IDENTIFICATION AND MANAGEMENT OF AMBIGUOUS GENITALIA.

Outline

Introduction Definition Embryogenesis Phenotypic differenciation Abnormal sexual development Aetiologic Classification Congenital Adrenal Hyperplasia(CAH)

Introduction

Ambiguous genitalia is a condition when the sex of a newborn infant is uncertain from examination of the external genitalia. Presently,it this now called disorder of sex development. This condition posses psychological and social distress to parents of this infant. It is important that such cases are managed with knowledge, experience, expedition, explanations and psychological support.

Definition

Ambiguous genitalia refers to a variance in the gonadal sex,chromosomal sex, phenotypic sex,resulting to ambiguity in external genitalia. Intersex is when an individual shows anatomical characteristics of both sexes. Ambiguous genitalia can be a traumatizing experience to the parents.

Embryogenesis

Bipotential gonads develops at 6weeks. In the presence of a Y chromosome the undifferentiated gonad develops into a testis and in the absence it develops into an ovary. The genetic information for this to happen is held on the short arm of the Y chromosome (the sex determining region or SRY). Anti-mullerian hormone(AMH) and testosterone initiates virilization of the wolffian duct. Epididymis, vas deferens, and seminal vesicle.

Embryogenesis cont`d

In the absence of AMH, and the pescence of XX chromosome,the mullerian structure persist to form fallopian tube, uterus, and upper vagina.

Phenotypic Differentiation

Male

Identical Urogenital tract until week 8 Mullerian ducts degenerated by week 10 Epididymis and rete testis form and join the urogenital sinus to form the seminal vesicles

External genitalia develop under the influence of DHT

Phenotypic differenciation

Male

Anal folds and genital tubercle move apart at week 10 Genital tubercle forms the penis Urethral folds fuse to form the urethra These folds are surrounded by prostate at the bladder Urogenital swellings fuse posteriorly to form the scrotum

Penile growth and testicular descent occur in the third trimester under the influence of testosterone

Phenotypic differenciation

Female

Wolffian ducts regress due to lack of testosterone Mullerian ducts grow in the absence of MIS

Cephalic end forms Fallopian tubes

Caudal end fuses to form the Uterus Meets the Urogenital sinus to form the Uterovaginal plate and ultimately the vaginal lumen

Phenotypic differenciation

Female

Genital tubercle develops into the clitoris Genital swellings become the labia majora

Urethral folds become the labia minora

The Introitus develops between the urethral folds

Abnormal Sexual Development - Intersex

Classified by Grumbach and Conte (1998)

1. Disorders of Gonadal Differentiation and Development
2. Female Pseudohermaphroditism

3. Male Pseudohermaphroditism
4. Unclassified forms

Disorders of Gonadal Differentiation

I. Seminiferous Tubule Dysgenesis (Klinefelters)

Most common major abnormality 47 XXY (1 in 1000 males), also 47 XXYY or mosaic 46XY/47XXY Seminiferous tubules degenerate and are replaced by hyaline Small firm testes, azoospermia, female body habitus, abnormal secondary sexual characteristics (tall, no facial hair)

Leydig cells are present but testosterone is low-normal, raised FSH/LH and raised oestrogen (gynaecomastia - x8 increase in breast ca).

Disorders of Gonadal Differentiation

II. 46 XX Males (sex reversal)

1 in 20000 males, 2% of infertile males. (All Infertile) Normal testes and ext. genitalia, but 10% have hypospadias 80% SRY positive - like Klinefelters but smaller and normal proportions Probably translocation of Y chromosome material to X chromosome or mutation of an X chromosome gene

Disorders of Gonadal Differentiation

III. Turners Syndrome (45 X0)

Presence of one functioning X Chromosome 1 in 2500 females. Mosaicism 45 X/46 XX (10%) or 45 X/46 XY (3%) Oocytes degenerate leaving streak gonads (in broad lig.) at birth Reduced Oestrogen, Raised FSH/LH. No pubertal development. Somatic changes

Disorders of Gonadal Differentiation

IV. 46 XX Pure Gonadal Dysgenesis. SWYER SYNDROME.

Similar to Turners Syndrome, but No somatic Effects

Phenotypically female with vagina, uterus and falopian tube but at puberty,breast development and menarchy fail to occur . Familial cases are x-link or sex limited autosomal dominant transmission. Gonadoblastoma and dysgerminomas occurs Pure gonadal dysgenesis requiring oestrogen and progesterone HRT

Disorders of Gonadal Differentiation

V. Mixed Gonadal Dysgenesis

Mosaicism: 45 XO/ 46 XY Second most common cause for Ambiguous genitalia Mostly phenotypic females, but entire spectrum covered Due to lack of AMH production in bilateral dysgenetic testis with ipsilateral fallopian tube

Disorders of Gonadal Differentiation

VI. Dysgenetic Male Pseudohermaphroditism

Unilateral Dysgenetic Testis (produce some testosterone / AMH) Either 45 X/46 XY or 46 XY Spectrum of Mullerian and Wolffian structures persist Increased risk of Gonadoblastoma (45% at 40 years)

Disorders of Gonadal Differentiation

VII. 46 XY Complete Gonadal Dysgenesis

Male genotype, Phenotypic females with sexual infantilism SRY gene is dysfunctional Most present in their teens with delayed puberty Raised FSH/LH may lead to increased androgen and clitoromegaly Increased risk of germ cell tumours (30% at 30 years)

Disorders of Gonadal Differentiation

VIII. Embryonic Testicular Regression

46 XY Karyotype with absent testes, but evidence of prior testicular function during embryogenesis

May be due to mutation or teratogen or bilateral torsion Vary from complete female, to male with microphallus, empty scrotum and absent prostate,perineal urethral opening

Timing of in utero event will influence development of mullerian / wolffian ducts

No testosterone but increase on stimulation with hCG, high FSH/LH. May have rudimentary cords/nubbins.

Disorders of Gonadal Differentiation

IX. True Hermaphroditism

Both healthy ovarian and testicular tissue in the form of one of each or one/two ovotestes 2/3 of patients are raised female as potentially reproductive as females Differentiation of both internal and external structures is highly variable Internal differentiation depends on the function of the ipsilateral gland 2/3 have an ovotestis, 2/3 of these having a fallopian tube Pregnancy is possible as ovarian tissue is normal, whereas testicular tissue is usually dysgenetic (infertile).

Female Pseudohermaphroditism

Phenotypic females (46 XX) have ovaries but are partially masculinised with ambiguous genitalia Most common cause is Congenital Adrenal Hyperplasia (CAH) Rarely maternal ingestion of androgens or virilizing tumours in the mother

Aetiologic classification
-Chromatin +ve -CAH -Drugs in pregnancy -Maternal arrhenoblastoma -True hermaphroditism -Chromatin ve -True hermaphroditism -Testosterone synthesis defect -Leydig cell agenesis -Feotal pituitary & hypothalamic disturbances

Congenital Adrenal Hyperplasia

Commonest adrenal disorder in childhood It can be define as congenital deficiency of enzymes involve in cortisol biosynthesis most importantly 21hydroxylase and 11B-hydroxylase.

Epidemiology

It is inherited as autosomal recessive disorder Incidence: 1 in 5,000 to 1 in 25,000 livebirths 21-hydroxylase deficiency account for 90% 11B-hydroxylase deficiency account for 5% Other enzymes deficiency account for 5%

CAH appears to be more common in those of Jewish, Hispanic, Slavic and Italian descent.

Pathogenesis

Deficiency of enzymes involve in cortisol biosynthesis (especially 21-OHase and 11B-OHase). Excessive ACTH production Adrenal hyperplasia Excess production of androgens due to increase stimulation of steps above the enzymes block.

Pathogenesis contd

Virilization of female fetus in utero results Masculinization may be intense and a condition of a male with cryptorchidism.

Clinical Features

Present with ambiguous genitalia Types of 21-Ohase -Salt losers 2/3

1/15,000-20,000 Vomiting Diarrhoea Failure to gain weight Tachycardia Dehydration Shock

Contd
Non salt losers -Mild to complete virilization -Late diagnosis 11B-Ohase deficiency -account for 5% -Hypertension -Virilization -without salt loss

Clinical Manifestion of Ambiguous Genitalia

Depends on the cause Sex is undetermined at birth Abnormal external genitalia