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