Disorders of the Sex Chromosomes

Question 1

Chromosomal sex in males

Answer 1

Embryo with Xy sex chromosomes

Question 2

Chromosomal sex in females

Answer 2

Embryo with XX sex chromosomes

Question 3

Hermaphrodite

Answer 3

An individual with both ovarian and testicular tissue

Question 4

Female psueudohermaphrodite

Answer 4

An individual with 46, XX karyotype and nl ovarian tissue, but with ambiguous or male external genitalia
A derogatory term

Question 5

Male pseudohermaphrodite

Answer 5

An individual with a 46, XY karyotype and nl testicular tissue but with ambiguous or female external genitalia
A derogatory term

Question 6

What is important for determining the sex chromosome constitution of pts with ambiguous development of the external genitalia?

Answer 6

A karyotype

Question 7

Disorders of Sex Development (DSD)

Answer 7

The term used to describe hermaphroditism and psuedohermaphroditism

Question 8

Cause of female pseudohermaphroditism

Answer 8

Congenital adrenal hyperplasia (CAH), an inherited autosomal recessive disorder of hormone synthesis by the adrenal glands
Mutation of CyP21A2 that causes lack of 21-hydroxylase, needed by the adrenal gland to produce cortisol and aldosterone
The body produces more androgen

Question 9

Tx for female pseudohermaphroditism

Answer 9

Medical, surgical and psychocsocial management is associated with improved fertility rates and nl female gender identity

Question 10

Cause of male pseudohermaphroditism

Answer 10

Disorders of testis development during embryogenesis
Abnormalities of gonadotropins
Inhertited disorders of testosterone biosynthesis and metabolism
Abnormalities of androgen target cells

Question 11

Androgen insensitivity syndrome

Answer 11

A mutation in the X-linked androgen receptor (AR) gene causes XY males to become phenotypic females
Gonads develop into testes and produce testosterone, dihydrotestosterone (DHT) and AMH
The body still responds to AMH, causing the female duct system to degenerate
The body cannot respond to testosterone and dHT because the AR gene is defective, so the male duct system degenerates and the genitalia develop as female structures

Question 12

Dosage compensation

Answer 12

A mechanism that regulates the expression of sex-linked gene products
Human females have random inactivation of one X chromosome in all somatic cells to balance the expression of X-linked genes in males and females

Question 13

Process of X chromosome inactivation

Answer 13

1. Pairing X chromosomes
2. Selecting which X chromosome to inactivate by expression of XIST gene (inactivated chromosome is coated with XIST RNA), located in a region of the X chromosome called the X inactivated center (Xic)
   - XIST is only expressed from the inactive X chromosome and it serves to silence most (but not all) genes on the inactive X

Question 14

Barr body

Answer 14

An inactivated X chromosome, tightly coiled

XY males have no inactive X chromosomes and no Barr bodies

Question 15

Mosaicism in females

Answer 15

Some cells express the mother’s X chromosome and some cells express the father’s X chromosome

• Inactivated chromosome can come from either mother or father
• Inactivation occurs early in development
• Inactivation is permanent; all descendants of a particular cell have the same X inactivated

Question 16

Hypohidrotic ectodermal dysplasia

Answer 16

Mutation in EDA gene
X-lined recessive
Affects skin, hair, nails, teeth, sweat glands
Females are mosaic bc of random X-chromosome inactivation

Question 17

Twins and X-chromosome inactivation

Answer 17

Random X inactivation can cause twins with identical genotypes to have different phenotypes

Question 18

What is the only stage of sex determination that is established at fertilization?

Answer 18

Chromosomal sex

Question 19

What are the three levels of sexual determination?

Answer 19

Chromosomal
Gonadal
Phenotypic

Question 20

Gonadal sex differentiation

Answer 20

For the first 7 or 8 wks, the embryo is neither male nor female
-Two undifferentiated gonads
-Both male and female reproductive duct systems develop
Genes cause gonads to develop as testes or ovaries, establishing gonadal sex

Question 21

SRY gene

Answer 21

Sex-determining region of the Y chromosome
Located near the end of the short arm of the Y chromosome
Plays a major role in causing the undifferentiated gonad to develop into a testis

Question 22

Testosterone

Answer 22

A steroid hormone produced by the testis
Male sex hormone
Stimulates development of the mesonephric ducts (formerly called Wolffian ducts) in the embryo; the male ducts

Question 23

Anti-Mullerian hormone (AMH)

Answer 23

Hormone produced by developing testis that causes breakdown of the paramesonephric ducts (formerly called Mullerian ducts) in the embryo; the female ducts

Question 24

Female development

Answer 24

Requires the absence of the Y chromosome (and SRY gene) and the presence of two X chromosomes
Embryonic gonad develops as an ovary
In the absence of testosterone, the mesonephric (Wolffian) duct system degenerates
In the absence of AMH, the paramesonephric (Mullerian) duct system forms female reproductive system

Question 25

Gonadal sex of males

Answer 25

Sex-determining region of the Y chromosome (SRY) brings about development of undifferentiated gonads into testes Testes secrete masculinizing hormones, including testosterone, a potent androgen

Question 26

Gonadal sex of females

Answer 26

No Y chromosome, so no SRY. With no masculinizing influence, undifferentiated gonads develop into ovaries No androgens secreted

Question 27

Phenotypic sex of males

Answer 27

In presence of testicular hormones, undifferentiated reproductive tract and external genitalia develop along male lines.

Question 28

Phenotypic sex of females

Answer 28

With no masculinizing hormones, undifferentiated reproductive tract and external genitalia develop along female lines

Question 29

What are clinical indicators of a sex chromosome abnormality and the need for cytogenetic and molecular analyses?

Answer 29

Delayed onset of puberty Amenorrhea Infertility Ambiguous genitalia

Question 30

What are the most common sex chromosome defects in liveborn infants?

Answer 30

Trisomies (XXY, XYY, and XXX) followed by monosomy for the X

Question 31

What is required for development in the sex chromosomes?

Answer 31

At least one copy of the X chromosome | Increasing numbers of X or Y chromosomes causes progressively greater disturbances in phenotype and behavior

Question 32

Klinefelter syndrome (47, XXY)

Answer 32

Chromosomal inheritance Due to nondisjunction in maternal or paternal meiosis I; some have additional X chromosomes 1 in 500-1,000 male live births

Question 33

Clinical features

Answer 33

``` Male phenotype, but may fail to develop nl secondary sex characteristics Tall and thin, relatively long limbs Small testes, produce few or no sperm Some degree of breast development Learning disabilities ```

Question 34

Management of Klinefelter syndrome

Answer 34

Tx with testosterone Counseling regarding probable infertility Intervention to manage learning disabilities

Question 35

Genetic counseling for Klinefelter

Answer 35

Recurrence is rare and can be detected by prenatal chromosomal analysis

Question 36

47,XYY syndrome

Answer 36

Chromosomal inheritance Due to nondisjunction in paternal meiosis II 1 in 1,000 male live births

Question 37

Clinical features of 47,XYY syndrome

Answer 37

Male phenotype and fertile Tend to have learning disabilities and behavioral problems Relatively tall stature

Question 38

Management of 47,XYY syndrome

Answer 38

Anticipatory guidance and support for learning disabilities

Question 39

Genetic counseling for 47,XYY syndrome

Answer 39

Recurrence is rare and can be detected by prenatal chromosomal analysis. Transmission is rare

Question 40

Trisomy X (47,XXX)

Answer 40

Chromosomal inheritance Nondisjunction in maternal meiosis I 1 in 1,000 live births

Question 41

Clinical features of Trisomy X

Answer 41

Female phenotype Fertile Somewhat above average in stature 70% of pts have some learning problems

Question 42

Management of Trisomy X

Answer 42

Anticipatory guidance and support for developmental impairment

Question 43

Genetic counseling for Trisomy X

Answer 43

Recurrence is rare

Question 44

Turner syndrome (45,X and variants)

Answer 44

Chromosomal inheritance Due to nondisjunction or loss of a structurally abnormal X or Y chromosome 70-80% of pts conceived from sperm lacking a sex chromosome Many are mosaics, with a cell line containing 46 chromosomes with a structurally abnormal X or Y 1 in 3,000-4,000 female live births

Question 45

Clinical features of Turner syndrome

Answer 45

Female phenotype but fail to develop nl secondary sex characteristics Short stature, primary amenorrhea and usually infertile Coarctation of aorta, renal anomalies Lymphedema common at birth, "webbing" of the neck Nl intelligence but learning disabilities, esp visual-spatial perceptual problems, are common

Question 46

Management of Turner syndrome

Answer 46

Tx with hormones to promote secondary sexual development Surgical correction of congenital heart defects Anticipatory guidance and early intervention to overcome learning disabilities GH therapy for stature

Question 47

Genetic counseling for Turner syndrome

Answer 47

Recurrence is rare