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Department of Pediatrics
University of Chieti
Italy
Disorders of
Sex Development (DSD)
Disorders of Sex Development (DSD):
Definition and Prevalence
• The term “disorders of sex development (DSD)”
defines congenital conditions in which
development of chromosomal, gonadal or
anatomical sex is atypical
• DSD occur in 1:4500 births
Hughes IA et al., Arch Dis Child 2005
The Components of Sex Development
• Chromosomal sex: the presence or
absence of X or Y chromosomes
• Gonadal sex: development of the gonad
into either testis or ovary
• Phenotypic sex: the appearance of the
internal and external genitalia
• Brain sex: gender identity, sex role
behavior and sexual orientation
Rey RA et al., Clin Endocrinol Metab 2011
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.
I
L
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Phenotypic Sex
Gonadal Sex
Sex Development
Dumic M et al., JCEM 2008
Sex Development: Genes(1)
Dumic M et al., JCEM 2008
Gonadal Differentiation
BIPOTENTIAL GONAD
GONADS
MULLERIAN DUCTS
WOLFIANN DUCTS
MALE HORMONES:
- MIS
NON MALE
HORMONE
-TESTOSTERONE
- Inlsn3
MALE GONAD
FEMALE GONAD
EPIDIDYMIS
OVARIES
TESTES
OVIDUCT
SEMINAL
VESCICLE
VAS DEFERENCE
VAGINA
UTERUSUTER
US
CERVIXUTERU
S
Nature Reviews, Genetics
DSD: Classification
Hughes IA et al., Arch Dis Child 2005
47,XXY: Klinefelter Syndrome(1)
46,XY
47,XXY
47,XXY: Klinefelter Syndrome(2)
G karyotype
47,XXY
Inheritance
Sporadic
Phenotypic sex
Male
Gonads
Testicular located in the scrotum
testes dysgenesis, azoospermia
Habitus
Normal or low virilisation at puberty,
gynecomastia, unproportional long legs
Hormone profile
High FSH and LH, low testosterone
Wikström AM et al., Best Pract Res Clin Endocrinol Met 2011
47,XXY: Klinefelter Syndrome(3)
Medical treatments
• Testosterone
replacement
therapy (TRT)
• TRT often starts when a boy
reaches puberty
• Some XXY males can also
benefit from fertility
treatment to help them
father children.
Wikström AM et al., Best Pract Res Clin Endocrinol Met 2011
45,X: Turner Syndrome
45,XX
45,X
Phenotype of Turner Syndrome
Rudimentary ovaries
Gonadal streak
Primary gonadal failure
Infertility
Short stature
Low posterior airline
Carbohydrate intolerance
High blood pressure
Short metacarpals
High arched palate
Structural abnormalities in kidney
Hypothyroidism (Hashimoto thiroiditis)
NIH Electronic Citation, 2002
45,X/46,XY Mixed Gonadal Dysgenesis
• Prevalence is not known
• Gonad: testis or dysgenetic gonad
• Anaphase lag during mitosis in the zygote
Features
• Phenotype:
- ambiguous
- normal female
- normal penis
• Short stature
• Increase risk of gonadal tumors
Barbaro M et al., Sem Fetal Neonatal Medicine 2011
DSD - Classification
Hughes IA et al., Arch Dis Child 2005
46,XY - Disorder of Testicular Development: Genes
INHERITANCE
GONAD
MULLERIAN
STRUCTURES
WT1
AD
dysgenetic testis
+/-
female or ambiguous
SF1
AD/AR
dysgenetic testis
+/-
female or ambiguous
SRY
Y
dysgenetic testis
+/-
female or ambiguous
SOX 9
AD
dysgenetic testis or
ovotestis
+/-
female or ambiguous
DHH
AR
dysgenetic testis
+
Microscopic
deletion
dysgenetic testis
+/-
female or ambiguous
DAX1
dupXp21
dysgenetic testis or
ovary
+/-
female or ambiguous
WNT4
dup1p35
dysgenetic testis
+
GENE
DMRTI
EXTERNAL GENITAL
female
ambiguous
Barbaro M et al., Semin Fetal Neonatal Med 2011
46,XY: Disorders of Testicular Development(4)
TESTIS REGRESSION SYNDROME
Phenotype: • Severe micropenis
• Anorchia or streak gonads
• If fetal testicular regression occurs between 8-10 of fetal weeks,
patients may have:
- Female external genitalia with or without ambiguity
- Lack of gonads
- Rudimentary ducts
- Hypoplastic uterus
Genetic anomaly: etherozigous missense mutation in SF1 gene
Marcantonio SM et al., AJMG 2005
DSD - Classification
Hughes IA et al., Arch Dis Child 2005
46,XY - Disorders of Androgen Synthesis:
Acute steroidogenesis protein deficiency(1)
Most severe form of Congenital Adrenal Hyperplasia
(CAH)
STAR mutations resulting in deficient
steroidogenesis
Affected subjects of CAH
Phenotypic females irrespective of gonadal sex
Miller ML et al., Endo Rev 2011
46,XY - Disorders of Androgen Synthesis:
Acute steroidogenesis protein deficiency(2)
Characteristics of CAH:
• Virilized external genitalia
• Underdeveloped internal male organs
• Enlarged adrenal cortex engorged with cholesterol
Principal problems:
• Mineralcorticoid deficiency
• Glucocorticoi deficiency
• Sex steroid deficiency:
• Damage to gonads caused by
lipid accumulation
Dangers:
• Hyponatriemia
• Acidosis
• Death in infancy:
Miller ML et al., Endo Rev 2011
Disorders in Androgen Action:
Androgen Insensitivity Syndrome AIS(1)
 Genetic background:
mutation of the Androgen receptor gene located on long arm on x
chromosome xq11-12 due to single nucleotide change resulting in
substitution of amino acid in protein sequence
 Approximately 65% of cases linked to x pattern of inheritance
 Clinical phenotypes: complete (CAIS) and partial (PAIS) form of AIS
Investigations:
 Hydroxyprogesterone, Androstenedione, Dehydroepiandrosterone,
Testosterone
 Ultrasound scan
Mullerian structures
 HCG stimulation test
Diagnosis of PAIS
 Analysis of androgen receptor gene
Hughes IA et al., Best Pract Res Clin Endocrinol Metab 2006
Disorders in Androgen Action:
Androgen Insensitivity Syndrome AIS(2)
Complete Androgen Insensitivity Syndrome CAIS
XY
• Amenorrhea
Testes
Sertoli cells
MIS
Leydig cells
T
Mullerian ducts
regression
Wolffian ducts
No Uterus
Fallopian tube
Upper unthird vagina
Epididymis
Vas deferents
Vescicula
seminalis
• Feminine habitus with
rudimental vagina
• Intra-abdominal
gonads or in
inguinal canal
• Normal or high levels of
testosterone
• Male karyotype
Hughes IA et al., Best Pract Res Clin Endocrinol Metab 2006
DSD: Classification
Hughes IA et al., Arch Dis Child 2005
46,XX - Disorders Of Ovarian Development:
Gonadal dysgenesis
Phenotype
• Female phenotype but does not reach puberty and
fail to develop female secondary characteristics
• Elevated gonadotrophins and streak gonads
• Streak gonads similar to those found in patients with
Turner syndrome
Diagnosis
• Associated with major X chromosome abnormalities
• Mutations in the FSH receptor gene detected
• Premature ovarian failure and pubertal arrest
Meyers CM et al., Am J Med Genet 1996
DSD: Classification
Hughes IA et al., Arch Dis Child 2005
46,XX - Androgen excess - Fetal: CAH(1)
21-hydroxilase deficiency (CYP21A2)
90-95% of CAH causes
Classic form
• 1:5000 live birth
Heterozygous mutations
• 1:60 live births
• Reflects the degree of
cortisol and aldosterone
deficiency
• Varied degree of
virilisation and variable
genotype-phenotype
correlation
Kousta E et al., Hormone 2010
When to Suspect a DSD?(1)
• Overt genital ambiguity
• A family history of DSD
• A discordance between genital appearance and a
prenatal karyotype
• Apparent female genitalia with an enlarged clitoris
and posterior labial fusion
• Apparent female genitalia with an inguinal/labial mass
Ahmed SF et al., Pract Res Clin Endocrinol Metab 2010
When to Suspect a DSD?(2)
• Apparent male genitalia with bilateral undescended
testes
• Apparent male genitalia with a microphallus
• Apparent male genitalia with proximal hypospadias
• Apparent male genitalia with distal or mid-shaft
hypospadias with undescended testis
Ahmed SF et al., Pract Res Clin Endocrinol Metab 2010
DSD – Gender Assignment
INVOLVES FAMILY
Requires prompt decision
18 months
Determining Factors:
• The underlying disease • Surgical options
• Genital Appearance
• Potential for fertility
• Cultural aspects
Identification
46,XX CAH
FEMALE
90-100% of patients
46,XY CAIS
60 % of patients
5-OX-RD2
MALE
Available data suggest: female rearing
male rearing
cloacal extrophy
micropenis
Lee PA et al., Pediatrics 2006
DSD – Risk of Gonadal Tumor
RISK GROUP
DISORDER
MALIGNANCY RISK
(%)
HIGH
GD (+Y) intrabdominal
PAIS nonscrotal
Frasier
Denys-Drash (+Y)
15-35
50
60
40
INTERMEDIATE
Turner (+Y)
17β-HSD
GD(+Y) scrotal
PAIS scrotal gonad
LOW
NO(?)
RECOMMENDED
ACTION
Gonadectomy
Gonadectomy
Gonadectomy
Gonadectomy
12
28
Unknown
Unknown
Gonadectomy
Monitor
Biopsy and irradiation
Biopsy and irradiation
CAIS
Ovotestis DSD
Turner (-Y)
2
3
1
Biopsy and?
Testis tissue removal
None
5αRD2
Leydig cell hypoplasia
0
0
Unresolved
Unresolved
–
Lee PA et al., Pediatrics 2006
DSD – PSYCHO-SOCIAL MANAGEMENT
Areas of Concern:
• Gender assignment/re-assignment
• Timing of surgery
• Sex-hormone replacement
• Psychology screening tools available for families at risk
for maladaptive coping with child’s medical condition
• Health care staff encourage discussion groups regarding
generality of life, interpersonal relationships, sexual
function and activity
• Mental health professionals should the consulted if
necessary
Lee PA et al., Pediatrics 2006