Andersons pediatric cardiology 1618

regulation of adrenocorticotrophin hormone, rather than its usual secretagogue, angiotensin II This chimeric gene product converts cortisol to its 18-oxo and 18hydroxy metabolites, leading to a pathognomonic profile of urinary steroids, with a raised ratio of 18-oxotetrahydrocortisol to tetrahydroaldosterone.358 Treatment with dexamethasone leads to the suppression of adrenocorticotrophic hormone, and hence suppression of the ectopically produced aldosterone Direct antagonists of aldosterone, such as spironolactone, have also been used successfully, and may avoid the side effects of dexamethasone.359 Liddle Syndrome Liddle syndrome is an autosomal dominant condition with a clinical presentation typical of primary hyperaldosteronism, and yet levels of aldosterone in the serum and urine, as well as activity of renin in the plasma, are suppressed.360,361 Patients have constitutive activation of the amiloride-sensitive distal renal epithelial sodium channel as a result of mutations in the β- or γ-subunit of the epithelial sodium channel.362–364 Analysis of urinary steroids reveals negligible aldosterone Treatment with triamterine or amiloride is successful Apparent Mineralocorticoid Excess A number of children have been observed with hypertension associated with suppressed activity of renin in the plasma, subnormal levels of aldosterone, hypokalemia with alkalosis, and a reduced excretion of all known steroids.348,356 Deficiency of 11β-hydroxysteroid dehydrogenase is the primary defect.365,366 In this autosomal recessive condition, these mutations cause increased intracellular cortisol that activates the mineralocorticoid receptor.367 In addition, the cortisol leads to suppression of adrenocorticotrophic hormone, and hence reduced excretion of other corticosteroids The condition responds to treatment with spironolactone, an antagonist of the mineralocorticoid receptor Gordon Syndrome Gordon syndrome is an autosomal dominant condition that is also known as pseudohypoaldosteronism type II It is characterized by hypertension with low plasma renin activity, hyperkalemia, metabolic acidosis, and normal glomerular filtration rates.368 Mutations in the with-no-lysine kinase 4 gene (WNK4) are associated with this condition.369 The gene normally inhibits the thiazidesensitive sodium-chloride cotransporter in the distal convoluted tubule Mutated genes fail to inhibit this cotransporter, leading to enhanced reabsorption of sodium chloride and water, with resultant expansion of volume, suppression of renin, and hypertension.370 The condition responds to restriction of sodium and therapy with thiazide diuretics Pheochromocytoma Benign pheochromocytomas, and the malignant pheochromoblastomas, develop from chromaffin tissue in the adrenal gland or sympathetic ganglions These tumors produce excessive amounts of catecholamines, and lead to an increase in the excretion of their metabolites in the urine Abnormal production of catecholamines is also observed with neuroblastomas, and occasionally with ganglion neuromas Adrenaline and noradrenaline are the principal biologically active catecholamines Noradrenaline is synthesized from tyrosine via dihydroxyphenylalanine and dopamine It is then methylated to produce adrenaline, this being the main hormone of the adrenal medulla Noradrenaline is principally produced by postganglionic sympathetic nerves Noradrenaline acts mainly on sympathetic α-adrenoceptors, while adrenaline stimulates both α- and β-adrenoceptors The catecholamines are metabolized to metadrenaline, also called metanephrine, and normetadrenaline, also called normetanephrine, and then oxidized to the principle urinary metabolite 3-methoxy-4-hydroxymandelic acid, also called vanillylmandelic acid The urine also contains homovanillic acid, produced from dopamine, as well as adrenaline and noradrenaline Malignant tumors excrete dopamine and homovanillic acid Because of the practical difficulties in obtaining accurately timed collections of urine over 24 hours in small children, spot samples may be used, expressing the excretion of vanillylmandelic acid relative to urinary creatinine.371 Excretion is usually raised in children with pheochromocytomas, especially if the urine is collected when the patient is hypertensive Collections over 24 hours may be necessary if the hypertension is episodic Levels of adrenaline and noradrenaline in the plasma should also be measured Typically, adrenal tumors produce a rise predominantly in adrenaline, while extra-adrenal tumors lead to raised noradrenaline levels Recent publications suggest that measurement of the levels of metanephrine and normetanephrine in the urine and plasma may be the most sensitive and specific assays for the confirmation of pheochromocytoma.226,227,372 While catecholamines may be secreted episodically, plasma-free metanephrines are produced continuously by the metabolism of catecholamines within pheochromocytoma tumor cells.372 Bananas, and drugs and foods containing vanilla, should be eliminated from the diet before urine is collected Methyldopa, clofibrate, and inhibitors of monoamine oxidase will reduce the excretion of catecholamines β-Blockers, and blockers of the calcium channels, may increase the levels of catecholamines in the plasma Labetalol may also interfere with assays Ideally, the patient should not be receiving these drugs when samples are collected for investigation for pheochromocytoma Stress may also lead to increased release of catecholamines, and thus the collection of blood should be done via a previously inserted cannula, when the child has been resting The hypertension is usually ascribed to the increased secretion of noradrenaline Thus, administration of phentolamine, which blocks αadrenoceptors, will lower the blood pressure by more than 20 mm Hg A loading dose of 20 to 100 μg/kg with subsequent infusion at 5 to 50 μg/kg per minute if no effect is observed False-positive results are common The majority of children also have high concentrations of renin in the plasma with secondary aldosteronism This has been ascribed to depletion of fluid volume, direct stimulation of secretion of renin by adrenaline, compression on the renal artery by the tumor, and associated renal arterial disease in those with neurofibromatosis.194 The adrenal medulla is the common site for the tumors, which vary in size from 1 to 10 cm They are more common on the right, and are bilateral in 20% of patients In 30%, tumors are situated in both the adrenal and extra-adrenal areas, or only in an extra-adrenal site Boys are affected twice as often as girls, and the incidence is highest between the ages of 11 and 15 years The most common extra-adrenal site is the aortic bifurcation, or the vicinity of the renal hilum Bladder tumors are described, which cause paroxysmal hypertension during micturition and, sometimes, hematuria.373 A dominant mode of inheritance is apparent in some families, and more than half of the patients have multiple tumors Pheochromocytoma is frequently associated with other conditions, such as neurofibromatosis and von Hippel–Lindau disease, and with the autosomally dominant multiple endocrine neoplasia syndrome, which includes medullary thyroid carcinoma, islet cell adenoma, and hyperparathyroidism.374 Hypertension is less common with other neurogenic tumors and only affects about 10% of children with neuroblastomas An increase in urinary dopamine, and its metabolite homovanillic acid, is a characteristic of neuroblastomas