Congenital Anomalies Flashcards
FActors to consider in gender assignment DSD
Most children with DSD will form a normal male or female gender identity
Natural history of the condition: Most likely future gender identification
Endocrine function, Surgical reconstructibility, Likelihood of future sexual function, Potential for fertility, Effect of Testosterone imprinting on brain, Parents perceptions and desire
- Small phallus
- Hypospadias
- Cryptorchidism
- Bifid scrotum
- Absence of scrotal rugation
Features of UNDERvirilized males
- Clitoromegaly
- Common Urogenital Sinus
- Fused labioscrotal folds
- Rugated labioscrotal folds
Features of Virilized female
46 XX DSD
- Excessive fetal androgen production leading to: Congenital adrenal hyperplasia:
- is the MOST COMMON CAUSE OF 46 XX DSD
21-hydroxylase deficiency
Other then 21 hydroxylase deficiency what are some 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-chromosom
- Defect in testicular differentiation: Genetic defects: SRY, X-loci, autosomes
- Defect in Sertoli Cell function: inadequate MIS or persistence of Mullerian ducts
- Defect in Leydig Cell function: _testosterone biosynthetic defec_t • LH/HCG response defect
ALL seen in
46 XY
50% of 46XY cases of infants with ambigious genitalia are
idiopathic
some associated with congenital abnomalities
46 XY DSD
Defect in function of androgen in target tissue:
- Defect in DHT production results in:
- Defect in androgen receptor action:
- DHT required for complete virilization before birth but not at puberty
- androgen insensitivty syndromes
46 XY DSD from congenital adnreal hyperplasia thus inhibiting testicular and adrenal steridogenesis:
causes
- 3 beta-Hydroxysteroid Dehydrogenase deficiency
- 17-Hydroxylase/17,20 Lyase combined deficiency
- Side Chain Cleavage deficiency
• Both ovarian and testicular tissue w/ normal
responsiveness to hormones
- Karyotype: 46XX (70%), 46XY, or 46XX/XY(20%)
- Phenotype is a spectrum from feminine to masculine
Ovotesticular DSD
Phenotype is a spectrum from feminine to masculine in Ovotesticular DSD
- 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.
fertility in ovotesticular DSD
uncommon
Tx for Ovotesticular DSD
Needs:
• Laparoscopy with gonad biopsy as infant
• Surgical reconstruction to match gender assignment.
• Excision of organs inconsistent with gender assignment
When do you consider DSD
BILATERAL NONPALPABLE GONADS
SEVERE HYPOSPADIAS ESP. WITH NONPALPABLE GONADS
CLITOROMEGALY (OR MICROPHALLUS?)
POSTERIOR FUSION OF VAGINAL OPENING (OR UNDERVIRILIZED SCROTUM?)
WHENEVER GENITALIA DO NOT LOOK COMPLETELY NORMAL
Androgen Insensitivity syndrome:
what is the genotype?
What are most common presentations?
Xlinked recessive with 46 XY
CAIS = complete insensitivity
Partial = variable spectrm
You have a female adolescent with primary amenorrhea and breast but NO pubic hair
OR
female child with testes discovered in inguinal hernia
THis presents as spectrum from ambigious female genetalia to normal male with infertility
its an x linked recessive disorder
Androgen Insensitivity Syndrome
Patient with Testes, androgen present, Wolfiann duct regress, MIS made thus no Mullerian ducts.
What do we expect for external genetalia?
what is teh karyotype
this is CAIS: 46 XY
have external female genetalia; get femenizing puberty but no menses bc no ovariain system
IN CAIS what do we see in adult in regard to 2nd sex characteristics
46 XY with complete androgen insufficiency
see breast devo (bs excess androgen–> estrogen)
No pubic hair or acne bc receptors don’t respond to androgens
will have high levels of testosterone
What are clues to Partial androgen insensitivity?
often present as male with fertility issues
micropenis and gynecomastia
PAIS is complex; what do we see with:
gonads:
ext genitalia:
internal genetalia:
- Karyotype: 46XY
- Gonads: testes vary in location. Abdominal-inguinal-scrotal
- Ext genitalia: variable spectrum of severely undervirilized male • Int genitalia: lack all mullerian duct structures
Hormone profile in PAIS individual
- Hormone profile: Normal-High testosterone. Normal MIS.
- Variable response to exogenous testosterone
Needs for children with PAIS
can be male or female: most satisfied with gender identity but unsatisfied by apperance or functionality of genetalia
Complex surgical reconstruction depending on gender identity often delayed until puberty when patient can express input
Psychological support
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
Ovotesticular DSD
- 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
Ovotesticular DSD : 46XX (mostly), 46XY or 46XY/46XX
There are two enzymes key in taking androstendione to DHT:
Androstendione–> enZ?
Testosterone –> enZ?
DHT
androstendione –> testosterone: **17-ketosteroid reductase: **
Testosterone –> DHT: 5-alpha reductase
Defects to what 2 enZ would lead to androgen biosynthetic defects?
17-ketosteroid reductase
5-alpha-reductase
Complete testosterone biosynthetic defect
Testes devo, no androgens (enZ defient), Wolff ducts regress, MIS made thus Mullerian regress, external genitals= female, feminizing puberty if given estrogen
Androgen levels in complete testosterone biosynthetic defec
What happens to wolfiann ducts
NO androgens thus wolfiann ducts regress
What happens to mullerian ducts in complete testosterone biosynthetic defect (karyo is XY)
MIS is made thus mullerian ducts regress
What do we see for external genetalia and puberty in complete biosynthetic testosterone defect (karyotype = 46XY) ?
External = female genatalia
feminizing puberty if given estrogen therapy
46 XY karyotype, autosomal recessive
Mutation in enZ needed to converts Testosterone (T) to Dihydrotestosterone (DHT)
5-alpha Reductase Deficiency
____is critical for virilization prior to birth, but ___is critical at
puberty
DHT
TEstosterone ****Experience surge of T at puberty, these males undergo dramatic virilization even in absence of DHT in 5 alpha reductase deficiency
5alpha reductasae defieicney: 46 XY autoR
Testes:
Androgens:
Wolffian ducts:
testes devo
testosterone but NO DHT produced
wolf ducts develope (supported by testosterone)
5alpha reductasae defieicney: 46 XY autoR
MIS made?
Mullerian Duct fate
External genitalia
MIS made thus mullerian ducts regress
external genitals are AMBIGIOUS
OPTIONS: testes left intact see partial masculinizing puberty
or feminizing puberty if testes removed and estrogen therapy
Causes of 46 XX DSD Congenital adrenal hyperplasia
21-OH deficinency
11-OH def or 3B-HSD
Causes of 46 XY DSD congenital adrenal hyperpasia
46 XY DSD
SCC def (CYP11A)
17-OH def (CYP17)
3-HSDDef
- Most common form of CAH and of 46,XX DSD
- Mild to severe virilization of female fetus due to adrenal
androgen excess
CAH due to 21-hydroxylase deficiency
How can we test for CAH d/t 21-hydroxylase deficiency in newborns?
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 for CAH due to 21-hydroxylase deficiency
cortisol replacement to suppress ACTH and reduce adrenal androgens
CAH due to 21-hydroxylase deficiency with 46 XX:
Ovaries:
androgen production:
Wolfian duct
Mullerian duct:
CAH due to 21-hydroxylase deficiency
ovaries devo, no testicular androgens but excessive adrenal androgens
Wolfiann regress, NO MIS thus Mullerian ducts devo
CAH due to 21-hydroxylase deficiency : external genitatila and puberty
ambigous external genitalia and feminizing puberty if treated with cortisol
- 12 day old “male with perineal hypospadius and cryptorchidism” • newborn screen 17-OH progesterone was normal
- urology consultant suggested endocrine evaluation
• high dose steroids for respiratory problem day of life 1-12
- day 12: 17-OH progesterone 169 ng/dl (normal)
- day 14: 17-OH progesterone 37,400 ng/dl
Moderate virilization
high dose steroids messed up test!; way elevated
- 2 week old infant
- positive newborn CAH screen, abnormal genitalia missed
• serum 17-OH progesterone = 30,690 ng/dl (<200)
Mild virilization
3 week old infant
• discharged after circumcision as bilateral cryptorchid
male with follow-up appointment in urology clinic
- presented near death with salt losing crisis
- karyotype 46 XX
Complete Virilization
What is the most accurate description of internal and external genitalia in 46XX DSD 21-hydroxylase deficiency CAH
Wolfiann duct absent, mullerian duct present, external genitalia virilized
• Making an accurate diagnosis is critical for what reasons
- Prediction of response to treatment (esp. androgen response)
- Predication of fertility potential
- Estimation of androgen effect on fetal brai
