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Infants with cystic fibrosis transmembrane conductance regulator-related metabolic syndrome/cystic fibrosis screen positive, inconclusive diagnosis and acute recurrent pancreatitis: what definition?

The identification of infants with an inconclusive cystic fibrosis (CF) diagnosis after a positive newborn bloodspot screening (NBS) result is an increasingly recognized outcome. Its frequency depends on the NBS algorithm performed, and the diagnostic uncertainty is a challenge for both families and healthcare professionals. These subjects are now classified as CF transmembrane conductance regulator-related metabolic syndrome (CRMS)/CF screen positive, inconclusive diagnosis (CFSPID), as they do not fulfil all criteria for a CF diagnosis (two CF-causing variants of the CF transmembrane conductance regulator (CFTR) gene and/or repeated sweat chloride (SC) values above 60mmol/L). The majority of these subjects remain healthy, but later in life a variable percentage of them will develop symptoms suggestive of CF or will present diagnostic SC results over time. Recently, CRMS/CFSPID infants suffering from acute recurrent pancreatitis have been described. They had no diagnostic SC results or CFTR gene alterations to support a CF diagnosis but had an isolated CF-like clinical feature with persistent normal SC, thus posing a diagnostic definition issue. It is likely that in the future, with the increasing identification and follow-up of CRMS/CFSPID infants, more subjects will show similar CF-like single clinical features; however, without fulfilling all CF diagnostic criteria, more proper definitions of these cases is a challenge that should be addressed. CFTR-related disorder (CFTR-RD) is a clinical presentation usually reserved for adults who present with single-organ involvement, such as acute recurrent or chronic pancreatitis, congenital bilateral absence of the vas deferens (CBAVD) in males or bronchiectasis at computed tomography scan, with evidence of abnormal CFTR function, without fulfilling all the diagnostic criteria for CF. It is known that CRMS/CFSPID carries an a priori risk of developing a CFTR-RD (even if we don’t know at what age this might be expected), as the genetic information from adults with CFTR-RD demonstrates a high frequency of variants that occur commonly in infants with CRMS/CFSPID. Nevertheless, to date, there is no definition for CRMS/CFSPID infants who develop a single clinical manifestation of CF without genetic or SC data for a CF diagnosis. Due to the short follow-up, diagnostic SC results over time are not reported. In some centres/countries, these infants may be classified as CF, although no diagnostic testing supported that conversion. In other centres/countries, their CRMS/CFSPID label might remain, increasing the negative psychological impact of this designation on parents. In the presence of CRMS/CFSPID infants with singleorgan involvement, such as pancreatitis, it could be necessary to modify the clinical management and provide adequate information to the family, and ultimately to change the diagnostic label. Given these implications, this is a crucial point and one that remains to be resolved. We highlight that it could be time to think about the possible diagnosis of CFTR-RD in paediatric patients. In these infants, it could be possible to identify CBAVD through clinical visits to facilitate labelling. Over time, data from longer follow-up studies should better characterize the a priori risk of CFTR-RD for infants with CRMS/CFSPID and better define if this condition can increase the risk to convert to a CF diagnosis.