Скачать или смотреть Cystic Fibrosis

In this video, I discuss the clinical features, diagnostic approach, and general principles of management for cystic fibrosis.

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). Symptoms include respiratory issues such as chronic bronchitis and bronchiectasis, as well as gastrointestinal symptoms like meconium ileus and pancreatic insufficiency. CF in the prenatal and newborn period presents predominantly with gastrointestinal manifestations including echogenic bowel, dilated bowel loops, and meconium ileus, an emergency that can present with vomiting and abdominal distention. Note that many newborns with CF can also be asymptomatic.

CF is screened for in all 50 states and is part of the Recommended Uniform Screening Panel (RUSP). All CF newborn screening (NBS) algorithms 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. However 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 “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), the test is followed up with a repeat IRT level, genetic testing, and a sweat chloride test.

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 quicker and cheaper than single gene sequencing, cover most pathogenic variants in CFTR, and can establish the diagnosis in most individuals with CF. Thus, they are preferred by most states as the initial DNA-based test for CF. 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 panel. 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 on the targeted sequencing panel. Though this was not an available answer choice, a sweat chloride level should also be sent to look for additional evidence of cystic fibrosis.

More info about cystic fibrosis can be found here:

GeneReviews: https://www.ncbi.nlm.nih.gov/books/NB...
Clinical and Functional Translation of CFTR: https://cftr2.org/
Rehani, MR, Marcus, MS, Harris, AB, Farrell, PM, Ren, CL. Variation in cystic fibrosis newborn screening algorithms in the United States. Pediatric Pulmonology. 2023; 58: 927-933. doi:10.1002/ppul.26279
ACMG ACT Sheets and Algorithms: https://www.ncbi.nlm.nih.gov/books/NB...
Jia S, Taylor-Cousar J. Cystic Fibrosis Modulator Therapies. Annu. Rev. Med. 2023. 74:413–26. https://doi.org/10.1146/annurev-med-0...
https://www.cff.org/intro-cf/newborn-...

Newsletter post with 2 board-style questions on this topic:
https://studyrare.substack.com/p/2024...

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Daniel