Complete gonadal dysgenesis is characterized by a total absence of functional testicular tissue in a 46,XY newborn resulting in the inability to produce both testosterone and MIS. Newborns affected by complete gonadal dysgenesis present with fully-formed Müllerian structures, bilateral streak gonads and female external genitalia (19-24). Affected newborns are reared female as a result of their female genital phenotype. The streak gonads should be removed in light of the high risk for developing germ cell malignancy in the dysgenic gonads of people with a 46,XY chromosomal complement (1, 18). Combined estrogen and progesterone replacement is needed to promote development of female secondary sexual characteristics and uterine maintenance at puberty, as well as to protect against osteoporosis (23). Importantly, affected women can successfully carry pregnancies as a result of egg donation due to their possession of a well-developed uterus (20). Physicians providing medical care to 46,XY women affected by complete gonadal dysgenesis should inform these women of their pregnancy options (21).

In partial gonadal dysgenesis, it is presumed that a gene mutation results in a partial abnormality of testicular formation from the early urogenital ridge or 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 underlying pathophysiology. Here we operationally define partial gonadal dysgenesis as the partial abnormality of both Leydig (testosterone production) and Sertoli cell (MIS production) function (24) during fetal development. The phenotypic result of this particular category of DSD is partial masculinization of the external genitalia along with variable degrees of Müllerian and Wolffian duct maintenance and development. Consensus regarding the optimal sex of rearing for newborns affected by partial gonadal dysgenesis does not currently exist. Fewer procedures are usually required for surgical feminization (mean = 2.1) compared to surgical masculinization (mean = 5.8). However, it is unclear if the functional outcome is optimal among newborns who receive feminizing procedures compared to those who receive masculinizing procedures (25). Additionally, rates of satisfaction with sex of rearing are similar for those raised female or male (1, 25). Further studies are needed to elucidate why some people who are affected by partial gonadal dysgenesis reject either their female or their male rearing. Newborns affected by partial gonadal dysgenesis are believed to have a high likelihood (15-35% risk) for developing germ cell tumors; thus, bilateral gonadectomy is recommended (1).

Also known as asymmetrical gonadal differentiation, mixed gonadal dysgenesis is characterized by unique anatomical abnormalities. On one side of the body a poorly developed testicular gonad exists, usually accompanied by Wolffian duct structures. On the other side of the body is a gonadal streak that is similar to that found in patients with Turner syndrome. Most people with mixed gonadal dysgenesis have deficient testosterone production related to their poorly developed testicular gonad, resulting in ambiguous external genitalia (18). These cases can be considered a subgroup of the larger group of partial gonadal dysgenesis. Newborns affected by mixed gonadal dysgenesis can present with a 46,XY karyotype but they can also present with a 45,XO/46,XY karyotype. The latter group are categorized as having a “sex chromosome DSD” as opposed to a 46,XY DSD (1). Furthermore, the clinical presentation between the two can be different, with 45,XO/46,XY individuals often presenting with short stature. Similar to the situation of partial gonadal dysgenesis, gonadectomy is usually recommended for patients with mixed gonadal dysgenesis whether they possess a 46,XY or 45XO/46,XY chromosomal complement (1).

Leydig cell aplasia or hypoplasia can be considered as a variant of gonadal dysgenesis. It is a condition of decreased numbers of Leydig cells that leads to a decrease in androgen production. The phenotype resulting from Leydig cell hypoplasia is incomplete masculinization of the external genitalia accompanied by incomplete development of the Wolffian ducts (18, 26). However, in many cases of Leydig cell hypoplasia variable degrees of Müllerian duct remnants can be found. In rare cases of complete Leydig cell aplasia, normal female external genitalia develop. Some of these rare cases are related to abnormal LH receptor activity (23). Newborns affected by complete Leydig cell aplasia or LH receptor mutations present similarly to those who are affected by a complete testosterone biosynthetic defect. The risk of developing germ cell tumors in newborns with Leydig cell hypoplasia, and thus the recommended action for gonadectomy, is not currently known (1).

A complete biosynthetic defect refers to a complete inactivity of any of the enzymes required for the biosynthesis of testosterone from cholesterol (18). Similar to complete gonadal dysgenesis, newborns affected by a complete testosterone biosynthetic defect are typically reared female as a result of their female external genital phenotype. First, steroidogenic acute regulatory protein (StAR) action is required for cholesterol to enter Leydig cells where testosterone is produced. Then, the enzymes CYP-11A1, 3 β-hydroxysteroid dehydrogenase type II (3β-HSDII), CYP-17 and 17-ketosteroid reductase are required to convert cholesterol to testosterone. With the exception of 17-ketosteroid reductase, these enzymes are also present in the adrenal cortex where they are required for the biosynthesis of cortisol. Hence, a deficiency of StAR, CYP-11A1, 3β-HSDII or CYP-17 will result in concomitant congenital adrenal hyperplasia (CAH). The reported risk for germ cell tumors in patients with 17-ketosteroid reductase deficiency is believed to be intermediate while the risk of germ cell malignancy for CYP-11A1, 3β-HSDII or CYP-17 deficiency is not known at this time (1).

Partial testosterone biosynthetic defect refers to conditions where there is reduced activity of any of the enzymes required for the biosynthesis of testosterone from cholesterol. As mentioned earlier, these enzymes are StAR, CYP-11A1, 3β-HSDII, CYP-17 and 17-ketosteroid reductase (18). Similar to partial gonadal dysgenesis, a partial testosterone biosynthetic defect results in ambiguous external genitalia and variable degrees of Wolffian duct development. However, unlike partial gonadal dysgenesis, Müllerian ducts are not maintained in newborns with partial testosterone biosynthetic defect. The risk of developing germ cell malignancy in newborns with CYP-11A1, 3β-HSDII or CYP-17 deficiency is unknown. Newborns affected by 17-ketosteroid reductase deficiency have a fairly low risk for malignancy (1). If gonads are located in the scrotum only periodic examination of the testes is advised.

Congenital micropenis refers to a penis that forms normally during the first trimester of fetal development, followed by a failure to lengthen in an appropriate manner during the second and third trimesters. The stretched length of a micropenis is 2.5 SDs below the mean for chronological age. In male newborns, a stretched penile length of 1.9 cm or less without hypospadias is considered a micropenis (1, 27, 28). As indicated earlier, masculinization of the external genitalia including growth of the phallus is induced by androgenic effects. During early fetal development, androgen secretion by Leydig cells is controlled by human chorionic gonadotropin (HCG). Later, androgen secretion is activated by fetal pituitary gonadotropins. Thus, a micropenis can result from normal androgen secretion during early development followed by decreased or absent androgen secretion later in gestation (4). Most cases of congenital micropenis are attributed to hypogonadotropic hypogonadism as seen in pituitary/hypothalamic disorders such as septo-optic dysplasia, panhyp-opituitarism and Kallmann’s syndrome. In some cases of congenital micropenis, there is a late dysfunction of Leydig cells resulting in hypergonadotropic hypogonadism. The so-called “Vanishing Testes” syndrome results in normal masculinization of the external genitalia during early fetal development followed by an absence of testes and micropenis later in development. Newborns with congenital micropenis treated with testosterone during infancy/childhood (25 to 50 mg testosterone enanthate IM one or twice per year) followed by testosterone replacement during adolescence and adulthood can obtain an adult penile length within 2 SDs of the mean for age (28, 29). Because no genital reconstructive surgery is needed for patients affected by congenital micropenis who are raised male, male sex of rearing is favored for this category of 46,XY DSD (1, 28, 29).

Newborns with CAIS present with female external genitalia and are therefore raised as girls. These newborns possess normally functioning testes that produce both testosterone and MIS, but due to mutations in their androgen receptor gene they are unresponsive to the androgenic effects of their testosterone. Unlike complete gonadal dysgenesis, newborns affected by CAIS do not possess Müllerian structures because their Sertoli cells produce MIS and their cells respond to this hormone. As a result, the vagina may be short and surgical lengthening may be necessary for peno-vaginal intercourse in affected individuals. However, about half of the women with CAIS studied by our group report satisfactory peno-vaginal intercourse despite never having received surgery for vaginal lengthening (37). Additionally, women affected by CAIS must consider adoption when ready for parenthood, as they do not possess ovaries or a uterus. Due to the risk, albeit low (< 5%; 1), of germ cell malignancy, removal of both testes following the completion of pubertal breast development is advised. After the testes are removed estrogen replacement is required to maintain secondary sexual characteristics and to protect against osteoporosis (37).

PAIS, like the complete form, results from androgen receptor gene mutations. Individuals with PAIS experience variable degrees of end-organ unresponsiveness to androgens resulting in variable degrees of Wolffian duct and external genital ambiguity. Individuals with the same androgen receptor gene mutation within a single family can express variable degrees of insensitivity to androgens (38). Thus, it is difficult to predict if a newborn with PAIS will show a response to future testosterone therapy based on androgen receptor gene mutation information alone. Similar to partial gonadal dysgenesis, consensus regarding the optimal sex of rearing for newborns affected by PAIS does not currently exist. While fewer procedures are usually required for surgical feminization compared to surgical masculinization in a person with ambiguous external genitalia, it is unclear if the functional outcome is optimal among newborns who receive feminizing procedures compared to those who receive masculinizing procedures. Rates of satisfaction with sex of rearing are similar for individuals with PAIS raised female or male (25). While reports exist of impaired sexual function in people with PAIS raised male, it is unknown if functional outcome in those raised female are similarly poor (31). Newborns affected by PAIS are considered to be at high risk (50%) for developing gonadal tumors and bilateral gonadectomy is recommended at the time of diagnosis (1).