Clinical Chemistry - Case Study
https://doi.org/10.1093/clinchem/hvae102
A 14-month-old female of European descent was referred to our hospital due to inconclusive sweat chloride tests (STs) and a previous positive newborn screening (NBS) for cystic fibrosis (CF).
Student Discussion Document (pdf)
Lucille De Maria, Marion Marlinge, Melisande Baravalle, Jean-Christophe Dubus, and Julien Fromonot
A 14-month-old female of European descent was referred to our hospital due to inconclusive sweat chloride tests (STs) and a previous positive newborn screening (NBS) for cystic fibrosis (CF).
The patient was born at full-term as the firstborn in a family with no history of genetic diseases. On her third day of life, NBS showed high immunoreactive trypsinogen levels (triplicate average: 109 ng/mL) above the reference level (99.5th percentile: 65 ng/mL). Molecular testing for the 29 recommended CFTR variants by the French NBS program was performed on a dried blood spot using the Elucigene® CF30V2 kit (Gen-Probe Inc.). She was found to carry the common CFTR heterozygous pathogenic variant: NM_000492.4:c.1521_1523del, (p.Phe508del; p.F508del). Since birth, she had been experiencing infant asthma, which was treated with fluticasone propionate or salmeterol aerosol. However, she did not present with the gastrointestinal phenotype including meconium ileus or diarrhea with steatorrhea. At 1 month of age, she underwent the first ST which was performed in accordance with the management guidelines (coulometric method, ChloroChek®, ELITechGroup Inc.). Results showed a chloride concentration within the intermediate range (44 mmol/L, reference level <30 mmol/L). The test was repeated after 1 week because of the initial result and this second ST was negative (chloride concentration: 29 mmol/L). Accordingly, further tests were not conducted at this point.
At 14 months of age, new examinations were performed as her parents wanted to have a second child. The patient’s medical history included persistent ear, nose, and throat obstructions with chronic cough leading to exertional dyspnea, nocturnal snoring with apnea, and 2 hospitalizations due to respiratory complications (COVID-19–induced asthma and viral retrocardiac pneumonia). Expanded analyses for 50 CFTR variants (Elucigene CF-EU2v1 kit) revealed compound heterozygosity for 2 pathogenic variants in trans: c.1521_1523del (p.F508del) inherited from her mother and c.3454G>C (p.D1152H) inherited from her father. Despite the combination of these pathogenic variants, the third ST was still negative (chloride concentration: 23 mmol/L), and the patient’s fecal elastase level over 800 μg/g (reference level >200 μg/g) confirmed exocrine pancreatic sufficiency.
At this stage, the diagnosis remained unclear because of the discrepancies between the ST results and the CFTR genotype. She was then hospitalized for the third time because of a viral-induced respiratory congestion with wet cough for 10 days. The respiratory congestion was associated with bacterial superinfection (Streptococcus pneumoniae and Moraxella catarrhalis) and mild diffuse bronchial thickening on chest radiography.