Abnormalities of sexual differentiation N. Ambalavanan MD Jan 2004 Material based on Chapter 47, Part 4 of Fanaroff and Martin, 7th Edition, 2002

What’s normal in a term newborn? Female: Vaginal opening fully visible: 3-4 mm slit or stellate orifice with heaped-up mucosa Clitoris width 2-6 mm Absence of gonads in labia majora or inguinal region Male: Urethra at tip of glans (may be inferred by a fully developed foreskin) Penis of normal stretched length (2.5-5 cm) and diameter (0.9-1.3 cm) Bilateral testes of normal size (8-14 mm) in the scrotal sacs

Ambiguous genitalia: what is it? Evaluation of intersex problem required for: Male-appearing genitalia with micropenis, mod/severe hypospadias, bilateral cryptorchidism, or two mild defects (e.g. mild hypospadias and unilateral cryptorchidism) Female-appearing genitalia with posterior labial fusion, clitorimegaly, or a labial or inguinal mass

Basic concepts Fetal sex differentiation: Occurs at 7-14 weeks’ fetal age only Is innately female and does not require ovaries or estrogens As a male requires: Sex-determining region of Y (SRY) gene Bilateral testes producing mullerian inhibiting substance (MIS/MIF/AMH) and testosterone 5a-reductase enzyme (external genitalia) Testosterone and dihydrotestosterone receptor (internal and external genitalia)

Human Gonadal Development and Differentiation Genital ridge Wolffian D. Male int genit. Testis Genit. Tub. Urogen. Sinus Penis Prostate SOX-9 SRY Leydig cells Testosterone DHT AMH Mullerian Duct Regression SF-1 WT-1 SF-1 Sertoli cells Bipotential gonad DSS Follicular cells Theca cells Mullerian Duct Female Internal Genitalia SF-1 Follicles Ovary

It’s a boy! (or..girl!)… maybe… Evaluation is a medical and psychosocial emergency Why? Diagnose CAH before an adrenal crisis Designate correct gender Correct problems early for correct body image and gender identity Provide genetic counseling for the future Identification of children at higher risk for gondal tumor

What should you do at the birth of a baby? Careful evaluation of genitalia of all neonates (does not need to be overtly ambiguous for diagnostic evaluation) Defer gender assignment Discuss with parents: “The genitalia are unfinished in their development, and we will need a few days to perform some studies to determine which sex your baby was intended to be” Most of the diagnostic evaluation for gender assignment can be done within 3 days.

Diagnostic evaluation - 1 History: Maternal androgens, drugs, teratogens Affected relatives, sibs who died in infancy (CAH?) Consanguinity

Diagnostic evaluation - 2 Physical examination: Genitalia Gonads Rectal Hyperpigmentation Turner syndrome? Dysmorphic features?

Diagnostic evaluation - 3 Chromosomes: Rapid test for X and Y chromosomes Karyotype Contact laboratory personally and ask for result ASAP Buccal smears are no longer recommended

Diagnostic evaluation - 4 Anatomic evaluation Ultrasound Uterus seen? seen in 94% of normal females If no uterus, suggests MIS production by testes If uterus +, suggests bilateral ovaries or gonads that do not produce MIS Intrapelvic gonads sometimes seen Endoscopy Retrograde genitography Anatomy of urethra and vagina. Presence of cervix confirms mullerian duct structures

Diagnostic evaluation - 5 Biochemical evaluation If patient is: XX with mullerian ducts: 17 OHP, 11-deoxycortisol, 17OHPe, T XX without mullerian ducts: T, E2, LH, FSH XY with mullerian ducts: T, E2, LH, FSH XY without mullerian ducts: T, DHT, LH, FSH

Management Gender Assignment: Usually made when chromosome status and mullerian duct status are known Occasionally need to defer until biochemical results are known Consultation with pediatric urologist and endocrinologist necessary If bilateral ovaries are present, usually reared as female Males with poor androgen insensitivity difficult to assign Psychological counseling to family (and later to patient)

Management Management of CAH if present Female: surgical correction of ambiguous genitalia (procedure depending on age) Male: Testosterone for micropenis Course of HCG followed by orchiopexy if necessary for cryptorchidism No circ if hypospadias Do not remove mullerian structures Gonadectomy if streak or dysgenetic gonads with Y chromosome (risk of malignancy high from infancy)

Congenital Adrenal Hyperplasia Defect in the adrenocortical synthesis of cortisol from cholesterol Low cortisol elevates ACTH Consequences of impaired synthesis of hormones (glucocorticoids, mineralocorticoids, gonadal sex steroids) and overproduction of precursors or side products

Steroid Biosynthetic Pathway Cholesterol Pregnenolone (Pe)  17-OH Pe  DHEA  D5-Androstenediol Progesterone (Pr)  17-OH Pr  Androstenedione  Testosterone 11-DeOxCorticost 11-DeOxCortisol Dihydrotestosterone Corticosterone Cortisol 18-OH Corticost Aldosterone Mineralocorticoids Glucocorticoids Androgens 3b-HSD 21-OH ase 5a-Reductase 11-b OH ase

Congenital Adrenal Hyperplasia 21-Hydroxylase deficiency 90% of CAH diagnosed by increased 17-OHP Simple virilizing (partial) and salt-wasting (complete absence of enzyme) Abnormal virilization of female fetus Males may develop penile enlargement, accel growth etc postnatally 11b-hydroxylase similar to 21-hydroxylase deficiency; but with hypertension 3b-OHSD deficiency leads to ambiguous genitalia in males and females

Rare syndromes True hermaphroditism: co-existence of ovarian and testicular tissue either in the same or opposite gonads 60% are 46 XX; 20% are 46XY or 45 X/46XY and rest are mosaics/chimeras