🧬 Chapter 23: Disorders of Sex Development (DSD)

Nelson's Pediatric Symptom-Based Diagnosis | 46,XX DSD · 46,XY DSD · Ovotesticular DSD · Congenital Adrenal Hyperplasia · Androgen Insensitivity · Gonadal Dysgenesis

🔍 Disorders of Sex Development (DSD): Key Concepts

📌 Terminology
DSD replaces "intersex". Categories: 46,XX DSD (virilized female), 46,XY DSD (undervirilized male), ovotesticular DSD, sex chromosome DSD (45,X/46,XY).
🧬 46,XX DSD (most common)
Congenital adrenal hyperplasia (21-hydroxylase deficiency) → cortisol deficiency, androgen excess → ambiguous genitalia in XX. Salt-wasting in 75% (hyponatremia, hyperkalemia, shock).
🔬 46,XY DSD
Complete androgen insensitivity (CAIS): female phenotype, testes, no uterus, normal AMH. Partial AIS: ambiguous. 5α-reductase deficiency: female-like at birth, virilization at puberty. Gonadal dysgenesis (Swyer syndrome).
⚕️ Diagnostic Workup
Karyotype (rapid FISH), 17-OHP (CAH), electrolytes, AMH, testosterone/DHT, hCG stimulation test, pelvic ultrasound, genitography, laparoscopy.
👶 Newborn with Ambiguous Genitalia
Emergency: rule out salt-losing CAH (life-threatening). Avoid gender assignment until complete evaluation. Multidisciplinary team (endocrinology, urology, genetics, psychology).
🚩 Red Flags
Hyponatremia, hyperkalemia, shock → CAH salt-wasting crisis. Palpable gonads in phenotypic female → rule out XY DSD. Family history of renal failure (Alport) or early puberty.

💡 Key Takeaway: Most common DSD is 46,XX CAH due to 21-hydroxylase deficiency. Always rule out salt-wasting adrenal crisis in any infant with ambiguous genitalia. Multidisciplinary, family-centered care is essential.

🩺 Clinical Approach to Newborn with Ambiguous Genitalia

🔹 Step 1: Immediate assessment (first hours)
• Rule out adrenal crisis: check electrolytes (Na, K, glucose), 17-OHP, renin, cortisol.
• Signs: vomiting, lethargy, poor feeding, hypotension, hyperpigmentation.
• If salt-wasting suspected: IV fluids, hydrocortisone, fludrocortisone.
• Do NOT assign gender until evaluation complete.
🔹 Step 2: History and physical exam
• Family history: CAH, DSD, infertility, neonatal deaths, consanguinity.
• Exam: phallus size, position of urethral meatus, labioscrotal fusion, palpable gonads.
• Palpable gonad in labioscrotal fold → likely testis → consider 46,XY DSD.
• Hyperpigmentation (scrotum, areolae) suggests ACTH elevation (CAH).
• Associated anomalies: renal (WT1), skeletal (campomelic), cardiac (Turner).
🔹 Step 3: Rapid diagnostic tests
• Karyotype (FISH, 24-48h) or qPCR for SRY.
• Serum 17-hydroxyprogesterone (17-OHP) → elevated in 21-hydroxylase deficiency.
• Electrolytes, glucose, renin, cortisol.
• Pelvic/abdominal ultrasound to detect Müllerian structures (uterus) and gonads.
🔹 Step 4: Further endocrine/genetic testing
• ACTH stimulation test for adrenal steroidogenesis defects.
• hCG stimulation test (after 6 months) to assess testosterone biosynthesis in 46,XY DSD.
• AMH and inhibin B: markers of testicular tissue presence/function.
• Targeted gene sequencing (CYP21A2, AR, SRD5A2, SRY, WT1, SF1, etc.).
• Urine steroid profiling by GC-MS.
🔹 Step 5: Gender assignment and long-term management
• Decision after complete diagnostic information, family counseling, multidisciplinary input.
• CAH females: usually reared female (fertility possible). Early genitoplasty controversial.
• 5α-reductase deficiency: many raised male (virilize at puberty).
• Complete androgen insensitivity: raised female (testes removed after puberty due to malignancy risk).
• Gonadal malignancy risk: any DSD with Y chromosome material (dysgenic gonads) → gonadectomy indicated.