Search Results (9)

The morbidity/mortality risks of cystic fibrosis (CF) with a delayed diagnosis have made newborn screening (NBS) attractive for the past 50 years. Initial efforts focused on meconium analyses, but these proved unsatisfactory. After dried blood spot specimens became valuable for NBS applied to other genetic disorders and immunoassay methods became routine, the discovery of immunoreactive trypsinogen (IRT) led to numerous CF NBS programs around the world. Excellent laboratorians led the way, but CF clinicians rightly questioned the benefit–risk relationship and unanswered questions about IRT. These issues were resolved by the combination of a positive randomized clinical trial and the discovery of the cystic fibrosis transmembrane conductance regulator gene (CFTR) and its principal pathogenic variant, F508del. Recommendations for universal screening and then the proliferation of IRT/DNA screening programs followed. But more knowledge has brought more complexity, including an enigmatic, distracting condition known as cystic fibrosis transmembrane conductance regulator-related metabolic syndrome (CRMS) or cystic fibrosis screen positive, inconclusive diagnosis (CFSPID). Recently, with the recognition that CF is not a “white person’s disease,” and that over 1000 CFTR pathogenic variants occur, attention has turned to achieving equity and timeliness for all babies. Continuous quality improvement has characterized the past decade, as greatly expanded CFTR panels in the DNA tier through next-generation sequencing offer promise and raise the prospect of a primary genetic screening test. Full article

Background/Objectives: The term ‘cystic fibrosis transmembrane conductance regulator-related metabolic syndrome/cystic fibrosis screen positive, inconclusive diagnosis (CRMS/CFSPID)’ refers to patients with positive screening tests but without a final diagnosis of Cystic Fibrosis (CF). Intestinal Current Measurement (ICM) is a novel diagnostic technique that may document the abnormal function of the cystic fibrosis transmembrane conductance regulator. Our study aims to compare the cumulative chloride secretory response in the ICM study in the Polish population of CF patients, CRMS/CFSPID, and in a control group. Methods: Forceps rectal biopsies were taken from 40 patients (CF; n = 17 mean age 9.10 ± 4.18 (0.7–17.20); CRMS/CFSPID: n = 16, mean age 6.66 ± 4.83 (0.6–18.0); healthy controls (HC): n = 7, mean age 23.7 ± 9.5 (7.8–34.6). ICM tests were performed in the Ussing Chamber according to standard protocol version 2.7 of the European Cystic Fibrosis Society Diagnostic Network Working Group. Delta short circuit-current (ΔIsc) was measured after carbachol (ΔIsc_carbachol), 3-isobutyl-1-methylxanthine with forskolin (ΔIsc_{IBMX/forskolin}), and histamine (Δisc_histamine) stimulation. Cumulative secretion was calculated for each study group. Results: We obtained statistically significant differences in cumulative chloride secretory response between CF and CRMS/CFSPID (CF ΔIsc_{carbachol+IBMX/forskolin+histamine} 15.32 ± 15.47 µA/cm² vs. CRMS/CFSPID ΔIsc_{carbachol+IBMX/forskolin+histamine} 86.84 ± 37.84 µA/cm²; p < 0.001), and between CF and healthy controls (CF ΔIsc_{carbachol+IBMX/forskolin+histamine} 15.32 ± 15.47 µA/cm² vs. HC ΔIsc_{carbachol+IBMX/forskolin+histamine} 80.16 ± 48.54 µA/cm²; p = 0.005). No differences in cumulative chloride secretion were observed between the CRMS/CFSPID and HC groups. Conclusions: The conducted study suggests that ICM may offer diagnostic value, especially in cases where sweat test results are equivocal. Full article

An unintended consequence of cystic fibrosis (CF) newborn screening (NBS) is the identification of infants with a positive NBS who do not meet the diagnostic criteria for CF (two CF-causing variants and/or sweat chloride > 60 mmol/L). This indeterminate diagnosis is called cystic fibrosis transmembrane conductance regulator (CFTR)-related metabolic syndrome (CRMS) or CF screen positive, inconclusive diagnosis (CFSPID). CRMS/CFSPID occurs when it is not clearly known whether CFTR variants are disease-causing. In 2024, the CFTR2 classification of many CFTR variants was changed from unknown significance to either CF-causing variants or variants of varying clinical consequences (VVCCs). We conducted a meta-analysis of CRMS/CFSPID cases from manuscripts to describe how the diagnoses would change using two different variant panels: (1) only CF-causing CFTR variants (Panel_CF-causing) and (2) CF-causing variants and VVCCs (Panel_{CF-causing+VVCCs}). Using the Panel_CF-causing, 8.7% had two CF-causing variants (reclassified as CF), while 91.3% had less than two CF-causing variants (reclassified as Undetected). Using the Panel_{CF-causing+VVCCs}, 51.4% had either two VVCCs or one VVCC with one CF-causing variant detected (reclassified as CRMS/CFSPD), 39.9% had less than two CF-causing variants detected (reclassified as Undetected), and 8.7% had two CF-causing variants (reclassified as CF). In conclusion, using the updated CFTR2 classification of CFTR variants significantly decreases the number of children with CRMS/CFSPID and gives a definitive diagnosis of CF to some children while not detecting as many children who are unlikely to develop CF. Full article

There is increasing interest in using extended genetic sequencing (EGS) in newborn screening (NBS) for cystic fibrosis (CF). How this is implemented will change the number of children being given an uncertain outcome of CRMS/CFSPID (cystic fibrosis transmembrane conductance regulator (CFTR)-related metabolic syndrome/CF Screen Positive Inconclusive Diagnosis), probable carrier results, and the number of missed CF diagnoses. An international survey of CF health professionals was used to gather views on two approaches to EGS—specific (may reduce detection of CRMS/CFSID but miss some CF cases) versus sensitive (may increase detection of CRMS/CFSPID but avoid missing more CF cases). Health professionals acknowledged the anxiety caused to parents (and health professionals) from the uncertainty surrounding the prognosis and management of CRMS/CFSPID. However, most preferred the sensitive approach, as overall, identifying more cases of CRMS/CFSPID was viewed as less physically and psychologically damaging than a missed case of CF. The importance of early diagnosis and treatment for CF to ensure better health outcomes and reducing diagnostic odysseys for parents were highlighted. A potential benefit to identifying more children with CRMS/CFSPID included increasing knowledge to obtain a better understanding of how these children should best be managed in the future. Full article

The project aimed to gather, analyse, and compare the views of stakeholders about the proposed UK cystic fibrosis (CF) screening protocol incorporating next generation sequencing (NGS). The study design was based on principles of Q-methodology with a willingness-to-pay exercise. Participants were recruited from 12 CF centres in the UK. The study contained twenty-eight adults who have experience with CF (parents of children with CF (n = 21), including parents of children with CF transmembrane conductance regulator (CFTR)-related metabolic syndrome (CRMS)/CF screen positive—inconclusive diagnosis (CFSPID), an uncertain outcome (n = 3), and adults with CF (n = 4)), and nine health professionals involved in caring for children with CF. Parents and health professionals expressed a preference for a sensitive approach to NGS. This was influenced by the importance participants placed on not missing any children with CF via screening and the balance of harm between missing a case of CF compared to picking up more children with an uncertain outcome (CRMS/CFSPID). Given the preference for a sensitive approach, the need for adequate explanations about potential outcomes including uncertainty (CFSPID) at the time of screening was emphasized. More research is needed to inform definitive guidelines for managing children with an uncertain outcome following CF screening. Full article

Most people with cystic fibrosis (CF) are diagnosed following abnormal newborn screening (NBS), which begins with measurement of immunoreactive trypsinogen (IRT) values. A case report found low concentrations of IRT in an infant with CF exposed to the CF transmembrane conductance regulator (CFTR) modulator, elexacaftor–tezacaftor–ivacaftor (ETI), in utero. However, IRT values in infants born to mothers taking ETI have not been systematically assessed. We hypothesized that ETI-exposed infants have lower IRT values than newborns with CF, CFTR-related metabolic syndrome/CF screen positive, inconclusive diagnosis (CRMS/CFSPID), or CF carriers. IRT values were collected from infants born in Indiana between 1 January 2020, and 2 June 2022, with ≥1 CFTR mutation. IRT values were compared to infants born to mothers with CF taking ETI followed at our institution. Compared to infants identified with CF (n = 51), CRMS/CFSPID (n = 21), and CF carriers (n = 489), ETI-exposed infants (n = 19) had lower IRT values (p < 0.001). Infants with normal NBS results for CF had similar median (interquartile range) IRT values, 22.5 (16.8, 30.6) ng/mL, as ETI-exposed infants, 18.9 (15.2, 26.5). IRT values from ETI-exposed infants were lower than for infants with abnormal NBS for CF. We recommend that NBS programs consider performing CFTR variant analysis for all ETI-exposed infants. Full article

CFTR-related metabolic syndrome (CRMS) is a novel diagnosis due to widespread use of and advances in the newborn screening (NBS) process for cystic fibrosis (CF) in the United States of America, allowing for the diagnosis of asymptomatic children with CF. Before 2015, a large Puerto Rican pediatric population was not screened for CF in the NBS test. Studies have shown that patients presenting with idiopathic recurrent or chronic pancreatitis have an increased frequency of cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations. We present a retrospective chart review of 12 pediatric cases (n = 12) that were presented to an outpatient community clinic with clinical manifestations associated with CF. The pancreatic insufficiency prevalence (PIP) score was calculated on CFTR mutations. The mutations considered for the calculation of the PIP score were: F508del (c.1521_1523del), V201M (c.601G > A), I507del (c.1519_1521del), and L1335P (c.4004T > C). V201M mutation was classified as mild in both PIP scores, and a correlation with pancreatitis was noted. Clinical manifestations vary in cases with the V201M variant (c.601G > A). One case was diagnosed with CFTR-related disorder (CRD) and recurrent pancreatitis. It is important to consider CRMS or CRD as a differential diagnosis in the pediatric population of Puerto Rico due to the implications and increased risk of pancreatitis and other CF-related complications. Full article

Background: An inconclusive diagnosis of cystic fibrosis (CF) after positive newborn screening (NBS) may cause parental distress. We compared the psychological impact of CF transmembrane conductance regulator-related metabolic syndrome (CRMS)/CF screen-positive, inconclusive diagnosis (CFSPID), and clear CF diagnosis, on parents. Methods: The participants were administered the Generalized Anxiety Disorder Scale, Patient Health Questionnaire-9, and the Italian version of the Impact of Event Scale-Revised as quantitative tools and semi-structured interviews as qualitative tools. Parental experience, child representation, relationships, future information, and perception of health status were investigated. Interviews were recorded and transcribed verbatim maintaining anonymity. Results: Thirty-two families were enrolled: sixteen with CF and CRMS/CFSPID, respectively. Anxiety and depression values were high in both groups, as were the measurement of traumatic impact subscales: avoidance, intrusiveness, and hyperarousal. The children’s health was evaluated by respective parents as being nearly healthy. Conclusions: Our results highlight negative psychological impacts, including emotional and affective representations, on parents of children with inconclusive CF diagnosis compared with those with clear diagnosis. Full article

An unintended consequence of newborn screening for cystic fibrosis (CF) is the identification of infants with a positive screening test but an inconclusive diagnostic testing. These infants are designated as CF transmembrane conductance regulator-related metabolic syndrome (CRMS) in the US and CF screen-positive, inconclusive diagnosis (CFSPID) in Europe. Recently, experts agreed on a unified international definition of CRMS/CFSPID which will improve our knowledge on the epidemiology and outcomes of these infants and optimize comparisons between cohorts. Many of these children will remain free of symptoms, but a number may develop clinical features suggestive of CFTR-related disorder (CFTR-RD) or CF later in life. Clinicians should to be prepared to identify these infants and communicate with parents about this challenging and stressful situation for both healthcare professionals and families. In this review, we present the recent publications on infants designated as CRMS/CFSPID, including the definition, the incidence across Europe, the assessment of the CFTR protein function, the outcomes with the rates of conversion to a final diagnosis of CF and their management. Full article