Disorders of Sex Development

When a child's gender is in question at birth, because the genitals may not appear clearly male or female, the child is said to have atypical genitalia, also known as ambiguous genitalia. Atypical genitalia can be a difficult experience for families.

What are disorders of sex development (DSD)?

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, depending on the genetics of the fetus. Humans have 46 chromosomes in each cell of their bodies, or 23 pairs. The 23rd pair determines our gender; females have two X chromosomes, while males have one X and one Y chromosome. The description of human chromosomes is written: 46, XX, typical female or 46, XY, typical male.

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 (indicating a male) around the 6th week of fetal life. At the same time, regression 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 7th to 8th month of the pregnancy, the testes will descend into the scrotum.

In the absence of the SRY gene, the gonad will differentiate into an ovary (indicating a female). Likewise, the female reproductive tract will continue to develop, forming the uterus and fallopian tubes. At the same time, regression of what would have become the male reproductive organs occurs.

Besides the SRY gene, certain hormones can influence the development of the sexual organs. These hormones are secreted during the early weeks of gestation and include the anti-Müllerian hormone, testosterone hormone, and dihydrotestosterone, an active derivative of testosterone.

A variety of genetic and environmental factors may influence this development, leading to atypical genitalia. Ambiguous genitalia, as the term implies, may make determining the child's gender more difficult. Very few infants with atypical genitalia have genitals that are so ambiguous that a gender determination is not made at birth. Far more common are the following observations at birth:

• A female with severe virilization (overproduction of male hormones) who appears to have a small penis
• A male with an abnormally small penis that resembles a female clitoris (due to an insensitivity to male hormones or failure to produce male hormones)

What causes atypical genitalia?

There are a number of different causes of atypical 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 atypical genitalia may fall into one of the following groups:

Ovotesticular DSD - children who have:

• Both ovarian and testicular tissues
• Both genders' internal reproductive organs
• External genitalia that are partially ambiguous
• Chromosomes that are either 46, XX, 46, XY, or a mixture (referred to as "mosaic") of the tow (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 mixture (referred to as "mosaic") (such as 45X/46XX)

46 XY DSD - children with a 46 XY karyotyope and one of the following conditions:

• Testes with normal female external genitalia. This is called Androgen Insensitivity Syndrome because male infants are not responsive to androgens (testosterone).
  
  Androgen insensitivity syndrome is inherited by a defect in the androgen receptor gene on the X chromosome, and the inheritance is therefore described as "X-linked recessive." Mothers who carry the gene have a 50/50 chance to have a son with androgen insensitivity syndrome, while daughters (of mothers who carry the gene) have a 50/50 chance to be carriers of the gene.

• 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.
  
  A 5-alpha-reductase deficiency is inherited by an autosomal recessive gene, which means that each parent carries one copy of the gene and transmits it to the child. Carrier parents have a one in eight, or 12.5 percent, chance, with each pregnancy, to have an affected child since only males are affected.

46 XX – children who have:

• Normal female internal structures (uterus, ovaries, fallopian tubes) but virilized external genitalia. 

The most common cause is congenital adrenal hyperplasia (CAH). CAH is most commonly caused by a defect in an enzyme (21-hydroxylase) in the steroid hormone synthesis pathway in the adrenal gland.  CAH the most common cause of atypical genitalia in newborns, present in about one in 15,000 newborns.  CAH is very serious and is often associated with electrolyte (such as sodium) imbalances in the newborn. Treatment is available if diagnosed early. CAH is inherited by an autosomal recessive gene. Autosomal recessive means that each parent carries one copy of the gene and transmits the gene at the same time to the child. Carrier parents have a one in four, or 25 percent chance, with each pregnancy of having an affected child. Affected females have atypical genitalia, but affected males do not. Overproduction of male hormones before birth:

• Exposure of the fetus to high levels of male hormones while in utero. High levels of male hormones may enter the placenta via the mother, such as when the mother receives progesterone to prevent a miscarriage or has a hormone-producing tumor.

There are a number of other syndromes in which atypical genitalia is one feature (characteristic) of the disorder, in addition to other features.

How is the gender determined in a child with atypical genitalia?

When a child's genitalia appear ambiguous at birth, your child's doctor will conduct both a medical history and a physical exam 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 doctor will make a diagnosis of the underlying cause of the disorder. Diagnostic procedures may include a newborn screening test for CAH, hormonal studies, and a biopsy of the reproductive organs.

To determine the sex, your child's doctors will consider the following:

• A pelvic ultrasound (to check for the presence of female reproductive organs) or by direct cystoscopy/vaginoscopy
• A genitourethrogram to look at the urethra and vagina if present
• A chromosomal analysis (to help determine genetic sex: 46, XX or 46, XY)
• Evaluation of SRY gene
• Fertility potential of a virilized female
• Size and potential for growth of a penis present in an undervirilized male
• Ability of an internal reproductive organ to produce appropriate sex hormones for the gender "assigned" to the child
• 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
• Your opinion or preference

Treatment for atypical genitalia

Sometimes, there is an increased risk for tumors in the gonads. Treatment for atypical genitalia depends of the type of the disorder, but will usually include corrective surgery to remove or create reproductive organs appropriate for the gender of the child. Treatment may also include hormone replacement therapy. Most important, the family should be involved early in the decision making of assigning the sex of the child, and long-term psychological support should be offered.

Long-term outlook for children born with atypical genitalia

Making a correct determination of gender is important both for treatment purposes, as well as for the emotional well-being of the child. Some children born with atypical genitalia may have normal internal reproductive organs that allow them to live normal, fertile lives. However, others may experience reduced or absent fertility (difficulty or inability to conceive a child).