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What

Also known as “intersex”, the presence of ambiguous genitalia describes any condition in which the physical appearance of the genitalia prevents clear designation of sex in a child, often initially noticed in a newborn but occasionally not discovered until later in life around the time of puberty.

Who

The prevalence varies according to the specific cause, and is therefore difficult to estimate. congenital adrenal hyperplasia, the most common cause, has an incidence of 1 per 15,000 live births, with the highest frequency in those babies of European Jewish, Hispanic, Slavic, and Italian descent.

Signs and Symptoms

The following should prompt further investigation in a newborn:

• Indeterminate: Difficult to ascertain any sex
  
• Apparent male  Both testes cannot be felt in a full-term baby  Hypospadias (urethra opens on the underside of the penis) with separation of the scrotal sacs  Undescended testis with hypospadias
  
• Apparent female  Enlarged clitoris of any degree  Foreshortened vulva with only one opening  Inguinal hernia containing a gonad (possible testis) Intersex condition may remain undiagnosed until later when a child or teenager is seen by a doctor for early or delayed puberty, virilization (masculinization in a female), or amenorrhea (no menstrual period when expected).

Possible Causes

There are many possible causes of ambiguous genitalia, requiring a brief explanation of the process of sexual differentiation. For the first six weeks after fertilization, gonadal tissues (parts of the embryo that eventually become testes or ovaries) appear the same, with the possibility of becoming either male or female genitalia. If certain gene and hormone products (testosterone and anti-Mullerian hormone) are present, the tissues will develop into male organs. However, if those factors are not available, the tissues will mature into female organs by default. Any interruption in the process or discrepancy between genes and products can lead to the appearance of ambiguous genitalia. One way to classify the many causes of ambiguous genitalia is according to the histology (microscopic appearance) of the gonads. The following list is by no means complete: • Ovary (female gonad tissue present):  congenital adrenal hyperplasia: enzyme defect leads to decreased production of cortisol (hormone involved in the body’s response to stress) and excess production of androgens. This can cause a female baby to have an enlarged clitoris.  Maternal source of virilization: Some drugs or maternal tumors may have hormonal effects on a female fetus, including development of a large clitoris. • Testis (male gonad tissue present):  Testosterone biosynthesis defect: Affects any of the enzymes (proteins with specific functions) involved in converting cholesterol to testosterone. This leads to decreased testosterone production, with a small penis and divided scrotal sacs that may appear like female labia.  5-alpha-reductase deficiency: This enzyme converts testosterone to DHT, the hormone that produces normal-appearing male genitalia. If it is lacking, the penis will be small and scrotal sacs may appear like labia.  Androgen insensitivity: Also known as testicular feminization, the affected individual has a mutation of the androgen receptor gene. Therefore they cannot respond to androgens which would have normally caused male genital development.  Klinefelter syndrome: Apparent males with an extra X chromosome (47,XXY) who may have breast development at puberty or remain undiscovered until problems with infertility arise. • Ovary and testis (both male and female gonad tissue present):  True hermaphroditism: <10% of intersex cases in North America, where both ovarian and testicular tissue are present. • Dysgenetic (improperly formed) gonads:  Gonadal dysgenesis: Abnormally formed testes that cannot produce androgens.  Turner syndrome: Apparent females with only one X chromosome (45,XO) and no functioning ovaries, therefore causing delayed or absent pubertal development. Also associated with cardiac and renal defects.  Denys-Drash syndrome: gene defect that causes congenital nephropathy (kidney disorder), Wilms tumor (mass originating in the kidney), and ambiguous genitalia.

Diagnosis

A history will be taken, especially in regards to the pregnancy and any family history of neonatal deaths, abnormal puberty, or infertility. Physical exam will include careful inspection of the genital and anal area, palpation of the inguinal canal (groin area) for any partially descended gonads, and examining for other possible organ problems as part of a syndrome. Initial laboratory tests may be sent from the blood, including hormone levels, electrolyte levels, and chromosomes to rule out some of the more common causes. Imaging studies are often performed, such as ultrasound to examine the kidneys and to look for internal female organs. A probe is placed on the belly and back to look inside the body, much like when a pregnant woman gets an ultrasound looking at the fetus. A genitogram may also be done to outline internal structures, and is done by putting contrast (a liquid material that shows up on X-ray) though the urethra (where urine leaves the body) and taking X-rays to see where the contrast goes. Definitive diagnosis will often require surgical biopsy of the gonads, where a small piece of tissue is taken out to examine under the microscope to determine what tissues are present, specifically ovary or testis or both.

Treatment

Further treatment centers around the very difficult issue of assigning sex of rearing, particularly in babies and younger children who are unable to voice their opinion. It is best to refer the family to a medical facility experienced in dealing with such disorders, as they will have specialists including geneticists, endocrinologists (specialize in hormones and glands), and urologists (special surgeons in the urine and genital systems) available for consultation. In newborns, naming the child and assigning the sex should be done early but not until parents have been fully informed regarding the benefits and risks of any proposed hormone therapies or surgical procedures. Performing the exam with parents present is especially helpful in describing the exact abnormalities. Issues to keep in mind when deciding on the sex of rearing include potential for bearing children, ability to function sexually in the future (understanding that it is often simpler to surgically create a functional vagina as opposed to a functional penis), gonadal production of sex hormones, potential of developing cancer in an undescended testis, and a not well understood phenomenon called testosterone imprinting. In recent years there has been more evidence that exposure to testosterone may impact the fetal brain towards male sexual orientation. The timing of any surgical procedures will also need to be discussed, as they often involve multiple stages and may still not achieve “normal” cosmetic and/or functional results.

Prognosis

Because society heavily influences views on gender, emotional distress is an undeniable part of the life of any intersex patient and their family. Recently a large amount of discussion focuses on whether genital surgeries should be delayed until the child is of an age where the child can make the decision, so as to avoid the psychologic problems associated with conflict between outer appearance and gender orientation. Ultimately, this question is a very personal one for each patient and their parents, and therapists and mental health workers should therefore be introduced at an early stage. This is also an appropriate time to give parents the names of support groups for families with intersex children. Other medical problems associated with a particular diagnosis will also require management and can affect a patient’s health and lifespan. The most urgent of such cases is congenital adrenal hyperplasia, which requires stabilization in the hospital for life-threatening electrolyte abnormalities. They will also need to take steroids for life in order to maintain their body’s ability to respond properly to stress.

Connect with other parents

In the spirit of community and support, Madisons Foundation offers the unique service of connecting parents of children with rare diseases. If you would like to be connected to other parents of children with this disease, please fill out this brief form.

Weblinks

Ambiguous Sex Syndromes
Lists contact information of several support groups for intersex and associated diagnoses.

Bodies Like Ours: Intersex Information and Peer Support
Group of intersex individuals with a website including personal stories, community resources, and a bulletin board where questions can be posted freely. Parents should be aware that they do take a strong stance on ending early genital surgeries before the child is old enough to voice their opinion.

Intersex Society of North America
This is another group opposed to early genital surgeries. Their website has a well-organized section discussing the medical issues associated with raising and treating intersex children, with much of the information guided by their medical advisory board, composed of physicians in pertinent specialties.

Johns Hopkins Children’s Center: Syndromes of Abnormal Sex Differentiation
Online version of a booklet provided to patients and parents at Johns Hopkins, a great resource for parents and doctors alike with a glossary and further information on causes and management. A specific pamphlet for congenital adrenal hyperplasia is also available.

Magic Foundation: Genital and Reproductive Anomalies
Straightforward question and answer format for parents of children with ambiguous genitalia.

Google Search for Ambiguous Genitalia

References and Sources

American Academy of Pediatrics (2000). Evaluation of the newborn with developmental anomalies of the external genitalia. Pediatrics 106(1): 138-142. Hutcheson J and HM Snyder (2004). eMedicine: Ambiguous genitalia and intersexuality. http://www.emedicine.com/PED/topic1492.htm