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INTERSEX Paul F Austin, MD, FAAP Associate Professor of Surgery
Division of Pediatric Urology St. Louis Children’s Hospital Washington University School of Medicine
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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
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DSD THIS IS THE COOL STUFF!
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SEXUAL DEVELOPMENT Genetic composition Gonadal differentiation
Genital expression
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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
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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
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GENETIC INFLUENCE GONADAL DIFFERENTIATION
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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.
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INTERNAL DUCTAL DIFFERENTIATION
Testosterone Leydig cells MIS Sertoli cells
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GONADAL DEVELOPMENT INTERNAL GENITALIA
7-8 weeks
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EXTERNAL DUCTAL DIFFERENTIATION
Testosterone Masculinizes external genitalia but……. Dihydrotestosterone Necessary for “complete” ♂ phenotypic expression T DHT 5 -reductase
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INTERSEX OLD CLASSIFICATION
Female pseudohermaphrodite Male pseudohermaphrodite True hermaphrodite Gonadal dysgenesis
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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
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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
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SEXUAL DEVELOPMENT Genetic composition Gonadal differentiation
Genital expression
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SEXUAL AMBIGUITY ANDROGEN-MEDIATED
Inappropriate over-exposure to androgens Deficiency of androgens Inability to recognize androgens
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46 XX DSD (FEMALE PSEUDOHERMAPHRODITE)
Androgen exposure Exogenous Endogenous
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46 XX DSD ETIOLOGY Congenital adrenal hyperplasia (CAH)
Maternal progesterone ingestion Maternal virilizing tumors Idiopathic
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CAH Most common cause of intersex 60% of intersex cases 1/15,000
Enzymatic defect
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CHOLESTEROL METABOLISM
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CHOLESTEROL METABOLISM 21-OH DEFICIENCY
90% of cases 75% salt wasting “Crisis” = 7-14 days
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CHOLESTEROL METABOLISM 21-OH DEFICIENCY
MEASURE 17-OH PROGESTERONE
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CHOLESTEROL METABOLISM 11-OH DEFICIENCY
2nd most common CAH Hypertensive
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46 XY DSD (MALE PSEUDOHERMAPHRODITE)
Deficiency of androgens Inability to recognize androgens Persistent Müllerian duct syndrome
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46 XY DSD
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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
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INADEQUATE TESTOSTERONE SYNTHESIS
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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: ♀ ♂
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INADEQUATE SYNTHESIS OF DIHYDROTESTOSTERONE
5 -reductase type 2 deficiency Serum T is normal Normal internal male genitalia Variable phenotypic expression
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5 -reductase deficiency
Pseudovaginal perineoscrotal hypospadias Autosomal recessive Dominican Republic Gender role reversal at puberty: ♀ ♂ DX = HCG stim test T:DHT > 14:1
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ANDROGEN INSENSITIVITY
Androgen receptor defect Partial Reifenstein’s Syndrome Gilbert-Dreyfus Syndrome Lubs Syndrome Complete Testicular feminization
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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
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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
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SEX CHROMOSOME DSD GONADAL DYSGENESIS
Mixed gonadal dysgenesis Pure gonadal dysgenesis
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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
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MIXED GONADAL DYSGENESIS
Testes are dysgenetic Absent germinal elements from seminiferous tubules Malignant degeneration Both testes and streak gonad Gonadoblastoma, seminoma, dysgerminoma Necessitate gonadectomy
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SYNDROMES WITH GONADAL DYSGENESIS
Denys-Drash syndrome Triad Wilm’s tumor DSD progressive nephropathy Frasier syndrome 46XY DSD & nephrotic syndrome
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PURE GONADAL DYSGENESIS
Bilateral streak gonads Present as failure to reach menarche Turner syndrome – 45XO 46XX Swyer’s syndrome – 46XY
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SEX CHROMOSOME DSD TRUE HERMAPHRODITE
Rare Testicular + Ovarian tissue Ovotestes + Ovotestes Testes & Ovary Ovotestes + Ovary/Testicle 46XX - majority
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WORKUP DSD History Maternal exposures Familial Infant deaths
Infertility & amenorrhea Fetal development
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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
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WORKUP DSD Gonads Palpable in scrotum Invariably testes
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WORKUP DSD Karyotype Hormonal/Endocrine Imaging U/S Genitogram
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DSD TEAM Multidisciplinary Endocrine Genetics Urology
Psychology/Psychiatry Gynecology Ethicist
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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
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GENDER / SEX ASSIGNMENT
Shared decision making Family DSD Team
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