Ambiguous genitalia, (Disorders of Sex Development, DSD) Congenital Adrenal Hyperplasia (CAH)

Question 1

Appearance of Genitalia

Answer 1

Bilateral testcles that are descended Complete formaton of scrotal folds with midline fusion Average penile length of 3.5 ± 0.4 cm
Bilateral separaton of labial folds No palpable gonads Separate urethral and vaginal openings
Newborn with Ambiguous Genitalia
Bilateral cryptorchidism in a male Bifd scrotum with hypospadias in a male Penoscrotal hypospadias in a male Labial fusion in a female Palpable gonads in a female

Question 2

Ambiguous genitalia

Answer 2

Ambiguous genitalia
Disorders of sex development (DSD) Undervirilized male XY-DSD or virilized female XX- DSD or ♂
♀
sex chromosomal-DSD ??

Question 3

Ambiguous genitalia

Answer 3

Ambiguous genitalia
Disorders of sex development (DSD) Undervirilized male XY-DSD or virilized female XX- DSD or ♂
♀
sex chromosomal-DSD ??

Question 4

Ambiguous genitalia

Answer 4

Ambiguous genitalia
Disorders of sex development (DSD) Undervirilized male XY-DSD or virilized female XX- DSD or ♂
♀
sex chromosomal-DSD ??

Question 5

Disorders of sexual development (DSD)

Answer 5

Disorders of sexual development (DSD)
• It is a conditon in which chromosomal sex is inconsistent with phenotypic sex.
• Lack of concordance of various aspects of gender. These include:
Chromosomal sex (46,YY, 46,YY, or other).
Gonadal or reproductve sex (ovaries, fallopian tubes, and uterus versus testes, seminal
vesicles, prostate gland, and ejaculatory ducts).
Genital sex (vagina and clitoris versus scrotum and penis), and gender-specifc behavior.
Classifcation of DSD
• 46, XX DSD. ( virilized female - Female pseudohermaphrodite)
• 46,XY DSD. (undervirilized male - Male (pseudohermaphrodite)
• Sex chromosome DSD (45, Y/46, YY MGD DSD (Mixed gonadal
dysgenesis)
• Ovotestcular DSD.(True hermaphrodite)

Question 6

DSD. (undervirilized male - Male (pseudohermaphrodite)

46,XY DSD

Answer 6

46,XY DSD. (undervirilized male - Male (pseudohermaphrodite)
Androgen insensitvity syndrome (AIS) (testcular feminizaton syndrome), X-linked
disease • Complete AIS has phenotypic female with an inguinal hernia • no internal müllerian structure • with amenorrhea
5 alfa reductase defciency
Testosterone synthesis defects

Question 7

Sex chromosome DSD

Answer 7

Sex chromosome DSD
 (45, Y/46, YY MGD DSD (Mixed gonadal dysgenesis)
Turner syndrome 45,Y0 , Klinefelter syndrome (KS) 47,YYY
High Risk of gonadal tumor
• Ovotestcular DSD.(True hermaphrodite)

Answer 8

Neonates with 46,YY DSD due to 21 hydroxylase defciency may have hyperpigmented
labioscrotal folds
• The external masculinizaton score (Prader score)

Question 9

Investigations Performed for the Evaluation of Ambiguous Genitalia

Answer 9

Investigations Performed for the Evaluation of Ambiguous Genitalia
• Karyotyping. • Fluorescence in situ hybridisaton (FISH) or quanttatve polymerase chain reacton (PCR) of the sex-determining region Y (SRY)
gene
• Imaging (US, genitography, MR imaging)
• Determinaton of hormone levels :
17-hydroxy-progesterone level
Testosterone level
HCG challenge test
Gonadotropin levels
• Endoscopy, laparoscopy before surgery
• Gonadal biopsy

Question 10

Adrenal and Steroidogenesis

Answer 10

1. The Adrenal Cortex : the 3 zones of the cortex secrete steroid
   hormones categorized, respectvely, as mineralocortcoids,
   glucocortcoids, and sex steroids.
2. The Adrenal Medulla : is regulated by the sympathetc nervous
   system and secretes catecholamines.

Question 11

Cortical Hormones
• Mineralocortcoid producton, Aldosterone, is principally regulated by
the renin-angiotensin axis and by ambient potassium levels.

Answer 11

Cortical Hormones
• Mineralocortcoid producton, Aldosterone, is principally regulated by
the renin-angiotensin axis and by ambient potassium levels.
• Mineralocortcoids govern sodium and potassium homeostasis, and
defciencies in their producton or acton cause :
Hyponatremia.
Hyperkalemia.
Dehydraton.

Answer 12

Cortsol is the main glucocortcoid, and De-hydro-epi-androsterone (DHEA) is the main adrenal sex hormone.
• DHEA is a weak androgen, but it may be converted via androstenedione to either estrogens or androgens. That can give rise to secondary sex characteristcs.

Answer 13

• Cortsol contributes to the maintenance of normal blood pressure through
several mechanisms, notably increasing vascular sensitvity to pressors
( catecholamines).
• Cortsol can act as a mineralocortcoid agonist, causing sodium and water
retenton.
• Cortsol and/or aldosterone defciencies ofen result in shock if
unrecognized and untreated . ( Adrenal crisis )

Question 14

Adrenal insufciency (AI)

Answer 14

Adrenal insufciency (AI) causes
• Withdrawal from long-term cortcosteroid therapy.
• Congenital adrenal hyperplasia.
• Addison disease.
• Aadrenal infltraton due to TB, HIV or haemorrhage.
• Secondary adrenal insufciency (hypothalamic or pituitary)
• All may result in an adrenal crisis requiring urgent treatment.
Clinical fndings Adrenal insufciency :
• Vomitng . • Lethargy . • Brown pigmentaton (gums, scars,
skin creases). • Dehydraton. • Hypotension. • Growth failure. • Circulatory collapse.
Lab fndings :
• Hyponatraemia. • Hyperkalaemia. • Hypoglycaemia. • Metabolic acidosis

Question 15

Acute Treatment of Adrenal Crises

Answer 15

Acute Treatment of Adrenal Crises
 Check A, B, C … (airway, breathing circulation…)  Secure IV line and Check blood sugar and urea & electrolytes including full blood count.  Fluid bolus is required (10-20ml/kg 0.9% saline).  Capillary glucose <3mmol/l give 2ml/kg of 10% dextrose.  Give IV hydrocortisone bolus (stress dose 50-100 mg/m2BSA) (IM if delay in IV access) and then start IV infusion or multiple doses every 6 hours.
(dose: 50-100 mg/m2BSA)  Start IV maintenance fluids + deficit (5% dextrose/0.45-0.9 % saline)  Consider hyperkalemia treatment.  Look for underlying cause.  Consider double dose hydrocortisone therapy once able to tolerate oral medications and during acute illnesses and stresses.  Consider fludrocortisone therapy.  Call the on-call Endocrinologist.

Question 16

What is CAH?
A group of AR disorders that arise from : “Defectve Adrenal Steroidogenesis”
• It is involving impaired synthesis of Cortsol and Aldosterone from
cholesterol by the adrenal cortex.

Answer 16

The producton of cortsol in the zona fasciculata of the adrenal
cortex occurs in fve major enzyme-mediated steps.
• Congenital adrenal hyperplasia (CAH) results from defciency in any
one of these enzymes.

Question 17

> 90% of CAH

Answer 17

21-hydroxylase dif

Question 18

Congenital adrenal hyperplasia

Answer 18

Congenital adrenal hyperplasia
• Congenital adrenal hyperplasia (CAH) is the most common non-iatrogenic cause of insufcient cortsol
and mineralocortcoid secreton.
• A number of autosomal recessive disorders of adrenal steroid biosynthesis result in congenital
adrenal hyperplasia, with an incidence of about 1 in 17 000 births.
• Over 90% have a defciency of the enzyme 21-hydroxylase, which is needed for cortsol biosynthesis.
• About 70% to 80% are also unable to produce aldosterone, leading to salt loss (low sodium and high
potassium).
• In the fetus, ( 6 weeks-12 weeks) the resultng cortsol defciency stmulates the pituitary to produce
ACTH, which drives overproducton of adrenal androgens. Virilizaton of female genitalia

Question 19

Clinical Picture (21-OHD CAH)

Answer 19

Clinical Picture (21-OHD CAH)
• ++ Androgens
• – Cortsol
• – Aldosterone in SW CAH salt wast

Question 20

Androgen overproduction

21-OHD CAH)

Answer 20

Androgen overproduction
• Virilisaton of the external genitalia in female infants, with clitoral
hypertrophy and variable fusion of the labia.
• In the infant male, the penis may be enlarged, and the scrotum pigmented, but these changes are ofen only noted once the diagnosis has been made.
• Both male and female may develop a muscular build, adult body odour,
pubic hair, and acne from excess androgen producton, leading to precocious
pubarche.

Question 21

Adrenal insufciency (21-OH CAH)

Answer 21

• A salt-losing adrenal crisis in the 75% of males who are salt losers; this
occurs at 1 week to 3 weeks of age, presentng with vomitng and
weight loss, hypotonia and circulatory collapse.
• A salt-losing crisis is less common in girls as the virilizaton is noted
early and treatment started before salt loss is signifcant.
• There may be a family history of neonatal death if a salt-losing crisis
had not been recognized and treated.

Question 22

21-OHD CAH

Testcular adrenal rest tumors (TART)

Answer 22

Adult • Menstrual irregularites. • Hirsutsm. • Short stature. • Obesity. • Subfertlity. • Testcular adrenal rest tumors (TART)

Question 23

Clinical Picture (21-OHD CAH)

Answer 23

External genitalia is not AMBIGIOUS in newborn males

Hyperpigmentaton may be the only clue suggestng increased ACTH secreton and cortsol defciency.

Question 24

Salt wasting crisis @ 1–4 weeks

75% OF CLASSICAL 21-OHD CAH

Answer 24

Salt wasting crisis  @ 1–4 weeks
75% OF CLASSICAL 21-OHD CAH
• Poor feeding • Weight loss & Failure to thrive • Vomitng & dehydraton • Hypotension  vascular collapse

 shock

 death
• ↓Na+ (↑ urine Na+) • ↑K+ • ↓Aldosterone (↓ urine Aldosterone) • ↑PRA • metabolic acidosis • Hypoglycemia

Question 25

21-OHD CAH)

Answer 25

Newborn screening (17-hydroxyprogesterone) (17-OHP).
Accuracy
• (+ive) False-positve results may occur on blood samples taken in the
frst 24 hours of life.
• (+ive) False-positve results may also be observed in low birth-weight
infants or premature infants.
• (-ive) False-negatve results may be observed in neonates receiving
dexamethasone for management of unrelated problems.

Question 26

Diagnosis of 21-OHD CAH

Answer 26

Diagnosis of 21-OHD CAH
• The diagnosis of classic 21-OHD CAH is established in newborns with:
1. Characteristc clinical and biochemical features 2. Elevated serum 17-OH-Progesterone. 3. Elevated adrenal androgens. 4. Plasma renin actvity is markedly elevated in individuals with the salt-
wastng form of 21-OHD CAH. 5. Genetc test of CYP21A2 gene confrms the clinical diagnosis and allows
for family studies.

• The diagnosis of non-classic 21-OHD is established by
• comparison of baseline serum 17-OHP and ACTH-stmulated serum
17-OHP
• Early morning elevated 17-OHP.

Answer 27

Precocious puberty. The true precocious puberty that may occur in
21-OHD CAH can be treated with analogs of luteinizing hormone-
releasing hormone (LHRH).