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 % with XY gonadal dysgenesis

6. GENE EXPRESSION GONADAL 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 INFLUENCE GONADAL DIFFERENTIATION

8. GENETIC INFLUENCE BRAIN 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.

10. INTERNAL DUCTAL DIFFERENTIATION
Testosterone
Leydig cells
MIS
Sertoli cells

11. GONADAL DEVELOPMENT INTERNAL GENITALIA
7-8 weeks

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

13. INTERSEX OLD CLASSIFICATION
Female pseudohermaphrodite
Male pseudohermaphrodite
True hermaphrodite
Gonadal dysgenesis

14. INTERSEX CLASSIFICATION GONADAL 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

15. DSD CLASSIFICATION Sex chromosome DSD 46 XX DSD 46 XY 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
Ovotesticular DSD- true speudohemaphrodite

16. SEXUAL DEVELOPMENT Genetic composition Gonadal differentiation
Genital expression

17. SEXUAL AMBIGUITY ANDROGEN-MEDIATED
Inappropriate over-exposure to androgens
Deficiency of androgens
Inability to recognize androgens

18. 46 XX DSD (FEMALE PSEUDOHERMAPHRODITE)
Androgen exposure
Exogenous
Endogenous

19. 46 XX DSD ETIOLOGY Congenital adrenal hyperplasia (CAH)
Maternal progesterone ingestion
Maternal virilizing tumors
Idiopathic

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

23. CHOLESTEROL METABOLISM

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

25. CHOLESTEROL METABOLISM 21-OH DEFICIENCY
MEASURE
17-OH PROGESTERONE

26. CHOLESTEROL METABOLISM 11-OH DEFICIENCY
2nd most common CAH
Hypertensive

27. 46 XY DSD (MALE PSEUDOHERMAPHRODITE)
Deficiency of androgens
Inability to recognize androgens
Persistent Müllerian duct syndrome

28. 46 XY DSD

29. 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

30. INADEQUATE TESTOSTERONE SYNTHESIS

31.  TESTOSTERONE SYNTHESIS 17- 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: ♀  ♂

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

33. 5 -reductase deficiency
Pseudovaginal perineoscrotal hypospadias
Autosomal recessive
Dominican Republic
Gender role reversal at puberty: ♀  ♂
DX = HCG stim test
T:DHT > 14:1

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

35. 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

39. MIS DEFICIENCY PERSISTENT 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

40. SEX CHROMOSOME DSD GONADAL DYSGENESIS
Mixed gonadal dysgenesis
Pure gonadal dysgenesis

41. 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

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

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

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

45. SEX CHROMOSOME DSD TRUE HERMAPHRODITE
Rare
Testicular + Ovarian tissue
Ovotestes + Ovotestes
Testes & Ovary
Ovotestes + Ovary/Testicle
46XX - majority

46. WORKUP DSD History Maternal exposures Familial Infant deaths
Infertility & amenorrhea
Fetal development

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

48. WORKUP DSD
Gonads
Palpable in scrotum
Invariably testes

49. WORKUP DSD
Karyotype
Hormonal/Endocrine
Imaging
U/S
Genitogram

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

51. GENDER / SEX ASSIGNMENT
Helps pts define the way they “see themselves” and interact with others
Gender Identity
Sexual orientation
Sex typical behavior (gender role)
Ability to reproduce

52. GENDER / SEX ASSIGNMENT
Shared decision making
Family
DSD Team