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Flashcards in Sex Development Deck (107):
1

Why Sex?

Allows for introduction of genetic variation to propagate new genetic traits

2

Sexual reproduction benefits organisms who live in what type of environment

Exist in a constantly changing environment

3

Sexual reproduction benefits organisms who encounter what? And need to what?

Encounter bacteria, viruses, and parasites, and need to fend off disease

4

Sexual reproduction benefits organisms who need to purge what?

Deleterious mutations

5

Sexual reproduction - 2 levels of variation

- each parent share's half genome via independent assortment
- recombination during meiosis

*note also that specific point mutations can occur that can confer advantage (or disadvantage) evolutionarily

6

What is sexual dimorphism?

The phenotypic difference between males and females -
includes reproductive organs as well as body habitus

7

Sex chromosomes anueploidy leads to

Disorders that don't have the normal number of X or Y chromosomes

8

Now matter how many X chromosomes you have, how many X chromosomes are active?

There is only one active X chromosome, no matter how many X chromosomes you have...
Thus,
46,XX
47,XXX
47,XXY
48,XXYY
all only have one active X chromosome

9

Turner Syndrome
Chromosome constitution

45, XO

10

Turner Syndrome
Signs at birth

Prenatal cystic hygroma - cyst-like cavity filled with lymph
Webbed neck
Puffy hands and feet
Head defects
Coarctation of the aorta

11

Turner Syndrome
Stature?

Short Stature

12

Turner Syndrome - intelligence?

Normal - sometime targeted learning disabilities

13

Turner Syndrome - fertility?

Infertile due to non-functioning ovaries

14

Turner Syndrome - hormones?

Hormone dysfunction - need hormone treatment for secondary puberty

15

Turner Syndrome - distinctive features?

Low set ears - broad chest

16

Turner Syndrome - incidence?

1/2,500 newborn girls

17

Kleinfelter Syndrome
Chromosome Constitution

47, XXY

18

Kleinfelter Syndrome - childhood and learning?

Can be seen -->
Learning disabilities
Delayed speech and language
Tendency toward being quiet

19

When does Kleinfelter become obvious?

Becomes more obvious as puberty - sometimes not even detected until infertility issues arise?

20

Kleinfelter statures?

Tall

21

Kleinfelter genital issues?

Small testes
Hypospadias - opening of urethra is on underside of penis

22

Kleinfelter - body habitus and hair?

Reduced facial and body hair
Gynecomastia
Feminized body habitus

23

Kleinfelter - incidence?

1/500 - 1/1000 newborn boys

24

What is 47, XYY?

Jacobs Syndrome

25

What is Klinefelters chromosome constitution?

47, XXY

26

Jacobs syndrome clinical features (6)

Learning disabilities
Speech delays
Developmental delays
Behavioral and emotional difficulties
Autism Spectrum disorders
Tall stature

27

Incidence of Jacobs Syndrome?

1/1000 newborn boys

28

So what is Jacobs vs. what is Klinefelters?

Jacobs = 47, XYY
Klinefelters = 47, XXY

29

What is 47,XXX called?

Triple X syndrome

30

What kind of stature do Triple X syndrome people have?

May have tall stature

31

Triple X syndrome increases risk of? (5)

Learning disabilities
Delayed speech
Delayed motor milestones
Seizures
Kidney abnormalities

32

Incidence of Triple X syndrome?

1/1000 newborn girls

33

So, if we know that only one X is expressed regardless of the number of Xs, what sense does it make that these variations in Xs manifest phenotypes?

Apparently there is a pseudoautosomal region on the X chromosome which is expressed in both Xs - this is why we see variation in phenotype from 45X, 46XX and 47XXX

34

Genetic regulation of sex development
Primary sex determination =

Determination of the gonads

35

Gonad determination is ______________

Chromosomal

36

What results in a male individual?

Generally the presence of a normal Y choromosom

37

What results in a female individual?

The presence of a normal X chromosome and the absence of a Y choromosome

38

Are there exceptions to the X Y rule and Sex differentiation?

Of course! But, these exceptions are due to genetic variants not on x or y

39

Do we still say that "female" is the default sex?

Not really.
Our current understanding is that both ovaries and testes result from a common bipotential gonad
Both are active, gene-directed processes

40

Secondary sex determination is determined by?

Gonadal development determines secondary sex characteristics

and recall that it was the chromosomes that determined gonads (primary sex determination)

41

What is included in secondary sex characteristics?

Includes sex-specific organs
- penis, seminal vesicles, prostate
- vagina, cervix, uterus, fallopian tubes, mammary gland

Includes other phenotypic features
- body habitus and musculature
- hair growth
- vocal cartilage

42

Embryology - what happens in the 4th week?

Primordial germ cells form in wall of yolk sac

43

At what week in development do primary germ cells form in the wall of yolk sac?

4th week

44

Embryology - what happens in the 5th week?

Coelomic epithelium becomes genital ridge

45

At what week in development does the coelomic epithelium become the genital ridge?

5TH

46

What happens at six week of conception with the primordial germ cells?
with the epithelial cells of the gonadal ridge?

They migrate to the dorsal mesentary of the hindgut and enter the undifferentiated gonad

The epithelial cells of the gonadal ridge proliferate and form primitive sex cords

47

At which week in development do the primordial germ cells migrate to the dorsal mesentary of the hindgut and enter the undifferentiated gonad? and the epithelial cells of the gonadal ridge proliferate to form primitive sex cords?

6th week

48

In males, what happen in the 7th week of conception?

Differentiation of genital ridge into sertoli cells and leydig cells

49

What do sertoli cells do?

They will eventually produce sperm

50

What do Leydig cells do?

The are intersitital cells that produce testosterone

51

In males, what happens in the 8th week of conception?

Leydig cells begin producing testosterone
Sertoli cells begin producing AMH
Primitive sex cords differentiate into testis and rete testis - eventually to become seminipherous tubules during puberty

52

What does Testosterone tell the male fetus to do?

start forming male structures

53

What week does male fetus start pumping out T?

Leydig cells begin producing T at 8th week

54

Which week do the cells of the genital ridge differentiate into Leydig and Sertoli?

7th

55

What do Sertoli cells produce?

AMH

56

What do Leydig cells produce?

T

57

At the 8th week of conception what do sex cords in male differentiate into?

Rete testis and testis cord - which will eventually become seminipherous tubules during puberty

58

What happens in the 7th - 8th week of female sex development?

With absence of SRY -->

Primitive cords dissociate into irregular clusters -->

Medullary (primitive) cords regress and cortical (secondary) cords are formed

secondary cords are destined to become follicular cells in the ovary

follicular cells will eventually surround and oogonium which together are the primary ovarian follicle

59

In female reproductive development, which week do the cortical cords form?

They form in the 7-8th week when the medullary (primitive) cords regress

60

In female repro, what are the cortical (secodary) cords destined to become?

follicular cells in the ovary

61

Genital Ducts - what is initially present (6 weeks)?

Initially, 2 pairs of genital ducts in both males and females
- Mesonephric (Wolffian)
- Paramesonephric (Mullerian)

62

Mesonephric Duct
Results in?

Male Structures
Under the influence of T --> elongate to form
- Epididymis
- Seminal Vesicles
- Vas deferens

63

SRY gene and SOX9
What are they
What do they do?

Both are transcription factors

Responsible for the production of AMH

Causes regression of the Mullerian duct

64

FGF9
What is it
What does it do?

Chemotactic factor that causes tubule from mesonephric (Wolffian) duct to penetrate the gonadal ridge

Essential for differentiation of testis

65

SNF1/NRFA1
What do they do?

Simulate differentiate of Sertoli and Leydig cells

66

Paramesonephric (Mullerian) Ducts - result in?

Female Structures
Under the influence of E (from maternal and placental sources) -->
Uterus
Cervix
Broad ligament
Fallopian Tubes
Upper 1/3 of the vagina

67

Female development
What is WNT4?

Extracellular signalling factor responsible for the differentiation of ovary
Inhibited by SOX9

68

Female development
What is DHH gene?

A nuclear hormone receptor
Up-regulates WNT4
Downregulates SOX9

69

Female development
What is RSPO1?

Coactivator in WNT pathway - which differentiates ovary :)

70

Development of external genitalia - what happens at 3 weeks?

Cells that originate from mesenchymal cells in the primitive streak migrate to form a genital tubercle and genital swellings

71

Male, what does genital tubercle become?

Glans of penis

72

Female, what does genital tubercle become?

Clitoris

73

Male, what do genital folds become?

Shaft of penis

74

Female, what do genital folds become?

Labia

75

External genitalia in both males and females originate from what?

Urogenital sinus

76

External genitalia - what signal in males to become what structures?

Androgen exposure (DHT) from the testis -->
penis
scrotum
urethral opening at tip

77

External genitalia - what signal in females to become what structures?

Estrogen from maternal and placenta -->
clitoris
labia majora and minora
lower 2/3 vagina

78

So to review
The first determinant is sex is

Chromosome and the genes on them

79

So to review... the chromosomes and genes on them determine what you gonads will be (primary sex determination)... what is secondary?

Once your gonads form, they will produce signals that tell your body what it is going to look like both internally (tracts) and externally (2sexChar)

80

What is the Prader scale?

Scale of virilization used to describe the external appearance of genitalia -
No virilization - female
100% virilization - male

81

If we are uncertain about sex... what are tests we can run to probe further?

FISH for sex chromosomes and a Karyotype (or microarray) ?SRY?

Hormone studies (important early) (LH/FSH/DHT/AMH)

Consider Ultrasound study (gonads?)

82

Teams to consult with disorders of sexual differentiation

Endocrinology
Genetics
Urology
Psychology

83

Issues to consider with sex differentiation disorders (7)

Underlying genetics
Family/cultural perspective
Medical/surgical outcomes
Risk for tumor
Fetal brain and hormone exp
Future sexuality
Future fertility

84

DIAGNOSTIC ALGORITHM

SLIDE 37 LOOK AT IT!

85

Androgen Insensivity Syndrome
Chromosome constitution?

46,XY

86

AIS mode of inheritance?

X-linked gene,
AR is apparently X-linked

87

Androgen insensitivity syndrome, what's the problem?

Mutation causes abnormality of the androgen receptor
- even though the body makes androgens (T), it does not recognize or respond

88

AIS - phenotype

Ranges from mild under-virilization (partial AIS) to full sex reversal (Complete AIS)

89

What was AIS called in the past?

Testicular feminization

90

Disorder - 5-Alpha Reductase Deficiency
Chromosome constitution

46, XY

Mutation causes decreased ability to convert T to DHT
Phenotype = undervirilized male with increased virilization at puberty

91

What specific disorder is characterized by undervirilization in youth but then starting to look more masculine at puberty?

5-alpha reductase deficiency

92

What is the chromosomal constitution of disorders associated with the SRY gene?

Can be
46, XY
46, XX

93

SRY is on which Chromosome

Y-linked

94

What happens if SRY is deleted?

Full sex reversal and phenotypically normal female (even though 46XY)

95

What happens if there is ectopic presence of SRY gene in 46XX

Phenotypically normal male

96

What happens if there is a mutation in the SRY of 46XY?

Decreased or absent production of AMH and undervirilization

97

Denys-Drash and Frasier Syndrome

Sex reversal with 46XY
Due to mutations in WT1 gene

98

Denys-Drash and Frasier Syndrome
What kind of disease do both cause

Chronic kidney disease
- diffuse mesangial sclerosis (nephrotic disease)
- focal segmental glomerulosclerosis

99

Denys-Drash and Frasier Syndrome
Increased risk for what?

Wilms tumor (malignant tumor of kidney)

100

What is WT1?

Transcription factor for SRY gene

101

Mutation in WT1 that causes sex reversal in XY ... syndrome name?

Denys Drash and Frasier Syndrome

102

Does Mutation in WT1 effect XX?

Not sexually, but causes other problems

103

Congenital adrenal hyperplasia

Ambiguous genitalia in 46XX
21 hydroxylase deficiency
Complicated by salt wasting in first weeks of life and when stressed
- decreased Na/Cl
- Increased K

104

FISH for XY --> 46XY DSD
T and DHT normal
Possiblitiles?

AIS
5-Alpha reductase deficiency

105

FISH fOR XY --> 46XY DSD
T and DHS low
Possiblities?

WT1 associated disease (Frasier and Denys Drash)
SRY Mutation/Deletion

106

FISH for XY --> 46XX DSD
Possiblities?

CAH
Ectopic SRY
Wnt4 Mutations

107

AIS and risk for gonadoblastoma?

Only if the testes are in the abdomen - not applicable if inguinal