Ambiguous Genitalia

When a child's gender is in question at birth, because genitals may not appear clearly male or female, the child is said to have ambiguous genitalia. Ambiguous genitalia can be a traumatizing experience for parents.

Pediatric urologists are often the first people to evaluate newborns whose outside genitals are abnormal. Sometimes the sex of the baby cannot be determined from the appearance of the organs. Testing and /or surgery may be needed to help a family decide which sex to raise the baby. It can be a very anxious and emotionally upsetting time for families. Frequently, other specialists such as geneticists and endocrinologists are needed to clarify the problem fully and make recommendations to families during sex assignment. These abnormalities are very complex but essentially come down to:

  • A female that looks like a male
  • A male that has a small or abnormal penis and scrotum.

Early in fetal development, the baby looks midway between boy and girl. Exposure to hormones will determine how the internal and external sex organs develop. Hormone production is genetically controlled and will ultimately guide the sexual organs’ development. If a male has too little male hormone, or is unable to respond to it, the baby will appear female. If a female is exposed to male hormone, she will appear male or partially male.

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 an ovary or a testis, depending on the genetics (chromosomes) 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 chromosome complement in humans is written: 46, XX, normal female or 46, XY, normal 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 sixth 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 seventh to eighth 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.

A variety of genetic and environmental factors may influence this development, leading to ambiguous genitalia. Ambiguous genitalia, as the word implies, may make determining the child's gender more difficult. Very few infants with ambiguous 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 virilizing (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 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:

  • True hermaphroditism, or children who have:
    • Both ovarian and testicular tissue
    • Male and female internal reproductive organs
    • External genitalia that may be ambiguous.
    • Chromosomes that are either 46, XX, 46, XY, or a mixture (referred to as mosaic)
  • Gonadal dysgenesis, or 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)
  • Pure gonadal dysgenesis—a female child who has a 46, XY karyotype, underdeveloped gonads, internal female reproductive organs and female external genitalia.
  • Pseudohermaphroditism—children who have ambiguous external genitalia, but have only one gender's internal reproductive organs. The term male (gonads are testes) or female (gonads are ovaries) pseudohermaphrodite refers to the gonadal sex (the gender of the internal reproductive organs).

There are two primary causes of male pseudohermaphroditism:

  • Androgen insensitivity syndrome, orchildren who have:
    • 46, XY karyotype.
    • 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 percent chance to have a son with androgen insensitivity syndrome, while daughters (of mothers who carry the gene) have a 50 percent chance to be carriers of the gene.

  • 5-alpha-reductase deficiency, orchildren who have:
    • 46, XY karyotype.
    • Genital ambiguity

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.

There are a number of causes of female pseudohermaphroditism:

  • Congenital adrenal hyperplasia (CAH): 
    • Is caused by a defect in an enzyme (21-hydroxylase) in the steroid hormone synthesis pathway in the adrenal gland.
    • Is the most common cause of ambiguous genitalia in newborns.
    • Causes females to be masculinized due to a deficiency of the enzyme 21-hydroxylase.
    • Is present in about one in 15,000 newborns.
    • 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 ambiguous genitalia, but affected males do not.

In some cases, the mother of a child with CAH can be given medications during pregnancy to lessen the effects of the enzyme deficiency, if the fetus is female.

Another type of CAH, called salt-losing, is very serious and often lethal due to an electrolyte collapse in the newborn. Treatment is available if diagnosed early. Males and females are equally affected. There are other, more rare enzyme problems, which can result in CAH, in either males or females.

  • Overproduction of male hormones before birth:
    • Is often due to adrenal gland abnormality (as described in CAH above)
    • high levels of male hormones may also 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 some conditions called syndromes in which ambiguous genitalia is only one of several features (characteristics) of the disorder.

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

When a child's genitalia appear ambiguous at birth, your child's physician will conduct both 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 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 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 or karyotype (to help determine genetic sex: 46, XX or 46, XY)
  • Fertility potential of a female pseudohermaphrodite
  • Size and potential for growth of a penis present in a male pseudohermaphrodite
  • 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 ambiguous genitalia

In some conditions causing ambiguous genitalia, there is an increased risk for tumors in the gonads. In these cases the gonads may need to be removed.

Treatment for ambiguous 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 (HRT).

Long-term outlook for children born with ambiguous genitalia

Making a correct determination of gender is both important for treatment purposes, as well as the emotional well-being of the child. Some children born with ambiguous 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).