Congenital malformations of the genitalia can result from an abnormality at any of the steps of sex differentiation described below. Genital ambiguity can exist by itself, or can occur in conjunction with other congenital malformations. It is important to investigate the etiology of genital ambiguity, as it can be accompanied by metabolic disorders such as congenital adrenal hyperplasia (CAH). CAH is a potentially life-threatening condition if left untreated.

Aside from detecting CAH, most parents and physicians recognize the difficulties experienced by a child who does not clearly fit into one of society's gender categories. Parental anxiety is usually great following the birth of an infant with ambiguous genitalia. An early diagnosis will aid families and physicians in deciding the optimal gender to which a baby with ambiguous genitalia will be assigned (1-3). Factors to be considered when deciding on an optimal gender for a newborn with ambiguous genitalia include the degree of genital ambiguity at birth, the ability to produce and respond to androgens, surgical options for constructing male or female genitalia and later potential for fertility.

The first step in sex differentiation is the establishment of genetic sex. Genetic sex is the result of fertilization of an egg that has a 23,X chromosome complement with a sperm that has either a 23,X or 23,Y chromosome complement. Fetal development is basically identical, regardless of a 46,XX or 46,XY chromosome complement, during the first 6 weeks of development.

In early fetal life the formation of undifferentiated structures common to males and females occurs: the Müllerian and Wolffian ducts, a bipotential gonadal ridge and neutral external genitalia that is female-appearing. The organization of undifferentiated cells into these specific organs is mainly controlled by various transcription factors (4). For example, development of the early urogenital ridge and bipotential gonads are controlled by homeodomain proteins such as LIM-1 (5), and nuclear receptor proteins such as SF-1 (6) and WT-1 (7). The sex ducts, gonadal ridge and external genitalia can all be observed by the sixth week of fetal development.

The formation of specialized gonads, either ovaries or testes, is the next step in normal sex differentiation. This important step is controlled by transcription factors including DAX-1 (8), SF-1 (9), WT-1 and SOX-9 (10). When the sex-determining-region of the Y chromosome (SRY) is present, testicular development of the bipotential gonad is initiated by 6 weeks of fetal life (11, 12). By 12 to 14 weeks, the differentiation of the testes and ovaries has been fully achieved.

The production of androgens and Müllerian inhibiting substance (MIS) drive the next step of sex differentiation. In males androgens are necessary for both the masculinization of the external genitalia and the development of the Wolffian ducts, and MIS is needed to suppress Müllerian duct development. The biosynthesis of androgens by the Leydig cells and of MIS by the Sertoli cells requires a series of enzymes. Expression of androgenic effects by the end organs requires a functioning androgen receptor (13). In females, fetal ovaries do not produce MIS until after the genitalia are committed to developing along female lines (14), hence permitting development of the Müllerian ducts. Since ovaries do not secrete androgens the Wolffian ducts become atrophic and the external genitalia remain female.

The neutral external genitalia start to masculinize in the presence of the potent androgen dihydrotestosterone (DHT) toward the end of the first trimester of development. DHT is required for fusion of the urethral and labioscrotal folds, lengthening of the genital tubercle, and regression of the urogenital sinus (15). Steroid 5-reductase is the enzyme required for the conversion of testosterone to DHT. This enzyme is located in androgen target cells, but is not found in the testes.

In the absence of androgens, the external genitalia develop along female lines. Specifically, the labioscrotal and urethral folds form the labia majora and minora respectively, the genital tubercle develops into a clitoris, and the urogenital sinus becomes the anterior portion of the vagina. The posterior portion of the vagina is derived from the Müllerian ducts.

As expected, abnormalities of sex differentiation result from mutations of any of the genes involved in male or female development. Some of these mutations are well-established. Undoubtedly, additional mutations remain to be described. For the purpose of simplicity, newborns presenting with ambiguous genitalia can be classified according to the following major categories: (a) intersex with a 46,XY karyotype (the bipotential gonads differentiate to variable degrees into testes), (b) intersex with a 46,XX karyotype (the bipotential gonads differentiate into ovaries but there is abnormally high androgen production). True hermaphroditism (a combination of ovarian and testicular differentiation occurs in the same individual) can occur in 46,XY or 46,XX subjects, as well as in individuals with an abnormal sex chromosome complement. Based on this classification of ambiguous genitalia, it is clear that results from karyotype analysis are essential to investigating affected newborns.

Ambiguous genitalia in a 46,XY newborn is due to either abnormal formation of the early fetal gonads (gonadal dysgenesis), low production of androgens (dysfunction of the Leydig cells) or the inability to respond to normal amounts of androgens (androgen insensitivity syndrome). Depending on the degree of endocrine abnormality, clinical presentation of the external genitalia can be categorized according to the following phenotypes: female appearance, ambiguous genitalia with a small phallus and hypospadias, or a micropenis without hypospadias.

Female external genitalia

The external genitalia appears entirely female in a 46,XY individual in cases of complete gonadal dysgenesis, complete deficiency of androgen biosynthesis by Leydig cells or complete androgen insensitivity syndrome (CAIS). Complete deficiency of androgen production results from a total defect in one of the enzymes needed to convert cholesterol to testosterone (complete biosynthetic defect). In complete gonadal dysgenesis (Swyers syndrome) (16) there is a defect in both androgen secretion and MIS formation by the Sertoli cells.

Complete gonadal dysgenesis resulting in female external genitalia in a 46,XY individual (Swyers syndrome)

Complete gonadal dysgenesis is characterized by a total absence of functional gonadal tissue that results in the inability to produce both testosterone and MIS. Accordingly, subjects affected by complete gonadal dysgenesis present with Müllerian structures and bilateral streak gonads in addition to their female external genitalia (17, 18). These streak gonads should be removed to prevent possible tumors from forming. Combined estrogen and progesterone replacement is needed to promote development of female secondary sexual characteristics and uterine maintenance, and also to protect against osteoporosis. Importantly, 46,XY individuals reared as women with complete gonadal dysgenesis can carry pregnancies with the use of egg donation, due to their well-developed uterus (19).

Complete testosterone biosynthetic defect resulting in female external genitalia in a 46,XY individual

A complete biosynthetic defect refers to a total abnormality of any of the four enzymes required for the biosynthesis of testosterone from cholesterol (Figure 1). These enzymes are CYP-11A, 3-hydroxysteroid dehydrogenase, CYP-17 and 17keto-steroid reductase.

Figure 1.

It should be noted that CYP-1A1, 3-hydroxysteroid dehydrogenase and CYP-17 are also present in the adrenal cortex where they are required for the biosynthesis of cortisol. Hence, a deficiency of these enzymes will result in concomitant congenital adrenal hyperplasia (CAH). CYP-11A and 3-hydroxysteroid dehydrogenase deficiencies can lead to salt-wasting forms of CAH, and CYP-17 deficiency results in a hypertensive form of CAH.

Complete dysfunction in androgen receptor activity resulting in female external genitalia in a 46,XY individual (CAIS)

Subjects with CAIS also present with female external genitalia. These newborns possess normally functioning testes that produce both testosterone and MIS, but due to an androgen receptor gene mutation (20) are unable to respond to the androgens they produce. Unlike the situation of complete gonadal dysgenesis, women with CAIS do not possess Müllerian structures. As a result, the vagina may be short and surgical lengthening may be necessary to allow for peno-vaginal intercourse. It is advised that the undescended testes of these subjects be removed after pubertal age to prevent testicular cancer from developing. Estrogen replacement should then be initiated to maintain secondary sexual characteristics and to protect against osteoporosis (21). These 46,XY subjects reared as women will need to consider adoption when ready to raise children, as they do not possess a uterus.

Ambiguous external genitalia with hypospadias

When deficiencies in gonadal development, androgen biosynthesis or androgen receptor activity are partial, the result will be ambiguous external genitalia with various degrees of hypospadias. The degree of genital ambiguity in such cases varies along a spectrum, ranging from an almost female phenotype with clitoromegaly at one extreme to an almost male phenotype with isolated hypospadias at the other (22).

Partial gonadal dysgenesis resulting in ambiguous genitalia with hypospadias in a 46,XY individual

In partial gonadal dysgenesis, it is presumed that a gene mutation resulted in a partial abnormality of testicular formation. This could be a gene necessary for the formation of the early urogenital ridge and bipotential gonad. Partial gonadal dysgenesis could also involve a mutation of a gene such as SRY needed to differentiate the bipotential gonads into testes. Hence, cases of partial gonadal dysgenesis have varied pathophysiology. We operationally define partial gonadal dysgenesis as cases where there is a partial abnormality of both Leydig cell (testosterone production) and Sertoli cell (MIS production) function (23). The result of this particular type of abnormality of male sex differentiation is partial masculinization of the external genitalia along with variable degrees of Müllerian duct maintenance (24).

Mixed gonadal dysgenesis, also called asymmetrical gonadal differentiation is characterized by unique anatomical abnormalities. On one side of the body a poorly developed testicular gonad exists, usually accompanied by Wolffian ducts. On the other side is a gonadal streak that is similar to that found in patients with Turner's syndrome (25). Most individuals with mixed gonadal dysgenesis have deficient testosterone production related to their poorly developed testicular gonad, resulting in ambiguous external genitalia. These cases can be considered a subgroup of the larger group of partial gonadal dysgenesis. Subjects with this condition also present with a 46,XY/45,XO karyotype.

Leydig cell hypoplasia is a condition of decreased numbers of leydig cells that leads to a decrease in androgen production. The result is incomplete masculinization of the external genitalia and incomplete development of the Wolffian ducts (26). However, in many such cases variable degrees of Müllerian duct remnants can be found. Therefore, we consider these cases to also fall in the broader category of partial gonadal dysgenesis. In rare cases of complete Leydig cell aplasia, the result is normal female external genitalia. It has been suggested that some of these cases are related to abnormal LH receptor activity (18).

Partial testosterone biosynthetic defect resulting in ambiguous genitalia with hypospadias in a 46,XY individual

Partial testosterone biosynthetic defect refers to conditions where there exists a partial abnormality of any of the four enzymes required for the biosynthesis of testosterone from cholesterol (Figure 1). As mentioned earlier, these enzymes are CYP-11A, 3-hydroxysteroid dehydrogenase, CYP-17 and 17keto-steroid reductase (18). Similar to partial gonadal dysgenesis a partial biosynthetic defect results in ambiguous external genitalia and variable degrees of Wolffian duct development. However, unlike gonadal dysgenesis, Müllerian ducts are not maintained.

Steroid 5-reductase deficiency is a condition in which testes develop normally with fully-functioning Leydig and Sertoli cells, but abnormal sex differentiation results from the inability to convert testosterone to DHT in androgen target cells (27). DHT has greater biological activity than testosterone and is needed for full masculinization of the external genitalia. Testosterone is sufficient for Wolffian duct development which occurs in affected individuals, but the Müllerian ducts regress as would be expected with normal Sertoli cell function. At puberty the testes of these subjects are capable of spermatogenesis as DHT is not required for germ cell maturation. Therefore, fertility is possible with the use of intrauterine insemination (28).

Partial dysfunction in androgen receptor activity resulting in ambiguous genitalia with hypospadias in a 46,XY individual (PAIS)

Partial androgen insensitivity syndrome (PAIS), like the complete form, is the result of an androgen receptor gene mutation. Individuals with PAIS experience variable degrees of end-organ responsiveness to androgens resulting in variable degrees of ambiguous genitalia (29). Individuals with the same androgen receptor gene mutations in a single family can express variable degrees of insensitivity to androgens (30). Thus, it is difficult to predict if a newborn with suspected partial androgen insensitivity syndrome will show a response to future testosterone therapy.

Congenital micropenis without hypospadias

Congenital micropenis refers to a penis that forms normally during the first trimester of fetal life, followed by a failure to lengthen in an age-appropriate manner during the second and third trimesters. Stretched length of a micropenis is 2.5 SDs below the mean for chronological age. In newborns, a stretched penile length of 1.9 cm or less without hypospadias is considered a micropenis (31).

Dysfunction in androgen production underlying congenital micropenis can be primary or secondary. Primary dysfunction of androgen production is referred to as hypergonadotropic hypogonadism. Individuals with hypergonadotropic hypogonadism presumably had normal testicular androgen production early in development allowing for the formation of a penile urethra.

Secondary testicular dysfunction resulting in congenital micropenis is referred to as hypogonadotropic hypogonadism. In such cases, pituitary or hypothalamic disorders such as panhypopituitarism and Kallmann's syndrome lead to the inability of the fetus to secrete the gonadotropins necessary to stimulate testicular androgen production. A normal penile urethra forms in these cases because maternal HCG is available to activate the fetal testes during the first trimester.

A 46,XX fetus with normal ovarian organogenesis can be exposed to excessive androgens originating either from the fetus itself or from the mother. On occasion, multiple congenital malformations may present in a 46,XX newborn in which ambiguous genitalia are included.

Abnormal fetal androgen production: Congenital adrenal hyperplasia

Congenital adrenal hyperplasia (CAH) includes several genetic adrenal disorders, each related to a mutation of one of the enzymes necessary for the biosynthesis of cortisol from cholesterol (32). These abnormalities result in increased ACTH secretion by the pituitary gland that in turn produces an increased secretion of cortisol precursors, and in some cases increased adrenal androgens. The enzymes and their corresponding genes required for cortisol synthesis are shown in Table 1.

Figure 1.

Table I Human adrenal steroidogenic enzymes and cofactors Name Location/action Choromosomal location Result of markedly altered activity CYPIIA (P450scc) (Mitochondrial) 20-hydroxylase, 22-hydroxylase, 20, 22-desmolase (cholesterol side-chain cleavage)  15q23–q24 Congenital lipoid adrenal hyperplasia (female phenotype in all) resulting from SrAR** defect 3b-HSD (Microsomal) 3b-hydroxysteroid dehydrogenase, D4 – D5 =isomerase 1p13.1 Salt-losing congenital adrenal hyperplasia (male or female pseudohermaphroditism) CYP17 (P450c17) (Microsomal) 17a-hydroxylase, 17, 20-lyase 10q24–q25 Hypertensive congenital adrenal hyperplasia (male pseudohermaphroditism) CYP2I, CYP2IP (P450c21)  (Microsomal) 21-hydroxylase 6p2I – active gene and pseudogene Congenir.al virilizing adrenal hyperplasia (female pseudohermaphroditism) CYPIIBI (P450c11)  (Zona fasciculata/reticularis, mitochondrial) 11b-hydroxylase 8q22 – two homologous CYPIIB genes Hypertensive virilizing adrenal hyperplasia (female pseudohermaphroditism) CYPIIB2 (aldosterone synthase) (Zona glomerulosa, mitochondrial) 11b-hydroxylase, 18-hydroxylase (CMO*I) I 8-dehydrogenase (CMO*II) 8q22 Aldosterone deficiency (renal salt loss) Dexamethasone-remediable aldosteronism (CYPIIBIIB2 fusion gene) Adrenodoxin Iron–sulfur protein intermediate 11q22: active gene 20: pseudogenes  Unkown Adrenodoxin reductase (Mitochondrial) flavoprotein intermediate for P450scc and P450c11 17q24-q25   Unkown *StAR, steroidogenic acute regulatory protein.  **CMO, corticosterone methyl oxidase. Deficiency of cholesterol side chain cleavage results in congenital lipoid adrenal hyperplasia manifested by salt loss and lack of androgen secretion. Female infants affected by this condition have normal external genitalia, but males are undermasculinized as discussed earlier. The 3-HSD deficiency results in salt-loss and limited androgen secretion. Affected females exhibit minimal genital masculinization while males are variably undermasculinized. Deficiency in CYP-17 leads to hypertension due to hypersecretion of corticosterone and lack of androgen secretion. Similar to congenital lipoid adrenal hyperplasia, females have normal external genitalia and males are undermasculinized. The 11-hydroxylase deficiency results in hypertension in males and females, and masculinization of the genitalia in females. In adulthood, women affected by congenital lipoid adrenal hyperplasia, 3-hydroxysteroid dehydrogenase deficiency or CYP-17 deficiency are unable to produce estrogen, as androgens are precursors to estrogen production. CAH due to 21-hydroxylase deficiency represents the most common form (more than 90% of cases) of CAH (33). In the milder simple-virilizing form of this condition there is no salt loss but masculinization of the female external genitalia does occur. In the more severe salt-losing form, salt loss occurs along with marked masculinization of the genitalia in females (on occasion resulting in a penile urethra). Excess maternal androgen production Because excessive androgen production adversely affects fertility leading to anovulation, cases of maternal androgen production during pregnancy are extremely rare. That said, maternally-derived androgens can cross the placenta to masculinize a female fetus. The origin of these maternal androgens is usually the ovaries or adrenal glands. Androgen-producing tumors of the ovary include hilar cell tumors, arrhenoblastomas, lipoid cell tumors and Krukenberg tumors. Androgen secreting tumors of the adrenals are also rarely observed during pregnancy. Placental aromatase deficiency During fetal life the fetal adrenals produce large amounts of 17-hydroxypregnenolone and 16-hydroxy-DHA. These steroids are transferred to the placenta which possesses the enzymes needed to convert these steroids into androgens and then estrogens. If an aromatase enzyme deficiency is present, then androgen precursors accumulate and return to fetal circulation. Such androgens can masculinize a female fetus (34). Drugs administered to the mother during gestation In 1959 Wilkins et al. (35) reported that some synthetic progestins administered to pregnant women such as 17-ethinyl-19-nortestosterone masculinize the external genitalia of female fetuses. These drugs were administered as they were thought to protect against spontaneous abortions. Multiple congenital anomalies Ambiguous genitalia in both female and male infants have been observed in association with syndromes of multiple congenital malformations. Abnormal development of the lower abdominal wall with pubic diastesis results in uro-genital anomalies. These include the VATER (36) and CHARGE syndromes. True Hermaphroditism True hermaphroditism refers to the presence of ovarian and testicular tissue in an individual. Most true hermaphrodites have a 46,XX chromosome complement and present with ambiguous genitalia as newborns; a few possess a 46,XY chromosome complement or 46,XX/46,XY mosaicism. Similar to other types of abnormal sex differentiation, the degree of testicular development will dictate the extent of Wolffian duct development and Müllerian duct regression in a newborn affected by true hermaphroditism (18). WORK-UP OF INFANTS BORN WITH AMBIGUOUS GENITALIA The birth of an infant with congenital malformations of the sex organs is viewed as a crisis by most parents. This crisis, along with the possibility for metabolic disorders that can be life threatening, warrants a thorough work-up of such infants as early in life as possible. Clinical evaluation of affected infants A comprehensive review of the systems of a newborn is very important, as ambiguous genitalia can occur in conjunction with several other congenital malformations. It is necessary to look for signs of dehydration with vomiting and diarrhea, as these can be symptoms of a salt-losing crisis. A careful examination of the external genitalia should also be performed. Such an exam must include a measure of stretched phallic length, evaluation of the quality of the corpora, and inspection of the labia, labio-scrotal folds or scrotum. The position of the urethral opening (and vaginal opening if applicable) should be documented, as well as the presence and location of palpable gonads. Status of body hydration Serum electrolytes and glucose levels should be monitored daily. Additionally, body weight should be documented as weight loss can indicate dehydration. Obtain a karyotype It is crucial to obtain a karyotype at birth. Laboratories should be informed to look for sex chromosome mosaicism. Studies of the fluorescence of the long arm of the Y chromosome and hybridization of an SRY gene probe can also be helpful. Hormone studies Hormone studies can be classified according to the following categories; androgens and androgen precursors (17-hydroxypregnenolone, 17-hydroxyprogesterone, androstenedione, testosterone, dihydrotestosterone), cortisol, aldosterone and their precursors (progesterone, 17-hydroxyprogesterone, 11-deoxycortisol, cortisol, 11-deoxycorticosterone, corticosterone, aldosterone) and Müllerian inhibiting substance (MIS) (37, 38). The following schedule for hormone studies is recommended: At Day 1 or 2 of life, measure plasma androstenedione, testosterone and dihydrotestosterone. These androgens must be measured from a single blood sample so that the ratios of androstenedione/testosterone and testosterone/DHT can be calculated. At Day 3 or 4 of life measure plasma 17-hydroxyprogesterone, 17-hydroxypregnenolone and progesterone. At Day 6 or 7 of life measure plasma MIS and obtain white cells for DNA studies such as androgen receptor gene mutations. At Day 8 repeat androstenedione, testosterone, DHT, and 17-hydroxyprogesterone measures. Imaging studies A sonogram or MRI can help in identifying both type and extent of internal sex organ development. Imaging can also detect abnormalities of the urinary tract (kidney, ureters, bladder) that can occur in individuals affected by syndromes of abnormal sex differentiation. An MRI may be better able to identify Müllerian structures (uterus, fallopian tubes, upper portion of the vagina) than a sonogram, and can also be useful for localizing the gonads. A genitogram is also needed for visualization of the urinary tract, and to determine the position of the urinary tract in relation to the vagina if present. It is helpful to establish the presence and size of the vagina or utricular pouch. Information obtained from a genitogram is particularly useful for surgical construction of the genitalia when needed. DIFFERENTIAL DIAGNOSIS Results from the karyotype will play a major role in the differential diagnosis. In most cases the chromosome complement will be either 46,XX or 46,XY. In rare instances the chromosome complement will be 45,X0/46,XY or 46,XX/46,XY mosaicism. Intersex with a 46,XX Chromosome Complement A 46,XX karyotype suggests that one is dealing with a female who was masculinized during fetal life (Figure 2). The most common cause for this is CAH due to 21-hydroxylase deficiency. The daily study of electrolytes will help to determine if salt loss is a problem, which is the case for most patients. Plasma steroid measures allow for the type of CAH to be identified. Marked elevation of plasma 17-hydroxypregnenolone, 17-hydroxyprogesterone and androstenedione along with male levels of testosterone are characteristic of 21-hydroxylase deficiency. A predominance of 3-hydroxy-delta-5 steroids is seen in 3-HSD deficiency. High values of corticosterone and 11-deoxycortisol, along with elevated androgens, are the hallmark of 11-hydroxylase deficiency. When excess maternal androgen production is the underlying cause for female pseudohermaphroditism, these steroids will stop their effects post-natally. Thus, the various steroids studied in these cases will be in the normal female range. In 46,XX true hermaphroditism masculinization arises from androgens secreted by the testicular portion of the gonads. Androgen production is similar to that produced by normal testes except that the amount is usually smaller. The degree of masculinization is related to the degree of testicular tissue present. On occasion, translocation of the pseudo-autosomal part of the Y chromosome along with a mutated SRY gene to an X chromosome occurs. The result is partial masculinization of a 46,XX individual. Very low values of MIS are expected in babies with masculinized female genitalia attributed to CAH or excess maternal androgen production during gestation. MIS is higher in true hermaphrodites, due to the extent of Sertoli cell development in the testicular portion of their gonads. Intersex with a 46,XY Chromosome Complement A 46,XY karyotype suggests that one is dealing with a male who was under-masculinized during fetal life (Figures 2 and 3). Laboratory findings of normal or elevated testosterone and dihydrotestosterone suggest a diagnosis of either complete androgen insensitivity (CAIS) or partial androgen insensitivity (PAIS). Similar laboratory results are expected with a timing defect. MIS has been reported to be elevated in PAIS, but should be normal in a baby with a timing defect in relation to normal male values. If testosterone levels are normal but DHT levels are low, a diagnosis of steroid 5-reductase deficiency can be made. Low levels of testosterone and DHT, along with a marked elevation of some androgen precursors, indicates a deficiency of one of the enzymes required for androgen biosynthesis. If the elevated precursors are androstenedione and 17-hydroxyprogesterone, then the defective enzyme is 17-ketosteroid reductase. Increased early precursors are characteristic of enzyme defects early in the biosynthetic pathway. These early enzyme defects also involve adrenocortical function. In all cases of testosterone biosynthetic defects, MIS levels are similar to those in unaffected male infants. Finally, when all androgens and their precursors are below normal one is dealing with either partial gonadal dysgenesis or 46,XY true hermaphroditism. In these cases, MIS values should be low. In contrast, for babies affected by Leydig cell hypoplasia, androgens and their precursors are low, but MIS values should be in the normal male range. Figure 2.   Figure 3. SEX OF REARING Whether or not the etiology of the genital ambiguity can be determined, a sex of rearing is usually elected as this is expected by society. We believe that the final choice of sex assignment should be made by parents after receiving education from the medical team. The role of this team (pediatric endocrinologist, pediatric surgeon, psychologist and others) is to inform parents about the process of sex differentiation and the abnormality that affects their child (2). As knowledge of long-term outcome of intersex patients is obtained, this too must be shared with parents (21, 39-47). Gender assignment for 46,XX infants The most common etiology of ambiguous genitalia in genetic females is congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Historically, female sex of rearing has been recommended for this group and the majority of women affected by 21-hydroxylase deficiency develop a female gender identity/role (42, 43). Gender assignment for 46,XY infants Newborns presenting with a 46,XY chromosome complement and normal-appearing, female external genitalia due to complete androgen insensitivity syndrome (CAIS) or complete gonadal dysgenesis (CGD) are most successful when assigned a female sex of rearing. Female assignment in such cases is widely accepted by patients throughout their lives (21, 39, 44). A second category of intersexuality in which a particular sex of rearing is optimal is in cases of 46,XY micropenis without hypospadias. Patients with congenital micropenis accept either a male or female gender assignment; however, female assignment is complicated by feminizing surgery of the genitalia. Because patients reared male require no genital surgery, we feel that a male gender assignment for newborns with congenital micropenis is optimal (39, 45, 46). The most difficult intersex cases, in terms of sex of rearing, are those patients with ambiguous external genitalia including a small phallus and perineo-scrotal hypospadias (47). In these cases genital surgeries are necessary regardless of sex of rearing, therefore other factors must be taken into consideration when assigning gender. These include the number of surgical procedures anticipated for male or female assignment, and the possibility for future fertility of patients. In terms of the number of genital surgeries, female sex of rearing typically requires fewer procedures. When judged by physicians, patients with ambiguous genitalia reared female show a superior cosmetic result of their genital reconstruction than their male counterparts. Despite these seeming advantages, patients raised female reported a similar degree of dissatisfaction with both the appearance and function of their genitalia compared to those raised male (41). Reproduction is relevant to specific intersex conditions. The most obvious of such conditions is CAH in genetic females. Because medical treatment allows for fertility in these patients, female sex of rearing is recommended. Additionally, for 46,XY cases in which a uterus is well-developed but gonadal development is poor (complete and partial gonadal dysgenesis), female sex of rearing is thought to be optimal. Finally, for 46,XY cases in which spermatogenesis is possible (timing defect, steroid 5-reductase deficiency) male sex of rearing is preferred. With all of this information, parents can make an informed choice about sex of rearing and must be supported by the medical team.

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