DISORDERS OF SEX DEVELOPMENT (DSD)

Classification of 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)

Components of Sex Determination

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

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

CHROMOSOMAL SEX

• 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.

GONADAL SEX

• 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.

PHENOTYPIC SEX

Male Differentiation

• 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).

Female Differentiation

• 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.

Psychosocial Development

• 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).

SEX CHROMOSOME DISORDERS OF SEX DEVELOPMENT

1. Klinefelter Syndrome (47,XXY):
2. Turner Syndrome (45,X):

Mixed Gonadal Dysgenesis (45,X/46,XY)

• 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.

Chimerism (46,XX/46,XY)

• Results from double fertilization or ovum fusion.
• Can lead to ovotesticular DSD (true hermaphroditism).

46,XX DISORDERS OF SEX DEVELOPMENT

• (Virilized XX Female)

Main Causes

1. Gonadal Dysgenesis (primary ovarian failure, minimal estrogen).
2. Ovotesticular DSD (ovary + testis tissue).
3. Testicular DSD (SRY translocation, SOX9 duplication).
4. 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).

Congenital Adrenal Hyperplasia

• Most frequent cause of virilized XX newborns (46,XX DSD).
• Usually 21-hydroxylase deficiency.

Ovotesticular DSD (True Hermaphroditism)

• 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.

46,XY DISORDERS OF SEX DEVELOPMENT

• (Undervirilized XY Male)

Main Causes

1. Abnormal Testis Development
   • Complete or partial gonadal dysgenesis (e.g., Swyer syndrome).
   • Ovotesticular DSD.
   • Testis regression (e.g., vanished testis syndrome).
2. 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).
3. 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.

Clinical Presentation

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

EVALUATION AND TREATMENT OF DSD

Initial Workup

1. History: Family occurrences, maternal exposures, prior pregnancies.
2. Physical Exam: External genitalia measurements (phallus size, fused labial/scrotal tissue), presence of gonads in labia/inguinal canal, TANNER staging if older.
3. 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.
4. Karyotype + FISH for SRY gene.
5. Imaging: Pelvic and abdominal ultrasound → uterus/vagina presence, gonad location/size.

Management Implications

• 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.