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Congenital adrenal hyperplasia due to 17 alpha-hydroxylase deficiencyCongenital adrenal hyperplasia due to 17α-hydroxylase deficiency is an uncommon form of congenital adrenal hyperplasiaresulting from a defect in the genefor the enzymeP450c17, which mediates several key transformations in the synthesis of both cortisoland sex steroids. Because P450c17 mediates several reactions and different defective allelescan result in different combinations of impaired activity, people affected by this type of CAH can display a wide variety of problems and effects. Some versions of this disease cause ambiguous genitaliain genetic males, failure of the ovaries to function at puberty in genetic females, and/or hypertensiondue to excessive mineralocorticoidproduction.
What is CAH?Congenital adrenal hyperplasia (CAH) refers to any of several autosomalrecessivediseases resulting from defects in steps of the synthesisof cortisolfrom cholesterolby the adrenal glands. All of the forms of CAH involve excessive or defective production of sex steroidsand can pervert or impair development of primaryor secondary sex characteristicsin affected infants, children, and adults. Many also involve excessive or defective production of mineralocorticoids, which can cause hypertensionor salt wasting, respectively. The most common type of CAH is due to deficiency of 21-hydroxylase and is covered in detail in the main article on congenital adrenal hyperplasia. 17α-Hydroxylase deficient congenital adrenal hyperplasia is one of the less common types of CAH due to deficiencies of other proteins and enzymes involved in cortisol synthesis. Other uncommon types are described in individual articles (links below).
Genetics of the various forms of P450c17 deficiencyThe gene for the cytochrome P450c17 enzyme resides on chromosome 10q24.3. Mutations of this gene result in altered activities of the enzyme and the various forms of congenital adrenal hyperplasia and sex steroid deficiency due to its impairment. As are most enzyme deficiencies, these disorders are inherited in an autosomal recessivemanner with a reported incidence of about 1 in 50,000 births. The OMIMnumber for diseases arising from mutations of this gene is 202110.
Pathophysiology and genetics of the various forms of P450c17 deficiencyThe enzyme itself is attached to the smooth endoplasmic reticulumof the steroid-producing cells of the adrenal cortexand gonads. P450c17 functions as both a 17α-hydroxylase and a 17,20-lyase. The dual activities mediate three key transformations in cortisoland sex steroidsynthesis:
The hydroxylase reactions are part of the synthetic pathway to cortisol as well as sex steroids, but the lyase reaction is only necessary for sex steroid synthesis. Different alleles of the P450c17 gene result in enzyme molecules with a range of impaired or reduced function that produces a range of clinical problems. The dual enzyme activities were for many decades assumed to represent two entirely different genes and enzymes. Thus, medical textbooks and nosologies until quite recently described two different diseases: 17α-hydroxylase deficient CAH, and a distinct and even rarer defect of sex steroid synthesis termed 17,20-lyase deficiency (which is not a form of CAH). In the last decade it has become clearer that the two diseases are different forms of defects of the same gene. However, the clinical features of the two types of impairment are distinct enough that they are described separately in the following sections.
17α-hydroxylase deficient CAHThe most common abnormal alleles of this condition impair both the 17α-hydroxylase activity and the 17,20-lyase activity. Like other forms of CAH, 17α-hydroxylase deficiency impairs the efficiency of cortisolsynthesis, resulting in high levels of ACTHsecretion and hyperplasia of the adrenal glands. Clinical effects of this condition include overproduction of mineralocorticoidsand deficiency of prenatal and pubertalsex steroids. Mineralocorticoid effects of 17α-hydroxylase deficient CAHThe adrenal cortex is hyperplastic and overstimulated, with no impairment of the mineralocorticoid pathway. Consequently, levels of DOC, corticosterone, and 18-deoxycorticosterone are elevated. Although these precursors of aldosteroneare weaker mineralocorticoids, the extreme elevations usually provide enough volume expansion, blood pressure elevation, and potassium depletion to suppress reninand aldosterone production. Some persons with 17α-hydroxylase deficiency develop hypertensionin infancy, and nearly 90% do so by late childhood. The low-renin hypertensionis often accompanied by hypokalemiadue to urinary potassium wasting and metabolic alkalosis. These features of mineralocorticoid excess are the major clinical clue distinguishig the more complete 17α-hydroxylase deficiency from the 17,20-lyase deficiency, which only affects the sex steroids. Treatment with glucocorticoid suppresses ACTH, returns mineralocorticoid production toward normal, and lowers blood pressure.
Glucocorticoid effects of 17α-hydroxylase deficient CAHAlthough production of cortisol is inefficient enough to raise ACTH, the 50-100-fold elevations of corticosteronehave enough weak glucocorticoidactivity to prevent glucocorticoid deficiency and adrenal crisis.
Effects of impaired sex steroid synthesis in 17α-hydroxylase deficient CAHGenetic XX females affected by 17α-hydroxylase deficiency are born with normal female internal and external anatomy. At the expected time of puberty, neither the adrenals nor the ovaries can produce sex steroids, so neither breast development nor pubic hair appear. Investigation of delayed puberty yields elevated gonadotropinsand normal karyotype, while imaging confirms the presence of ovaries and an infantile uterus. Discovery of hypertension and hypokalemic alkalosis usually suggests the presence of one of the proximal forms of CAH, and the characteristic mineralocorticoid elevations confirm the specific diagnosis. A few milder forms of this deficiency in genetic females have allowed relatively normal breast development and irregular menstruation. Evidence suggests that only 5% of normal enzyme activity may be enough to allow at least the physical changes of female puberty, if not ovulationand fertility. In these girls, the elevated blood pressure was the primary clinical problem. 17α-Hydroxylase deficiency in genetic males (XY) results in moderate to severe reduction of fetal testosteroneproduction by both adrenals and testes. Undervirilizationis variable and sometimes complete. The appearance of the external genitaliaranges from normal female to ambiguous to mildly underdeveloped male. The most commonly described phenotype is a small phallus, perinealhypospadias, small blind pseudovaginal pouch, and intra-abdominal or inguinaltestes. Wolffian ductderivatives are hypoplastic or normal, depending on degree of testosterone deficiency. Some of those with partial virilization develop gynecomastia at puberty even though masculinization is reduced. The presence of hypertension in the majority distinguishes them from other forms of partial androgen deficiency or insensitivity. Fertility is impaired in those with more than minimal testoserone deficiency.
17,20-lyase deficiencyA very small number of people have reportedly had an abnormal gene that resulted primarily in a reduction of 17,20-lyase activity, rather than both the hydroxylase and lyase activities as described above. In these people the defect had the effect of an isolated impairment of sex steroidsynthesis, with no significant effects on mineralocorticoidor glucocorticoidproduction, and no adrenal hyperplasia, mineralocorticoid overproduction, or hypertension. The sex steroid deficiency produces effects similar to 17α-hydroxylase deficiency. Severely affected genetic females (XX) are born with normal internal and external genitalia and there are no clues to abnormality until adolescence, when both the androgenic and estrogenic signs (e.g., breasts and pubic hair) of puberty fail to occur. Gonadotropins are high and the uterus infantile in size. The ovaries may contain enlarged follicular cysts, and ovulation may not occur even after replacement of estrogen.
Management of 17α-hydroxylase and 17,20-lyase deficienciesHypertension and mineralocorticoid excess is treated with glucocorticoidreplacement, as in other forms of CAH. Most genetic females with both forms of the deficiency will need replacement estrogen to induce puberty. Most will also need periodic progestin to regularize menses. Fertility is usually reduced because egg maturation and ovulation is poorly supported by the reduced intra-ovarian steroid production. The most difficult management decisions are posed by the more ambiguous genetic (XY) males. Most who are severely undervirilized, looking more female than male, are raised as females with surgical removal of the nonfunctional testes. If raised as males, a brief course of testosterone can be given in infancy to induce growth of the penis. Surgery may be able to repair the hypospadias. The testes should be salvaged by orchiopexyif possible. Testosterone must be replaced in order for puberty to occur and continued throughout adult life.
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