Chromosome Abnormalities: Sex chromosomes

Question 1

Males and females develop from the same ___, but differ in the presence/absence of ____

Answer 1

same primordia

sex depends on presence/absence of Y chromosomes

Question 2

SRY complex

Answer 2

on the p arm the Y chromosome

gene that initiates the cascade leading to male sexual differentiation

Question 3

Undifferentiated gonad in the presence of the SRY gene

Answer 3

Promotes differentiation into testes:

• Leydig cells produce testosterone –> stimulates male genital duct formation from mesonephric ducts
• Sertoli cells produce Mullerian inhibiting factor –> stimulates regression of paramesomephric ducts (which normally lead to female organs)

Question 4

Undifferentiated gonad in the absence of SRY gene

Answer 4

• Mesonephric ducts regress bc no testosterone
• Paramesonephric ducts persist bc no mullerian-inhibiting hormone

Question 5

The majority of genes that cause sexual differentiation are autosomal/sex chromosomal

Answer 5

Autosomal.

• Ex) No 5-a reductase -> no 3a dihydrotestosterone -> no external male sexual characteristics.
• Ex) Absent cholesterol biosynthesis -> incomplete sexual differentiation

Question 6

Lyonization

Answer 6

Transriptional silencing of one of the female X chromosomes, usually ~2wks post-conception

XIST: X-inactivation gene on the X-chromosome

Question 7

Lyonization in Factor 8 definciency’s

Answer 7

Factor VIII deficiency is X-linked and men are more likely to be symptomatic.

• Most female carriers have normal Factor8 levels because they have sufficient active normal X chromosomes that do not carry the mutation
• ~1% of women have skewed inactivation: majority of active X’s happen to be those with the mutation.
  
  • –> Lower factor 8 levels –> menorrhagia and excessive surgical bleeding

Question 8

Gonadal dysgenesis

Answer 8

poorly developed or streak gonads

Question 9

Most common cause of male genotype but unclear phenotype (male pseudohermaphrodite) is

Answer 9

androgen insensitivity

Question 10

Most common cause of female genotype but unclear phenotype (female pseudohermaphrodite) is..

Answer 10

congenital adrenal hyeprplasia (21 hydroxylase deficiency)

Question 11

Turner syndrome

What is it? What causes it?

Other important things

Answer 11

45,X or mosaic with 45,X

Caused by paternal nondisjunction

Short, but intellectually normal!

Only ~5% are born; makes up ~20% of first trimester miscarriages

Question 12

Turner syndrome abnormalities at prenatal and at birth

Answer 12

Prenatal: acumulation of lymphatics around the neck (hygroma) can get really bad -> hydrops

Birth: webbed neck, lowset ears, wide nipples, low posterior hairline, broad chest, edema, renal & cardiovascular abnormalities at birth

Question 13

What percentage of turner syndrome patients are just 45, X?

Answer 13

Only ~53%

The other half are all mosaics.

Question 14

Webbed neck is often seen in what?

Answer 14

Turner syndrome

cystic hydromas

Question 15

What happens to the gonads in turner’s syndrome?

Answer 15

Gonadal dysplasia - no gonads

Pulsatile secretion of FSH at puberty (normal), but there are no ovarian follicles to be stimulated to make estrogen & progesterone in response–> rapid or excessive atresia of their follicle by the time they reach puberty.

No secondary sex characteristics - short, cubitus valgus (stance); and no body hair, breasts, etc

Question 16

Klinefelter syndrome

Karyotype?

Cause?

Prenatal vs Birth?

Answer 16

• 47, XXY
• Maternal nondisjunction
• 50% lost in miscarriage, but birthed as normal male with azoospermia

Question 17

Kline felter syndrome abnormalities

Answer 17

• Tall, thin; slightly lower IQ; behavioral problems
• Small testis, hypogonadism, gynecomastia
• Azoospermia!

Question 18

Someone who is 46, XX ( normal female) has how many barr bodies in a cell?

Answer 18

1

Question 19

What is the phenotype for

48, XXXY?

49, XXXXY?

Answer 19

Question 20

Androgen insensitivity inheritance pattern, presentation

Answer 20

46, XY

X-linked inheritance; No androgen receptors

-> phenotype: normal girl but with testis/hernia bc still have the SRY

• Testis makes testosterone but it doesn’t work, so mesonephric ducts don’t develop.
• Mullerian inhibiting factor works, so the paramesonephric duct doesn’t develop either.
  
  • Thus, no uterus, no upper 1/3 of vagina, no ovaries; just a short vagina
• Extra testosterone converts to estrogen in peripheral tissue–> breasts, no pubic or axillary
• Risk of gonadal neoplasia: 2-5%

Question 21

What kind of patient would you consider removing the testis in? What are you worried about?

Answer 21

Anyone with an XY cell line and gonadal dysgenesis.

Ex) Mosaic Turner (45,X / 46, XY) ; most common

Ex) Androgen insensitive patients

Worried with gonadoblastoma, dysgerminoma; existence of poorly differentiated gonadal tissue in the intraabdominal environment increases risk

Question 22

Fragile X

When do you start seeing abnormalities?

Answer 22

• Prepubertal
  
  • developmental delay
  • tantrums, hyperactivity
  • autism
• Postpubertal
  
  • intellectual incapacity
  • large ears, long face
  • macroorchidism (enlarged testis)

Question 23

What is the Fragile X mutation?

Answer 23

Question 24

Full mutation in Fragile X requires you to have how many CGG repeats?

Why do CGG repeats cause Fragile X?

Answer 24

over 200

Occurs upstream of the FMR 1 –> causes hypermethylation of the CpG island –> protein does not get formed

Question 25

What is this?

Answer 25

Break points at the end of X --\> fragile X ## Footnote This was the old way to diagnose FragileX. Now we can do **Southern analysis** & **PCR** to just look at how many repeats there are.

Question 26

Anticipation in Fragile X

Answer 26

* **Anticipation:**The more generations the disease is passed on in, the more severe the disease becomes. * In Fragile X, the # of triplet repeats in the fragile area of the x chromosome increases

Question 27

**Sherman Paradox** of Fragile X

Answer 27

Expansion of the trinucleotide repeat occurs more readily when the permutation is passed from **mom to son** Less likely to occur when **dad passes to daughter**