31.2 Embryology	639

•The management of patients with DSD has also changed over the years.

•In the past, corrective surgeries were often performed in infancy, but in recent years the tendency has been to postpone surgery until the child has expressed a clear gender preference and is old enough to participate actively in decisions about his/her medical treatment.

•The optimal management of patients with DSD must be individualized and multidisciplinary, considering all aspects, including psychological care and full disclosure of alternatives relating to surgery type and timing.

•Modern treatment of infants with ambiguous genitalia involves a team-oriented approach. This gender-assignment team usually involves neonatologists, geneticists, endocrinologists, surgeons, counselors, and ethicists. The goal is to provide appropriate medical support and counseling regarding care and therapy.

31.2Embryology

•Normal sexual differentiation is based on the genetic sex (XX or XY), which is established at the time of conception.

•Until about 7 weeks of gestation, the fetus is sexually indifferent with two different bipotential gonads and two internally developing wolffian and mullerian ducts.

•Embryologically, there are two undifferentiated bipotential gonads in every embryo.

•These bipotential gonads develops from the urogenital ridge and ultimately develop into either a testis or an ovary.

•In addition to these bipotential gonads, fetuses of both sexes have two sets of internal ducts: the Müllerian ducts and the Wolffian ducts which develop by 6–7 weeks of intra-uterine life.

•At about 7 weeks of gestation:

–The indifferent gonads and in the presence of a Y chromosome begin to develop into testes.

–The indifferent gonads and in the absence of a Y chromosome begins to develop into ovaries.

•Thereafter, gonadal differentiation and function determine the final phenotype.

•Many genes are involved in normal sexual differentiation.

–The sex-determining region on the Y chromosome (SRY) initiates the development of the indifferent gonads into testes.

–The SOX9 gene is required for Sertoli-cell differentiation.

–Steroidogenic factor 1 (SF-1) plays a critical role in steroidogenesis, fertility and male sexual differentiation.

–DAX-1 on the X chromosome is upregulated in the ovary and functions as an anti-testis factor.

–The Wilms tumor (WT-1) gene is involved in both gonadal and renal development. Three distinct phenotypes are seen with WT-1 mutations:

•The Wilms tumor, aniridia, genitourinary anomalies, and mental retardation syndrome, caused by continuous deletion of the WT-1 and PAX-6 genes.

•Denys–Drash syndrome (a triad of progressive renal disease, 46,XY karyotype with undervirilization, and Wilms tumor. Affected individuals usually have ambiguous genitalia or normal female external genitalia, and streak gonads. Nephrotic syndrome presents within the first 2 years of life and progresses rapidly to end-stage renal failure within a few years.

•Frasier syndrome (46,XY DSD, gonadal dysgenesis, and renal failure), in which there is an altered ratio of the two splice isoforms of the WT-1 protein. Affected individuals have normal female external genitalia but fail to develop secondary sexual characteristics. Patients are at risk of gonadoblastoma developing in the dysgenetic gonads. Glomerulonephropathy gradually progresses to renal failure in the second or third decade of life.

	640			31 Disorders of Sexual Development
		“Y”		NO “Y”
		CHROMOSOME		CHROMOSOME
		(SRY)		(SRY)
		“SOX9”GENE		NO “SOX9” GENE
	INDIFFERENT		INDIFFERENT
			GONAD
	GONAD			NO STEROIDOGENIC
		STEROIDOGENIC
				FACTOR 1 (SF-1)
		FACTOR 1 (SF-1)
				THE WILMS
				TUMOR (WT-1)
		THE WILMS		GENE
	TESTIS	TUMOR (WT-1)		DAX-1 ON THE X
		GENE	OVARY
				CHROMOSOME

•Embryologically, two pairs of ducts are present in each fetus whether a male or female:

–The Wolffian ducts

–The Müllerian ducts

•In males (XY):

–The indifferent gonads develop into testes.

–The testis has two types of cells:

•The Sertoli cells

•The Leydig cells

–The testicular Sertoli cells begin secreting Müllerian-inhibiting substance (MIS) in the seventh week.

–The MIS acts only locally (paracrine) to induce ipsilateral Müllerian duct regression.

–The Leydig cells begin producing testosterone through stimulation via placental human chorionic gonadotrophin (hCG).

–Testosterone acts both locally (paracrine) and systemically (endocrine) to stabilize the Wolffian duct, and promotes the development of the epididymis, the vas deferens and the seminal vesicle.

–The Wolffian duct leads to the development of:

•The epididymis

•The vas deference

–The seminal vesicle

•In females (XX):

•The lack of MIS permits Müllerian duct maturation into Fallopian tubes, uterus, cervix and upper vagina.

–The lack testesterone leads to Wolffian duct regression.

–The Müllerian duct leads to the development of:

•The uterus

•The Fallopian tubes

•The cervix

•The upper vagina

•The testosterone produced by testicular Leydig cells undergoes peripheral conversion

to dihydrotestosterone, under the effect of the enzyme 5α-reductase.

•Dihydrotestosterone is important for the development of the external genitalia in males.

•It induces posterior fusion of the genital folds and growth of the genital tubercle into a phallic structure.

•The development of male external genitalia is complete by 12–16 weeks.

•Subsequent phallic growth is a result of fetal pituitary luteinizing hormone stimulation of testicular Leydig cell testosterone production.

31.2 Embryology			641
THE	THE
MULLERIAN	WOLLFIAN
DUCT	DUCT
			TESTIS
		THE	THE
	LEIDGE		SERTOLI
	CELLS		CELLS

TESTESTERONE

THE MULLERIAN INHIBITING

SUBSTANCE (MIS)

	THE	THE VAS	THE
			SEMINAL
	EPIDIDYMIS	952DEFERENCE
			VESICLE

	THE	THE		THE UPPER
		FALLOPIAN	THE CERVIX
	UTERUS			VAGINA
		TUBES

•In females, the non-hormone-dependent separation of the vagina and the urethra is complete by 12 weeks.

•Excess androgen exposure before this separation can cause labial fusion and development of a phallic urethra or urogenital sinus, but later exposure causes only clitoral enlargement and scrotalization of the labial folds.

•Psychosexual development:

–Psychosexual development has three main components:

•Gender identity:

–This signifies the child’s selfrecognition as a boy or a girl, and usually starts at 3 years of age.

•Gender role:

–This refers to sex-typical behaviors such as toy preferences and physical aggression.

•Sexual orientation:

–This refers to the direction(s) of sexual interest (heterosexual, bisexual, and homosexual).

642	31 Disorders of Sexual Development

–Many factors affect psychosexual development, e.g. exposure to androgens, sex chromosome genes and brain structure, as well as the society and family perspectives.

–Gender dysphoria indicates unhappiness with the assigned sex and it results from an inconsistency between the assignment and the inherent identity later in life.

–Although gender dissatisfaction occurs more frequently in individuals with DSD than in the general population it cannot be easily predicted from the karyotype, prenatal androgen exposure, degree of genital virilization, or assigned gender.

–Several factors influence prenatal androgen exposure including the timing, dose and type of androgen exposure, and brain receptor availability, as well as the social environment.

–The prenatal period is thought to be critical for brain masculinization.

–Girls with congenital adrenal hyperplasia (CAH) with marked genital virilization play more with boys’ toys, and the incidence of homosexuality later in life is higher in this group.

–Moreover, sex chromosome genes might also influence the brain structure and behavior directly.

–Individuals with complete androgeninsensitivity syndrome (CAIS) however, do not indicate a behavioral role for Y-chromosome genes.

31.3Sexual and Gonadal Differentiation

•It is important to know that there three types of sex:

–Phenotypic sex

–Genetic (chromosomal) sex

–Gonadal sex

•Chromosomal sex determines gonadal sex, which determines phenotypic sex.

•The type of gonad present determines the differentiation/regression of the internal ducts (Müllerian and Wolffian ducts) and ultimately determines the phenotypic sex.

•Gender identity is determined not only by the

phenotypic appearance of the individual but also by the brain’s prenatal and postnatal development as influenced by the environment.

•Early during embryonic development, there are two indifferent or bipotential gonads.

•During the second month of fetal life, the indifferent (Bipotential) gonad is guided to develop into a testis by genetic information present on the short arm of the Y chromosome.

•This is under the influence of the testisdetermining factor.

•The testis-determining factor (TDF) is a 35– kilobase pair (kbp) sequence on the 11.3 subband of the Y chromosome.

•This is called the sex-determining region of the Y chromosome (SRY).

•When the SRY is absent or altered, the indifferent gonad develops into an ovary.

•Other genes important to testicular development include:

–DAX1 on the X chromosome

–SF1 on band 9q33

–WT1 on band 11p13

–SOX9 on bands 17q24-q25

–AMH on band 19q13.3

•This explain the existence of testicular tissue in patients with 46, XX testicular DSD, in the absence of an obvious Y chromosome or SRY genetic material.

•The indifferent gonad develops into fetal ovaries when the TDF gene (or genes) is absent.

•The internal ducts (Müllerian and Wolffian ducts) development results from a paracrine effect from the ipsilateral gonad.

31.3 Sexual and Gonadal Differentiation	643

•In the absence of testicular tissue, the fetus internal sex duct and external phenotypic development is that of a female.

•The presence of testicular tissue leads to the production of testosterone and Müllerianinhibiting substance (MIS) or AMH which are important for development of male internal sex ducts and an external male phenotype.

•Testesterone:

–Testosterone is produced by testicular Leydig cells and induces the primordial Wolffian (mesonephric) duct to develop into:

•The epididymis

•The vas deferens

•The seminal vesicle

–A spatial relation is important in the effect of testosterone.

–Wolffian structures located closest to the source of testosterone undergo the greatest degree of male differentiation.

–This explains why patients with ovotesticular DSDs often have a degree of Wolffian development near testicular tissue, even when joined with an ovary as an ovotestis.

–No Wolffian development occurs in association with a streak gonad or a non– testosterone-producing dysgenetic testis.

–High local testosterone levels (paracrine effect) appear to be necessary for Wolffian duct differentiation because maternal ingestion of androgens does not cause male internal differentiation in a female fetus, nor does this differentiation occur in females with CAH (adrenogenital syndrome).

•MIS (Mullerian inhibiting substance):

–MIS is produced by the Sertoli cells of the testis.

–It is important to normal male internal duct development.

–MIS is a 15-kd protein that is secreted by the testis beginning in the eighth fetal week.

–It prime role is to repress passive development of the Müllerian ducts:

•Fallopian tubes

•Uterus

•Upper vagina

–In a normal male fetus with normal testicular function, MIS represses Müllerian duct development, whereas testosterone stimulates Wolffian duct development.

•Local testosterone production appears to enhance the inhibition of Müllerian duct development produced by MIS, whereas estrogens may interfere with MIS action, resulting in a degree of Müllerian duct development.

•This may explain the variable internal sex duct anatomy that occurs in some of the more complex DSDs.

•The external genitalia:

–The external genitalia of both sexes are identical during the first 7 weeks of gestation.

–Without the hormonal action of the androgens testosterone and dihydrotestosterone (DHT), external genitalia appear phenotypically female.

–In the gonadal male, differentiation of the external genitalia is moderated by testosterone.

–Testosterone is converted to 5-DHT by the action of the enzyme, 5-alpha reductase, which is present within the cytoplasm of cells of the external genitalia and the urogenital sinus.

–DHT is bound to cytosol androgen receptors within the cytoplasm and is subsequently transported to the nucleus, where it leads to translation and transcription of genetic material.

644	31 Disorders of Sexual Development

The SRY gene (located on the short arm of the Y- chromosome (Yp11.3))

Bipotential gonad (Indifferent gonad)

Testes

Sertoli cells

Leydig cells

Testesterone

Anti-Mullerian hormone

Wollfian ducts

956

Mullerian ducts

Epidiymis

Ejaculatory ducts

Dihdrotestesterone

Seminal vesicles

Regression

Prostate and external genitalia

Masculinization

–As a result, these actions lead to normal male external genital development from primordial parts:

•The scrotum develops from the genital swellings

•The shaft of the penis develops from the folds

•The glans penis develops from the tubercle

•The prostate develops from the urogenital sinus

–Incomplete masculinization occurs when:

•Testosterone fails to convert to DHT

•DHT fails to act within the cytoplasm or nucleus of the cells of the external genitalia and urogenital sinus.

–The timing of this testosterone-related

developmental change begins at

approximately 6 weeks of gestation with a testosterone rise in response to a surge of luteinizing hormone (LH).

–Testosterone levels remain elevated until the 14th week. Most phenotypic differentiation of males occurs during this period.

–After the 14th week, fetal testosterone levels settle at a lower level and are maintained more by maternal stimulation through human chorionic gonadotropin (hCG) than by LH.

–Testosterone’s continued action during the latter phases of gestation is responsible for continued growth of the phallus, which is directly responsive to testosterone and to DHT.

–In the gonadal females, differentiation of the external genitalia is moderated by estrogen.

31.4 Classification	645

–Absence of testosterone leads to regression of the Wollfian ducts.

–Estrogen secreted by the developing ovary leads to the development of the external genitalia of the female.

–In the female, the genital tubercle becomes the clitoris, the labio-scrotal folds become the labia majora, and the urethral folds become the labia minora.

31.4Classification

•In the past, several names were used to describe disorders of sexual development.

•These include:

–Intersex

–Ambiguous genitalia

–Hermaphroditism

–Sex reversal

•In 2006, the Lawson Wilkins Pediatric Endocrine Society (LWPES) and the European Society for Pediatric Endocrinology (ESPE) published proposed changes to the previously used nomenclature and definitions of disorders in which the development of chromosomal, gonadal, or phenotypic sex is atypical.

•The rationale behind these proposals was to change the nomenclature to reflect advances in our understanding of the pathophysiology of these disorders while being sensitive to the needs and concerns of patients affected by them.

•The previous terminology and the revised LWPES-ESPE nomenclature are compared below.

•The LWPES-ESPE terminology mainly reflects the chromosomal sex or the gonadal tissue associated with the disorder.

Absence of the SRY gene (located on the short arm of the Y-chromosome(Yp11.3)

Bipotential gonad (Indifferent gonad)

Ovary

No Sertoli cells

958

No Anti-Mullerian hormone

Mullerian ducts

The fallopian tubes, Uterus

The upper two-third of the vagina

Estrogen

External Genitalia

Feminization

646	31 Disorders of Sexual Development

Previous Terminology and Revised Nomenclature of

Disorders of Sexual Development

PREVIOUS

•Female pseudohermaphrodite

•Male pseudohermaphrodite

•True hermaphrodite

•XX male

•XY sex reversal

REVISED

•46,XX DSD

•46,XY DSD

•Ovotesticular DSD

•46,XX testicular DSD

•46,XY complete gonadal dysgenesis

•Currently, all these are grouped under one common name, disorders of sexual development, “DSD”.

•This term is broad and includes common entities such as Turner syndrome and Klinefelter syndrome as well as rare disorders such as cloacal exstrophy and aphallia.

•There are several classifications for DSD.

•In the past, intersex disorders were subdivided into three main groups:

–Those associated with gonadal dysgenesis

–Those associated with undervirilization of 46,XY individuals

–Those associated with prenatal virilization of 46,XX individuals

•Another commonly used classification divides intersex disorders into four main groups:

–Female pseudohermaphroditism

–Male pseudohermaphroditism

–True hermaphroditism

–Mixed gonadal dysgenesis

•The new classification of DSD was proposed by The Lawson Wilkins Pediatric Endocrine Society (LWPES) and the European Society for Paediatric Endocrinoloy (ESPE) group as follows:

–Sex chromosome DSDs

–46,XY DSDs

–46,XX DSDs

•Sex chromosome DSDs:

–This occurs when the number or structure of the sex chromosomes (X, Y chromosomes) is abnormal.

–The abnormalities include:

•XX male (46XX)

•46 XX/45X

•46XY/45X Mixed gonadal dysgenesis

•45,XO Turner (Gonadal dysgensis) and variants

•47,XXY Klinefelter and variants

•45X/46XY mixed gonadal disgenesis (MGD)

•Chromosomal ovotesticular (True hermaphroditism) DSD “46XX/46XY chimeric type or mosaic type”), (The DSD nomenclature has recently divided “ovotesticular DSD” (formerly true hermaphroditism) into 46,XY ovotesticular DSD, 46,XX ovotesticular DSD, and chromosomal ovotesticular DSD (46,XX/46,XY” chimerism or 45,X/46,XY” mosaic type).

–Sex chromosome DSD was formerly termed as gonadal dysgenesis.

–If a testis is poorly formed, it is called a dysgenetic testis, and if an ovary is poorly formed, it is called a streak gonad.

–A patient with a Y chromosome is at high risk of developing a tumor in a streak or dysgenetic gonad.

–Klinefelter and Turner syndromes are the most frequently encountered sex chromosomal abnormalities.

–The most common genotype of Klinefelter syndrome is XXY.

31.4 Classification	647

Sex Chromosomes Sexual Disorders

of Development (DSD)

•XX male (46XX)

•46 XX/45X

•46XY/45X

•45,XO Turner (Gonadal dysgensis) and variants

•47,XXY Klinefelter and variants

•45X/46XY mixed gonadal disgenesis (MGD)

•Chromosomal ovotesticular:

–46,XY ovotesticular DSD

–46,XX ovotesticular DSD

–Chromosomal ovotesticular DSD (46,XX/46,XY” chimerism or 45,X/46,XY” mosaic type)

–More than half of girls with Turner syndrome have chromosomal mosaicism.

–The clinical manifestations of patients with 45X/46XY MGD, are highly variable, ranging from partial virilization and ambiguous genitalia at birth to a completely normal male or female phenotype.

–The most common feature of MGD is asymmetric development of the testes, often with a dysgenetic testis on one side and a streak gonad on the other.

–Asymmetrical external and internal genitalia may also be present.

–Chromosomal ovotesticular DSD (chimeric type or mosaic type) is associated with ovarian and testicular tissues found in either the same or opposite gonad just as in 46,XX and 46,XY ovotesticular DSD. The genital duct develops according to the ipsilateral gonad.

•46,XY disorders of sex development (46,XY DSD):

–Here, the chromosomes are male but the external genitals are either ambiguous or those of a female.

–The testes may be absent, malformed or normal.

–In the past, the term “male pseudohermaphrodite” was used to describe patients

with 46,XY chromosomes and incompletely masculinized external genitalia.

–These patients are characterized by ambiguous or female external genitalia, caused by incomplete intrauterine masculinization.

–Infants with this condition tend to have penoscrotal hypospadias, abnormal development of the testes, and reduced to no sperm production.

–Some individuals with 46, XY DSD have fully to underdeveloped female reproductive organs (e.g., uterus and fallopian tubes), while others do not.

–People with 46, XY DSD may be raised as males or females.

–People with 46, XY DSD are at an increased risk for gonadal tumors and benefit from regular surveillance or surgery to remove abnormally developed gonads.

–The two main causes of 46,XY DSDs are:

•Disorders of testicular development

•Disorders of androgen synthesis/androgen action

–The spectrum of 46,XY DSDs include:

•Complete or partial forms of gonadal dysgenesis with or without syndromic phenotype

•Ovotesticular DSD

•Testicular regression syndrome

•Androgen synthesis defects

•Disorders of androgen action

–46,XY partial gonadal dysgenesis is characterized by partial testicular differentiation and ambiguous genitalia.

–46,XY complete gonadal dysgenesis (Swyer syndrome) is characterized by:

•A female phenotype with full development of unambiguous female genitalia

•Normally developed Müllerian structures

•Streak gonads

•These streak gonads should be removed due to their association with gonadoblastoma.

•These patients usually present because of delayed puberty.

–Patients with agonadism (vanishing testicular syndrome, testicular regression

648	31 Disorders of Sexual Development

syndrome) are boys with normal male genitalia.

–This indicates that these patients must have had testicular function in the fetal period followed by bilateral anorchia.

–Androgen synthesis defect can be secondary to:

•Leydig cell aplasia/hypoplasia, due to abnormalities in hCG/LH receptor

•Testesterone biosynthesis defects:

–STAR deficiency

–P450scc deficiency

–3-b hydroxysteroid dehydrogenase type II deficiency

–17a-hydroxylase and 17,20-lyase deficiency

–Isolated 17,20-lyase deficiency

–P450 oxidoreductase “POR gene” defect

–17b-hydroxysteroid dehydrogenase III deficiency

–Disorders of Anti-Mullerian Hormone (AMH) and Anti-Mullerian Hormone receptors result in persistent Müllerian duct syndrome (PMDS).

•PMDS is inherited as a sex-limited autosomal recessive type.

•It is caused by a mutation in the AMH or AMH-receptor genes.

•These patients are males and usually present with undescended testis or a hernia.

•They also have a uterus, Fallopian tube and rudimentary vagina.

–Disorders of androgen action:

•5a-reductase type 2 deficiency

•Complete/partial forms of androgen insensitivity syndromes

•46,XX disorders of sex development (46,XX DSD):

–In this condition, the chromosomes (46,XX) and ovaries are of a female but the external genitals appear to be male (masculinized external genitalia).

–In the past, this was called female pseudohermaphroditism.

–46,XX DSDs can result either from:

•Disorders of ovarian development.

•Excess exposure to fetal androgen.

–SRY positivity; WNT4, RSPO1, b-catenin gene defects; and duplication of SOX9 gene lead to testis-like formation within the ovary (streak gonad, dysgenetic testis or ovotestis) in the 46,XX patients.

46,XY Disorders of Sexual Development (DSD)

•46,XY disorders of sexual development can be caused by:

–Defects in testicular development

–Defects in testosterone biosynthesis

–Defects in testosterone action

–Defects in anti-Mullerian hormone

•Defects in testicular development:

–46,XY complete gonadal dysgenesis (Swyer syndrome)

–46,XY partial gonadal dysgenesis (Denys-Drash syndrome, Frasier syndrome)

–Ovotesticular DSD

–Testicular regression syndrome (vanishing testes syndrome)

–Leydig cell aplasia/hypoplasia

•Defects in testosterone biosynthesis:

–STAR deficiency

–P450scc

–3-b hydroxysteroid dehydrogenase deficiency

–17a-hydoxlase and 17,20-lyase deficiency

–Isolated 17,20-lyase deficiency

–P450 oxidoreductase “POR” gene defect

–17b-hydroxysteroid dehydrogenase III deficiency

–POR gene abnormality (defective 17,20-lyase activity of P450c17)

•Defects in anti-Mullerian hormone:

–Persistent Mullerian duct syndrome

•Defects in testosterone action:

–5a-reductase type 2 deficiency

–Complete androgen insensitivity syndromes

–Partial androgen insensitivity syndromes

31.4 Classification	649

–In ovotesticular DSDs, the most common karyotype is 46,XX followed by 46,XX/46,XY chimerism or mosaicism, and 46,XY.

–Most 46,XX ovotesticular DSDs are SRYnegative, and the genes responsible have not yet been identified.

–The main cause of a virilized females with two ovaries, XX karyotype and ambiguous genitalia is excess exposure to testosterone before birth.

•The excess testosterone exposure is usually of fetal origin

•Rarely this excess is of maternal origin.

–The majority of virilized 46,XX infants will have congenital adrenal hyperplasia (CAH) secondary to enzyme deficiency:

•21a-hydroxylase deficiency (most common)

•11bhydroxylase deficiency

•3b-hydroxysteroid dehydrogenase deficiency (rare)

–A combined P450c17 and P450c21 deficiency is a very rare variant of CAH.

–Cytochrome POR is a protein that transfers electrons from NADPH to all microsomal cytochrome P450 enzymes and three steroidogenic enzymes, namely:

•P450c17 (17a-hydroxylase/17,20 lyase)

•P450c21 (21-hydroxylase)

•P450aro (aromatase)

–Mutations of POR gene cause disordered steroidogenesis with prenatal virilization.

–Causes of fetal androgen excess in XX infants are rare and include:

•Maternal androgen ingestion

•Maternal virilizing disease

•Fetoplacental aromatase deficiency

•Virilizing luteoma of pregnancy

•Glucocorticoid receptor mutation

–Aromatase enzyme deficiency:

•This is rare type of enzyme deficiency.

•Aromatase is the enzyme that catalyzes conversion of androgens into estrogens.

•As a result of this enzyme deficiency, DHEA produced by the fetal adrenal glands cannot be converted to estrogen

by the placenta, and is converted to testosterone peripherally.

•This results in virilization of both fetus and mother.

•These patients can present during childhood and adolescence with cystic ovaries and delayed bone maturation. They may also present at puberty with:

–Primary amenorrhea

–Failure of breast development

–Virilization

–Hypergonadotrophic hypogonadism

•Another way of classifying disorders of sexual development is as follows:

–Disorders of sex chromosomes

–Disorders of gonads

–Disorders of phenotype

46,XX Disorders of Sexual Development (DSD)

•46,XX disorders of sex development:

–Disorders of ovarian development

–Excess exposure to fetal androgen

•Disorders of ovarian development.

–Ovotesticular DSD

–Gonadal dysgenesis

–Vaginal atresia

–Cloacal exstrophy

•Excess exposure to fetal androgen

–Congenital adrenal hyperplasia

•21a-hydroxylase deficiency (most common)

•11bhydroxylase deficiency

•3b-hydroxysteroid dehydrogenase deficiency (rare).

–P450c17 (17a-hydroxylase/17,20 lyase) deficiency

–P450c21 (21-hydroxylase) deficiency

–P450aro (aromatase) deficiency

–Maternal excess of androgens:

•Maternal androgen ingestion during pregnancy

•Fetoplacental aromatase deficiency

•Virilizing luteoma of pregnancy

650	31 Disorders of Sexual Development

A comprehensive classification (Aaronson’s classification) based on gonadal histology

1.Ovarian DSD:

•The gonads are composed of normal ovarian stroma with numerous follicles.

2.Ovotesticular DSD:

•The gonads are essentially composed of both ovarian and testicular tissues, either in two separate gonads or within a single gonad.

•At the least, a well-defined ovarian follicle should be seen to diagnose the ovarian element.

•The testicular component comprises architecturally ordered tubules, although the intervening stroma may be more abundant than normal.

3.Testicular DSD:

•The seminiferous tubules are normal, although Leydig cells might be prominent.

4.Dysgenetic DSD:

•The tubules are disordered, often sparse, and the stromal tissue is abundant.

•These gonads have a strong propensity to undergo malignant degeneration.

•Disorders of sex chromosomes (Chromosomal sex):

– This occurs when the number or structure of the sex chromosomes (X, Y chromosomes) is abnormal.

– The abnormalities include:

•Klinefelter syndrome 47 XXY

•XX male (46XX)

•Turner syndrome (gonadal dysgenesis) 45 XO

•46 XX/45X

ATROPHIC

TESTIS

VAS

DEFERENCE

Fig. 31.10 A clinical intraoperative photograph showing atrophic testis. Note the presence of a vas

•Mixed gonadal dysgenesis 46XY/45X

•True hermaphroditism 46 XX, 46XY or mosaics

•Disorders of gonads (Gonadal sex) (Figs. 31.10 and 31.11):

–Disorders of gonadal sex result when chromosomal sex is normal but differentiation of the gonads is abnormal.

–The abnormalities include:

•Pure gonadal dysgenesis

•Dysgenetic testes

•Absent testes

•Disorders of phenotype (Phenotypic sex):

–In these disorders the gonads and sex chromosomes are normal but with abnormal urogenital tract.

–The abnormalities include:

•Female pseudohermaphrodite

•Congenital adrenal hyperplasia

•Nonadrenal female pseudohermaphroditism

•Developmental disorders of mullerian duct

•Male pseudohermaphrodite

•Abnormalities in androgen synthesis

•Abnormalities in androgen action

•Persistent mullerian duct synd

•Developmental defects of male genitalia