(32) Characteristics of 225 infants with CFSPID/CRMS identified in New York State over a three-year period

Background: New York State (NYS) added third-tier sequencing to the IRT-DNA CF newborn screening (CF NBS) algorithm on December 1, 2017 to reduce false positive referrals. NYS refers infants with elevated IRT and two or more CFTR variants, including variants of potential clinical significance for diagnostic evaluation to one of 10 CF Specialty Care Centers (SCCs). Findings of intermediate or normal sweat Cl- levels (< 60 mmol/L Cl-) in these infants, consistent with published criteria for CF screen positive, inconclusive diagnosis (CFSPID)/CFTR transmembrane conductance regulator-related metabolic syndrome (CRMS), poses challenges to clinicians and families. The aim of this descriptive study is to describe NYS CF NBS results and findings from initial and follow up evaluations of CFSPID/CRMS infants identified since the algorithm change.

Methods: As part of longer-term follow up, a clinical and demographic dataset was compiled from SCCs for infants with elevated IRT and at least two CFTR variants, (where one or more were not clearly CF-causing), referred between December 1, 2017 and November 30, 2021. Genotypes and CFTR phasing were abstracted from NYS NBS records. Sweat Cl-, oropharyngeal culture (OPS), fecal elastase, CF status, and race/ethnicity data were requested from the SCCs. The project was considered exempt by the NYSDOH IRB.

Results: Over the 3-year period, 290 infants without CF were identified by the NBS, CFTR phasing was determined for 193/290 infants, 14.5% (28/193) confirmed in cis and re-classified as likely carriers; 5.5% (16/290) also are carriers after variant reclassification; 5.8% (17/290) were lost to follow up or parental refusal; 77% (225/290) were evaluated at least once at a SCC, and classified as CFSPID/CRMS. The most common variant was 5T-12TG [40% (90/225) carried at least one copy]. Sweat Cl- values for CFSPID/CRMS infants were higher compared to carriers, although there was overlap. None of the infants with CFTR variants in cis had sweat Cl- >25, 2 had QNS result and 3 were not sweat tested. For the reported highest sweat Cl- value for each infant classified as CFSPID/CRMS, the majority of infants had low sweat Cl- [39% (88/225) with < 20 mmol/L; 42% (95/225) within 20-29 mmol/L; 11.5% (26/225) within 30-39 mmol/L; 5% (12/225) within 40-49 mmol/L]; 1.7% (only 4 infants) had sweat Cl- within 50-59 mmol/L [W1282X//5T-12TG (N=3 infants); R117H-5T//5T-12TG (N=1)]. Decreasing sweat Cl- trend was seen in 5.3% (N=12), increasing trend in 7.1% (N=16) and variable trend in 2 infants (0.9%). Results on OPS cultures from 110 infants showed 2 that isolated Pseudomonas aeruginosa, who had sweat Cl- levels of 12 and 10 mmol/L. Of 113 infants with fecal elastase value, 112 were reported as “normal”. One infant with sweat Cl- of 28 and 31 mmol/L at 17 days of life had a low initial value indicative of malabsorption, which was normal on repetition.

Conclusions: None of the 225 CFSPID/CRMS infants converted to a CF diagnosis during the 3-year period. Sweat Cl- values remain low in the majority of cases. There is variability among SCCs, including rate of follow up and repeat sweat Cl- testing. Baseline data on CFSPID/CRMS infants in the large, race/ethnically diverse population of NYS point to the need for ongoing evaluation to determine the conversion rate to CF.

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