TREATMENT OF CONGENITAL

ADRENAL HYPERPLASIA

PRESENTATION BY : DR MAHESH YADAV REFERENCE ( THE NEW ENGLAND JOURNAL

OFMEDICINE

CLASSIFICATION 21- HYDROXYLASE DEFECIENCY (>90%)• Classical – Salt Wasting Simple Virilizing • Non Classical OTHERS • 11 hydroxylase deficiency • 17 alpha hydroxylase deficiency• 3 hydroxysteroid dehydrogenase

deficiency • Congenital lipoid adrenal hyperplasia • P450 oxidoreductase deficiency

DISORDER GENE AFFECTED AND CHOROMOSOME

SIGN AND SYMP. THERAPEUTIC MEASURES

21 Hydroxylase Deficiency ,classic form

CYP216p21.3

Glucocorticoids deficiency

Mineralocorticoid deficiency (salt –wasting crisis)

Ambiguous genitalia in femalesPostnatal virilization in males and females

Glucocorticoids replacement Mineralocorticoids +sodium chloride supplements Vaginoplasty and clitoral recession Suppression with glucocorticoids

21-Hydroxylase deficiency ,non classic form

CYP216p21.3

Asymptomatic ,precocious adrenarche ,hirsutism,acne,menstrual irregularity ,infertility

Suppression with glucocorticoids

11beta-hydroxylase deficiency

CYP11B18q24.3

Glucocorticoids deficiency

Ambiguous genitalia in femalesPostnatal virilization in males and females Hypertension

Glucocorticoids replacement Vaginoplasty and clitoral recession Suppression with glucocorticoids Suppression with glucocorticoids

DISORDER

AFFECTED GENE AND CHROMOSOME

SIGN AND SYMPTOMS THERAPEUTIC MEASURES

3beta-hydroxysteroid dehydrogenase deficiency ,classic form

HSD3B21p13.1

Glucocorticoids deficiency

Mineralocorticoid deficiency (salt –wasting crisis)

Ambiguous genitalia in females and males

Precocious adrenarche ,disordered puberty

Glucocorticoids replacement Mineralocorticoids +sodium chloride supplements Surgical correction + sex hormone replacement Suppression with glucocorticoids

17alpha-hydroxylase/17,20-lyase deficiency

CYP1710q24.3

Cortisol deficiency

Ambiguous genitalia in males

Sexual infantilism

Hypertension

Glucocorticoids administration Orchidopexy or removal of intraabdominal testes ,sex hormone replacment Sex homone replacement Suppression with glucocorticoids

DISORDER

AFFECTED GENE AND CHROSOME

SIGN AND SYMPTOMS THERAPEUTIC MEASURES

Congenital lipoid adrenal hyperplasia

STAR8p11.2

Glucocorticoids deficiency

Mineralocorticoid deficiency (salt –wasting crisis)

Ambiguous genitalia in males

Poor pubertal development or premature ovarian failure in females

Glucocorticoids replacement Mineralocorticoids +sodium chloride supplements Orchidopexy or removal of intraabdominal testes,sex hormone replacement

Estrogen replacement

P450 oxidoreductase deficiency

POR 7q11.3

Glucocorticoids deficiency

Ambiguous genitalia in males and females

Maternal virilization ANTLEY BIXLER SYNDROME

Glucocorticoids replacement Surgical correction of genitals and sex hormone replacement

TREATMENT CLASSIC 21- HYDROXYLASE

DEFICIENCY GLUCOCORTICOIDS ( For children) Dose =

Hydrocortisone 10 – 20 mg/m sq./day in three divided dose .

For adults Prednisolone 5-7.5 mg daily in two divided dose .

Look for signs of Iatrogenic Cushing’s

Syndrome rapid weight gain Hypertension pigmented striae osteopenia .

Male with testicular adrenal rests requires higher doses of dexamethasone to suppress corticotrophin .

Treatment is not indicated in asymptomatic children non classic 21-hydroxylase deficiency .

MINERALOCORTICOIDS Supplemental mineralocorticoid

(0.1 – 0.2 mg of fludrocortisone daily ) sodium chloride

(17 – 34 mmol od sodium chloride daily in addition to glucocorticoids treatment ).

Breast milk or infant formulas ( sodium contents 8mmol per litre ) is insufficient to compensate sodium losses .

Monitor Plasma renin activity levels or direct renin immunoassays .

Signs of inadequate dose Hypotension Hyperkalemia elevated renin levels

Signs of overdose Hypertension Edema Tachycardia suppresses plasma renin activity .

Adjustment dose is 0.05 – 0.1 mg .

TREATMENT OF AMBIGUOUS GENITALIA Surgical correction

PRENTAL DIAGNOSIS AND TREATMENT Prenatal genetic counselling is

advised for all affected females . Maternally administered

dexamethasone reduces genital ambiguity in affected females foetuses .

Dose =20ug per kg /day . Long term safety of prenatal

treatment remains uncertain. No congenital malformations have

been attributable to such therapy

ALGORITHM FOR DECISIONS PERTAINING TO THE PRENATAL DIADNOSIS AND TREATMENT OF 21 HYDROXYLASE DEFEICIENCY ....

Both parents carrier

Pregnancy test (<6 week of gestation )

Positive

Begin dexamethasone Chronic villus sampling

Fetal sex Male-stop Dexa.

Female

long term follow up

CYP21 GENOTYPE

Affected Unaffected

Continue dexa. Stop dexa.

Confrim diagnosis postnatally long term follow up

DIAGNOSIS AND TREATMENT OF CONGENITAL ADRENAL HYPERPLASIA

DISORDER

AFFECTED GENE AND CHROMOSOME

SIGNS AND SYMPTOMS

LABORATORY FINDINGS

THERAPEUTIC MEASURES

21-Hydroxylase deficiency,classic form

CYP216p21.3

Glucocorticoid deficiency ↓ Cortisol↑ACTH↑↑ Baseline and ACTH stimulated 17-hydroxyprogesterone

Glucocorticoid (hydrocortisone) replacement

Mineralocorticoiddeficiency (salt-wasting crisis)

HyponatremiaHyperkalaemia↑ Plasma renin

Mineralocorticoid (fludrocortisone)Replacementsodium chloridesupplementation

Ambiguous genitalia in females

↑ Serum androgens Vaginoplasty and clitoral recession

Postnatal virilisation in males and females

↑ Serum androgens Suppression with glucocorticoids

21-HydroxylaseDeficiencynonclassic form

CYP216p21.3

May be asymptomaticprecocious adrenarchehirsutismacnemenstrualIrregularityinfertility

↑ Baseline and ACTH-stimulated 17 hydroxyprogesterone↑ Serum androgens

Suppression with glucocorticoids