2025.06.01 | Questions 96-97
Prenatal genetics (3/3): Fetal genetic disorders affecting maternal health
Hello,
This is the third in a series of three posts related to prenatal genetics.
In the first post of this series, we discussed how maternal disorders can adversely impact fetal development (e.g. maternal PKU, maternal diabetes). This post focuses on the opposite: fetal genetic disorders that affect the mother’s health.
Also, we have extended our early-bird deadline for the 2025 ABGC board review bootcamp to Fri, June 6th, 2025. Please consider signing up before this date to take advantage of the discount. The bootcamp will take place between June 12th - July 24th, 2025 and is for genetic counselors taking the ABGC exam in August 2025. We also have a separate ongoing bootcamp for laboratory and clinical geneticists preparing for the ABMGG exam. For more information and to register, please visit our website.
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-Daniel
Questions
Question 96
A 28-year-old G2P1 woman presents at 24 weeks gestation for a prenatal visit. Over the last several weeks, she has developed facial hair, new-onset acne, and a deeper voice. She is otherwise generally healthy, and her first pregnancy was uneventful. Laboratory testing in the mother reveals elevated androgens and low estriol. An ultrasound of the fetus shows ambiguous genitalia, and an amniocentesis shows a 46,XX karyotype. Which of the following disorders affecting the fetus best explains the maternal and fetal findings?
Question 97
A 33-year-old G1P0 woman presents at 34 weeks gestation with new-onset right upper quadrant pain, nausea, vomiting, and fatigue. Her blood pressure is 140/90. Laboratory studies show elevated liver transaminases, low platelets, and hypoglycemia. A prenatal ultrasound shows a female fetus with no structural abnormalities. Which of the following fetal conditions is most likely responsible for the symptoms seen in the mother?
Explanations
Question 96: Aromatase deficiency
Question 97: LCHAD deficiency
Fetal genetic disorders that affect maternal health
Most genetic disorders that affect the fetus do not directly impact the pregnant mother’s health. However, there are a handful of fetal disorders that do. These generally fall into one of two categories: disorders of hormone metabolism and disorders of fatty acid metabolism. Hormones produced by the fetus or by the placenta (which is mostly fetal in origin) can enter the maternal circulation. These hormones, particularly estrogen, support fetal development and promote maternal adaptations to pregnancy (e.g. uterine growth, breast development). In addition, certain fetoplacental hormones serve as biomarkers of fetal health and form the basis of the quad screen in pregnancy (e.g. alpha-fetoprotein, hCG, estriol, and inhibin-A). Maternal symptoms that result from fetal genetic anomalies typically resolve after delivery.
Placental aromatase converts androgens to estrogens
During pregnancy, the fetal adrenal glands produce large amounts of androgens. These androgens travel to the placenta, where they are converted into estrogens by the placental enzyme aromatase (aka estrogen synthase, encoded by CYP19A1). Most of the circulating estrogens in both the mother and the fetus (particularly in later trimesters) are generated by the synergy between the fetal adrenal glands and placental aromatase.
Aromatase deficiency results in excess androgens
When there is a deficiency of placental aromatase (e.g. due to biallelic variants in CYP19A1 in the fetus), androgens from the fetal adrenals are not converted to estrogen and instead enter the maternal circulation directly as androgens (e.g. testosterone). This causes the virilization (aka masculinization) seen in the mother in Question 96 that includes voice deepening, the development of facial hair, male-pattern baldness, and clitoromegaly. The excess androgens also remain in the fetal circulation, which can result in a 46,XX fetus with ambiguous genitalia. (Note that ultrasound in a 46,XY male fetus with aromatase deficiency is typically normal).
Laboratory studies in aromatase deficiency show elevated androgens and low estrogen levels in the maternal circulation (see diagram below). During the prenatal period, this condition may also present with low estriol as part of the second trimester maternal serum screen. The combination of elevated maternal androgens, low maternal estrogen, maternal virilization, and ambiguous genitalia in a 46,XX fetus all point toward aromatase deficiency.
💡 To remember the function of aromatase, look at the first and last letters. AromatasE: Androgen → Estrogen
Acute fatty liver of pregnancy (AFLP) and LCHAD deficiency
Question 97 presents a case of acute fatty liver of pregnancy (AFLP), a rare and serious complication that typically occurs in the third trimester. The mother’s symptoms (right upper quadrant pain, nausea, vomiting, fatigue, hypertension) combined with laboratory findings (elevated liver enzymes, low platelets, hypoglycemia) are classic for AFLP. These symptoms can be life-threatening for the mother (e.g. acute liver failure), and the treatment for AFLP is immediate delivery of the fetus.
About 20% of cases of AFLP are associated with fetal long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency. This condition impairs mitochondrial fatty acid β-oxidation, a process that converts fatty acids into acetyl-CoA, a versatile cellular energy precursor. LCHAD deficiency is caused by biallelic variants in the HADHA gene, which encodes the α-subunit of the mitochondrial trifunctional protein complex that is responsible for several steps in fatty acid β-oxidation.
Testing for LCHAD deficiency involves sending a maternal plasma acylcarnitine profile (which will show elevated long-chain 3-hydroxyacylcarnitine species) and an amniocentesis to obtain a sample for genetic testing of the fetus. In addition, newborn screening (which includes the equivalent of an acylcarnitine profile) after delivery will flag positive (see this video for more on the postnatal complications of LCHAD). Prenatal ultrasound in a fetus with LCHAD deficiency is typically normal.
While the exact mechanism by which LCHAD deficiency affects the mother is unclear, there are two leading hypotheses. First, excessive hydroxyacyl derivatives produced by the affected fetus may cross the placenta and cause direct hepatic toxicity. Second, maternal heterozygosity* for LCHAD deficiency may cause hepatic insufficiency that predisposes to AFLP.
💡 *When a child is found to have an autosomal recessive disorder like LCHAD deficiency, the parents are almost always heterozygous carriers for that disorder.
Incorrect answers
Question 96
Androgen insensitivity syndrome (Choice A) typically presents with external female genitalia in a patient with a 46,XY karyotype. This is due to the inability of the body to respond to androgens, which promote the development of male genitalia in utero. Patients with a 46,XX karyotype would not be expected to have ambiguous genitalia, and maternal virilization does not occur during pregnancy. Steroid sulfatase deficiency (X-linked ichthyosis) (Choice C) affects estrogen metabolism and can present with a low estriol on maternal serum screening. It does not cause maternal or fetal virilization. Smith-Lemli-Opitz syndrome (Choice D) is a cholesterol biosynthesis disorder that causes multiple congenital anomalies in the fetus. In some cases, a fetus with a 46,XY karyotype can present with female-appearing or ambiguous genitalia due to the deficiency of sex hormones, which are derived from cholesterol. While SLO can present with low estriol on maternal serum screening, this condition does not cause maternal virilization or ambiguous genitalia in a 46,XX fetus.
Question 97
Antley-Bixler syndrome (ABS) (Choice A) is a skeletal dysplasia that is associated with short, bowed femurs and ambiguous genitalia on fetal ultrasound. One of the causes of ABS is deficiency of cytochrome P450 oxidoreductase, which plays an important role in steroid metabolism. ABS does not cause AFLP, and the absence of major abnormalities on ultrasound in this question points away from this diagnosis. 21-hydroxylase deficiency (Choice B) is the most common cause of congenital adrenal hyperplasia and can cause ambiguous genitalia in 46,XX fetuses due to excess adrenal androgens. It can cause adrenal insufficiency with hypotension in a newborn but not AFLP in the mother. A partial hydatidiform mole (Choice C) can cause maternal hypertension due to excessive production of beta-HCG. However, ultrasound would show a cystic placenta and a growth-restricted fetus, and genetic testing of the fetus would show a triploid karyotype (with 69 chromosomes), not a diploid karyotype. In addition, molar pregnancies typically become symptomatic and are diagnosed in the first trimester, not the third trimester.
Learning objective
There are several disorders that, when present in the fetus, directly affect the pregnant mother’s health. Examples include aromatase deficiency, which should be considered when a pregnant woman develops virilization in the setting of a 46,XX fetus with ambiguous genitalia. The combination of elevated maternal androgens and low estrogens in this clinical context is diagnostic. Another example is fetal LCHAD deficiency, a fatty acid oxidation disorder associated with AFLP in the mother. In most cases, symptoms in the mother that are caused by a genetic disorder in the fetus resolve with delivery of the fetus and placenta.
2025 ABMGG General Exam Blueprint | V. Single gene inheritance → d) Single gene disorders → ix) Metabolic disease & VII. Reproductive Genetics
2023 ABGC Exam Content Outline | Domain 3C. Reproductive Risk Management → 3. Prenatal screening & Domain 1B. Human development → 1. Fetal development
Additional resources
LCHAD deficiency (GeneReviews)