lecture 22: diseases and disorders 1: human sex differentation Flashcards
1
Q
What are disorders of sexual differentiation (DSD)?
A
- discordance between any aspect of sexual phenotype
- genetic sex
- gonadal sex
- phenotypic sex
- brain sex
2
Q
What is discordance of genetic sex?
A
- XY females
- XX males
- ~15% of XY females have SRY mutation
- ~80% of XX males are SRY positive
- XXY Kleinfelters (1:1000) (Downs is 1:1250)
- frontal baldness absent
- tendency to grow fewer chest hairs
- breast development
- female-type pubic hair patter
- small testicular size
- poor beard growth
- narrow shoulders
- wide hips
- long legs
- XO Turners (1:2500)
- short stature
- low hairline
- characteristic facial features
- fold of skin on neck
- constriction of aorta
- shield-shaped thorax
- poor breast development
- widely spaced nipples
- elbow deformity
- shortened metacarpal IV
- rudimentary ovaries gonadal streak (underdeveloped gonadal structures)
- small finger nails
- brown spots (nevi)
- no menstruation
- Single X required for normal male development
- 2 X chromosomes needed for normal female development
- small % of genes escape X-inactivation and X-imprinted genes
- SRY gene is right next to the pseudoautosomal region → occasionally gets switched across to X chromosome
3
Q
What is the SRY switch gene?
A
- single exon gene
- high mobility group box (HMG box)
- binds to DNA and bends it
- structural protein
- POORLY conserved (~60% marsupial/human)
- expressed in brain and testes
4
Q
What is the testis determinant?
A
- SOX9
- SRY-like HMG-box containing gene #9
- mutations throughout the gene
- HIGHLY conserved between species (more than 90%)
- expressed in developing cartilage and testes
- autosomal - needed in both male and female
- sox9 is necessary and sufficient to drive testicular development in mammals
5
Q
What is the sox9 promoter?
A
- SRY binds to elements in promoter to turn on Sox9
- can then autoregulate (same DNA binding region)
- very hard to switch off once on
6
Q
What is discordance of phenotypic sex?
A
- external genitalia = most common
7
Q
What is hypospadias?
A
- ectopic placement of urethral opening
- most common birth defect
- affects 1/125 live males births in Victoria
- increased by 50% in past 40 years – and still 1% PA in WA
- Low T
- excess E
- early androgen priming
- surgical repair
- endocrine disruption
8
Q
What are disorders of internal reproductive tract?
A
- hermaphroditism (v rare) vs pseudohermaphroditism
- AMH or AMH-receptor inadequacy
- persistent mullerian duct syndryom (PMDS)
- failure of testicular descent
- defects in steroidogenesis or androgen action
- various phenotypes
- congenital adrenal hyperplasia (CAH)
- androgen insensitivty (CAIS/PAIS)
- 5alpha-reductase deficiency (5ARD)
9
Q
What is failure of testicular descent?
A
- 1:100 boys
- testes migrate (descend) from abdomen to scrotum via inguinal canal
- androgens, INSL3 and AMH from testes
- CGRP from the genitofemoral nerve
- scrotal location → 2-3 degrees C cooler
- failure of descent (Cryptorchidism)
- no sperm production
- high risk of testicular cancer
10
Q
What is persistant mullerian duct syndrome?
A
- incidence unknown (rare)
- affects genetic males
- autosomal recessive; mutations
- AMH
- AMHR
- almost always cryptorchid
11
Q
What is congenital adrenal hyperplasia?
A
- autosomal recessive inheritance
- defect in 21-hydroxylase gene (P450c21)
- reduced cortisol (therefore increased ACTH) and aldosterone
- increased adrenal androgen secretion
- affected female foetus is masculinised
- but phenotype is intersex
- genital surgery → female appearance
12
Q
What are examples of genetic females with CAH?
A
13
Q
What is complete androgen insensitivity syndrome?
A
- complete AIS
- laboratory
- XY karyotype (SRY positive)
- AR gene mutation usually detected (allows carrier identification, prenatal diagnosis)
- adult blood levels: high LH and T, slightly high FSH
- oestradiol level higher than normal male, less than adult female
- ?effect on gonads and urogenital system?
- clinical
- relatively tall, with normal breast development
- absent or sparse body hair
- no uterus (therefore no menses)
- short vagina
- inguinal/abdominal testes
- partial forms have reduced AR activity or androgen synthesis and intermediate phenotypes
14
Q
What is 5alpha-reducatase deficiency?
A
- clinical: present as females at birth
- puberty – masculinization of body, clitoral enlargement, male pattern body hair
- Lab: 5AR mutation
15
Q
How does gender identity develop?
A
- bee (1998) suggests 3 stages:
- gender identity: 1-3 years
- gender stability: 3-4 years
- gender constancy: 5-6 years
- gender identity is distinct from homosexuality (men still identify as men, women as women)
