Laboratory and Radiographic tests for Ambiguous Genitalia

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Ambiguous Genitalia
Maternal history ingestion of drugs, alcohol, or hormonal agents during pregnancy progestational therapy for threatened abortion or androgen therapy for endometriosis Maternal S/S of androgen overproduction, such as acne, deepening of the voice, or hirsutism during pregnancy Family history previous occurrence of genital ambiguity, prior neonatal deaths, consanguinity, and infertility

Physical Examination
Palpable gonads or not Dysmorphic features and multiple anomalies B.P. &#0; 11-OH ase deficiency CAH Areolar or genital hyperpigmentation, R/O CAH Stigmata of Turner syndrome Phallus length: normal penis> 2.5 cm Female clitoris normal < 1 cm Hypospadias &#0; position of urethral meatus 1st degree &#0; glans 2nd degree &#0; shaft 3rd degree &#0; perineum A rectal examination to palpate the uterus The presence of a vagina, vaginal pouch, or urogenital sinus The degree of fusion of labioscrotal folds

Androgenital Ratio: Measure of fetal virilization in

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premature and full-term newborn infants

Grading Scheme for Clinical Classification of AIS

Stretch penile lengths in normal males

2.5 (0.4) cm for a 30-week newborn 3.0 (0.4) cm for a 34-week newborn 3.5 (0.4) cm for a full-term newborn 3.9 (0.8) cm for a 0- to 5-month-old 4.3 (0.8) cm for a 6- to 12-month-old A good rule of thumb in evaluating the full-term newborn is that the normal male penis should be > 2.5 cm (2.5 standard deviations below the mean).

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Reference: Holm IA: Ambiguous genitalia in the newborn. In: Emans SJ, Laufer MR, Goldstein DP eds. Pediatric adolescent gynecology. 4th eds. Lippincott-Raven: Philadelphia. 1998:58. Bin-Abbas B, Conte FA, Grumbach MM, Kaplan SL. Congenital hypogonadotropic hypogonadism and micropenis: Effect of testosterone treatment on adult penile size - Why sex reversal is not indicated. J Pediatr 1999;134:579-83. Meyers-Seifer CH, Charest NJ: Diagnosis and management of patients with ambiguous genitalia. Seminars in Perinatology 1992;16:332-339.

Laboratory and Radiographic tests for Ambiguous Genitalia

1. assays of steroid hormones, such as 17-hydroxyprogesterone (17OHP) 2. FSH, LH, Testosterone, DHT, dehydroepiandrosterone (DHEA), AMH (Mullerian inhibiting substance) 17OHP and DHEA determination should be obtained after 24 hours of life. AMH correlates with the degree of mullerian duct development and is a reliable marker for the presence of functional testicular tissue. AMH is nondetectable in normal females, detectable in normal males, and detectable but low in true hermaphrodites and patients with other disorders of testicular dysgenesis. 3. Blood karyotype 4. radiological investigations ultrasound examination Retrograde genitogram (retrograde injection of contrast material via the urogenital orifice) Voiding cystourethrogram (VCUG) 3. hCG stimulation test 3000 U/M2/dose once a day for three to five days 2000 U/ M2/day for three days 5000 U/M2 for one day Ingrid Holm in Childrens Hospital 1500 U IM qOD x 3 doses 2000 U IM qD x 3 days 5000 U IM x 1 times Testosterone and DHT are measured 24 hours after hCG. 6.endoscopy 7.Genetic studies DNA probe for SRY androgen receptor assays 21-hydroxylase gene in CAH
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5-reductase 2 gene in patients with 5-reductase deficiency AMH gene in persistent mullerian duct syndrome 8. a therapeutic trial of hCG and testosterone, which take 6-8 weeks hCG (3000 U/M2/dose biweekly for about 5 weeks) Three monthly intramuscular injections of testosterone enanthate, propionate, or cypionate 25-50 mg, should produce lengthening of the penis by 2.00.6 cm, and in this case, the patient is assigned a male gender. 9. genetic counseling -- CAH: autosomal recessive trait androgen insensitivity syndrome: X-linked Reference: Warne GL, Hughes IA: The clinical management of ambiguous genitalia. In: Brook CGD eds. Clinical Paediatric Endocrinology. 3rd ed. 1989. Oxford: Blackwell Science. pp 53-68. Holm IA: Ambiguous genitalia in the newborn. In: Emans SJ, Laufer MR, Goldstein DP eds. Pediatric adolescent gynecology. 4th eds. Lippincott-Raven: Philadelphia. 1998:49-73. Table 4.1 A differential diagnosis based on the presence or absence of the uterus in an infant with ambiguous genitalia Uterus present Genotypic female with CAH Uterus absent Androgen-insensitivity syndrome

Female virilized by transplacental 5-Reductase deficiency androgen or by endogenous tumour Block in testosterone biosynthesis Partial gonadal dysgenesis Primary gonadotrophin deficiency Absence of Leydig cells Drug-induced blockade of androgen action Table 4.2 Steps in establishing the diagnosis in an infant of uncertain sex
Clinical diagnosis 21-Hydroxylase Gonadal dysgenesis Partial androgen deficiency with Y chromosome insensitivity + + Block in testosterone biosynthesis +

Clinical feature Palpable gonad(s)

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Uterus present

+ -

-/+

Increased skin + pigmentation Sick baby Dysmorphic appearance Investigation Serum 17-OHP Electrolytes Karyotype Testosterone response to hCG Gonadal biopsy Abnormal 46,XX Not indicated +/-

+/-

-/+ -

Normal

Normal

Normal

Normal

Normal

Possibly abnormal 46,XY

45, X/46,XY or other 46,XY Definite response

Good response (both Blunted or T and DHT) absent

Not indicated

Dysgenetic gonad, +/- tumour -

Normal testis (+/Leydig cell hyperplasia) Genital skin fibroblast culture for AR assay

Normal testis

Other

Urine steroid profile

Measure testosterone precursors

THE KARYOTYPE Table 4.3 Causes of ambiguous genitalia in infants with a 46,XX karyotype Problem Cause Specific examples 21-Hydroxylase deficiency 11-Hydroxylase deficiency 3-Hydroxysteroid dehydrogenase deficiency Androgens crossing the placenta Testis or ovotestis present Partial gonadal dysgenesis

Excessive androgens Congenital adrenal of fetal origin hyperplasia

Maternal ingestion of Danazole, progestogens virilizing drug Adrenal tumour or

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Virilizing disease in hyperplasia the mother Ovarian tumour Non-androgenic Placental aromatase deficiency

Isolated clitoromegaly due to neurofibromatosis

Table 4.4 Causes of ambiguous genitalia in infants with a 46,XY karyotype Problem Insufficient androgen Cause Gonadal dysgenesis Block in testosterone biosynthesis Specific examples SRY gene mutation 17-Ketosteroid reductase deficiency 3-Hydroxysteroid dehydrogenase deficiency Primary Leydig cell hyperplasia Impaired response to Abnormal androgen androgen receptor Unresponsiveness to LH/hCG Partial androgen insensitivity

Deficient conversion 5-Reductase deficiency of testosterone to DHT DHT, dihydrotestosterone, hCG, human chorionic gonadotrophin, LH, luteinizing hormone.

Approaches to Severe Hypospadias

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Figure. Scheme for a standard diagnostic approach to the evaluation of severe hypospadias. Albers N, Ulrichs C, Gliier S, Hiort O, Sinnecker GHG, Mildenberger H, Brodehl J: Etiologic classification of severe hypospadias: Implications for prognosis and management. J Pediatr 1997;131:38692.

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