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 Division of Pediatric Urology St. Louis Children’s Hospital Washington University School of Medicine

DSD THIS IS THE COOL STUFF!

SEXUAL DEVELOPMENT Genetic composition Gonadal differentiation Genital expression

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

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

GENETIC INFLUENCE GONADAL DIFFERENTIATION

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.

INTERNAL DUCTAL DIFFERENTIATION Testosterone Leydig cells MIS Sertoli cells

GONADAL DEVELOPMENT INTERNAL GENITALIA 7-8 weeks

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

INTERSEX OLD CLASSIFICATION Female pseudohermaphrodite Male pseudohermaphrodite True hermaphrodite Gonadal dysgenesis

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

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

SEXUAL DEVELOPMENT Genetic composition Gonadal differentiation Genital expression

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

46 XX DSD (FEMALE PSEUDOHERMAPHRODITE) Androgen exposure Exogenous Endogenous

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

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

CHOLESTEROL METABOLISM

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

CHOLESTEROL METABOLISM 21-OH DEFICIENCY MEASURE 17-OH PROGESTERONE

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

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

46 XY DSD

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

INADEQUATE TESTOSTERONE SYNTHESIS

 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: ♀  ♂

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

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

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

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

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

SEX CHROMOSOME DSD GONADAL DYSGENESIS Mixed gonadal dysgenesis Pure gonadal dysgenesis

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

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

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

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

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

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

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

WORKUP DSD Gonads Palpable in scrotum Invariably testes

WORKUP DSD Karyotype Hormonal/Endocrine Imaging U/S Genitogram

DSD TEAM Multidisciplinary Endocrine Genetics Urology Psychology/Psychiatry Gynecology Ethicist

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

GENDER / SEX ASSIGNMENT Shared decision making Family DSD Team