IV. Specific Syndromes of Sex Differentiation

1. Androgen Insensitivity Syndrome (AIS)

Androgen Insensitivity Syndrome occurs when an individual, due to a mutation of the androgen receptor gene, is incapable of responding to androgens. Two forms of AIS exist, Complete AIS (CAIS) and Partial AIS (PAIS).

CAIS

CAIS affects 46,XY individuals. CAIS patients have normal appearing female external genitalia due to the their complete inability to respond to androgens. This is because the genital tubercle, genital swellings, and genital folds can not masculinize in these patients despite the presence of functional testes located in the abdomen. Similarly, Wolffian duct development does not occur because the Wolffian duct structures can not respond to androgens produced by CAIS patients. Mullerian duct development is inhibited in CAIS individuals because MIS is secreted by the testes.

In addition to possessing normal female external genitalia, CAIS individuals also experience normal female breast development along with sparse pubic and axillary hair growth at puberty. The following chart illustrates the steps of sex differentiation associated with CAIS compared to those of unaffected males and females.

PAIS

PAIS also affects 46,XY individuals. PAIS patients are born with ambiguous external genitalia due to their partial inability to respond to androgens. The genital tubercle is larger than a clitoris but smaller than a penis, a partially fused labia/scrotum may be present, the testes may be undescended, and perineal hypospadius is often present. Wolffian duct development is minimal or nonexistent and the Mullerian duct system does not develop properly.

PAIS patients will experience normal female breast development at puberty, along with a small amount of pubic and axillary hair. The chart on the following page illustrates the steps of sex differentiation associated with PAIS compared to those of unaffected males and females.

2. Gonadal Dysgenesis

Unlike AIS in which affected individuals possess functioning testes but can not respond to the androgens their testes produce, patients with Gonadal Dysgenesis can respond to androgens but develop abnormal testes which are incapable of producing androgens. Like AIS, two forms of Gonadal Dysgenesis exist (Complete and Partial).

Complete Gonadal Dysgenesis

Complete Gonadal Dysgenesis affects 46,XY individuals and is characterized by abnormally formed gonads which were originally on the path to testis differentiation (these abnormally formed gonads are referred to as gonadal streaks), female external genitalia, Mullerian duct development, and Wolffian duct regression. Female external genitalia develop due to the failure of the gonadal streaks to produce androgens necessary to masculinize the genital turbercle, genital swellings, and genital folds. Additionally, because the gonadal streaks are incapable of producing either androgens or MIS, the Wolffian duct system regresses while the Mullerian duct system develops. The following chart illustrates the steps of sex differentiation associated with Complete Gonadal Dysgenesis compared to those of unaffected males and females.

Partial Gonadal Dysgenesis

Partial Gonadal Dysgenesis also affects 46,XY individuals, and this condition is characterized by partial testes determination usually accompanied by ambiguous external genitalia at birth. Affected patients may have a combination of Wolffian and Mullerian duct development. The combination of both Wolffian and Mullerian duct development, along with ambiguity of the external structures, indicates that the testes produced more androgens and MIS than those of Complete Gonadal Dysgenesis patients, but not as much as would be seen in normal male development. The chart on the following page illustrates the steps of sex differentiation associated with Partial Gonadal Dysgenesis compared to those of unaffected males and females.

3. 5-Reductase Deficiency

During fetal development, the genital tubercle, genital swellings, and genital folds masculinize when exposed to androgens. Androgens, or male hormones, are a general term for two specific hormones Ñ testosterone and dihydrotestosterone (DHT). DHT is a stronger androgen than testosterone, and DHT is formed when the enzyme 5-Reductase converts testosterone to DHT.

5- reductase enzyme
Testosterone	----------->	Dihydrotestosterone

5-Reductase deficiency affects 46,XY individuals. During fetal development, the gonads differentiate into nomal testes, secrete appropriate amounts of testosterone, and patients are able to respond to this testosterone. However, affected individuals are unable to convert testosterone to DHT , and DHT is necessary for the external genitalia to masculinize normally. The result is a newborn baby with functioning testes, normally developed Wolffian ducts, no Mullerian ducts, a penis resembling a clitoris, and a scrotum resembling labia majora.

At puberty, testosterone (not DHT), is the essential androgen for masculinization of the external genitalia. Therefore, stereotypical signs of masculine pubertal development will be observed in patients. These signs include an increase in muscle mass, lowering of the voice, growth of the penis (although it is unlikely that it will reach a normal male length), and sperm production if the testes remain intact. These patients have a fair amount of pubic or axillary hair growth, but they have little or no facial hair. They do not experience female breast development. The following chart illustrates the steps of sex differentiation associated with 5-Reductase Deficiency compared to those of unaffected males and females.

Normal Female Development	5-Reductase Deficiency	Normal Male Development
XX	XY	XY
ovaries develop	testes develop	testes develop
no androgen produced	testosterone but no DHT produced	androgen produced
Wolffian Ducts regress	Wolffian Ducts develop	Wolffian Ducts develop
no MIS produced	MIS produced	MIS produced
Mullerian Ducts develop	Mullerian Ducts regress	Mullerian Ducts regress
external genitalia are female	ambiguous external genitalia	external genitalia are male
feminizing puberty	testes left intact, partial masculinizing puberty OR feminizing puberty with removal of testes and estrogen therapy	masculinizing puberty

4. Testosterone Biosynthetic Defects

Testosterone is produced from cholesterol through a number of biochemical conversions. In some individuals, one of the enzymes needed for these conversions is deficient. In such cases, patients are unable to make normal amounts of testosterone despite the presence of testes. Testosterone Biosynthetic Defects affect 46,XY individuals and can be complete or partial, which leads to newborns who appear either completely female or ambiguous, respectively. Four Testosterone Biosynthetic Defects are listed below:

1. Cytochrome P450,CYP11A Deficiency
2. 3B-Hydroxysteroid Dehydrogenase Deficiency
3. Cytochrome P450,CYP17 Deficiency
4. 17-Ketosteroid Reductase Deficiency

The first three enzyme deficiencies listed above result in Congenital Adrenal Hyperplasia (CAH) (described later) as well as decreased testosterone production by the testes. The fourth enzyme, 17-Ketosteroid Reductase Deficiency, is not associated with CAH. The following chart illustrates the steps of sex differentiation associated with Testosterone Biosynthetic Defects compared to those of unaffected males and females.

Complete Biosynthetic Defect

Partial Biosynthetic Defect

5. Micropenis

Androgens are necessary at two different points in fetal development for a normal penis to form: (1) early in fetal life to masculinize the genital tubercle, genital swellings, and genital folds into a penis and scrotum, and (2) later in fetal life to enlarge the penis. Individuals with a micropenis possess a normally developed penis, except that the penis is extremely small. The condition of micropenis is thought to occur in 46,XY individuals if androgen production is insufficient for penile growth after the first part of masculinization of the external genitalia has already occurred. The chart on the following page illustrates the steps of sex differentiation associated with micropenis compared to those of unaffected males and females.

6. Timing Defect

The many steps of sex differentiation are further complicated by the fact that proper timing of these steps is necessary for normal development. If all of the steps required for male sex differentiation are working, yet these steps are delayed by even a few weeks, the result can be ambiguous differentiation of the external genitalia in a 46,XY individual. The following chart illustrates the steps of sex differentiation associated with a Timing Defect compared to those of normal males

7. Congenital Adrenal Hyperplasia (CAH) in 46,XX Individals

In CAH excess adrenal androgens are produced as an indirect result of a cortisol biosynthetic defect (by far the most frequent defect is a cytochrome P450,CYP21 deficiency). In 46,XX individuals, excess adrenal androgens can lead to ambiguous development of the external genitalia, so that these babies have an enlarged clitoris and a fused labia which resembles a scrotum. The chart on the following page illustrates the steps of sexual differentiation associated with 46,XX CAH (21-hydroxylase deficiency) individuals compared to those of unaffected males and females.

8. Klinefelter Syndrome

Klinefelter Syndrome is the term given to individuals with a 47,XXY karyotype. At puberty Klinefelter men can experience female breast growth, low androgen production, small testes, and decreased sperm production. Additionally, although Klinefelter men undergo normal male differentiation of the external genitalia, they often possess a penis that is smaller than that of normal men. The following chart illustrates the steps of sexual differentiation associated with individuals who have Klinefelter Syndrome, compared to those of unaffected males and females.

9. Turner Syndrome

Turner Syndrome is the term given to individuals with a 45,XO karyotype. Turner patients can exhibit webbing of the neck, a broad chest, horseshoe kidneys, cardiovascular abnormalities, and short stature. Turner patients do not possess ovaries, but instead possess gonadal streaks. Turner patients have normal female external genitalia, but because they lack functioning ovaries (and thus the estrogens produced by ovaries) neither breast development, nor menstruation occurs spontaneously at puberty. The following chart illustrates the steps of sexual differentiation associated with Turner Syndrome compared to those of unaffected males and females.

10. 45,XO/46,XY Mosaicism

Individuals born with 45,XO/46,XY Mosaicism can appear male, female, or ambiguous at birth. Males experience normal male sex differentiation and females are essentially identical to girls born with Turner Syndrome. For the purpose of this booklet, only patients with 45,XO/46,XY Mosaicism, who experience ambiguous sex differentiation, will be described on the following chart.

Mosaicism means that two or more sets of chromosomes influence the development of an individual. 45,XO/46,XY Mosaicism represents the most common mosaic condition involving the Y chromosome. Because the Y chromosome is affected, abnormal sex differentiation can result from this condition. The following chart illustrates the steps of sex differentiation associated with 45,XO/46,XY Mosaicism compared to those of unaffected males and females.