Transcript DSD Lecture
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 5 -reductase DHT INTERSEX OLD CLASSIFICATION • • • • Female pseudohermaphrodite Male pseudohermaphrodite True hermaphrodite Gonadal dysgenesis INTERSEX CLASSIFICATION GONADAL TISSUE DISORDER GONADS PRESENT Female pseudohermaphrodite Male pseudohermaphrodite True hermaphrodite Mixed gonadal dysgenesis Pure gonadal dysgenesis Ovaries only Testes only Ovary & testis Testis & streak Streak gonad only 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 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 • 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