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Congenital adrenal hyperplasia, Ola Elgaddar, 2012
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Congenital adrenal hyperplasia, Ola Elgaddar, 2012

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Role of lab in diagnosing congenital adrenal hyperplasia (CAH) ...

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

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  • 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.
  • 3. 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
  • 4. 21-hydroxylase deficiency- Accounts for 90 % of CAH cases.- Mutation in CYP21A2 gene, results in complete orpartial 21-hydroxylase deficiency.- The normal synthesis of cortisol is impaired, andACTH levels increase because of loss of normalnegative feedback inhibition, resulting in an increasein adrenal steroid precursors proximal to the block.-The results are cortisol deficiency, variablemineralocorticoid deficiency, and excessive secretionof adrenal androgens.
  • 5. DIFFERENT FORMS OF 21-HYDROXYLASE DEFICIENCY ClassicalPhenotype 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 ♀virilized21-Hydroxylase activity 0% 1% 20% to 50%Hormones:Aldosterone Reduced Normal NormalRenin Increased Normal or increased NormalCortisol Reduced Reduced Normal17 (OH) progesterone 500 to 2500 >5000 2500 to 5000 (nmol/L) (ACTH stimul.)Testosterone Increased Increased Variable, increased
  • 6. Diagnosis of 21-hydroxylase deficiencySuspect a newborn with:-Genital ambiguity-Salt-wasting-Hypotension-Hypoglycemia-Hyponatremia-Hyperkalemia-Raised plasma renin activity
  • 7. 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
  • 8. Prenatal diagnosis:-17-OHP assay in amniotic fluid.-Genotyping of fetal cells obtained by CVS.N.B:Maternally administered dexamethasone preventmasculinization in utero.
  • 9. 11β- hydroxylase deficiency- Accounts for 7% of CAH cases.-Mutations in the CYP11B1 gene, which result in lossof enzyme activity and a block in the conversion of 11-deoxycortisol to cortisol-Loss of negative cortisol feedback and enhancedACTH-mediated adrenal androgen excess (virilized female fetus, sexual ambiguity)-Hypertension, secondary to the mineralocorticoideffect of the excess DOC (D.D: 21-hydroxylase deficiency)
  • 10. 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 otheradrenal androgens.
  • 11. 17α- hydroxylase deficiency-Approximately 150 cases have been reported.-A single enzyme is expressed in adrenal and gonadsthat possesses both 17-hydroxylation and 17,20 lyaseactivities.-Mutations within the CYP17 gene result in the failureto synthesize cortisol, adrenal androgens and gonadalsteroids.-Loss of negative feedback results in increasedsecretion of steroids proximal to the block, andmineralocorticoid synthesis is enhanced.
  • 12. Diagnosis of 17α-hydroxylase deficiencyAt 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.
  • 13. 3β- hydroxysteroid dehydrogenase II deficiency-A rare form of CAH.-Mutation in HSD3B2 gene encoding 3ß-HSDII.-Secretion of all classes of adrenal and ovariansteroids is impaired.-Loss of mineralocorticoid secretion results in variabledegrees of salt-wasting- The spectrum of genital development is variable inboth sexes:♂:pseudohermaphroditism, hypospadias, normal♀:mild virilization, premature pubarche, PCOS-likephenotype
  • 14. Diagnosis of 3ß-HSDII deficiency- Because activity of the 3ß-HSDI enzyme, present inskin and other peripheral tissues, is intact,circulating D4 steroids (progesterone, 17α-hydroxyprogesterone, androstenedione) may benormal-Diagnosis is established by demonstrating anincreased ratio of D5 steroids (pregnenolone, 17α-hydroxy pregnenolone, DHEA) to D4 steroids inplasma or urine.
  • 15. StAR deficiency:-Mutations in the gene encoding steroidogenic acuteregulatory protein (StAR)-Results in a failure of transport of cholesterol fromthe outer to inner mitochondrial membrane insteroidogenic tissues.-As a result, there is deficiency of all adrenal andgonadal steroid hormones.-The condition is fatal in infancy in 2/3 of all cases.-The adrenal glands are often massively enlarged andfull of lipid; before the characterization of StAR, thecondition was termed congenital “lipoid” hyperplasia
  • 16. THANK YOU