Inflammatory and infectious upper respiratory diseases associate with 41 genomic loci and type 2 inflammation.

Inflammatory and infectious upper respiratory diseases (ICD-10: J30-J39), such as diseases of the sinonasal tract, pharynx and larynx, are growing health problems yet their genomic similarity is not known. We analyze genome-wide association to eight upper respiratory diseases (61,195 cases) among 260,405 FinnGen participants, meta-analyzing diseases in four groups based on an underlying genetic correlation structure. Aiming to understand which genetic loci contribute to susceptibility to upper respiratory diseases in general and its subtypes, we detect 41 independent genome-wide significant loci, distinguishing impact on sinonasal or pharyngeal diseases, or both. Fine-mapping implicated non-synonymous variants in nine genes, including three linked to immune-related diseases. Phenome-wide analysis implicated asthma and atopic dermatitis at sinonasal disease loci, and inflammatory bowel diseases and other immune-mediated disorders at pharyngeal disease loci. Upper respiratory diseases also genetically correlated with autoimmune diseases such as rheumatoid arthritis, autoimmune hypothyroidism, and psoriasis. Finally, we associated separate gene pathways in sinonasal and pharyngeal diseases that both contribute to type 2 immunological reaction. We show shared heritability among upper respiratory diseases that extends to several immune-mediated diseases with diverse mechanisms, such as type 2 high inflammation.

Congenital Midline Cervical Cleft: First Report and Genetic Analysis of Two Related Patients.

OBJECTIVES: Congenital midline cervical cleft (CMCC) is a rare congenital anterior neck anatomical anomaly. We present the case of two related patients (grandchild and maternal grandmother) who were both born with a congenital midline cervical cleft along with genetic analysis. METHODS: Clinical examination of both patients and surgical excision of the grandchild was performed. Genetic analysis with exome sequencing (ES) was conducted for both patients. RESULTS: Genetic analysis with exome sequencing (ES) revealed apparently novel single nucleotide variants in 66 genes present in both proband and grandmother. Five of these variants are predicted to cause frameshifting in the coding region of the respective genes and truncated proteins (OVGP1, TYW1B, ZAN, SSPO, FOLR3). Two of these genes (TYW1B and SSPO) have homozygous indel mutations in both patients. CONCLUSIONS: To our knowledge, this is the first case of two related patients with a congenital midline cervical cleft. The results of our genetic analysis reveal potential relevance to CMCC development.

A mutant MATR3 mouse model to explain multisystem proteinopathy.

Mutations in the Matrin 3 (MATR3) gene have been identified as a cause of amyotrophic lateral sclerosis (ALS) or vocal cord and pharyngeal weakness with distal myopathy (VCPDM). This study investigated the mechanism by which mutant MATR3 causes multisystem proteinopathy (MSP) including ALS and VCPDM. We first analyzed the muscle pathology of C57BL/6 mice injected with adeno-associated viruses expressing human WT or mutant (S85C) MATR3. We next generated transgenic mice that overexpress mutant (S85C) MATR3, driven by the CMV early enhancer/chicken ß-actin promoter, and evaluated their clinicopathological features. Intramuscular injection of viruses expressing WT and mutant MATR3 induced similar myogenic changes, including smaller myofibers with internal nuclei, and upregulated p62 and LC3-II. Mutant MATR3 transgenic mice showed decreased body weight and lower motor activity. Muscle histology demonstrated myopathic changes including fiber-size variation, internal nuclei and rimmed vacuoles. Spinal cord histology showed a reduced number of motor neurons, and activation of microglia and astrocytes. Comprehensive proteomic analyses of muscle demonstrated upregulation of proteins related to chaperones, stress response, protein degradation, and nuclear function. Overexpression of WT and mutant MATR3 similarly caused myotoxicity, recapitulating the clinicopathological features of MSP. These models will be helpful for analyzing MSP pathogenesis and for understanding the function of MATR3. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Serotonin Transporter Gene (SLC6A4) Polymorphism May Be Associated with Chinese Globus Pharyngeus and Its Antidepressant Effects.

BACKGROUND: Although globus pharyngeus is not rare in clinical practice, little is known about its associated gene polymorphism. We investigated the association between the SLC6A4 polymorphism and globus pharyngeus and its response to treatment with antidepressants. METHODS: A total of 84 patients were diagnosed with globus pharyngeus according to Rome III, and 160 healthy controls were genotyped for the SLC6A4 polymorphism using polymerase chain reaction amplification and agarose gel electrophoresis. All patients with globus were studied using high-resolution manometry pre-therapy. Globus patients were randomized into paroxetine or amitriptyline groups for a 6-week treatment and asked to complete the following pre- and post-therapy questionnaires: the Glasgow Edinburgh Throat Scale (GETS), the Pittsburgh Sleep Quality Index, and the Hamilton Rating Scale Anxiety/Depression. Treatment response was defined as a >50% reduction in the GETS scores. RESULTS: A significant difference was observed in the globus S/S genotype with anxiety compared to that without anxiety (χ2 = 14.579, p = 0.006). The L/S genotype showed a significant difference between high upper esophageal sphincter pressure (>104 mm Hg) and non-high upper esophageal sphincter pressure patients (χ2 = 14.433, p = 0.006). A significant association between the S/S genotype and the response to antidepressant treatment was also observed, while patients with sleep disorders or depression showed no association. CONCLUSION: A significant association was observed between the S/S genotype of the SLC6A4 polymorphism and globus pharyngeus, suggesting that SLC6A4 is a potential candidate gene involved in the pathogenesis of globus pharyngeus.

MBL, P2X7, and SLC11A1 gene polymorphisms in patients with oropharyngeal tularemia.

CONCLUSION: A significant association was found of oropharyngeal tularemia with SLC11A1 allele polymorphism (INT4 G/C) and MBL2 C + 4T (P/Q). These results indicate C allele and Q allele might be a risk factor for the development of oropharyngeal tularemia. AIM: This study aimed to investigate the relationship of SLC11A1, MBL, and P2X7 gene polymorphism with oropharyngeal tularemia. METHODS: The study included totally 120 patients who were diagnosed with oropharyngeal tularemia. Frequencies of polymorphisms in the following genes were analyzed both in the patient and control groups in the study: SLC11A1 (5'(GT)n Allele 2/3, Int4 G/C, 3' UTR, D543N G/A), MBL (MBL2 C + 4T (P/Q), and P2X7 (-762 C/T and 1513 A/C). RESULTS: Among all polymorphisms that were investigated in this study, SLC11A1 gene showed a significance in the distriburtion of polymorphism allelle frequency at the INT4 region. Frequency of C allele was 54 (28%) in patients with oropharyngeal tularemia, and 31 (13%) in the control group (p = 0.006 and OR = 1.96 (1.21-3.20)). An association was detected between MBL2 C + 4T (P/Q) gene polymorphism and oropharyngeal tularemia (p < 0.005 and OR = 0.30 (0.19-0.48)). No significant relation was found between P2X7 (-762 C/T and 1513 A/C) gene polymorphism and oropharyngeal tularemia in this study (p > 0.05).

Phenotype of matrin-3-related distal myopathy in 16 German patients.

OBJECTIVE: To characterize the phenotype of patients with distal myopathy with vocal cord and pharyngeal weakness due to the p.S85C mutation in the matrin-3 gene (MATR3, Mendelian Inheritance in Man 164015). Recently, it has been suggested that patients with this mutation may suffer from familial amyotrophic lateral sclerosis. METHODS: Sixteen patients from 6 families with late onset distal myopathy associated with the p.S85C MATR3 mutation were characterized. RESULTS: Patients had a predominantly distal muscle weakness, most severely affecting ankle and wrist dorsiflexion. Relevant proximal and axial weakness was found in 6 and respiratory impairment in 5 patients. Dysphagia was diagnosed in 6 and mild voice abnormalities were found in 7 patients. However, laryngoscopy revealed normal vocal cord function. Creatine kinase was normal or mildly elevated. Electromyographically, spontaneous activity was found in 10 of 14 patients and complex repetitive discharges in 9 of 14 patients. Magnetic resonance imaging revealed severe fatty degeneration of distal and upper posterior leg and of paraspinal muscles. Histopathology ranged from mild myopathic to severe dystrophic changes including vacuoles. Absence of sarcomeres in the perinuclear region and abnormal invaginations of nuclei were found ultrastructurally. Haplotype analysis showed a common disease-specific haplotype of the 6 families and suggested that these families form a separate cluster. INTERPRETATION: In contrast to the 2 previously reported families, MATR3-related distal myopathy might be associated with relevant axial, proximal, and respiratory muscle weakness but without vocal cord palsy. There were no clinical, electrophysiological, or histopathological signs of lower motor neuron involvement.

Effect of nucleic acid amplification testing on detection of extragenital gonorrhea and chlamydial infections in men who have sex with men sexually transmitted disease clinic patients.

BACKGROUND: In 2010, the Centers for Disease and Control and Prevention recommended using nucleic acid amplification tests (NAATs) for extragenital gonorrhea (GC) and chlamydia (CT) testing because of NAATs' improved sensitivity compared with culture. METHODS: In 2011, the Public Health-Seattle & King County Sexually Transmitted Disease Clinic introduced NAAT-based testing for extragenital GC and CT infection in men who have sex with men (MSM) using AptimaCombo2. We compared extragenital GC and CT test positivity and infection detection yields in the last year of culture-based testing (2010) to the first year of NAAT testing (2011). RESULTS: Test positivity of GC increased by 8% for rectal infections (9.0%-9.7%) and 12% for pharyngeal infections (5.8%-6.5%) from 2010 to 2011; CT test positivity increased 61% for rectal infections (7.4%-11.9%). Pharyngeal CT was identified in 2.3% of tested persons in 2011 (not tested in 2010). We calculated the ratio of extragenital cases per 100 urethral infections to adjust for a possible decline in GC/CT incidence in 2011; the GC rectal and pharyngeal ratios increased 77% and 66%, respectively, and the CT rectal ratio increased 127%. The proportion of infected persons with isolated extragenital infections (i.e., extragenital infections without urethral infection) increased from 43% in 2010 to 57% in 2011. CONCLUSIONS: Extragenital testing with NAAT substantially increases the number of infected MSM identified with GC or CT infection and should continue to be promoted.

Bilateral first branchial cleft anomaly with evidence of a genetic aetiology.

Anomalies of the first branchial cleft (FBC) are uncommon, and recognizing them can be difficult. Although present at birth, many cases do not become evident until later in childhood or adolescence, with an initial clinical presentation in adulthood being encountered only rarely. Typically, FBC anomalies present as a unilateral cyst, sinus, or fistula associated with the external auditory canal, or with swelling or an inflammatory opening in the peri-auricular/parotid area. They are commonly misdiagnosed and are often treated inadequately before being excised completely. A 40-year-old woman presented to the maxillofacial outpatient clinic with an episode of bilateral pre-auricular tumefaction, initially diagnosed as temporomandibular dysfunction syndrome. This was associated with bilateral pre-auricular pain that increased with mandibular movements. In relation to the patient's history, and given the bilateral presence of a pre-auricular pit, a diagnosis of FBC anomaly was made. Further investigation showed a related asymptomatic history in five other cases across four generations of the same family. The authors describe here the case, the diagnostic methodology, and the wide local excision technique used for removal of the branchial sinus.

[The role of cytokine gene polymorphisms in the development of hypertrophy of the tonsils of the lymphoid pharyngeal ring and atopic march in the children].

Interleukin 1-beta (IL-1b), its endogenous receptor antagonist (IL-1 Ra), and interleukin IL-4 have been shown to play a role in immunopathological processes, such as the development of hypertrophy of the tonsils of the lymphoid pharyngeal ring and atopic march. However, the influence of Il-1 and IL-4 gene polymorphisms as etiological factors of this pathology remains obscure. The objective of the present work was to study characteristics of gene polymorphisms of proinflammatory and proallergic cytokines depending on the degree of hypertrophy of the tonsils of the lymphoid pharyngeal ring (LPR) and atopic march to selected species of the opportunistic pathogenic biota. Polymorphisms of the following genes were investigated in the children, residents of the Kemerovo region, presenting with hypertrophic tonsils of LPR: IL-1b+3953 (C->T), IL4 (70 bp VNTR), and IL-1Ra (86 bp VNTR). IL-1b, IL-1Ra, and IL-4 genotypes were determined by PCR of autosomal DNAs obtained from 129 children presenting with hypertrophic tonsils and 41 healthy children with the use of conventional genetic-statistical methods. Odds ratios (ORs) were estimated by the logistic regression models for each locus and after adjusting polymorphisms for the neighbouring loci. The 2R, 2R, Il-1Ra and T, T IL-1b genotypes occurred more frequently in the patients with isolated adenoid vegetations (20.93% and 25.58% respectively) than in the healthy children (4.95%) (OR=3.78, p=0.049; OR=3.25, p=0.047). The results of this study indicate that IL-1b and IL-1Ra gene polymorphisms play a role in the development of clinically significant features in the lymphoid pharyngeal ring.

Gene expression in the oropharynx of children exposed to secondhand smoke.

OBJECTIVES/HYPOTHESIS: To compare gene expression in oropharyngeal mucosa of children with (ex+) and without (ex-) secondhand smoke exposure. STUDY DESIGN: Prospective case-control. METHODS: Forty-one age- and gender-matched children (2-6 years old) undergoing tonsillectomy for sleep disordered breathing at a tertiary care children's hospital were assessed for secondhand smoke exposure. Parental response to a validated questionnaire relating to secondhand smoke exposure governed inclusion. Sixteen samples were selected for microarray analysis (7 ex+, 9 ex-). Following tonsillectomy, ex vivo brushing of the mucosa isolated total RNA. Genome-wide expression profiles were generated by comparing sample RNA to a reference of all samples, assessing 27,323 cDNA clones. Microarray clones were ranked according to their ability to distinguish between the two groups using a Student t test. RESULTS: A total of 318 cDNA clones distinguished the two groups (P < .01); 180 genes were overexpressed and 138 underexpressed in ex+ samples relative to the ex- group. Independent analysis of these two groups sorted genes into disease processes and molecular functional groups, including cancer (34 genes in the overexpressed group, 29 underexpressed, P < .05), cell cycle (14 and 10), and cell growth and proliferation (7 and 11). Two of the upregulated genes, LCN2 and IQGAP1, have been previously linked to inflammation in smokers and response/repair to cellular injury in bronchial epithelium. CONCLUSIONS: Findings in this pilot study support the hypothesis that secondhand smoke exposure seems to induce gene expression changes in the oropharyngeal mucosa of exposed children, which may have significant implications for current and future disease processes.

Whole-genome scan for guttural pouch tympany in Arabian and German warmblood horses.

Equine guttural pouch tympany (GPT) is a hereditary disease in foals of several breeds, including thoroughbreds, Arabian, Quarter and warmblood horses. We performed a whole-genome scan for GPT in 143 horses from five Arabian and five German warmblood families and genotyped 257 microsatellites. Chromosome-wide significant linkage was detected on ECA2 and ECA15 using multipoint non-parametric linkage analyses. Analyses stratified by sex revealed chromosome-wide significant linkage on ECA2 for fillies and chromosome-wide significant linkage on ECA15 for colts. For Arabian colts, the quantitative trait locus (QTL) on ECA15 was genome-wide significant. Haplotypes including two to four microsatellites within the QTL on ECA2 and 15 in fillies and colts, respectively, were significantly associated with GPT for both breeds. Thus, our analysis indicated sex-specific QTL, a fact which is in agreement with a two- to fourfold higher incidence of GPT in females. This is the first report of QTL for equine GPT and a first step towards identifying genes responsible for GPT.

Molecular pathways and genetic factors in the pathogenesis of laryngopharyngeal reflux.

The prevalence of laryngopharyngeal reflux (LPR) has been constantly rising in the western world and affects today an alarmingly high percentage of the general population. Even though LPR and gastroesophageal reflux disease (GERD) are both the product of gastroesophageal reflux and seem to be sibling disorders, they constitute largely different pathological entities. While GERD has been for a long time identified as a source of esophageal disease, LPR has only recently been associated with head and neck disorders. Despite the high incidence of LPR and its great impact on patients' quality of life, little is known regarding its pathogenesis. On the other hand, studying the molecular and genetic basis of a disease is of fundamental importance in medicine as it offers better insight into the pathogenesis and opens new, disease-specific therapeutic trends. The aim of this study is to enlighten any known or suspected molecular mechanisms that contribute to the pathogenesis of LPR, and to suggest new trends for future research.

Prominent oromandibular dystonia and pharyngeal telangiectasia in atypical ataxia telangiectasia.

Ataxia telangiectasia (A-T) typically presents with early-onset progressive cerebellar ataxia, oculomotor apraxia and later, oculo-cutaneous telangiectasia. Extrapyramidal symptoms, apart from chorea, are rare. In this paper, we report a case of A-T with an atypically mild and slowly progressive disease course. Although by history there was mild gait clumsiness in early childhood, the leading problem was that of dystonia with onset at age 15, in the absence of gross gait imbalance or ocular motor apraxia. Dystonia was generalized and with prominent oromandibular involvement. Unusually, a leash of telangiectasia was present on the posterior pharyngeal wall, while other features frequently associated with A-T were absent.

[Intraductal breast papillomas in patients with Costello syndrome]. / Papilomas intraductales de mama en paciente afectada de síndrome de Costello.

Costello syndrome is a multisystemic congenital disorder with a very low prevalence. The pathogenesis remains unclear and predisposes to the development of tumors of ectodermal origin. Diagnosis is clinical, based on findings of mental and growth retardation and a characteristic phenotype. We report the case of a patient with Costello syndrome who was referred to our unit with a suspected diagnosis of intraductal papilloma based on the presence of various episodes of nipple discharge. Postoperative histopathological study confirmed the diagnosis of multiple intraductal papilloma. We review the literature on the topic and discuss the advisability of aggressive surgical therapy, given the predisposition of these patients to develop both benign and malignant tumors.

[Population genetic analysis of the heritability of gutteral pouch tympany in Arabian purebred foals]. / Populationsgenetische Untersuchung zur Erblichkeit der Luftsacktympanie beim Arabischen Vollblutfohlen.

The objective of the present study was to analyse the importance of the influences of the sex, inbreeding coefficient and the additive genetic contribution to the occurrence of guttural pouch tympany in Arabian foals. Horses affected by guttural pouch tympany were ascertained in the Clinic for Horses, School of Veterinary Medicine Hannover. The data comprised 27 Arabian purebred foals with guttural pouch tympany. Of these 27 animals 22 were patients of the Clinic for Horses between 1994 and 2001 and 5 Arabian foals were sampled on the studs. Information on the pedigrees of these patients allowed us to sort in the affected foals into four families with a total of 276 animals. Female foals were more often affected by guttural pouch tympany. The difference was 11.9% in favour of female foals. The size of the inbreeding coefficient was not important for the occurrence of guttural pouch tympany. The heritability estimate for the frequency of guttural pouch tympany using a threshold model was 0.49 +/- 0.28. This is the first report that could show a genetic component responsible for guttural pouch tympany in foals.

[Gutteral pouch tympany in German warmblood foals: influence of sex, inbreeding and blood proportions of founding breeds as well as estimation of heritability]. / Luftsacktympanie bei Deutschen Warmblutfohlen: Einflüsse von Geschlecht, Inzucht und Blutanteilen der Gründerrassen sowie Schätzung der Heritabilität.

The objective of the present study was to analyse the importance of the influences of sex, inbreeding coefficient, proportion of genes of the original breeds and the additive genetic contribution to the occurrence of guttural pouch tympany in foals belonging to German Warmblood breeds. Foals affected by guttural pouch tympany were ascertained in the Clinic of Horses, School of Veterinary Medicine Hannover. This data set comprised 22 German Warmblood foals with guttural pouch tympany, which were patients of the Clinic for Horses between 1994 and 2001. Information on the pedigrees and all available relatives of these patients allowed us to group the affected foals into five families with a total of 289 animals. Female foals were significantly more often affected by guttural pouch tympany. The difference was 16.6% in favour of female foals. The size of the inbreeding coefficient was not important for the occurrence of guttural pouch tympany. The proportion of the genes of the breeds Arabian, Thoroughbred and Trakehner were not significantly different from a randomly selected sample of 10% of foals born in the same birth years and the same region. The heritability estimates for the frequency of guttural pouch tympany using a threshold model was 0.81 +/- 0.16. This is the first report that could show a genetic component responsible for guttural pouch tympany in horses.