IL-1RN VNTR, IL-2(-330), and IL-4 VNTR gene polymorphisms in patients with chronic rhinosinusitis with sinonasal polyposis

Background/aim: Sinonasal polyposis is a complex chronic disease displaying contributions from multiple genetic and environmental factors. In this study, we analyzed possible genetic factors that increase susceptibility to this widespread inflammatory disease. Materials and methods: A total of 176 adult patients, including 78 patients with sinonasal polyposis and 98 healthy controls, were analyzed for IL-1RN VNTR, IL-2(-330), and IL-4 VNTR gene polymorphisms using polymerase chain reaction and enzyme restriction. Results: IL-1RN and IL-4 VNTR polymorphisms were notably associated with sinonasal polyposis (P = 0.0001 and P = 0.036, respectively); however, regarding the IL-2(-330) gene polymorphism, no significant difference was shown between the patient and control groups (P = 0.235). Conclusions: Our study indicates that the RN2 allele of IL-1RN and the RP1 allele of IL-4 might be risk factors for developing sinonasal polyposis.

Aneurysmal Bone Cyst of the Maxillary Sinus with USP6 Rearrangement: Case Report of a Rare Entity and Review of the Literature.

Aneurysmal bone cysts (ABCs) are benign lesions which most frequently occur in the long bones of pediatric patients. Long thought to be reactive, recent molecular advances have demonstrated that the majority of primary ABCs harbor rearrangements of the USP6 gene, confirming their neoplastic nature. Secondary ABCs arising from other lesions do not demonstrate this recurrent genetic anomaly. ABCs rarely occur in the craniofacial bones, and sinonasal ABCs are exceedingly rare. We report a case of a primary ABC arising the maxillary sinus of a 14-year-old female, which was found to harbor USP6 rearrangement. We describe the clinical, radiologic, and pathologic features of this case, and review the current literature on craniofacial ABCs. Careful histologic evaluation and genetic studies are warranted in order to confirm the rare occurrence of a primary sinonasal ABC.

Resveratrol and ivacaftor are additive G551D CFTR-channel potentiators: therapeutic implications for cystic fibrosis sinus disease.

BACKGROUND: Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene result in defective Cl- transport and cause chronic bacterial infections in the upper and lower airways of cystic fibrosis (CF) patients. Ivacaftor is a CFTR potentiator that improves Cl- transport in CF patients with at least 1 copy of the G551D mutation. Resveratrol is also a potent CFTR potentiator that increases determinants of mucociliary transport. The objective of this study is to determine whether resveratrol and ivacaftor improve Cl- secretion in G551D CFTR over either agent alone. METHODS: Fisher rat thyroid cells (FRT) transfected with G551D CFTR and human sinonasal epithelial cells (HSNE) containing the CFTR G551D mutation were subjected to pharmacologic manipulation of transepithelial ion transport in Ussing chambers. Activity was further evaluated using whole-cell patch clamp methods in G551D FRT cells. RESULTS: In G551D FRT cells, resveratrol (100 µM) and ivacaftor (10 µM) significantly increased Cl- transport (change in short-circuit current, δISC = µA/cm2 ) compared with single-agent and dimethylsulfoxide vehicle controls (resveratrol + ivacaftor 4.97 ± 0.57 vs ivacaftor 0.74 ± 0.12 vs resveratrol 2.96 ± 0.52 vs control 0.74 ± 0.12; p < 0.001). Maximal Cl- secretion (20 µM forskolin) was also significantly enhanced (p < 0.0001). Activity was confirmed in G551D HSNE (resveratrol + ivacaftor 4.48 ± 0.39 vs ivacaftor 1.05 ± 0.11 vs. resveratrol 0.84 ± 0.3 vs control, 0.0 ± 0.02; p < 0.001), and whole-cell patch clamp analysis in G551D FRT cells (resveratrol + ivacaftor -2535 ± 179.3 pA vs ivacaftor -1408.9 ± 101.3 pA vs resveratrol; -766.2 ± 71.2 pA; p < 0.0001). CONCLUSION: Additive improvement in G551D CFTR-mediated Cl- secretion suggests that resveratrol could enhance ivacaftor therapy in these patients and improve CF-related rhinosinusitis.

Impact of high- versus low-risk genotype on sinonasal radiographic disease in cystic fibrosis.

OBJECTIVE: Understanding of how specific mutations impact the cystic fibrosis transmembrane conductance regulator (CFTR) protein has given rise to the classification of CF patients into low-risk and high-risk genotypes. Few prior studies have investigated differences in sinonasal disease between low-risk and high-risk CF genotypes. This multi-institutional review aimed to evaluate radiographic sinus disease severity based on genotype. METHODS: A review was conducted on adult patients with CF evaluated between 2005 to 2017 at three academic institutions. Data including age, gender, CFTR mutation, and presence of a maxillofacial/sinus computed tomography scan was collected. A modified Lund-Mackay score (MLMS) was assigned to each scan, and the presence of sinus aplasia or hypoplasia was determined. Patients were further grouped depending on genotype into low- or high-risk for comparison. RESULTS: A total of 126 patients were included with 99 patients in the high-risk and 21 in the low-risk groups. The high-risk group had significantly higher MLMS than the low-risk group (mean 13.88 vs. 8.06, P < 0.0001, 95% CI -8.196 to -3.462) The rate of frontal (P < 0.01), maxillary (P = 0.04), and sphenoid (P < 0.001) hypoplasia/aplasia was significantly higher in high-risk patients compared to low-risk. CONCLUSION: This is one of the largest studies to date evaluating the impact of CF genotype on paranasal sinus development and disease. Genotype appears to impact sinonasal disease severity and also potentially paranasal sinus cavity development to a degree, although the exact mechanism is unknown. LEVEL OF EVIDENCE: 4 Laryngoscope, 129:788-793, 2019.

USP6 gene rearrangement differentiates primary paranasal sinus solid aneurysmal bone cyst from other giant cell-rich lesions: report of a rare case.

Aneurysmal bone cysts (ABCs) mostly occur in the metaphysis of long bones. Primary paranasal ABCs are extremely rare, and most reported cases reveal typical histopathological features including cystic space with fibrous septa and hemorrhage. Solid-variant ABCs or solid ABCs lacking cyst formation may be histologically indistinguishable from giant cell reparative granulomas, giant cell tumor of bone, and brown tumor. Here we report the case of a 24-year-old woman with a paranasal mass diagnosed as USP6-rearranged solid ABC, mimicking giant cell reparative granuloma, giant cell tumor of bone, and brown tumor. For paranasal sinus bone or soft tissue tumors containing numerous giant cells, molecular analysis including the USP6 gene may serve as a useful diagnostic tool to distinguish solid ABCs from other giant cell-rich lesions.

What is the evidence for genetics in chronic rhinosinusitis?

PURPOSE OF REVIEW: To perform analysis of evidence in current literature on the topic of genetics and chronic rhinosinusitis (CRS), with a particular focus on recent findings in the cystic fibrosis transmembrane regulator (CFTR), genes associated with primary ciliary dyskinesia, and taste receptor T2R38. Other genes that have been found to have association with CRS are also presented and discussed. RECENT FINDINGS: Recent studies in CFTR and CRS research have investigated possible CFTR-potentiators for treatment of refractory CRS. The T2R38 gene has been shown to be applicable in the clinical setting with a testable phenotype and may have a role in the prognosis and influencing management strategies of CRS patients. Many genes of the immune system have been studied, with genome-wide association studies and candidate-gene approaches identifying new associations that will need replication and further elucidation. SUMMARY: CRS is a multifactorial disease, with strong evidence of a genetic component in its pathophysiology for some cases. Currently, there are over 70 genes that have been genetically associated with CRS in the past 15 years. Future investigations into genetic causes and predispositions of CRS may allow for improved prognostication and development of disease-prevention strategies as well as novel therapeutic targets.

Nasal Chondromesenchymal Hamartoma (NCMH): a systematic review of the literature with a new case report.

BACKGROUND: Nasal chondromesenchymal hamartoma (NCMH) is a very rare, benign tumour of the sinonasal tract usually presenting in infants. We present a systematic review of NCMH cases alongside a case report of an adult with asymptomatic NCMH. METHODS: A systematic review was conducted in accordance with PRISMA guidelines. A PubMed, EMBASE and manual search through references of relevant publications was used to identify all published case-reports of NCMH. Data was collected from each case-report on: patient demographics, laterality, size and location of NCMH, presentation, co-morbidities, investigations, treatment and follow-up. RESULTS: The systematic review identified 48 patients (including ours): 33 male, 15 female. Mean age was 9.6 years (range: 1 day-69 years) with the majority aged 1 year or younger at presentation (n = 18). Presentations included: nasal congestion (n = 17), nasal mass (n = 15) and eye signs (n = 12). NCMH also involved the paranasal sinuses (n = 26), orbit (n = 16) and skull-base (n = 14). All patients underwent operative resection of NCMH. A small 2014 case-series found DICER1 mutations in 6 NCMH patients, establishing a link to the DICER1 tumour spectrum. CONCLUSIONS: NCMH is a rare cause of nasal masses in young children and adults. In light of the newly established link between NCMH and DICER1 mutations surgeons should be vigilant for associated DICER1 tumours, as NCMH may be the 'herald tumour' of this disease spectrum.

Sinonasal manifestations of cystic fibrosis: a correlation between genotype and phenotype?

BACKGROUND: Patients with Cystic Fibrosis are prone to develop sinonasal disease. Studies in genotype-phenotype correlations for sinonasal disease are scarce and inconclusive. METHODS: In this observational study several aspects of sinonasal disease were investigated in 104 adult patients with CF. In each patient a disease specific quality of life questionnaire (RSOM-31), nasal endoscopy and a CT scan of the paranasal sinuses were performed. Patients were divided into two groups, class I-III mutations and class IV-V mutations, based on their CFTR mutations. RESULTS: The prevalence of rhinosinusitis in adult patients with CF was 63% and the prevalence of nasal polyps 25%. Patients with class I-III mutations had significantly smaller frontal sinuses, sphenoid sinuses, more opacification in the sinonasal area and more often osteitis/neoosteogenesis of the maxillary sinus wall compared to patients with class IV and V mutations. CONCLUSION: These data suggest more severe sinonasal disease in patients with class I-III mutations compared to patients with class IV-V mutations.

Temporal bone pneumatization in cystic fibrosis: a correlation with genotype?

OBJECTIVES/HYPOTHESIS: Paranasal sinus pneumatization in patients with cystic fibrosis (CF) is less extensive compared to the general population and seems to be correlated to CF genotype. Interestingly, in CF patients temporal bone pneumatization (TBP) is more extensive compared to the general population, and middle ear pathology is generally uncommon in CF. It is debated whether TBP is influenced environmentally or genetically. The aim of the present study was to investigate pneumatization of the temporal bone in patients with CF and to correlate this with genotype and paranasal sinus volume. STUDY DESIGN: Prospective collection of data. METHODS: In 104 adult CF patients, computed tomography of the temporal bone and the paranasal sinuses was performed. TBP was graded using a validated scoring system. Patients were divided into two groups, mild and severe CF, based on their mutations in the CF transmembrane conductance regulator gene. RESULTS: Of the 31 patients with mild CF, 71% had extensive TBP, and of the 73 patients with severe CF, 82% had extensive pneumatization of the temporal bone. TBP did not differ significantly for CF genotype, and TBP was not correlated to paranasal sinus volume. CONCLUSIONS: Whereas paranasal sinus pneumatization in CF patients seems to be related to CF genotype among other influencing factors, this study showed no correlation between TBP and CF genotype. TBP was not correlated to paranasal sinus volume. Hypothetically, in CF, pneumatization of the temporal bone is under a different influence than paranasal sinus pneumatization. LEVEL OF EVIDENCE: 4.

Nasal polyposis: is there an inheritance pattern? A single family study.

BACKGROUND: Nasal Polyposis (NP) is defined as a chronic inflammatory disease of sinonasal mucosa leading to diffuse formation of benign polyps. Although family histories are frequently suggested in medical literature, no specific study focused on this point has been reported. The purpose of this study is to determine whether a hereditary factor could be implied for NP in a family where several members were affected. We included 99 members of this family. METHODS: All patients were assessed for conditions known to be associated with the development or presence of NP. Concerning NP, patients were screened with a validated questionnaire and selected patients had a medical examination by an Ear, Nose and Throat practitioner. RESULTS: Thirteen patients had a personal history of NP without asthma, aspirin intolerance, Churg Strauss syndrome, cystic fibrosis, Young's syndrome, bare lymphocyte syndrome, or primary ciliary dyskinesia. Within this family, 19.7% of those older than 17 years were affected by NP, as compared with the national French prevalence of 2.1%. CONCLUSIONS: Regarding the pedigree, we discuss different modes of inheritance. The presence of consanguineous unions in this family suggests the possibility of a common ancestor and thus a recessive autosomal mode of inheritance.

Gene expression analysis in sinonasal polyposis before and after oral corticosteroids: a preliminary investigation.

OBJECTIVE: To characterize gene expression in sinonasal polyps and to gain insight into change in expression after oral corticosteroid treatment. STUDY DESIGN AND METHODS: Nasal polyps were obtained before and after oral corticosteroid treatment and gene expression was analyzed with a focused gene array technique. RESULTS: Pretreated sinonasal polyps demonstrated high gene expression for chemokine and leukotriene receptor genes (CCR2, CCR5, CX3CL1, and LTB4R) in all patients. After treatment, the global effects of corticosteroids were evident on gene expression. CONCLUSIONS: Gene array techniques hold promise as a research method in sinonasal polyposis. The potential benefits, as well as the potential challenges, in using these research methods will be discussed.

The delta F508 mutation in cystic fibrosis and impact on sinus development.

BACKGROUND: Cystic fibrosis (CF) patients often have widespread inflammatory paranasal sinus disease with an increased incidence of frontal, maxillary, and sphenoid hypoplasia. The most common genetic defect in CF is the delta F508 mutation. The effect of specific CF genotypes on phenotypic sinus development and infections is not well understood. The purpose of this study was to determine whether the homozygous delta F508 mutation is associated with an increased incidence of sinus hypoplasia when compared with other mutations. METHODS: This study is a retrospective review of all adult patients seen at our CF center from 1996 to 2005. Patients > or =18 years old with a CF diagnosis using genetic and sweat chloride testing and sinus CT scans were included. Frontal sinus aplasia/hypoplasia and maxillary and sphenoid sinus hypoplasia were documented using published criteria. Data collected included patient demographics, genetic mutations, and prior sinus surgeries. RESULTS: Forty-five patients were identified with an average age of 32 years (range, 18-48 years). Thirty-one patients had prior sinus surgeries. Delta F508 homozygotes (n = 25) had a significantly increased frequency of underdeveloped frontal (98%), maxillary (70%), and sphenoid (100%) sinuses (p < 0.001) when compared with other mutations (69, 8, and 50%, respectively). CONCLUSION: CF patients homozygous for the delta F508 mutation have a greater incidence of hypoplastic or underdeveloped sinuses. Whether this is secondary to an increased frequency of sinus infections or a phenotypic expression of the genetic mutation itself remains an area for further investigation.

Clinical aspects of the link between chronic sinonasal diseases and asthma.

Chronic sinonasal diseases (CSDs) are common comorbidity of asthma. The aim of this study was to assess comprehensively CSD in a population of asthma patients and determine whether the clinical factors in both diseases were related to each other. Eighty adult stable asthmatic patients with sinonasal symptoms (SNSs) of 3 months and who were nonresponsive to aggressive medical treatment were prospectively investigated. All patients underwent a detailed ear, nose, and throat examination and were evaluated by paranasal sinus computed tomography (PNS-CT). The severity of asthma was compared with SNS scores (SNSSs) and sinonasal involvement on PNS-CT. Asthma was severe in 12.5%, moderate in 55%, and mild in 32.5% of cases. There were 15 (18.7%) patients in stage 0, 16 (20%) patients in stage 1, 21 (26.2%) patients in stage 2, and 28 (35%) patients in stage 3 according to PNS-CT scoring. There was no correlation between asthma severity and CT stages, total opacification scores (TOSs), anatomic variations, and SNSSs. Although SNSSs were similar in patients with nasal polyps (NPs) and without NPs, patients with NPs showed significantly higher TOSs and CT stages (p < 0.05). The presence of NPs and age and duration of disease were related to severity of asthma (p < 0.05). Nonatopic asthmatic patients had both more severe asthma (p = 0.05) and more extensive CT findings (p = 0.01). The use of clinical symptoms alone is not very reliable in predicting the presence or severity of CSD. Therefore, SNSs should be supported with objective criteria such as nasal endoscopy and PNS-CT scan. Furthermore, sinonasal involvement may exist independently from severity of asthma.

Familial aggregation of sinonasal polyps correlates with severity of disease.

OBJECTIVE: Investigate familial aggregation of sinonasal polyps (NP) and correlate the severity of chronic rhinosinusitis (CRS) with a family history of NP. STUDY DESIGN AND SETTING: A questionnaire documenting NP, asthma, or aspirin intolerance was completed by 174 CRS patients. Severity of sinus disease was stratified as isolated NP, NP with concomitant asthma, and Samter's triad (polyps, asthma, and aspirin intolerance). RESULTS: Compared to controls, CRS patients had a higher incidence of a family history of NP. Additionally, patients stratified with severe CRS had a higher incidence of relatives with NPs. CONCLUSIONS: Familial aggregation of NP is demonstrated in CRS patients and correlates with disease severity. EBM RATING: B-2b.

Aneurysmal bone cyst of the nose with 17p13 involvement.

We report on a 6-year-old girl with a polypoid mass, filling up the entire right nasal cavity as shown on a magnetic resonance imaging scan. Histologically, the tumor had the characteristics of an aneurysmal bone cyst, which is extremely rare in this location. Cytogenetic analysis disclosed a single (6:17)(p21;p13) translocation, confirming a specific genetic involvement in the development of aneurysmal bone cysts. Fluorescent in situ hybridization analysis mapped the putative gene between the p53 (17p13.1) and the Mieller-Dieker gene (17p13.3) loci.

Hypoplasia of the sphenoid sinuses as a diagnostic tool in cystic fibrosis.

PURPOSE: To measure and compare the size of the sphenoid sinuses in patients with cystic fibrosis (CF) to patients with inflammatory sinonasal disease, and to correlate the size with number of CF mutations in each patient. MATERIAL AND METHODS: Ninety-six CF patients aged 5-47 years (median 19 years) and 130 control patients aged 7-51 years (median 32 years) were examined using coronal CT of the paranasal sinuses. In each patient, the CT image with the largest coronal area of the sphenoid sinuses was scanned into a Macintosh computer with image processing and analysis software. Largest coronal area and largest circumference of the right and left sphenoid sinuses were automatically measured. Additionally, antero-posterior extension of the sphenoid sinuses was calculated from the lateral scanograms. CF patients were grouped according to number of confirmed mutations (CF-0, CF-1, or CF-2). RESULTS: CF patients generally had small sphenoid sinuses. The largest differences for all parameters were observed between the CF-2 and the control groups (p<0.0001). No CF-2 patient had pneumatization beyond the presphenoid. The CF-0 and CF-1 groups consisted of two populations, one overlapping the CF-2 group and another overlapping the control group. CONCLUSION: Hypoplasia of the sphenoid sinuses is a characteristic finding in CF patients. When pneumatization of the basisphenoid is present, the existing CF diagnosis should be questioned.

Genotype-phenotype correlations for the paranasal sinuses in cystic fibrosis.

Genotype-phenotype correlations in cystic fibrosis (CF) have been found for lung and pancreatic function, but not for paranasal sinus disease. Because such correlations may have pathophysiological and clinical implications, the correlation of mutations, in particular DeltaF508, with paranasal sinus disease was investigated in 113 CF patients with known genotype. The clinical importance of paranasal sinus disease was evaluated using three parameters: polyps, overall clinical severity of upper airway problems, and surgery. Polyps were evaluated by nasal endoscopy and graded on a five-point scale. Four severity groups were distinguished based on history, clinical records, and examination: no upper airway problems; more problems than in control subjects; severe, recurrent or chronic problems; and paranasal sinus surgery cases. DeltaF508 homozygosity correlated with clinical severity (p < 0.02) and with the presence of polyps on endoscopy (p < 0.05). The relative risk for paranasal sinus surgery in DeltaF508 homozygous CF patients was 2.33. In conclusion, there are genotype-phenotype correlations for paranasal sinus disease in CF. DeltaF508 homozygosity is a risk factor for paranasal sinus disease in CF.

Rapid characterization of the variable length polythymidine tract in the cystic fibrosis (CFTR) gene: association of the 5T allele with selected CFTR mutations and its incidence in atypical sinopulmonary disease.

The CFTR intron 8 variable length polythymidine tract modulates the cystic fibrosis (CF) phenotype associated with the mutation R117H. To explore whether other mutations reside on multiple intron 8 backgrounds with discernible impacts on phenotype, we developed an allele-specific PCR assay to characterize this locus. Our approach types samples rapidly without the use or radioisotopes. Polythymidine alleles were identified for mutations either associated with a wide range of clinical phenotypes (R117H, R347P, G85E, D1152H, R334W, 2789 + 5 G > A, 3849 + 10kb C > T), and/or located at hypermutable CpG loci (R117H, 3845 + 10kb C > T, R553X, R334W, S945L and R75Q). R117H was detected in cis with each of three alleles (5T, 7T, 9T) at the intron 8 locus. The novel R117H-9T association was detected in a 10-month African-American male with borderline-to-mildly elevated sweat chloride values (approximately 50-66 mEq/L). All other mutations studied were associated with 7T except 3849 + 10kb C > T, which was detected on both 7T and 9T backgrounds, but not 5T. Three individuals with a delta F508/3849 + 10kb C > T genotype were 9T,9T and had pancreatic sufficiency and normal sweat chloride values, whereas 15 others who carried 3849 + 10kb C > T on a 7T background had variable pancreatic function (sufficient, n = 12, insufficient, n = 3), and variable sweat chloride values (normal, n = 12, elevated, n = 3). Surprisingly, when not associated with known CFTR mutations, 5T was detected with elevated frequency among individuals with sinopulmonary disease of ill-defined etiology, but with some characteristics of variant CF. In summary, the 5T allele was not found in cis with CF-causing mutations besides R117H, but an elevated 5T allele frequency in variant CF patients suggests 5T may be associated with disease in some situations.

Endoscopic endonasal sinus surgery. A long-term follow-up study.

This study presents 230 patients who have been selected for endoscopic endonasal sinus surgery on the basis of a standardised diagnostic procedure. Surgery was performed by one surgeon during the period 1987 to 1991 and the Messerklinger technique (MT) was used exclusively. The selection was made from patients with nasal/paranasal complaints remitted for further treatment. Diagnostic procedures comprised a thorough anamnesis including questions about additional factors such as specific allergy of the upper airways, unspecified hyperreactivity of the nasal/paranasal mucosa, asthma, smoking, exposure to air pollution, heritage and systemic diseases, in addition to a conventional ENT-examination, endoscopy of the nasal/paranasal cavities, and tomography (conventional or computed). The patients were thereafter divided into the following groups: 1) acute recurrent and/or chronic sinusitis, 2) nasal/paranasal polyposis, 3) sinogenic headache, 4) mucoceles, and 5) olfactory dysfunction. More than 90% of the patients were treated on a day care out-patient basis, under local/topical anaesthesia combined with intravenous sedation. The extent of surgery varied in the different groups. There were no serious peroperative complications and no postoperative sequelaes. The patients were closely followed postoperatively for 1-5 years (mean 3 years and 5 months) until the study was closed at the end of 1992. We conclude that endoscopic endonasal sinus surgery demands several postoperative controls. Meticulous postoperative care is one of the basic requisites for securing optimal long-term results.