G40. Anomalies of Sexual Differentiation

I. Normal Sexual Differentiation

Terminology

• DSD: differences/disorders of sex development.
• Definition: congenital condition with atypical chromosomal, gonadal or anatomical sex development.

Developmental Sequence

1. Chromosomal sex: established at fertilization, usually 46,XX or 46,XY.
2. Gonadal sex: indifferent gonad → ovary or testis.
3. Internal genitalia: Mullerian vs Wolffian duct development.
4. External genitalia: depends mainly on androgen/DHT effect.

Male Pathway

• SRY/testis-determining pathway → testis development.
• Sertoli cells → AMH → Mullerian duct regression.
• Leydig cells → testosterone → Wolffian ducts.
• Testosterone → DHT by 5-alpha-reductase → male external genitalia and prostate.

Female Pathway

• No testis → no AMH → Mullerian ducts persist.
• Mullerian derivatives: fallopian tubes, uterus, cervix, upper vagina.
• No strong androgen effect → Wolffian ducts regress.
• External genitalia: genital tubercle → clitoris; urogenital folds → labia minora; labioscrotal swellings → labia majora.

II. Classification and Key Diagnoses

Classification

1. Sex-chromosome DSD: Turner syndrome, 45,X/46,XY mosaicism, Klinefelter syndrome.
2. 46,XX DSD: most important is congenital adrenal hyperplasia.
3. 46,XY DSD: androgen insensitivity, 5-alpha-reductase deficiency, gonadal dysgenesis, testosterone-synthesis defects.

46,XX DSD: Congenital Adrenal Hyperplasia

• Most important cause of virilized 46,XX newborn: 21-hydroxylase deficiency.
• Inheritance: autosomal recessive.
• Pathway: cortisol ↓ → ACTH ↑ → adrenal hyperplasia → androgen excess.
• Salt-wasting form: aldosterone ↓ → hyponatremia, hyperkalemia, dehydration, shock.
• Anatomy: ovaries + uterus/tubes present; external genitalia may show clitoromegaly/labioscrotal fusion.
• Key clue: 46,XX + uterus present + virilized external genitalia → CAH.
• Diagnosis: 17-hydroxyprogesterone ↑, electrolytes, androgens, karyotype, pelvic US.
• Treatment: glucocorticoid replacement; mineralocorticoid + salt replacement if salt-wasting.

46,XY DSD: Complete Androgen Insensitivity

• Cause: androgen receptor dysfunction.
• Karyotype: 46,XY; gonads are testes.
• Sertoli AMH → Mullerian regression → uterus/fallopian tubes absent.
• Androgen receptor defect → tissues cannot respond to testosterone/DHT → female external phenotype.
• Breasts develop because testosterone aromatizes to estrogen.
• Typical features: normal breasts, sparse/absent pubic and axillary hair, short/blind vagina, primary amenorrhea.
• Testes may be intra-abdominal, inguinal or labial; testosterone is in male range.
• Management: specialist counseling; gonadectomy/timing individualized, often after puberty; estrogen replacement after gonadectomy.

5-Alpha-Reductase Deficiency

• Karyotype: 46,XY; testes present.
• AMH present → uterus absent; testosterone present → Wolffian structures may develop.
• Defect: impaired testosterone → DHT conversion.
• Result: undervirilized/ambiguous external genitalia at birth; virilization may occur at puberty.
• Distinction: AIS = receptor cannot respond; 5-alpha-reductase deficiency = DHT production impaired.

MRKH and Turner as Differentials

• Mullerian agenesis / Mayer-Rokitansky-Kuster-Hauser syndrome: 46,XX, normal ovaries, normal breasts/pubic hair, absent uterus/upper vagina.
• Turner syndrome: 45,X or variant, streak gonads, uterus present, low estrogen, high FSH/LH, short stature.

III. Presentation and Diagnostic Evaluation

Presentation

• Newborn: atypical/ambiguous genitalia, bilateral nonpalpable gonads, discordance between prenatal genetic sex and genital appearance.
• Emergency newborn clue: vomiting, dehydration, hypotension, hyponatremia, hyperkalemia → salt-wasting CAH until proven otherwise.
• Child/adolescent: delayed puberty, virilization, inguinal mass, atypical puberty, primary amenorrhea or infertility.

Initial Evaluation: Practical 4-Step Answer

1. Clinical assessment: external genitalia, palpable gonads, secondary sexual characteristics, BP, hydration, family/pregnancy history.
2. Chromosomal sex: karyotype plus SRY/FISH or targeted genetic testing when needed.
3. Internal anatomy: pelvic/abdominal ultrasound or MRI → uterus present? gonads/testes/ovaries where?
4. Hormonal/metabolic tests: 17-hydroxyprogesterone, electrolytes, cortisol/ACTH, testosterone/DHT, LH/FSH, estradiol, AMH, renin/aldosterone as indicated.

Uterus Shortcut

• Uterus present: no effective AMH exposure → think 46,XX CAH, Turner syndrome, gonadal dysgenesis.
• Uterus present + virilization: think 46,XX androgen excess, especially CAH.
• Uterus absent: either 46,XY testes produced AMH, e.g. AIS, or 46,XX Mullerian agenesis, e.g. MRKH.
• Distinguish absent-uterus causes by karyotype, testosterone, pubic hair and gonadal anatomy.

IV. Management Principles

Newborn With Atypical Genitalia

• Do not assign diagnosis only from external appearance.
• Stabilize first; urgently exclude salt-wasting CAH.
• Multidisciplinary team: neonatology, pediatric endocrinology, genetics, gynecology/urology/surgery and psychology/ethics when needed.
• Communicate carefully with parents; avoid rushed irreversible decisions.
• Surgery: individualized; urgent only for medical indications, not cosmetic pressure alone.

Fast Comparison

• CAH: 46,XX, ovaries, uterus present, virilization, 17-OHP ↑.
• Complete AIS: 46,XY, testes, uterus absent, female phenotype, sparse pubic hair, testosterone male range.
• MRKH: 46,XX, ovaries, uterus absent, normal pubic hair and breasts.
• Turner: 45,X, streak gonads, uterus present, short stature, estrogen ↓, FSH ↑↑.