A 13-year-old girl is brought to the clinic by her mother for a yearly physical examination. The patient feels well but is worried that she has not yet started puberty. Temperature is 36.7 C (98 F), blood pressure is 152/91 mm Hg, pulse is 75/min, and respirations are 18/min. Physical examination is significant for a lack of secondary sexual characteristics; a blind vagina is noted on pelvic examination. Laboratory studies reveal hypokalemia and low testosterone and estradiol levels. Cytogenetic analysis shows a 46,XY karyotype. This patient most likely has deficiency of which of the following enzymes?

Question

A 13-year-old girl is brought to the clinic by her mother for a yearly physical examination.  The patient feels well but is worried that she has not yet started puberty.  Temperature is 36.7 C (98 F), blood pressure is 152/91 mm Hg, pulse is 75/min, and respirations are 18/min.  Physical examination is significant for a lack of secondary sexual characteristics; a blind vagina is noted on pelvic examination.  Laboratory studies reveal hypokalemia and low testosterone and estradiol levels.  Cytogenetic analysis shows a 46,XY karyotype.  This patient most likely has deficiency of which of the following enzymes?

Quizplus · Accepted Answer

11ec160b_3ab0_33d8_9249_8190abb355b0_MD0001_00 This patient is genetically male (46,XY) with features suggestive of 17 alpha-hydroxylase deficiency, a rare cause of congenital adrenal hyperplasia (CAH). The enzyme 17 alpha-hydroxylase is active in the adrenal glands and gonads and is responsible for converting pregnenolone to 17-hydroxypregnenolone and progesterone to 17-hydroxyprogesterone. Deficiency of this enzyme impairs synthesis of sex hormones (eg, testosterone, estradiol) and cortisol but does not inhibit mineralocorticoid production. Due to the absence of androgens in utero, genetic males (46,XY) with 17 alpha-hydroxylase deficiency have undervirilized, ambiguous genitalia. In severe cases, they appear phenotypically female but lack internal female genitalia, as in this case. In contrast, genetic females (46,XX) develop normal internal and external genitalia. At puberty, impaired synthesis of sex hormones in the gonads leads to absent secondary sexual characteristics in both sexes and primary amenorrhea in girls. Excess mineralocorticoid production results in hypertension and hypokalemia that are usually detected around the expected time of puberty. Low cortisol provides positive feedback to increase ACTH production, further stimulating the mineralocorticoid pathway. This allows for the excess production of weak glucocorticoids (ie, corticosterone), preventing the detrimental effects of low cortisol. (Choice A) 5 alpha-reductase deficiency prevents conversion of testosterone to dihydrotestosterone, the hormone responsible for male external genitalia development. Affected genetic males have ambiguous genitalia at birth but develop normal secondary sexual characteristics (eg, increased muscle mass, phallus enlargement) at puberty because these features are testosterone dependent. Blood pressure and electrolytes are unaffected. (Choice B) 11 beta-hydroxylase deficiency causes decreased glucocorticoid synthesis and increased production of adrenal androgens. Because the production of 11-deoxycorticosterone (weak mineralocorticoid) is also increased, individuals with this deficiency have features of mineralocorticoid excess (eg, hypertension, hypokalemia). However, genetic males appear phenotypically normal. (Choice D) 20,22-desmolase (side chain cleavage enzyme) deficiency results in impaired synthesis of all steroid hormones with accumulation of cholesterol esters in the adrenal glands and gonads. Complete deficiency is lethal, and partial deficiency typically presents in infancy with signs of adrenal insufficiency (eg, hypotension, hyperkalemia). (Choice E) The most common form of CAH is 21-hydroxylase deficiency. It causes decreased glucocorticoid and mineralocorticoid synthesis and increased adrenal androgen production. In contrast to this patient, genetic males with 21-hydroxylase deficiency appear phenotypically normal. Educational objective: Deficiency of 17 alpha-hydroxylase is a rare form of congenital adrenal hyperplasia characterized by impaired synthesis of androgens, estrogens, and cortisol with excess production of mineralocorticoids. Genetic males with this deficiency may have phenotypically female external genitalia and present with hypertension and hypokalemia around the expected time of puberty. __________ References: Steroid 17-hydroxylase and 17,20-lyase deficiencies, genetic and pharmacologic. (http://www.ncbi.nlm.nih.gov/pubmed/26862015)

A 13-Year-Old Girl Is Brought to the Clinic by Her