Abnomalities in sex determination III. Non-sex-linked disorders with abnomalities in sex determination

Question 1

Swyers sydrome

Answer 1

sex reversion
46, XY 
No SRY
-streak gonads
-no AMH (uterus +)
-no sex steroids

female external and internal genitalia

Question 2

specific effects of testosterone

Answer 2

gonadotrophin feedback
spermatogenesis
sexual differentiation
wolffian ducts

Question 3

intersex

Answer 3

an individual in whom there is discordance between chromosomal, gonadal, internal genital, and phenotypic sex or the sex of rearing

Question 4

children born with intersex

Answer 4

1 in 2000

98% due to congenital adrenal hyperplasia

Question 5

classification of intersexuality

Answer 5

true hermaphroditism
mixed ggonadal dysgenesis
male pseudohermaphroditism
female pseudohemaphroditism

Question 6

sexual differentiation- external genitalia

Answer 6

Primordia of the external genitalia
are bipotential.
Either phenotypic male or female structures can develop under the appropriate hormonal conditions, regardless of either the genetic or gonadal sex

Question 7

male external genitalia differentiation

Answer 7

develops normally under influence of dihydrotestosterone (DHT)
direct metabolite of testosterone

Question 8

female external genitalia differentiation

Answer 8

Normal female external genitalia develop spontaneously (?) in the absence of exposure to the androgenic hormone products of the fetal testis.

Question 9

True Hermaphrodite

Answer 9

Hermes + Aphrodite
Individual with both ovarian and testicular tissue (eg. bilateral ovotestis or testis on one side and ovary on the other)
Both Mullerian- and Wolffian-ducts are present
Rare (e.g., mosaicism, chimerism, or 46, XX with SRY sequence translocated to X chromosome; most frequently 46,XX (57%); XY(13%) és XX/XY(30%))

Question 10

gonadal dysgenesis and its variants

Answer 10

Turner syndrome (45, X0)
Mosaicism (X0/XX, X0/XY, X0/XXX, X0/XYY)
X0/XY Mosaicism

Question 11

turner syndrome phenotype

Answer 11

short stature
skeletal anomalies
cognitive deficits
gonadal failure
minor physical features

Question 12

Mixed gonadal dysgenesis

Answer 12

combined features of turners syndrome and male pseudohermaphroditism
short stature
streak gonad on one side with a testis on the other
unicornuate uterus and fallopian tube- side of streak gonad
karyotype 46 XY/45X0
considerable variation in the sexual phenotype

Question 13

Male pseudohermaphroditism:

failure to produce testosterone

Answer 13

Pure XY gonadal dysgenesis (Swyer syndrome)
Anatomical testicular failure (testicular regression syndrome)
Leydig-cell agenesis
Enzymatic testicular failure

Question 14

Male pseudohermaphroditism:

failure to utilise testosterone

Answer 14

5-alpha-reductase deficiency
Androgen receptor deficiency
Complete androgen Insensitivity (AIS)
Incomplete androgen Insensitivity

Question 15

46, XY/SRY but defects in testosterone synthesis

Answer 15

increased testosterone precursors, decreased DHT

ambiguous external genitalia
male internal genitalia

Question 16

Leydig cell agenesis

Answer 16

46, XY/SRY
testis ==> AMH (partial/complete absence of leydig cells)

no or low testosterone
no or low DhT

female ambiguous external genitalia

+/- male internal genitalia

Question 17

testosterone action in differentition

Answer 17

fetal tissue produces T

in target organ cell binds to receptor

goes to nucleus

DNA to mRnA to protein synthesis to cell differentiation

Question 18

Androgen insensitivity syndrome (AIS) = testicular feminisation syndrome (TFM)

Answer 18

Genetic male with androgen insensitivity
Form of male pseudohermaphroditism
Testis (inguinal)
Deleted or dysfunctional androgen receptor (X-linked recessive or dominant)
Phenotypic females (blind vagina, no Müllerian derivatives)

Treatment: Counseled for “infertility”. Testes removed due to neoplasia risk (usually with estrogen therapy)
Incidence: 1/60,000 male births

Question 19

5-reductase deficiency in 46,XY males

Answer 19

SRY gene  testis
Testosterone and MIS
No DHT  female external genitalia
At puberty  masculinizes and switches from female to male gender… “Huevas a doce”
Form of male pseudohermaphroditism
Prevalent among a group of families in the Dominican Republic

Question 20

specific action of 5alpha-dihydrotestosterone (DHT)

Answer 20

prostate development
external virilization
sexual maturation at puberty

Question 21

sex influenced traits

Answer 21

are inherited autosomally, but has higher penetrance in one sex than the other (e.g. pattern baldness is dominant in males, recessive in females).
The allele is dominant in one sex and recessive in the other

Question 22

putative cause of baldness

Answer 22

testostone to DHT via 5 alpha reductase

Question 23

tissues where aromatase is expressed

Answer 23

brain, bone, adipose, skin, vascular endothelium vascular smooth muscle, ovary, placenta

Question 24

tissue where 5alpha reducatase expressed

Answer 24

type 1
skin sweat glands hiar follicules

type 2 hair follicules and genital skin

Question 25

female pseudohermaphroditism

Answer 25

genetic female

masculinzed genitalia

Question 26

female pseudohermaphroditism: excess fetal androgens

Answer 26

• Congenital adrenal hyperplasia
• 21-hydrxylase deficiency
• 11-hydroxylase deficiency
• 3ß-hydroxysteroid
  dehydrogenase deficiency

Question 27

female pseudohermaphroditism: excess maternal androgens

Answer 27

• Maternal androgen secreting tumours (ovary, adrenal)

- Maternal ingestion of androgenic drugs

Question 28

drugs with andorgenic side effects igested during pregnancy

Answer 28

• Testosterone
• Synthetic progestins (progestagen, contraceptives)
  Danocrine (testosterone derivative, treatment for endometriosis )
• Diazoxide (antihypertensive, K-channel inducer)
• Minoxidil (antihypertensive, vasodilatator)
• Phenytoin sodium (antiepileptic)
• Streptomycin (antibiotic)
• Penicillamine (immunosuppressant)

Question 29

congenital adrenal hyperplasia

Answer 29

accounts for most of patients with female pseudohermaphroditism
specific enzyme defects in steroid biosynthesis
autosomal recessive

Error in cortisol synthesis causing increased ACTH leading to adrenal hyperplasia
Clinical expression:
— Impaired cortisol synthesis
— (Impaired aldosterone synthesis)
— Increased steroid precursors which are androgenic
— Masculinization of female genitalia

Question 30

C21 Hydroxylase deficiency

Answer 30

Most common
17-OH Progesterone cant form 11 Deoxycortisol
Masculinization of female genitalia
Aldosterone synthesis superficially OK… but clinically, often salt losing (renin compensated)
Yupik Eskimos: 1/400 live birthsOverall: 1/10,000 live births

Question 31

complete C21 Hydroxylase defect

Answer 31

absolutely no production of DOC 
masculinzation of female genitalia
sald-loosing
infants:
-adrenal crisis day 4-10
letargic, poor feeding, vomiting, dehydration
-death without treamtent

Question 32

3ßHydroxysteroid Dehydrogenase Deficiency

Answer 32

uncommon
probably incomplete block
masculinization of female genitalia
adrenal insufficiency
high neonatal mortality

Question 33

C11 hydroxylase deficiency

Answer 33

no production of corticosterone or cortisol

masculinzation of female genitalia

Question 34

SLOS: Smith-Lemli-Opitz syndrome

Answer 34

7-dihydro-cholesterol reductase mutation
 Chromosomal locus = 11q12.13
 Prevalence 1/20.000-40.000 livebirth
 Autosomal recessive
 Carrier frequency (Caucasian) 1:30
 Therapy – high cholesterol diet ???

Question 35

main symptoms of SLOS

Answer 35

growth retardation 
developmental delay
microcephaly
broad nasal bridge
phosensitivity
autistic features
urogenital: renal malformation, hypospadias, cryptorchidism, ambiguous genitalia