Combating Diagnostic Wandering and Impasse for Cystic Fibrosis

Combating Diagnostic Wandering and Impasse for Cystic Fibrosis: Assessment of Patients Not Concluded After Neonatal Screening of Cystic Fibrosis

After cystic fibrosis (CF) neonatal screening, some children remain with a not concluded diagnosis. In France, the medical follow-up is not standardized, some of them may be lost of follow-up. The aim of the study is to identify children at risk of developing CF. Other children carry mutation at risk of CFTR related disorder (CFTR-RD) but remain asymptomatic during childhood. The aim of the study is to evaluate those children by microbiology, respiratory function test and lung imaging tests to reclassify them in the CFTR spectrum.

Cystic fibrosis (CF) is a life-limiting genetic disorder related to the mutation of the CF Transmembrane Conductance Regulator (CFTR) gene. Cystic fibrosis neonatal screening in France has been generalized in 2002. Patients with hypertrypsinemia and two CF mutations are diagnosed CF and followed in CF center with standards of care.

But some children with hypertrypsinemia may have an intermediate chloride sweat test and only one CFTR mutation, or a negative sweat test and two CFTR mutations at least one of which is of unknown pathogenicity.

Some other patients may present with two CFTR-RD mutations and may unravel a monosymptomatic disease in adulthood (CFTR-related disorder) such as congenital bilateral absence of vas deferens (CBAVD), acute recurrent or chronic pancreatitis, disseminated bronchiectasis, chronic rhinosinusitis...We have very few data about age of onset, type of symptoms, and infraclinical disease.

Patients will be identified according to neonatal screening data and genetic database, and will undergo clinical evaluation, pancreatic and lung disease evaluation to reclassify them in the CFTR spectrum.

Inclusion Criteria:

• undiagnosed patients with hypertrypsinemia at CF neonatal screening and :

  1. either an intermediate chloride sweat test (30-59 mmol/L) and at most one CFTR mutation
  2. or negative chloride sweat test (< 30 mmol/L) and two CFTR mutations one of wich is of unknown significance (VUS)

• patients with two CFTR mutations at least one of which is of Varying Clinical Consequence according to "CFTR2" database or "CFTR-RD" according to "CFTR-France" database.

Exclusion Criteria:

• CF patients with 2 CF causing mutations