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Flashcards in Disorders of Sexual Differentiation Deck (56):

What are differences (disorders) of sexual development?

congenital conditions in which development of chromosomal, gonadal, or anatomical sex is atypical


How common are DSD?

About 1 in 5000 (Klinefelter's is about 1:500- 1:1000 live births)


What is sexual determination?

The determination of a gonad becoming a testis or an ovary


What is sexual differentiation?

changes in the interal and external sexual structures that are not gonads- i.e. do you have a uterus, vagina, vas deferens etc. 






When does sexual determination begin?

Between weeks 4 and 6 of gestation when premordial germ cells arising from yolk sac endoderm migrate from the hindgut to the gonadal ridge, a thickening of intermediate mesoderm and overlaying coelomic mesothelium, in response to a series of signaling changes to organize. At the gonadal ridge, a genome wide demethylation occurs where parental imprints are erased (and the silenced X chromosome if reactivated if XX embryo).

Germ cells are later methylated in a sperm or oocyte specific manner


Describe how germ cells are menthylated

If XY, methylation occurs at birth. If XX, methylation starts at birth, is arrested in prophase, and continues later


What genes have been found to be involved in recruiting premordial germ cells to the gonadal ridge early in life to establish a gonad?

WT1 (important in males), Lim1, Emx2, Lhx9



Once premordial germ cells are recruited to the gonadal ridge, a bipotential gonad develops. What genes promote formation of an ovary?

RSPO1, WNT4, and DAX1

Not just the lack of SRY


Once premordial germ cells are recruited to the gonadal ridge, a bipotential gonad develops. What genes promote formation of an testis?

WTI1, Gata4/Fog2






With the presence of ovary stimulating genes such as WNT-4, the premordial germ cells turn into a ovary and begin producing theca and granuosa cells. What is the result of this?


-Estradiol begins to be produced

-The lack of AMH allows the Mullerian structures to be retained and for the formation of a uterus and fallopian tubes

-The lack of testosterone causes wolffian structures to regress, stimulating the formation of a vagina and external female genitalia

NOTE: Proliferation, meiotic entry and oocyte formation depend on the interaction with primarily granulosa cells, for which FOXL2 is essential. The primordial follicle consists of an individual oocyte, arrested in meiosis I, and surrounded by a layer of pre-granulosa cells 


If male, Germ cells proliferate until weeks 17-18 GA at which time they mature into presermatogonia and migrate to the basement membrane 


What is the time frame for the development of male testes and sex cells?

The gonad is still bipotential by week 5-6 of gestation when it differentiates into a testis and sertoli cells begin to be produced and production of AMH by week 6-7, while Leydig cells develop around week 8 and begin to produce testosterone


What is the time frame for the development of female ovaries and sex cells?

Again, the gonad differentiates at week 5-6 to produce an ovary, BUT granulosa and theca cell production do not become noticable until around weeks 12-13.

NOTE: The ovary will not develop in the absence of germ cells


Mutations in WT1 (Wilm's Tumor 1) gene have been implicated in what pathologies?

•Nephrotic syndrome

•Wilms tumor

•Ambiguous genitalia/ DSD (so since this gene is involved in the production of a functioning male testis, the infant will be a phenotypic female or have ambiguous genitalia)


What is Denys Drash Syndrome?

a mutation in WT1 that causes:

–Nephropathy (mesangial sclerosis)

–Wilms tumor

–genital abnormalities with XY gonadal dysgenesis or XX chromosome- infants will have ambiguous genitalia


What is Frasier syndrome?

–normal female external genitalia with XY karyotype

–streak gonads that frequently develop into gonadoblastoma

–Nephrotic syndrome that can progress to ESRD

Caused by WT1 mutation


What causes regression of the mullerian ducts? Retaining of the wolffian ducts? In males

Regression of the mullerian- AMH

Retention of the wolffian ducts- testosterone


The formation of both interal (Mullerian/Wolffian ducts) and external genital structures occurs when?

8-12 weeks in gestation


What is a main function of INSL3 in males?

It promotes descent of the testes down to the inguinal canal (and testosterone brings them down into the scrotum)



The phenotype would be female because you cant make testosterone


Whats the first thing you'd do if an infant came out with ambiguous genitalia?

palpate for goands, regardless if they are present or not, the next step will be an MRI or ultrasound for mullerian structures.

Then get a measurement of 17-hydroxy progesterone and karyotype 


What is the diagnosis if gonads are palpable, mullerian structures are absent, 17OHP is normal and kayotype is XY?

Male pseudohermaphrotitism


What is the most common form of Male pseudohermaphrotitism?

androgen insensitivity syndrome (testicular feminization)


What is the diagnosis if gonads are palpable, mullerian structures are absent, 17OHP is normal and kayotype is XXY?

Variant of seminiferous tubules dysgenesis


What is the diagnosis if gonads are palpable, mullerian structures are present, 17OHP is normal and kayotype is XY or XO/XY?

Dysgenetic Male Pseudohermaphroditism


What is the diagnosis if gonads are palpable, mullerian structures are present, 17OHP is normal and kayotype is 46XX or 47XXY?

True hermaphroditism- in this disorder, both ovary and testicular tissue are present (ovotestis) and genitalia are ambiguous (very rare)


What is the diagnosis if gonads are not palpable, mullerian structures are present, 17OHP is normal and kayotype is XX?

Non-adrenal female pseudohermaphroditism in which the ovaries are present but external genitalia are virilized or ambiguous.

If 17OHP is elevated, it is most likely due to CAH


T or F. CAH has an increased frequency in Ashkenazi Jews and Yupik Native Americans ( 1:400) and decreased frequency in African Americans



Cant make testosterone even if 46, XY


Androgen receptors are coded where?

Short arm of the X


How would complete absence of androgen receptors present phenotypically? Partial? Mild?

Complete- phenotype would be female b/c test would convert to estrogen. These females would be phenotypically normal

Partial- may present as undescended testes, failure of fusion of scortal/labial folds, hypospadias on the perineum, microphallis

Mild- may have fertility problems but may develop normally


What is Klinefelter's Syndrome?

The presence of a XXY karyotype in a MALE 


How does Klinefelter present in labs?

Dysgenesis of seminiferous tubules causes decreased inhibin production leading to increased FSH AND
Abnormal Leydig cell function decreases testosterone production leading to increased LH and estrogen levels


How does Klinefelter present?

testicular atrophy

tall, long extremities


female hair distribution and body shape (wide hips)



What is a Barr body?

an inactivated X chromosome (as seen in Klinefelter)


What is the syndrome associated with an XO karyotype?

Turner syndrome in FEMALES (hugs and kisses XOs from Tina Turner)


How does Turner syndrome present clinically?

Short stature (if left untreated, udner 5 ft.)

ovarian dysgenesis (Streak ovary with infertility)

neck webbing (cystic hygroma)

primary amenorrhea due to possible dysgerminoma


What are some other symptoms of Turner syndrome?

bicuspid aortic valve

lymphatic defects (cause lymphedema in feet and hands)

preductal coractation of the aorta

horseshow kidney

menopause before menarche 


How would LH and FSH levels be in Turner?

elevated due to lack of estrogen


How do Double Y males present?

They are phenotypically normal but are very tall, have extreme acne, and tend to be very antisocial (autism is common)

Fertility is not affected


Androgen insensitivity syndrome (46, XY)

Defect in androgen receptor (X chromosome) resulting in normal appearing female (presence ofbreast due to aromatase)

female external genitalia with rudimentary lower vagina

uterus and fallopian tubes are generally absent

presents with no sexual hair and the development of internal testes because SRY is present (usually in the labia majora) which are typically surgically removed to present malignancy


How would Androgen insensitivity syndrome (46, XY) present in labs? Associations?

elevated testosterone, estrogen, and LH

Associations: Gonadoblastoma (40-50%)

NOTE: Prenatal diagnosis is possible


How would a 5a-reductase deficiency present? Karyotype?

Ambiguous or female external genitalia until puberty when increased testosterone causes masculinization and increased growth of external genitalia (aka penis at 12). Internal genitalia are normal and MALE (usually a wolffain duct terminating into a vagina) but the pt. may have lived their whole life as a woman until diagnosis

Karyotype would be 46, XY


How would 5a-reductase deficiency present in labs? MOI?

testosterone and estrogen levels normal/evelated

DHT low

LH normal or elevated



What is Kallman Syndrome?

Defective development of GnRH cells and olfactory placode leading to decreased synthesis of GnRH in the hypothalamus, anosmia, and lack of secondary sexual characterisitcs. 



How would Kallman Syndrome present in labs?

decreased GnRH, FSH, LH, testosterone, and sperm count





If CAH is in your differential, next step is a ______

17OH progesterone- will be elevated

•CAH may be complete (no enzyme activity) or partial (females may have hirsuitism and infertility)