Sex Chromosomes & Disorders Of Development

Question 0

Why is X chromosome inactivation important?

Answer 0

Only one copy of the majority of X chrom genes is necessary

Two copies of some of the genes may be deleterious

Question 1

What is the biological advantage of sexual reproduction?

Answer 1

It allows the introduction of genetic variation to propagate new genetic traits.
Benefits organisms who:
Exist in a constantly changing environment
Need to fend off disease
Need to purge deleterious mutations

Question 2

Why are all females considered “functionally mosaic”?

Answer 2

Functional mosaicism results from cells independently inactivating the paternally or maternally derived X chromosome. “Random X inactivation”

Question 3

What is the role of the XIST gene in X chromosome inactivation?

Answer 3

It is expressed only from the inactivated X, and inactivation cannot occur in its absence. Mechanism is unknown.

Question 4

When can non-random X chromosome inactivation?

Answer 4

When there is a structurally abnormal X chromosome.

Question 5

What is “skewed” X inactivation and when is it observed?

Answer 5

Skewed inactivation occurs when one parental X-chromosome is expressed >50% of the time by an unknown mechanism. It is observed when a female shows signs or symptoms of an X-linked recessive trait (Duchene Muscular Dystrophy, Fragile X Syndrome)

Question 6

Signs, symptoms and karyotype of Turner Syndrome.

Answer 6

45,XO (developmentally female)
Signs at birth:
Prenatal cystic hygroma, Webbed neck, Puffy hands and feet, Heart defects like coarctation of the aorta
Short stature, normal intelligence, infertility

Question 7

Signs, symptoms, and karyotype of Kleinfelter Syndrome

Answer 7

47,XXY (developmentally male)
Signs in childhood:
Learning disabilities, delayed speech and language, quiet tendency
Tall stature, small testes, reduced facial/body hair, infertility

Question 8

Signs, symptoms, and karyotype of Jacobs Syndrome

Answer 8

47,XYY (developmentally male)
Learning disabilities, Speech delays, developmental delays
Behavioral and emotional difficulties
Autism spectrum, tall stature

Question 9

Signs, symptoms, and karyotype of Triple X syndrome

Answer 9

47,XXX (developmentally female)
May have tall stature
Risk of: learning disabilities, delayed speech, delayed motor milestones, seizures, kidney abnormalities

Question 10

What occurs during primary sex determination?

Answer 10

Gonadal determination is set by the chromosomes. Generally, the presence of a normal Y chromosome results in a male individual, and it’s absence results in a female.

Question 11

What occurs during secondary sexual determination?

Answer 11

Secondary sexual characteristics are determined by gonads. Includes external or internal genitalia, body habitus, musculature, hair growth, and vocal cartilage.

Question 12

Two primary male cell lines that develop during the 7th and 8th weeks and their products. What transcription factor is present?

Answer 12

Sertoli cells - Anti-Mullerian Hormone (eventually sperm)
Leydig cells - Testosterone (interstitial cells)
Develop in the presence of SRY

Question 13

The development of which duct results in male genitalia and which genes are involved?

Answer 13

Mesonephric (Wolffian) duct
SRY, SOX9 - TFs, responsible for production of AntiMullerian Hormone
FGF9 - differentiation of the testes
SF1/NR5A1 - stimulates differentiation of Sertoli & Leydig cells

Question 14

The development of which duct results in female genitalia and which genes are involved?

Answer 14

Paramesonephric (Mullerian) ducts
WNT4 - differentiates ovaries, inhibited by SOX9
DHH - Up-regulated by WNT4, down regulates SOX9
RSPO1 - Coactivator of WNT pathway

Question 15

What tests are applicable to disorders of sexual differentiation (DSD)?

Answer 15

1 FISH studies for sex chromosomes and karyotype (poss. microarray)
2 Hormone studies (LH, FSH, testosterone, AMH)
3 Ultrasound study (evaluate for gonads and uterus
4 Surgical consult with urology

Question 16

What are the karyotype, causes and consequences of androgen insensitivity syndrome?

Answer 16

46,XY
Mutation of X-linked AR (androgen receptor) gene causes inability to recognize testosterone.
Phenotypes range from mild under-virilization to full sex reversal.

Question 17

What is the karyotype, cause, and consequence of 5-Alpha Reductase deficiency?

Answer 17

46,XY
Mutation of X-linked AR gene (androgen receptor) causes decreased ability to convert testosterone to dihydrotestosterone.
Phenotype shows undervirilized male with increased virilization at the time of puberty.

Question 18

Three disorders of sexual development associated with the SRY gene.

Answer 18

Deletion or absence of SRY in 46,XY results in phenotypically normal female.
Ectopic presence of SRY in 46,XX results in phenotypically normal male.
Mutations in SRY in 46,XY result in decreased AMH and under virilized male.

Question 19

Consequences of 21-hydroxylase deficiency

Answer 19

Congenital Adrenal Hyperplasia
Ambiguous genitalia in 46,XX
Complicated by salt wasting and times of metabolic stress
Decreased sodium and chloride
Increased potassium