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RDS Test 4 > B8.059 Disorders of Sex Development > Flashcards

B8.059 Disorders of Sex Development Flashcards

1
Q

what are DSDs

A

congenital conditions associated with atypical development of internal and external genital structures
atypical chromosomal, gonadal, or anatomical sex

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2
Q

chromosomal sex

A

presence of absence of a Y chromosome

determines gonadal sex

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3
Q

gonadal sex

A

determines the hormonal environment which directs development of internal and external genitalia (embryo) and secondary sex characteristics (puberty)

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4
Q

primordia of the reproductive system

A

BIPOTENTIAL (have potential to be male or female regardless of XX or XY designation)

  1. gonads
    - gonadal ridges
  2. internal genitalia
    - mullerian ducts
    - wolffian ducts
  3. external genitalia
    - genital tubercle
    - urethral folds
    - labioscrotal folds
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5
Q

gonadal ridge outcomes

A

female: ovaries
male: testes

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6
Q

mullerian duct outcomes

A

female: uterus, fallopian tubes, upper vagina
male: regression

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7
Q

wolffian duct outcomes

A

female: regression
male: epididymis, vas deferens, seminal vesicles

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8
Q

genital tubercle outcomes

A

female: clitoris
male: penis

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9
Q

urethral fold outcomes

A

female: labia minora
male: penile urethra

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10
Q

labioscrotal fold outcomes

A

female: labia majora
male: scrotum

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11
Q

what is SRY and what is its function

A

sex determining region on the Y chromosome

-initiates testis and male development

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12
Q

male gonad development genes

A

SRY

SOX9

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13
Q

female gonad development genes

A

WNT4
RSPO1
FOXL2

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14
Q

shared gonad development genes

A

NR5A1

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15
Q

function of SOX9 + FGF9

A

promote SOX9
antagonize WNT4
inhibit b-catenin ( this turns off ovarian pathway)

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16
Q

function of RSPO1, WNT4

A

repress SOX9

stabilize B-catenin

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17
Q

at what time point does the bipotential gonad start to differentiate?

A

week 6ish

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18
Q

arrest of germ cells

A

male: mitosis
female: meiosis
germ cells stabilize the ovary, w/o germ cells, follicles degenerate and the ovary does not synthesize hormones
*not true for testis

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19
Q

what hormones are made by the developing testes that influence male development

A 
Leydig cells: T and INSL3
-these control testicular descent
-T stimulates wolffian duct differentiation
sertoli cells: MIS
-this inhibits mullerian duct formation
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20
Q

do fetal ovaries make hormones for female sexual development?

A

nOooOOO

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21
Q

how does developmental timing differ between sexes

A

females develop much later than males

males start around 20 days, females around 80 days

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22
Q

when can DSDs occur?

A

can occur with variations at any of the 3 stages of sex development

  • atypical chromosome
  • atypical gonadal development
  • atypical hormone production and response
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23
Q

prenatal DSDs

A

karyoptype-phenotype disorders

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24
Q

neonatal DSDs

A

atypical genitalia

salt losing crisis (CAH)

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25
Q

childhood DSDs

A

hernia (CAIS)
androgenization (CAH)
poor growth (turners, 45X/46XY)

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26
Q

puberty DSDs

A 
androgenization (17B-HSD, 5areductase, SF1)
absent puberty (gonadal dysgenesis, CAH, turners)
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27
Q

postpuberty DSDs

A

amenorrhea (CAIS)

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28
Q

adult DSDs

A

infertility (klinefelters, 45X/46XY, SF1)

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29
Q

46, XY DSD

A

phenotypic XY female with or without testes

includes undervirilized and under masculinized XY male

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30
Q

46, XX DSD

A

phenotypic XX male with or without testes

includes masculinized and over-virilized 46 XX female

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31
Q

sex chromosome DSDs

A

47, XXY (klinefelters)
45, X (turners)
45X/46XY mosaicism (mixed gonadal dysgenesis)
46XX/46XY (chimerism, mosaicism)

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32
Q

gonadal dysgenesis

A

gonads completely or partially fail to develop, resulting in atypical sexual development

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33
Q

ovotesticular/testicular DSDs (46 XX)

A

both ovarian follicles and seminiferous tubules are present in the same patient, or only testicular tissue present

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34
Q

gonadal regression

A

complete absence of one or both testicles

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35
Q

causes of 46 XY complete gonadal dysgenesis

A
  1. sertoli cells defective: no MIS production, Mullerian ducts develop
  2. Leydig cells defective: no T or INSL3 production, wolffian duct regresses, gonads undescended
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36
Q

lab findings in 46 XY complete gonadal dysgenesis

A
  1. undetectable T and unresponsive to hCG challenge
  2. undetectable MIS
  3. high LH and FSH
  4. normal adrenal steroids
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37
Q

46 XY complete gonadal dysgenesis appearance

A

external genitalia is female
uterus and fallopian tubes present
gonadoblastoma common

38
Q

diagnosis of 46 XY complete gonadal dysgenesis

A

usually not suspected until puberty, when girls present with absence of thelarche and menarche

39
Q

46 XY partial gonadal dysgenesis

A

degree of mullerian duct regression, wolffian duct development, and external genitalia virilization depends on the amount of functional testicular tissue secreting androgens

40
Q

scales for analyzing 46 XY partial gonadal dysgenesis external genital phenotype

A

Quigley scales

41
Q

etiologies of 46 XY complete gonadal dysgenesis

A 
genetic changes/environmental agents that interfere with the process and/or timing of testis development
SRY
SOX9
NR5A1
WT1
ATRX
DHH
MAP3K1
42
Q

SRY defect

A

complete/partial GD
does not result in ovarian differentiation
accounts for 15% of 46XY complete GD

43
Q

SOX9 defect

A 
complete/partial GD
campomelic dysplasia (autosomal dominant disorder of the skeleton - causes bowing of long bones)
44
Q

function of SRY

A

induces SOX9

both critical for sertoli cell differentiation

45
Q

function of NR5A1 and WT1

A

induce SRY

can have both adrenal and gonadal defects

46
Q

NR5A1 defect

A

testicular dysgenesis

+/- adrenal insufficiency

47
Q

WT1 defect

A 
Denys-Drash syndrome (gonadal dysgenesis, nephropathy, Wilms tumor)
Frasier syndrome (gonadal dysgenesis, progressive nephropathy, gonadoblastoma)
48
Q

ATRX function

A

expressed in and maintains Sertoli cells differentiation

49
Q

DHH function

A

produced by sertoli cells to induce differentiation of Leydig cells
activates NR5A1

50
Q

ATRX defects

A

ATRX syndrome (a thalassemia, mental retardation with facial dysmorphism, ambiguous genitalia)

51
Q

DHH defects

A

testicular dysgenesis with minifascicular neuropathy

difficult to detect in newborns

52
Q

MAP3K1 defects

A

certain mutations interfere with destabilization of B-catenin
shifts balance in favor of ovarian development, diminishing SOX9 and disrupting testis development

53
Q

dysgenetic DSDs (sex chromosome DSDs)

A 
ovotesticular DSD
asymmetrical gonadal dysgenesis
Turner
Klinefelter
Triple X
54
Q

characterize Klinefelters

A

most common cause of male hypogonadism

47, XXY

55
Q

presentation of Klinefelters in puberty

A

most common time of presentation
features: taller stature, less muscle mass, less facial and body hair, small testicles, small to normal penis, gynecomastia (33%)

56
Q

Klinefelter gonad defects

A

sertoli, leydig, and meiotic defects
seminiferous tubules do not enlarge and undergo fibrosis and hyalinization resulting in small, firm testes and azoospermia
leydig cell function progressively deficiency, declining T and elevated LH

57
Q

treatment of Klinefelters

A

T replacement often useful at puberty and through adulthood

58
Q

clinical presentation of Turner

A 
gonadal dysgenesis
short stature
short, thick, webbed neck
epicanthus and ptosis of eyelids
low posterior hairline
broad chest
59
Q

gonadal defects in Turners

A

ovarian follicles undergo premature apoptosis resulting in streaked ovaries (normal tissue replaced by functionless fibrous tissue)
fallopian tubes, uterus, and vagina are present
no wolffian duct derivatives
undetectable AMH

60
Q

presentations of ovotesticular DSDs

A
  1. bilateral ovotestes

2. one testis and one ovary or one ovotestis and one testis or ovary

61
Q

who gets ovotesticular DSDs

A

most individuals with 46XX/46XY karyotype (mosaicism)

3-10% of DSDs

62
Q

features of ovotesticular DSDs when testicular tissue predominates

A

patients may be almost completely virilized, with mild signs of androgen insufficiency (hypospadias or undescended testes)
serum androgen and AMH levels within male range
gonadotropins not elevated
at puberty:
-exaggerated follicular development may cause abdominal pain
-E may increase and result in breast development
-cyclic urethral bleeding may indicate existence of mullerian remnants

63
Q

features of ovotesticular DSDs when ovarian tissue predominates

A

newborn is feminized, with cliteromegaly and labial fusion
androgens and AMH elevated for a girl, but low for a boy
gonadotropins normal
mullerian derivatives usually present in less virilized patients

64
Q

what is a 46XX ovotesticular/testicular DSD

A

testicular tissue develops entirely from the gonad primordium, or together with ovarian tissue
most patients are normal until mid-puberty, but are infertile

65
Q

46 XX SRY + etiology

A

translocation of SRY blocks the female pathway and drives testis development

66
Q

46 XX SRY + etiology presentation

A

testes with only mild dysgenetic features
present as 46XX males
90% of XX males are SRY+

67
Q

46 XX SRY - etiology

A

translocation of SOX9, SOX3, SOX10

reduce/prevent inhibition of SOX9 and allow testis development

68
Q

outcome of androgen related 46XY DSDs

A

individuals with androgen deficiency (synthesis or action) leads to undervirilization

69
Q

effects of androgens on development

A
  1. synthesized in Leydig cells
  2. onset of T synthesis at 9 weeks gestation
  3. T is major steroid produced by testis
  4. DHT produced in periphery
  5. DHT responsible for differentiation, growth promoting, and functional aspects of male sexual development and virilization
  6. DHT is 2x as potent as T
  7. estrogens can act in conert w androgens or oppose them
70
Q

T to DHT conversion

A

irreversible
occurs in periphery by 5a reductase
type 2, encoded by SRD5A2 is critical for sexual development

71
Q

how do androgens act

A

via AR (NR3C4), a zinc finger transcription factor located on the X chromosome

72
Q

Leydig Cell Aplasia/ Hypoplasia

46 XY DSD

A

due to inactivating mutations on the LH/CG receptor

phenotypic spectrum from female external genitalia to mild undervirilization

73
Q

androgen synthesis defects

A

glucocorticoid and androgen synthesis pathways share many of the same genes/enzymes
defects in enzymes involved in androgen synthesis result in underandrogenization of the 46,XY fetus

74
Q

important androgen synthesis defects

A

HSD17B3 > 17B hydroxysteroid dehydrogenase 3

SRD5A2 > 5a reductase

75
Q

features of HSD17B3 deficiency in 46XY individuals

A 
female genitalia
wolffian ducts present
mullerian ducts absent
undescended testes
virilization at puberty
76
Q

hormone profile of HSD17B3 deficiency in 46XY individuals

A

increased plasma estrone and androstenedione
decreased ratio of plasma T/androstenedione after hcg stimulation test
increased FSH and LH

77
Q

function of HSD17B3

A

makes T from androstenedione

78
Q

features of 5a reductase type 2 deficiency in 46XY individuals

A 
ambiguous genitalia
normal wolffian ducts
absent mulelrian ducts
normal testes
decreased facial and body hair, no temporal hair recession, prostate not palpable
79
Q

hormone profile in 5a reductase type 2 deficiency in 46XY individuals

A

decreased ratio of 5a/5b C21 and C19 steroids in urine
increased T/DHT ratio before and after hcg stimulation
modest increase in plasma LH
decreased conversion of T to DHT in vitro

80
Q

androgen insensitivity syndrome

A

result from mutations in androgen receptor
more than 400 mutations recorded
activity of receptor depends on location and amino acid change

81
Q

CAIS

A

complete androgen insensitivity syndrome
complete loss of function
NO androgen activity

82
Q

PAIS

A

partial androgen insensitivity syndrome

partial loss of function, range of androgen activity

83
Q

clinical features of CAIS

A

female with blind vaginal pouch
wolffian duct derivative present
mulelrian duct derivatives absent or vestigial
testes
scant or absent pubic and axillary hair, breast development at puberty, primary amenorrhea

84
Q

hormone profile of CAIS

A

increased LH and T levels
increased E
FSH levels normal or increased
resistance to androgenic and metabolic effects of T

85
Q

characterize features of CAIS

A

testes present and functional (leydig cells make T/sertoli cells make MIS)
no uterus, fallopian tubes, or upper vagina (MD development blocked by MIS)
inactive AR = inactive T (external genitalia is female)

86
Q

46 XX DSD due to elevated andorgens

A

fetus becomes masculinized

**21-hydroxylase deficiency

87
Q

congenital adrenal hyperplasia (CAH)

A

group of genetic conditions that affect the adrenal glands

affected individuals are deficient in one or more adrenal hormones and often overproduce androgens

88
Q

girl with severe CAH

A

may be born with ambiguous genitalia
allows condition to be diagnosed before other associated health problems (poor feeding, vomiting, dehydration, abnormal heart beat) develop

89
Q

boys with CAH

A

appear unaffected at birth

without proper diagnosis, will develop associated health problems within 2-3 weeks after birth

90
Q

etiology of androgen excess in CAH

A

defects in CYP21A2 and CYP11B1 shunt steroid precursors into the androgen pathway and cause androgenization of the 46 XX fetus
HSD3B2 defects cause mild androgenization due to elevated DHEA levels

91
Q

disorders of MIS synthesis and action

A

mutations in MIS or its receptor (AMHR2) result in persistent mulelrian duct syndrome
uterus and fallopian tubes in a normally virilized male

RDS Test 4 (17 decks)

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