Abnormalities of the sex chromosomes and sex differentiation

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Transcript Abnormalities of the sex chromosomes and sex differentiation

BESHG Postgraduate course in human genetics
2013 - 2014
Disorders of gonadal and
sexual development
1.Normal Sexual differentiation
A. History
B. General picture
C. Genes implicated
2. Anomalies of sexual differentiation
A. Abnormal number of sex Chromosomes:
B. Abnormal sex differentiation with normal Karyotype
C. True Hermaphrodism
D. Induced pseudohermaphrodism
1.Normal Sexual differentiation
A. History
-1940 role of the gonads
-1960 discovery of the role of Y chromosome.
(Welshons and Russel)
-1989 discovery of SRY
B. General picture
-Karyotypic ( genetic) sex:
presence of a Y chromosome results in testicular development.
-Gonadal sex:
Presence of ovarian or testicular tissue
-Ductal Sex:
Presence of Mullerian (female) or Wolffian (male) ducts
-Phenotypic ( genital ) sex:
external appearance of the genitalia.
Until 7 week of gestation , gonads are bipotential
In male fetus the Y chromosome acts as a dominant
male determinant
this result of the action
of a single gene, SRY.
SRY initiate testis
rather than ovary development
C. Genes implicated
Active in Male and Female fetuses
- WT1 (11p13): formation of the primitive gonads
- SF1 (9q33): regulation of steroidogenesis
Active in Male fetuses
- SRY (Yp11.3):
Induce testis differentiation
- SOX9 (17q24):
Activate expression of AMH
- AMH (19p13.3):
Induce regression of Müllerian ducts
Active in Female fetuses
- DAX1 (X p21.3):
Inhibit SRY and SOX9
- WNT4 (1p35):
regulation of female development,
antagonism of testosterone
- RSPO1(1p34):
Inhibit SOX9
C. Genes implicated
WNT 4a 1p35
2.Abnormal Sexual differentiation
Between 0.1% and 0.2% of live births are ambiguous enough
to become the subject of specialist medical attention.
But for a lot of the following syndromes, problems may only
appear at puberty or later (infertility).
The specialists use the term « DSD »:
Disorders of Sex Development.
A. Abnormal number of sex Chromosomes:
46 YY and 45 Y are fatal.
We need at least one X chromosome to survive
Trisomy X (47 XXX)
Female, generally asymptomatic
extra Xs are inactivated
mild mental retardation
(more severe in 48 XXXX and 49 XXXXX patients)
1/2000 birth
Turner Syndrome (45 X, monosomy X)
•Cystic hygroma and Hydrops fetalis.
•Congenital Heart disease, including coarction of the aorta
•Short stature
•Common cause of female hypogonadism
•Failure to develop secondary sex characteristics
•Atrophic streaked ovaries
•Primary amenorrhea
> Infertility
•No Barr body present
Turner Syndrome
1/5000 birth
Turner Syndrome
short stature;
short webbed neck;
cubitus valgus;
Turner Syndrome
- Klinefelter syndrome (47,XXY)
& Klinefelter variants
(48,XXXY 49,XXXXY,etc)
•Caused by meiotic nondisjunction
•Common cause of male hypogonadism
•Testicular atrophy
•Infertility due to azoospermia
•Female distribution of hair
•Long limbs, narrow shoulders
1/2000 birth
- 47, XYY syndrome
not associated to a particular phenotype
normal intelligence, not dysmorphic
normally fertile
> hyperactivity and impulsivity is frequent,
True psychopathology (« crime chromosome ») is
not common.
1/2000 birth
B. Abnormal sex differentiation with normal Karyotype
Alteration (duplication, deletion or mutation)
of any of the implicated genes could result
in sex reversal and/or gonadal dysgenesis
46XY female
- SRY deletion / mutation (Swyer Syndrome)
- WNT4 duplication
- DAX1duplication
- SOX9 deletion (campomelic dysplasia)
- WT1 mutation (Frasier & Denys-Drash Syndrome)
46 XX male
- SRY translocation
- SOX9 duplication
- RSPO1 mutation
Campomelic dysplasia
mutation of SOX9
- Dysmorphic
- bowing of long bones
- abnormal extremities
- Sex Reversal
- Gonadal Dysgenesis
Congenital Adrenal Hyperplasia (CAH)
Deficiency of 21-Hydroxylase
(90 % of the cases)
mineralocorticoid deficiency
> Female pseudohermaphrodism
60 % of the intersex cases at birth
1/15000 live birth
Congenital Adrenal Hyperplasia (CAH)
Ambiguous genitalia in CAH
Virtually all enzymes of the chain may be deficient and
cause more or less severe disorder including DSD
5 alpha-reductase deficiency
Testosterone is not converted in DHT
Male pseudohermaphrodism
Mostly female phenotype
or ambiguous genitalia
Virilisation at puberty
The gene is located in 2p23
Autosomal recessive
5 alpha-reductase deficiency
5 alpha-reductase deficiency
Androgen Insensitivity Syndrome (AIS)
mutations in AR,
gene for the human Androgen Receptor,
located at Xq11-12
three subtypes : complete * (female phenotype)
partial (male, female or ambiguous)
mild (male genitalia)
* =(Testicular feminization Syndrome)
1/20.000 birth
Androgen Insensitivity Syndrome (AIS)
Mild form
Persistent Müllerian Duct Syndrome (PMDS)
Mutation of AMH gene
Autosomal recessive
normally virilised XY patients
Develop both wolffian and müllerian structures
Often a late discovery during surgery
or during investigation for undescended testis
Sporadic and/or environmental syndromes (1)
* Mayer Rokitansky Kuster Hauser Syndrome (MRKH)
Vaginal agenesis or incomplete vagina
Between 1940 and 1980, cases were associated to maternal
intake of Diethylstilbestrol (DES)
* MURCS association
Mullerian ducts hypoplasia (aplasia)
Renal agenesis
Cervical Somite dysplasia
Sporadic and/or environmental syndromes (2)
* Caudal regression syndrome
Variable defects of lumbar spine and inferior limbs
Uro-genital anomaly
extreme form > Sirenomelia
Associated to gestational diabetes
Caudal regression
Caudal regression (2)
Caudal regression (3) /
C. True Hermaphrodism
Presence of both ovarian and testicular tissue
Genetic Sex: 46XX/46XY, 45X/ 46XY mosaics
Gonadal Sex:
Ovotestes: A gonad with both testicular and ovarian tissue.
or more rarely ovary on one side and testes on the other.
Ductal Sex: Often mixed
Phenotypic sex : Ambigous genitalia
Exceptionally rare.
C. True Hermaphrodism
C. True Hermaphrodism ovotestes
D. Induced pseudohermaphrodism
- iatrogenic: female pseudohermaphrodism due to an intake of
progestational agents or androgens during the first trimester.
- maternal endocrine disorders:
most endocrine maternal abnormalities usually prevent pregnancy
if initially present.
Some ovarian tumours have been reported as a cause of virilisation
of female fetus.
Questions ?
• This part of the course covers the chapters “The sex
chromosomes and their abnormalities” and “disorder of
gonadal and sexual development” of the Thompson &
Thompson genetics in medicine” p98 to 113.
• A summary of the course is available on our website:
• Info or questions: [email protected]