17-Hydroxylase deficiency results from mutations in the cytochrome P450C17 enzyme which functions both as steroid 17α-hydroxylase and as 17, 20-lyase. (40) The structural gene for cytochrome P450C17 (CYP17A1) has been mapped to chromosome 10q24.3. (41) Over 50 mutations in this gene have been described. Nucleotide substitution causing missense or nonsense alterations account for majority of the patients reported worldwide. (3) It is a rare disease identified in approximately 120 patients worldwide. The enzyme deficiency causes diminished production of cortisol and sex steroids, whose production requires the 17, 20-lyase function of the same 17α-hydroxylase enzyme (Figure 1). Because both adrenals and gonads share the enzyme defect, there is decreased biosynthesis of (i) androgens, resulting in males (46,XY) with an undervirilized sexual phenotype at birth, and later failure of pubertal development, and of (ii) estrogens, resulting in females at pubertal age presenting with primary amenorrhea and lack of development of secondary sex characteristics.

Reciprocal elevation of ACTH secondary to low cortisol increases synthesis of DOC and corticosterone via the 17-deoxy pathway. Therefore hypertension and hypokalemia may comprise the primary presentation at any age or can be associated with the abnormal sexual phenotype. As in 11β- hydroxylase deficiency, the formation of aldosterone is reduced secondary to suppressed renin as a result of excess DOC.PHEOCHROMOCYTOMA

PHEOCHROMOCYTOMAS

Pheochromocytomas are reported to account for hypertension in 1 to 2% of children. (42) They are catecholamine-producing tumors that arise from the chromaffin cells of the adrenal medulla and the sympathetic ganglia and present with signs and symptoms that are related to the action of catecholamines. Although the peak incidence is in the third to fourth decades, 10% to 20% occur in children, with increased frequency in boys, and a median age at presentation between 9.5 and 12.5 years. (43)

A rule of "10" is often used when describing pheochromocytomas: 10% are extra-adrenal, 10% are multiple or bilateral, 10% are malignant, and 10% are familial. Extra-adrenal and bilateral tumors are more frequent in children, who also have a higher incidence of familial syndromes include familial pheochromocytoma, multiple endocrine neoplasia type 2 (MEN 2), neurofibromatosis type 1, and von Hippel-Landau (VHL) disease.

Pheochromocytomas usually present with symptoms that result from the catecholamine effects that include hypertension, sweating, pallor, flushing and palpitations (Table 1).

Certain symptoms are reported as occurring more commonly in children than adults and include sweating, visual disturbances, nausea, vomiting, loss of weight, polyuria and polydipsia. (44) In comparison with adults in whom the hypertension is often paroxysmal, it is sustained in 70 to 90% of children. (45) However, hypertension is not invariable and can be absent in up to 20% of children.(46) Furthermore, many pheochromocytomas, especially associated with MEN 2 and VHL disease, can be clinically silent.

The biochemical diagnosis of pheochromocytoma has been based on the detection of elevated levels of catecholamines and their metabolites in plasma or urine. However a number of factors make this problematic, including episodic secretion of catecholamines by pheochromocytomas, silent pheochromocytomas that do not secrete catecholamines, and increased secretion of catecholamines in certain physiological and pathological states such as physical activity and febrile episodes, and certain medications. The difficulty of biochemical diagnosis has led to a number of commonly used tests which are discussed in more detail under adrenal function and disease. Plasma free metanephrines is recommended because it carries uniquely high specificity. Once the biochemical diagnosis is established, the tumor must be localized. A variety of imaging techniques are utilized including magnetic resonance imaging (MRI), computed tomography (CT), and scintigraphy using I 123 or I 131 labeled m-iodobenzylguanidine (MIBG).

Surgical removal of the tumor is the primary treatment. Perioperative management is important in order to control hypertension and other sequelae of the hyperadrenergic state. Malignant pheochromocytomas require additional therapy, which includes chemotherapy, 131I MIBG, and radiation therapy.

Post-operatively catecholamine measurements are performed in order to confirm cure of the tumor. Long-term follow-up is also essential for detection of metachronous lesions. Finally, children diagnosed with a pheochromocytoma should be evaluated for one of the familial syndromes; conversely those with MEN 2 or VHL disease should undergo routine screening for the development of a pheochromocytoma.