(1)
Pediatric Surgery, AlSadik Hospital, Qatif, Saudi Arabia
31.1 Introduction
The birth of a new baby is one of the most dramatic events in a family, and the first question is usually “is it a boy or a girl?”
When a child is born with ambiguous external genitalia it often comes as a surprise for the parents and diagnostic dilemma for the treating physicians.
It is also considered as an endocrine emergency situation presenting a problem of sex assignment.
It is important for clinicians to promptly make an accurate diagnosis and counsel parents on therapeutic options.
It is also important to understand the psychological and social implications of gender assignment in some of these patients.
In the past several names such as intersex or ambiguous genitalia were used to describe disorders of sexual development but they were not accurately descriptive.
Intersex (Figs. 31.1, 31.2, 31.3, 31.4, 31.5, 31.6, and 31.7):
Figs. 31.1 and 31.2
Clinical photographs showing severe hypospadias with abnormal genitalia
Fig. 31.3
A clinical photograph of a patient with DSD. It is difficult to decide whether this is a true male or not. This patient was investigated and found to have severe virilization secondary to congenital adrenal hyperplasia leading to enlargement of the clitoris resembling a male penis
Figs. 31.4 and 31.5
Clinical photographs of two new born with cloacal exstrophy. Note there are no clear external genitalia and these patients need further evaluation prior to sex assignment. The external genitalia in these patients are usually small and not well developed
Fig. 31.6
Clinical photograph of a newborn with imperforated hymen with hydrocolpos causing abnormalities of external genitalia
Fig. 31.7
A clinical photograph showing abnormal external genitalis. This female patient was found to have a dermoid cyst over the clitoris causing abnormaliities of the external genitalia
Intersex literally means that the body is between the two sexes, male and female.
This is a term that is no longer used; it has now been replaced by disorders of sexual development (DSD).
In the past the term “hermaphrodite” was sometimes erroneously used to describe people with intersex/DSD conditions. The term hermaphroditism, was used after the Greek god of sexuality Hermes and the goddess of love and sexuality, Aphrodite. The correct technical definition of a hermaphrodite is a single organism that has complete sets of both male and female sexual organs. This term is also no longer used to describe humans.
The nomenclatures such as ‘intersex’, ‘hermaphrodite’, and ‘pseudohermaphrodite’ are no longer used. They are confusing terms and could be perceived to be pejorative by some affected families.
All these were replaced by the term Disorders of Sexual Development (DSD).
This was coined by International Consensus Conference on Intersex organized by the Lawson Wilkins Pediatric Endocrine Society and the European Society for Pediatric Endocrinology in 2006.
It replaces the earlier terms Intersex and ambiguous genitalia which were controversial and associated with a lot of social stigma and confusion.
Disorders of sex development (DSD) are defined as congenital conditions in which development of chromosomal, gonadal, or anatomical sex is atypical.
The use of the term disorder of sex development (DSD) is controversial among many activists and community organizations.
Although there are potential criticisms to the new nomenclature, the DSD terminology has been generally accepted and is now popularly used in the literature.
The medical term disorders of sex development (DSDs) is used to describe individuals with an atypical composition of chromosomal, gonadal and phenotypic sex, which leads to differences in the development of the urogenital tract and reproductive system.
The term DSD has a comprehensive definition including any problem noted at birth in which the genitalia are atypical in relation to the chromosomes or gonads. The karyotype is used as a prefix defining the classification of DSD.
The newly proposed terminology and classifications have eliminated some confusion for both the patient and the family, as well as for health professionals.
DSDs are rare and complex.
It is estimated that the overall incidence of DSDs is 1 in 4,500–5,500 live births.
Congenital adrenal hyperplasia (CAH) and mixed gonadal dysgenesis are the most common causes of ambiguous genitalia, constituting approximately over 50 % of all cases of genital ambiguity in the newborn period (Figs. 31.8 and 31.9).
Figs. 31.8 and 31.9
Clinical photographs showing two patients with congenital adrenal hyperplasia. Note the abnormal external genitalia which show severe virilization
The incidence of CAH and mixed gonadal dysgenesis is 1:15,000 and 1:10,000, respectively.
Currently, many countries screen newborns for CAH by use of filter-paper blood spot 17-hydroxyprogesterone measurements.
Disorders of sexual development includes a variety of conditions in which the reproductive system or the external genitalia are not normal for a female or male.
There are three general descriptive terms to describe the sex of a person:
Genotypic sex (Chromosomal sex): This refers to the sex based on the number of sex chromosomes. This depends on the presence of 46,XX or 46,XY chormosomes.
Anatomical sex (Gonadal sex): This refers to the sex according to the gonadal differentiation. This depends on the presence of a uterus, ovaries and tubes or testes, epididymis, seminal vesicles, ejaculatory ducts and prostate.
Phenotypic sex: This refers to the sex based on the external anatomy of the genitalia. This results from the differentiation of the external genitalia under the influence of sex-determining genes and hormones.
Abnormalities in any of these result in a range of conditions that lead to abnormal development of the sex organs and genitalia (Disorders of sex development).
Children with DSD often have both male and female characteristics internally as well as externally.
Gender identity:
This refers to the individual’s perception about his/her own gender. In some individuals, gender identity is different from the phenotypic sex.
When a child is born with DSD, the gender may not be obvious.
The development of sex organs and external genitalia is a very complex process that starts at around 7–8 weeks of pregnancy in the developing fetus and is complete by 12 weeks.
Great advances have been made over recent years in understanding the genetics and pathology of DSD.
The Chicago Consensus new nomenclature is based on the primary genetic defect.
It includes three broad categories:
- 1.
Sex chromosome DSD
- 2.
46, XX DSD
- 3.
46, XY DSD
- 1.
The most common DSD is Congenital Adrenal Hyperplasia (CAH).
This results in a female (XX chromosomes) having genitals that look somewhat masculine.
In mild cases, CAH results in a slightly enlarged clitoris.
In more severe cases it can be difficult to decide whether a baby is male or female.
Most children with CAH think of themselves as girls.
CAH when it occurs in males (XY chromosomes), the result is over-masculinization and premature puberty.
Mixed gonadal dysgenesis (MGD) is the second most common cause of DSDs.
Another common DSD is Androgen Insensitivity Syndrome (AIS).
This occurs in males (XY chromosomes) who do not respond to testosterone normally.
This results in a feminine appearance.
There are two types, complete and partial.
In Complete Androgen Insensitivity Syndrome (CAIS) the result is a totally feminine appearance, including typical female breast development.
Diagnosis in 46,XY phenotypic females with complete androgen insensitivity usually occurs after puberty during an evaluation for primary amenorrhea.
In the Partial Androgen Insensitivity Syndrome (PAIS), the genitals can vary from mostly female to almost completely male.
One of the more unusual DSDs is 5-Alpha Reductase Deficiency (5ARD), popularly known as “Penis at 12.”
It is caused by a deficiency of the enzyme 5-Alpha Reductase which converts testesterone to dihydrotestesterone in males (XY).
Dihyrotestesterone is responsible for the development of the male external genitalia.
The classic presentation of MIS (Mullerian inhibiting substance) deficiency is a boy with a hernia on one side and an impalpable contralateral gonad. At the time of surgery, a uterus and fallopian tubes are noted along with normal Wolffian structures.
Clinicians should suspect the possibility of a DSD in patients with both hypospadias and cryptorchidism.
Infants born with ambiguous genitalia represent a true medical and social emergency.
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.
31.2 Embryology
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 up-regulated 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.
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.
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 self-recognition 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).
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 androgen-insensitivity syndrome (CAIS) however, do not indicate a behavioral role for Y-chromosome genes.
31.3 Sexual 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 testis-determining 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.
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 Müllerian-inhibiting 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.
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.
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.
31.4 Classification
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.
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.
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 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
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 SRY-negative, 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)
11b- hydroxylase 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)
11b- hydroxylase 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
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
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
Fig. 31.10
A clinical intraoperative photograph showing atrophic testis. Note the presence of a vas
Fig. 31.11
Intraoperative photograph showing bilateral atrophic testes
31.5 Evaluation of a Newborn with DSD
The evaluation, diagnostic approach and management of a newborn with DSD involves a multidisciplinary team approach.
This team include:
Neonatologists
Geneticists/genetic counselor
Pediatric endocrinologists
Pediatric surgeons
Social worker
Pediatric urologist
Psychologist
The most common disorder of sexual development (DSD), congenital adrenal hyperplasia (CAH), results in virilization of a 46,XX female.
The clinician’s challenge is to distinguish CAH from other less common causes of ambiguous genitalia.
Classification of DSD
- 1.
Sex chromosome DSD
45,X0/46,XY Mixed gonadal dysgenesis (MGD)
45,X0/46,XY Partial gonadal dysgenesis
46,XX/XY or 45,X0/46,XY Ovotesticular DSD
45,X0 or 45,X0/46,XY (Turner’s syndrome)
Seminiferous tubule dysgenesis: Klinefelter’s syndrome (47,XXY)
- 2.
46,XX (DSD)
Androgen excess: (60–70 %)
CAH (vast majority)
21-Hydroxylase deficiency (95 %)
11β-Hydroxylase deficiency (5 %)
3β-Hydroxysteroid dehydrogenase deficiency
Maternal androgens (very rare)
Endogenous: Virilising tumours in the mother
Exogenous (very rare)
Disorders of ovarian development
Ovotesticular DSD
46,XX testicular DSD (SRY translocation)
Pure gonadal dysgenesis (e.g. SOX9 duplication
Meyer–Rokitansky syndrome (Müllerian aplasia)
- 3.
46,XY DSD
Disorders of testicular development
Gonadal dysgenesis (Swyer syndrome = Pure, DAX-1 Duplication. SF-1 mutation)
Ovotesticular DSD
Bilateral vanishing testis/testicular regression syndromes
Disorders of androgen synthesis or action
Leydig cell agenesis, unresponsiveness
Enzyme deficiency
StAR deficiency (lipoid adrenal hyperplasia
3β-Hydroxysteroid dehydrogenase deficiency
17α-Hydroxylase deficiency
17,20-Lyase deficiency
17β-Hydroxysteroid oxidoreductase deficiency
5α-Reductase deficiency
Disorders of androgen-dependent target tissue
CAIS (testicular feminisation)
PAIS
Persistent Müllerian duct syndrome
- 4.
Others: Severe hypospadias and cryptorchidism, penile agenesis and cloacal exstrophy
A detailed family history is essential; the following considerations should be kept in mind:
A family history of genital ambiguity, infertility, or unexpected changes at puberty may suggest a genetically transmitted trait.
Recessive traits tend to occur in siblings, whereas X-linked abnormalities tend to appear in males who are scattered sporadically across the family history.
A history of early death of infants in a family may suggest a previously missed adrenogenital deficiency
Maternal drug ingestion is important, particularly during the first trimester, when virilization may be produced exogenously in a gonadal female.
Although extremely rare, a history of maternal virilization may suggest an androgen-producing maternal tumor (arrhenoblastoma)
Sex assignment:
It is important not to assign a sex immediately and delay it till after full evaluation.
During the evaluation stage, the newborn is referred to as “baby,” not boy or girl.
The family should be encouraged to delay naming the baby until the sex has been assigned.
There are other factors that must be taken in consideration during this process including:
The social and cultural background.
Expectations of the parents.
Religious factors.
The parents are also involved, educated and should participate in the process and should understand that a children with a DSD can live normal live and function well in society.
Although different DSDs may present with similar findings on physical examination, there are certain clinical and laboratory aspects that are important and will help define the type of DSD.
It is important to rule out a malformation syndromes that may present as ambiguous genitalia (Fig. 31.12).
Clinical evaluation of the gonads and external genitalia is very important:
It is important to note the size and degree of differentiation of the phallus.
Note the phallus length:
A normal-term male penis is 3.5 ± 0.7 cm.
A length of less than 2.0 cm is considered abnormal.
A normal-term female clitoris is less than 1.0 cm.
Micropenis is thus defined as a stretch penile length of less than 2.0 cm in a term male infant, and clitoromegaly as a clitoris greater than 1.0 cm in a term female. In preterm infant males, the penile length is shorter.
Note the position of the urethral meatus:
Labioscrotal folds may be separated or be fused at the midline, giving an appearance of a scrotum.
Newborns with 46XX DSD due to CAH may have hyperpigmented labioscrotal folds.
The anogenital ratio:
This is the distance between the anus and posterior fourchette divided by the distance between the anus and base of the clitoris/phallus.
A ratio greater than 0.5 suggests virilization.
In a fully virilized male the ratio is 1.0.Related posts:
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