Causes and management of a 6 months old infant with ambiguous external genitalia

Discuss the causes and management of a 6 months old infant with ambiguous external genitalia

Ambiguous eternal genitalia occur as a result of under masculinisation of an XY individual or virilisation of a XX individual. This can be caused by:

Gene mutations/chromosomal abnormalities
Inappropriate hormone levels
End organ resistance

If palpable gonads are present the infant is an undervirilised male.

Ambiguous external genitalia can occur as a result of

Sex chromosome DSD—

Chimera karyotypes (46XX/46 XY)

46 XY DSD –

Undervirilisation of 46 XY individuals

Causes

A defect in expression of 17β-Hydroxy dehydrogenase steroid 3

Results in the inability to convert androstenedione to testosterone. The external genitalia are atypical or of female phenotype because of insufficient testosterone and, consequently, DHT. AMH cause regression of mullarian structures and male internal genitalia occur due to presence of isoenzymes of 17β-HSD3

5 alpha reductase deficiency, preventing the conversion of testosterone to DHT.

In 5AR deficiency, the karyotype is XY, the gonads are testes, müllerian structures have appropriately regressed with the presence of AMH and the wolffian ducts have developed into male internal reproductive tracts under the influence of testosterone. The external genitalia, however, have developed in the female-specific pattern in the absence of DHT.

46XY ovotesticular DSD
Resistance of the androgen receptor or its mediators to the binding of testosterone and DHT results in partial insensitivity.
Complete androgen insensitivity may be diagnosed as ambiguous external genitalia if the testes are palpable in the “vulva”.

46 XX DSD

Masculinisation of XX females

Causes

46XX ovotesticular DSD- true hermophrodites
Virilisation caused by androgen excess ( commonest is CAH);
Exposure to exogenous androgens in utero

Maternal androgen secreting ovarian tumours

Maternal adrenal tumours

Maternal drugs

Fetal tumours which produce androgens

Placental aromatase deficiency

Diagnosis

Diagnosis includes taking a history, examination, biochemical analysis, genetic scrutiny,

imaging and possible surgical exploration and biopsy

History

Obstetric history

Drug exposure
History of androgen secreting tumours or adrenal disorders
Prematurity as the clitoris will be more prominent and testes will be undescended
History of previous unexplained neonatal death, stillbirth, multiple miscarriage
infertility

Family history

Congemital abnormalities and dysmorhic features

Examination

Examination of the external genitalia includes assessment for the location of palpable gonads, position and presence of urethral meatus, degree of fusion of the labio-scrotal folds, presence of a vaginal opening separate from the labioscrotal folds and size of the clitoris

Investigations

Karyotyping is the first investigation.

46XX

Further tests and diagnosis of the cause

First step is to exclude CAH by performing 17 hydroxy progesterone levels and urinary steroid profile If positive exclude a life-threatening salt-wasting crisis. Perform tets to establish the following:
Serum electrolytes
Plasma glucose
If negative consider maternal source of androgens ( ovarian tumour , adrenal tumour, use of drugs with an androgenic effect) or placental aromatase deficiency. Perform adenal hormones and testosterone levels in the mother. Perform USS to exclude ovariam and adrenal tumours.
Perform USS of the neonate for internal genitalia and gonads and to exclude a hormone secreting tumour. MRI may be needed
Laparoscopy and gonadal biopsy should be done to exclude true hermaphroditism.( XX/XY mosaic)

46XY

Investigations

hCG stimulation test followed by testing levels of testosterone, androstenedione and DHT, – poor testosterone response may due to lack of 17hydroxysteroid dehydrogenase or a block in conversion to DHT due to 5 alpha reductase deficiency.
Testosterone levels
Gonadotropin levels
AMH levels to determine the presence of testicular tissue. AMH levels are a marker of Sertoli cell function and, as such, can differentiate between those without functioning testicular tissue and those with androgen biosynthetic defect or insensitivity
USS for internal genitalia and inguinal gonads
Laparoscopy and gonadal biopsy

Ovotesticular DSD – true hermophraditism

May have a mosaic karyotype XX/XY
Perform laparoscopy and gonadal biopsy

Management

Carried out in a Tertiary centre

(MDT) approach is necessary. Should include a consultant paediatrician with subspecialists in endocrinology, surgery, urology, genetics, neonatology, psychology/ psychiatry, gynaecology and medical ethics.

Psychosocial management is required to promote positive adaptation.

Gender assignment

Avoid gender assignment before expert evaluation of the newborn.

However, it should be made as soon as diagnostic evaluation permits.

Factors which influence gender assignment are:

Diagnosis of the abnormality
Genital appearance
Therapeutic options and prospects of surgical correction
Need for life long replacement therapy,
Potential for fertility and sexual function,
Views of the,family,
Sometimes circumstances relating to cultural practices.

Recommendations are to raise infants with:

46,XY complete androgen insensitivity syndrome, 46 XY gonadal agenesis and 46,XX CAH as females.
46 XY 5a-reductase as males – At puberty, alternative isoenzymes that are capable of converting testosterone to DHT are produced, resulting in virilisation of the external genitalia.12 Antenatal and postnatal exposure of the brain to testosterone is thought to contribute to a male gender identity in many individuals with 5AR deficiency
17-hydroxysteroid dehydrogenase-3 deficiency as males. At puberty, increasing levels of LH result in higher levels of androstenedione, which is converted by isoenzymes in extragonadal tissues to testosterone. This causes the development of male secondary sexual characteristics, such as growth of the external genitalia, increased muscle mass, body hair and deepening of the voice.
46 XY gonadal dysgenesis, partial androgen insensitivity and true hermaphrodites may be reared as males or females depending on the degree of virilism.

2.Hormone replacement

Those reared as males will need testosterone for pubertal development and to maintain bone mineral density.
Complete recovery occurs with treatment in congenital adrenal hyperplasia and hormone replacement is not necessary.
Those with 46,XY complete androgen insensitivity syndrome and 46 XY gonadal agenesis will be reared as females and may need oestrogens for 1—2 years at the time of puberty for breast development ( may not be necessary for CAIS if good breast development is present) followed by HRT for life. ( combined HRT for gonadal agenesis as the uterus is present and oestrogen only for complete androgen insensitivity as the uterus is absent)

3 surgical treatment

May be done during infancy to allow adaptation and to avoid stigma.
However further corrections may be needed after puberty.

Surgery in those reared as males:

Correction of hypospadias

Surgery in those reared as females:

Clitoral reduction
Separation of fused labia
Urogenital sinus repair
Vaginal reconstruction and dilatationis done later

4.Excision of the gonads

Risk of gonadal malignancy is high in those with a Y chromosome. Risk is highest in those with gonadal dysgenesis and PAIS with abdominal gonads. Risk is lower with CAIS and the gonads are removed after breast development is complete because testicular oestrogens play a role in breast development