Genitalia, Ambiguous Health Article

Definition

Ambiguous genitalia is a congenital anomaly in which the genital organs do not appear to be male or female.

Description

Ambiguous genitalia, also called indeterminate sex and intersexuality, is a condition present at birth in which an individual has what appears to be both male and female external sex organs. This diagnosis is usually preliminary, based on an initial physical examination. After further evaluation and diagnostic procedures, specific genital anomalies are usually diagnosed and the underlying syndrome or condition that caused them identified.

When the genitals are abnormal, a genetic screening is usually performed to determine the genetic sex of the infant and to rule out chromosomal abnormalities.

In a genetic female with ambiguous genitalia, the clitoris may be enlarged, having the appearance of a small penis, the labia may be fused, resembling a scrotum, and the opening to the urinary tract may be located anywhere along the clitoris.

In a genetic male with ambiguous genitalia, the penis may be small, measuring less than .78 in (2 cm); it can be mistaken for an enlarged clitoris. The clitoris often appears enlarged in newborns. The testicles may be undescended, a condition in which they remain inside the body, and they may have a groove or cleft resembling labia. The urinary tract opening may be located anywhere from the tip of the penis to any point along the underside, an anomaly known as hypospadias.

Ambiguous genitalia is not a medically threatening anomaly, but it can be an extremely emotional issue for parents. Often parents must decide in which gender the child will be raised. This is a complex and difficult decision. There are health care professionals who can help inform and support parents. Counselors, doctors, and surgeons should be consulted before this decision is made.

The assignment of gender is not always based solely on the genetic sex of the child. When surgical treatment is necessary, parents may choose to raise a genetic male as a female because it is easier to surgically create functional female genitalia than male genitalia.

Children with ambiguous genitalia generally have one of the following conditions that cause the external genitalia to be abnormal:

• Congenital adrenal hyperplasia: This is the most common cause of ambiguous genitalia in infants. It is a condition affecting only females, in which the fetus cannot process an enzyme called 21-hydroxylase, causing an inability to process steroids in the body. It is characterized by a genetic female with internal female sex organs and ambiguous or masculine external genitalia.
• True hermaphroditism: In this extremely rare condition, an individual has both ovarian and testicular tissue, the internal sex organs of both genders, external genitalia that are ambiguous or of both genders, and abnormalities of the X or Y chromosome.
• Pseudohermaphroditism: In this condition, the individual has ambiguous external genitalia, but the internal sex organs of only one gender.
• Gonadal dysgenesis: In this condition, an individual has the internal sex organs of a female, external genitalia that have characteristics of both genders, but are predominantly female, abnormalities of the X or Y chromosome, and poorly developed ovaries or testicles.
• Klinefelter's syndrome: This is a chromosomal abnormality in which males have an extra X chromosome. It is characterized by small testicles, infertility, and, in some cases, mental retardation.

Genetic profile

The development of normal genitalia is a complex sequential process, beginning with the information stored on the X and Y chromosomes. Gonadal development in the fetus is first regulated by genetic information found on the short arm of the Y chromosome. Testis-determining factor (TDF) is a genetic sequence on the 11.3 subband of the Y chromosome. In the presence of TDF, testes develop. If TDF is absent, either because of a mutation of the Y chromosome or because the fetus is a female and therefore has no Y chromosome, then ovaries develop.

Testicular tissue produces two hormones essential for the development of normal male external genitalia: testosterone and mulerian-inhibiting substance (MIS). If these hormones are present, the internal male sex organs develop. These hormones work in two ways. Testosterone promotes development of male genitalia, both external and internal, and MIS prevents the development of female internal sex organs. In the absence of these two hormones, female genitalia develop.

Until these hormones are produced, all external fetal genitalia are identical and resemble female genitalia. In males, around week eight of fetal development, testosterone and another hormone, dihydrotestosterone (DHT), cause the external sex organs to become those of a normal male.

Ambiguous genitalia as a condition is caused by an interruption in some part of this process. Such interruptions may be caused by genetic mutations, exposure to substances in utero, such as steroids, or, in very rare cases, maternal endocrine abnormalities.

The exact genetic or metabolic cause of ambiguous genitalia is determined by the underlying condition that leads to the anomaly. The following are the most common syndromes causing ambiguous genitalia:

• In cases of congenital adrenal hyperplasia, the most common cause of abnormal external genital formation is defect in production of the 21-hydroxylation enzyme. This is an autosomal recessive trait thought to be linked to the human leukocyte antigen (HLA) locus on chromosome 6.
• True hermaphroditism is extremely rare and involves development of both male and female internal and external genitalia. The most common karyotype of individual with this condition is 46, XX. Researchers suspect that mosaicism is present and that a translocation of one antigen from a Y chromosome to one X chromosome or to an autosome may explain the development of male sex organs. True hermaphroditism does occur in individuals with a 46, XY karyotype. Explaining the development of ovarian tissue in this individual is difficult since two X chromosomes must be present for this to occur. Researchers theorize that there may be an undetected XX cell line within these individuals.
• Pseudohermaphroditism is generally caused by a failure in the production or absorption of the hormones testosterone and DHT. There are several different types of this condition, but they all appear to be passed on to the individual via either X-linked or autosomal recessive transmission. The anomalies are caused by a failure to produce sufficient levels of testosterone or a deficiency of enzymes, namely 5-alpha-reductase, necessary for DHT production.
• Individuals with gonadal dysgenesis have an abnormality of the sex chromosomes. Karyotypes often seen in these individuals are 46,XO/XY mosaicism, and 46,XO.