Congenital Anomalies of the GU tract

Question 1

Features of Undervirilized Males:

Answer 1

1. Small phallus
2. Hypospadias
3. Cryptorchidism
4. Bifid scrotum
5. Absence of scrotal rugation

Question 2

Features of Virilized Females (4):

Answer 2

1. Clitoromegaly
2. Common Urogenital Sinus
3. Fused labioscrotal folds
4. Rugated labioscrotal folds

Question 3

What is the most common cause of 46 XX DSD?

Answer 3

Excessive fetal androgen production

• Congenital adrenal hyperplasia:
  
  • 21-hydroxylase deficiency is the MOST COMMON CAUSE OF 46 XX DSD

Question 4

What are other causes of 46 XX DSD?

Answer 4

• Excessive maternal androgens (virilizing tumors)
• Maternal Drugs
• Associated with other congenital anomalies
• Patients with Ovotesticular DSD are usually 46XX
• XX males (presence of SRY sequences on X-chromosome)

Question 5

What is the most common cause of 46 XY DSD?

Answer 5

Idiopathic

• 50% of cases of 46XY infants with ambiguous genitalia

Question 6

What are other causes of 46 XY DSD?

Answer 6

• Associated with syndromes of multiple congenital anomalies
• Defect in testicular differentiation
  
  • Genetic defects: SRY, X-loci, autosomes
• Defect in Sertoli Cell function: inadequate MIS
  
  • persistence of Mullerian ducts
• Defect in Leydig Cell function:
  
  • testosterone biosynthetic defect
  • LH/HCG response defect

Question 7

46 XY DSD: Pathogenesis

1. Defect in function of androgen target tissues:
2. Gonadal dysgenesis:
3. Congenital Adrenal Hyperplasia:

Answer 7

1. Defect in function of androgen target tissues:
   
   • defect in dihydrotestosterone (DHT) production
     
     • DHT required for complete virilization before birth but not at puberty
   • defect in androgen receptor action (androgen insensitivity syndromes)
2. Gonadal dysgenesis:
   
   • XY (complete or partial)
   • XY ovotesticular DSD
   • “vanishing testes”
3. Congenital Adrenal Hyperplasia –forms that prevent testicular as well as adrenal steroidogenesis
   
   • 3 beta-Hydroxysteroid Dehydrogenase deficiency
   • 17-Hydroxylase/17,20 Lyase combined deficiency
   • Side Chain Cleavage deficiency

Question 8

Ovotesticular DSD:

• Definition:
• Karyotype:

Answer 8

• Both ovarian and testicular tissue w/ normal responsiveness to hormones
• Karyotype:
  
  • 46XX (70%)
  • 46XY
  • 46XX/XY (20%)

Question 9

Ovotesticular DSD

• Phenotype:

Answer 9

• Gonads:
  
  • bilateral ovotestes, or testis on one side and ovary on other
  • In one gonad, each element may be well-defined or admixture of testicular and ovarian elements
• Ext genitalia:
  
  • variable spectrum from feminine to masculine
• Int genitalia:
  
  • parallels the nature of the ipsilateral gonad
• Hormone profile:
  
  • testosterone levels reflect amount of testicular tissue
• Variable MIS:
  
  • depends on testicular elements

Question 10

What needs to be done for a Ovotesticular DSD patient?

Answer 10

1. Laparoscopy with gonad biopsy as infant
2. Surgical reconstruction to match gender assignment.
3. Excision of organs inconsistent with gender assignment

Question 11

When should you consider DSD?

Answer 11

• Bilateral nonpalpable gonads
• Severe hypodyspasias
  
  • Esp. w/ nonpalpable gonads
• Clitoromegaly (maybe microphallus?)
• Posterior fusion of vaginal opening (or undervirilized scrotum?)
• WHENEVER GENITALIA DO NOT LOOK COMPLETELY NORMAL

Question 12

What do you not do when DSD is a possible diagnosis?

Answer 12

• assume cryptorchidism when it could be a female
• assume clitoromegaly when it could be a male
• assume hypospadias when it could be a female
• assume you know the genetic sex based on the phenotype
• refer to the baby as “she” or “he” until gender assignment is decided upon

Question 13

List Examples of DSD:

Answer 13

1. Androgen Insensitivity Syndrome
   
   • Complete AIS
   • Partial AIS
2. Ovotesticular DSD
3. Androgen Biosynthetic Defect
   
   • 5 αreductase deficiency
4. Congenital Adrenal Hyperplasia
   
   • 21-hydroxylase deficiency

Question 14

Androgen Insensitivity Syndrome

• Where is the defect?
• Most common presentations:

Answer 14

• Androgen receptor defect
  
  • X-linked recessive, karyotype 46 XY
  • Complete and Partial forms
• Most common presentations:
  
  • CAIS:
    
    • female adolescent with primary amenorrhea and breasts, no pubic hair
    • female child with testes discovered in inguinal hernia
  • PAIS: highly variable

Question 15

Why may it be difficult to assign gender in PAIS?

Answer 15

• Karyotype: 46XY
• Gonads: testes vary in location. Abdominal-inguinal-scrotal
• Ext genitalia: variable spectrum of severely undervirilizedmale
• Intgenitalia: lack all mullerianduct structures
• Hormone profile: Normal-High testosterone. Normal MIS.
• Variable response to exogenous testosterone

Question 16

What are the medical needs for a PAIS patient?

Answer 16

• Complex surgical reconstruction depending on gender identity often delayed until puberty when patient can express input
• Psychological support

Question 17

What is the genotype and karyotype in Ovotesticular DSD?

Answer 17

• Karyotype variable: 46XX (mostly), 46XY or 46XY/46XX
• Both ovarian and testicular tissue present
  
  • May be bilateral ovotestes, or testis on one side and ovary on other
• External genitalia of variable appearance: spectrum from masculine to feminine in appearance
• Internal anatomy and endocrine function parallels the nature of the ipsilateral gonad
• Fertility is uncommon
• Sex of rearing can be complex decision

Question 18

Example of a patient with Ovotesticular DSD:

• 7 day old infant w/ ? genitalia
• Karyotype: ?
• serum testosterone: ?
• MIS: ?
• T:DHT ?

Answer 18

• 7 day old infant w/ambiguous genitalia
• Karyotype: 46 XX
• serum testosterone: normal for male
• MIS: (normal)
• T:DHT (normal)

Question 19

What are the defects of androgen biosynthesis?

Answer 19

• Low androstenedione production
  
  • Rare forms of CAH with adrenal and gonadal enzyme defects
• 17-ketosteroid reductase (17-KR)
  
  • def. (testis)
• 5-α reductase (5α-Red)
  
  • def. (skin)

Question 20

5α Reductase Deficiency:

• Karyotype & Genetics:
• Definition:
• Why is DHT critical prior to birth?
• What happens at puberty in these patients?

Answer 20

• 46 XY karyotype, autosomal recessive
• Mutation in 5α reductase enzyme
  
  • converts Testosterone (T) to Dihydrotestosterone (DHT)
• DHT is critical for virilization prior to birth, but T is critical at puberty
• Experience surge of T at puberty, these males undergo dramatic virilization even in absence of DHT

Question 21

Congenital Adrenal Hyperplasia:

• 46 XX DSD:
  
  • ​Defects?
• 46 XY DSD:
  
  • Defects?

Answer 21

• 46 XX DSD
  
  • 21-OH def (CYP21)
  • 11-OH def (CYP11B)
  • 3β-HSD Def
• 46 XY DSD
  
  • SCC def (CYP11A)
  • 17-OH def (CYP17)
  • 3β-HSD Def

Question 22

What does CAH cause a compensatory increase in?

Answer 22

ACTH

Question 23

What is the most common form of CAH?

Answer 23

21-hydroxylase deficiency

Question 24

CAH due to 21-hydroxylase deficiency

• Pathogenesis:
• How is it tested for?
• Treatment:

Answer 24

• Mild to severe virilization of female fetus due to adrenal androgen excess
• 1:10,000 to 1:15,000 cases per live birth in severe enzyme deficiency
  
  • Tested by measuring level of 17-hydroxyprogesterone on state newborn screens
  • Late onset form presents in adolescent or young adult females; no congenital virilization
• Treatment is cortisol replacement to suppress ACTH and reduce adrenal androgens