Ambiguous genitalia is a congenital anomaly in which the genital organs do not appear to be male or female.
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.
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.
Ambiguous genitalia is a very rare condition. Researchers estimate that the most common cause, congenital adrenal hyperplasia, may occur in one of every 15,000 live births worldwide. Other conditions that affect the formation of external genitalia are even rarer.
Signs and symptoms
Primarily, ambiguous genitalia is a physical condition characterized by an abnormal appearance of the external genitals; however, the internal sex organs are typically malformed as well. There may be partially formed testes, ovaries, or both, or a complete absence of internal sex organs. Typically, individuals with ambiguous genitalia are infertile.
In some cases of pseudohermphroditism, the genitalia may appear to be slightly abnormal female at birth, but at puberty, the genitals may become more masculine as testosterone levels rise. What appeared to be an enlarged clitoris may develop into a penis of up to 2.7 in (7 cm) in length.
The long-term health risks of this condition include an increased risk of tumors. Abnormal testicular tissue is vulnerable to tumor formation. As many as 40% of genetic males with ambiguous genitalia develop tumors within this tissue by the time they reach the age of 50. For this reason, regular screening is important.
Ambiguous genitalia is usually diagnosed initially during a newborn's physical exam or during subsequent well-baby check-ups. Once it is suspected that the infant has abnormal genitalia, diagnostic tests may be performed to identify the child's genetic gender; the presence of a chromosomal abnormality; the presence, absence, and type of internal sex organs; and the potential for production of sex hormones.
Diagnostic test that may be performed include:
- Chromosomal analysis to determine which sex chromosomes are present and if there are any abnormalities.
- Abdominal ultrasound to assess internal sex organs, if present, and to view the adrenal gland that is enlarged in females with congenital adrenal hyperplasia.
- Tests to assess the levels of male and female hormones present and the child's ability to process them; to determine if the infant can process enzymes; and to screen for other metabolic conditions that may accompany ambiguous genitalia.
Treatment and management
Treatment of ambiguous genitalia will depend on the extent of the abnormalities present, the underlying cause, and associated conditions. Treatment options include hormone replacement therapy (HRT) and surgical correction.
In some cases, gender assignment may be necessary. This can be a difficult and emotional decision for parents. Complicating the situation is the fact that when surgery is required to reconstruct external genitalia, the genetic sex of the child may not be the primary determining factor. It is far more difficult for surgeons to create functional male genitalia than female. For many years, it was thought that, in children for whom gender assignment surgery was considered the best treatment, a gender assignment should be made in the first few days of life. It was believed that environment or the influence of being raised as a girl or boy was enough to ensure gender identity. Recent data about individuals who were "assigned" a gender different from their genetic gender contradict this theory. Some individuals, who were assigned a gender different from their genetic gender as infants and were raised as the reassigned gender, chose to assume the gender identity of their genetic gender as adults. Currently, many doctors believe that gender assignment involving surgical reconstruction of the external genitalia should be delayed until the individual has an established gender identity and can be involved in the decision.
Other factors that must be considered are issues of fertility, the ability of the internal sex organs to produce gender-appropriate sex hormones, the effects of sex hormone exposure on the fetus while in the womb, and the risk of additional health problems that may develop later in life either from HRT or internal sex organs.
If gender assignment is successful, the prognosis for children diagnosed with ambiguous genitalia is excellent. Depending on the underlying diagnosis and associated conditions, some additional medical management may be necessary. In children with congenital adrenal hyperplasia, steroid treatment is necessary for survival. Despite the complications from long-term steroid use, if the condition is properly diagnosed and treated, children with congenital adrenal hyperplasia can have healthy and normal lives.
Committee on Genetics. "Evaluation of the Newborn with Developmental Anomalies of the External Genitalia." Pediatrics 106, no 1 (July 2000): 138–142.
Phornphutkul, Chanika. "Experience and Reason: Gender Self-Reassignment in an XY Adolescent Female Born with Ambiguous Genitalia." Pediatrics 106, no 1 (July 2000): 135–137.
Ambiguous Genitalia Support Network. P. O. Box 313, Clements, CA 95227-0313.
National Adrenal Diseases Foundation. 505 Northern Blvd., Great Neck, NY 11021. (April 10, 2005.) <http://www.nlm.nih.gov/medlineplus/ency/article/003269.htm>.
Hutchenson, Joel, and Howard M. Snyder, III. "Ambiguous Genitalia and Intersexuality." eMedicine. (Accessed April 1, 2005; April 10, 2005.) <http://www.emedicine.com/PED/topic1492.htm>.
Deborah L. Nurmi, MS