Ambiguous genitalia, (Disorders of Sex Development, DSD) Congenital Adrenal Hyperplasia (CAH) Flashcards
Appearance of Genitalia
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
Ambiguous genitalia
Ambiguous genitalia
Disorders of sex development (DSD) Undervirilized male XY-DSD or virilized female XX- DSD or ♂
♀
sex chromosomal-DSD ??
Ambiguous genitalia
Ambiguous genitalia
Disorders of sex development (DSD) Undervirilized male XY-DSD or virilized female XX- DSD or ♂
♀
sex chromosomal-DSD ??
Ambiguous genitalia
Ambiguous genitalia
Disorders of sex development (DSD) Undervirilized male XY-DSD or virilized female XX- DSD or ♂
♀
sex chromosomal-DSD ??
Disorders of sexual development (DSD)
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)
DSD. (undervirilized male - Male (pseudohermaphrodite)
46,XY DSD
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
Sex chromosome DSD
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)
Neonates with 46,YY DSD due to 21 hydroxylase defciency may have hyperpigmented
labioscrotal folds
• The external masculinizaton score (Prader score)
Investigations Performed for the Evaluation of Ambiguous Genitalia
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
Adrenal and Steroidogenesis
- The Adrenal Cortex : the 3 zones of the cortex secrete steroid
hormones categorized, respectvely, as mineralocortcoids,
glucocortcoids, and sex steroids. - The Adrenal Medulla : is regulated by the sympathetc nervous
system and secretes catecholamines.
Cortical Hormones
• Mineralocortcoid producton, Aldosterone, is principally regulated by
the renin-angiotensin axis and by ambient potassium levels.
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.
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.
• 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 )
Adrenal insufciency (AI)
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
Acute Treatment of Adrenal Crises
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.
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.
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.
> 90% of CAH
21-hydroxylase dif
Congenital adrenal hyperplasia
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
Clinical Picture (21-OHD CAH)
Clinical Picture (21-OHD CAH)
• ++ Androgens
• – Cortsol
• – Aldosterone in SW CAH salt wast
Androgen overproduction
21-OHD CAH)
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.
Adrenal insufciency (21-OH CAH)
• 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.
21-OHD CAH
Testcular adrenal rest tumors (TART)
Adult • Menstrual irregularites. • Hirsutsm. • Short stature. • Obesity. • Subfertlity. • Testcular adrenal rest tumors (TART)
Clinical Picture (21-OHD CAH)
External genitalia is not AMBIGIOUS in newborn males
Hyperpigmentaton may be the only clue suggestng increased ACTH secreton and cortsol defciency.
Salt wasting crisis @ 1–4 weeks
75% OF CLASSICAL 21-OHD CAH
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
21-OHD CAH)
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.
Diagnosis of 21-OHD CAH
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.
Precocious puberty. The true precocious puberty that may occur in 21-OHD CAH can be treated with analogs of luteinizing hormone- releasing hormone (LHRH).
