What question did this study set out to answer?

To explore the clinical implications of a novel CFTR genotype in an asymptomatic child identified as CRMS/CFSPID.

May 20, 2026

C61-15 A Case of an Asymptomatic Child With a Novel CF Transmembrane Conductance Regulator Genotype: When Is It Cystic Fibrosis?

NBN BulangIcahn School of Medicine at Mount Sinai ESE Langfelder- SchwindLenox Hill Hospital NAN AmbroiseLenox Hill Hospital

Key Points

To explore the clinical implications of a novel CFTR genotype in an asymptomatic child identified as CRMS/CFSPID.
Case report of a 3-year-old female identified through newborn screening with elevated IRT and uncertain CFTR genotype.
Monitoring sweat chloride levels and bacterial colonization over time without treatment due to clinical well-being.
The child's initial sweat chloride level was 29mmol/L, increasing to above 60mmol/L by age 3.
Despite rising sweat chloride levels, the child remains asymptomatic with normal growth and pancreatic function.
Bacterial culture revealed positive Staphylococcus aureus and Acinetobacter baumannii; however, no treatment was initiated due to the child's stable condition.

Abstract

Abstract Introduction Newborn screening (NBS) for cystic fibrosis (CF) has been highly successful in enabling early detection and intervention. However, the expansion of genetic testing has uncovered CF transmembrane conductance regulator (CFTR) variants with variable or uncertain significance, resulting in a cohort of screen- positive infants who do not meet the diagnostic criteria. Rather, the children are classified as CFTR- related metabolic syndrome/ cystic fibrosis screen positive, inconclusive diagnosis (CRMS/ CFSPID). Approximately, 10% later convert to CF owing to updated classification of CFTR variants as CF causing, an increase in sweat chloride test to ≥ 60mmol/L, or development of symptoms. Clear definitions and guideline-based surveillance were published in 2024 and are essential for family counseling and for timely recognition of their evolving status. Case Report A 3-year-old female from Bangladesh was identified through New York State newborn screening with elevated IRT (146.1ng/mL) and genotype: p.Leu240Arg// p.Leu240Arg (cDNA: c.719TG//c.719TG; Legacy: L240R// L240R) that was reported to be of uncertain significance. There is no known family history of CF. Parental testing confirmed trans carriage of the variant. She is being followed in a CF center with a diagnosis of CRMS/CFSPID for monitoring. Initial sweat test as a newborn was 29mmol/L, at 6 months of age it increased to 35mmol/L and has continued in an upward trend each year, until age 3 when it became positive with values above 60mmol/L, and repeated 2 months later with a value of 53mmol/L. She has remained asymptomatic, with normal growth and development, pancreatic sufficient, and no chronic respiratory symptoms or frequent infections. Surveillance culture was negative forPseudomonas aeruginosa and positive for Staphylococcus aureus and Acinetobacter baumannii that is not being treated given clinical well-being. At this time, we are closely monitoring with plans for a repeat sweat test. Discussion Children diagnosed with CRMS/CFSPID remain at risk for conversion to CF, particularly as variant classification and sweat chloride testing results evolve. An increased conversion risk is associated with Pseudomonas aeruginosa colonization, high IRT (80ng/mL), an initial intermediate level of sweat chloride, and progressively rising sweat chloride, sometimes preceding symptoms and emphasizes the need for guideline- based surveillance. Notably, our patient is homozygous for variant L240R which is not registered in major databases. Describing our experience with this variant broadens the evidence base, informs future reclassification, improves risk counseling for similar families, and helps refine newborn screen variant panels. This abstract is funded by: None

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