THE GENETICS, PATHOPHYSIOLOGX, AND MANAGEMENT OF HUMAN DEFICIENCIES OF P450c17

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P450C17 AND CYP17

Patients who carry the diagnosis of 17-hydroxylase deficiency harbor alterations in the CYP17 gene that encodes the P450c17 enzyme. P450c17 actually performs multiple chemical transformations. Human P450c17 17α-hydroxylates Δ5-pregnenolone and Δ4-progesterone with roughly equal catalytic efficiency,3, 35 whereas all other reactions show prominent differences between Δ5 and Δ4 substrates. The 17,20-lyase activity is roughly 50 times more efficient for the

PATHOPHYSIOLOGY

P450c17 deficiencies are a form of congenital adrenal hyperplasia in which not only adrenal but also gonadal steroidogenesis is impaired. In humans, one gene for P450c17 is expressed in the adrenals and gonads11 instead of two tissue-specific isozymes. A single 2.1-kb mRNA species yields a 57-kd protein in these tissues, and mutations in this gene produce a spectrum of deficiencies in 17-hydroxysteroids and C19 steroids. Loss of P450c17 in the adrenal gland impairs cortisol and DHEA production,

DIAGNOSIS

Unlike forms of congenital adrenal hyperplasia, such as the lipoid type and 21-hydroxylase deficiency, in which glucocorticoid and mineralocorticoid production are impaired, patients with 17-hydroxylase deficiency do not have an adrenal crisis in the postnatal period. Consequently, the diagnosis is often not entertained until hypertension, hypokalemia, or pubertal delay is evaluated during adolescence or early adulthood. Patients with a 46,XY karyotype and incomplete deficiency may be

Deletions, Premature Truncations, Frameshifts, and Splicing Errors

Among the genetic abnormalities described in the CYP77 gene, the largest deletion reported involves the substitution of 518 bp (most of exon 2 and part of exon 3) with 469 bp of unknown DNA, disrupting the protein near its beginning and causing complete 17α-hydroxylase deficiency.6 A 4-bp duplication of the sequence CATC following Ile47930 was originally observed in Canadian Mennonites29 and has been subsequently found in at least six Dutch Frieslander families.28 This duplication leaves 95% of

MANAGEMENT

The child with 17-hydroxylase deficiency is chronically exposed to elevated circulating mineralocorticoid (DOC) concentrations but roughly normal amounts of glucocorticoids (as corticosterone). Mineralocorticoid excess in the neonatal period is of no consequence because mineralocorticoid (aldosterone) production is normally high in infants17; however, as the child ages and begins to consume solid foods, sodium intake rises, and mineralocorticoid excess can lead to sodium retention,

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