A newborn is being evaluated in the nursery. The patient was born at term via spontaneous vaginal delivery to a 23-year-old woman. The mother developed dark terminal facial hair and a deepened voice during the pregnancy. The delivery was unremarkable, and the patient's vital signs are within normal limits. Examination shows ambiguous genitalia and clitoromegaly. Laboratory studies reveal elevated serum levels of testosterone and androstenedione. Karyotype testing shows a 46,XX genotype. Ultrasound of the pelvis shows a normal-sized uterus. This infant's presentation is most likely due to deficiency of which of the following enzymes?

Question

A newborn is being evaluated in the nursery.  The patient was born at term via spontaneous vaginal delivery to a 23-year-old woman.  The mother developed dark terminal facial hair and a deepened voice during the pregnancy.  The delivery was unremarkable, and the patient's vital signs are within normal limits.  Examination shows ambiguous genitalia and clitoromegaly.  Laboratory studies reveal elevated serum levels of testosterone and androstenedione.  Karyotype testing shows a 46,XX genotype.  Ultrasound of the pelvis shows a normal-sized uterus.  This infant's presentation is most likely due to deficiency of which of the following enzymes?

Quizplus · Accepted Answer

11ec160b_3b1b_9fb4_9249_0d46316a8420_MD0001_00 This genotypically female (46,XX) infant with ambiguous genitalia was born to a mother who developed masculinizing features during pregnancy, findings which are consistent with aromatase deficiency. Aromatase, a key enzyme in estrogen synthesis, normally converts androstenedione to estrone and testosterone to estradiol in various body tissues, including the gonads, adrenal glands, and adipose tissue. However, the majority of fetal estrogen is synthesized by aromatase within the placenta, which is genetically derived from the fetus. Aromatase deficiency is an autosomal recessive disorder characterized by high androgen and low estrogen levels in the fetus and placenta. Excess placental androgens transfer into the maternal circulation, resulting in maternal gestational virilization (eg, acne, hirsutism, deep voice). Newborn girls with aromatase deficiency have normal internal genitalia but ambiguous external genitalia (eg, clitoromegaly). At puberty, estrogen synthesis is impaired due to absent ovarian aromatase, which results in primary amenorrhea, osteoporosis, and tall stature due to delayed fusion of the epiphyses. Boys with aromatase deficiency have phenotypically normal genitalia but develop tall stature and osteoporosis as adults. (Choice A) 5-Alpha reductase deficiency results in decreased synthesis of dihydrotestosterone, which is responsible for the development of external male genitalia (eg, scrotum, penis). Affected boys have underdeveloped genitalia, whereas girls are unaffected at birth. (Choice B) 17-Alpha hydroxylase deficiency is a form of congenital adrenal hyperplasia. Symptoms result from decreased production of glucocorticoids and androgens (ambiguous genitalia in boys) and increased production of mineralocorticoids (hypertension, hypokalemia). Girls have phenotypically normal genitalia. (Choice C) 21-Hydroxylase deficiency is the most common type of congenital adrenal hyperplasia and is associated with salt wasting and adrenal crises due to decreased aldosterone and cortisol synthesis. Increased androgen production causes ambiguous genitalia in girls, but maternal virilization does not occur due to intact placental aromatase activity (prevents androgens from entering the maternal circulation). (Choice E) HMG-CoA reductase is the rate-limiting enzyme in the cholesterol synthesis pathway; statins inhibit this enzyme and reduce endogenous cholesterol synthesis. It is not involved in sexual differentiation. Educational objective: Aromatase is responsible for converting androgens into estrogens. Deficiency of this enzyme causes accumulation of androgens during pregnancy, resulting in ambiguous external genitalia in newborn girls and maternal gestational virilization. __________ References: Aromatase and estrogen receptor a deficiency. (http://www.ncbi.nlm.nih.gov/pubmed/24485503)

A Newborn Is Being Evaluated in the Nursery