2 - pediatric genital abnormalities Flashcards
source of problem if appropriate gonadotropins but low testosterone in neonatal period
gonadal
source of problem if low gonadotropinsat expected surge in neonatal period
central
most common cause of 46 xx DSD
CAH
non-CAH cause of 46xx DSD
maternal virilizing condiitons
2 examples of maternal virilizing conditions causing 46xx DSD
p450 aromatase deficiency with no T to E, or elevated maternal androgens
46 xx dsd - CAH effect on males and females
males already virilized, females virilize
46 xx dsd - CAH missing hormone
cortisol insufficiency +/- aldosterone- shunt of steroid toward sex steroi
enzyme deficiencies for 3 types of CAH involved in virilization
21-hydroxylase
11b- hydroxylase
3-b hydroxysteroid dehydrogenase
physical location of these enzyme deficiencies
adrenal cortex
most common enzyme CAH
21-oh - 90%
CAH inheritance
autosomal recessive
what precourser is elevated in 21-OH deficiency - 2
elev 17-oh progesterone and androstenedione
2 genes responsible for 21-OH deficiency
CYP21A and B
location of CYP21A/B genes for 21-OH deficiency
chr 6
symptoms of 21-OH deficiency
classic - simple virilization, salt wasting 75%
medication for 21-OH deficiency
fludrocortisone
2nd most comm CAH
11 b-hydroxylase
symptoms of 11b-OH deficincy - 2
virilization, HTN
what precourser is elevated in 11b-OH deficiency
deoxy corticosterone (DOC) and elevated 17-oh progesterone
steroids for 11-b OH deficiency?
no fludrocortisone
symptoms of 3b-hydroxysteroid dehydrogenase deficiency
salt wasting, male ambiguous gniralia
what is elevated in 3b-hydroxysteroid dehydrogenase deficiency
pregnenalone (DHEA)
workup for suspected CAH
karyotype, pelvic us, genitogram, hormone assays
who gets prenatal treatment for possible CAH
when family hx CAH
what is prenatal tx for CAH
dexamethasone given by 9th wk to prevent virilization
caveat with prenatal tx for CAH
7/8 tx’d unnecessarily because inheritance is AR
implication of nonclassic CAH
infertility may be only implication
treatment of nonclassic CAH
dexamethasone
what does STAR stand for (star mutation)
steroidogenic acute regulatory protein
what is STAR mutation
proximal steroid synthesis disorder
presentation of STAR mutation
severe glucocorticoid and mineralocorticoid production deficiency at 1 mo, severe secondary hyperpigmentation
what is implication of STAR mutation
female phenotype in XX/XY, no androgen production or potential
what does TART stand for
testicular adrenal rest tumors
who gets TART
poorly controlled 46 XY CAH w increased ACTH
puberty and nodules in TART
puberty contributes to increased size of lesions due to LH receptors on nodules
where are TART nodules found
nodular growth in rete testis
TART histology
similar to leydig cells but no reinke crystals
TART outcome
often result in primary gonadal failure
how does TART result in primary gonadal failure
obstructive azoospermia, peritubular fibrosis
how to treat TART
maximize compliance w steroid therapy. Remove only in pain
what is swyler syndrome
pure gonadal dysgenesis - 46XY with no testosterone or MIS
swyler syndrome phenotype
normal F internal and external genitalia (but 46 xy), normal height, primary amenorrhea, delayed puberty
swyler and SRY mutation
found in 20%
initial mgmt of swyler syndrome
gonadectomy due to risk of malignancy
partial gonadal dysgenesis definition
mix of mullerian and wolfian structures
partial gonadal dysgenesis phenotype
depends on amount of testosterone child exposed to
partial gonadal dysgenesis- gonads
gonads - poorly differentiated testicular tubules and ovarian like stroma
genotype for mixed gonadal dysgenesis
45 XO, 46 XY
significance of mixed gonadal dysgenisis found on amniocentesis
95% boys have nl phenotype –> expression of mosiacism varies
phenotype for mixed gonadal dysgenisis
wide range - turner stigmata - female external and internal genitalia to nl male w subfertility
turner syndrome genotype
45 XO
turner syndrome - phenotype
Female but no pubic hair, breast, or menses. and short stature
turner gonads
streak
turner mosaic genotype
45XO, 46 XX
turner mosiac presentation - 2
pubertal development uncommon, secondary amenorrhea (similar to regular turners)
turner stigmata - 7
short stature coarctation of aorta horseshoe kidney broad chest webbed neck, low hairline, low ears
what is 46 XY DSD
UNDERvirilization +/- DSD
potential causes of 46 xy DSD - 3
androgen synthesis, conversion, insensitivity
androgen syn defect outcome
micropenis +/- hypospadius, mullerian tissue absent b/c testicular tissue present
structure of penis in micropenis
urethra/prepuce small but formed
main cause of micropenis
failed stimulation after 14 wks due to primary hypogonadism, hypogonadotrophic hypogonadism
micropenis tx
early testosterone tx
inheritance of androgen conversion defect
AR
phenotype of androgen conversion defect
pseudovaginal perineoscrotal hypospadius -no tubularization of urethra or elongation of phallus. no mullerian structures present b/c nl sertoli function and nl T
what enzyme is involved in androgen conversion defect
5alphareductase-type 2 defic
enzyme missing in androgen conversion defect
low DHT
outcome of androgen converson defect
masculinize with puberty
androgen insensitivity - pathophys
wide number of mutations - some bind DHT but not T
androgen insensitivity inheritance
x-linked recessive
complete androgen insensitivity - phenotype
internal female genital tract abscent but distal vag and hymen present - from UG sinus.
rudimentary wolfian structures present because no response to T. often hernia
how does complete androgen insensitivity present
primary amenorrhea
mgmt of complete androgen insensitivity
do karyotype
what is ovotesticular DSD
both ovarian and teticular tissue on gonadal biopsy
ovotesticular DSD - karyotype
most 46 XX some 46 XY, some mosaic
ovotesticular DSD - gonad phenotype
unilat or bilat ovary, testis, or ovotstis.
ovotesticular DSD mgmt
removal of discordant genital organs with assigned sex. ex - if ovarian protion remains in male, may get breast development.
what is ovotesticular DSD
true hermaphrodite
what is MRKH
mullerian agenesis
MRKH - whats missing - 2
absence of uterus, upper vagina, renal agenesis/anomaly common
MRKH whats present
distal 1/3 vag- from ug sinus, ovaries present and have nl pubertal development
MRKH - how do they present
primary amenorrhea
tumors in DSD - 3
GCT, gonadoblastoma, itgcn
what tumor presents in turner syndroe and why
gonadoblastoma b/c have streak gonad
tumors in turner synd - gonad mgmt
Gonadectomy in childhood if 45 XO/46XY mosaic
mixed gonadal dysgenisis - gonadal mgmt - streak vs descended gonad
in streak gonad, early gonadectomy due to presence of Y
if descended nl testis, do bx @ 10 yo to r/o itgcn and consider XRT
relative risk of testicular tumor - H/I/L
hi - XY gonadal dysgenesis int - XO/XY low - CAIS - 5-10% postpubertal ovotesticular DSD - cryptorchid risk other XY DSD - no inc risk other than cryptorchid
descent of urorectal septum - destination and function
destination of septum is mature colacal membrane and splits cloaca into ug sinus membrane and anal menbrane
when is urorectal septum descended
complete by 7 wks
urorectal septum descent is temporally related to what?
mullerian fusion
classic vs cloacal exstrophy and relation to urorectal septum
classic - after complete descent
cloacal - before complete descent
exstrophy epispadius complex - 5
exstrophic bladder (halves) abd wal efect pubic diastasis penile/clitoral malformations vaginal duplication
persistent cloaca
extreme anorectal malformation in females
highly variable anatomy
rectal atresia
single vs duplicate vag /atresia
classic bladder exstrophy assd w/?
nothing
cloacal exstrophy assd w/?
midline defects (omphalocele, cardiac, spinal dysraphism (905) GI - duplications renal abn cryptorchidism lower ext malformations
persistent exstrophy assd w/?
obstructive uropathy (w/ hydrocolpos)
cardiac
renal abn
sacral abd/ tethered cord
what % teticles are not descended by 1 yr
1%
when do most testicles descend by
6 mo
what initiates masculinization in fetus
SRY gene
primary amenorrhea DDX
MRKH, complete androgen insensitivity
at how many wks are genital organs first seen
5 wks
what genital organs are seen at 5 wks - 3
indifferent gonad, mesonephric duct, and mullerian ducts
gene determining sexual differentiation
sex determining region y (SRY)
what is the gene product of SRY
high mobility group box sequence
function of high mobility group box
DNA binding motief that kinks DNA altering gene expression and leading to formatin of testis and male phenotype.
what if SRY is absent in XY
phenotypic females
how does rete testis develop
once induced to form testis, gonad develops clustered cords of germ cells that converge to form rete testis
source of germ cells for spermatogenisist?
cells converging to form rete testis serve as renewing source of germ cells for spermatogenisis
testosterone produciton in first 12 wks
testosterone made by differentiating leydig cells at 8 wks, then declines by 12 wks
testosterone and mesonephric duct
testosterone stimulates mesonephric duct to form ureter in both sexes
mesonephric duct develops into what 4 structures
vas deferens, epididumis, ejaculatory duct, and SV
WT1 and early secual development
helps genital ridge become bipotential gonad
2 genes involved in differentiation of indifferent gonad from urogenital ridge
WT1 (may explain association with genital abn in denys drach and WAGR), SF1 (steroidogenic factor 1)
2 genes involved in formation of testis
SRY and SOX 9
2 genes involved in formation of ovary
Wnt4, and DAX1 (doseage sensitive sex reversal region of x chromosome)
3 structures that come from mullerian duct
fallopian tubes, uterus, and upper vagina
2 vestigial structures of mullerian duct in male
appendix testis and prostatic utricle
persistent mullerian duct syndrome inheritance
x linked or autosomal dominant
persistent mullerian duct syndrome -what is it?
male with nl phenotype but also fully developed uterus and fallopian tube due to incomplete involution of mullerian derivatives
what is persistent mullerian duct syndrome
mullerian inhibitory substance not secreted
what is hernia uteri unguinalis
hernia containing uterus and fallopian tubes in persistent MDS
what secretes insulin-like 3
leydig cells
what does insulin like 3 do?
promotes transabdominal testis migration that begins testis descent into scrotum
how does testis descent begin
result of differential growth of gubernaculum tesis
how long after birth can it take for descent to occur
upto 1 yr
role of DHT
masculinizes genital ridge to form external genitalia, including penis, scrotum, and prostate
MIS deficiency - what is it
problem with production of MIS by sertoli cells or its action on target receptors
MIS deficiency AKA
heria uteri inguinale
MIS defciency presentation
encountering fallopian tubes and uterus during hernia surgery or exploration for undescended testis
MIS deficiency undescended testicle problem
both testicles can be on one side with vas running within the wall of the uterus
mis deficiency found at orchiopexy mgmt
proceed with orchiopexy, split uterus sagitally if the vas is tethered
hypospadius - when doesandrogen stimulation play its role
9-12 wks of delopment
androgen effect on urethral development
genital tubercle to elongate and UG folds to migrate toward midline and fuse, enclosing urethral groove
root cause of hypospadius
arrested penile development
associated gu abnormalities with hypospadius
none
when to do hypospadius surgery
> 3 mo and < 18 mo (genital awareness)
when does normal testicular descent happen
28th wk
timing of correction for cryptorchidism
wait until atleast 4 months - most undescended will come down by then with neonatal T surge. best to do by 1 yr old to maximize fertility
why do orchidopexy by 1 yr ideally
fertility - germ cell counts decrease after 1 yo. initially normal
treatment for testicle found in groin on us
surg not indicated for us findings for undescended testis.
tests to order if bilateral nonpalpable testis
FSH, LH, and testosterone
what lab result indicates anorchia
FSH > 3x nl
if FSH/LH < 3x nl and bilateral udt - what next
give HCG stim to detect any rise in testosterone
bilateral nonpalpable testis and any phallic development - significance
considered female with CAH regardless of phallic development
hematologic problem mimmicing torsion
henoch-schonlein purpura
small or large communicating hydrocele in infants
usually resolve within 1-2 yrs of life
varicocele management in adolescents - 3 mgmt steps
- initial observation, catchup growth happens often, 2. varicocele ligation if ipsilateral volume loss > 20%, 3. abnormal semen analysis in tanner 5 teenager
bilateral testicles found at hernia repair in female - meediate mgmt?
finish hernia repair. che has complete androgen insensitivity
mgmt of testicles in complete androgen insensitiviy
will eventually need to be removed, can remain during childhood
