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Reproductive System I > Disorder of Sexual Development DSA (Dr. Cole) > Flashcards

Disorder of Sexual Development DSA (Dr. Cole) Flashcards

1
Q

Sexual Determination and Differentiation

A
  • A Dynamic Process
  • A Sequential Process

1) Establishment of SEX at Fertilization
2) Development of Gonadal Sex
3) Development of Secondary Sexual Characteristics

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2
Q

In the Beginning

A

Zygotes…..

WEEK 4: PRIMORDIAL GERM CELLS

  • Recognizable in the Yolk Sac Wall
  • Mitosis
  • Migrate through the DORSAL MESENTERY of the HINDGUT

WEEK 5: MEDIOVENTRAL Border of the UROGENITAL Ridge thickens to become the GONADAL RIDGE

WEEK 6: Primordial Germ Cells INCORPORATED into the PRIMARY SEX CORDS

BEFORE WEEK 6: Sex is INDISTINGUISHABLE!!!!!!!!!!

  • **Late Germ Cells:
  • Disintegrated
  • May Develop in EXTRAGONADAL TUMORS

**EXTERNAL GENITALIA of BOTH Sexes IDENTICAL top to about Week 8*****

MALES:

  • Y Chromosome
  • Testis Organization BEGINS in Week 6 and 7!!!!!

FEMALES:
- Development BEING Week 12!!!!

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3
Q

Development of Male Genitalia

A
  • At the 8TH WEEK, the External Genitalia of BOTH SEXES are IDENTICAL and have the Capacity to DIFFERENTIATE in BOTH DIRECTIONS: Male or Female
  • DHT stimulates GRWOTH of the GENITAL TUBERCLE and INDUCES FUSION of URETHRAL FODLS and LABIOSCROTAL SWELLINGS
  • DHT INHIBITS Growth of VESICOVAGINAL SEPTUM preventing the Development of the Vagina

**Male External Genitalia is ENTIRELY FORMED at the END of 12 Weeks!!!!!!!!!

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4
Q

Historically

A
  • Search for the hypothetical TESTIS DETERMINING FACTOR (TDF)
  • SED determining REGION was discovered on the Y Chromosome (SRY GENE!!!!!!!!!)
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5
Q

Sry Gene

A
  • ONE EXON
  • GC Rich in 5’ REGION
  • 2 ZINC FINGER RECOGNITION Sites for SP1!!!!!!!!!!!!!!
    1) SP1 binding to the GC Rich 5” Region causes for an INCREASE in TRANSCRIPTION
    2) The DNA made has a HMG OCTOBER on it
    3) The Protein made has a HMG OCTAMER which binds to the MINOR GROOVE and induces CONFORMATIONAL CHANGE for other Factors to Bind and Direct Transcription

*** This HMG MOTIF is a Conserved protein sequence originally recognized by Electrophoretic properties; these proteins participate in Transcription, Replication, Recombination and Repair. Three groups are Recognized with Similar Functions

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6
Q

SRY Mutations

A

1) HMG October Mutations
- —>
2) NO Binding to DNA
- —->
3) NO MALE Differentiation
- —->
4) 46, XY FEMALE!!!!!!!!

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7
Q

SRY Translocation to X Chromosome

A

PSEUDO AUTOSOMAL REGION (PAR): Pairs and Recombines with X Chromosome**

  • SRY is near but not in the PAR> Recombination may TRANSLOCATE this Gene to the X Chromosome!!!!!!!!!!
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8
Q

Steriodogenic Factor 1

A
  • SRY discovered FIRST but SF1 is REQUIRED for SRY Expression
  • Gonads and Adrenal Development REQUIRE SF1!!!!!!

Required for:

  • Sexual Determination
  • Sexual Differentiation
  • Steriodogenesis
  • Lipid Metabolism
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9
Q

SOX 9 Gene (SRY- Related HMG- Box 9)

A
  • WT1 and SF1 expression si REQUIRED for SRY
  • SRY Expression in SERTOLI Cells UP-REGUALTES SOX9 Expression

*** SOX9 MUTATION —> CAMPTOMELIA DYSPLASIA!!!!!!!!!!

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10
Q

Campomelia Dysplasia

A

A) BOWING OF LONG BONES!!!

B) Shortened Long Bones

C) Skeletal DYSLPASIA

  • Hypoplastic Scapulae
  • Narrowed Iliac Bones
  • Chest Hypoplasia (Respiratory Distress)
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11
Q

Campomelia Dysplasia Cont

A

ASSOCIATED with SEX REVERSAL due to GONADAL DYSGENESIS in 46, XY**

A) The only Target for SOX 9 is ANTI-MULLERIAN HORMONE (AMH)

B) NO SOX9 —-> Mullein Ducts DO NOT GENERATE!!!!!!!! (Ovary Development Occurs)

C) AMH Diffuses from SERTOLI CELLS to Paired MULLEIN Duct PRIMORDIAL
- Attached to Receptors (SERINE-THREONINE Protein Kinases: Single Transmembrane)

  • Apoptosis
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12
Q

Mullerian Ducts vs Wolffian Duct

A

MULLERIAN DUCT (Paramesonephric):

  • Uterine Tubes
  • Uterus
  • Cervix
  • Upper THIRD of Vagina
  • Hormone Dependent Development

WOLFFIAN DUCT (Mesonephric):

  • Ductus Deferens
  • Seminal Vesicles
  • Androgen Dependent Development
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13
Q

DAX 1 Gene

A
  • DOSAGE Sensitive Sex Reveral: ADRENAL Sensitive Sex Reversal on X Chromosome!!!!
  • DAX 1 is normally DOWN-REGULATED in developing TEstes but NOT in Ovary
  • A MUTATION or DELETION of DAX1 results in CONGENITAL ADRENAL HYPOPLASIA and HYPOGONADOTROPIC HYPOGONADISM!!!!!!!!!!
    (Testicular Development Occurs)

*****SRY may INHIBIT DAX1 Normally. IN the Duplicated state, there may be Insufficient SRY to repress DAX2 Expression!!!!

  • DAX 1 Gene Duplication in Males —-> 46, XY Females
  • DAX 1 Gene Duplication in Females —> No Affect!!!!!!
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14
Q

Sex Reversal

A

1) SRY MUTATION
a) 46, XY Females
b) 46, XX Males with SRY Transocated to the X

2) SOX9 Mutation
3) DAX1 Duplication

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15
Q

Steroid Hormones

A
  • Androgens, Estrogens, Progesterone (Progesterone)
  • Made of Transformed in Gonads, Adrenal Cortex, and PERIPHERAL SITES
    a) Skin
    b) Fat
    c) Brain
    d) Placenta
  • GENETIC DISORDERS
    a) Androgens or Estrogens ONLY
    b) Adrenocortical and Sex Steroidegenesis Together
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16
Q

3 Beta- Hydroxysteroid Dehydrogenase Deficiency

A
  • NO Glucocorticoids, Mineralocorticoids, Androgens, Estrogens
  • Salt EXCRETION in URINE
  • EARLY DEATH
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17
Q

21 Alpha Hydroxylase Deficiency

A
  • MOST COMMON Form of Congenital Adrenal HYPERPLASIA
  • Usually a PARTIAL DEFICIENCY
  • ACTH ELEVATED, Causing an INCREASED Shift to SEX HORMONES and Masculinization
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18
Q

11 Beta Hydroxylase

A
  • DECREASED Cortisol Aldosterone, Corticosterone
  • Increased DEOXYCORTICOSTERONE leading to FLUID RETENTION and HYPERTENSION

*** Also MASCULINIZATION occurs

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19
Q

17 Alpha Hydroxylase Deficiency

A

1) ** PREGNOLONE to 17 ALPHA HYDROXY PREGNOLONE*
2) * PROGESTERONE to 17 ALPHA HYDROXY PROGESTERONE*
3) *** 17 ALPHA HYDROXY PREGNOLONE to DHEA*
4) *** 17 ALPHA HYDROXY PROGESTERONE to ANDROSTENEDIONE**
- NO Sex Hormones or Cortisol
- Elevated production of MINERALOCORTICOIDS causes SODIUM and FLUID RETENTION leading to HYPERTENSION
- Phenotypically FEMALE but UNABLE to Mature

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20
Q

17 Beta Hydroxysteroid Dehydrogenase Deficiency

A

1) ** DHEA to ANDROSTENEDIOL**
2) *** ANDROSTENEDIONE to TESTOSTERONE*****
- NO TESTOSTERONE!!!!
- ELEVATED Estrogens from Androstenedione
- INCREASED FSH and LH
- Phenotypically FEMALE
- VIRILIZATION at PUBERTY!!!!!

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21
Q

Aromatase Deficiency

A

1) * TESTOSTERONE to 17 BETA ESTRADIOL**
2) **ANDROSTENEDIONE to ESTRONE**
- ELEVATED Testosterone and Androstenedione
- MASCULINIZATION of Female Genitalia
- PUBERTAL FAILURE!!!

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22
Q

5 Alpha Reductase Deficiency

A

TESTOSTERONE to DHT*

  • Female GENITALIA!!!
  • Partial VIRLIZATION at Puberty
  • Elevated Testosterone to DHT Ratio!!!
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23
Q

Intersex and Fetal Mosaicism

A
  • 46 XX/ 46 XY
  • Presence of BOTH Genotypes may yield Male and Female Structures!!!!!!
  • Penis is often Underdeveloped
  • One or Both Testes may be Palpable but Undescended

***Whenever an Infant has BOTH Hypospadias and an Undescended Testis, the possibility of Intersex should be Considered

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24
Q

Hypospadias

A
  • Hypospadias is an abnormality of ANTERIOR URETHRAL DEVELOPMENT in which the Urethral Opening is ECTOPICALLY located on the VENTRUM of the Penis PROXIMAL to the Tip of the Glans Penis
  • The opening may be as PROXIMAL as the Scrotum or Perineum
  • The Penis is more likely to have associated VENTRAL Shortening and Curvature, called CHORDEE, with more Proximal Urethral Defects (Defect in development occurring between WEEKS 8-20.!!!!!!!!!!!!!!!!!!!!)
25
Q

Urogenital Sinus

A
  • Normally forms the LOWER TWO-THIRDS of the Vagina in Female
  • Along with the Mesonephric Ducts, the Urogenital Sinus develops into the PROSTATE, SEMINAL VESICLES and BULBOURETHRAL GLANDS!!!
26
Q

Ovotesticular Disorder of Sexual Development

A
  • BOTH Ovarian and Testicular Tissue is ONE or BOTH Gonads
  • Internal and External Differentiation is Variable
    a) Often Ambiguous
    b) CRYPTORCHIDISM Common
    c) HYPOSPADIAS is Common
  • OVOTESTIS is the MOST COMMON GONAD FOUND!!!!!!!
27
Q

46, XY Disorder of Sexual Development

A
  • Abnormalities of Gonad Development
  • Cholesterol SYNTHESIS Defects
  • Testosterone SYNTHESIS Defets
  • Testosterone METABOLISM Defects
  • ANDROGEN action Defects
  • Persistence of MULLEIRAN DUCTS Syndrome
  • Congenital Non-Genetic 46, XY DSD!!!!!!!
28
Q

Abnormalities of GOnad Development

A
  • Gonadal Genesis
  • Gonadal Dysgenesis: Complete and Partial Forms
  • Embryonic Testicular REGRESSION Syndrome
29
Q

Abnormal Cholesterol Synthesis

A
  • 7 DIHYDROCHOLESTEROL REDUCTASE!!!!!!!!!!
30
Q

Cholesterol Synthesis Defects

A

SMITH-LEMLI-OPTIZ SYNDROME:
- A Congenital Multiple Anomaly syndrome caused by an abnormality in Cholesterol Metabolism resulting from deficiency of the enzyme 7-DEHYDROCHOLESTEROL (7-DHC) REDUCTASE.

  • Characterized by Prenatal and Postnatal GROWTH RETARDATION, MICROCEPHALY, moderate to severe MENTAL RETARDATION, and multiple major and minor Malformations.
  • Malformations include distinctive facial features, CLEFT PALATE, CARDIAC DEFECTS, UNDERDEVELOPED External Genitalia in males, POSTAXIAL POLYDACTYLY, and 2-3 SYNDACTYLYL of the Toes.
  • Clinical spectrum is wide and individuals have been described with normal development and only minor malformations.
31
Q

Testosterone Synthesis Defects

A

MULTIPLE CAUSES
- Impaired LEYDIG Cell Differentiation

  • Defects in Adrenal and Testicular Steroidogenesis
  • STAR Deficiency
  • P450scc Deficiency
  • 3 Beta HYDROXYSTEROID DEHYDROGENASE Deficiency
  • 17 ALPHA HYDROXYLASE DEFICIENCY
  • 17 BETA HYDROXYSTEROID DEHYDROGENASE Deficiency
32
Q

Testosterone Metabolism Defects

A
  • 5 ALPHA REDUCTASE Deficiency
33
Q

ANDROGEN INSENSITIVITY SYNDROME

A
  • ** ANDROGEN INSENSITIVITY SYNDROME:
  • Complete and Partial Forms
  • Mutations in the ANDROGEN Receptor
34
Q

Defects in Androgen Action Cont

A
  • XY sex chromosomes!!!!!!!!!
  • Complete and partial forms
  • Enlarged breasts with juvenile nipples
  • Mutations in the Androgen Receptor
  • Female external genitalia with SMALL LABIA
  • Female body shape
  • ABSENT or scanty Axillary or Pubic hair
  • BLIND-ENDING Vagina
  • ABSENT or Rudimentary Internal
    Genitalia
  • CRYPTOCHIDISM
  • NORMAL male Testosterone levels
  • Testes produce androgens and estrogen
  • ELEVATED Gonadotrophins: FSH, LH, hCG
  • No male pattern baldness
35
Q

Androgen Receptor

A
  • NUCLEUS HORMONE Receptor Family

- Mediates Growth and Differentiation in AR Responsive Tissues

36
Q

Persistence of Mullein Ducts Syndrome

A
  • Defects in AMH SYNTEHSIS!!!!!!

- Defect in AMH Receptor

37
Q

Congenital Non-Genetic 46, XY DSD

A

MATERNAL INTAKE OF ENDOCRINE DISRUPTORS:
- Chemicals that Disrupt the Endocrine System

COMMON ENDOCRINE DISRUPTERS

  • Bisphenol-A
  • Phthalates
  • Parabens
  • Polybrominates Diphenyl Esters (PBDE)
  • Polychlorinated Biphenyls (PCB)
  • Dioxin
  • Pesticides/ Herbicides
  • Heavy Metals
38
Q

Disorders of Sex Development

A

1) Breast Development is USUAL at PUBERTY

2) Menses occur in > 50%
a) Ovarian tissue may function Normally
b) Testicular Tissue is almost always Diagenetic (Abnormal Embryonic Development of Tissue)

3) 46, XX DSD
a) SRY+
b) SRY - (MAJORITY)!!!!!!!!

4) 46, XY/ 46, XY DSD

5) OVOTESTICULAR DSD
- “True hermaphrodite”

6) MALE 46,XY DSD
- “Pseudohermaphrodite”

7) FEMALE 46,XX DSD
- “Pseudohermaphrodite”

39
Q

Ovotesticular Disorder of Sexual Development

A

OVOTESTICULAR DSD
- Both Ovarian and Testicualr Tissue in One or Both Gonads

  • Internal and External Differentiation is VARIABLE
    a) Often Ambiguous
    b) Cryptorchidism Common
    c) Hypospadias Common
  • Ovotestis is the MOST COMMON Gonad Found
40
Q

Male 46 XY DSD

A

1) 17 BETA HYDROXYSTEROID DEHYDROGENASE (17 BHSD)**
- 5 Isoenzymes (Different forms of Enzymes)

  • Type 3 - MOST COMMON CAUSE
    a) Component of ER
    b) MOST FREQUENT cause of Male PSEUDOHERMAPHRODITISM due to Testosterone Deficiency

2) 5 ALPHA REDUCTASE***

41
Q

17β-Hydroxysteroid Dehydrogenase Deficiency

A
  • 46,XY with Female EXTERNAL GENETALIA
  • TESTES and WOLFFIAN Derivatives
  • At Puberty – VIRILIZATION
    a) Deepening voice
    b) Clitoral enlargement
    c) Hirsutism
    d) Male muscularity
    e) Breast development
42
Q

5α-Reductase Deficiency

A

A) DEFICIENT CONVERSION of TESTOSTERONE to DHT:
- DEFICIENT DHT to bind to Androgen Receptor

B) TWO ISOZYMES:

  • Type 2:
    1) Expressed BEFORE and AFTER BIRTH
    2) PROSTATE, WOLFFIAN Derivatives, SCROTUM, LIVER
  • Type 1:
    1) Expressed in NON-GENITAL Tissues

C) In Females – genitalia NORMAL; MENARCHE DELAYED

43
Q

5α - Reductase Deficiency Cont

A
  • EXTERNAL GENITALIA appear Female at Birth
  • TESTES Extra-Abdominal; usually Inguinal
  • Hypospadic MICROPHALLUS
  • BLIND Vaginal Pouch

***Strongly suspected with NORMAL BLOOD TESTOSTERONE but elevated T: DHT Ratio!!!!!!!!

44
Q

Female 46, XX DSD

A

A) AROMATASE (Cytochrome P450- Aromatase) Deficiency

B) Expressed in OVARY and TESTIS

1) Also in Skin
2) Fat
3) Brain
4) Placenta

C)Tissue Specific PROMOTERS

1) OVARINA GRANULOSA CELLS
- Induced by FSH and cAMP!!!

2) FIBROBLASTS
- Induced by GLUCOCORTICOIDS!!!

3) Placenta is Constitutively HIGH

45
Q

Excess Androgen

A
  • MASCULINIZE External Genitalia during Female Development
  • Prematurely Virile External Genitalia of affected Male
  • Virile a Woman during Pregnancy of affected Child
46
Q

Virilization in Pregnant Female

A
  • Acne
  • LOW PITCH VOICE
  • Clitoral HYPERTROPHY
  • Child: AMBIGUOUS GENITALIA
47
Q

Klinefelter Syndrome

A
  • Most common cause of MALE HYPOGONADISM
  • 1 in 500 Male Births
  • 47, XXY
  • Variants: XXY, XXXXy, XXYY, and XXY/ Mosaics
  • Usually from Maternal Nondisjuction
48
Q

Kleinfelder Syndrome Clinical Presentation

A

A) Birth: Normal

B) Childhood: Normal

C) Puberty: May be DELAYED
- As Gonadotropins INCREASE, Seminiferous Tubules DO NOT Enlarge; Undergo Fibrosis and Hyalinization —> SMALL FIRM TESTES

  • Obliterated Seminiferous Tubules —–> AZOOSPERMIA!!!
49
Q

Kleinfelder Syndrome Clinical Presentation CONT 1

A

A) LEYDIG Cells: Functionally Abnormal
- Testosterone production DECREASED

  • Serum LH INCREASED (Causes Leydig Cells to Secrete ESTRADIOL)

B) Secondary Sexual Development Variable
- None to Normal

C) High E: T Ratio responsible for Feminization and Gynecomastia

D) Estradiol INCREASES SHBG —–> REDUCES Free Testosterone (Total [T] may be Low/ Normal)

**** In the classic form of Klinefelter syndrome, postpubertal levels of FSH and LH are well ABOVE NORMAL. TESTOSTERONE levels VARY but are usually BELOW NORMAL or at the low end of the normal range!!!

50
Q

Kleinfelder Syndrome Clinical Presentation CONT 2

A

A) GYNECOMASTIA can Occur
- Increased Risk of BREAST CANCER

B) Abnormal Skeletal Proportions: LS> US
- Increased HEIGHT Variable

C) INTELLIGENT
- ~20%

51
Q

Monosomies

A
  • Autosome MONOSOMES are LETHAL!!!!!!!!!!
  • Y Chromosome Monosomy is LETHAL (45, Y)
  • X Chromosome Monosomy is VIABLE (45, X)
52
Q

Turner Syndrome

A
  • 45, X
  • 1 in 2000 live Female Births
  • 98-99% of 45, X Fetuses DIE in UTERO
  • 20% of all ABORTUSES with ABNORMAL Chromosomes
  • Normal Intelligence
53
Q

Tuner Syndrome Clinical Presentation

A

A) Gonadal Dysgenesis

B) Short Stature

C) Webbed Neck

D) Coarctation of Aorta

E) High Arched PALATE

F) Shild like Chest with WIDELY Spaced Nipples

54
Q

Tuner Syndrome Clinical Presentation CONT 1

A

A) Short Metatarsals

B) Renal Abnormalities

C) Cubitus Valgus

D) Edema of Hands and Feet

E) MICROGNATHIA

55
Q

Tuner Syndrome Clinical Presentation CONT 2

A

A) LACK of OVARIAN Development leads to DEFICIENT Secretion of SEX STEROIDS

B) Elevated LH/ FSH

C) Decreased Estrogen

D) Increased incidence of DIABETES MELLITUS, Inflammatory Bowel Disease, and Autoimmune Disease

56
Q

Turner Syndrome and Mosaics

A
  • 45,X = 50%!!!!!!!!!!!!!!
  • 45,X/46,XX = 15%
  • 46,X,iXq = 15%
  • 45,X/46,X,iXq ~ 5%
  • 45,X, other X abnormality ~ 5%
  • Other 45,X/?mosaics ~ 5%
57
Q

45,X/46XY Mosaics

A
  • Important to have KARYOTYPE of all Turner Females to rule out Mosaicism
  • Presence of any Y Chromosome material INCREASES the risk of GONADOBLASTOMA to Greater than 95%

REMOVE GONADAL TISSUE REMOVES RISK!!!!!!**

58
Q

Noonan Syndrome

A

A) “Male Turner” Syndrome

B) AUTOSOMAL DOMINANT

C) Mutations in PTPN11 Gene (About Half of Cases)
- KRAS: More SEVERE FORM!!!!!!!

  • RAF1: Heart Problems (Hypertrophic Cardiomyopathy)
59
Q

Noonan Syndrome Characteristics

A
  • Delayed Puberty
  • Down-slanting or WIDE-SET EYES
  • Hearing loss (varies)
  • Low-set or Abnormally shaped EARS
  • MILD Mental RETARDATION (only in about 25% of cases)
  • Pulmonary STENOSIS
  • Sagging EYELIDS (PTOSIS)!!!!!
  • SHORT STATURE!!!!!!!!!!!
  • SMALL PENIS
  • UNDESCENDED TESTES
  • Unusual Chest SHAPE (usually a sunken chest called PECTUS EXCAVATED)!!!!!!!!!!!!!!
  • WEBBED and SHORT-APPEARING NECK!!!!!!!!!
  • Fertility problems but FERTILE

Reproductive System I (18 decks)

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