deck_5491486 Flashcards

1
Q

What are differences (disorders) of sexual development?

A

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

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2
Q

How common are DSD?

A

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

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3
Q

What is sexual determination?

A

The determination of a gonad becoming a testis or an ovary

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4
Q

What is sexual differentiation?

A

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

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5
Q

When does sexual determination begin?

A

Between weeks 4 and 6 of gestation when premordial germ cells arising from yolk sac endodermmigrate 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 ifreactivated if XX embryo).Germ cells are later methylated in a sperm or oocyte specific manner

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6
Q

Describe how germ cells are menthylated

A

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

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7
Q

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

A

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

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8
Q

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

A

RSPO1, WNT4, and DAX1Not just the lack of SRY

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9
Q

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

A

WTI1, Gata4/Fog2SF1SOX9SRYPod1

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10
Q

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?

A

-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 genitaliaNOTE: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

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11
Q

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

A
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12
Q

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

A

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

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13
Q

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

A

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

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14
Q

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

A

•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)

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15
Q

What is Denys Drash Syndrome?

A

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

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16
Q

What isFrasier syndrome?

A

–normal female external genitalia with XY karyotype–streak gonads that frequently develop into gonadoblastoma–Nephrotic syndrome that can progress to ESRDCaused by WT1 mutation

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17
Q

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

A

Regression of the mullerian- AMHRetention of the wolffian ducts- testosterone

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18
Q

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

A

8-12 weeks in gestation

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19
Q

What is a main function of INSL3 in males?

A

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

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20
Q

The phenotype would be female because you cant make testosterone

A
21
Q

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

A

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

22
Q

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

A

Male pseudohermaphrotitism

23
Q

What is the most common form ofMale pseudohermaphrotitism?

A

androgen insensitivity syndrome (testicular feminization)

24
Q

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

A

Variant of seminiferous tubules dysgenesis

25
Q

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

A

Dysgenetic Male Pseudohermaphroditism

26
Q

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

A

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

27
Q

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

A

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 dueto CAH

28
Q

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

A

T.

29
Q

Cant make testosterone even if 46, XY

A
30
Q

Androgen receptors are coded where?

A

Short arm of the X

31
Q

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

A

Complete- phenotype would be female b/c test would convert to estrogen. These females would be phenotypically normalPartial- may present as undescended testes, failure of fusion of scortal/labial folds, hypospadias on the perineum, microphallisMild- may have fertility problems but may develop normally

32
Q

What is Klinefelter’s Syndrome?

A

The presence of a XXY karyotype in a MALE

33
Q

How does Klinefelter present in labs?

A

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

34
Q

How does Klinefelter present?

A

testicular atrophytall, long extremitiesgynecomastiafemale hair distribution and body shape (wide hips)

35
Q

What is a Barr body?

A

an inactivated X chromosome (as seen in Klinefelter)

36
Q

What is the syndrome associated with an XO karyotype?

A

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

37
Q

How does Turner syndrome present clinically?

A

Short stature (if left untreated, udner 5 ft.)ovarian dysgenesis (Streak ovary with infertility)neck webbing (cystic hygroma)primary amenorrhea due to possible dysgerminoma

38
Q

What are some other symptoms of Turner syndrome?

A

bicuspid aortic valvelymphatic defects (cause lymphedema in feet and hands)preductal coractation of the aortahorseshow kidneymenopause before menarche

39
Q

How would LH and FSH levels be in Turner?

A

elevated due to lack of estrogen

40
Q

How do Double Y males present?

A

They are phenotypically normal but are very tall, have extreme acne, and tend to be very antisocial (autism is common)Fertility is not affected

41
Q

Androgen insensitivity syndrome (46, XY)

A

Defect in androgen receptor (X chromosome)resulting in normal appearing female(presence ofbreast due to aromatase)female external genitalia with rudimentary lower vaginauterus and fallopian tubes are generally absentpresents 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

42
Q

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

A

elevated testosterone, estrogen, and LHAssociations: Gonadoblastoma (40-50%)NOTE:Prenatal diagnosis is possible

43
Q

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

A

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 diagnosisKaryotype would be 46, XY

44
Q

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

A

testosterone and estrogen levels normal/evelatedDHT lowLH normal or elevatedMOI: AR

45
Q

What is Kallman Syndrome?

A

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

46
Q

How wouldKallman Syndrome present in labs?

A

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

47
Q

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

A

17OH progesterone- will be elevated•CAH may be complete (no enzyme activity) or partial (females may have hirsuitism and infertility)

48
Q

CAH Tx

A