assigned the female sex and go unrecognized at birth. Streak gonads may be inherited in an autosomal dominant, autosomal recessive, X-linked, or Y-linked manner depending on the gene involved.
Diagnosis is made during adolescence or adulthood due to pubertal delay, lack of secondary sexual characteristics, or primary amenorrhea. In CGD, if breast tissue develops or menstruation occurs, an estrogen-secreting tumor should be suspected and must be investigated. Stature is normal to tall with eunuchoid habitus. A pelvic ultrasound reveals a normal vagina, uterus, and fallopian tubes with the absence of Wolffian structures and ovaries. Serum markers showing hypergonadotropic hypogonadism along with a karyotype and ultrasound of the internal organs can help make the proper diagnosis. Diagnosis is based on the appearance and histologic features of both gonads. The risk of gonadal tumors is 30% if testicular tissue is identified.
Mixed or partial gonadal dysgenesis (GD):
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