Lecture 2.2: Sex-Linked Disorders

Question 1

Pathology Terms:
1) Gonadal dysgenesis refers to what?
2) What does this cause?

Answer 1

1) Progressive loss of germ cells,
2) Underdeveloped and dysfunctional “Streak” gonads, consequent failure to develop mature secondary sex characteristics

Question 2

“Complete gonadal dysgenesis” is characterized by what phenotype?

Answer 2

Normal-appearing external genitalia of the opposite chromosomal sex

Question 3

“Partial gonadal dysgenesis” is characterized by what phenotype?

Answer 3

Phenotypically ambiguous external genitalia, which does not quite match the chromosomal sex

Question 4

1) In embryos, initially the developing gonad is ___________, whether it is chromosomally XX or XY
2) By what week of development have primordial germ cells have migrated from extraembryonic location to paired genital ridges?

Answer 4

1) ambipotent
2) 6th

Question 5

1) Thickening of what indicate developing genital ducts?
2) What are the two genital ridges?
3) What surround them?

Answer 5

1) Paired genital ridges
2) Mesonephric = Wolffian ducts
Paramesonephric = Mullerian
3) Sex cords, to form a pair of primitive gonads

Question 6

1) For the first ____ or ______ weeks, then, the gonads of an embryo are neither male nor female
2) Differentiation begins about week ____, at which point genes will eventually cause gonads to develop as testes or ovaries, establishing gonadal sex

Answer 6

1) 7 or 8 weeks (two undifferentiated gonads, both male and female reproductive duct systems develop)
2) 8

Question 7

1) What is the SRY gene?
2) Where is it?
3) What cause the undifferentiated gonad to develop into a testis? (2 things)

Answer 7

1) Sex-determining region of Y chromosome
2) Near short arm of Y chromosome
3) SRY gene, along with testis determining factor (TDF)

Question 8

1) What type of hormone is testosterone? Where is it produced?
2) What effect does it have in embryos?
3) What is Anti-Mullerian Hormone (AMH)?

Answer 8

1) A steroid hormone (male sex hormone) produced by the testis
2) Stimulates development of the mesonephric ducts (Wolffian ducts; the male ducts)
3) Hormone produced by developing testis that causes breakdown of the paramesonephric ducts (Mullerian ducts/ female ducts) in the embryo

Question 9

1) What does female development require?
2) What develops as an ovary?
3) What duct degenerates? Why?
4) In the absence of _______, the _________ duct forms female reproductive system

Answer 9

1) Absence of the Y chromosome (and thus the SRY gene) and the presence of two X chromosomes
2) Embryonic gonad
3) Bc of absence of testosterone, the mesonephric (Wolffian) duct degenerates
4) AMH, Mullerian

Question 10

List the 4 stages of sex determination

Answer 10

1) Establishment of chromosomal sex: XX, XY
2) Initiation of one or the other pathway to establish gonadal sex
3) Continuation of sex-specific differentiation of internal and external sexual organs
4) After puberty, development of distinctive secondary sexual characteristics to create the corresponding phenotypic sex

Question 11

1) The Y chromosome is extremely gene poor: contains fewer than ______ genes, specifying only _____________ proteins, most of which pertain to __________________.
2) True or false: there are also pseudoautosomal regions on X and Y are virtually identical, and these are the only parts that match

Answer 11

1) 100; 2 dozen; gonadal development
2) True

Question 12

1) Where are the pseudoautosomal regions on X and Y?
2) In male meiosis, these pseudoautosomal regions are paired when?

Answer 12

1) Occur at matching regions on q and p arms.
2) During recombination in meiosis I

Question 13

Sex Reversal:
1) Normally, recombination swaps the _______________ region of X and Y. What usually occurs to cause a 46xx male?
2) Where else can this occur?
3) What can this sex reversal lead to?

Answer 13

1) pseudoautosomal; illegitimate recombination centromeric to the pseudoautosomal regions (Xp and Yp) on sex chromosomes
2) SRY gene which lies in close proximity is exchanged
3) Male XX, and female XY chromosomes

Question 14

46,XX Male
1) What’s this disorder’s category?
2) Age at onset?
3) Is the pt always sterile?
4) What is the phenotype?

Answer 14

1) Sex development disorder
2) Prenatal
3) Yes
4) Reduced secondary sexual features; unambiguous genitalia mismatched to chromosomal sex (i.e. XX man has male genitalia)

Question 15

46XX male:
1) Explain how the phenotype is achieved
2) Why are these pts infertile?

Answer 15

1) SRY is necessary for formation of male genitalia, and absence is permissive for formation of female genitalia; hence, complete gonadal dysgenesis
2) Bc the Y chromosome carries additional genes for sperm development which are not passed on with this recombination error (azoospermic factor AZFa, AZFb, AZFc), they will not develop normal sperm

Question 16

Describe the phenotype of 46 XX males. Who will have more pronounced phenotypic Sx?

Answer 16

1) Complete gonadal dysgenesis (external genitalia does not match chromosomal sex).
2) Hypogonadism, azoospermia, gynecomastia.
3) Decreased testosterone production: though most will still enter puberty spontaneously, some require testosterone supplementation.
-Patients with larger segments of Y chromosome left behind have more pronounced phenotypic symptoms.

Question 17

True or false: there are some patients who have XX chromosomes without translocated SRY gene

Answer 17

True

Question 18

1) 46 XX males who don’t have a translocated SRY gene have what phenotype?
2) What are the two ways this can happen?

Answer 18

1) Usually have ambiguous genitalia
2) 2 types of duplications:
a) One enhances activity of masculinizing SOX 9 gene which has some effect, even in the absence of the SRY gene
b) Second is increased activity of X-linked SOX3 gene which can also enhance activity of masculinizing SOX 9 gene

Question 19

Describe the 4 ways a female can have XY chromosomes

Answer 19

1) Deletion in SRY gene or point mutations on it; this inhibits development of male characteristics during embryonic development (15% of cases)
2) Normal SRY gene, but DAX1 gene which is duplicated on extant short arm of X chromosome. This gene competes with SRY, leading to ovarian development.
3) Loss of function mutation of SOX9 gene on Chromosome 17 which is required for normal testis formation
4) Other rare complications effect potency of DAX and SOX genes

Question 20

The X chromosome carries the genes necessary for ovary development and maintenance, and since 46XY females only have one, what does this mean?

Answer 20

-Female fetuses with 46XY develop oocytes, but their ovarian follicles degenerate by birth or shortly after
-46XY pts are infertile

Question 21

Describe the typical XY female phenotype

Answer 21

1) Complete gonadal dysgenesis
2) Usually taller than average women
3) They will not enter puberty spontaneously because they have “streak ovaries”

Question 22

46,XX Male / 46,XY Female
1) When is it usually diagnosed?
2) How are each treated?
3) These are usually de novo diseases; what does this imply?

Answer 22

1) Diagnosis usually occurs after fetal ultrasound and fetal karyotype
-Investigation may be spurred later when secondary sex characteristics are halted; delayed puberty
2) 46,XX may require supplementation may be needed for effective virilization (testosterone)
-46,XY will require estrogen supplementation to finish puberty (can have menses after)
3) If their parents have more kids, they’re not any more likely to be intersex than the rest of the population

Question 23

Many disorders of sex chromosomes highlight the mild effect of altering gene dose on chromosome X; why is there only a mild effect?

Answer 23

Much of the dose difference is compensated for by X deletion

Question 24

True or false: Remember, sex is determined by presence/absence of the Y chromosome in humans; other species can operate differently

Answer 24

True
XX = female
XY = male

Question 25

1) Is the methylation of an X chromosome random? Will all the daughter cells have the same X chromosome turned off? 2) Women are mosaic for the X chromosome. What does this allow to be well tolerated? Explain.

Answer 25

1) This is done randomly; yes 2) Polyploidy of the X chromosome is well tolerated; any number of X chromosomes more than one will be inactivated

Question 26

1) When there is a structurally abnormal X, that is the one turned off. What does this do? 2) Monosomy of the X chromosome, which causes _____________, is frequently discovered in spontaneous abortion

Answer 26

1) Further lessens the impact of abnormal gene content 2) Turner Syndrome

Question 27

1) Describe the phenotype of Sex Chromosome Aneuploidy. 2) List 2 common types of this

Answer 27

1) This group, in general, demonstrates reduced levels of psychosocial adaptation, educational achievement, occupational performance, economic independence, and on average have lower IQ -That said, expression of these traits is highly variable and generalizations cannot be made of the group 2) Turner Syndrome and Klinefelter Syndrome

Question 28

Turner syndrome (45X): 1) Age at onset? 2) Stature and ovary status? 3) Sex development? 4) List 2 other features

Answer 28

1) Prenatal 2) Short Stature; Streak Ovaries 3) No secondary sex development 4) Coarctation of the aorta; Webbed Neck

Question 29

Turner Syndrome: 1) Most commonly caused by what? 2) Where else can it come from?

Answer 29

1) Failure to transmit X chromosome during meiosis 2) Loss of sex chromosome from zygote or early embryo

Question 30

Turner syndrome: 1) What development can occur with one X chromosome? What cannot occur with only one? 2) If X activation occurs in every female, how do any of them develop this with only one “active” X?

Answer 30

1) Oocyte development can, ovary development cannot. 2) There are a few loci on the inactivated X that do no undergo methylation -with only one X, these few duplicate genes are missing!

Question 31

Turner Syndrome (45X): 1) What hormone therapy, if any, is required? Explain your answer. 2) What are 3 complications?

Answer 31

1) Give estrogen therapy to develop secondary sex characteristics and reduce osteoporosis -Progesterone therapy to induce menses 2) Watch for blood clots, get echocardiogram to check for coarctation, & they will not be able to have children

Question 32

Klinefelter Syndrome 1) What is the karyotype and what causes it? 2) What are the 3 main Sx?

Answer 32

1) 47,XXY; MC error in maternal meiosis 2) -Infertility (often when disease is discovered) -Androgen deficiency -Some have learning disability

Question 33

Klinefelter syndrome (47,XXY): 1) Makes up ___% of infertile males 2) What usually causes it? 3) List 2 Sx

Answer 33

1) 4% 2) Failure of germ cell development 3) Androgen insensitivity, and some have a learning disability

Question 34

List 3 Sx of androgen deficiency (caused by Klinefelter syndrome)

Answer 34

1) Decreased muscle tone 2) Decreased bone mineral density 3) Loss of libido

Question 35

Klinefelter Syndrome: Describe the phenotype

Answer 35

1) Tall and thin, long legs 2) Narrow shoulders and chest 3) Physically normal until puberty; hypogonadism develops then 4) Underdeveloped secondary sex characteristics 5) Sometimes have gynecomastia

Question 36

Klinefelter Syndrome: How do you Tx it?

Answer 36

Treatment centers on androgen (testosterone) replacement therapy

Question 37

Triple X Syndrome 1) What is the karyotype? 2) Frequency? 3) What are the Sx? 4) Is it also possible to have even further additions of X chromosome? Explain

Answer 37

1) 47XXX karyotype 2) 1/1000 female births 3) Hypotonia, delayed milestones, language and learning difficulties, increased height -No behavioral problems 4) Yes, and it increases the severity of the disease

Question 38

List two conditions that often have “partial gonadal dysgenesis”

Answer 38

1) Congenital Adrenal Hyperplasia: virilization of 46XX infants 2) Androgen Insensitivity Syndrome: incomplete masculinization of 46XY infants

Question 39

Congenital Adrenal Hyperplasia (Virilization of 46XX infants) 1) How's it inherited? 2) How does it arise? 3) What are the two types of genitalia possible with this condition? What % of cases does each make up?

Answer 39

1) CAH inherited disorder 2) Specific defects in enzymes of the adrenal cortex required for cortisol biosynthesis, resulting in virilization of 46XX infants 3) Masculinization of female genitalia involving clitoral enlargement and labial fusion to form scrotum-like structure (50%) -Ambiguous genitalia (50%)

Question 40

Congenital Adrenal Hyperplasia (Virilization of 46XX infants) 1) What is the most common cause? 2) What % of pts with that cause have virilizing type? What does the other percent have?

Answer 40

1) Deficiency of 21-hydroxolase 2) 75% have virilizing type; 25% also have salt-losing type due to mineralocorticoid deficiency

Question 41

Incomplete Masculinization of 46, XY infants: Androgen Insensitivity Syndrome 1) What causes it? 2) What are the gonads? 3) What are the genitalia?

Answer 41

1) Disorder of testosterone biosynthesis and metabolism, and abnormality of androgen target cells (receptors) 2) Exclusively testes; genital ducts and external genitalia are not masculinized 3) Have blind vagina, no uterus, no uterine tubes

Question 42

Fragile X: 1) Age at onset? 2) What are 3 sx?

Answer 42

1) Childhood 2) Intellectual disability, dysmorphic facies, male post-pubertal macroorchidism

Question 43

Fragile X: 1) What is it? 2) Who does it affect? 3) What is it the most common form of? What % of cases does it make up?

Answer 43

1) X-linked mental retardation disorder that is caused by mutation in the FMR1 gene on Xq27.3 2) 1/4000 males 1/8000 females 3) MC form of heritable retardation; 3-6% of mental retardation among boys -Second to Down syndrome in total cases of MR

Question 44

Fragile X pathogenesis: 1) FMR1 gene is expressed mainly where? What does its protein appear to play a role in? 2) FMR1 mutations are almost always expansion of what and where?

Answer 44

1) In brain and testes; translation of other mRNAs into proteins 2) (CGC)n in the 5’ untranslated region of the gene

Question 45

Fragile X: 1) FMR1 mutations are almost always expansion of what? Where? 2) In normal alleles how often does this happen? 3) What about in fragile X? What does this lead to?

Answer 45

1) (CGC)n; 5’ untranslated region of the gene 2) 6-50 times 3) As many as 200 repeats or more; leads to methylation of the CGC repeat **AND** the adjacent FMR1 promotor, causing loss of FMRP expression

Question 46

Fragile X: 1) Length of the repeat increases each time it is transmitted by who? 2) What does this lead to? What is this called?

Answer 46

1) Females 2) Families develop worse disease along the line -Called “anticipation”

Question 47

Fragile X: 1) Nearly all males who inherit a ______________- (at least 200 repeats) will have fragile x syndrome. 2) What percent of heterozygous females who inherit the full mutation will have fragile X? 3) What is the female phenotype dependent on?

Answer 47

1) full mutation 2) Appx 50% 3) The degree of skewing of X chromosome inactivation

Question 48

Fragile X: 1) What degree of mental retardation does it typically cause? 2) List 5 behavioral abnormalities associated with it. 3) What is the phenotype in males? 4) How does it affect lifespan?

Answer 48

1) Moderate MR in males, Mild in females 2) Hyperactivity, hand flapping or biting, temper tantrums, poor eye contact, autistic features 3) Males have long face with prominent jaw and forehead, large ears, macro-orchidism 4) It doesn't; normal life span

Question 49

How do you treat Fragile X?

Answer 49

No curative treatments; therapy focuses on educational intervention and management of any behavioral problems that may arise