2024.07.10 | Questions 82-83
Cardiovascular genetics (3/3) - A newborn with congenital heart disease
Hello,
This is the 3rd in a series of 3 posts related to cardiovascular genetics. We will discuss the case of an infant with congenital heart disease. There is also a video on congenital heart disease that is now available on the StudyRare YouTube channel.
We are also proud to announce Sonia Nessari, a genetic counselor and graduate of the GC program at Boise State, as the recipient of the StudyRare scholarship. This award will cover her ABGC board exam registration fee and enrollment in our ongoing board review course. We recorded an interview with Sonia here. Congratulations, Sonia — we are proud to be able to support you!
Please let me know if you have any feedback on this post or suggestions for future posts. I hope you are having a great week!
-Daniel
Questions
Question 82
A newborn girl is admitted to the NICU due to respiratory distress. She was born large for her age and her skin has a bluish discoloration. An echocardiogram shows truncus arteriosus. Genetic testing is sent for the newborn and is pending. Her mother does not receive routine medical care. Which of the following studies would be most useful in determining the likely cause of the baby’s symptoms?
Question 83
A hemoglobin A1c level is checked on the mother of the newborn in Question 82 and is 9.0% (normal < 5.7%). Which of the following genetic disorders is associated with truncus arteriosus and should also be tested for in this newborn?
Explanations
Question 82: Maternal hemoglobin A1c
Question 83: DiGeorge syndrome
The patient in question 82 has truncus arteriosus (TA), a congenital heart defect that occurs when the aorta and pulmonary artery fail to separate properly during fetal development. This results in a single large vessel, or "trunk," exiting the heart. When deoxygenated blood from the pulmonary artery mixes with oxygenated blood from the aorta, as is the case with TA, circulating oxygen levels decrease and can cause cyanosis (bluish skin). Complications of TA include pulmonary hypertension, which results from too much blood going to the lungs, congestive heart failure, and poor growth. Management of TA is with surgical repair within the first few days to weeks of life.
Classification of congenital heart disease
Broadly speaking, congenital heart disease (CHD) can be subdivided into cyanotic and acyanotic lesions, based on whether or not the lesion lowers systemic oxygen levels. A list of some of the more common forms of congenital heart disease within each of these categories is listed below.
Risk factors for truncus arteriosus
There are several risk factors (both environmental and genetic) for truncus arteriosus (TA). First, pregestational diabetes (discussed further below) is a well-established risk factor for conotruncal anomalies like TA, which is why checking a maternal hemoglobin A1c level (Question 82) is important in this scenario. Genetic associations with TA can be divided into syndromic and non-syndromic causes. DiGeorge syndrome (22q11.2 deletion syndrome) is an example of a syndromic cause of TA and is also associated with cleft palate, immunodeficiency, hearing loss, and learning difficulties. Up to 1 in 3 cases of TA have been associated with DiGeorge syndrome. Non-syndromic causes of TA include variants in genes such as NKX2-6 and GATA6.
Even in the presence of a clear environmental risk factor like pregestational diabetes, genetic testing for babies with congenital heart disease should still be considered. This is because not all IDM will develop congenital heart disease (CHD), and patients may have multiple factors (both environmental and genetic) that contribute to their CHD. If an underlying monogenic disorder were identified, this can inform recurrence risk and also guide management, as in the case of DiGeorge syndrome. However, many cases of CHD (including truncus arteriosus) occur sporadically and without an identifiable environmental or genetic cause.
Infants of diabetic mothers
Babies born to mothers with diabetes are known as infants of diabetic mothers (IDM). There are two types of diabetes in pregnancy, both of which can cause complications in the fetus:
Pregestational diabetes is present before pregnancy. Persistently elevated maternal glucose levels can act as a teratogen during the first trimester, which is a critical period for organ development. This increases the risk of congenital anomalies affecting the heart (e.g., conotruncal defects like truncus arteriosus), gastrointestinal tract (small left colon syndrome), lower limbs (caudal regression syndrome), and spine (spina bifida). The risk for congenital heart disease (CHD) and other anomalies is correlated with the control of maternal blood glucose levels. Pregestational diabetes is typically diagnosed with an elevated hemoglobin A1c level prior to pregnancy.
Gestational diabetes develops during the second or third trimester of pregnancy. It is not associated with an increased risk of congenital malformations because it occurs after the critical period of organogenesis. However, both pregestational and gestational diabetes can result in an infant who is large for gestational age, which may cause delivery complications like shoulder dystocia, as well as metabolic and hematologic issues including hypoglycemia, polycythemia, and hyperbilirubinemia that present shortly after birth. Gestational diabetes is diagnosed with an oral glucose tolerance test in the late second or third trimester and usually resolves after delivery.
💡 Hemoglobin A1c is not used to diagnose gestational diabetes, as it can underestimate the glucose intolerance due to lower maternal hemoglobin levels in pregnancy.
Incorrect answers
Question 82
Maternal phenylalanine levels (choice A) should be checked in patients with phenylketonuria. Elevated phenylalanine levels in mothers with PKU are teratogenic and can cause maternal PKU, which is characterized by multiple fetal anomalies including congenital heart disease (though not typically truncus arteriosus), microcephaly, and intrauterine growth restriction (vs the infant in this question, who was large for their age). A maternal folate level (Choice C) could be considered if the newborn had been diagnosed with a neural tube defect, which is linked to maternal folate deficiency. Congenital heart disease, however, is not linked to folate deficiency. A maternal karyotype (Choice D) could be considered if there were a history of recurrent miscarriage or infertility. However, most patients with congenital heart disease (and their parents) will have a normal karyotype, which lacks the resolution to detect copy number variants that are seen in some patients with congenital heart disease.
Question 83
While Down syndrome (Choice A) is associated with congenital heart defects, truncus arteriosus is not typically seen in these patients. Common cardiac anomalies in Down syndrome include atrioventricular septal defects (AVSD), also known as endocardial cushion defects. Specific defects include ventricular septal defects (VSD), atrial septal defects (ASD), and malformed tricuspid and mitral valves. Williams syndrome (7q11.23 deletion syndrome, Choice C) is often associated with supravalvular aortic stenosis but not with truncus arteriosus. Noonan syndrome (Choice D) can present with various cardiac anomalies including pulmonary valve stenosis and hypertrophic cardiomyopathy, though truncus arteriosus is not typically associated with this condition.
Learning objective
Truncus arteriosus is a cyanotic congenital heart defect where the aorta and pulmonary artery do not properly separate. The risk for truncus arteriosus, among other congenital anomalies, is increased in the offspring of mothers with pregestational diabetes but not gestational diabetes. Genetic testing for DiGeorge syndrome should be considered in patients with TA, as ~1/3 of patients with truncus arteriosus have DiGeorge syndrome.
2023 ABMGG General Exam Blueprint | V. Single gene inheritance → d. Single gene disorders → iii) Cardiac disorders
2023 ABGC Exam Content Outline | Domain 1C. Genetic Conditions → 1. Clinical features, 5. Management options, and 8. Etiology
References
Frequency of 22q11 deletions in patients with conotruncal defects
Truncus arterious (Mott Children’s hospital)
Infant of a diabetic mother: clinical presentation, diagnosis and treatment