Normal sexual development is the result of
numerous genes. Mutation or chromosomal
rearrangements of any of these genes cause partial
or total failure of sex differentiation. The
classification of genetically determined disorders
of sexual development takes the different
developmental processes into account. Pinpointing
the basic defect is a prerequisite for diagnosis
and treatment.
Sunday, April 12, 2009
Male-determining region SRY on the Y chromosome
Normally, the male-determining Y-specific DNA
sequences (SRY) remain on the Y chromosome
during the homologous pairing and crossingover
during meiosis. However, since the maledetermining
region SRY is located very close to
the pseudoautosomal region (PAR), crossingover
in the PAR border region may result in a
transfer of the SRY region to the X chromosome.
This results in a male individual with an XX
karyotype (XX male). Conversely, if the SRY region
is missing from a Y chromosome, a female
phenotype with XY chromosomes (XY female)
results.
sequences (SRY) remain on the Y chromosome
during the homologous pairing and crossingover
during meiosis. However, since the maledetermining
region SRY is located very close to
the pseudoautosomal region (PAR), crossingover
in the PAR border region may result in a
transfer of the SRY region to the X chromosome.
This results in a male individual with an XX
karyotype (XX male). Conversely, if the SRY region
is missing from a Y chromosome, a female
phenotype with XY chromosomes (XY female)
results.
Point mutations in the SRY gene
The human SRY gene has a single exon and encodes
a 204-amino-acid protein from a 1.1 kb
transcript. The middle section of the SRY protein
consists of 79 highly conserved amino acids
with DNA-bending and DNA-binding capability,
the HMG box (high mobility group protein).
Complete or partial gonadal dysgenesis results
from point mutations and deletions in the SRY
gene, in particular the HMG box. (Figure
adapted fromWolf et al., 1992; for an update of
mutations see McElreavey and Fellous, 1999).
Sex reversal also results from mutations in the
SOX9 gene on chromosome 17 at q24 in campomelic
dysplasia.
a 204-amino-acid protein from a 1.1 kb
transcript. The middle section of the SRY protein
consists of 79 highly conserved amino acids
with DNA-bending and DNA-binding capability,
the HMG box (high mobility group protein).
Complete or partial gonadal dysgenesis results
from point mutations and deletions in the SRY
gene, in particular the HMG box. (Figure
adapted fromWolf et al., 1992; for an update of
mutations see McElreavey and Fellous, 1999).
Sex reversal also results from mutations in the
SOX9 gene on chromosome 17 at q24 in campomelic
dysplasia.
Androgen receptor
The fetal testis produces testosterone, the hormone
that induces male sexual differentiation.
Testosterone is taken up by cells of the target
tissues (wolffian ducts and urogenital sinus)
(1). In the urogenital sinus, testosterone is converted
into dihydrotestosterone (DHT) by the
enzyme 5!-reductase. Both testosterone and
dihydrotestosterone bind to an intracellular receptor
(androgen receptor). The activated hormone–
receptor complex (TR* or DR*) acts as a
transcription factor for genes that regulate the
differentiation of thewolffian ducts and the urogenital
sinus. Thus, normal male fetal development
is dependent on normal biosynthesis of
testosterone and normal receptors. Androgen
receptor mutations lead to disorders of sexual
development (2) with X-chromosomal inherited
complete or incomplete androgen resistance
(testicular feminization, TFM).
that induces male sexual differentiation.
Testosterone is taken up by cells of the target
tissues (wolffian ducts and urogenital sinus)
(1). In the urogenital sinus, testosterone is converted
into dihydrotestosterone (DHT) by the
enzyme 5!-reductase. Both testosterone and
dihydrotestosterone bind to an intracellular receptor
(androgen receptor). The activated hormone–
receptor complex (TR* or DR*) acts as a
transcription factor for genes that regulate the
differentiation of thewolffian ducts and the urogenital
sinus. Thus, normal male fetal development
is dependent on normal biosynthesis of
testosterone and normal receptors. Androgen
receptor mutations lead to disorders of sexual
development (2) with X-chromosomal inherited
complete or incomplete androgen resistance
(testicular feminization, TFM).
Classification of genetically determined disorders of sexual development
1. Defects of sex determination due to mutation
or structural aberration of the SRY region
on the Y chromosome (e.g., XY gonadal
dysgenesis, XX males, and others)
2. Defects of androgen biosynthesis (e.g.,
adrenogenital syndrome due to 21-hydroxylase
deficiency, see p. 392)
3. Defects of androgen receptors (testicular
feminization)
4. Defects of the müllerian inhibition substance
(so-called hernia uteri syndrome)
5. XO/XY gonadal dysgenesis
or structural aberration of the SRY region
on the Y chromosome (e.g., XY gonadal
dysgenesis, XX males, and others)
2. Defects of androgen biosynthesis (e.g.,
adrenogenital syndrome due to 21-hydroxylase
deficiency, see p. 392)
3. Defects of androgen receptors (testicular
feminization)
4. Defects of the müllerian inhibition substance
(so-called hernia uteri syndrome)
5. XO/XY gonadal dysgenesis
Congenital Adrenal Hyperplasia
This disorder, also called adrenogenital syndrome
(AGS, McKusick 201910), is caused by a
genetically determined deficiency of cortisol, a
steroid hormone produced in the fetal adrenal
cortex. A compensatory increase in adrenocortical
hormone (ACTH) excretion leads to secondary
enlargement (hyperplasia) of the
adrenal cortex (congenital adrenal hyperplasia),
increased production of prenatal
steroids and their metabolites with androgenic
effects, and incomplete female sex differentiation.
(AGS, McKusick 201910), is caused by a
genetically determined deficiency of cortisol, a
steroid hormone produced in the fetal adrenal
cortex. A compensatory increase in adrenocortical
hormone (ACTH) excretion leads to secondary
enlargement (hyperplasia) of the
adrenal cortex (congenital adrenal hyperplasia),
increased production of prenatal
steroids and their metabolites with androgenic
effects, and incomplete female sex differentiation.
Clinical phenotype and genetics
Girls are born with ambiguous or virilized genitalia
(1). The adrenal cortex is enlarged (2). Increased
production of androgenic metabolites
causes masculinization. The cortisol deficiency
(3) leads to life-threatening crises due to loss of
sodium chloride (salt-wasting) that require
prompt treatment. AGS is an autosomal recessive
heritable disorder (4). Untreated girls
develop amale physical appearance (5). In boys,
the early signs are limited to salt-wasting. Initially,
skeletalmaturation is accelerated and the
children are tall for their age; however, they
stop growing prematurely and eventually are
too short. Besides the classic form of the disorder
with a frequency of 1:5000, there are
other forms with less pronounced masculinization
due to different mutations.
(1). The adrenal cortex is enlarged (2). Increased
production of androgenic metabolites
causes masculinization. The cortisol deficiency
(3) leads to life-threatening crises due to loss of
sodium chloride (salt-wasting) that require
prompt treatment. AGS is an autosomal recessive
heritable disorder (4). Untreated girls
develop amale physical appearance (5). In boys,
the early signs are limited to salt-wasting. Initially,
skeletalmaturation is accelerated and the
children are tall for their age; however, they
stop growing prematurely and eventually are
too short. Besides the classic form of the disorder
with a frequency of 1:5000, there are
other forms with less pronounced masculinization
due to different mutations.
Subscribe to:
Comments (Atom)
