What are ambiguous genitalia? 

Early in fetal development, the tissue that will become the gonads (ovaries or testes) is undifferentiated and has the potential to become either ovaries or testes. Gonadal development is the result of a complex interaction between chromosomes and hormones. Humans have 46 chromosomes in each cell of their bodies, or 23 pairs. The 23rd pair determines our gender; females usually have two X chromosomes, while males usually have one X and one Y chromosome. The chromosome complement (karyotype) in humans is usually written: 46 XX or 46 XY.

There is a gene located on the short arm (top half) of the Y chromosome, called "SRY," which, if present, will cause the undifferentiated gonad to become testes around the sixth week of fetal life. At the same time, shrinkage of what would have been the female reproductive tract occurs. As the testes produce testosterone, the phallus (penis), scrotum and urethra form. Later, during the seventh to eighth month of the pregnancy, the testes will descend into the scrotum.

If there is no SRY gene, the gonad will usually differentiate into an ovary. Likewise, the female reproductive tract will continue to develop, forming the uterus and fallopian tubes. At the same time, shrinkage of what would have become the male reproductive organs occurs.

A variety of genetic, hormonal, and environmental factors may influence development and lead to ambiguous genitalia. There is great variability in how the genitals may appear.

Causes of ambiguous genitalia

There are a number of different causes of ambiguous genitalia, with the most common described below. The cause, in many cases, is not known and the disorder appears to occur by chance. Children who are born with ambiguous genitalia may fall into one of the following groups:

46 XX – children who have:

• Normal female internal structures (uterus, ovaries, fallopian tubes), but masculinized external genitalia. The most common cause of 46 XX DSD is congenital adrenal hyperplasia (CAH). CAH is a serious medical condition which can be associated with severe electrolyte (such as sodium) imbalances.
  
  46 XX DSD can also result from exposure of the fetus to high levels of male hormones while in utero. This can occur if hormones enter the placenta, such as when the mother receives progesterone to prevent a miscarriage or has a hormone-producing tumor.

46 XY DSD – children with a 46 XY karyotype and one of the following conditions:

• Testes with normal female external genitalia. This is called Androgen Insensitivity Syndrome because the baby is not responsive to androgens (testosterone)
• Testes with ambiguous genitalia. This may be caused by a condition called 5-alpha-reductase deficiency. The enzyme 5-alpha reductase is deficient; therefore, it cannot carry out its task of converting testosterone into dihydrotestosterone (DHT), which is necessary for complete masculinization of a male fetus

Ovotesticular DSD – children who have:

• Both ovarian and testicular tissue
• External genitalia that are partially ambiguous
• Chromosomes that are either 46 XX, 46 XY, or a mixture (referred to as "mosaic") of the two (46XX/46XY)

Gonadal dysgenesis - children who have:

• An undeveloped gonad
• Internal sex organs that are usually female
• External genitals that may vary between normal female and normal male, with the majority female
• Chromosomes that are 45 X, 46 XY, 46 XX, or a mosaic (such as 45X/46XX)

Gender development

When a child's genitalia appear ambiguous at birth, your child's physician will conduct a medical history and a physical examination of your child's external genitalia. The medical history will include the mother's health during pregnancy and a family history of any neonatal deaths or genital abnormalities. First, your child's physician will make a diagnosis of the underlying cause. Diagnostic procedures may include a newborn screening test for CAH, hormonal studies and a biopsy of the reproductive organs.

Your child's physicians will consider the following:

• A pelvic ultrasound to check for the presence of female reproductive organs
• A genitourethrogram to look at the urethra and vagina if present
• A chromosomal analysis to help determine genetic sex: 46 XX or 46 XY
• Fertility potential
• Ability of an internal reproductive organ to produce appropriate sex hormones for the gender of rearing
• Risk of future health conditions (i.e., cancer) that may develop in the original reproductive organs later in life
• The actions of male or female hormones on the fetal brain
• The family’s opinion

Treatment for ambiguous genitalia

Sometimes there is an increased risk for tumors in the gonads. Treatment for ambiguous genitalia depends on the type of condition and may include diagnostic or reconstructive surgery. Treatment may also include hormone replacement therapy (HRT). Treatment is decided on a case-by-case basis through discussions with the family. Our team of providers will help each family decide what makes the most sense for their child.

Children's Hospital of Philadelphia's STRIVE for Kids Program provides multidisciplinary care, including psychosocial support, for children with ambiguous genitalia and other related disorders.