B8.059 Disorders of Sex Development Flashcards
what are DSDs
congenital conditions associated with atypical development of internal and external genital structures
atypical chromosomal, gonadal, or anatomical sex
chromosomal sex
presence of absence of a Y chromosome
determines gonadal sex
gonadal sex
determines the hormonal environment which directs development of internal and external genitalia (embryo) and secondary sex characteristics (puberty)
primordia of the reproductive system
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
gonadal ridge outcomes
female: ovaries
male: testes
mullerian duct outcomes
female: uterus, fallopian tubes, upper vagina
male: regression
wolffian duct outcomes
female: regression
male: epididymis, vas deferens, seminal vesicles
genital tubercle outcomes
female: clitoris
male: penis
urethral fold outcomes
female: labia minora
male: penile urethra
labioscrotal fold outcomes
female: labia majora
male: scrotum
what is SRY and what is its function
sex determining region on the Y chromosome
-initiates testis and male development
male gonad development genes
SRY
SOX9
female gonad development genes
WNT4
RSPO1
FOXL2
shared gonad development genes
NR5A1
function of SOX9 + FGF9
promote SOX9
antagonize WNT4
inhibit b-catenin ( this turns off ovarian pathway)
function of RSPO1, WNT4
repress SOX9
stabilize B-catenin
at what time point does the bipotential gonad start to differentiate?
week 6ish
arrest of germ cells
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
what hormones are made by the developing testes that influence male development
Leydig cells: T and INSL3 -these control testicular descent -T stimulates wolffian duct differentiation sertoli cells: MIS -this inhibits mullerian duct formation
do fetal ovaries make hormones for female sexual development?
nOooOOO
how does developmental timing differ between sexes
females develop much later than males
males start around 20 days, females around 80 days
when can DSDs occur?
can occur with variations at any of the 3 stages of sex development
- atypical chromosome
- atypical gonadal development
- atypical hormone production and response
prenatal DSDs
karyoptype-phenotype disorders
neonatal DSDs
atypical genitalia
salt losing crisis (CAH)
childhood DSDs
hernia (CAIS)
androgenization (CAH)
poor growth (turners, 45X/46XY)
puberty DSDs
androgenization (17B-HSD, 5areductase, SF1) absent puberty (gonadal dysgenesis, CAH, turners)
postpuberty DSDs
amenorrhea (CAIS)
adult DSDs
infertility (klinefelters, 45X/46XY, SF1)
46, XY DSD
phenotypic XY female with or without testes
includes undervirilized and under masculinized XY male
46, XX DSD
phenotypic XX male with or without testes
includes masculinized and over-virilized 46 XX female
sex chromosome DSDs
47, XXY (klinefelters)
45, X (turners)
45X/46XY mosaicism (mixed gonadal dysgenesis)
46XX/46XY (chimerism, mosaicism)
gonadal dysgenesis
gonads completely or partially fail to develop, resulting in atypical sexual development
ovotesticular/testicular DSDs (46 XX)
both ovarian follicles and seminiferous tubules are present in the same patient, or only testicular tissue present
gonadal regression
complete absence of one or both testicles
causes of 46 XY complete gonadal dysgenesis
- sertoli cells defective: no MIS production, Mullerian ducts develop
- Leydig cells defective: no T or INSL3 production, wolffian duct regresses, gonads undescended
lab findings in 46 XY complete gonadal dysgenesis
- undetectable T and unresponsive to hCG challenge
- undetectable MIS
- high LH and FSH
- normal adrenal steroids
46 XY complete gonadal dysgenesis appearance
external genitalia is female
uterus and fallopian tubes present
gonadoblastoma common
diagnosis of 46 XY complete gonadal dysgenesis
usually not suspected until puberty, when girls present with absence of thelarche and menarche
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
scales for analyzing 46 XY partial gonadal dysgenesis external genital phenotype
Quigley scales
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
SRY defect
complete/partial GD
does not result in ovarian differentiation
accounts for 15% of 46XY complete GD
SOX9 defect
complete/partial GD campomelic dysplasia (autosomal dominant disorder of the skeleton - causes bowing of long bones)
function of SRY
induces SOX9
both critical for sertoli cell differentiation
function of NR5A1 and WT1
induce SRY
can have both adrenal and gonadal defects
NR5A1 defect
testicular dysgenesis
+/- adrenal insufficiency
WT1 defect
Denys-Drash syndrome (gonadal dysgenesis, nephropathy, Wilms tumor) Frasier syndrome (gonadal dysgenesis, progressive nephropathy, gonadoblastoma)
ATRX function
expressed in and maintains Sertoli cells differentiation
DHH function
produced by sertoli cells to induce differentiation of Leydig cells
activates NR5A1
ATRX defects
ATRX syndrome (a thalassemia, mental retardation with facial dysmorphism, ambiguous genitalia)
DHH defects
testicular dysgenesis with minifascicular neuropathy
difficult to detect in newborns
MAP3K1 defects
certain mutations interfere with destabilization of B-catenin
shifts balance in favor of ovarian development, diminishing SOX9 and disrupting testis development
dysgenetic DSDs (sex chromosome DSDs)
ovotesticular DSD asymmetrical gonadal dysgenesis Turner Klinefelter Triple X
characterize Klinefelters
most common cause of male hypogonadism
47, XXY
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%)
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
treatment of Klinefelters
T replacement often useful at puberty and through adulthood
clinical presentation of Turner
gonadal dysgenesis short stature short, thick, webbed neck epicanthus and ptosis of eyelids low posterior hairline broad chest
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
presentations of ovotesticular DSDs
- bilateral ovotestes
2. one testis and one ovary or one ovotestis and one testis or ovary
who gets ovotesticular DSDs
most individuals with 46XX/46XY karyotype (mosaicism)
3-10% of DSDs
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
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
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
46 XX SRY + etiology
translocation of SRY blocks the female pathway and drives testis development
46 XX SRY + etiology presentation
testes with only mild dysgenetic features
present as 46XX males
90% of XX males are SRY+
46 XX SRY - etiology
translocation of SOX9, SOX3, SOX10
reduce/prevent inhibition of SOX9 and allow testis development
outcome of androgen related 46XY DSDs
individuals with androgen deficiency (synthesis or action) leads to undervirilization
effects of androgens on development
- synthesized in Leydig cells
- onset of T synthesis at 9 weeks gestation
- T is major steroid produced by testis
- DHT produced in periphery
- DHT responsible for differentiation, growth promoting, and functional aspects of male sexual development and virilization
- DHT is 2x as potent as T
- estrogens can act in conert w androgens or oppose them
T to DHT conversion
irreversible
occurs in periphery by 5a reductase
type 2, encoded by SRD5A2 is critical for sexual development
how do androgens act
via AR (NR3C4), a zinc finger transcription factor located on the X chromosome
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
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
important androgen synthesis defects
HSD17B3 > 17B hydroxysteroid dehydrogenase 3
SRD5A2 > 5a reductase
features of HSD17B3 deficiency in 46XY individuals
female genitalia wolffian ducts present mullerian ducts absent undescended testes virilization at puberty
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
function of HSD17B3
makes T from androstenedione
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
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
androgen insensitivity syndrome
result from mutations in androgen receptor
more than 400 mutations recorded
activity of receptor depends on location and amino acid change
CAIS
complete androgen insensitivity syndrome
complete loss of function
NO androgen activity
PAIS
partial androgen insensitivity syndrome
partial loss of function, range of androgen activity
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
hormone profile of CAIS
increased LH and T levels
increased E
FSH levels normal or increased
resistance to androgenic and metabolic effects of T
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)
46 XX DSD due to elevated andorgens
fetus becomes masculinized
**21-hydroxylase deficiency
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
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
boys with CAH
appear unaffected at birth
without proper diagnosis, will develop associated health problems within 2-3 weeks after birth
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
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
