CONGENITAL ADRENAL HYPERPLESIA (CAH)

Objectives By the end of these lectures, the student will be able to: Define (CAH). State the etiology and list the types of (CAH). Describe the clinical presentation of (CAH). List the diagnostic tests of (CAH). Identify the treatment options of (CAH). Define pheochromocytoma and outline its etiology. Describe the clinical features of pheochromocytoma. List the diagnostic tests and state the treatment plan of pheochromocytomas.

(CAH) is a group of inherited autosomal- recessive disorders in which a genetic defect results in the deficiency of an enzyme essential for synthesis of cortisol and, at times, aldosterone. Most common and clinically important Enzymes deficiency are: 21-Hydroxylase 11-β-Hydroxylase 17-α-Hydroxylase

Reduction in end-products, accumulation of hormone precursors, impaired negative feedback and increased ACTH production and adrenal hyperplasia. The C/F reflects the effects of: 1- Inadequate production of cortisol & aldosterone 2- Increased production of androgens & steroid metabolites.

21-Hydroxylase Deficiency Most common type, accounts for 90- 95% 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.

21-Hydroxylase Deficiency

It is characterized by reduced production of cortisol and aldosterone and increased production of adrenal androgen. Diagnostic markers: serum (and urine) 17-OH-progesterone, pregnanetriolone, and 17-hydroxypregnanolone. 2 forms, classic early virilization type with or without salt-losing crisis and non-classic type with late-onset virilization.

In one third of cases of 21-OH deficiency, pat have severe salt wasting from reduced aldosterone. If not diagnosed at birth, the neonate will develop a life- threatening hyponatremia, hyperkalemia, and hypovolemia by day 10-14 of life (adrenal crisis). Mass neonatal screening using filter paper blood sample from the heal for 17-OH-Progesterone is used in the USA.

The excess androgens causes virilization of girls & ambiguous genitalia & dark scrotum in boys. The other two third of cases have adequate mineralocorticoid and will present later with premature adrenarche (pubic hair development), accelerated growth velocity, advanced bone age, acne, and hirsutism.

11-b-Hydroxylase Deficiency Gene is located on the long arm of chromosome 8. It is characterized by: Glucocorticoid deficiency, mineralocorticoid excess, adrenal androgen excess low plasma renin activity elevation of serum 11-Deoxycortisol and 11- deoxycorticosterone (DOC) which exerts mineralocorticoid activity. - salt retention, hypertension & hypokalemic alkalosis.

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.

17α-hydroxylase is necessary to convert pregnenolone to 17-hydroxypregnenolone (17-OH Preg) and progesterone to 17-hydroxyprogesterone (17-OH Prog). Thus, absence of this enzyme impairs all sex steroid and cortisol production. This results in increased secretion of pregnenolone, progesterone, (DOC), and corticosterone.

17-a-Hydroxylase deficiency

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

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

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.

Laboratory Findings In 21-hydroxylase deficiency: very high serum 17-hydroxyprogesterone very high urinary pregnanetriol (metabolite of 17- hydroxyprogesterone).

11-b-hydroxylase deficiency is characterized by: - high serum 11- (DCS) and 11-deoxycortisol, elevation of its urinary metabolites (tetrahydrocompound-S). Both are accompanied by elevated 24-hour urinary 17-ketosteroids.

In salt wasting forms of adrenal hyperplasia: low serum aldosterone, - hyponatremia, hyperkalemia - elevated plasma renin activity (hypovolemia) In (11-b-hydroxylase deficiency and 17-a- hydroxylase deficiency): HT suppressed plasma renin activity hypokalemia.

Treatment is life-long Treatment goals are: 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 Plastic surgery for ambiguous genitalia at early age Genetic counseling Psychological support

Long Term Therapy Glucocorticoids Replacement For children, 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. For adults, predinsolone is used

Mineralocorticoids Treatment Fludrocortisone acetate 0.05-0.2 mg once daily orally is indicated for patients who have salt-wasting forms of CAH. 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)

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.

Pheochromocytoma

Are catecholamine- producing tumors derived from the sympathetic or parasympathetic nervous system. They may arise sporadically or be inherited as features of MEN type 2. It is estimated to occur in 2–8 of 1 million persons/ year, and about 0.1% of hypertensive patients harbor a pheochromocytoma. The mean age at diagnosis is about 40 y. The "rule of tens" for pheochromocytomas states that about 10% are bilateral, 10% are extraadrenal, and 10% are malignant.

Etiology Well-vascularized tumors that arise from cells derived from the sympathetic (e.g., adrenal medulla) or parasympathetic (e.g., carotid body) paraganglia. They are catecholamine-producing tumors, including those in extra-adrenal retroperitoneal, pelvic, and thoracic sites

Clinical Features Episodes of palpitations, headaches, and profuse sweating are typical (triad), in association with HT (sustained or paroxysmal). It can be asymptomatic for years, and some tumors grow to a considerable size before symptoms. Other CF associated with pheochromocytoma: Anxiety and panic attacks, Pallor, Nausea, Abdominal pain, Weakness, Weight loss, Constipation, Orthostatic hypotension, Dilated cardiomyopathy, glucose intolerance.

The dominant sign is hypertension Catecholamine crises can lead to HF, pulmonary edema, arrhythmias, and intracranial hemorrhage. The paroxysms last less than an hour and may be precipitated by surgery, positional changes, exercise, pregnancy, and various medications (e.g., tricyclic antidepressants, opiates, metoclopramide).

Diagnosis Biochemical testing and localization of the tumor by imaging. Elevated plasma and urinary levels of catecholamines and the methylated metabolites, (metanephrines) are the cornerstone for the diagnosis. Urinary tests for (VMA), metanephrines (total or fractionated), and catecholamines are used commonly for initial testing. The fractionated metanephrines and catecholamines are the most sensitive. Plasma tests are the most sensitive. Suppression test using clonidine may be valuable (3 h after oral administration of 300 g of clonidine).

Abdominal CT or MRI. MIBG scintigraphy. Somatostatin receptor scintigraphy. Dopa (dopamine) PET.

(A) Anterior (left) and posterior (right) whole-body images of 51-y-old woman with right adrenal tumor on CT, confirmed as pheochromocytoma at surgery. (B) Anterior (left) and posterior (right) whole-body images of 28-y-old woman with paraganglioma metastatic to bone. (A) Anterior (left) and posterior (right) whole-body images of 51-y-old woman with right adrenal tumor on CT, confirmed as pheochromocytoma at surgery. Gregory A. Wiseman et al. J Nucl Med 2009;50:1448-1454 (c) Copyright 2014 SNMMI; all rights reserved

Treatment Complete tumor removal is the goal. Preoperative preparation for 6w is essential before surgery. α-Adrenergic blocker (phenoxybenzamine) should be initiated at relatively low doses (5–10 mg orally 3X per day) and increased every few days up to 20–30 mg 3X/d. Good hydration is necessary to avoid orthostasis.

Intravenous phentolamine can be used to manage paroxysms while awaiting adequate alpha blockade. It is also used during surgery Before surgery, BP should be below 160/90 mmHg. Beta blockers (10 mg propranolol 3-4 times daily) can be added if tachycardia persists. Nitroprusside infusion is useful for intraoperative hypertensive crises.