B8-059 Disorders of Sex Development Flashcards
most common cause of male hypogonadism
klinefelter syndrome
gyencomastia
tall
less body hair
small, firm testes
klinefelter syndrome
in klinefelters, the […] do not enlarge and undergo fibrosis, resulting in small firm testes and azoospermia
seminiferous tubules
why do patients with klinefelter’s exhibit declining T levels and elevating LH secretion?
leydig cells become progressively deficient
streaked ovaries
Turners
(normal tissue replaced by fibrous tissue –> gonadal dysgenesis)
why should cryptorchidism be corrected? [3]
increased risk of germ cell tumors
increased risk of torsion
impaired fertility
mutations in AMH or it’s receptor (AMHR-2), result in
46 XY, PMDS
(persistent mullerian duct syndrome)
absence of sertoli cells or AMH would result in
both male and female internal genitalia with streak gonads
male external genitalia
absence of 5-a reductase would result in
male internal genitalia
female/atypical external genitalia until puberty
(cannot convert T to DHT)
[…] duct gives rise to internal male genitalia
mesonepheric
[…] duct gives rise to internal female genitalia
paramesonepheric
presence of SRY gene activates […] and […] cells and ultimately leads to the formation of male external genitalia
leydig (mesonepheric ducts persist)
sertoli (paramesonepheric ducts degenerate)
absence of SRY gene activates […] and […] cells and ultimately leads to the formation of female external genitalia
thecal (mesonepheric duct degenerates)
follical (paramesonepheric persists)
when SRY is present, leydig cells produce […] which allows for mesonepheric duct to persist
testosterone
when SRY is present, sertoli cells produce […] which allows for paramesonepheric duct to degenerate
AMH
testicular descent into the scrotum is dependent on […]
INSL3 and T
SRD5A1 is the gene for […]
5-a reductase
what hormones drive development of the labioscrotal folds and clitorophallus?
T and DHT
[…] cause the urethral plate to give rise to the penile urethra
androgens
testes present
but external genitalia feminized or atypical
most commonly caused by androgen insensitivity syndrome
46 XY DSD
ovaries present
external genitalia are virilized/atypical
most commonly due to congenital adrenal hyperplasia
46 XX DSD
(due to excessive exposure to androgens in early development)
markedly elevated 17-hydroxyprogesterone is diagnostic for
CAH
in CAH, if a deficient enzyme starts with 1, it causes
hypertension
in CAH, if a deficient enzyme ends with 1 it causes
virilization in females
ovotesticular DSDs are most commonly observed in individuals with […]
mosaicisms
(46, XX/ 46XY karyotype)
ovotesticular DSD is more common in 46 […]
46,XX
both ovarian and testicular tissue present
atypical genitalia
ovotesticular DSD
most patients with 46 XX DSDs have normal testicular function but are infertile due to […] defect
spermatogenic
translocations of […] can block the female pathway and drive testicular development
SRY
(results in 46XX SRY+)
mutations in RSPO1 or WNT4 can allow for partial or complete […] development in 46 XX SRY- DSD patients
testis
typically, RSPO1 and WNT4 inhibit SOX9, inducing female pathway
46, XX SRY- DSD is typically a result of translocation of […] gene
SOX9
typically, RSPO1 and WNT4 inhibit SOX9, inducing female pathway
defect in androgen receptor resulting in female appearing genetic male
androgen insensitivity syndrome
(46, XY DSD)
testes present and functional
blind vaginal pouch
no T or DHT activity (no hair)
complete androgen insensitivity syndrome
(46, XY DSD)
46, XY DSDs are […] virilized
under
46, XX DSDs are […] virilized
over
one of the most common causes of atypical genitalia in newbowns
21-hydroxylase deficiency
classic CAH is characterized by [hormone] deficiency
cortisol
(75% are salt-losers due to aldosterone)
SRY activates [gene]
SOX9
SOX9 and FGF9 destabilize […] to inhibit ovarian development
b-catenin
[…] induces and maintains sertoli cell differentiation
SOX9
sertoli cells induce leydig cell development. leydig cells induce […]
NR5A1
stabilize b-catenin and induce the ovarian pathway [2]
RSPO1 and WNT4
[…] induces granulosa cell differentiation
FOXL2
treatment for 21-hydroxylase deficiency
dexamethasone
low T and poor response to hCG
normal AMH
high LH/FSH
absent paramesonephric derivatives
leydig cell hypoplasia
reduced T and INSL3 would be consistent with
undescended testes
enhanced SOX9 levels in XX individuals drive […] development
testis
(but no Y chromosome, so testes don’t make sperm=infertility)
a mutation that modestly impacts the WNT pathway would result in
ovotestes
(only partially divert ovarian pathway)
what is the most likely presentation for an individual with 46, XY DSD with inactivated SRY?
streaked gonads
female external genitalia
uterus
SRY inactivation= gonad dysgenesis
also no production of AMH/MIS = female genitalia
NR5A1 mutations cause […] dysgenesis
testes
(no sertoli/leydig cells –> no AMH –> female)
RSPO1 mutations divert the ovarian pathway to the testicular pathway by destabilizing […]
b-catenin
complete loss of RSPO1 function would result in
testis development
infertility
partial loss of RSPO1 function would result in
ovotestes
