Pediatric 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 confusing and scary experience for parents, but these children are usually healthy.

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, depending on the genetics of the fetus. Humans have 46 chromosomes in each cell of their body, or 23 pairs. The 23rd pair is important for gender determination; females usually have two X chromosomes, while males usually have one X and one Y chromosome. The chromosome complement in humans is written: 46, XX, normal female or 46, XY, normal male.

For example, 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 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 hormonal factors may influence this development, leading to ambiguous genitalia. Ambiguous genitalia, as the word implies, may make determining the child's gender more difficult.

More recently, the term Differences (or Disorders) of Sex Development (DSD) has been used to describe conditions in which the child’s genetics, hormones, internal organs, or external genitalia are atypical.

It is important to know:

  1. These conditions are not as rare as most think and affect about 1 in 4,500 newborns.
  2. There is a wide variety of conditions which can cause ambiguous genitalia and sometimes a detailed evaluation needs to take place before the sex of the child is clear.
  3. Children with DSD can sometimes have other congenital problems, but in general these children are healthy.
  4. One of the more common conditions known as congenital adrenal hyperplasia needs to be diagnosed and treated soon after birth to avoid serious illness in the baby.

What causes Differences in Sex Development (DSD)?

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.

Types of DSD

Children who are born with ambiguous genitalia may fall into one of the following groups:

  • Sex chromosome DSD - children who have:
    • Chromosomes can be a mixture of 45 X, 46 XX, 46 XY, and 46 XXY
    • Some people with sex chromosome DSD can have both ovarian and testicular tissue as well as both male and female internal organs
  • 46 XY DSD entail cases where the chromosomes are 46 XY but the testes did not develop (gonadal dysgenesis), the hormones are not produced, or the body does not respond or only partially responds to the hormones. These include:
    • Complete Androgen insensitivity syndrome - children who have:
      • 46, XY karyotype
      • Normal female external genitalia
    • Partial Androgen Insensitivity- children who have:
      • 46 XY karyotype
      • Can have female external anatomy, male external anatomy or have features of both.
      • This is called androgen insensitivity syndrome, because the body does not respond 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 46 XY daughter with androgen insensitivity syndrome, while 46 XX daughters (of mothers who carry the gene) have a 50/50 chance to be carriers of the gene and thus pass it on to their children
    • 5-alpha-reductase deficiency – children 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 46 XY infants are affected   
  • 46 XX DSD happens when babies are exposed to excess male hormone due to a problem in their adrenal gland, because they have the SRY gene and thus developed testes, or due to external exposure to male hormones while they were developing in their mother’s uterus. The most common cause of 46 XX DSD is due to congenital adrenal hyperplasia (CAH).
    • About congenital adrenal hyperplasia (CAH):
      • Caused by a defect in an enzyme (21-hydroxylase) in the steroid hormone synthesis pathway in the adrenal gland
      • Most common cause of ambiguous genitalia in newborns
      • Causes females to be masculinized due to a deficiency of the enzyme 21-hydroxylase
      • Present in about one in 15,000 newborns
      • 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, but this still remains experimental.
      • Another type of CAH, called salt-losing, is very serious and often lethal due to changes in the blood levels of sodium and potassium in the newborn. Treatment is available and, if diagnosed early, lethal side effects are avoided. Males and females are equally affected. There are other, rarer enzyme problems, which can result in CAH, in either males or females.

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

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. Then diagnostic procedures are performed which may include a newborn screening test for CAH, hormonal studies and an ultrasound.

The physicians at the Positive Reevaluation of Urogenital Differences (PROUD) Clinic, formerly known as the Disorders of Sexual Development Clinic, will work with you and your family to determine what sex to assign based on many issues. In addition, the Children’s PROUD team will provide expertise in many fields, as well as support through social work and psychology.

The DSD team and it’s sensitive Doctors will work with you and your family to determine what sex to assign based on many issues. In addition, we will provide expertise in many fields as well as support through social work and psychology.


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