Another iceberg of genetic testing: more questions than answers

Abstract

We describe a case series of six patients who presented to our allergy/immunology clinic for evaluation of chronic rhinosinusitis (CRS) and were subsequently found to have pathogenic mutations in primary ciliary dyskinesia (PCD) or cystic fibrosis (CF) genes.All patients were initially evaluated as adults with CRS. All but one had nasal polyps. Patients 1–3 had severe recurrent infections with one Pseudomonas aeruginosa (PA) infection. Patients 4–6 reported sinusitis without other infections. Spirometry for three patients (1, 2, 6) showed severe obstruction; patient 3 had a restrictive defect; and two patients (4, 5) had normal spirometry. All patients had quantitative immunoglobulin and complement levels checked. Those with history of infections had more extensive immune workup (Table 1). All six had genetic testing that identified heterozygous pathogenic mutations in either PCD- or CF-related genes.Recent research has highlighted the heterogenous nature of CRS, including different phenotypes and endotypes with predominant TH1, TH2, or TH3 inflammation. Patients 5 and 6 with aspirin exacerbated respiratory disease (AERD) have obvious TH2-predominant endotype. Presentations of patients 1–4 are more consistent with non-TH2 endotype: three patients have recurrent infections, including PA, and patient 4 has no features of eosinophilic inflammation. Patient 2, with a history of AERD/eosinophilic granulomatosis with polyangiitis, lost features of TH2 disease likely due to profound immunosuppression, which resulted in secondary immunodeficiency. Elevated immunoglobulin E level in patient 3 is likely due to concomitant chronic autoimmune urticaria.Diagnosis of CF or PCD should be considered in patients who present with CRS and PA infections, even when they present as older adults. Furthermore, this case series highlights the heterogeneity of CRS in adult patients with pathogenic CF/PCD mutations. Carrier status is likely clinically significant and can present with predominant TH2, non-TH2 or mixed inflammatory pattern. Genetic testing provides a Pandora’s Box of information. More work is needed to understand how it can be best applied in clinical care.