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 traumatizing experience for parents.

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 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 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 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:

  • Female with severe virilizing (overproduction of male hormones) who appears to have a small penis
  • 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 - 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)
  • Gonadal dysgenesis - children who have:
    • 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 questionable 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 - children 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 50/50 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.
  • 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 males are affected.

There are a number of causes of female pseudohermaphroditism:

  • 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.

    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, rarer 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 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. 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:

  • Pelvic ultrasound (to check for the presence of female reproductive organs)
  • Genitourethrogram to look at the urethra and vagina if present
  • Chromosomal analysis (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
  • Actions of male or female hormones on the fetal brain
  • Your opinion or preference
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