Phenotype of children with inconclusive cystic fibrosis diagnosis after newborn screening

Abstract

Objective To characterize the phenotypic expression of children with conductance regulator‐related metabolic syndrome (CRMS)/cystic fibrosis screen positive inconclusive diagnosis (CFSPID) designation after positive newborn screening, reassign labeling if applicable and better define these children's prognosis. Methods A multicenter cohort with CRMS/CFSPID designation was matched with cystic fibrosis (CF)‐diagnosed cohort. Cohorts were prospectively compared on baseline characteristics, cumulative data and when they reached 6 to 7 years at endpoint assessment. Results Compared to infants with CF (n = 63), the CRMS/CFSPID cohort (n = 63) had initially lower immunoreactive trypsinogen (IRT) and sweat chloride (SC) values, delayed visits, less symptoms, and better nutritional status; during follow‐up, they had fewer hospitalizations, Pseudomonas aeruginosa and methicillin‐resistant Staphylococcus aureus identification, CF comorbidities, and treatment burden. At endpoint assessment, they presented a milder pulmonary phenotype on Brody computed tomography scores (0.0[0.0; 2.0] vs 13[2.0; 31.0]; P < .0001, respectively), Wisconsin and Brasfield chest radiograph scores, pulmonary function tests, and improved nutritional status. Among the inconclusive CF diagnosis cohort, 28 cases (44%) converted to CF diagnosis based on genotype (44%), SC (28%) or both (28%); yet, comparing those with or without final CF diagnosis, we found no differences, possibly related to their young age and mild degree of lung disease. In the total cohort, we found significant associations between Brody scores and IRT, SC values, genotype, Wisconsin and Brasfield score and spirometry. Conclusions The matched CRMS/CFSPID and CF cohorts showed differences in outcomes. By a mean age of 7.6 years, a high proportion of the CRMS/CFSPID cohort converted to CF. Our results highlight that monitoring at CF clinics until at least 6 years is needed as well as further studies.

The Role of Extended CFTR Gene Sequencing in Newborn Screening for Cystic Fibrosis

“…EGA without applying any bioinformatic filter or without any additional step as IRT or PAP to limit the number of infants subjected to sweat testing might be detrimental, as long as the clinical impact and penetrance data associated with variants are not well documented. In view of this, the collection of data on the extended follow-up of neonates detected with an inconclusive diagnosis is of the utmost importance [58].…”

“…The risk that neonates with an inconclusive diagnosis will develop symptoms consistent with CF, even in a less typical form, with a possible delayed positive conversion of the sweat test [57,58] is still unknown. Nevertheless, parents should be informed on the longer-term risks that their child may develop clinical symptoms of CF.…”

“…Ex vivo electrophysiological explorations on nasal epithelium, organoids, or rectal biopsies and in vitro experiments on heterologous immortalized cell systems reproducing DNA changes may help interpret variant pathogenicity and better evaluate the risk of developing clinical CF. A follow-up longer than two years is then critical [56,58]. However, the full penetrance associated with some VVCC may not be apparent until adulthood [55].…”

Setting a new standard in cystic fibrosis newborn screening illustrates controversial issues as new data emerge

“…Both CFSPID and CFTR heterozygote detection are byproducts of IRT-based NBS that create follow-up issues and necessitate expert genetic counselling to mitigate parental misunderstandings. Yet, with emergence of recent data [ 7 , 8 ], the practice of selecting screening strategies to avoid CFSPID cases and the group often called “heathy carriers” can be challenged. It has been learned in recent years that at least 10% and perhaps as many as 44% of children initially classified as CFSPID will develop symptoms of CF and/or a higher, diagnostic sweat chloride level [ 4 , 7 , 8 ].…”

“…Yet, with emergence of recent data [ 7 , 8 ], the practice of selecting screening strategies to avoid CFSPID cases and the group often called “heathy carriers” can be challenged. It has been learned in recent years that at least 10% and perhaps as many as 44% of children initially classified as CFSPID will develop symptoms of CF and/or a higher, diagnostic sweat chloride level [ 4 , 7 , 8 ]. Thus, it is predictable that the ROI’s limitations inherent in short-term studies will be overcome by longer follow up of the 32 CFSPID cases and will eventually identify at least 3 more CF patients who may even appear “classic.”…”