Laboratory and Radiographic tests for Ambiguous Genitalia

Ambiguous Genitalia 常用的工具

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.  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  position of urethral meatus

1^st degree  glans

2^nd degree  shaft

3^rd degree  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 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).

Reference:

Holm IA: Ambiguous genitalia in the newborn. In: Emans SJ, Laufer MR, Goldstein DP eds. Pediatric adolescent gynecology. 4^th 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

assays of steroid hormones, such as 17-hydroxyprogesterone (17OHP)
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.

Blood karyotype
radiological investigations

ultrasound examination
Retrograde genitogram (retrograde injection of contrast material via the urogenital orifice)
Voiding cystourethrogram (VCUG)

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 Children’s 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
5α-reductase 2 gene in patients with 5α-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 2.0±0.6 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. 4^th 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

Uterus absent

Genotypic female with CAH Female virilized by transplacental androgen or by endogenous tumour Partial gonadal dysgenesis

Androgen-insensitivity syndrome

5α-Reductase deficiency

Block in testosterone biosynthesis

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 deficiency	Gonadal dysgenesis with Y chromosome	Partial androgen insensitivity	Block in testosterone biosynthesis
Clinical feature Palpable gonad(s)	-	+	+	+
Uterus present	+	+	-	-
Increased skin pigmentation	+	-	-	-/+
Sick baby	+/-	-	-	-/+
Dysmorphic appearance	-	+/-	-	-
Investigation Serum 17-OHP	↑	Normal	Normal	Normal
Electrolytes	Abnormal	Normal	Normal	Possibly abnormal
Karyotype	46,XX	45, X/46,XY or other	46,XY	46,XY
Testosterone response to hCG	Not indicated	Definite response	Good response (both T and DHT)	Blunted or absent
Gonadal biopsy	Not indicated	Dysgenetic gonad, +/- tumour	Normal testis (+/- Leydig cell hyperplasia)	Normal testis
Other	Urine steroid profile	-	Genital skin fibroblast culture for AR assay	Measure testosterone precursors

THE KARYOTYPE

Table 4.3 Causes of ambiguous genitalia in infants with a 46,XX karyotype

Problem	Cause	Specific examples
Excessive androgens of fetal origin	Congenital adrenal hyperplasia	21-Hydroxylase deficiency 11β-Hydroxylase deficiency 3β-Hydroxysteroid dehydrogenase deficiency
	Testis or ovotestis present	Partial gonadal dysgenesis
Androgens crossing the placenta	Maternal ingestion of virilizing drug Virilizing disease in the mother	Danazole, progestogens Adrenal tumour or hyperplasia Ovarian tumour
	Placental aromatase deficiency
Non-androgenic	Isolated clitoromegaly due to neurofibromatosis

Table 4.4 Causes of ambiguous genitalia in infants with a 46,XY karyotype

Problem	Cause	Specific examples
Insufficient androgen	Gonadal dysgenesis	SRY gene mutation
	Block in testosterone biosynthesis	17-Ketosteroid reductase deficiency 3β-Hydroxysteroid dehydrogenase deficiency
	Primary Leydig cell hyperplasia	Unresponsiveness to LH/hCG
Impaired response to androgen	Abnormal androgen receptor	Partial androgen insensitivity
	Deficient conversion of testosterone to DHT	5α-Reductase deficiency

DHT, dihydrotestosterone, hCG, human chorionic gonadotrophin, LH, luteinizing hormone.

Approaches to Severe Hypospadias

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;131:386-92.