Diaz-Thomas/Phillips - DSD

Question 1

Sexual determination

Answer 1

GENETICS (XX or XY): what gonad looks like

Question 2

Sexual differentiation

Answer 2

HORMONES: process whereby internal and external repro organs are formed

Question 3

Genotypic/chromosomal sex

Answer 3

XX or XY

Question 4

Phenotypic/gonadal sex

Answer 4

Secondary sex characteristics

Question 5

Sexual identification

Answer 5

Sex you identify with

Question 6

Sexual preference

Answer 6

Same of different sex partner preference

Question 7

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

Answer 7

• 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

Question 8

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

Answer 8

• WT1
• SF1

Question 9

When/how does sexual determination begin in fetal devo?

Answer 9

• 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

Question 10

What are some of the important genes in sex determination?

Answer 10

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

Question 11

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

Answer 11

Question 12

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

Answer 12

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

Question 13

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

Answer 13

• 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

Question 14

What are the consequences of SF1 mutations?

Answer 14

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

Question 15

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

Answer 15

• 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

Question 16

What is persistent mullerian duct syndrome?

Answer 16

• 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

Question 17

What is vanishing testis syndrome?

Answer 17

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

Question 18

Describe the devo of the fetal adrenal glands.

Answer 18

• 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

Question 19

What is Smith Lemli Optiz?

Answer 19

• 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

Question 20

What is “guevedoce?”

Answer 20

• 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

Question 21

What is androgen insensitivity syndrome?

Answer 21

• 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

Question 22

LH receptor mutations presentation?

Answer 22

• 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)

Question 23

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

Answer 23

• 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

Question 24

What are the 3 degrees of hypospadias?

Answer 24

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

Question 25

What is cryptorchidism?

Answer 25

- 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

Question 26

What tests should you order?

Answer 26

- 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

Question 27

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

Answer 27

50%

Question 28

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

Answer 28

- _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