Disorders of Sex Development

DISORDERS OF SEX DEVELOPMENT (DSD)

Definition: Congenital discrepancies between external genitalia and gonadal/chromosomal sex.
Prevalence: Ambiguous genitalia in ~1:4000 births.
Three Main Categories:
1. Sex Chromosome DSD
  - Turner syndrome (45,X)
  - Klinefelter syndrome (47,XXY)
  - Mixed gonadal dysgenesis (45,X/46,XY)
  - Chimerism (46,XX/46,XY)
2. 46,XX DSD (Virilized XX Female)
  - Disorders of gonadal development (gonadal dysgenesis, ovotesticular DSD, testicular DSD)
  - Androgen excess (fetal or maternal in origin)
3. 46,XY DSD (Undervirilized XY Male)
  - Disorders of testis development (complete/partial gonadal dysgenesis, ovotesticular DSD, testis regression)
  - Disorders of androgen synthesis or action (e.g., CAH, LH receptor mutations, 5α-reductase 2 deficiency)

Chromosomal Sex (e.g., 46,XX or 46,XY)
Phenotypic Sex (external genitalia: male or female)
Gonadal Sex (presence of ovaries or testes)
Psychosocial Development (gender identity, gender role, sexual orientation).

DSD = congenital disorder in which the development of chromosomal, phenotypic, or gonadal sex is atypical.

Usually: 46,XX (female), 46,XY (male).
Aneuploidy: Meiotic nondisjunction → gain/loss of sex chromosome (e.g., 47,XXY [Klinefelter], 45,X [Turner]).
Mosaicism: Mitotic nondisjunction → 45,X/46,XX or 45,X/46,XY, etc.

Determined by presence of ovaries or testes.
Y chromosome has SRY (testis-determining gene); it + SOX9 → testis development, AMH production → müllerian duct regression.
Ovarian development: Absence of SRY/SOX9 expression and lack of AMH secretion → normal female internal duct formation.

Sertoli cells: Produce AMH → müllerian duct regression (uterus, fallopian tubes, upper vagina).
- If AMH or its receptor is defective → Persistent Müllerian Duct Syndrome (PMDS).
Leydig cells: Secrete androgens (testosterone) by 9th week.
- Stimulated first by hCG (1st–2nd trimesters), then by fetal LH (3rd trimester).
- Testosterone stabilizes wolffian duct structures (vas deferens, epididymis, seminal vesicles).
- DHT (via 5α-reductase type 2) → male external genitalia (penis, scrotum).
Testicular Descent: Two stages—transabdominal (~12 wks) and transinguinal (androgen + LH dependent).

Müllerian ducts → uterus, upper vagina, fallopian tubes in absence of testicular factors.
Wolffian ducts regress without local testosterone.
External Genitalia:
- Genital tubercle → clitoris.
- Urogenital folds → labia minora.
- Urogenital swellings → labia majora.
Ovarian estrogen is minimal in fetus; female ductal development does not require gonadal hormones.

Gender identity, gender role, sexual orientation are influenced by prenatal hormone levels + postnatal environment.
Example: Complete Androgen Insensitivity Syndrome (CAIS) (46,XY) → typical female psychosocial development.
Some changes may occur at puberty (e.g., 5α-reductase deficiency).

Phenotypic Range: From typical female external genitalia to ambiguous or typical male.
Gonadal Range: Streak gonads to normal testes.
Uterus may be present if AMH is insufficient → persistent müllerian structures.
Management:
- If raised as girl (with minimal virilization), remove dysgenic gonads (high tumor risk), then start estrogen therapy at puberty.
- If raised as boy (hypospadias, partial testis function), then hypospadias repair, orchiopexy if needed, possibly testosterone at puberty.
- In very ambiguous cases, complex decisions are made with a multidisciplinary team.

Gonadal Dysgenesis (primary ovarian failure, minimal estrogen).
Ovotesticular DSD (ovary + testis tissue).
Testicular DSD (SRY translocation, SOX9 duplication).
Androgen Excess (most common):
- Congenital Adrenal Hyperplasia (CAH), typically 21-hydroxylase deficiency.
- Gestational hyperandrogenism (e.g., maternal androgen-secreting tumor, theca-lutein cysts, placental aromatase deficiency).

Presence of both testicular and ovarian tissue in one or both gonads.
Typically 46,XX karyotype (~60%), less commonly 46,XX/46,XY chimeric.
Gonads can be: ovotestis on one side + ovary/testis on other, bilateral ovotestes, or testis on one side + ovary on the other (least common).
External phenotype can vary from near male to near female; many have ambiguous genitalia.
Management: Complex; depends on functional aspects, tumor risk, potential fertility, and desired gender assignment.

Abnormal Testis Development
- Complete or partial gonadal dysgenesis (e.g., Swyer syndrome).
- Ovotesticular DSD.
- Testis regression (e.g., vanished testis syndrome).
Impaired Androgen Synthesis
- CAH due to 17α-hydroxylase deficiency, 3β-HSD deficiency, P450scc deficiency.
- LH receptor defects (Leydig cell hypoplasia).
- 5α-reductase 2 deficiency → inadequate DHT → undervirilized external genitalia.
- 17β-HSD type 3 deficiency (most common testosterone synthesis defect).
Impaired Androgen Action
- Androgen Insensitivity Syndrome (AIS):
  - Complete (CAIS) → phenotypic female with undescended testes, no uterus, no pubic/axillary hair.
  - Partial (PAIS) → ambiguous or predominantly male or female with some undervirilization.
- Mutations in AR gene; range of clinical phenotypes.

Ranges from ambiguous genitalia, micropenis, hypospadias to near-female external appearance.
Gonads may be undescended (risk of tumors).

History: Family occurrences, maternal exposures, prior pregnancies.
Physical Exam: External genitalia measurements (phallus size, fused labial/scrotal tissue), presence of gonads in labia/inguinal canal, TANNER staging if older.
Laboratory:
- Serum electrolytes (to rule out salt-wasting CAH).
- 17-hydroxyprogesterone, cortisol, DHEA, androstenedione, testosterone, LH, FSH, TSH.
- ± β-hCG, α-fetoprotein if germ cell tumor suspected.
Karyotype + FISH for SRY gene.
Imaging: Pelvic and abdominal ultrasound → uterus/vagina presence, gonad location/size.

Determine underlying cause: Key for deciding sex assignment, surgical interventions, hormone treatments, tumor risk.
Sex Assignment: Typically guided by the probability of future gonadal function, potential fertility, surgical complexity, and psychosocial considerations.
Hormone Therapy: E.g., glucocorticoid for CAH, GnRH analog for central precocious puberty if relevant.
Surgical: Gonadectomy of dysgenic gonads (tumor risk), correction of ambiguous genitalia (urogenital sinus anomalies), orchiopexy for undescended testis, or hypospadias repair.
Long-Term Follow-Up: Involves endocrinologists, surgeons, geneticists, psychologists for counseling on fertility, psychosocial identity, risk of neoplasms, etc.