Ambiguous Genitalia

Ambiguous genitalia refers to a condition of the genitals in which there is a question about whether the sex of the child is male or female. Proper male or female assignment to a newborn with ambiguous genitalia should be expeditious and timely, but it is crucial that it be proper and accurate. Proper gender assignment should entail an approach that includes, but is not limited to, input from pediatric endocrinology, surgery, urology, psychiatry, and radiology consultants and the parents. When an appropriate sex assignment has been made, it is possible to proceed with an operation procedure in a timely fashion, if one is required.

EMBRYOLOGY
Normal sexual development during gestation requires a coordination among the following factors: the correct chromosome number and type, proper movement of germ cells to form the ovaries and testes, appropriate hormone production by the ovary or testes, and proper response by the tissues that develop from the secreted hormones. A problem in any one of these steps can result in the development of a child with ambiguous genitalia (those genitalia that appear to be a cross between male and female). Humans normally have 46 chromosomes and have two sex chromosomes. Boys have an X and a Y chromosome and girls have two X chromosomes and no Y chromosome.

During development all humans have what is called a gonad that can develop into either a testis and thus a male or into an ovary and thus a female. The developmental path depends on whether a Y chromosome is present or not. In the absence of the Y chromosome the path of development is automatically directed torward a girl. The presence of the Y chromosome changes the path of development towards a boy. The Y chromosome of the male leads to formation of a testis, and the SRY antigens (sex-determining region of the Y chromosome) is what initiates this change of the primitive gonad into a testis. Although the SRY antigens can be found on all male cells, the only cells that have receptors for SRY antigens are those that eventually form the testis. SRY antigens binding to these tissues are responsible for the change into a testis. Once the testes are formed they begin to produce m u llerian inhibitory substance, which causes M u llerian ducts (the ducts that from the tubes and uterus in a female) to disappear. The testicle then starts to produce testosterone. Testosterone stimulates the development of the wolffian duct system which forms the structures of the male such as the vas deferens, seminal vesicles, and epididymis. In addition, testosterone is transformed to dihydrotestosterone which is responsible for the development of the external genitalia (penis and scrotum) in the male.

In the absence of the Y chromosome and the SRY antigens, the primitive gonad develops into an ovary. Female development of the M u llerian duct system (the uterus and upper part of the vagina) and external genitalia (vagina, clitoris, and vulva) thus occurs. The normal female is not exposed to M u llerian inhibitory substance so that the M u llerian ducts do not disappear and instead go on to form the fallopian tubes, uterus, cervix, and upper portion of the vagina. Simultaneously, in the absence of testosterone, the male wolffian ducts disappear. The clitoris, labia minora, labia majora, and lower vagina develop when testosterone and dihydrotestosterone are not present.

DIAGNOSTIC EVALUATION

There are four types of ambiguous genitalia: female pseudohermaphroditism, male pseudohermaphroditism, true hermaphroditism, and gonadal dysgenesis.

Initial evaluation of the newborn with ambiguous genitalia.

During the initial evaluation of an infant with ambiguous genitalia, it is often possible to differentiate these four entities accurately by noting the symmetry of the gonads: Are one or both gonads in or absent from the scrotum? Preliminary analysis of the chromosomes is performed. This generally permits appropriate gender assignment by determining whether a child carries an XX chromosome (girl) or an XY chromosome (boy). If the gonads are different on opposite sides (asymmetric) in a karyotypic female (XX) this frequently indicates a true hermaphrodite. The child has both a testis and an ovary. If a boy has asymmetric gonads, ie. both an ovary and a testis, this usually indicates the presence of a condition called mixed gonadal dysgenesis. It should be determined initially if other family members have a history of ambiguous genitalia, whether female relatives died in infancy suggestive of a disease called congenital adrenal hyperplasia, or whether there is infertility in the family. A detailed evaluation of drug ingestion during pregnancy is important, especially for androgenic agents such as pro-gesterone. Urinary mineralocorticoid and glucocorticoid steroid measurements and serum electrolyte (blood chemicals) levels should be obtained since some of the ambiguous genitalia problems may lead to steroid and electrolyte problems. Pelvic ultrasound, endoscopy (using a scope to look inside the body), and contrast genitography (a type of X-ray study where dye is injected into a possible vagina if one is present) are performed to clarify the status of the internal genital structures and to show the vaginal entrance. Occasionally, laparoscopy is required for sex identification, particularly with true hermaphrodites. Laparoscopy allows the doctor to look inside the body and directly see whether there are ovaries present.

In general, most infants with ambiguous genitalia are best reconstructed as females because of the practicality of surgical reconstruction based on the size of the phallus. Although there is a great deal of discussion of the subject, it is likely that regardless of genotype (chromosome number, XX or XY), if an inadequate phallus cannot be corrected surgically, the patient will fare better in the female gender role. The matter of testosterone imprinting on the brain requires careful consideration and more research than is available at present. Genetic males with severe penoscrotal hypospadias (a type of condition where the opening to the penis is not in the correct anatomic location) and bilateral undescended testes (the testes are not in the scrotum but may be in the abdomen) frequently may be reconstructed successfully, however, so they usually are reared as males.

SPECIFIC DISORDERS

Female Pseudohermaphroditism (Adrenogenital Syndrome)
Infants with congenital adrenal hyperplasia have 46 chromosomes with two X sex chromosomes , so they should be girls. However, they are missing one of three enzymes which serve to process normal steroids into the sex hormones. If one of the enzymes is missing, too much of the steroids will become testosterone. As a result, the external genitalia will be masculinized: they will look more like a male. The common enzymes that are missing are 21-hydroxylase, 11-hydroxylase, and 3-hydroxysteroid dehydrogenase. How masculine they will look is variable. There may be mild clitoral enlargement alone at one extreme and complete masculinization with a normal-appearing but small penis with the urethra at the end of the penis. The vagina may enter into the urethra way up inside instead of coming out onto the perineum between the legs. This common tube of the vagina and the urethra is called a urogenital sinus. During normal development the genital, urinary and intestinal structures empty into a common cavity and then split apart into separate structures. All three structures emptying into a common cavity is called a cloaca. If only the urinary and genital structures share a common opening, it is called a urogenital sinus. Normally this structure would have gone on to form the normal openings for the urinary tract and the vagina.

All of these children are reared as females and should have normal fertility because they have normal internal genitalia (ovaries, vagina and uterus). Surgical treatment is designed to correct the appearance of and functional deformities of the external genitalia, primarily the enlargement of the clitoris and the malformation of the vaginal entrance. In the usual form of this malformation, surgery is usually performed at 3 to 6 months of age. In infants with the very masculinized form of congenital adrenal hyperplasia in which the vagina inserts up high into the urethra, surgery is delayed until at least 2 years of age so that a pull-through of the vagina to the perineum can be performed safely. This may be corrected at an earlier age with what is called a posterior sagittal approach or a total urogenital sinus mobilization technique.

One of the additional problems with the adrenogenital syndrome which can cause them to be sick as newborns is that some of the steroids that control the chemicals in the blood (electrolytes) and blood pressure may be low. The two types of steroids, that are problematic are called mineralocorticoids and glucocorticoids. Each of these types does different things. Patients with a low glucocorticoid steroids require cortisol replacement (a type of steroid). Additionally, patients with mineralocorticoid deficiency require fludrocortisone acetate replacement.

Mixed Gonadal Dysgenesis
The syndrome of mixed gonadal dysgenesis is associated with dysgenetic (abnormal) gonads and persistent Mullerian structures. Most commonly, there is a streak gonad like an ovary on one side with Mullerian structures (uterus, tube, vagina) and a testis on the opposite side with a vas and epididymis. In general, these individuals have mixed chromosomes: 45 chromosomes with only one X chromosome in some cells and 46 chromosomes with XY sex chromosomes in others. Half of these individuals eventually develop malignancy in their gonads. Gonadoblastoma is the most common malignancy overall, but seminoma and dysgerminoma may occur in the streak gonad. For this reason, removal of the streak gonad is recommended in all patients with mixed gonadal dysgenesis early in childhood. Surgical reconstruction is similar to that for congenital adrenal hyperplasia. Those with adequate male genitalia may be raised as males with careful surveillance of the scrotally placed testis.

Male Pseudohermaphroditism
Male pseudohermaphroditism occurs in infants with 48 chromosomes and XY sex chromosomes, but deficient masculinization of their external genitalia. This disorder used to be called testicular feminization syndrome, but it is best referred to as androgen insensitivity syndrome, which is more descriptive of the problem. This condition can result from inadequate testosterone production, inability to convert testosterone to dihydrotestosterone, Mullerian inhibitory factor (MIF) deficiency, and most commonly, inability of the external genitalia to respond to testosterone or dihydrotestosterone. The sex of rearing is dependent on whether the genitalia looks more like a female or male.

In many of these children, the diagnosis is made at the time of routine inguinal hernia repair in a child that has female genitalia, but also has gonads that can be felt within the groin. Given the risk of eventual malignant degeneration to gonadoblastoma or seminoma of the intra-abdominal gonads, removal is required. There is some discussion as to whether this is best done at the time of discovery or whether the gonads should be removed at puberty because these gonads can induce breast development. The best answer to this question probably is based on determination of urinary steroid levels because individuals with high androgen levels probably should have early gonadectomy to prevent masculinization during puberty. The current opinion is that it is probably best to perform gonadectomy (gonad removal) early in these patients. Occasionally a patient does not present until puberty with amenorrhea (never develops menses). Under these circumstances, when the diagnosis is confirmed, bilateral gonadectomy and vaginal reconstruction should be performed if needed. All patients with androgen insensitivity syndrome have a short vagina because the upper two thirds of the vagina are not produced if a Y chromosome is present. Some can be treated with vaginal dilation. However, to produce a functionally adequate vaginal cavity most require vaginal augmentation with the large intestine. Although most of these individuals do not have clitoral enlargement, a few require an operation to make that clitoris smaller.

True Hermaphroditism
The rarest form of ambiguous genitalia is true hermaphroditism. These patients have normal male and female gonadal tissue with an ovary on one side and a testis on the other or a combination of an ovary and testis on one or both sides. Streak ovaries are common. Of these patients, 80% have 46, XX chromosomes, and others have a mixture of different chromosomes. Most of these children have an inadequate penis and are raised as females. In these patients, the testis and the testicular portion of the ovotestis should be removed, leaving the ovarian tissue in place. The surgical goals of reconstruction are similar to those for children with other forms of ambiguous genitalia. When the phallus is adequate for the male gender role, all ovarian and Mullerian structures are removed. Occasionally, testosterone treatment is needed for these patients. After puberty, a testicular prosthesis may be inserted into the scrotum in individuals to be raised as males.

SURGICAL RECONSTRUCTION

The timing of surgical reconstruction for patients with ambiguous genitalia represents a balance between the desirability of early reconstruction and the technical limitations imposed by the small size and delicacy of the structures involved. The earlier reconstruction can be performed safely, the better. One of the most common considerations has to do with the enlarged clitoris. Because the clitoris is essential for normal female sexual function, all procedures are designed to preserve all or part of the clitoris with its nerve supply. Surgery ranges from putting the clitoris under the pubic symphysis (pelvic bone) to a procedure in which just the end of the clitoris is preserved with its nerves and blood supply and the middle part is partially or completely removed. The latter procedure may be necessary to allow the clitoris to be placed underneath the symphysis bone in patients with an extremely large clitoris. Experienced evaluation of each individual patient determines the best approach to this problem. Either way, long-term functional evaluations are needed to indicate which is the preferred approach to this problem.

The figure above describes one approach to fixing the vagina as it is commonly seen in congenital adrenal hyperplasia with minimal to moderate masculinization. When the vagina joins the urethera way up inside, more substantial operations are required.

PENILE AGENESIS

Penile agenesis is a rare problem in which the urethral opening may lie in front of the rectum on the perineum or be located in front of the scrotum or pubic symphysis. The testes and scrotum are usually normal, although the testes may be undescended. Because penile reconstruction is not feasible, raising the child as a female appears to be the most practical approach. It is best to remove the testes in infancy to reduce androgen imprinting and masculinization, and a vagina should be constructed from the scrotal skin or intestine. Use of the sigmoid colon may be a desirable approach. Estrogen administration should be initiated at 10 to 12 years of age to promote breast development and development of female sex characteristics.

SUGGESTED READINGS

Baskin LS, Erol A, Li YW, et al: Anatomical studies of the human clitoris. J Urol 162:1015-1020, 1999.

This article provides detailed anatomic information related to the clitoris and can serve as a basis for determining approaches to surgical procedures to correct clitoral hypertrophy.

Diamond DA: Sexual differentiation—normal and abnormal. In Walsh PC, Retik AB, Vaughan ED Jr, Wein AJ (eds): Campbell’s Urology, 8th ed. Philadelphia, WB Saunders, 2002.

This chapter provides an in-depth description of the embryology of sexual differentiation and development and serves as an excellent guide to understanding ambiguous genitalia and approaches to treatment.

Donahoe PK , Hendren WH: Perineal reconstruction of ambiguous genitalia in infants raised as females. Ann Surg 200:363, 1984.

Hendren WH, Donahoe PK: Correction of congenital abnormal- ities of the vagina and perineum. J Pediatr Surg 15:751, 1980.

These two articles by Donahoe and Hendren are classic in that they represent one of the largest series ever reported, and they provide information on appropriate reconstructive approaches to all of the various forms of ambiguous genitalia.

Newman K, Randolph J, Anderson K: The surgical management of infants and children with ambiguous genitalia: Lessons learned from 25 years. Ann Surg 215:643-653, 1992.

The value of this article is that it not only provides current information on approaches to diagnosis and treatment, but also it emphasizes the need for an ongoing care program encompassing the physical, endocrinologic, and psychological needs of each patient and each parent involved so that late maladjustment, sexual failure, and psychic distress can be avoided.

Article and graphics adapted from O'Neill: Principles of Pediatric Surgery. © 2003, Elsevier.