Disorders of Sexual Differentiation Flashcards
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
SF1
SOX9
SRY
Pod1
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