Sex Development Flashcards
Why Sex?
Allows for introduction of genetic variation to propagate new genetic traits
Sexual reproduction benefits organisms who live in what type of environment
Exist in a constantly changing environment
Sexual reproduction benefits organisms who encounter what? And need to what?
Encounter bacteria, viruses, and parasites, and need to fend off disease
Sexual reproduction benefits organisms who need to purge what?
Deleterious mutations
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
What is sexual dimorphism?
The phenotypic difference between males and females -
includes reproductive organs as well as body habitus
Sex chromosomes anueploidy leads to
Disorders that don’t have the normal number of X or Y chromosomes
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
Turner Syndrome
Chromosome constitution
45, XO
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
Turner Syndrome
Stature?
Short Stature
Turner Syndrome - intelligence?
Normal - sometime targeted learning disabilities
Turner Syndrome - fertility?
Infertile due to non-functioning ovaries
Turner Syndrome - hormones?
Hormone dysfunction - need hormone treatment for secondary puberty
Turner Syndrome - distinctive features?
Low set ears - broad chest
Turner Syndrome - incidence?
1/2,500 newborn girls
Kleinfelter Syndrome
Chromosome Constitution
47, XXY
Kleinfelter Syndrome - childhood and learning?
Can be seen –>
Learning disabilities
Delayed speech and language
Tendency toward being quiet
When does Kleinfelter become obvious?
Becomes more obvious as puberty - sometimes not even detected until infertility issues arise?
Kleinfelter statures?
Tall
Kleinfelter genital issues?
Small testes
Hypospadias - opening of urethra is on underside of penis
Kleinfelter - body habitus and hair?
Reduced facial and body hair
Gynecomastia
Feminized body habitus
Kleinfelter - incidence?
1/500 - 1/1000 newborn boys
What is 47, XYY?
Jacobs Syndrome
What is Klinefelters chromosome constitution?
47, XXY
Jacobs syndrome clinical features (6)
Learning disabilities Speech delays Developmental delays Behavioral and emotional difficulties Autism Spectrum disorders Tall stature
Incidence of Jacobs Syndrome?
1/1000 newborn boys
So what is Jacobs vs. what is Klinefelters?
Jacobs = 47, XYY Klinefelters = 47, XXY
What is 47,XXX called?
Triple X syndrome
What kind of stature do Triple X syndrome people have?
May have tall stature
Triple X syndrome increases risk of? (5)
Learning disabilities Delayed speech Delayed motor milestones Seizures Kidney abnormalities
Incidence of Triple X syndrome?
1/1000 newborn girls
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
Genetic regulation of sex development
Primary sex determination =
Determination of the gonads
Gonad determination is ______________
Chromosomal
What results in a male individual?
Generally the presence of a normal Y choromosom
What results in a female individual?
The presence of a normal X chromosome and the absence of a Y choromosome
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
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
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)
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
Embryology - what happens in the 4th week?
Primordial germ cells form in wall of yolk sac
At what week in development do primary germ cells form in the wall of yolk sac?
4th week
Embryology - what happens in the 5th week?
Coelomic epithelium becomes genital ridge
At what week in development does the coelomic epithelium become the genital ridge?
5TH
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
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
In males, what happen in the 7th week of conception?
Differentiation of genital ridge into sertoli cells and leydig cells
What do sertoli cells do?
They will eventually produce sperm
What do Leydig cells do?
The are intersitital cells that produce testosterone
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
What does Testosterone tell the male fetus to do?
start forming male structures
What week does male fetus start pumping out T?
Leydig cells begin producing T at 8th week
Which week do the cells of the genital ridge differentiate into Leydig and Sertoli?
7th
What do Sertoli cells produce?
AMH
What do Leydig cells produce?
T
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
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
In female reproductive development, which week do the cortical cords form?
They form in the 7-8th week when the medullary (primitive) cords regress
In female repro, what are the cortical (secodary) cords destined to become?
follicular cells in the ovary
Genital Ducts - what is initially present (6 weeks)?
Initially, 2 pairs of genital ducts in both males and females
- Mesonephric (Wolffian)
- Paramesonephric (Mullerian)
Mesonephric Duct
Results in?
Male Structures Under the influence of T --> elongate to form - Epididymis - Seminal Vesicles - Vas deferens
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
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
SNF1/NRFA1
What do they do?
Simulate differentiate of Sertoli and Leydig cells
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
Female development
What is WNT4?
Extracellular signalling factor responsible for the differentiation of ovary
Inhibited by SOX9
Female development
What is DHH gene?
A nuclear hormone receptor
Up-regulates WNT4
Downregulates SOX9
Female development
What is RSPO1?
Coactivator in WNT pathway - which differentiates ovary :)
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
Male, what does genital tubercle become?
Glans of penis
Female, what does genital tubercle become?
Clitoris
Male, what do genital folds become?
Shaft of penis
Female, what do genital folds become?
Labia
External genitalia in both males and females originate from what?
Urogenital sinus
External genitalia - what signal in males to become what structures?
Androgen exposure (DHT) from the testis –>
penis
scrotum
urethral opening at tip
External genitalia - what signal in females to become what structures?
Estrogen from maternal and placenta –>
clitoris
labia majora and minora
lower 2/3 vagina
So to review
The first determinant is sex is
Chromosome and the genes on them
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)
What is the Prader scale?
Scale of virilization used to describe the external appearance of genitalia -
No virilization - female
100% virilization - male
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?)
Teams to consult with disorders of sexual differentiation
Endocrinology
Genetics
Urology
Psychology
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
DIAGNOSTIC ALGORITHM
SLIDE 37 LOOK AT IT!
Androgen Insensivity Syndrome
Chromosome constitution?
46,XY
AIS mode of inheritance?
X-linked gene,
AR is apparently X-linked
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
AIS - phenotype
Ranges from mild under-virilization (partial AIS) to full sex reversal (Complete AIS)
What was AIS called in the past?
Testicular feminization
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
What specific disorder is characterized by undervirilization in youth but then starting to look more masculine at puberty?
5-alpha reductase deficiency
What is the chromosomal constitution of disorders associated with the SRY gene?
Can be
46, XY
46, XX
SRY is on which Chromosome
Y-linked
What happens if SRY is deleted?
Full sex reversal and phenotypically normal female (even though 46XY)
What happens if there is ectopic presence of SRY gene in 46XX
Phenotypically normal male
What happens if there is a mutation in the SRY of 46XY?
Decreased or absent production of AMH and undervirilization
Denys-Drash and Frasier Syndrome
Sex reversal with 46XY
Due to mutations in WT1 gene
Denys-Drash and Frasier Syndrome
What kind of disease do both cause
Chronic kidney disease
- diffuse mesangial sclerosis (nephrotic disease)
- focal segmental glomerulosclerosis
Denys-Drash and Frasier Syndrome
Increased risk for what?
Wilms tumor (malignant tumor of kidney)
What is WT1?
Transcription factor for SRY gene
Mutation in WT1 that causes sex reversal in XY … syndrome name?
Denys Drash and Frasier Syndrome
Does Mutation in WT1 effect XX?
Not sexually, but causes other problems
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
FISH for XY –> 46XY DSD
T and DHT normal
Possiblitiles?
AIS
5-Alpha reductase deficiency
FISH fOR XY –> 46XY DSD
T and DHS low
Possiblities?
WT1 associated disease (Frasier and Denys Drash)
SRY Mutation/Deletion
FISH for XY –> 46XX DSD
Possiblities?
CAH
Ectopic SRY
Wnt4 Mutations
AIS and risk for gonadoblastoma?
Only if the testes are in the abdomen - not applicable if inguinal
