Non pathological sweat test, pancreatic insufficiency and Cystic Fibrosis: an unusual case in a child with F508del-duplication of exons 1-3 CFTR genotype

Abstract

While Cystic Fibrosis is characterized by a high phenotypic variability, a correlation is reported between the pancreatic status and the CFTR genotype. Here we report an unusual case of a child with Cystic Fibrosis (F508del-duplication of exons 1-3 genotype) diagnosed at 8 years old for pancreatic insufficiency and non-pathological sweat test, in absence of respiratory symptoms and acute episodes of pancreatitis. Nasal potential differences and intestinal current measurements were normal, while the short-circuit current measured on patient-derived colonoids grown on Transwell^® indicated the presence of a reduced CFTR-dependent current relative to non-CF colonoids with, a modest improvement of CFTR activity record following treatment with elexacaftor/tezacaftor/ivacaftor.This case opens the discussion on the importance of performing CFTR sequencing and the search for large gene rearrangements in cases of pancreatic insufficiency of unclear etiology, also in the presence of non-pathological sweat test. Children with CF and non-pathological sweat chloride are likely to develop higher concentrations if they truly have CF.

Keywords: CFTR; Diagnosis; Duplication; Genotype; Normal; Sweat chloride.

Fig. 1

Representative image of CFTR-dependent and -independent sweat secretion rates for the CF subject under evaluation. (A) Each image focuses on a small region of stimulated forearm skin of the selected subjects to show blue-stained sweat droplets by single sweat glands that responded to methacholine (M-sweating) and to the β-adrenergic cocktail (C-sweating), demonstrating the activity of the CFTR channel (C-sweat); grid scale = 0.5 mm. (B) Comparison of average C/M sweat rates measured in each group (control: non-CF, healthy carriers: HC, and cystic fibrosis: CF) and patient analyzed (subject)

Fig. 2

Functional evaluation of modulator treatment on F508del/dup. exons 1–3 rectal organoids. (A) Representative Isc traces of the effect of the vehicle alone (DMSO; black trace), or the correctors ELEXA/TEXA; (ET, 3µM each; blue trace). During the recordings, the colonoids were sequentially treated (as indicated by downward arrows) with amiloride (10 µM), forskolin (10 µM), ivacaftor (0.3 µM), and the CFTR inhibitor PPQ-102 (20 µM). (B) Column bar graphic showing mean ± SEMm (n = 4). Data reported are the maximal amplitude of the current after addition of forskolin in colonoids pre-treated with vehicle (Veh.) or CFTR modulators. Non-CF mean of ΔIsc values from a minimum of three independent experiments obtained from five non-CF subjects (black column bar) are shown here as reference. Ordinary one-way ANOVA, *p > 0.05, **p > 0.005. (C) Light microscopy analysis of the morphology of Non-CF (used here as reference) and F508del/dup.exons 1–3 intestinal organoids in culture at steady-state condition