Clinical outcomes of a large cohort of individuals with the F508del/5T;TG12 CFTR genotype

Tosco, Antonella; Castaldo, Alice; Colombo, Carla; Claut, Laura; Carnovale, Vincenzo; Iacotucci, Paola; Lucarelli, Marco; Cimino, Giuseppe; Fabrizzi, Benedetta; Caporelli, N.; Ciciriello, Fabiana; Padoan, Rita; Poli, Piercarlo; Taccetti, Giovanni; Centrone, Claudia; Casciaro, R.; Castellani, Carlo; Salvatore, Donatello; Colangelo, Carmela; Bonomi, Paolo; Castaldo, Giuseppe; Terlizzi, Vito

doi:10.1016/j.jcf.2022.04.020

Cited by 17 publications

(13 citation statements)

References 43 publications

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“…As we previously reported, 38% of children with a CF‐causing variant and 5T;TG13 reclassified to CF in their first 8 years of life 20 . This is aligned with previous reports that the determination of TG repeat number allows for more accurate prediction of benign versus pathogenic 5T alleles 26,27 . Other variants in the second allele of the CF‐reclassified group were missense variants of varying clinical consequence per CFTR2, and which are approved for CFTR modulators: c.1853T > C (I618T), c.3454G > C (D1152H), and c.3154T > G (F1052V) (https://cftr2.org).…”

Section: Discussionsupporting

confidence: 87%

“…However, the small number of assays and the small ( n = 2) subset that progressed to a diagnosis of CF limits the interpretation of these results. We recruited a selected genotype group to evaluate using HNE assays based on a higher risk of reclassification: a CF‐causing variant on one allele and R117H;7T, 5T;TG12, or 5T;TG13 on the other, but a larger sample is needed to draw conclusions based on genotype 20,22,27,33 . A nonlinear association between HNE and sw[Cl − ] has been reported in a cohort of individuals with CF; however, this association was difficult to interpret when sw[Cl − ] was <60 mmol/l 18 .…”

Section: Discussionmentioning

confidence: 99%

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Gradual increase in sweat chloride concentration is associated with a higher risk of CRMS/CFSPID to CF reclassification

Salinas

Ginsburg

Wee

et al. 2023

Pediatric Pulmonology

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Objectives Universal implementation of cystic fibrosis (CF) newborn screening (NBS) has led to the diagnostic dilemma of infants with CF screen‐positive, inconclusive diagnosis (CFSPID), with limited guidance regarding prognosis and standardized care. Rates of reclassification from CFSPID to CF vary and risk factors for reclassification are not well established. We investigated whether clinical characteristics are associated with the risk of reclassification from CFSPID to a CF diagnosis. Methods Children with a positive CF NBS were recruited from two sites in California. Retrospective, longitudinal, and cross‐sectional data were collected. A subset of subjects had nasal epithelial cells collected for CF transmembrane conductance regulator (CFTR) functional assessment. Multivariate logistic regression was used to assess the risk of reclassification. Results A total of 112 children completed the study (CF = 53, CFSPID = 59). Phenotypic characteristics between groups showed differences in pancreatic insufficiency prevalence, immunoreactive trypsinogen (IRT) levels, and Pseudomonas aeruginosa (PSA) colonization. Spirometry measures were not different between groups. Nasal epithelial cells from 10 subjects showed 7%–30% of wild‐type (WT)‐CFTR (wtCFTR) function in those who reclassified and 27%–67% of wtCFTR function in those who retained the CFSPID designation. Modeling revealed that increasing sweat chloride concentration (sw[Cl−]) and PSA colonization were independent risk factors for reclassification to CF. Conclusion Increasing sw[Cl−] and a history of PSA colonization are associated with the risk of reclassification from CFSPID to CF in a population with high IRT and two CFTR variants. A close follow‐up to monitor phenotypic changes remains critical in this population. The role of CFTR functional assays in this population requires further exploration.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Gradual increase in sweat chloride concentration is associated with a higher risk of CRMS/CFSPID to CF reclassification

Salinas

Ginsburg

Wee

et al. 2023

Pediatric Pulmonology

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“…These individuals likely have a very low risk of progressing to CF, but we cannot exclude that during the follow-up, these children develop a mono-organ involvement for CFTR-related disorder. Furthermore, the two remaining CRMS/CFSPID carried a genetic profile F508del/5T;TG12 and F508del/S737F, both found in Italian CRMS/CFSPID progressed to CF [ 35 , 36 ]. In fact, we recently reported that, after a median follow-up of 6.7 years, 10.3% of CRMS/CFSPID subjects with F508del/5T;12TG genotype progressed to CF, which was a higher percentage than that previously reported in a large cohort of Italian CRMS/CFSPID [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, the two remaining CRMS/CFSPID carried a genetic profile F508del/5T;TG12 and F508del/S737F, both found in Italian CRMS/CFSPID progressed to CF [ 35 , 36 ]. In fact, we recently reported that, after a median follow-up of 6.7 years, 10.3% of CRMS/CFSPID subjects with F508del/5T;12TG genotype progressed to CF, which was a higher percentage than that previously reported in a large cohort of Italian CRMS/CFSPID [ 35 ]. Finally, S737F is a CFTR variant typical of the Tuscany region and associated with CF evolution [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

Impact of Pancreatitis-Associated Protein on Newborn Screening Outcomes and Detection of CFTR-Related Metabolic Syndrome (CRMS)/Cystic Fibrosis Screen Positive, Inconclusive Diagnosis (CFSPID): A Monocentric Prospective Pilot Experience

Bianchimani

Dolce

Centrone

et al. 2022

IJNS

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Pancreatitis-Associated Protein (PAP)-based Cystic Fibrosis (CF) newborn bloodspot screening (NBS) protocols detect less CFTR-Related Metabolic Syndrome (CRMS)/CF Screen Positive, Inconclusive Diagnosis (CFSPID). We prospectively evaluated the impact of PAP as the second step of the CF NBS protocol, before the CFTR genetic analysis, on NBS outcomes and CRMS/CFSPID detection in the Tuscany region, Italy. In parallel to the usual protocol (IRT/DNA, protocol 1), PAP was analyzed in IRT-positive infants (IRT/PAP/DNA, protocol 2) from 1 June 2020 until 31 May 2022. We defined an infant as NBS positive if PAP was >1.8 μg/L for IRT value 99th percentile-100 μg/L or >0.6 μg/L for IRT value >100 μg/L. To increase the positive predictive value (PPV) of protocol 2, we retrospectively lowered the upper IRT range value from 100 to 90 μg/L (modified protocol 2). We identified 8 CF and 13 CRMS/CFSPID with protocol 1, 5 CF and 5 CRMS/CFSPID with protocol 2 and 8 CF and 5 CRMS/CFSPID with modified protocol 2. With the PAP-based protocols, we observed a reduction of sweat tests, healthy carrier detection and a significant increase in PPV to 15.38%. Further data are needed in order to evaluate the outcomes of CRMS/CFSPID after a long follow-up.

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“…Advent of the NBS has led to the identification of asymptomatic infants found to have a positive NBS with at least one mutation and a SC concentration between 30 and 59 mmol/L, who are considered to have an inconclusive diagnosis and may be designated to have CF Screen Positive, Inconclusive Diagnosis (CFSPID), also known as CFTR-related metabolic syndrome (CRMS) (8)(9)(10)(11)(12)(13)(14)(15). Repeated SCT in the diagnostic range or identification of two known CF disease-causing mutations can subsequently confirm the diagnosis of CF (15,16).…”

Section: Introductionmentioning

confidence: 99%

Outcomes of children with cystic fibrosis screen positive, inconclusive diagnosis/CFTR related metabolic syndrome

et al. 2023

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BackgroundSome infants undergoing newborn screening (NBS) tests have inconclusive sweat chloride test (SCT) results that lead to the designation of Cystic Fibrosis Screen Positive, Inconclusive Diagnosis/CFTR-related metabolic syndrome (CFSPID/CRMS). Some proportion of them transition to a CF diagnosis, but no predictive markers can stratify which are at risk for this transition. We report single-center outcomes of children with CRMS.MethodsWe retrospectively identified all infants born in Alabama from 2008 through 2020 referred to our CF Center with an elevated immunoreactive trypsinogen level (IRT) associated with a cystic fibrosis transmembrane conductance regulator (CFTR) mutation (IRT+/DNA+) who had at least one SCT result documented. Infants were classified per established guidelines as Carrier, CRMS, or CF based on the IRT+/DNA+ and SCT results. The electronic health record was reviewed for follow-up visits until the children received a definitive diagnosis (to carrier or CF) according to current diagnostic guidelines for CF, or through the end of the 2020 year.ResultsOf the 1,346 infants with IRT+ and at least 1 CFTR mutation identified (IRT+/DNA+), 63 (4.7%) were designated as CRMS. Of these infants, 12 (19.1%) transitioned to Carrier status (CRMS-Carrier), 40 (63.5%) of them remained CRMS status (CRMS-Persistent) and 11 (17.5%) of them transitioned to a diagnosis of CF (CRMS-CF). Of the 11 children in the CRMS-CF group, 4 (36%) had an initial SCT 30–39 mmol/L, 4 (36%) had an initial SCT 40–49 mmol/L and 3 (27%) had an initial SCT 50–59 mmol/L. These children also had higher initial sweat tests and greater yearly increases in sweat chloride values than others with CRMS. We found that in comparison to children in the CRMS-P group, a greater proportion of children in the CRMS-CF group cultured bacteria like methicillin-resistant Staphylococcus aureus, Stenotrophomonas maltophilia, and Pseudomonas aeruginosa, had smaller weight-for-height percentiles and remained smaller over time despite slightly greater growth.ConclusionInfants with an inconclusive diagnosis of CF should continue to receive annual care and management given their potential risk of transition to CF. Further research is needed to assess whether certain phenotypic patterns, clinical symptoms, diagnostic tests or biomarkers could better stratify these children.

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Clinical outcomes of a large cohort of individuals with the F508del/5T;TG12 CFTR genotype

Cited by 17 publications

References 43 publications

Gradual increase in sweat chloride concentration is associated with a higher risk of CRMS/CFSPID to CF reclassification

Gradual increase in sweat chloride concentration is associated with a higher risk of CRMS/CFSPID to CF reclassification

Impact of Pancreatitis-Associated Protein on Newborn Screening Outcomes and Detection of CFTR-Related Metabolic Syndrome (CRMS)/Cystic Fibrosis Screen Positive, Inconclusive Diagnosis (CFSPID): A Monocentric Prospective Pilot Experience

Outcomes of children with cystic fibrosis screen positive, inconclusive diagnosis/CFTR related metabolic syndrome

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