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Repro > Diaz-Thomas/Phillips - DSD > Flashcards

Diaz-Thomas/Phillips - DSD Flashcards

1
Q

Sexual determination

A

GENETICS (XX or XY): what gonad looks like

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2
Q

Sexual differentiation

A

HORMONES: process whereby internal and external repro organs are formed

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3
Q

Genotypic/chromosomal sex

A

XX or XY

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4
Q

Phenotypic/gonadal sex

A

Secondary sex characteristics

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5
Q

Sexual identification

A

Sex you identify with

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6
Q

Sexual preference

A

Same of different sex partner preference

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7
Q

What are the 5 general concepts of care when working with the families of pts with DSD?

A
  • Gender assignment must be avoided before expert eval in newborns
  • Eval and long-term mgmt must be performed at center w/experienced, multi-disciplinary team
  • All individuals should receive gender assignment
  • Open communication w/pts and families essential, and participation in decision-making encouraged
  • Pt, family concerns should be respected and addressed in strict confidence
  • NOTE: these disorders are usually not life-threatening, so can often REASSURE pts/families
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8
Q

What genes are important in the devo of the urogenital ridge?

A
  • WT1
  • SF1
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9
Q

When/how does sexual determination begin in fetal devo?

A
  • Weeks 4-6 of gestation
  • Primordial germ cells: arise from yolk sac endoderm and migrate to gut, then through dorsal mesentery to reach gonadal/genital ridge
    1. Gonadal ridge: thickening of intermediate mesoderm and overlaying coelomic mesothelium
  • Germ cells NOT required for initial devo of testes: migrate in response to signals, so there may be a lack of germ cells if there is a signaling problem
  • Permission or restriction of meiosis favors oocyte or spermatogoonia development
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10
Q

What are some of the important genes in sex determination?

A
  • Urogenital ridge: WT1, SF1
  • Male: SRY (sertoli cells by wks 8-9), SOX9, SF1, DHH
  • Female: RSPO1, WNT4, DAX1
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11
Q

What genes/hormones are involved in the sex determination of males (image)?

A
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12
Q

What genes/hormones are involved in the sex determination of females (image)?

A
  • Note: the ovary does NOT develop in the absence of germ cells
  • Also DAX1: INH devo of the testes (on X chrom)
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13
Q

What two syndromes are associated with mutations in WT1? How will they present?

A
  • WT1: wilms tumor suppression gene on chrom 11
  • Undervirilized males -> FEMALES
  • Denys Drash: genital abnormalities w/XY gonadal dysgenesis or XX
    1. Nephropathy that progresses to renal failure in first 3 years of life
    2. Wilms tumor
    4. Insomnia, abdominal pain, constipation, anuria, growth delay, loss of playfulness
  • Frasier: normal female external genitalia w/XY
    1. Streak gonads that freq devo into GU tumor (gonadoblastoma)
    2. Nephrotic syndrome (FSGS) that can progress to ESRD (later than with DD)
    3. Auto dom, de novo mutations
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14
Q

What are the consequences of SF1 mutations?

A
  • Associated with adrenal and gonadal dysgenesis
  • Adrenal insufficiency congenita
  • External female, or undervirilized male presentation
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15
Q

When do internal and external sexual differentiation occur? What things are necessary for male sex devo?

A
  • 8-12 weeks
  • Male sex devo:
    1. Androgen receptors and 5-alpha reductase are essential for this process: internal and external male genital development
    2. Testosterone needed for Wolffian duct to remain, and for descent of the testes into the scrotum (w/help of Ins3)
    a. Hypospadias: disorder of testosterone action or timing
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16
Q

What is persistent mullerian duct syndrome?

A
  • Male phenotype: no ambiguous genitalia, but may have cryptorchidism or hernia uteri inguinale, and present with these
  • Few males are fertile, and there is a high incidence of post-natal testicular degeneration
  • MIS/AMH mutation or deficiency
17
Q

What is vanishing testis syndrome?

A
  • 46 XY male who may have no palpable gonads
  • May have gotten caught up somewhere, or lost blood supply and died
18
Q

Describe the devo of the fetal adrenal glands.

A
  • Source of androgen important for placental estrogen biosynthesis
  • Wk 4: distinct adrenal gland
  • Wk 7: expression of steroidogenic enzymes
  • Wks 8-9: ACTH can be detected in anterior pituitary
19
Q

What is Smith Lemli Optiz?

A
  • Mutations in 7-dehydrocholesterol reductase (DHCR7) gene -> elevated 7-dehydroxycholesterol concentrations and low cholesterol
  • Autosomal recessive
  • Multiple malformation syndrome
  • Ambiguous or female-like genitalia: undervirilized male bc can’t make androgens
    1. PHENOTYPIC FEMALES
20
Q

What is “guevedoce?”

A
  • XY children who are born with female genitalia, but develop testes and a penis at puberty
  • 5-alpha reductase deficiency (small prostates), but surge of testosterone at puberty overcomes this, resulting in the virilization of the external genitalia
  • Esp. prevalent in the Dominican Republic
21
Q

What is androgen insensitivity syndrome?

A
  • Short arm of X chromosome: X-linked recessive inheritance (maternal aunt w/hx of amenorrhea)
  • Genetically male (XY), but female-bodied: normal breast tissue and external F genitals, but vagina ends in a pouch
  • High testosterone, LH, and estrogen: HCG test will yield INC testosterone
  • Most common cause of 46 XY DSD (w/5-alpha reductase deficiency)
  • Complete, partial, and mild phenotypes
22
Q

LH receptor mutations presentation?

A
  • Testes (Leydig cells) not responsive to LH or HCG, leading to NO wolffian duct + NO mullerian duct (bc AMH still released)
  • Cryptorchidism: absence of one or both testes from the scrotum
  • 46 XY with female phenotype
  • Testosterone is low, LH is elevated (Leydig cells atrophic/resistant to LH)
23
Q

What physical findings are important in examining a child with potential DSD?

A
  • Asymmetry of gential devo may indicate ovotesticular DSD
  • Inguinal area and labial scrotal folds should be palpated for presence of gonads
  • Measurements:
    1. Stretched genital anlagen: >1cm in length and 0.6cm in width suggests VIRILIZATION
    2. Anogenital ratio (AF/AC) >0.5 consistent with VIRILIZATION
    a. Correlated with serum testosterone levels, sperm density, and paternity. Can be used in endocrine studies
24
Q

What are the 3 degrees of hypospadias?

A
  • 1st degree: glanular
  • 2nd degree: penile
  • 3rd degree: perineal -> penoperineal, perineal, or perineal w/o bulb
25
Q

What is cryptorchidism?

A
  • Absence of one or both testes from the scrotum
  • Most common DSD, affecting 3% of male infants
    1. Prevalence DEC to 1% by 6 months of age
  • Associated with/can result in:
    1. Decreased number of germ cells
    2. Impaired germ cell maturation
    3. Decreased number of Leydig cells
  • Long list of causes
26
Q

What tests should you order?

A
  • Karyotype
  • Diagnostic laparoscopy
  • MRI of the brain
  • Blood chemistry
  • Testosterone level, Estrogen level
  • 17 hydroxyprogesterone level
  • Pelvic ultrasound
  • Additional: HCG stimulation test w/DHT/T ratio, AMH, Inhibin B, other genetic testing, 7-dehydroxycholesterol, CAH6 panel
27
Q

What % of children with 46 XY DSD are not found to have a definitive diagnosis?

A

50%

28
Q

What are the risks for gonadal tumors in children with DSD?

A
  • CIS or gonadoblastoma are most common germ cell tumors -> gonadoblastoma prevalence 15-30%
    1. Depends on age of the patient
    2. Gonadal histology
    3. Diagnostic criteria
  • Mixed germ cell sex cord-stromal tumors that arise in dysgenetic gonads
    1. Immature germ cells and sex cord-stromal cells of indeterminate differentiation
    2. Precede devo of more invasive neoplasms like dysgerminoma, seminoma, nonseminoma

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