Role of lab in diagnosing congenital adrenal hyperplasia (CAH) ola.elgaddar@alex-mri.edu.eg

1. ROLE OF LAB IN DIAGNOSING
CONGENITAL ADRENAL
HYPERPLASIA
Ola H. Elgaddar
MBChB, MSc, MD, CPHQ
Lecturer of Chemical Pathology
Medical Research Institute
Alexandria University

2. Suprarenal (adrenal) gland
- Lies immediately superior and
slightly anterior to the upper pole of
either kidney.
- Golden yellow in color.
- Each gland possesses two
functionally and structurally distinct
areas: an outer cortex and an inner
medulla.

6. CONGENITAL ADRENAL
HYPERPLASIA (CAH)
• These inherited syndromes are
caused by deficient adrenal
corticosteroid biosynthesis.
• In each case, there is reduced
negative feedback inhibition of
cortisol, and depending on the
steroidogenic pathway involved,
there is an alteration in adrenal
mineralocorticoid and androgen
secretion

8. 21-hydroxylase deficiency
- Accounts for 90 % of CAH cases.
- Mutation in CYP21A2 gene, results in complete or
partial 21-hydroxylase deficiency.
- The normal synthesis of cortisol is impaired, and
ACTH levels increase because of loss of normal
negative feedback inhibition, resulting in an increase
in adrenal steroid precursors proximal to the block.
-The results are cortisol deficiency, variable
mineralocorticoid deficiency, and excessive secretion
of adrenal androgens.

9. DIFFERENT FORMS OF 21-HYDROXYLASE DEFICIENCY
Classical
Phenotype Simple Virilizing Non-classical
Salt Wasting
Newborn to 2 Ys (♀)
Age at diagnosis Newborn to 6 M. Child to adult
2 to 4 Ys (♂)
♂ normal; ♂ normal; ♂ normal;
Genitalia
♀ ambiguous ♀ambiguous ♀virilized
21-Hydroxylase activity 0% 1% 20% to 50%
Hormones:
Aldosterone Reduced Normal Normal
Renin Increased Normal or increased Normal
Cortisol Reduced Reduced Normal
17 (OH) progesterone 500 to 2500
>5000 2500 to 5000
(nmol/L) (ACTH stimul.)
Testosterone Increased Increased Variable, increased

10. Diagnosis of 21-hydroxylase deficiency
Suspect a newborn with:
-Genital ambiguity
-Salt-wasting
-Hypotension
-Hypoglycemia
-Hyponatremia
-Hyperkalemia
-Raised plasma renin activity

11. In later life :
-PCOS-like phenotype.
-Adrenal androgen excess (DHEAS, androstenedione)
•Suppressed following glucocorticoid administration
-Elevated 17-hydroxyprogesterone (17-OHP)
•Basal,
•After synacthen stimulation in heterozygous cases

12. Prenatal diagnosis:
-17-OHP assay in amniotic fluid.
-Genotyping of fetal cells obtained by CVS.
N.B:
Maternally administered dexamethasone prevent
masculinization in utero.

14. 11β- hydroxylase deficiency
- Accounts for 7% of CAH cases.
-Mutations in the CYP11B1 gene, which result in loss
of enzyme activity and a block in the conversion of 11-
deoxycortisol to cortisol
-Loss of negative cortisol feedback and enhanced
ACTH-mediated adrenal androgen excess
(virilized female fetus, sexual ambiguity)
-Hypertension, secondary to the mineralocorticoid
effect of the excess DOC
(D.D: 21-hydroxylase deficiency)

15. Diagnosis of 11β -hydroxylase deficiency
- Synacthen stimulates an increase of plasma 11 DOC,
three times the upper reference range.
(Doesn’t stimulate 11 DOC in heterozygotes)
- May be associated with elevated DHEA and other
adrenal androgens.

17. 17α- hydroxylase deficiency
-Approximately 150 cases have been reported.
-A single enzyme is expressed in adrenal and gonads
that possesses both 17-hydroxylation and 17,20 lyase
activities.
-Mutations within the CYP17 gene result in the failure
to synthesize cortisol, adrenal androgens and gonadal
steroids.
-Loss of negative feedback results in increased
secretion of steroids proximal to the block, and
mineralocorticoid synthesis is enhanced.

18. Diagnosis of 17α-hydroxylase deficiency
At Puberty, patients present with:
- Hypertension
- Hypokalemia
-Hypogonadism
 Elevated LH and FSH.
 Female patients (XX) have primary amenorrhea
with absent sexual characteristics
 Males (46XY) have complete
pseudohermaphroditism with female external genitalia
but absent uterus and fallopian tubes.

20. 3β- hydroxysteroid dehydrogenase II deficiency
-A rare form of CAH.
-Mutation in HSD3B2 gene encoding 3ß-HSDII.
-Secretion of all classes of adrenal and ovarian
steroids is impaired.
-Loss of mineralocorticoid secretion results in variable
degrees of salt-wasting
- The spectrum of genital development is variable in
both sexes:
♂:pseudohermaphroditism, hypospadias, normal
♀:mild virilization, premature pubarche, PCOS-like
phenotype

21. Diagnosis of 3ß-HSDII deficiency
- Because activity of the 3ß-HSDI enzyme, present in
skin and other peripheral tissues, is intact,
circulating D4 steroids (progesterone, 17α-
hydroxyprogesterone, androstenedione) may be
normal
-Diagnosis is established by demonstrating an
increased ratio of D5 steroids (pregnenolone, 17α-
hydroxy pregnenolone, DHEA) to D4 steroids in
plasma or urine.

23. StAR deficiency:
-Mutations in the gene encoding steroidogenic acute
regulatory protein (StAR)
-Results in a failure of transport of cholesterol from
the outer to inner mitochondrial membrane in
steroidogenic tissues.
-As a result, there is deficiency of all adrenal and
gonadal steroid hormones.
-The condition is fatal in infancy in 2/3 of all cases.
-The adrenal glands are often massively enlarged and
full of lipid; before the characterization of StAR, the
condition was termed congenital “lipoid” hyperplasia

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