Congenital Anomalies of the GU tract Flashcards
Features of Undervirilized Males:
- Small phallus
- Hypospadias
- Cryptorchidism
- Bifid scrotum
- Absence of scrotal rugation
Features of Virilized Females (4):
- Clitoromegaly
- Common Urogenital Sinus
- Fused labioscrotal folds
- Rugated labioscrotal folds
What is the most common cause of 46 XX DSD?
Excessive fetal androgen production
- Congenital adrenal hyperplasia:
- 21-hydroxylase deficiency is the MOST COMMON CAUSE OF 46 XX DSD
What are other causes of 46 XX DSD?
- 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)
What is the most common cause of 46 XY DSD?
Idiopathic
- 50% of cases of 46XY infants with ambiguous genitalia
What are other causes of 46 XY DSD?
- 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
46 XY DSD: Pathogenesis
- Defect in function of androgen target tissues:
- Gonadal dysgenesis:
- Congenital Adrenal Hyperplasia:
-
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)
- defect in dihydrotestosterone (DHT) production
-
Gonadal dysgenesis:
- XY (complete or partial)
- XY ovotesticular DSD
- “vanishing testes”
-
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
Ovotesticular DSD:
- Definition:
- Karyotype:
- Both ovarian and testicular tissue w/ normal responsiveness to hormones
-
Karyotype:
- 46XX (70%)
- 46XY
- 46XX/XY (20%)
Ovotesticular DSD
- Phenotype:
- 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
What needs to be done for a Ovotesticular DSD patient?
- Laparoscopy with gonad biopsy as infant
- Surgical reconstruction to match gender assignment.
- Excision of organs inconsistent with gender assignment
When should you consider DSD?
- 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
What do you not do when DSD is a possible diagnosis?
- 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
List Examples of DSD:
-
Androgen Insensitivity Syndrome
- Complete AIS
- Partial AIS
- Ovotesticular DSD
-
Androgen Biosynthetic Defect
- 5 αreductase deficiency
-
Congenital Adrenal Hyperplasia
- 21-hydroxylase deficiency
Androgen Insensitivity Syndrome
- Where is the defect?
- Most common presentations:
-
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
-
CAIS:

Why may it be difficult to assign gender in PAIS?
- 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
What are the medical needs for a PAIS patient?
- Complex surgical reconstruction depending on gender identity often delayed until puberty when patient can express input
- Psychological support
What is the genotype and karyotype in Ovotesticular DSD?
- 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
Example of a patient with Ovotesticular DSD:
- 7 day old infant w/ ? genitalia
- Karyotype: ?
- serum testosterone: ?
- MIS: ?
- T:DHT ?

- 7 day old infant w/ambiguous genitalia
- Karyotype: 46 XX
- serum testosterone: normal for male
- MIS: (normal)
- T:DHT (normal)
What are the defects of androgen biosynthesis?

-
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)
5α Reductase Deficiency:
- Karyotype & Genetics:
- Definition:
- Why is DHT critical prior to birth?
- What happens at puberty in these patients?
- 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
Congenital Adrenal Hyperplasia:
-
46 XX DSD:
- Defects?
- 46 XY DSD:
- Defects?
-
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
What does CAH cause a compensatory increase in?
ACTH
What is the most common form of CAH?
21-hydroxylase deficiency
CAH due to 21-hydroxylase deficiency
- Pathogenesis:
- How is it tested for?
- Treatment:
- 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