Disorders of Sexual Development: A. Diaz Thomas, M.D. Flashcards
Describe the formation of the urogenital ridge and what genes are involved.
4-6 wks of gestation, UG ridge begins to form under the influence of the following genes:
WT1 (Lim1, Emx2, Lhx9)
WT1kts (Gata4/Fog2)
SF1 (Fgf9/Fgfr2)
Primordial germ cells arise from yolk sac endoderm and migrate to the gut and then through dorsal mesentery to reach the gonadal/genital ridge.
You now have a bipotential gonad.
Gonadal ridge- a thickening of intermediate mesoderm and overlaying coelomic mesothelium.
Describe the genes involved in sexual determination.
Testes: SRY, SOX9, SF1
Ovaries: RSPO1, WNT4, DAX1
What is responsible for sexual differentiation?
Male:
Once sertoli/leydig cells are formed after sexual determination, these cells with release factors (sertoli-AMH; Leydig- testosterone) that will affect sexual differentiation in weeks 6-8.
Females:
Granulosa and theca cells begin functioning later than male sertoli/leydig cells. They will eventually begin secreting Androgens (theca) and estrogens (granulosa) that mediate sexual differentiation in weeks 12-13.
What is the difference in sexual determination and differentiation as far as signalling mediators?
Determination is a genetic signalling process.
Differentiation is a hormonal signalling process.
Mutations in WT1 classically are associated with a triad of:
- Nephrotic syndrome
- Wilms tumor (malignant renal tumor occurring in kids)
- Ambiguous genitalia
Describe Denys Drash Syndrome.
MCC is WT1 mutation (96%)
Characterized by nephropathy, Wilms tumor, and gonadal dysgenesis.
Phenotypically: males are undervirilized, undescended testes. Females have normal phenotype.
Describe Frasier Syndrome.
Associated with WT1 mutation (AD).
Presents with female external genitalia phenotype (whether XX or XY), streak gonads, and progressive glomerulonephropathy.
Inc. risk for gonadoblastoma (not wilms tumor).
The streak gonads are extremely hypoplastic (underdeveloped) and mainly composed of fibrous tissue, hence the name streak gonads - i.e., a form of aplasia in which the gonad is replaced by functionless tissue.
The nephrotic syndrome can progress to ESRD.
Describe the result of mutations in SF1.
Adrenal and gonadal dysgenesis.
Congenital adrenal insufficiency.
Ambiguous genitalia (external female, undervirilized male)
Discuss the normal progression of internal genitalia during gestation and the hormones that mediate this.
Female is default. In order to have a male, sertoli cells secrete anti-mullerian hormone that causes regression of mullerian ducts (paramesonephric ducts). Leydig cells produce testosterone that maintains Wolffian ducts (mesonephric ducts).
What controls the longitudinal closure and lengthening of the genital tubercle and urethra (becomes penis)?
Testosterone and DHT
The mullerian duct forms into what mature structures?
fallopian tube, uterus, upper 1/3 of vagina (lower 2/3 develops in absence of testosterone action)
What is Smith Lemli Opitz Syndrome?
A block in cholesterol modification that would normally result in conversion of 7-dehydrocholesterol to cholesterol. Due to mutation in 7-dehydrocholesterol reductase enzyme.
Expected phenotype: undervirilized male due to inability to make androgens.
What hormonal disaster will lead to an overvirilized female?
CAH- too many androgens produced due to shunting b/c no 21-hydroxylase to produce mineral/glucocorticoids.
You’ve got a baby with ambiguous genitalia. Where should you palpate to search for gonads?
Inguinal area and labial scrotal folds
Describe the physical findings in a baby girl that would suggest overvirilization.
Genital tubercle (clitoris) longer than 1cm and wider than 0.6cm. Also, elongated distance from anus to base of vagina (long gooch).
