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INTERSEX

INTERSEX. Paul F Austin, MD, FAAP Associate Professor of Surgery Division of Pediatric Urology St. Louis Children’s Hospital Washington University School of Medicine. CURRENT CONCEPTS OF DISORDERS OF SEXUAL DEVELOPMENT. Paul F Austin, MD, FAAP Associate Professor of Surgery

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INTERSEX

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  1. INTERSEX Paul F Austin, MD, FAAP Associate Professor of Surgery Division of Pediatric Urology St. Louis Children’s Hospital Washington University School of Medicine

  2. CURRENT CONCEPTS OF DISORDERS OF SEXUAL DEVELOPMENT Paul F Austin, MD, FAAP Associate Professor of Surgery Division of Pediatric Urology St. Louis Children’s Hospital Washington University School of Medicine

  3. DSD THIS IS THE COOL STUFF!

  4. SEXUAL DEVELOPMENT • Genetic composition • Gonadal differentiation • Genital expression

  5. CHROMOSOMAL COMPOSITION • TDF • Testes determining factor • Male phenotype determination • Short arm of Y chromosome • SRY gene • HMG-box • Mutations = gonadal dysgenesis & sterility • Only 15 - 20% with XY gonadal dysgenesis

  6. GENE EXPRESSIONGONADAL DIFFERENTIATION • SOX genes • S = SRY Related • OX = HMG-box • Autosomal genes • Other genes • WT1 • Denys-Drash syndrome • Wilm’s tumor & genital abnormalities • SF-1

  7. GENETIC INFLUENCEGONADAL DIFFERENTIATION

  8. GENETIC INFLUENCEBRAIN SEXUAL DIFFERENTIATION • Sexually dimorphic gene expression in mouse brain precedes gonadal differentiation • > 50 candidate genes for differential sex expression • > 7 murine genes • Differential expression between the developing brains of male and female mice at stage 10.5 days post coitum before any gonadal hormone influence. Dewing et al, Molecular Brain Research 118 (2003) 82–90.

  9. INTERNAL DUCTAL DIFFERENTIATION • Testosterone • Leydig cells • MIS • Sertoli cells

  10. GONADAL DEVELOPMENTINTERNAL GENITALIA 7-8 weeks

  11. 5 -reductase T DHT EXTERNAL DUCTAL DIFFERENTIATION • Testosterone • Masculinizes external genitalia but……. • Dihydrotestosterone • Necessary for “complete” ♂ phenotypic expression

  12. INTERSEXOLD CLASSIFICATION • Female pseudohermaphrodite • Male pseudohermaphrodite • True hermaphrodite • Gonadal dysgenesis

  13. INTERSEX CLASSIFICATIONGONADAL TISSUE DISORDER GONADS PRESENT Female pseudohermaphrodite Ovaries only Male pseudohermaphrodite Testes only True hermaphrodite Ovary & testis Mixed gonadal dysgenesis Testis & streak Pure gonadal dysgenesis Streak gonad only

  14. DSD CLASSIFICATION • Sex chromosome DSD • Kleinfelter • Turner • Mixed gonadal dysgenesis • Ovotesticular DSD • 46 XX DSD • Disorders of gonadal development • Androgen excess (CAH, ect.) • 46 XY DSD • Disorders of : • Gonadal development • Androgen synthesis • Androgen action

  15. SEXUAL DEVELOPMENT • Genetic composition • Gonadal differentiation • Genital expression

  16. SEXUAL AMBIGUITYANDROGEN-MEDIATED • Inappropriate over-exposure to androgens • Deficiency of androgens • Inability to recognize androgens

  17. 46 XX DSD(FEMALE PSEUDOHERMAPHRODITE) • Androgen exposure • Exogenous • Endogenous

  18. 46 XX DSDETIOLOGY • Congenital adrenal hyperplasia (CAH) • Maternal progesterone ingestion • Maternal virilizing tumors • Idiopathic

  19. CAH • Most common cause of intersex • 60% of intersex cases • 1/15,000 • Enzymatic defect

  20. CHOLESTEROL METABOLISM

  21. CHOLESTEROL METABOLISM21-OH DEFICIENCY • 90% of cases • 75% salt wasting • “Crisis” = 7-14 days

  22. CHOLESTEROL METABOLISM21-OH DEFICIENCY MEASURE 17-OH PROGESTERONE

  23. CHOLESTEROL METABOLISM11-OH DEFICIENCY • 2nd most common CAH • Hypertensive

  24. 46 XY DSD(MALE PSEUDOHERMAPHRODITE) • Deficiency of androgens • Inability to recognize androgens • Persistent Müllerian duct syndrome

  25. 46 XY DSD

  26. INADEQUATE TESTOSTERONE SYNTHESIS • Leydig cell agenesis or hypoplasia = rare • Enzymatic defects • Cholesterol  Testosterone • 3 involve adrenal gland or testes • 20,22-desmolase defect • 3-  hydroxysteroid dehydrogenase deficiency • 17-  hydroxylase defect • 2 involve testes only • 17,20 desmolase deficiency • 17- hydroxysteroid dehydrogenase deficiency

  27. INADEQUATE TESTOSTERONE SYNTHESIS

  28.  TESTOSTERONE SYNTHESIS17- hydroxysteroid dehydrogenase deficiency • Most common • Autosomal recessive or X-linked • No interference to adrenal steroids • Initially female with complete virilization at puberty • Gender role reversal: ♀ ♂

  29. INADEQUATE SYNTHESIS OF DIHYDROTESTOSTERONE • 5 -reductase type 2 deficiency • Serum T is normal • Normal internal male genitalia • Variable phenotypic expression

  30. 5 -reductase deficiency • Pseudovaginal perineoscrotal hypospadias • Autosomal recessive • Dominican Republic • Gender role reversal at puberty: ♀ ♂ • DX = HCG stim test • T:DHT > 14:1

  31. ANDROGEN INSENSITIVITY • Androgen receptor defect • Partial • Reifenstein’s Syndrome • Gilbert-Dreyfus Syndrome • Lubs Syndrome • Complete • Testicular feminization

  32. TESTICULAR FEMINIZATION COMPLETE ANDROGEN INSENSITIVITY • Normal testes • No Wolffian duct development • No Müllerian duct development • Typically discovered: • Inguinal exploration for bilateral hernias • Testicle found during primary amenorrhea workup

  33. MIS DEFICIENCYPERSISTENT MÜLLERIAN DUCT SYNDROME • Hernia uteri inguinalis • Found during hernia repair in a boy • Autosomal recessive or X-linked • No need to remove uterus and fallopian tubes • Closely adherent • Risk devascularization • No malignancy risk

  34. SEX CHROMOSOME DSDGONADAL DYSGENESIS • Mixed gonadal dysgenesis • Pure gonadal dysgenesis

  35. MIXED GONADAL DYSGENESIS • 2nd most common DSD disorder • 45XO/46XY • Testes + Streak • Asymmetry of internal and external genitalia • Rule of 3’s • Penis & 2 gonads

  36. MIXED GONADAL DYSGENESIS • Testes are dysgenetic • Absent germinal elements from seminiferous tubules • Malignant degeneration • Both testes and streak gonad • Gonadoblastoma, seminoma, dysgerminoma • Necessitate gonadectomy

  37. SYNDROMES WITH GONADAL DYSGENESIS • Denys-Drash syndrome • Triad • Wilm’s tumor • DSD • progressive nephropathy • Frasier syndrome • 46XY DSD & nephrotic syndrome

  38. PURE GONADAL DYSGENESIS • Bilateral streak gonads • Present as failure to reach menarche • Turner syndrome – 45XO • 46XX • Swyer’s syndrome – 46XY

  39. SEX CHROMOSOME DSDTRUE HERMAPHRODITE • Rare • Testicular + Ovarian tissue • Ovotestes + Ovotestes • Testes & Ovary • Ovotestes + Ovary/Testicle • 46XX - majority

  40. WORKUPDSD • History • Maternal exposures • Familial • Infant deaths • Infertility & amenorrhea • Fetal development

  41. WORKUPDSD • Physical exam • Phallus size • Penis < 2 cm stretched • Clitoris > 7 mm • Labia/scrotum • Fusion abnormalities • Rugation • Color • Gonads • Palpable in scrotum • Invariably testes

  42. WORKUPDSD • Gonads • Palpable in scrotum • Invariably testes

  43. WORKUPDSD • Karyotype • Hormonal/Endocrine • Imaging • U/S • Genitogram

  44. DSD TEAM • Multidisciplinary • Endocrine • Genetics • Urology • Psychology/Psychiatry • Gynecology • Ethicist

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