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REI Written Boards > Disorders of Sexual Development > Flashcards

Disorders of Sexual Development Flashcards

1
Q

Effect of Leydig cell dysfunction

A

Underproduction of testosterone

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2
Q

Describe the phenotype of males with no LH (eg. male with anencephaly and other forms of congenital hypopituitarism)

A
  • Leydig cells all but disappear

- Internal and external genitalia do not develop fully

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3
Q

Effect of Sertoli cell dysfunction

A

Underproduction of AMH -> lack of mullerian duct regression

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4
Q

Describe complete Swyer Syndrome

A
  • No testes (leydig cells) -> no testosterone -> female external genitalia
  • No testes (no Sertoli cells) -> no AMH -> intact Mullerian structures, streak gonads
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5
Q

What is the risk of gonadoblastoma in a patient with gonadal dysgenesis and a Y chromosome?

A

20-30%

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6
Q

What is the most common tumor in gonadal dysgeneiss?

A

Bilateral gonadoblastoma

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7
Q

What are cellular types found in gonadoblastomas?

A

Granulosa, theca, germ cells

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8
Q

Describe incomplete XY gonadal dysgenesis

A

Wide range of testicular function

Leads to wide range of phenotypes (some testicular tissue +/- streak)

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9
Q

What are some malignancies that can be found in gonadoblastomas?

A

Dysgerminoma, embryonal carcinoma seen (can be found WITHIN gonadoblastoma)

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10
Q

What is NR5A1?

A

Encodes steroidogenic factor 1 (SF1), transcription factor essential for development of gonads and the adrenal cortex

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11
Q

Describe implications of mutation in NR5A1

A
  • Homozygous loss-of-function mutations in NR5A1 are rare and result in gonadal dysgenesis and adrenocortical insufficiency
  • Heterozygous loss-of-function mutations in NR5A1 account for approximately 10-15% of cases of testicular dysgenesis and are usually not associated with adrenal insufficiency
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12
Q

What is SRY?

A

Sex-determining region on the Y chromosome

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13
Q

Describe presentation of loss of SRY function

A

Loss of SRY function can result in complete or partial testicular dysgenesis, XY ovarian DSD, or XY ovotesticular DSD

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14
Q

Describe mutations in WT1 and associated diseases (2)

A

WT1 mutations are associated with a variety of conditions, some include partial or complete gonadal dysgenesis

  1. Denys-Drash syndrome is associated with renal failure and high risk for Wilms tumor.
  2. Frasier syndrome is associated with nephrotic syndrome, usually due to focal segmental glomerulosclerosis, and high risk for gonadoblastoma (~50%).
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15
Q

What is the role of WT1?

A

WT1 is involved in both renal development and gonadal development

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16
Q

Name the loss-of-function mutations and inheritance patterns of genes essential for testicular development that can lead to XY dysgenesis (9 genes)

A

Rare causes of XY gonadal dysgenesis are inherited in an autosomal recessive manner
-Mutations in: MAP3K1, CBX2, DHH, DMRT1, FGF9, FOG, GATA4, SOX9, and ZFPM2

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17
Q

Describe effect of gain-of-function mutations in NR0B1

A

Duplications of NR0B1 (DAX1) can cause gonadal dysgenesis (inhibiting activity of NR5A1/SF1)

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18
Q

What is NR0B1?

A
  • Encodes protein for DAX1
  • Does not appear to have a direct role in normal human gonadal development
  • Loss-of-function mutations in NR0B1 do not have a gonadal phenotype, although they do cause adrenal insufficiency (males) and hypogonadotropic hypogonadism (delayed puberty – females)
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19
Q

Loss of function of what genes leads to XY ovarian DSD

A

SRY, CBX2, NR5A1

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20
Q

Describe the presentation of XY ovarian DSD

A
  • XY individual develops ovaries
  • Rare
  • Cells only have one X chromosome; ovarian function similar to Turner’s
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21
Q

What causes testicular dysfunction without atypical genitalia?

A

Persistent Mullerian duct syndrome
Mutations in AMH gene or AMH-R
Normal external male genitalia; variable testicular descent

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22
Q

Describe Leydig cell hypoplasia (LH/HCG receptor defects)

A
  • XY with mutation in this gene will have female external genitalia but lack uterus and fallopian tubes
  • Epididymis and vas deferens may be present
  • Lab findings: Low testosterone despite elevated LH levels; unresponsive to exogenous HCG
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23
Q

What encodes LH/HCG receptor and where is it located?

A

LHCGR gene on chromosome 2p21

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24
Q

Describe Smith-Lemli-Opitz syndrome

A
  • Defect in enzyme that catalyzes last step in cholesterol synthesis, sterol delta-7-reductase (DHCR7 gene)
  • Presentation: Developmental delays, microcephaly, cleft palate, syndactyly, varying degrees of virilization
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25
Q

What causes 17-beta-hydroxysteroid dehydrogenase type 3 deficiency?

A

Caused by at least 15 different mutations in the HSD17B3 gene, which encodes an enzyme required for conversion of androstenedione to testosterone

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26
Q

Describe presentation and lab findings in 17-beta-hydroxysteroid dehydrogenase type 3 deficiency

A
  • Virilization at puberty due to extra-testicular (peripheral) conversion of androsentedione to testosterone
  • Serum testosterone concentrations are often in the lower normal range, whereas serum concentrations of androstenedione, the intermediate before the enzymatic block, are elevated several-fold
  • Ratio of testosterone to androstenedione is usually < 0.8, which distinguishes this disorder from other forms of undervirilization
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27
Q

What causes 5-alpha-reductase type 2 deficiency?
Inheritance pattern?
Chromosome location?

A

Mutations in SRD5A2
Autosomal recessive
Chromosome 2

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28
Q

5-alpha-reductase type 2 deficiency presentation in 46XY

A
  • XY individuals with bilateral testes and normal testosterone formation have impaired external virilization during embryogenesis due to defective conversion of testosterone to dihydrotestosterone
  • External Genitalia: Female (underdevelopment of phallus, urethra, prostate)
  • Internal genitalia: Male (testosterone present, AMH present)
  • Virilization at puberty – increased testosterone or some DHT made (type I enzyme intact)
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29
Q

What is androgen insensitivity?

A

X-linked defect in androgen receptor function

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30
Q

How does androgen insensitivity present in males and females?

A
  • Males: Blind ending vagina, undervirilization, gynecomastia, infertility secondary to oligo/azoospermia
  • Females: Ambiguous genitalia, inguinal hernias/labial masses, primary amenorrhea, normal pubertal development (but diminished pubic hair), virilization at adolescence (clitromegaly)
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31
Q

What is the only clinical instance where gonadectomy can be delayed due to decreased risk of tumor formation?

A

Complete AIS, carries risk of 5-10% of tumor formation

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32
Q

When should gonadectomy be considered for patients with incomplete AIS?

A

Earlier surgery than complete AIS is indicated to prevent the virilization at puberty

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33
Q

How does androgen insensitivity affect mullerian structures in 46XY?

A

Mullerian (paramesonephric) ducts absent as testes (sertoli cells) make AMH normally

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34
Q

How does androgen insensitivity affect Wolffian structures?

A

Wolffian (mesonephric) ducts absent – testosterone cannot act on ducts secondary to absence of AR

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35
Q

How does Lipoid CAH present?

A
  • Caused by deficiency of steroidogenic acute regulatory (StAR) protein
  • Severe adrenal insufficiency very soon after birth, presenting with vomiting, diarrhea, volume depletion, hyponatremia, and hyperkalemia, often with hyperpigmentation
  • XY individuals have phenotypically female external genitalia
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36
Q

What causes P450 side-chain-cleavage (SCC) enzyme deficiency?

A

Mutations in CYP11A1

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37
Q

P450 side-chain-cleavage (SCC) enzyme deficiency presentation

A

Similar to lipoid CAH

  • Characterized by adrenal insufficiency and hyperpigmentation presenting in infancy or childhood,
  • Phenotypically female external genitalia in XY individuals
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38
Q

17-alpha-hydroxylase deficiency genetics

A

Autosomal recessive mutations in CYP17A1 (chromosome 10); encodes protein with both 17-alpha-hydroxylase and 17,20-lyase activities

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39
Q

17-alpha-hydroxylase deficiency presentation

A

-Characterized by severe undervirilization in XY; may result in typical female external genitalia.
-Most affected individuals have hypertension and HYPOkalemia because of overproduction of mineralocorticoids (no salt wasting)
-Symptomatic adrenal insufficiency is rare
-Mutations in CYP17A1 that affect only 17,20-lyase activity are rare and produce undervirilization without cortisol deficiency (sexual infantilism; Tanner I/11)
Presentation: most are hypertensive (increase mineralocorticoids)

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40
Q

17-alpha-hydroxylase deficiency anatomic/reproductive presentation in males and females

A

Males – phenotypically female (no androgen) with blind vagina, neither mullerian or wolffian structures, intra abdominal testes
Females – normal Mullerian structures, primary amenorrhea, hypergonadotrophic hypogonadism

41
Q

What forms of CAH lead to XY DSD?

A
  1. 3-beta hydroxysteroid dehydrogenase type 2 deficiency
  2. 17-alpha-hydroxylase deficiency
  3. P450 oxidoreductase (POR) deficiency
  4. Lipoid CAH
  5. P450 side-chain-cleavage (SCC) enzyme deficiency
42
Q

What is the inheritance pattern for all androgen insensitivity disorders?

A

X linked recessive

43
Q

Describe external genitalia for complete vs incomplete AIS?

A

Complete AIS- female

Incomplete AIS- female with cliteromegaly

44
Q

Describe Wolffian structures for complete vs incomplete AIS?

A

Complete AIS- absent

Incomplete AIS- underdeveloped

45
Q

Define totipotency

A

Ability of single cell to divide/produce all the differentiated cells in an organism (until 16-cell stage)

46
Q

Define pluripotent

A

Stem cells that have the potential to differentiate into the three germ cell layers (endoderm, mesoderm, ectoderm). Can give rise to any fetal/adult cell type but alone can’t develop into fetal/adult organism.

47
Q

Define multipotent

A

Progenitor cells that have the potential to give rise to cells from multiple but a limited number of lineages (ex. mesechymal stem cells - differentiate into osteoblasts, chondrocytes and adipocytes)

48
Q

Define unipotent

A

Capacity to differentiate into only one cell type (ex. hepatocytes, skin) aka precursor cells

49
Q

4 genes important in ovarian development

A
  • RSPO1 (respondin 1)
  • WNT4 (wingless family of genes)
  • DAX-1 (dosage sensitive adrenal hypoplasia)
  • FOX-L2 (Forkhead box L2)
50
Q

What happens with sex chromosomes during meiosis?

A

In males, X and Y align and can recombine during meiosis (Y has pseudo-autosomal region)

51
Q

Where are genes involved in testis formation and development located?

A

Y chromosome

52
Q

What cells secrete FGF-9 and what does it do?

A

Sertoli cells

Reinforces SOX-9

53
Q

What cells secrete PGD2 and what does it do?

A

Sertoli cells

Play a role in testis determination

54
Q

What is SRY and where is it?

A

Sex-determining region Y chromosome

Distal p-arm of Y (adjacent to psuedoautosomal region)

55
Q

What does SF-1 do?

A

Steroidogenic factor 1, a nuclear “orphan receptor”: binds and activates the SRY promoter

56
Q

What does WT-1 do?

A

Transcription factor that can activate promoter of SRY

57
Q

What does GATA-4 do?

A

Transcription factor that can activate promoter of SRY

58
Q

What are SRY HMG box protein family involved in?

A

Downstream events of sexual differentiation

59
Q

What is the most likely SRY target gene?

A

SOX-9

60
Q

What can virtually all male-female sex reversal be explained by?

A

Failure to generate sufficient levels of SOX-9 to promote the positive feedback loops

61
Q

Causes of XX DSD (3)

A

Adrenal overproduction of androgens
Gonadal overproduction of androgens
Gestational hyperandrogenism

62
Q

Genetics of classic CAH (mutation, inheritance, chromosome)

A
  • Mutation in CYP21A2 gene that encodes 21-hydroxylase (P450c21)
  • Autosomal recessive, chromosome 6
63
Q

Most frequent enzymatic defect to cause ambiguous genitalia

A

Classic CAH (95% of CAH)

64
Q

Diagnosis of classic CAH

A

Elevated 17-OHP (may have false positive in luteal phase), low DOC and 11-deoxycortisol, low aldosterone, low cortisol -> adrenal crisis

65
Q

Androstenedione and DHEA in classic CAH

A

Overproduced

66
Q

Electrolytes in classic CAH and physiologic result

A

Salt-wasting: hypoNa, hyperK -> HTN

67
Q

Most common cause of endocrine death

A

Classic CAH

68
Q

Genetics of most non-classical CAH patients

A

Compound heterozygotes

69
Q

Second most common cause of CAH in the US

A

11-beta hydroxylase deficiency

70
Q

Genetics of 11-beta hydroxylase deficiency (mutation, inheritance, chromosome)

A
  • Mutation in CYP11B1 gene encoding 11-beta hydroxylase (P45011b)
  • Autosomal recessive, chromosome 8
71
Q

Labs in 11-beta hydroxylase deficiency

A

Significant elevation in 11-deoxycortisol and mild elevation in 17-OHP

72
Q

Electrolytes in 11-beta hydroxylase deficiency and physiologic result

A

Hypernatremia, hypokalemia (mineralocorticoid effects of elevated 11-deoxycortisol) -> hypertension

73
Q

3rd most common enzymatic deficiency in CAH

A

3-beta hydroxysteroid dehydrogenase type 2 deficiency

74
Q

Inheritance of 3-beta hydroxysteroid dehydrogenase type 2 deficiency

A

Autosomal recessive

75
Q

Presentation of 3-beta hydroxysteroid dehydrogenase type 2 deficiency

A

Cortisol + aldosterone deficiency (XX->mild virilization; XY->undervirilization)
• Elevated 17-hydroxypregnenolone and elevated 17-OHpregnenolone/cortisol ratio
• Another isoform of 3-beta-HSD that is encoded by a different gene (HSD3B1) and expressed in the liver, converts 17-hydroxypregnenolone to 17-OHP and DHEA to androstenedione (weak androgen)

76
Q

P450 oxidoreductase deficiency mutation

A

Mutations in POR gene -> combined CYP21A2 and CYP17A1 deficiency

77
Q

Labs in P450 oxidoreductase (POR) deficiency

A

Mild 17-OHP elevation; variable glucocorticoid deficiency; risk of salt-wasting and adrenal crisis

78
Q

Sexual differentiation phenotypes in POR deficiency

A

XX->mild virilization; XY->undervirilization; similar to 3B-HSD deficiency

79
Q

Glucocorticoid resistance genetics

A

Mutations in the NR3C1 gene that encodes the glucocorticoid receptor

80
Q

Glucocorticoid resistance pathophysiology

A

Impaired response to cortisol results in loss of negative feedback and high levels of ACTH –> overproduction of mineralocorticoids (HTN, hypoK, alkalosis) and androgens (ambiguous genitalia, hyperandrogenism later in life in females)

81
Q

Glucocorticoid resistance phenotype

A

Can cause features similar to those of virilizing forms of CAH, though cortisol synthesis is not disrupted

82
Q

What is XX testicular DSD and how does it present?

A

Conditions in which the gonads develop along testicular rather than the ovarian pathway
Labial/scrotal mass

83
Q

What is XX ovotesticular DSD?

A

Both ovarian follicular and testicular tubular tissue are present; diagnosis is made based on histology (formerly true hermaphrodite)

84
Q

What is the % of patients with each histology in XX ovotesticular DSD?

A
  • 20% bilateral ovotestis
  • 50% unilateral ovotestis + unilateral ovary or testis
  • 30% ovary + testis
85
Q

Fertility potential in XX testicular DSD

A

Infertile: no spermatogenesis due to lack of Y chromosome

86
Q

Fertility potential in XX ovotesticular DSD

A

May have some fertility potential if intact ovarian tissue present

87
Q

Causes of XX testicular or ovotesticular DSD (5)

A
  • Presence of SRY (de la Chapelle syndrome):
  • Mutations in NR5A1 (SF1)
  • Duplication of SOX9:
  • Inappropriate expression of SOX3:
  • Loss-of-function mutations in genes that repress testicular pathways (WNT4, RSPO1)
88
Q

de la Chapelle syndrome

A

Presence of SRY. Due to translocation of SRY to the X chromosome or an autosome and accounts for roughly one-half of cases of XX testicular DSD

89
Q

Mutations in NR5A1 (SF1)

A

Gain-of-function mutations that cause inappropriate activation of testicular pathways in the XX gonad; described in ~10-20% of XX testicular or ovotesticular DSD cases

90
Q

Duplication of SOX9

A

SOX9 encodes a transcription factor that functions downstream of SRY and is both necessary and sufficient for testicular development.

91
Q

Inappropriate expression of SOX3

A

SOX3 encodes a transcription factor similar to SOX9. SOX3 does not have role in normal gonadal development, but activates testicular pathways when inappropriately expressed

92
Q

Two loss of function mutations in genes that repress testicular pathways (lead to XX testicular/ovotesticular DSD)

A

WNT4 and RSPO1

93
Q

Syndrome a/w WNT 4 mutation, inheritance, and phenotype

A

Associated with the autosomal recessive SERKAL syndrome (sex reversal with dysgenesis of kidneys, adrenals, and lungs)

94
Q

Syndrome a/w RSPO1 mutation and inheritance

A

Autosomal recessive cause of palmoplantar hyperkeratosis in combination with testicular or ovotesticular DSD

95
Q

Genetics of aromatase deficiency

A

Mutations in CYP19A1

96
Q

Phenotypes in aromatase deficiency

A
  • Female: Can result in overproduction of testosterone by an otherwise normal ovary -> ambiguous genitalia, hyperandrogenism, hypergonadotrophic hypogonadism, multicystic ovaries
  • Males: Normal sexual differentiation/puberty; E2 deficiency -> continued linear growth due to lack of epiphyseal closure (extremely tall) and osteoporosis
97
Q

Maternal effect when carrying infant with aromatase deficiency

A

Deficient placental expression of aromatase -> androgens from fetus cross the placenta and also cause maternal virilization

98
Q

Why is gestational hyperandrogenism so rare?

A

Because the placenta produces the aromatase enzyme, which converts androgens to estrogens, only very high levels of maternal androgens can overcome placental aromatase to cause virilization of the fetus

99
Q

Causes of gestational hyperandrogenism (2)

A

Maternal luteoma or theca lutein cyst

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