Congenital Adrenal Hyperplasia Dr. Abdelaziz Elamin. MD, PhD, FRCPCH Professor of Child Health Sultan Qaboos University, Muscat, Oman

What is CAH? It is a familial disorder of adrenal steroid biosynthesis with autosomal recessive mode of inheritance. The defect is expressed as adrenal enzyme deficiency. 5 major Enzymes deficiency are clinically important 21-Hydroxylase 11-b-Hydroxylase 17-a-Hydroxylase 3-b-Hsteroid hydrogenese 20,22 Desmolase deficiency

CAH The enzyme deficiency causes reduction in end-products, accumulation of hormone precursors & increased ACTH production. The clinical picture reflects the effects of inadequate production of cortisol & aldosterone and the increased production of androgens & steroid metabolites.

21-Hydroxylase Deficiency Most common type, accounts for >80% of cases. Incidence is 1:5000 to 1:15000 live birth. Gene is located on the short arm of chromosome 6 near the C4 locus in close association with HLA genes. Heterozygous carriers can be detected by ACTH stimulation test.

21-Hydroxylase deficiency/2 It is characterized by reduced production of cortisol and aldosterone and increased production of progesterone; 17-OH-progesterone, and sex steroids. The urinary steroid metabolites (17-ketosteroids and pregnanetriol) are elevated above normal levels.

21-Hydroxylase deficiency/3 Decreased secretion of aldosterone results in salt loss with hyponatremia and hyperkalemia; plasma renin activity is therefore elevated. In partial enzyme deficiencies, the aldosterone deficiency is not expressed, and patients remain normonatremic and normokalemic. The excess androgens causes virilization of girls & ambiguous genitalia & dark scrotum in boys.

21-Hydroxylase Deficiency/4 2 forms, classic early virilization type with or without salt-losing crisis and non-classic type with late-onset virilization. Male babies with non salt-losing non-classic type remains asymptomatic till late childhood when they may show signs of sexual precocity.

21-Hydroxylase Deficiency/5 Because members of the same family may have classic, non-classic & asymptomatic forms, the disorder may be due to allelic variations of the same enzyme. Mass neonatal screening using filter paper blood sample for 17-OH-Progesterone is used in the USA.

11-b-Hydroxylase Deficiency Accounts for 5-10% of cases of CAH. Gene is located on the long arm of chromosome 8. It is characterized by low plasma renin activity & elevation of serum 11-Deoxycortisol and 11-deoxycorticosterone. Because of the strong mineralocorticoid activity of deoxycorticosterone, the condition is characterized by salt retention, hypertension & hypokalemic alkalosis. The elevated plasma androgens may cause virilization of the female fetus.

17-a-Hydroxylase deficiency Genetic defect is on chromosome 10. Presents with similar features of those of 11-Hydroxylase deficiency except that Androgens are low, so no virilization in girls & genitalia is ambiguous in boys.

3-b-hydroxysteroid dehydrogenase deficiency This is a very rare disorder that results in accumulation of DHEA, which is converted to testosterone in peripheral tissues. It can cause virilization of female fetus and leads to ambiguous genitalia in the newborn.

Pathophysiology Anatomically, the adrenal gland can be divided into 3 zones: Zona glomerulosa, which produces predominately mineralocorticoid Zona fasciculata, which produces predominately glucocorticoid Zona reticularis, which produces predominately androgens

Enzyme pathway

Result of a 21-Hydroxylase Deficiency

ESSENTAILS OF DIAGNOSIS Increased linear growth with advanced bone age and eventual short stature Pseudohermaphorditism in girls due to androgen virilizing effect Isosexual precocity in boys with small infantile testes.

ESSENTAILS OF DIAGNOSIS/2 Adrenal crisis with salt-loss & metabolic acidosis or Hypertension & hypokalemic alkalosis. Low cortisol with high androgens, ACTH and steroid precursors e.g. 17-OH-Progest. or 11-Deoxycortisol.

ESSENTIALS OF DIAGNOSIS/3 Diagnosis is confirmed by measurement of ACTH, Cortisol, Aldosterone, 17-OH-progesterone, Testosterone & urinary 17-ketosteroids. Needs alertness for the possibility in all babies with Diarrhea & Vomiting, hypoglycemia or  BP.

CLINICAL COURSE The clinical phenotype depends upon the nature and severity of the enzyme deficiency. Approximately 50% of patients with classic congenital adrenal hyperplasia due to 21-hydroxylase (CYP21) deficiency have salt wasting due to inadequate aldosterone synthesis. Girls are usually recognized at birth because of ambiguous genitalia.

CLINICAL COURSE/2 Non salt losing CAH present late in childhood with precocious pubic hair and/or clitoromegaly, often accompanied by accelerated growth and advanced bone age. Those individuals with mild deficiencies of the enzyme present in adolescence or adulthood with varying virilizing symptoms ranging from oligomenorrhea to hirsutism and infertility.

GIRLS WITH CAH Have ambiguous genitalia at birth: complete fusion of the labioscrotal folds and a phallic urethra. clitoromegaly and partial fusion of the labioscrotal folds In less severe forms, genitalia is normal at birth. Precocious pubic hair & clitoromegaly and excess facial or body hair appear later in childhood, often accompanied by tall stature.

BOYS WITH CAH Are unrecognized at birth because their genitalia are normal. They are not diagnosed until later, often with a salt wasting crisis resulting in dehydration, hypotension, hyponatremia and hyperkalemia or later in childhood with early pubic hair & phallic enlargement accompanied by accelerated linear growth and advancement of skeletal maturation. High blood pressure & hypokalemia may occur in those with 11-b-hydroxylase deficiency and 17-a-hydroxylase deficiency due to the accumulation of the mineralocorticoid desoxycorticosterone

Laboratory Findings Demonstration of inadequate production of cortisol and/or aldosterone in the presence of accumulation of excess concentrations of precursor hormones is diagnostic. In 21-hydroxylase deficiency, very high serum 17-hydroxyprogesterone is characteristic together with very high urinary pregnanetriol (metabolite of 17-hydroxyprogesterone).

Laboratory Findings/2 11-b-hydroxylase deficiency is characterized by high serum 11-deoxycorticosterone and 11-deoxycortisol concentrations with elevation of its urinary metabolites (tetrahydrocompound-S). Both are accompanied by elevated 24-hour urinary 17-ketosteroids, the urinary metabolites of adrenal androgens.

Laboratory Findings/3 Salt wasting forms of adrenal hyperplasia are accompanied by low serum aldosterone, hyponatremia, hyperkalemia and elevated plasma renin activity indicating hypovolemia. In contrast hypertensive forms of adrenal hyperplasia (11-b-hydroxylase deficiency and 17-a-hydroxylase deficiency) are associated with suppressed plasma renin activity and hypokalemia.

Other Tests A karyotype is essential in the evaluation of the infant with ambiguous genitalia in order to establish the chromosomal sex. Prenatal diagnosis of adrenal hyperplasia is possible through biochemical and genetic tests.

Imaging studies A pelvic ultrasound: in the infant with ambiguous genitalia to demonstrate the presence or absence of a uterus or associated renal anomalies A urogenitogram is often helpful to define the anatomy of the internal genitalia. A CT scan of the adrenal gland to R/O bilateral adrenal hemorrhage in the patient with signs of acute adrenal failure A bone age study is useful in the evaluation of the child who develops precocious pubic hair, clitoromegaly, or accelerated linear growth.

TREATMENT PRINCIPLES Treatment is life-long Treatment goals are: to maintain growth velocity & skeletal maturation. to normalize electrolytes & hormone levels using the smallest dose of glucocorticoids that will suppress the ACTH to normal. Mineralocorticoid replacement may be needed to sustain normal electrolyte homeostasis.

MODES OF TREATMENT Steroid replacement Supportive therapy when needed Treatment is life-long Plastic surgery for ambiguous genitalia at early age Genetic counseling Psychological support

Acute Medical Management Fluid therapy in babies with salt losing crisis 0.9% sodium chloride 20 ml/kg as IV bolus, followed by a continuous IV infusion of 0.9% or 0.45% saline 3200 ml/m2/day. If the patient is hypoglycemic, 2-4 ml of 10% dextrose will correct the hypoglycemia. Patients with 11-b-hydroxylase and 17-alpha-hydroxylase deficiency, may be hypokalemic and require potassium.

Long Term Therapy Glucocorticoids Replacement Hydrocortisone 10-15 mg/m2/day divided in 3 oral doses. Dose should doubled during crisis & stressful conditions. The goals of therapy are: To replace the body's requirement under normal conditions and during stress. To suppress ACTH secretion, which drives the adrenal gland to overproduce adrenal androgens in virilizing forms of congenital adrenal hyperplasia.

Long Term Therapy/2 Mineralocorticoids Treatment Fludrocortisone acetate 0.05-0.2 mg once daily orally is indicated for patients who have salt-wasting forms of CAH to replace the aldosterone that is insufficiently produced by the adrenal cortex. It will restore the sodium- potassium balance.

New Trends of treatment A New approach therapy is the combined use of 4 drugs: glucocorticoid (to suppress ACTH and adrenal androgen production), mineralocorticoid (to reduce angiotensin II concentrations), aromatase inhibitor (to slow skeletal maturation), flutamide (an androgen blocker to reduce virilization)

Surgical Management Infants with CAH may require surgical evaluation and, if needed, corrective surgery. Traditional approach is clitroplasty early in life, followed by vaginoplasty after puberty. Some female infants with adrenal hyperplasia are only mildly virilized and may not require corrective surgery if they receive adequate medical therapy to prevent further virilization.

Further Outpatient Care Monitor patients adequacy of dosing of glucocorticoid and/or mineralocorticoid. Too little glucocorticoid results in symptoms of adrenal insufficiency (e.g., anorexia, nausea, vomiting, abdominal pain, asthenia) and will result in progressive virilization and advancement of skeletal maturation in virilizing forms of CAH. Too much glucocorticoid results in excess weight gain, cushingoid features, hypertension, hyperglycemia, cataracts, and growth failure.

Patient Education Educate the caretakers and patients about the nature of the disease. Patients & parents must understand the need for additional glucocorticoids in times of illness and stress in order to avoid an adrenal crisis which may be life-threatening.

Neonatal Screening Is done by measuring 17-hydroxyprogesterone from heel blood samples collected on filter paper. Mass neonatal screening program is adopted in the USA. This approach has permitted early identification of newborns with CAH and prevented salt wasting crisis in boys who are unrecognized at birth. It also identifies the completely virilized girls with ambiguous genitalia who may be mistaken for boys with cryptorchidism

Prenatal diagnosis Done by chorionic villus sampling at 8-12 wk & amniocentesis at 18-20 wk. HLA typing in combination with measurement of 17-OH-progesterone & androstenedion in amniotic fluid is used for antenatal diagnosis.

Prenatal Treatment Prenatal treatment of 21-hydroxylase deficiency prevents intrauterine virilization of female fetuses. According to the protocol proposed by Carlson et al, the mother is treated with dexamethasone (20 m/kg/d in 3 divided doses) as soon as the pregnancy is recognized to suppress fetal ACTH secretion & prevent the fetal adrenal gland from overproducing adrenal androgens.

PROGNOSIS Is good and complications like short stature, sexual precocity & metabolic effects are not seen with early adequate therapy. However, children with CAH are at  risk of developing mesodermal tumours e.g. osteogenic sarcoma, pulmonary liposarcoma, uterine leiomyomata and brain tumours.

PROGNOSIS /2 Late diagnosis & inadequate therapy may cause: Death of newborns with salt-losing types & if patients are not provided with stress doses of glucocorticoid in times of illness, trauma, or surgery. Psychological problems in girls with ambiguous genitalia. Short stature and infertility.