Nazım Bozan

Comprehensive analysis via exome sequencing uncovers genetic etiology in autosomal recessive nonsyndromic deafness in a large multiethnic cohort

Purpose:Autosomal recessive nonsyndromic deafness (ARNSD) is characterized by a high degree of genetic heterogeneity, with reported mutations in 58 different genes. This study was designed to detect deafness-causing variants in a multiethnic cohort with ARNSD by using whole-exome sequencing (WES).Methods:After excluding mutations in the most common gene, GJB2, we performed WES in 160 multiplex families with ARNSD from Turkey, Iran, Mexico, Ecuador, and Puerto Rico to screen for mutations in all known ARNSD genes.Results:We detected ARNSD-causing variants in 90 (56%) families, 54% of which had not been previously reported. Identified mutations were located in 31 known ARNSD genes. The most common genes with mutations were MYO15A (13%), MYO7A (11%), SLC26A4 (10%), TMPRSS3 (9%), TMC1 (8%), ILDR1 (6%), and CDH23 (4%). Nine mutations were detected in multiple families with shared haplotypes, suggesting founder effects.Conclusion:We report on a large multiethnic cohort with ARNSD in which comprehensive analysis of all known ARNSD genes identifies causative DNA variants in 56% of the families. In the remaining families, WES allows us to search for causative variants in novel genes, thus improving our ability to explain the underlying etiology in more families.Genet Med 18 4, 364–371.

The possible underlying pathophysiological mechanisms for development of multiple sclerosis in familial Mediterranean fever

Patients with familial Mediterranean fever (FMF) have a susceptibility to the development of multiple sclerosis (MS). Here, we will propose the possible underlying pathophysiological mechanisms of this predisposition. Inflammation, disruption of blood-brain barrier (BBB), mitochondrial energy deficit, demyelination, and axonal damage, which play an important role in the pathogenesis of MS, may occur during the course of FMF. Most FMF patients have homozygous mutations in the MEFV gene that codes for the protein pyrin. Also, pyrin mutations were found about 3.5 times higher in the MS patients than the healthy control group. Pyrin is implicated in the maturation and secretion of the proinflammatory cytokine IL-1β. IL-1β is a major mediator of fever and systemic inflammation, and mononuclear cells from FMF patients release higher levels of IL-1β. Moreover, IL-1 plays a significant role in the regulation of the T-cells, and it is considered an essential cytokine for the Th cell differentiation that implicated in the MS pathogenesis. In addition, endothelial dysfunction and vasculitis in FMF may cause BBB breakdown that is the first step in the development of MS lesions. Apart from this, damage can occur in myelin and mitochondria proteins due to high body temperature that arises during the FMF attacks. Whereas the protein damage in myelin results in demyelination, and the protein damage in mitochondria causes lack of energy. Both situations play a part in the pathogenesis of MS. Due to mitochondrial energy deficit, remyelination may not be achieved, and therefore, axonal damage increases. Thus, at the end of these pathophysiological processes, MS findings may occur in the FMF patients especially with irregular use of colchicine.

Variations in Multiple Syndromic Deafness Genes Mimic Non-syndromic Hearing Loss

The genetics of both syndromic (SHL) and non-syndromic hearing loss (NSHL) is characterized by a high degree of genetic heterogeneity. We analyzed whole exome sequencing data of 102 unrelated probands with apparently NSHL without a causative variant in known NSHL genes. We detected five causative variants in different SHL genes (SOX10, MITF, PTPN11, CHD7, and KMT2D) in five (4.9%) probands. Clinical re-evaluation of these probands shows that some of them have subtle syndromic findings, while none of them meets clinical criteria for the diagnosis of the associated syndrome (Waardenburg (SOX10 and MITF), Kallmann (CHD7 and SOX10), Noonan/LEOPARD (PTPN11), CHARGE (CHD7), or Kabuki (KMT2D). This study demonstrates that individuals who are evaluated for NSHL can have pathogenic variants in SHL genes that are not usually considered for etiologic studies.

Assessment of pulmonary artery pressure and right ventricular function in children with adenotonsillar hypertrophy using different parameters

OBJECTIVE Our aim was comparison of preoperative and postoperative right ventricular functions of children with adenotonsillar hypertrophy (ATH) who have findings of upper airway obstruction, using new echocardiographic parameters. METHODS Forty-one children who have admitted to our hospital with symptoms suggestive of upper airway obstruction, whose history and physical examination findings suggest upper airway obstruction and who have undergone adenoidectomy/adenotonsillectomy and 40 healthy children, all of whom between 2 and 12 years of age, were included in the study. Patient group was evaluated by pulsed wave tissue Doppler echocardiography as well as with conventional echocardiography before the operation and 6 months after the operation. RESULTS Of 41 children in study group, 26 (63.4%) had adenotonsillectomy and 15 (36.6%) had adenoidectomy. Tricuspid annular plane systolic excursion (TAPSE) was significantly lower in preoperative group compared to control group (18.46±1.67, 19.77±1.62; p=0.000, respectively). Myocardial performance index (MPI) was significantly higher in preoperative group than postoperative and control group (0.40±0.07, 0.36±0.06, 0.35±0.07; p=0.032, respectively). Tricuspid isovolumic acceleration (TIVA) was significantly lower in preoperative group than preoperative and control group (2.97±0.8, 3.43±0.7, 3.43±0.9; p=0.020, respectively). Disappearance of this difference was found between postoperative and control groups (p=0.984). Pulmonary acceleration time (PAcT) was found to be significantly lower in preoperative group compared to postoperative and control group (109.68±18.03, 118.93±17.46, 120.0±14.07; p=0.010, respectively). Mean pulmonary artery pressure (mPAP) was significantly higher in preoperative group than control group (29.64±8.11, 24.95±6.33; p=0.010, respectively). In postoperative group mPAP was found to be similar to control group (25.48±7.85, 24.95±6.33; p=0.740, respectively). CONCLUSIONS TAPSE, PAcT, MPI and TIVA are useful markers for evaluation of preoperative and postoperative ventricular function in children with ATH who have findings of upper airway obstruction. We think that using these practical and easy-to perform parameters may be relevant for evaluation and postoperative follow-up of patients with ATH who have findings of upper airway obstruction. Besides adenotonsillectomy is a beneficial treatment option for these patients.

Thiol/disulfide homeostasis as a novel indicator of oxidative stress in obstructive sleep apnea patients.

The aim of the present study was to assess thiol/disulfide (SS) homeostasis as a novel indicator of oxidative stress in patients with obstructive sleep apnea (OSA) and to investigate the effect of continuous positive airway pressure (CPAP) therapy on oxidative parameters.

Effect of inhaled steroids on laryngeal microflora

Abstract Conclusions As is known, this study is the first study to evaluate the effect of inhaled steroids on laryngeal microflora. The data support that ICS usage causes changes in the larynx microflora. Purpose The aim of this study was to determine the alteration in larynx microbial flora of the patients treated with ICS comparing the culture results of a control group. In addition, laryngeal microflora was compared to the smears obtained from the vallecula and pharynx. Materials and methods The study included 39 patients (mean age = 45.56 ± 12.76 years) who had been using a corticosteroid inhaler and control group consisting of 27 persons (mean age = 43.07 ± 13.23 years). Culture samples were obtained from the pharynx, larynx, and vallecula in the patient and control groups, and they were evaluated in the microbiology laboratory. Obtained culture results were named by the same microbiologist according to the basic microorganism classification method. Results Coagulase-negative staphylococci (CNS), Streptococcus viridians (VGS) and candida albicans were detected to grow significantly more in the patient group in all three anatomic localizations compared to the control group. Neisseria spp, basillus spp, and Non-viridans alpha-hemolytic streptococcus were detected to grow significantly more in the control group in all three anatomic localizations compared to the patient group.

Is Nasal Polyposis Related to Levels of Serum Vitamin D and Vitamin D Receptor Gene Expression

Background Nasal polyposis (NP) is the most frequent cause of nasal masses. Despite considerable research on the subject, its etiology has not been fully elucidated, and effective treatment methods have not been developed. Some etiological factors causing low or high expression of genes in genetically predisposed individuals may play a role in the pathogenesis of the disease. The purpose of this study was to assess the relation between levels of vitamin D receptor (VDR) gene expression and serum vitamin D with NP. Material/Methods The study included 46 subjects with NP (NP group) and 40 volunteers (control group). Nasal polyp tissue samples were taken from the NP group and nasal mucosa samples were taken from the control group. Levels of VDR gene expression in the tissue samples were assessed using the real-time polymerase chain reaction (RT-PCR) method. Results Mean serum 25(OH)D levels were 13.38±14.08 ng/ml in the NP group and 10.57±6.44 ng/ml in the control group (p=0.249). VDR gene expression was present in 17.5% of the NP group and 3.3% of the control group, and the difference between the 2 groups was statistically significant (likelihood ratio χ2=3.887; p=0.049). Conclusions This is the first study to assess levels of VDR gene expression in subjects with NP. Our results suggest that VDR gene expression may be associated with the pathogenesis or progression of NP.

Suppurative Cervical Tuberculous Lymphadenitis Mimicking a Metastatic Neck Mass.

Tuberculosis is an important publics health problem in developing countries. Although tuberculosis is commonly found in lungs, it could also be found in lymph nodes, mouth, tonsils, tounge, nose, epiglottis, larynx, and pharynx of head-neck region. The most common form of extrapulmonary tuberculosis placed outside the lungs is tuberculous lymphadenitis. Tuberculosis lymphadenitis is the most commonly seen form of the extrapulmoner tuberculosis and usually invades the lymph nodules of the cervical region. An adult patient with tuberculous lymphadenitis has been presented within the context of the literature reviewed. A 42-year-old woman, who has admitted to our clinic with a fistulized mass in the right side of her neck, has been diagnosed and treatment has been performed. No other problems were found in the systemic examination of the patient. Since there is no specific finding of pulmonary tuberculosis, detailed investigations are required in patients admitted with the sypmtomps of neck mass.

Serum Trace Elements and Heavy Metal Levels in Patients Diagnosed with Chronic Otitis Media and Their Association with Surgical Treatment Outcomes

OBJECTIVE To determine the serum iron (Fe), zinc (Zn), manganese (Mn), copper (Cu), magnesium (Mg), cobalt (Co), and lead (Pb) levels in patients with chronic otitis media (COM) and to evaluate the association of the serum levels of these elements with treatment outcomes. MATERIALS AND METHODS Thirty-one healthy volunteers and 31 patients with COM were prospectively included in this study. Serum levels of Fe, Zn, Mn, Mg, Cu, Co, and Pb were determined by an atomic absorption UNICAM-929 spectrophotometer. RESULTS Serum Co, Pb, and Fe levels were significantly increased (p<0.001) and serum Cu, Zn, Mg, and Mn levels were significantly reduced in patients with COM compared with controls (p<0.001). Serum Co and Mn levels were significantly decreased (p<0.001 and p<0.005, respectively) and serum Cu levels were significantly increased after surgery (p<0.005). The other evaluated blood chemicals and heavy metals did not exhibit significant differences (p>0.05). CONCLUSION Significant alterations in the serum chemical composition of patients with COM were observed. Moreover, with surgical treatment, serum levels of some of these chemicals were significantly altered. Further prospective studies are warranted to elucidate the exact association of these alterations in the etiopathogenesis of COM.

The Relationship Between Hearing Thresholds and Hyperandrogenism in Polycystic Ovary Syndrome.

Background The purpose of our study was to investigate the association between polycystic ovary syndrome (PCOS) and hearing thresholds. Material/Methods Forty women diagnosed with PCOS (mean age, 24.33±6.38 years) and 40 healthy women controls (mean age, 26.38±6.75 years) were included in prospective study. Each case was tested with low (250, 500, 1000, and 2000 Hz), high (4000, 6000, and 8000 Hz) and extended high (EH) (9000–20000 Hz) frequency audiometry. The fasting plasma glucose, insulin, FSH, LH, total testosterone, and sex hormone-binding globulin were measured in all patients. Results The mean hearing thresholds at EH frequencies were statistically significantly higher in the PCOS group than in the control group (p=0.001 right ear and p=0.015 left ear). There were significant positive correlations among free testosterone index (FTI) values and hirsutism scores with EH frequency hearing thresholds. Conclusions At pure-tone audiometry (PTA) EH frequencies, we detected significantly higher hearing thresholds in PCOS patients than in controls. We also determined that elevated FTI and hirsutism score were positively correlated with elevated hearing thresholds in EH frequencies. These findings support that hyperandrogenism can play a role in the elevation of hearing thresholds in PCOS.