(23) Outcomes of Children with CFTR-Related Metabolic Syndrome (CRMS)

Background: Newborn screening (NBS) evaluation for elevated immunoreactive trypsinogen level (IRT) associated with a cystic fibrosis transmembrane conductance regulator (CFTR) mutation (IRT+/DNA+) has led to early identification and treatment of children with severe cystic fibrosis (CF). However, it has also identified children with genetic and biochemical findings indicating risk for CF, but without symptoms or conclusive diagnostic results (designated CRMS). A proportion of these children transition to CF, but impact of early diagnosis and treatment is unclear. This study evaluated outcomes of children designated with CRMS after NBS referral.

Methods: Children with IRT+/DNA+ on NBS referred to our CF Center from 2008-2020 had charts reviewed and data collected for results of IRT, genotype, sweat chloride test (SCT) values, stool elastase, and sputum swab cultures. Children were categorized per most recent CFF diagnostic guidelines into CFTR mutation carrier (Carrier), CF, or CRMS. CRMS group was further sub-categorized by child’s final diagnosis in 2020 into CRMS transitioned to CF (CRMS-CF), CRMS transitioned to carrier (CRMS-carrier), or CRMS-persistent (CRMS-P).

Results: Of 1,346 children referred for IRT+/DNA+ with a SCT, 86% were initially designated as Carrier, 10% as CF, and 5% as CRMS. Mean first SCT was significantly elevated for CRMS compared to Carrier (p< 0.0001). Of those initially designated CRMS (n=63), 17.5% transitioned to CF (CRMS-CF) due to either repeat SCT reaching diagnostic threshold, clinical symptoms, expanded genetics, or re-classification of their CFTR mutation. Within CRMS-CF, 36% had initial SCT between 30-39 mEq/L, 36% between 40-49 mEq/L, and 27% between 50-59 mEq/L. Age of transition for this group ranged between 2.2 months to 8.4 years. Mean first SCT value was significantly higher for CRMS-CF (45 mEq/L) compared to CRMS-P (30.27 mEq/L, p< 0.0001) and CRMS-carrier (35 mEq/L, p=0.0027). CRMS-CF had significantly elevated values at all repeat SCTs compared to CRMS-P (p< 0.0001), with mean values by fourth SCT within positive range compared to CRMS-P (p=0.001). No association between IRT and first SCT nor difference in stool elastase levels noted for CRMS subgroups. CRMS-CF cultured a greater number of bacterial species compared to CRMS-carrier (p=< 0.0001) or CRMS-P (p=0.0103). Of children with CRMS that cultured Pseudomonas aeruginosa, 50% transitioned to CRMS-CF. Pseudomonas cultured at least once in 19% of CRMS-CF, 7.7% of CRMS-P and 0% of CRMS-carrier.

Conclusions: Expanded genetics and repeat SCT were beneficial to diagnose children initially designated as CRMS at our CF Center that eventually transitioned to CF. Importantly, we found 36% of the CRMS-CF group had a first SCT < 40 mEq/L, in contrast to prior studies demonstrating no children with initial SCT < 40 mEq/L transitioning to CF. Majority of the CRMS-CF group had increasing SCT values prior to transitioning to CF, but not all reached diagnostic threshold before genotype or clinical symptoms confirmed diagnosis. Notably, 37% of CRMS-CF transitioned after 6 years of age. Annual sputum culture appears warranted in children designated with CRMS given known deleterious effects of certain pathogens on lungs of children at risk of CF. Prospective evidence-based monitoring will provide greater insight into the risk for diagnosis of CF in this population.

Acknowledgements: Cystic Fibrosis Foundation; University of Alabama Heersink School of Medicine; Pediatric Pulmonary and Sleep Medicine Department

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