B8.059 Disorders of Sex Development Flashcards
(91 cards)
1
Q
what are DSDs
A
congenital conditions associated with atypical development of internal and external genital structures
atypical chromosomal, gonadal, or anatomical sex
2
Q
chromosomal sex
A
presence of absence of a Y chromosome
determines gonadal sex
3
Q
gonadal sex
A
determines the hormonal environment which directs development of internal and external genitalia (embryo) and secondary sex characteristics (puberty)
4
Q
primordia of the reproductive system
A
BIPOTENTIAL (have potential to be male or female regardless of XX or XY designation)
- gonads
- gonadal ridges - internal genitalia
- mullerian ducts
- wolffian ducts - external genitalia
- genital tubercle
- urethral folds
- labioscrotal folds
5
Q
gonadal ridge outcomes
A
female: ovaries
male: testes
6
Q
mullerian duct outcomes
A
female: uterus, fallopian tubes, upper vagina
male: regression
7
Q
wolffian duct outcomes
A
female: regression
male: epididymis, vas deferens, seminal vesicles
8
Q
genital tubercle outcomes
A
female: clitoris
male: penis
9
Q
urethral fold outcomes
A
female: labia minora
male: penile urethra
10
Q
labioscrotal fold outcomes
A
female: labia majora
male: scrotum
11
Q
what is SRY and what is its function
A
sex determining region on the Y chromosome
-initiates testis and male development
12
Q
male gonad development genes
A
SRY
SOX9
13
Q
female gonad development genes
A
WNT4
RSPO1
FOXL2
14
Q
shared gonad development genes
A
NR5A1
15
Q
function of SOX9 + FGF9
A
promote SOX9
antagonize WNT4
inhibit b-catenin ( this turns off ovarian pathway)
16
Q
function of RSPO1, WNT4
A
repress SOX9
stabilize B-catenin
17
Q
at what time point does the bipotential gonad start to differentiate?
A
week 6ish
18
Q
arrest of germ cells
A
male: mitosis
female: meiosis
germ cells stabilize the ovary, w/o germ cells, follicles degenerate and the ovary does not synthesize hormones
*not true for testis
19
Q
what hormones are made by the developing testes that influence male development
A
Leydig cells: T and INSL3 -these control testicular descent -T stimulates wolffian duct differentiation sertoli cells: MIS -this inhibits mullerian duct formation
20
Q
do fetal ovaries make hormones for female sexual development?
A
nOooOOO
21
Q
how does developmental timing differ between sexes
A
females develop much later than males
males start around 20 days, females around 80 days
22
Q
when can DSDs occur?
A
can occur with variations at any of the 3 stages of sex development
- atypical chromosome
- atypical gonadal development
- atypical hormone production and response
23
Q
prenatal DSDs
A
karyoptype-phenotype disorders
24
Q
neonatal DSDs
A
atypical genitalia
salt losing crisis (CAH)
25
childhood DSDs
hernia (CAIS)
androgenization (CAH)
poor growth (turners, 45X/46XY)
26
puberty DSDs
```
androgenization (17B-HSD, 5areductase, SF1)
absent puberty (gonadal dysgenesis, CAH, turners)
```
27
postpuberty DSDs
amenorrhea (CAIS)
28
adult DSDs
infertility (klinefelters, 45X/46XY, SF1)
29
46, XY DSD
phenotypic XY female with or without testes
| includes undervirilized and under masculinized XY male
30
46, XX DSD
phenotypic XX male with or without testes
| includes masculinized and over-virilized 46 XX female
31
sex chromosome DSDs
47, XXY (klinefelters)
45, X (turners)
45X/46XY mosaicism (mixed gonadal dysgenesis)
46XX/46XY (chimerism, mosaicism)
32
gonadal dysgenesis
gonads completely or partially fail to develop, resulting in atypical sexual development
33
ovotesticular/testicular DSDs (46 XX)
both ovarian follicles and seminiferous tubules are present in the same patient, or only testicular tissue present
34
gonadal regression
complete absence of one or both testicles
35
causes of 46 XY complete gonadal dysgenesis
1. sertoli cells defective: no MIS production, Mullerian ducts develop
2. Leydig cells defective: no T or INSL3 production, wolffian duct regresses, gonads undescended
36
lab findings in 46 XY complete gonadal dysgenesis
1. undetectable T and unresponsive to hCG challenge
2. undetectable MIS
3. high LH and FSH
4. normal adrenal steroids
37
46 XY complete gonadal dysgenesis appearance
external genitalia is female
uterus and fallopian tubes present
gonadoblastoma common
38
diagnosis of 46 XY complete gonadal dysgenesis
usually not suspected until puberty, when girls present with absence of thelarche and menarche
39
46 XY partial gonadal dysgenesis
degree of mullerian duct regression, wolffian duct development, and external genitalia virilization depends on the amount of functional testicular tissue secreting androgens
40
scales for analyzing 46 XY partial gonadal dysgenesis external genital phenotype
Quigley scales
41
etiologies of 46 XY complete gonadal dysgenesis
```
genetic changes/environmental agents that interfere with the process and/or timing of testis development
SRY
SOX9
NR5A1
WT1
ATRX
DHH
MAP3K1
```
42
SRY defect
complete/partial GD
does not result in ovarian differentiation
accounts for 15% of 46XY complete GD
43
SOX9 defect
```
complete/partial GD
campomelic dysplasia (autosomal dominant disorder of the skeleton - causes bowing of long bones)
```
44
function of SRY
induces SOX9
| both critical for sertoli cell differentiation
45
function of NR5A1 and WT1
induce SRY
| can have both adrenal and gonadal defects
46
NR5A1 defect
testicular dysgenesis
| +/- adrenal insufficiency
47
WT1 defect
```
Denys-Drash syndrome (gonadal dysgenesis, nephropathy, Wilms tumor)
Frasier syndrome (gonadal dysgenesis, progressive nephropathy, gonadoblastoma)
```
48
ATRX function
expressed in and maintains Sertoli cells differentiation
49
DHH function
produced by sertoli cells to induce differentiation of Leydig cells
activates NR5A1
50
ATRX defects
ATRX syndrome (a thalassemia, mental retardation with facial dysmorphism, ambiguous genitalia)
51
DHH defects
testicular dysgenesis with minifascicular neuropathy
| difficult to detect in newborns
52
MAP3K1 defects
certain mutations interfere with destabilization of B-catenin
shifts balance in favor of ovarian development, diminishing SOX9 and disrupting testis development
53
dysgenetic DSDs (sex chromosome DSDs)
```
ovotesticular DSD
asymmetrical gonadal dysgenesis
Turner
Klinefelter
Triple X
```
54
characterize Klinefelters
most common cause of male hypogonadism
| 47, XXY
55
presentation of Klinefelters in puberty
most common time of presentation
features: taller stature, less muscle mass, less facial and body hair, small testicles, small to normal penis, gynecomastia (33%)
56
Klinefelter gonad defects
sertoli, leydig, and meiotic defects
seminiferous tubules do not enlarge and undergo fibrosis and hyalinization resulting in small, firm testes and azoospermia
leydig cell function progressively deficiency, declining T and elevated LH
57
treatment of Klinefelters
T replacement often useful at puberty and through adulthood
58
clinical presentation of Turner
```
gonadal dysgenesis
short stature
short, thick, webbed neck
epicanthus and ptosis of eyelids
low posterior hairline
broad chest
```
59
gonadal defects in Turners
ovarian follicles undergo premature apoptosis resulting in streaked ovaries (normal tissue replaced by functionless fibrous tissue)
fallopian tubes, uterus, and vagina are present
no wolffian duct derivatives
undetectable AMH
60
presentations of ovotesticular DSDs
1. bilateral ovotestes
| 2. one testis and one ovary or one ovotestis and one testis or ovary
61
who gets ovotesticular DSDs
most individuals with 46XX/46XY karyotype (mosaicism)
| 3-10% of DSDs
62
features of ovotesticular DSDs when testicular tissue predominates
patients may be almost completely virilized, with mild signs of androgen insufficiency (hypospadias or undescended testes)
serum androgen and AMH levels within male range
gonadotropins not elevated
at puberty:
-exaggerated follicular development may cause abdominal pain
-E may increase and result in breast development
-cyclic urethral bleeding may indicate existence of mullerian remnants
63
features of ovotesticular DSDs when ovarian tissue predominates
newborn is feminized, with cliteromegaly and labial fusion
androgens and AMH elevated for a girl, but low for a boy
gonadotropins normal
mullerian derivatives usually present in less virilized patients
64
what is a 46XX ovotesticular/testicular DSD
testicular tissue develops entirely from the gonad primordium, or together with ovarian tissue
most patients are normal until mid-puberty, but are infertile
65
46 XX SRY + etiology
translocation of SRY blocks the female pathway and drives testis development
66
46 XX SRY + etiology presentation
testes with only mild dysgenetic features
present as 46XX males
90% of XX males are SRY+
67
46 XX SRY - etiology
translocation of SOX9, SOX3, SOX10
| reduce/prevent inhibition of SOX9 and allow testis development
68
outcome of androgen related 46XY DSDs
individuals with androgen deficiency (synthesis or action) leads to undervirilization
69
effects of androgens on development
1. synthesized in Leydig cells
2. onset of T synthesis at 9 weeks gestation
3. T is major steroid produced by testis
4. DHT produced in periphery
5. DHT responsible for differentiation, growth promoting, and functional aspects of male sexual development and virilization
6. DHT is 2x as potent as T
7. estrogens can act in conert w androgens or oppose them
70
T to DHT conversion
irreversible
occurs in periphery by 5a reductase
type 2, encoded by SRD5A2 is critical for sexual development
71
how do androgens act
via AR (NR3C4), a zinc finger transcription factor located on the X chromosome
72
Leydig Cell Aplasia/ Hypoplasia
| 46 XY DSD
due to inactivating mutations on the LH/CG receptor
| phenotypic spectrum from female external genitalia to mild undervirilization
73
androgen synthesis defects
glucocorticoid and androgen synthesis pathways share many of the same genes/enzymes
defects in enzymes involved in androgen synthesis result in underandrogenization of the 46,XY fetus
74
important androgen synthesis defects
HSD17B3 > 17B hydroxysteroid dehydrogenase 3
| SRD5A2 > 5a reductase
75
features of HSD17B3 deficiency in 46XY individuals
```
female genitalia
wolffian ducts present
mullerian ducts absent
undescended testes
virilization at puberty
```
76
hormone profile of HSD17B3 deficiency in 46XY individuals
increased plasma estrone and androstenedione
decreased ratio of plasma T/androstenedione after hcg stimulation test
increased FSH and LH
77
function of HSD17B3
makes T from androstenedione
78
features of 5a reductase type 2 deficiency in 46XY individuals
```
ambiguous genitalia
normal wolffian ducts
absent mulelrian ducts
normal testes
decreased facial and body hair, no temporal hair recession, prostate not palpable
```
79
hormone profile in 5a reductase type 2 deficiency in 46XY individuals
decreased ratio of 5a/5b C21 and C19 steroids in urine
increased T/DHT ratio before and after hcg stimulation
modest increase in plasma LH
decreased conversion of T to DHT in vitro
80
androgen insensitivity syndrome
result from mutations in androgen receptor
more than 400 mutations recorded
activity of receptor depends on location and amino acid change
81
CAIS
complete androgen insensitivity syndrome
complete loss of function
NO androgen activity
82
PAIS
partial androgen insensitivity syndrome
| partial loss of function, range of androgen activity
83
clinical features of CAIS
female with blind vaginal pouch
wolffian duct derivative present
mulelrian duct derivatives absent or vestigial
testes
scant or absent pubic and axillary hair, breast development at puberty, primary amenorrhea
84
hormone profile of CAIS
increased LH and T levels
increased E
FSH levels normal or increased
resistance to androgenic and metabolic effects of T
85
characterize features of CAIS
testes present and functional (leydig cells make T/sertoli cells make MIS)
no uterus, fallopian tubes, or upper vagina (MD development blocked by MIS)
inactive AR = inactive T (external genitalia is female)
86
46 XX DSD due to elevated andorgens
fetus becomes masculinized
| **21-hydroxylase deficiency
87
congenital adrenal hyperplasia (CAH)
group of genetic conditions that affect the adrenal glands
| affected individuals are deficient in one or more adrenal hormones and often overproduce androgens
88
girl with severe CAH
may be born with ambiguous genitalia
allows condition to be diagnosed before other associated health problems (poor feeding, vomiting, dehydration, abnormal heart beat) develop
89
boys with CAH
appear unaffected at birth
| without proper diagnosis, will develop associated health problems within 2-3 weeks after birth
90
etiology of androgen excess in CAH
defects in CYP21A2 and CYP11B1 shunt steroid precursors into the androgen pathway and cause androgenization of the 46 XX fetus
HSD3B2 defects cause mild androgenization due to elevated DHEA levels
91
disorders of MIS synthesis and action
mutations in MIS or its receptor (AMHR2) result in persistent mulelrian duct syndrome
uterus and fallopian tubes in a normally virilized male
