Incidence

In the Americas and Western Europe, congenital adrenal hyperplasia (CAH) is the most common cause of neonatal ambiguous genitalia, accounting for approximately 70% of cases.11,12 The overall incidence is approximately 1 in 15,000 live births. The rate is much higher in stillborns and in certain regional populations (Yupic Eskimos and the people of La Réunion, France).¹³ In the United States, mixed gonadal dysgenesis is the next most common intersex disorder, with ovotesticular DSD (true hermaphroditism) being the third most common.

Classification

Until recently, the most commonly used classification system was the one proposed by Allen in 1976 and was based primarily on gonadal histology.¹⁴ This system categorized the most common DSD well, but did not accommodate less common syndromes easily. Also, the older ‘hermaphrodite’ terminology has become offensive to some. A newer classification released by the International Consensus Conference on Intersex has largely replaced Allen’s system. This newer system incorporates an evolving understanding of the molecular basis of these disorders and replaces more offensive gender-based labels. The new terminology is used primarily in this text.¹⁵

46,XX DSD (Female Pseudohermaphrodite)

The majority of neonates with external genital ambiguity fall into this category. All patients have a 46,XX genotype and exclusively ovarian tissue in nonpalpable gonads. Simplistically, the cause of the gender ambiguity is an excess of androgen. More than 95% are due to CAH, with the remainder due to maternal androgen exposure. These patients have a normal female Müllerian ductal system with an upper vagina, uterus, and fallopian tubes (see Table 62-1). They also have normal regression of the Wolffian ducts. The level of virilization is largely dependent on the timing and magnitude of androgen exposure to the external genitalia. The phenotype can range from mild clitoromegaly to a normal male appearance.

Virilization in CAH is due to the inability of the adrenal gland to form cortisol. The precursors above the enzymatic defect are shunted into the mineralocorticoid or sex-steroid pathways. Also, the end products generally have some, albeit weak, glucocorticoid function. The lack of cortisol for negative feedback inhibition of adrenocorticotropic hormone (ACTH) production by the pituitary leaves this pathway unchecked. Excess androgen is produced and is responsible for the virilization. The corticosteroid synthetic and alternative pathways are shown in Figure 62-2. The most common form of CAH is 21-hydroxylase deficiency (21-OHD), which accounts for more than 90% of CAH.¹⁶ 21-OHD has been mapped to the short arm of chromosome 6. The variable location of the adrenal defect and relative function of the gene results in salt-wasting and nonsalt-wasting forms.^17–19 Type 1 results in virilization but no salt wasting. The gene defect affects only the fasciculata zone of the adrenal, resulting in blocking cortisol production. However, the gene is normally expressed in the glomerulosa zone with preservation of mineralocorticoid production. In type 2, also called the classic type, the gene abnormality affects both adrenal zones. Salt wasting results in dehydration or vascular collapse, and hyperkalemia develops because of the block in mineralocorticoid production.

11β-Hydroxylase deficiency (type 3) is a less common cause of CAH. This gene has been mapped to the long arm of chromosome 8. This abnormality results in virilization associated with hypertension due to the synthetic block being below deoxycorticosterone (DOC). DOC has potent mineralocorticoid function resulting in sodium resorption, fluid overload, hypertension, and hypokalemic acidosis.

Finally, 3β-hydroxylase deficiency (type 4) is a rare form of CAH. It results in severe salt wasting, and survival is unusual. It is the only type of CAH to occur in both genders.

Virilization of the female fetus can be caused by exogenous androgen exposure from the mother. This occurs primarily with the use of progesterone, commonly used as an adjunct to assist with fertility and in-vitro fertilization. Endogenous androgen exposure due to virilizing maternal ovarian tumors also has been reported, but these tumors are usually virilizing to the mother with the fetus being unaffected.²⁰

46,XY DSD (Male Pseudohermaphrodite)

This group is the most heterogeneous in the new classification system. All patients have a 46,XY genotype and testicular tissue only. The gonads are sometimes palpable. The condition can be simplistically thought of as a deficit of either production or reception of androgen.

The androgen deficit may result from a defect in synthesis. Several rare adrenal enzyme deficiencies have been implicated, including 3β-hydroxylase, 17α-hydroxylase, and 20,22-desmolase. All are involved in the steps from cholesterol to androstenedione and testosterone, and are associated with severe CAH and often death. 3β-Hydroxylase and 20,22-desmolase deficiencies are associated with cortisol and aldosterone deficits with hyponatremia, hyperkalemia, and metabolic acidosis. In 17α-hydroxylase deficiency, mineralocorticoid production is preserved, resulting in excess salt and water retention, hypertension, and hypokalemia. In the male, the phenotype is variable, ranging from the appearance of a proximal hypospadias with cryptorchidism to that of a phenotypic female with a blind-ending vagina.

Defects in 17,20-desmolase and 17β-hydroxysteroid oxidoreductase act at the testicular level to convert androstenedione to testosterone. Because the adrenal is unaffected, CAH does not occur. The phenotype can be quite variable, but those with complete feminization can escape detection at birth and be reared as female. Progressive virilization is related to excess gonadotropin production at puberty, which may partially compensate for the lack of testosterone synthesis. Phallic growth and the development of male secondary sex characteristics create a conundrum with regard to gender reassignment when the diagnosis is made later in life.²³

Despite adequate production of androgen, receptor defects can render cells blind to the virilizing effects of the hormone. The phenotype is variable and depends on the degree of insensitivity of the receptor for androgen.

The extreme is normal female external genitalia resulting from complete androgen insensitivity syndrome (CAIS, also termed testicular feminization). The incidence of this syndrome is approximately 1 in 40,000. It usually results from a point mutation in the androgen receptor gene, located on the X chromosome.24,25

Receptor defects seen in CAIS result in normal female external genitalia and a blind-ending vagina. Testes are present but may be nonpalpable. MIS production is intact, so no Müllerian ductal structures are present. These patients usually are initially seen at puberty with amenorrhea, but can be encountered earlier with the finding of a testis at the time of inguinal hernia repair.

Partial androgen insensitivity is associated with a large spectrum of phenotypic variation (e.g., Gilbert–Dreyfus, Lub, and Reifenstein syndromes). It can be a sporadic or inherited condition, and gender assignment and treatment are individualized.²⁶

Testosterone is converted to DHT by 5α-reductase, type 2. DHT is a much more potent androgen with regard to virilization of the external genitalia and prostate. The phenotype is ambiguous, but virilization occurs at puberty related to the increased testosterone production and peripheral conversion by nongenital 5α-reductase, type 1. Unfortunately, the virilization is incomplete, and a small phallus and infertility are likely.

Müllerian-Inhibitory Substance Deficiency (Hernia Uterine Inguinale)

MIS is produced by the Sertoli cells in the testis and causes regression of the Müllerian ductal structures. In this rare syndrome of abnormal MIS production or MIS-receptor abnormality, Wolffian ductal development is unimpaired, but the Müllerian ducts also persist. Because the infant has a normal male phenotype, this syndrome is rarely encountered in the neonatal period. The most common presentation to the surgeon is that of finding a fallopian tube adjacent to an undescended testis in the hernia sac at the time of orchiopexy.³⁴

If this scenario is encountered, a biopsy of the gonad should be performed, the hernia should be repaired, and all structures left intact until completion of a full evaluation with karyotype and MIS levels. Apparent males can also present with bilateral nonpalpable testes, and Müllerian structures are found at laparoscopy (Fig. 62-3). Abnormal MIS-receptor gene assays also can be helpful for verifying the diagnosis in those with a normal MIS level. Subsequent management is primarily orchiopexy. This, however, can be difficult because the vas deferens can be closely adherent or ectopic to the fallopian tube or uterus. Excision of discordant ductal structures may be attempted, but given the relatively low risk associated with leaving these structures, the risk of damage to the vas during this dissection outweighs the benefit of removal. Despite normal testosterone levels, the patient often has impaired spermatogenesis.^35–37

Leydig Cell Abnormalities

As the Leydig cell is responsible for testosterone production in the testes, impaired testosterone production can also manifest from Leydig cell hypoplasia, agenesis, or abnormal Leydig cell gonadotropin receptors. These disorders are rare. Although the karyotype is 46,XY, the phenotype tends to be female, with a blind-ending vaginal pouch and absence of internal Müllerian structures. These patients usually are seen initially around puberty with amenorrhea and, therefore, are reared as female. Management is similar to that for CAIS, with orchiectomy and estrogen replacement.38,39

Ovotesticular DSD (True Hermaphrodite)

Ovotesticular DSD exists when both ovarian and testicular tissue are present. The gonadal configuration also can be quite variable, with the ovary/ovotestis combination being most common in the United States, but any combination can occur. Ovotestes are usually polar with an ovary at one end and a testis at the other, but the distribution can be longitudinal, requiring deep longitudinal biopsy to sample the gonad adequately. Because of the paracrine effect of the gonad, the ipsilateral internal duct structures correlate with the type of gonad present. Ovotestes are associated with a variable duct structure, but usually fallopian tubes prevail. A decisively Müllerian or Wolffian duct structure is usually found rather than an ipsilateral combination.⁴⁰

Ovotesticular DSD can be associated with a variety of karyotypes, with 46,XX being the most common, but different chromosomal content has been correlated with different races. It is thought that a translocation of the SRY gene or associated genes to an X chromosome or autosome explains the development of testicular tissue in the 46,XX karyotype. It is more difficult to explain ovarian tissue in a patient with a 46,XY karyotype. Likely, key genes in ovarian development are present, but undetected to complement the normal X chromosomal content. An unappreciated mosaicism could also have occurred.

The phenotype covers the entire spectrum, with ambiguity and asymmetry the rule, but with a tendency toward masculinization. Although it is unusual for ovaries to be found in the labioscrotum, testes and ovotestes are often palpable. Fertility has been described in those raised as female, but testicular fibrosis makes this unlikely in those raised as male.25,41

Mixed Gonadal Dysgenesis

Mixed gonadal dysgenesis (MGD) is the second most common form of neonatal ambiguous genitalia. The patient will have a testis on one side and a streak gonad on the other, characterized microscopically by normal ovarian stroma without oocytes (Fig. 62-4). The internal duct structure mirrors the ipsilateral gonad, with the streak associated with a fallopian tube and uterus resulting from the lack of MIS. The karyotype is generally a mosaic of 45,XO/46,XY, and the stigmata of Turner syndrome are variably present. The phenotype is ambiguous, but masculinized, and the testis may be descended, but more commonly is not.⁴⁴

The risk of a gonadal tumor, usually gonadoblastoma, is as high as 20%, and tumors can develop in either the testis or streak gonad.⁴⁵ An increased risk of Wilms tumor also is present in MGD. The Denys–Drash syndrome occurs in approximately 5% of patients with MGD and is classically described as ambiguous genitalia, Wilms tumor, and glomerulopathy, which is often associated with hypertension.⁴⁶

Pure Gonadal Dysgenesis

Pure gonadal dysgenesis (PGD) is characterized by streak gonads bilaterally. The external phenotype and internal duct structures are female. These patients generally are seen at puberty with primary amenorrhea. The chromosomal makeup is classically 46,XX. PGD is an autosomally recessive trait, so genetic counseling is warranted. This implies that the condition can be caused by abnormalities in the X chromosome or supporting autosomal genes involved in gender differentiation. The gonads do not carry risk of malignant degeneration.

Other conditions are also closely related to bilateral streak gonads. The chromosomal makeup is quite variable and can be 46,XY (XY sex reversal, Swyer syndrome, or male Turner syndrome), 45,XO, or a mosaic. Variants with a Y chromosome differ in that they carry a high rate of malignancy in the retained streak gonads. The phenotype is as described earlier, but these patients may be first seen in infancy with gonadoblastomas or dysgerminomas, or with germ cell tumors that become more common in adolescence. The stigmata of Turner syndrome are often present. Multiple chromosomal deletions and mutations have been described causing this syndrome.

Other Syndromes of Aberrant Sexual Differentiation

Several syndromes worth mentioning do not neatly fit into the described classification systems.

Vanishing testis syndrome is characterized by a 46,XY karyotype, but absent testes bilaterally. This generally results in virilization to the point of normal external genitalia and internal duct structure, but absent testes. The testes were thought to have produced androgen at some point, resulting in masculinization, but subsequently vanished related to torsion or regression. Patients are generally raised as boys, and hormonal supplementation at puberty is required.⁴⁷

Klinefelter syndrome is characterized by a male karyotype containing two or more X chromosomes (47,XXY, 48,XXXY, etc.). Although phenotypically male prepubertally, these patients acquire abnormal male secondary sexual characteristics (tall stature with disproportionately long legs, sparse facial hair, decreased muscle mass, and a feminine fat distribution) and infertility. The testes are small and hard, with decreased androgen production and elevated estradiol levels related to primary hypergonadotropic hypogonadism. Gynecomastia often occurs with an increased risk of breast cancer.⁴⁸ Fertility has been reported but requires assisted means, such as intracytoplasmic sperm injection.⁴⁹

46,XX Testicular DSD (XX sex reversal) is characterized by a male phenotype with a 46,XX karyotype. Most commonly, this occurs from translocation of Y chromosomal material to the X chromosome, but it also can occur from mutation of the X chromosome or from mosaicism. The phenotype and management are similar to those of Klinefelter syndrome, with the exception of shorter stature.⁵⁰

Mayer–Rokitansky–Küster–Hauser syndrome is characterized by a 46,XX karyotype with normal female external genitalia but a short, blind-ending vagina. Normal ovaries and fallopian tubes are present, but the uterus is generally rudimentary. Patients are seen initially with primary amenorrhea, but may have cyclical pain related to functioning endometrium. Treatment is geared toward vaginal reconstruction to allow menses or intercourse, or both.⁵¹

Controversies and Considerations

For more than 20 years, largely based on the work of John Money and the ‘John/Joan Case,’ the overwhelming bias was that gender identity was largely inducible and loosely dependent on chromosomal constitution.⁵⁵ The focus was on one of two twin boys who was reassigned to the female gender early in life after a demasculinizing circumcision injury. The child reportedly developed normally from a psychosocial standpoint and adapted well to life as a girl. Only with extended follow-up into adulthood was it discovered that the individual converted back to the male gender after severe dissatisfaction with a female identity (including attempted suicide).⁵⁶ This rattled the fundamental concepts on which gender assignment had been based for decades and brought to the forefront a tremendous controversy regarding the appropriate management of children with ambiguous genitalia and gender reassignment.

As reconstruction is rarely done in response to any life-threatening issues, support groups for individuals with DSD have advocated delaying any reconstruction until the child can express his or her wishes regarding gender assignment.⁵⁷ Although this would decrease the likelihood of a mismatch between physical and psychological gender, the period of genital ambiguity could be quite challenging for child and family in our society. Despite the controversy, the International Consensus Panel on Intersex stated that the evidence is currently insufficient to abandon the practice of early genital reconstruction.¹⁵ However, this must be discussed thoroughly with the family before embarking on any reconstructive operations.

In general, if genital reconstruction is thought to be appropriate, it is planned in the first 3 to 6 months of life. For feminizing reconstruction, the vaginal tissue is thicker as a result of maternal hormonal influence and the distance from the vagina to perineum is shorter at this age. Because parents have a great degree of anxiety surrounding the gender of their child, earlier repair may help reduce this anxiety and encourage parent/child bonding.⁵⁸

Male Gender Assignment

Reconstructive efforts for the male gender of rearing include orchiopexy or orchiectomy, when appropriate, and hypospadias repair. These techniques are described elsewhere in this book. It bears mentioning again that orchiopexy may be extremely difficult because the vas deferens can be closely adherent to Müllerian duct remnants, such as a fallopian tube or uterus. A portion of these structures may be left in situ if the risk of damage to the vas deferens or testicular vasculature is significant, but this adherence may severely limit mobility of the testis and preclude orchiopexy. Methods of total penile reconstruction in cases of aphallia, demasculinizing penile trauma, or female-to-male gender reassignment by using local skin flaps, a radial forearm flap, or osteocutaneous fibula flap have been described with reasonable success.59–61

Female Gender Assignment

Feminizing genitoplasty includes three major components: monsplasty, clitoroplasty, and vaginoplasty (Figs 62-7 and 62-8). The timing of the vaginoplasty depends on the level of confluence of the urogenital sinus. For a low confluence, the vaginoplasty is performed in the neonatal period with the monsplasty and clitoroplasty. Even with a high confluence, the vaginoplasty can be performed with the monsplasty and clitoroplasty in the newborn. However, because vaginal dilation is often necessary after repair, it may better to defer the vaginoplasty until the patient is peripubertal and more capable and interested in this requirement. Cystoscopy is invaluable for this assessment. We generally insert a Fogarty balloon catheter in the vagina and a catheter in the urethra and bladder to define the confluence during the dissection.

The procedure is initiated by placing a traction suture in the glans. A dorsolateral circumcising incision is made, leaving a 4–5 mm distal preputial cuff, much like is done in a hypospadias repair. The lateral borders of the mucosalized plate are incised, taking this back adjacent to the urogenital sinus. The shaft of the phallus is then degloved of skin superficial to Buck’s fascia. Fascial incisions are then made lateral to the neurovascular bundles. A plane is created just beneath Buck’s fascia from the level just proximal to the glans back to the pubic symphysis. The mucosalized plate is elevated on the ventrum and preserved to fill naturally the void between the urethral meatus and clitoris. The dorsal pedicles, including the neurovascular bundles, are preserved. The base of the corporeal bodies are suture ligated at the level of the pubic symphysis, and the distal corporeal tissue is excised. An alternative technique preserving the corporeal bodies has been described to maintain the potential for reversibility, but long-term functional outcome is pending.⁶²

No clitoral reduction is performed to avoid nerve injury. It can be recessed and has a quite normal appearance in adulthood.⁶³ The clitoris is anchored to the corporal stumps to secure its position, being sure not to compromise the dorsal neurovascular pedicle.

A posterior inverted U-shaped flap is then made from the level of the ischial tuberosities to just posterior to the urogenital meatus. For a very low confluence, dissection is carried along the posterior aspect of the urogenital sinus to the level of the confluence, the posterior wall is incised until the vaginal introitus is normal in caliber, and the U-flap is advanced to complete the posterior vaginal wall (Fig. 62-9). With higher confluences, total urogenital mobilization is favored.^64–66

For total urogenital mobilization, the urogenital sinus is incised circumferentially and mobilized as one unit to the level of the confluence (Fig. 62-10). At this point, the vagina can be carefully separated from the urethra under direct vision and the defect in the urethra is closed. The urogenital sinus can be incised in the ventral and dorsal midline and rotated posterolaterally to lengthen the distal vagina. Using this technique, a long distance to the perineum can be bridged.

Total urogenital mobilization is attractive as one can approach even the high urogenital confluences in the neonatal period without vaginal substitution or grafting, but the family must be appropriately cautioned. Although early results are favorable, descent of the bladder neck is counterintuitive when considering our knowledge of adult female stress incontinence and long-term continence could be an issue. To complete the monsplasty, the dorsal phallic shaft skin is incised vertically, a preputial hood is formed for the clitoris, and the majority of this tissue is used to construct the labia minor with V-shaped advancement flaps (Fig. 62-11). Other techniques for the high urogenital sinus include a posterior approach that requires incising the rectum and an anterior transvesical approach.^67,68

In some patients with a high urogenital confluence, vaginal reconstruction is delayed until the peripubertal period, just before menarche. The techniques described are still used, but in some patients, especially those who are obese, these methods are insufficient. In such cases, vaginal substitution with a colonic segment is preferred, but ileal substitutions and split-thickness skin grafts also have been used. The benefit of vascularized bowel substitution is less vaginal stenosis and the natural formation of lubricating mucus, but this may require wearing a pad if there is excessive mucus production. Colonic segments appear to have a lower rate of stenosis than do ileal segments.⁶⁹ Conversely, skin grafts have a tendency to become stenotic and may require frequent dilation and revision, but long-term satisfaction also has been reported.⁷⁰ The barrier function to sexually transmitted diseases is likely superior with skin grafts when compared with intestine.⁷¹ If a rudimentary vagina or depression exists, sequential dilation with the technique described by Frank and modified to a dilating seat by Ingram may be successful.^72,73

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