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Introduction: A risk associated with cystic fibrosis newborn screening (CFNBS) is parental misunderstanding of genetic information generated by the over 6600 positive screens reported annually in the United States. CFNBS algorithms incorporating DNA analysis can generate genetic information that requires clinical interpretation and has significance for the newborn, parents, and other relatives. Engagement between CF care centers and trained genetic counseling providers, such as licensed and/or certified genetic counselors (GCs), is variable and limited in providing information to CFNBS positive (CFNBS+) families., Methods: Using a modified Delphi process, a workgroup of CFNBS experts developed recommendation statements for engagement of genetic counseling services in CF care centers where CFNBS + diagnostic evaluations are performed. Statements were assessed over three rounds of surveys, one face-to-face meeting, and through public feedback., Results: Seventeen statements achieved >80% consensus (range: 82%-100%). The workgroup affirmed prior CFF policy statements recommending genetic counseling for parents of infants with CFNBS+. The remaining statements addressed infrastructure and logistics of genetic counseling services, including defining appropriate training for genetic counseling providers and counseling content, establishing a path to equal access to genetic counseling providers across CF care centers, and setting a standard for client-centered CFNBS genetic counseling that is respectful of diverse patient needs and autonomy., Conclusions: Implementation of client-centered genetic counseling for CFNBS+ families in CF care centers by providers with expertise in both CF and genetic counseling will require efforts to further define core concepts, enhance the education of providers, and develop opportunities for access via telemedicine., (© 2021 Wiley Periodicals LLC.)

Families of infants with a positive newborn screen for cystic fibrosis (CFNBS+) have well-characterized genetic counseling needs, including understanding the implications of diagnostic categorization. However, degree of involvement of genetic counselors (GCs) in the CFNBS+ diagnostic resolution process varies. This project explored GC engagement with US CF care centers in the diagnostic resolution process for CFNBS+ infants. Surveys were emailed to 713 Cystic Fibrosis Foundation-accredited CF center directors and clinic coordinators and 4,517 GCs. Respondents from institutions providing CFNBS+ diagnostic resolution were categorized by level of engagement between the CF center and GC: GC is part of or embedded in CF center (GC-engaged); GC is independent of CF center but receives CFNBS+ referrals (GC-referral); GC is uninvolved (non-engaged)] in CF center or CFNBS+ diagnostic resolution process. Responses from 125 CF center directors and clinic coordinators (17.5%) and 174 GCs (3.8%) were received. Analysis targeted responses from 84 center directors and clinic coordinators and 52 GCs, estimated to represent 24%-48% and 29% of 175 pediatric CF care centers, respectively. Nearly 40% of CF center directors or clinic coordinators never refer CFNBS+ infants to GCs. Respondents from GC-engaged CF centers reported that GCs provide unique and valuable services, understand CF at a high level, improve efficiency of the CFNBS+ diagnostic resolution process, and should be part of the CF care team; respondents from non-engaged CF centers reported negative views of GCs' value and knowledge (all p < .05). GCs engaged with CF centers were more likely to report that their services were valued by and accessible to CF centers (both p < .05). At all levels of engagement with CF centers, GCs were comfortable discussing CF genotype-phenotype correlation, variants of unknown significance, quality of life, and therapies. These results highlight a need to address practice variation in CFNBS+ genetic counseling and improve access to GCs' services., (© 2019 National Society of Genetic Counselors.)

Objective: Cystic fibrosis (CF) can be difficult to diagnose, even when newborn screening (NBS) tests yield positive results. This challenge is exacerbated by the multitude of NBS protocols, misunderstandings about screening vs diagnostic tests, and the lack of guidelines for presumptive diagnoses. There is also confusion regarding the designation of age at diagnosis., Study Design: To improve diagnosis and achieve standardization in definitions worldwide, the CF Foundation convened a committee of 32 experts with a mission to develop clear and actionable consensus guidelines on diagnosis of CF with an emphasis on screened populations, especially the newborn population. A comprehensive literature review was performed with emphasis on relevant articles published during the past decade., Results: After reviewing the common screening protocols and outcome scenarios, 14 of 27 consensus statements were drafted that apply to screened populations. These were approved by 80% or more of the participants., Conclusions: It is recommended that all diagnoses be established by demonstrating dysfunction of the CF transmembrane conductance regulator (CFTR) channel, initially with a sweat chloride test and, when needed, potentially with newer methods assessing membrane transport directly, such as intestinal current measurements. Even in babies with 2 CF-causing mutations detected via NBS, diagnosis must be confirmed by demonstrating CFTR dysfunction. The committee also recommends that the latest classifications identified in the Clinical and Functional Translation of CFTR project [http://www.cftr2.org/index.php] should be used to aid with CF diagnosis. Finally, to avoid delays in treatment, we provide guidelines for presumptive diagnoses and recommend how to determine the age of diagnosis., (Copyright © 2016. Published by Elsevier Inc.)

Background: At the cystic fibrosis transmembrane conductance regulator (CFTR) gene (IVS8)-(TG)m(T)n locus, a lower number of thymidines (legacy names 9T vs. 7T vs. 5T) and a higher number of (TG) repeats (TG-11 vs. 12 vs. 13) are associated with decreasing translation of functional CFTR protein in vitro., Methods: Retrospective cohort study comparing phenotypes of California CF newborn screen-positive children (followed 2-8 years) who had two CF-causing mutations (diagnosed as CF) with those who had one mutation from a panel of 40 CF-causing mutations (CF40mut) and one (IVS8)-(TG)11, 12, or 13-5T mutation detected by sequencing (diagnosed as CFTR-related metabolic syndrome [cRMS])., Results: The study included 428 children, of which 234 had two CF-causing mutations, and were used to compare with the other 194 children with one CF-causing mutation and one isolated 5T allele [CF40mut/(TG)13-5T = 21, CF40mut/(TG)12-5T = 85, and CF40mut/(TG)11-5T = 88]. Among children with CF40mut/(TG)13-5T, 38% were diagnosed with CF by 8 years, based on sweat chloride results and clinical presentation. Six percent of those with CF40mut/(TG)12-5T, and none with CF40mut/(TG)11-5T, reached diagnostic criteria., Conclusions: CFTR (IVS8)-(TG)m-5T allele (TG) tract length determination provides valuable information in predicting the risk of developing a CF phenotype. Of the three types of 5T alleles evaluated, screen-positive children with genotype CF40mut/(TG)13-5T progressed from CRMS to CF at a high rate, while there was little evidence of clinical disease in those with CF40mut/(TG)11-5T. Additional data from longer follow-up intervals are needed to fully understand the natural history of individuals with a CF40mut/(TG)m-5T genotype.

Newborn screening (NBS) for cystic fibrosis (CF) offers the opportunity for early diagnosis and improved outcomes in patients with CF and has been universally available in the state of Massachusetts since 1999 using an immunoreactive trypsinogen (IRT)-DNA algorithm. Ideally, CF NBS is incorporated as part of an integrated NBS system that allows for comprehensive and coordinated education, laboratory screening, clinical follow-up, and evaluation so that evidence-based data can be used to maximize quality improvements and optimize the screening algorithm. The New England Newborn Screening Program (NENSP) retrospectively analyzed Massachusetts's CF newborn screening data that yielded decisions to eliminate a screen-positive category, maintain the IRT cutoff value that prompts the second tier DNA testing, and communicate CF relative risk to primary care providers (PCPs) based on categorization of positive CF NBS results.

Newborn screening for cystic fibrosis (CF) offers the opportunity for early medical and nutritional intervention that can lead to improved outcomes. Management of the asymptomatic infant diagnosed with CF through newborn screening, prenatal diagnosis, or sibling screening is different from treatment of the symptomatically diagnosed individual. The focus of management is on maintaining health by preventing nutritional and respiratory complications. The CF Foundation convened a committee to develop recommendations based on a systematic review of the evidence and expert opinion. These guidelines encompass monitoring and treatment recommendations for infants diagnosed with CF and are intended to help guide families, primary care providers, and specialty care centers in the care of infants with CF.

Through early detection, newborn screening (NBS)(1) for cystic fibrosis (CF) offers the opportunity for early intervention and improved outcomes. NBS programs screen for hypertrypsinogenemia, and most also identify mutations in the CF transmembrane conductance regulator (CFTR) gene. Individuals identified by NBS are diagnosed with CF if they have an elevated sweat chloride level or if they have inherited 2 disease-causing mutations in the CFTR gene. Mutations in the CFTR gene can cause CF, but not all CFTR mutations are disease-causing. The term CFTR-related metabolic syndrome (CRMS) is proposed to describe infants identified by hypertrypsinogenemia on NBS who have sweat chloride values <60 mmol/L and up to 2 CFTR mutations, at least 1 of which is not clearly categorized as a "CF-causing mutation," thus they do not meet CF Foundation guidelines for the diagnosis of CF. With what is now near-universal CF NBS in the United States, an increasing number of infants with CRMS are being identified. Given our inadequate knowledge of the natural history of CRMS, standards for diagnosis, monitoring, and treatment are absent. This document aims to help guide the monitoring and care of individuals with CRMS while our knowledge base on appropriate management evolves.

Newborn screening (NBS) for cystic fibrosis (CF) is increasingly being implemented and is soon likely to be in use throughout the United States, because early detection permits access to specialized medical care and improves outcomes. The diagnosis of CF is not always straightforward, however. The sweat chloride test remains the gold standard for CF diagnosis but does not always give a clear answer. Genotype analysis also does not always provide clarity; more than 1500 mutations have been identified in the CF transmembrane conductance regulator (CFTR) gene, not all of which result in CF. Harmful mutations in the gene can present as a spectrum of pathology ranging from sinusitis in adulthood to severe lung, pancreatic, or liver disease in infancy. Thus, CF identified postnatally must remain a clinical diagnosis. To provide guidance for the diagnosis of both infants with positive NBS results and older patients presenting with an indistinct clinical picture, the Cystic Fibrosis Foundation convened a meeting of experts in the field of CF diagnosis. Their recommendations, presented herein, involve a combination of clinical presentation, laboratory testing, and genetics to confirm a diagnosis of CF.

Newborn screening for cystic fibrosis offers the opportunity for early intervention and improved outcomes. This summary, resulting from a workshop sponsored by the Cystic Fibrosis Foundation to facilitate implementation of widespread high quality cystic fibrosis newborn screening, outlines the steps necessary for success based on the experience of existing programs. Planning should begin with a workgroup composed of those who will be responsible for the success of the local program, typically including the state newborn screening program director and cystic fibrosis care center directors. The workgroup must develop a screening algorithm based on program resources and goals including mechanisms available for sample collection, regional demographics, the spectrum of cystic fibrosis disease to be detected, and acceptable failure rates of the screen. The workgroup must also ensure that all necessary guidelines and resources for screening, diagnosis, and care be in place prior to cystic fibrosis newborn screening implementation. These include educational materials for parents and primary care providers; systems for screening and for providing diagnostic testing and counseling for screen-positive infants and their families; and protocols for care of this unique population. This summary explores the benefits and risks of various screening algorithms, including complex situations that can occur involving unclear diagnostic results, and provides guidelines and sample materials for state newborn screening programs to develop and implement high quality screening for cystic fibrosis.

Objective: To quantitate the proportion of infants identified through cystic fibrosis (CF) newborn screening (NBS) by an immunoreactive trypsinogen (IRT)/DNA screening algorithm who have an unclear diagnosis as defined by the findings of an elevated IRT level and either 1) 2 CF gene (CFTR) mutations detected and sweat chloride level <60 mEq/L; or 2) 0 or 1 CFTR mutations and a "borderline" sweat chloride level >or=30 and <60 mEq/L., Study Design: Using the 4-year cohort of CF-affected infants recently described by the Massachusetts CF NBS program, we identified and described the number of infants with the diagnostic characteristics (diagnostic dilemmas) aforementioned., Results: Of infants with positive results on CF NBS who had 1 CFTR mutation detected and a borderline sweat chloride concentration, nearly 20% displayed a second CFTR mutation on further evaluation. Of all infants with positive CF NBS results considered affected with CF, 11% had a diagnosis that fell into 1 of the diagnostic dilemma categories aforementioned., Conclusions: Four problematic diagnostic categories generated by CF NBS are defined. In the absence of data on the natural history of such infants, careful follow-up is recommended for infants in whom a definitive diagnosis is elusive.

Policy decisions for newborn screening (NBS) are particularly challenging when the balance of benefits and risks is not tipped dramatically in 1 direction. When this is the case, as with cystic fibrosis (CF), the traditional approach of mandatory testing of all newborns in all states may not be appropriate. Alternative approaches may produce a substantial reduction in psychosocial risks, at the cost of a small reduction in medical benefits, and thus improve the benefit/risk balance. At the provider level, this could include greater engagement and discussion with parents before testing. At the program implementation level, specific decisions about tradeoffs between sensitivity and specificity that could result in not identifying all infants with CF may be appropriate. At the policy decision level, deciding whether to implement CF NBS in a particular state could involve consideration of the availability of the financial resources, clinical services, and systems for assessing outcomes. Although CF NBS can be justified in settings in which the specific approach has a favorable benefit/risk balance, an inadequately designed screening program has the potential for being less favorable than the current approach of diagnosis on the basis of clinical criteria or family history.

Objective: Describe and define limitations of early pilocarpine iontophoresis (sweat testing) for cystic fibrosis (CF) newborn screening (NBS)., Study Design: Population-based results from follow-up of CF NBS-positive newborns., Results: Insufficient quantity of sweat is more likely if the sweat test is done too early, but testing is generally successful after 2 weeks of age. Sweat chloride levels drop over the first weeks of life. CF carriers have higher sweat chloride concentrations than non-carriers., Conclusions: Sweat testing can be performed effectively after 2 weeks of age for CF NBS-positive newborns. Earlier testing has a higher risk of insufficient sweat for completing testing.

Objectives: Newborn screening for cystic fibrosis (CF) provides a model to investigate the implications of applying multiple-mutation DNA testing in screening for any disorder in a pediatric population-based setting, where detection of affected infants is desired and identification of unaffected carriers is not. Widely applied 2-tiered CF newborn screening strategies first test for elevated immunoreactive trypsinogen (IRT) with subsequent analysis for a single CFTR mutation (DeltaF508), systematically missing CF-affected infants with any of the >1000 less common or population-specific mutations. Comparison of CF newborn screening algorithms that incorporate single- and multiple-mutation testing may offer insights into strategies that maximize the public health value of screening for CF and other genetic disorders. The objective of this study was to evaluate technical feasibility and practical implications of 2-tiered CF newborn screening that uses testing for multiple mutations (multiple-CFTR-mutation testing)., Methods: We implemented statewide CF newborn screening using a 2-tiered algorithm: all specimens were assayed for IRT; those with elevated IRT then had multiple-CFTR-mutation testing. Infants who screened positive by detection of 1 or 2 mutations or extremely elevated IRT (>99.8%; failsafe protocol) were then referred for definitive diagnosis by sweat testing. We compared the number of sweat-test referrals using single- with multiple-CFTR-mutation testing. Initial physician assessments and diagnostic outcomes of these screened-positive infants and any affected infants missed by the screen were analyzed. We evaluated compliance with our screening and follow-up protocols. All Massachusetts delivery units, the Newborn Screening Program, pediatric health care providers who evaluate and refer screened-positive infants, and the 5 Massachusetts CF Centers and their affiliated genetic services participated. A 4-year cohort of 323 506 infants who were born in Massachusetts between February 1, 1999, and February 1, 2003, and screened for CF at approximately 2 days of age was studied., Results: A total of 110 of 112 CF-affected infants screened (negative predictive value: 99.99%) were detected with IRT/multiple-CFTR-mutation screening; 2 false-negative screens did not show elevated IRT. A total of 107 (97%) of the 110 had 1 or 2 mutations detected by the multiple- CFTR-mutation screen, and 3 had positive screens on the basis of the failsafe protocol. In contrast, had we used single-mutation testing, only 96 (87%) of the 110 would have had 1 or 2 mutations detectable by single-mutation screen, 8 would have had positive screens on the basis of the failsafe protocol, and an additional 6 infants would have had false-negative screens. Among 110 CF-affected screened-positive infants, a likely "genetic diagnosis" was made by the multiple-CFTR-mutation screen in 82 (75%) versus 55 (50%) with DeltaF508 alone. Increased sensitivity from multiple-CFTR-mutation testing yielded 274 (26%) more referrals for sweat testing and carrier identifications than testing with DeltaF508 alone., Conclusions: Use of multiple-CFTR-mutation testing improved sensitivity and postscreening prediction of CF at the cost of increased referrals and carrier identification.

CF newborn screening benefits growth and prevents malnutrition in children with CF. Increasing evidence suggests long-term pulmonary benefits, but these data are still accumulating. With a standardized approach to clinical care for these pre-symptomatic patients, we should be able to ask questions about the optimal treatment strategy for therapies that are currently available, perhaps through randomized clinical trials in this group. For developing therapies, Massachusetts will have identified its CF patients before they have sustained significant malnutrition and lung injury, and it may be these patients who will benefit most from therapies still on the horizon.