2024.01.01 | Questions 71-72
Newborn screening (1/3) - A positive NBS for cystic fibrosis
Hello,
This is the 1st in a series of 3 posts related to newborn screening. This post focuses on the diagnostic approach to cystic fibrosis (CF) in the context of newborn screening (NBS). Knowing about the diagnosis of CF and about newborn screening in general is important clinically and is high-yield for ABMGG and ABGC exams. I also uploaded a video to YouTube on the basics of CF.
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Happy New Year!
-Daniel
Questions
Question 71
A 1-week-old boy presents for a follow-up visit with his pediatrician after his newborn screen came back positive for cystic fibrosis (CF). Prenatally, echogenic bowel was noted during the second trimester fetal ultrasound. His delivery was uncomplicated, and he was discharged home at 3 days of life. He is feeding well and his weight and length are within normal limits. In the United States, which of the following is used as part of newborn screening on dried blood spots to assess newborns for the presence of CF?
Question 72
Based on the initial newborn screening result, his pediatrician sends a targeted panel consisting of 23 common CFTR variants. The results from this panel show a heterozygous variant in CFTR, F508del, with no second variant found. What is the next best step in this patient’s workup?
Explanation
Q71: Immunoreactive trypsinogen
Q72: CFTR gene sequencing
Cystic fibrosis (CF) is a multi-systemic disease that affects the lungs, pancreas, liver, and intestine. The different features of CF are the result of the accumulation of thick secretions within the tubular structures of different organs (e.g. bronchioles, pancreatic ducts, small intestine). Fetuses and newborns with CF primarily present with gastrointestinal symptoms and may be asymptomatic, hence the importance of newborn screening. Echogenic bowel and dilated bowel loops can be seen on prenatal ultrasounds, while meconium ileus, a life-threatening bowel obstruction, and failure to thrive due to pancreatic insufficiency can be seen in neonates. Pulmonary complications such as chronic bronchitis and bronchiectasis are uncommon in neonates and typically present later in infancy or early childhood. Difficulty with weight gain and short stature are also common in patients with CF of all ages. Most men with CF are infertile (but not sterile) due to congenital absence of the vas deferens, though conceiving is possible through testicular sperm extraction and in vitro fertilization.
💡The thick mucus that accumulates in the GI tract explains the echogenic bowel seen in the fetus with CF as well as meconium ileus, which results from a thick mucus plug that becomes stuck in the ileum (the last part of small intestine) and prevents the passage of stool.
Newborn screening for CF
CF is screened for in all 50 states and is part of the Recommended Uniform Screening Panel (RUSP), a list of conditions that the federal government suggests that all states test for. All newborn screening (NBS) protocols in the U.S. look for elevated levels of immunoreactive trypsinogen (IRT) from dried blood spots as an initial screen for CF (Question 71). Trypsinogen is a pancreatic precursor enzyme that is normally produced in the exocrine pancreas and helps digest dietary protein in the small intestine. In CF, due to the blockage of pancreatic exocrine ducts, trypsinogen instead backs up and enters the bloodstream, resulting in elevated IRT that is detected on newborn screen. (The term “immunoreactive” in IRT is in reference to the diagnostic assay itself, which uses antibodies). Because IRT can also be elevated in infants without CF (due to prematurity, low birth weight, and sample collection errors, among other reasons), additional testing (discussed below) is needed to definitively diagnose the condition.
Diagnosing Cystic Fibrosis
The definitive diagnosis of CF is with a combination of genetic testing (biallelic pathogenic variants in CFTR) and an elevated sweat chloride level. Targeted CFTR variant panels are preferred by most states as the initial DNA-based test for CF because they are quick to result, cheaper than complete CFTR gene sequencing, and cover most pathogenic variants in CFTR. However, false negative results, which occur more often in ethnic minorities, can result if a patient has a pathogenic variant that is not on the targeted CFTR variant panel. (Note that the composition of most targeted CFTR variant panels is biased toward pathogenic variants found in European populations). Therefore, in the case of the patient in Question 72 where only a single pathogenic variant on a panel is identified, sequencing of the entire CFTR gene should be performed to look for the presence of a second pathogenic variant in CFTR (as CF is an autosomal recessive condition) that was not included on the targeted sequencing panel. Though this was not an available answer choice, a sweat chloride level would also have been a reasonable option to look for functional evidence of cystic fibrosis.
Management of CF
Management of CF is multimodal and requires a team of specialists including pulmonology, gastroenterology, respiratory therapy, and dietitians. While there is no cure, oral CFTR modulators are available for many CFTR genotypes and have dramatically improved outcomes for many patients with CF. Certain CFTR modulators are available for infants as young as 1 month old and help improve both lung and pancreatic function. To manage pulmonary congestion, chest physical therapy (e.g. manual percussion or vibrating vest therapy) and mucolytics (e.g. dornase alfa) can be used. Prophylactic antibiotics help prevent pulmonary infections in infants and toddlers. Pancreatic enzyme replacement and a high-calorie diet help ensure adequate growth. In some cases with severe respiratory compromise, lung transplantation may be indicated. Newborn screening is crucial in enabling early intervention and access to therapies, such as CFTR modulators, that can improve lung and pancreatic function.
Newborn screening
Newborn screening (NBS) is an important and cost-effective public health tool that helps quickly diagnose newborns with treatable, early-onset conditions. In most cases, early identification of a condition on NBS improves long-term clinical outcomes. While most states screen for the majority of disorders on the RUSP (mentioned above), each state ultimately determine what disorders their NBS program will screen for. Furthermore, many states screen for disorders beyond those included on the RUSP, and there are guiding principles (for example, Wilson and Jungner’s 10 principles of screening) to help decide which conditions to include on NBS. A practical workflow for how NBS is performed is shown below.
Learning objective
Cystic fibrosis (CF) is a multi-systemic disease that is screened for in all 50 states in the U.S. CF is caused by pathogenic variants in the CFTR gene, which encodes a chloride transporter. Alterations in salt and water balance due to a defective or absent chloride transporter result in thick secretions that clog multiple organs, including the lungs, pancreas, and small intestine. Newborn screening for CF measures immunoreactive trypsinogen (IRT), and a definitive diagnosis is made with molecular testing and a sweat chloride test. New FDA-approved treatments known as CFTR modulators are available for patients with certain types of variants in CFTR.
2023 ABMGG General Exam Blueprint | IX. Population screening → a. Newborn screening → i) Blood spot screening
2023 ABGC Exam Content Outline | Domain 1. Clinical Information, Human Development, and Genetic Conditions → C. Genetic Conditions → 3. Screening, surveillance, and risk reduction
References
GeneReviews article on cystic fibrosis.
Clinical and Functional Translation of CFTR is a database to help determine whether a given combination of variants is CF-causing.
Cystic Fibrosis Modulator Therapies. Jia S, Taylor-Cousar J. (2023)
Newborn Screening for CF (from the Cystic Fibrosis Foundation)