Download Clinical Genetics

The Sex Chromosomes and Their
Abnormalities
The Chromosomal Basis of Sex Determination
The fundamental basis of the XX/XY system of sex
determination:
 Males with Klinefelter syndrome: karyotype
47,XXY, whereas most Turner syndrome females
have only 45 chromosomes with a single X
chromosome.
 The the Y chromosome is crucial in normal male
development.
 Furthermore, the effect of varying number of X
chromosomes is moderate in either males or
females.

In addition to sex chromosomes, a number of
genes located on both the sex chromosomes and
the autosomes are involved in sex determination
and subsequent sexual differentiation.
 In most instances, the role of these genes has come
to light as a result of patients with abnormalities in
sexual development, whether cytogenetic,
mendelian, or sporadic.

The structure of the Y chromosome and its role in
sexual development have been determined at both
the molecular and genomic levels.
 In male meiosis, the X and Y chromosomes
normally pair by segments and undergo
recombination at the pseudoautosomal region of
the X and Y chromosomes.
 The Y chromosome is relatively gene poor and
contains only about 50 genes. The functions of a
high proportion of these genes are related to
gonadal and genital development.
The Y chromosome in sex determination and in disorders of
sexual differentiation. Individual genes and regions
implicated in sex determination, sex reversal, and defects of
spermatogenesis are indicated.
Embryology of the Reproductive System

By sixth week of development in both sexes, the
primordial germ cells have migrated from their earlier
extraembryonic location to the gonadal ridges, where they
are surrounded by the sex cords to form a pair of primitive
gonads. The developing gonad is bipotential and is often
referred to as indifferent.
 The development into an ovary or a testis is determined by
the coordinated action of a sequence of genes that leads
normally to ovarian development when no Y chromosome
is present or to testicular development when a Y is present.
 The ovarian pathway is followed unless a Y-linked gene,
designated testis-determining factor (TDF), acts as a
switch, diverting development into the male pathway.
Scheme of developmental
events in sex determination
and differentiation of the
male and female gonads.
Involvement of individual
genes in key developmental
steps or in genetic disorders
is indicated in blue boxes.
The Testis-Determining Gene, SRY

Whereas the X and Y chromosomes normally
exchange in meiosis I within the Xp/Yp PAR, in
rare instances, genetic recombination occurs
outside of the PAR, leading to two rare but
highly informative abnormalities: XX males and
XY females.
 Each of these sex-reversal disorders occurs with
an incidence of approximately 1 in 20,000 births.

XX males are phenotypic males with a
46,XX karyotype who usually possess some
Y chromosomal sequences translocated to the
short arm of the X.
 Similarly, a proportion of phenotypic females
with a 46,XY karyotype have lost the testisdetermining region of the Y chromosome.
 The SRY gene (sex-determining region on the
Y) lies near the pseudoautosomal boundary
on the Y chromosome, is present in many
46,XX males, and is deleted or mutated in a
proportion of female 46,XY patients, thus
strongly implicating SRY in male sex
determination.

SRY is expressed only briefly early in development in
cells of the germinal ridge just before differentiation of
the testis.
 SRY encodes a DNA-binding protein that is likely to be
a transcription factor, although the specific genes that it
regulates are unknown. SRY is equivalent to the TDF
gene on the Y chromosome.
 However, the presence or absence of SRY does not
explain all cases of abnormal sex determination. SRY is
not present in about 10% of unambiguous XX males and
in most cases of XX true hermaphrodites or XX males
with ambiguous genitalia.
 Further, mutations in the SRY gene account for only
about 15% of 46,XY females. Thus, other genes are
implicated in the sex-determination pathway.
Figure 6-12 Etiological
factors of XX male or
XY female phenotypes
by aberrant exchange
between X- and Ylinked sequences.
Y-Linked Genes in Spermatogenesis

Interstitial deletions in Yq have been associated
with at least 10% of cases of nonobstructive
azoospermia and with approximately 6% of
cases of severe oligospermia.
 These findings suggest that one or more genes,
termed azoospermia factors (AZF), are located
on the Y chromosome, and three
nonoverlapping regions on Yq (AZFa, AZFb,
and AZFc) have been defined.

Molecular analysis of these deletions has led to
identification of a series of genes that may be
important in spermatogenesis. E.g., the AZFc
deletion region contains several families of genes
expressed in the testis, including the DAZ genes
(deleted in azoospermia) that encode RNAbinding proteins expressed only in the premeiotic
germ cells of the testis.
 De novo deletions of AZFc arise in about 1 in
4000 males and are mediated by recombination
b/w long repeated sequences.

AZFa and AZFb deletions, although less
common, also involve recombination.
 Approximately 2% of otherwise healthy males
are infertile because of severe defects in sperm
production, and it appears likely that de novo
deletions or mutations account for at least a
proportion of these.

Thus, men with idiopathic infertility should
be karyotyped, and Y chromosome
molecular testing and genetic counseling
may be appropriate before the initiation of
assisted reproduction for such couples.
 Not all cases of male infertility are due to
chromosomal deletions. For example, a de
novo point mutation has been described in
one Y-linked gene, USP9Y, the function of
which is unknown but which must be
required for normal spermatogenesis.
The X Chromosome
Chromosome Inactivation

The relative tolerance of the human karyotype for X
chromosome abnormalities can be explained in terms of
X chromosome inactivation, the process by which
most genes on one of the two X chromosomes in
females are silenced epigenetically and fail to produce
any product.
 The theory of X inactivation is that in somatic cells in
normal females, one X chromosome is inactivated early
in development, thus equalizing the expression of Xlinked genes in the two sexes.
Figure 6-15 Profile of gene expression of the X chromosome. Each symbol indicates X
inactivation status of an X-linked gene. Location of each symbol indicates its approximate
map position on the X chromosome. Genes not expressed from the inactive X (subject to
inactivation) are on the left. Genes expressed from the inactive X (escape from
inactivation) are on the right; genes represented in light blue are those that escape
inactivation in only a subset of females tested. The location of the XIST gene and the X
inactivation center (XIC) are indicated in Xq13.2.
Cytogenetic Abnormalities of the Sex Chromosomes

As a group, disorders of the sex chromosomes
tend to occur as isolated events without
apparent predisposing factors, except for an
effect of late maternal age in the cases that
originate from errors of maternal meiosis I.
 clinical indications that raise the possibility of
a sex chromosome abnormality and thus the
need for cytogenetic or molecular studies
include delay in onset of puberty, primary or
secondary amenorrhea, infertility, and
ambiguous genitalia.

X and Y chromosome aneuploidy is relatively
common, and sex chromosome abnormalities
are among the most common of all human
genetic disorders, with an overall incidence
of about 1 in 400 to 500 births.
 The phenotypes associated with these
chromosomal defects are, in general, less
severe than those associated with comparable
autosomal disorders because X chromosome
inactivation, as well as the low gene content
of the Y, minimizes the clinical consequences
of sex chromosome imbalance.

By far the most common sex chromosome
defects in live-born infants and in fetuses are
the trisomic types (XXY, XXX, and XYY),
but all three are rare in spontaneous
abortions.
 In contrast, monosomy for the X (Turner
syndrome) is less frequent in live-born
infants but is the most common chromosome
anomaly reported in spontaneous abortions.

Structural abnormalities of the sex
chromosomes are less common; the defect
most frequently observed is an
isochromosome of the long arm of the X,
i(Xq), seen in complete or mosaic form in at
least 15% of females with Turner syndrome.
 Mosaicism is more common for sex
chromosome abnormalities than for
autosomal abnormalities, and in some
patients it is associated with relatively mild
expression of the associated phenotype.
Incidence of Sex Chromosome Abnormalities
Sex
Disorder
Karyotype
Male
Klinefelter syndrome
47,XXY
47,XYY syndrome
1/1000 males
48,XXXY
1/25,000 males
Others (48,XXYY;
49,XXXYY; mosaics)
1/10,000 males
47,XYY
Other X or Y chromosome
abnormalities
XX males
Approximate Incidence
1/1000 males
1/1500 males
46,XX
1/20,000 males
Overall incidence: 1/400
males
Female
Turner syndrome
Trisomy X
45,X
1/5000 females
46,X,i(Xq)
1/50,000 females
Others (deletions, mosaics)
1/15,000 females
47,XXX
Other X chromosome abnormalities
1/1000 females
1/3000 females
XY females
46,XY
Androgen insensitivity syndrome
46,XY
1/20,000 females
1/20,000 females
Overall incidence: 1/650
females

The four well-defined syndromes associated with
sex chromosome aneuploidy are important causes of
infertility or abnormal development, or both.
 As a group, those with sex chromosome aneuploidy
show reduced levels of psychological adaptation,
educational achievement, occupational
performance, and economic independence, and on
average, they scored slightly lower on intelligence
(IQ) tests.

However, each group shows high variability,
making it impossible to generalize to specific
cases. In fact, the overall impression is a high
degree of normalcy, particularly in adulthood,
which is remarkable among those with
chromosomal anomalies.
 Because almost all patients with sex chromosome
abnormalities have only mild developmental
abnormalities, a parental decision regarding
potential termination of a pregnancy in which the
fetus is found to have this type of defect can be a
very difficult one.
Follow-up observations on patients with sex chr. aneuploidy
Sexual
Development
Intelligence
Behavioral
Problem
Disorder
Karyotype
Phenotype
Klinefelter
syndrome
47,XXY
Tall male
Infertile;
hypogonadism
Learning
Difficulties
(some
patients)
May have poor
Psychosocial
adjustment
XYY syndrome
47,XYY
Tall male
Normal
Normal
Frequent
Trisomy X
47,XXX
Female,
usually tall
Usually
normal
Learning
Difficulties
(some
patients)
Occasional
Turner syndrome
45,X
Short
female,
Distinctive
Features
Infertile; streak Slightly
gonads
reduced
Rare
Klinefelter syndrome

Klinefelter syndrome patients are tall and thin
and have relatively long legs. They appear
physically normal until puberty, when signs of
hypogonadism become obvious.
 Puberty occurs at a normal age, but the testes
remain small, and secondary sexual
characteristics remain underdeveloped.
 Gynecomastia is a feature of some patients;
because of this, the risk of breast cancer is 20
to 50 times that of 46,XY males.

Klinefelter patients are almost always infertile
because of the failure of germ cell
development, and patients are often identified
clinically for the first time because of
infertility.
 Klinefelter syndrome is relatively common
among infertile males (about 3%) or males
with oligospermia or azoospermia (5% to
10%).
 In adulthood, persistent androgen deficiency
may result in decreased muscle tone, a loss of
libido, and decreased bone mineral density.

The incidence is at least 1 in 1000 male live births (1
in 2000 total births). Because of the relatively mild
yet variable phenotype, many cases are presumed to
go undetected.
 About half the cases of Klinefelter syndrome result
from errors in paternal meiosis I because of a failure
of normal Xp/Yp recombination in the
pseudoautosomal region.
 Among cases of maternal origin, most result from
errors in maternal meiosis I and the remainder from
errors in meiosis II
 or from a postzygotic mitotic error leading to
mosaicism.

Maternal age is increased in the cases
associated with maternal meiosis I errors.
 About 15% of Klinefelter patients have
mosaic karyotypes. As a group, such mosaic
patients have variable phenotypes; some
may have normal testicular development.
 The most common mosaic karyotype is
46,XY/47,XXY, probably as a consequence
of loss of one X chromosome in an XXY
conceptus during an early postzygotic
division.

There are several variants of Klinefelter syndrome,
including 48,XXYY, 48,XXXY, and 49,XXXXY.
As a rule, the additional X chromosomes (even
though they are mostly inactive) cause a
correspondingly more severe phenotype, with a
greater degree of dysmorphism, more defective
sexual development, and more severe mental
impairment.
 Although there is wide phenotypic variation, some
consistent phenotypic differences have been
identified between patients with Klinefelter
syndrome and chromosomally normal males:
– Verbal comprehension and ability are below those
of normal males, and 47,XXY males score slightly
lower on certain intelligence performance tests.
– Patients with Klinefelter syndrome have a severalfold increased risk of learning difficulties,
especially in reading, that may require educational
intervention.
– Klinefelter syndrome is over-represented among
boys requiring special education. Many of the
affected boys have relatively poor psychosocial
adjustment, in part related to poor body image.
Language difficulties may lead to shyness,
unassertiveness, and immaturity
47,XYY Syndrome

Among all male live births, the incidence of the
47,XYY karyotype is about 1 in 1000.
 The 47,XYY chromosome constitution is not
associated with an obviously abnormal
phenotype
 The origin of the error that leads to the XYY
karyotype must be ?????
 The less common XXYY and XXXYY variants,
which share the features of the XYY and
Klinefelter syndromes, probably also originate in
the father as a result of sequential nondisjunction
in meiosis I and meiosis II.

XYY males identified in newborn screening
programs without ascertainment bias are tall
and have an increased risk of educational or
behavioral problems in comparison with
chromosomally normal males. They have
normal intelligence and are not dysmorphic.
 Fertility is usually normal, and there appears to
be no particularly increased risk that a 47,XYY
male will have a chromosomally abnormal
child.
 About half of 47,XYY boys require educational
intervention as a result of language delays and
reading and spelling difficulties. Their IQ
scores are about 10 to 15 points below average.

Parents whose child is found, prenatally or postnatally,
to be XYY are often extremely concerned about the
behavioral implications.
 Attention deficits, hyperactivity, and impulsiveness
have been well documented in XYY males.
 reports in the 1960s and 1970s showed that the
proportion of XYY males was elevated in prisons and
mental hospitals, especially among the tallest inmates.
This stereotypic impression is now known to be
incorrect.
 Nonetheless, inability to predict the outcome in
individual cases makes identification of an XYY fetus
one of the more difficult genetic counseling problems
in prenatal diagnosis programs.
Trisomy X (47,XXX)



Trisomy X occurs with an incidence of 1 in 1000
female births.
Trisomy X females, although somewhat above
average in stature, are not abnormal phenotypically.
Some are first identified in infertility clinics, but
probably most remain undiagnosed.
Follow-up studies have shown that XXX females
develop pubertal changes at an appropriate age, and
they are usually fertile although with a somewhat
increased risk of chromosomally abnormal
offspring.
 There
is a significant deficit in
performance on IQ tests, and about 70% of
the patients have some learning problems.
 Severe psychopathological and antisocial
behaviors appear to be rare; however,
abnormal behavior is apparent, especially
during the transition from adolescence to
early adulthood

In 47,XXX cells, two of the X chromosomes are
inactivated. Almost all cases result from errors in
maternal meiosis, and of these, the majority are in
meiosis I.
 There is an effect of increased maternal age,
restricted to those patients in whom the error was
in maternal meiosis I.
 The tetrasomy X syndrome (48,XXXX) is
associated with more serious retardation in both
physical and mental development.
 The pentasomy X syndrome (49,XXXXX),
despite the presence of four inactive X
chromosomes, usually includes severe
developmental retardation with multiple physical
defects.
Turner Syndrome (45,X and Variants)

Unlike patients with other sex chromosome
aneuploidies, females with Turner syndrome can
often be identified at birth or before puberty by
their distinctive phenotypic features.
 Turner syndrome is much less common than other
sex chromosome aneuploidies. The incidence of
the Turner syndrome phenotype is approximately
1 in 4000 female live births.

The most frequent chromosome constitution
in Turner syndrome is 45,X.
 However, about 50% of cases have other
karyotypes.
 About one quarter of Turner syndrome
cases involve mosaic karyotypes, in which
only a proportion of cells are 45,X.
The most common karyotypes and their
approximate relative prevalences are as
follows:
45,X
50%
46,X,i(Xq)
15%
45,X/46,XX mosaics
15%
45,X/46,X,i(Xq) mosaics
about 5%
45,X, other X abnormality
about 5%
Other 45,X/? mosaics
about 5%

The chromosome constitution is clinically significant.
For example, patients with i(Xq) are similar to classic
45,X patients, whereas patients with a deletion of Xp
have short stature and congenital malformations, and
those with a deletion of Xq often have only gonadal
dysfunction.
 Typical abnormalities in Turner syndrome include short
stature, gonadal dysgenesis (usually streak gonads
reflecting a failure of ovarian maintenance),
characteristic unusual faces, webbed neck, low posterior
hairline, broad chest with widely spaced nipples, and
elevated frequency of renal and cardiovascular
anomalies. At birth, infants with this syndrome often
have edema of the dorsum of the foot, a useful
diagnostic sign.

Many patients have coarctation of the aorta, and
Turner syndrome females are at particular risk for
cardiovascular abnormalities. Lymphedema may
be present in fetal life, causing cystic hygroma
(visible by ultrasonography), which is the cause of
the neck webbing seen postnatally.
 Turner syndrome should be suspected in any
newborn female with edema of the hands and feet
or with hypoplastic left-sided heart or coarctation
of the aorta.
 The diagnosis should also be considered in the
teenage years for girls with primary or secondary
amenorrhea, especially if they are of short stature.
Growth hormone therapy should be considered for
all girls with Turner syndrome and can result in
gains of 6 to 12 cm to the final height.

Intelligence in Turner syndrome females is
usually considered to be normal, although
approximately 10% of patients will show
significant developmental delay requiring
special education.
 Even among those with normal intelligence,
however, patients often display a deficiency in
spatial perception, perceptual motor
organization, or fine motor execution.
 As a consequence, the nonverbal IQ score is
significantly lower than the verbal IQ score, and
many patients require educational intervention,
especially in mathematics.

Turner syndrome females have an elevated risk of
impaired social adjustment. A comparison of 45,X
girls with a maternal X and those with a paternal X
provided evidence of significantly worse social
cognition skills in those with a maternally-derived
X.
 The high incidence of a 45,X karyotype in
spontaneous abortions has already been mentioned.
This single abnormality is present in an estimated
1% to 2% of all conceptuses; survival to term is a
rare outcome, and more than 99% of such fetuses
abort spontaneously.

The single X is maternal in origin in about 70% of
cases; in other words, the chromosome error
leading to loss of a sex chromosome is usually
paternal.
 Furthermore, it is not clear why the 45,X
karyotype is usually lethal in utero but is
apparently fully compatible with postnatal
survival.
 The "missing" genes responsible for the Turner
syndrome phenotype must reside on both the X
and Y chromosomes. It has been suggested that the
responsible genes are among those that escape X
chromosome inactivation, particularly on Xp,
including those in the pseudoautosomal region.

Small ring X chromosomes are occasionally
observed in patients with short stature,
gonadal dysgenesis, and MR. Because MR is
not a typical feature of Turner syndrome, the
presence of mental retardation with or
without other associated physical anomalies
in individuals with a 46,X,r(X) karyotype has
been attributed to the fact that small ring X
chromosomes lack the X inactivation center.

The failure to inactivate the ring X in these
patients leads to overexpression of X-linked genes
that are normally subject to inactivation.
 The discovery of a ring X in a prenatal diagnosis
can lead to great uncertainty, and studies of XIST
expression are indicated.
 Large rings containing the X inactivation center
and expressing XIST predict a Turner syndrome
phenotype; a small ring lacking or not expressing
XIST predicts a much more severe phenotype.
DISORDERS OF GONADAL AND
SEXUAL DEVELOPMENT

Various X-linked and autosomal genes play
role in ovarian and testicular development
and in the development of male and female
external genitalia.

For some newborn infants, determination of sex is
difficult or impossible because the genitalia are
ambiguous, with anomalies that tend to make
them resemble those of the opposite chromosomal
sex.
 Such anomalies may vary from mild hypospadias
in males (a developmental anomaly in which the
urethra opens on the underside of the penis or on
the perineum) to an enlarged clitoris in females.
 In some patients, both ovarian and testicular tissue
is present, a condition known as
hermaphroditism.

Abnormalities of either external or internal
genitalia do not necessarily indicate a
cytogenetic abnormality of the sex
chromosomes but may be due to
chromosomal changes elsewhere in the
karyotype, to single-gene defects, or to nongenetic causes.
 Nonetheless, determination of the child's
karyotype is an essential part of the
investigation of such patients and can help
guide both surgical and psychosocial
management as well as genetic counseling.
 The
detection of cytogenetic
abnormalities, especially when seen in
multiple patients, can also provide
important clues about the location and
nature of genes involved in sex
determination and sex differentiation.
Abnormal Sexual Phenotype
Cytogenetic Locus
Gene
XY female (mutation)
Yp11.3
SRY
17q24
SOX9
XY sex reversal and adrenal insufficiency
9q33
SF1
XY female (Frasier syndrome) or male
pseudohermaphrodite (Denys-Drash syndrome)
11p13
WT1
XY female (gene duplication)
Xp21.3
DAX1
XY sex reversal (variable)
Xq13.3
ATRX
XY female, cryptorchidism (gene duplication)
1p35
WNT4
Premature ovarian failure
3q23
FOXL2
XX male (gene translocated to X)
XY female (with camptomelic dysplasia)
XX male (gene duplication)
Gonadal Dysgenesis
Table 6-6. Cytogenetic Abnormalities Associated with
Cases of Sex Reversal or Ambiguous Genitalia
Cytogenetic Abnormality
Phenotype
dup 1p31-p35
XY female (WNT4 gene duplication)
del 2q31
XY female, mental retardation
del 9p24.3
XY female, ambiguous genitalia
del 10q26-qter
XY female
del 12q24.3
XY ambiguous genitalia, mental
retardation
dup 22q
XY true hermaphroditism
dup Xp21.3
XY female (DAX1 gene duplication

A number of autosomal and X-linked genes have been
implicated in conversion of the bipotential gonad to
either a testis or ovary.
 Detailed analysis of a subset of sex-reversed 46,XY
females in whom the SRY gene was not deleted or
mutated revealed a duplication of a portion of the short
arm of the X chromosome.
 The DAX1 gene in Xp21.3 encodes a transcription
factor that plays a dosage-sensitive role in
determination of gonadal sex, implying a tightly
regulated interaction between DAX1 and SRY. An
excess of SRY at a critical point in development leads to
testis formation; an excess of DAX1 resulting from
duplication of the gene can suppress the normal maledetermining function of SRY, and ovarian development
results.





Camptomelic dysplasia, due to mutations in the SOX9 on 17q,
is an autosomal dominant disorder with usually lethal skeletal
malformations.
However, about 75% of 46,XY patients with this disorder are
sex reversed and are phenotypic females.
SOX9 is normally expressed early in development in the genital
ridge and thus appears to be required for normal testis
formation (in addition to its role in other aspects of
development).
In the absence of one copy of the SOX9 gene, testes fail to
form, and the default ovarian pathway is followed.
Interestingly, duplication of SOX9 has been reported to lead to
XX sex reversal, suggesting that overproduction of SOX9, even
in the absence of SRY, can initiate testis formation.

Other autosomal loci have also been implicated in gonadal
development.
 Chromosomally male patients with Denys-Drash syndrome
have ambiguous external genitalia; patients with the more
severe Frasier syndrome show XY complete gonadal
dysgenesis.
 The WT1 gene in 11p13 (also implicated in Wilms tumor, a
childhood kidney neoplasia) encodes a transcription factor
that is involved in interactions between Sertoli and Leydig
cells in the developing gonad.
 Dominant WT1 mutations apparently disrupt normal
testicular development.
 The X-linked ATRX gene is responsible for an X-linked MR
syndrome with α-thalassemia and, in many patients, genital
anomalies ranging from undescended testes to micropenis to
varying degrees of XY sex reversal.
Ovarian Development and Maintenance



In contrast to testis determination, much less is known about
development of the ovary, although a number of genes (e.g.,
RSPO1, FOXL2) have been implicated in normal ovarian
maintenance.
It has long been thought that two X chromosomes are necessary
for ovarian maintenance, as 45,X females, despite normal
initiation of ovarian development in utero, are characterized by
germ cell loss, oocyte degeneration, and ovarian dysgenesis.
Patients with cytogenetic abnormalities involving Xq frequently
show premature ovarian failure. Because many nonoverlapping deletions on Xq show the same effect, this finding
may reflect a need for two structurally normal X chromosomes
in oogenesis or simply a requirement for multiple X-linked
genes (or probably imprinted genes?????).
Female Pseudohermaphroditism

Pseudohermaphrodites are "pseudo" because, unlike true
hermaphrodites, they have gonadal tissue of only one sex
that matches their chromosomal constitution.
 Female pseudohermaphrodites have 46,XX karyotypes
with normal ovarian tissue but with ambiguous or male
external genitalia.
 Male pseudohermaphrodites are 46,XY with
incompletely masculinized or female external genitalia.
 In general, ambiguous development of the genital ducts
and external genitalia should always be evaluated
cytogenetically, both to determine the sex chromosome
constitution of the patient and to identify potential
chromosome abnormalities frequently associated with
dysgenetic gonads.

Female pseudohermaphroditism is usually due to
congenital adrenal hyperplasia (CAH), an
inherited disorder arising from specific defects in
enzymes of the adrenal cortex required for cortisol
biosynthesis and resulting in virilization of female
infants.
 In addition to being a frequent cause of female
pseudohermaphroditism, CAH accounts for
approximately half of all cases presenting with
ambiguous external genitalia.
 Ovarian development is normal, but excessive
production of androgens causes masculinization of
the external genitalia, with clitoral enlargement and
labial fusion to form a scrotum-like structure.

Although any one of several enzymatic steps may be
defective in CAH, the most common defect is deficiency
of 21-hydroxylase, which has an incidence of about 1 in
12,500 births.
 Deficiency of 21-hydroxylase blocks the normal
biosynthetic pathway of glucocorticoids and
mineralocorticoids. This leads to overproduction of the
precursors, which are then shunted into the pathway of
androgen biosynthesis, causing abnormally high
androgen levels in both XX and XY embryos.
 Whereas female infants with 21-hydroxylase deficiency
are born with ambiguous genitalia, affected male infants
have normal external genitalia and may go unrecognized
in early infancy.
Steroid Hormone
Synthesis

Of patients with classic 21-hydroxylase deficiency,
25% have the simple virilizing type, and 75% have a
salt-losing type due to mineralocorticoid deficiency
that is clinically more severe and may lead to
neonatal death.
 A screening test developed to identify the condition
in newborns, in which heel-prick blood specimens
are blotted onto filter paper, is now in use in many
countries.
 It is valuable in preventing the serious consequences
of the salt-losing defect in early infancy and in
prompt diagnosis, and hormone replacement therapy
for affected males and females.
 Prompt medical, surgical, and psychosocial
management of 46,XX CAH patients is associated
with improved fertility rates and normal female
gender identity.
Male Pseudohermaphroditism:

In addition to disorders of testis formation during
embryological development, causes of
pseudohermaphroditism in 46,XY individuals
include abnormalities of gonadotropins, inherited
disorders of testosterone biosynthesis and
metabolism, and abnormalities of androgen target
cells.
 These disorders are heterogeneous both genetically
and clinically, and in some cases they may
correspond to milder manifestations of the same
cause underlying true hermaphroditism.
 Whereas the gonads are exclusively testes in male
pseudohermaphroditism, the genital ducts or
external genitalia are incompletely masculinized

In addition to mutation or deletion of any of the
genes involved in testes determination and
differentiation, there are several forms of androgen
insensitivity that result in male
pseudohermaphroditism.
 One example is deficiency of the steroid 5αreductase, the enzyme responsible for converting
the male hormone testosterone to its active form
dihydrotestosterone. This inherited condition
results in feminization of external genitalia in
affected males. Although testicular development is
normal, the penis is small, and there is a blind
vaginal pouch. Gender assignment can be difficult.

Another well-studied disorder is an X-linked
syndrome known as androgen insensitivity
syndrome (formerly known as testicular
feminization).
 In this disorder, affected persons are
chromosomal males (karyotype 46,XY), with
apparently normal female external genitalia,
who have a blind vagina and no uterus or
uterine tubes.
 The incidence of androgen insensitivity is about
1 in 20,000 live births.

Axillary and pubic hair is sparse or absent.
 As the original name "testicular feminization"
indicates, testes are present either within the
abdomen or in the inguinal canal, where they are
sometimes mistaken for hernias in infants who
otherwise appear to be normal females.
 Thus, gender assignment is not an issue, and
psychosexual development and sexual function are
that of a normal female (except for fertility).

Although the testes secrete androgen normally, endorgan unresponsiveness to androgens results from
absence of androgen receptors in the appropriate
target cells.
 The receptor protein, specified by the normal allele at
the X-linked androgen receptor locus, has the role of
forming a complex with testosterone and
dihydrotestosterone. If the complex fails to form, the
hormone fails to stimulate the transcription of target
genes required for differentiation in the male
direction.
 The molecular defect has been determined in
hundreds of cases and ranges from a complete
deletion of the androgen receptor gene to point
mutations in the androgen-binding or DNA-binding
domains of the androgen receptor protein.