Prevalence:

• 1 in 5,000 births.

Ultrasound diagnosis:

• Female fetus: clitoromegaly with normal labia.
• Male fetus: micropenis, hypospadias, undescended testes, bifid scrotum.
• On the basis of the cause, the condition is divided into:
  • True hermaphrodite: both ovarian and testicular tissue are found within the same gonad. The karyotype is female 46,XX, but there is a chromatinic material from the Y chromosome.
  • Female pseudohermaphrodite: virilized females with normal female karyotype and ovarian gonadal tissue. The causes include congenital adrenal hyperplasia (1 in 15,000), ingestion of androgens by the mother and maternal virilizing tumors. 
  • Male pseudohermaphrodite: undervirilized males with normal male karyotype and testicular tissue. The causes include inadequate synthesis of testosterone or the presence of an androgen receptor defect.

Associated abnormalities:

• Chromosomal abnormalities, mainly trisomy 13, triploidy and 13q syndrome, are found in a few cases.
• The condition is commonly associated with genetic syndromes:
  • Smith-Lemli-Opitz syndrome: autosomal recessive; ambiguous genitalia, microcephaly, cardiac, renal and gastrointestinal defects, syndactyly and polydactyly.
  • WAGR syndrome: sporadic; Wilms tumor, aniridia (absence of the iris), geniturinary malformations, neurodevelopmental delay.

• Other defects, mainly facial clefts and cardiac defects are often found.

Investigations:

• Detailed ultrasound examination.
• Look for maternal signs of hyperandrogenism (acne, deep voice, development of hirsuitism during pregnancy) and enquire about ingestion of androgens during the first trimester and family history of ambiquous genitalia.
• Determine genetic sex by invasive testing or cfDNA in maternal blood.
• Families at risk of congenital adrenal hyperplasia: invasive testing for DNA analysis.
• Cases suspected of Smith–Lemli–Opitz syndrome: amniocentesis and measurement of 7-dehydrocholesterol; high levels suggest the diagnosis.

Follow up:

• In families with congenital adrenal hyperplasia, administering dexamethasome to the pregnant woman from 6 weeks’ gestation can minimize the effect of androgens on the genitalia and the developing brain. If the fetus is male, steroids should be discontinued.
• Follow-up scans every 4 weeks to monitor growth and evolution of genitalia.

Delivery:

• Standard obstetric care but delivery should be in a tertiary center.

Prognosis:

• Treatment of a neonate with ambiguous genitalia should be performed by a multidisciplinary team, including geneticists, pediatric endocrinologists, and pediatric urologist. There is controversy concerning sex assignment and the need or not of reconstructive surgery.

Recurrence:

• Congenital adrenal hyperplasia: 25%.