Disorders of Sexual Development

DSD Basics - What's in a Name?

• Definition: Disorders of Sex Development (DSD) are congenital conditions with atypical development of chromosomal, gonadal, or anatomical sex.
• Normal Sexual Differentiation: Key players include:
  • SRY gene: Primary testis-determining factor on Y chromosome.
  • SOX9: Testis development.
  • AMH (Anti-Müllerian Hormone): From Sertoli cells; causes Müllerian duct regression.
  • Testosterone: From Leydig cells; develops Wolffian ducts.
  • DHT (Dihydrotestosterone): From testosterone via 5α-reductase; virilizes external genitalia.

• Classification:
  • Sex Chromosome DSD (e.g., Turner syndrome, Klinefelter syndrome).
  • 46,XY DSD (e.g., Androgen Insensitivity Syndrome, 5α-reductase deficiency).
  • 46,XX DSD (e.g., Congenital Adrenal Hyperplasia).

⭐ SRY gene on Y chromosome is the primary testis-determining factor.

46,XX DSD - Ovaries & Androgens

• Ovaries present; virilization due to excess androgens.
• Congenital Adrenal Hyperplasia (CAH): Most common cause.
  • 21-Hydroxylase Deficiency (most frequent):
    • Ambiguous genitalia in females.
    • Salt-wasting (↓aldosterone, ↑renin) in ~75%.
    • Diagnosis: ↑17-hydroxyprogesterone (17-OHP).
  • 11β-Hydroxylase Deficiency:
    • Ambiguous genitalia.
    • Hypertension (↑deoxycorticosterone).
    • Diagnosis: ↑11-deoxycortisol.
  • Management: Glucocorticoids, mineralocorticoids (if salt-wasting), surgical correction.
• Maternal Androgen Exposure:
  • Androgen-secreting tumors (e.g., luteoma).
  • Exogenous androgens.

⭐ The most common cause of 46,XX DSD is 21-hydroxylase deficiency, leading to increased 17-hydroxyprogesterone (17-OHP).

46,XY DSD - Testes & Targets

• 46,XY karyotype with undervirilization due to issues with testes or androgen targets.
• Disorders of Testicular Development:
  • Gonadal dysgenesis (e.g., Swyer syndrome): Streak gonads, female phenotype.
• Disorders of Androgen Synthesis/Action:
  • 5-alpha-reductase deficiency (5-ARD): "Guevedoces." Ambiguous genitalia at birth, virilization at puberty. ↓DHT. T/DHT ratio > 20.
  • Androgen Insensitivity Syndrome (AIS): Defective androgen receptor.
    • Complete (CAIS): Female external genitalia, absent uterus. Testes present.
    • Partial (PAIS): Ambiguous genitalia.
• Diagnosis: Karyotype, hormones (T, DHT, LH, AMH), hCG stim test, genetics.

⭐ Complete Androgen Insensitivity Syndrome (CAIS) presents with a 46,XY karyotype, female external genitalia, absent uterus, and testes producing normal testosterone.

Chromosomal DSDs - Gene Juggle

• Turner Syndrome (45,X): Streak gonads, ovarian dysgenesis, primary amenorrhea.
• Klinefelter Syndrome (47,XXY): Testicular dysgenesis (small testes), azoospermia, gynecomastia.
• Ovotesticular DSD: Ovotestis (ovarian & testicular tissue); variable karyotype (46,XX; 46,XY).
• Gonadal Dysgenesis (e.g., Swyer - 46,XY): Female phenotype, streak gonads.

⭐ Swyer syndrome (46,XY pure gonadal dysgenesis): streak gonads; gonadectomy vital due to high gonadoblastoma risk.

DSD Approach - Clue Cracking Care

Newborn with ambiguous genitalia: prompt, systematic evaluation.

• History: Maternal (drugs, virilization, family Hx DSD, consanguinity), neonatal.
• Examination: Genital (phallus, gonads, meatus, fusion - Prader staging), dysmorphic features.
• Initial Investigations (Key):
  • Karyotype (STAT).
  • Serum electrolytes (Na+, K+), glucose.
  • Hormones: 17-OHP, Testosterone, AMH.
  • Pelvic USG (müllerian structures, gonads).
• Management: MDT essential. Gender assignment: complex decision (diagnosis, surgery, fertility, family values).

⭐ Karyotyping is the cornerstone initial investigation in evaluating a newborn with ambiguous genitalia.

High‑Yield Points - ⚡ Biggest Takeaways

• Karyotyping is the crucial first investigation for ambiguous genitalia.
• CAH (21-hydroxylase deficiency) is the most common cause of 46,XX DSD virilization.
• AIS (46,XY): female external genitalia, absent uterus, undescended testes; prophylactic gonadectomy.
• 5α-reductase deficiency (46,XY): ambiguous genitalia at birth, virilizes at puberty.
• Swyer Syndrome (46,XY): female, streak gonads, uterus present; high tumor risk, gonadectomy.
• MGD (45,X/46,XY mosaicism): variable phenotype, asymmetric gonads, high tumor risk.