The Association between Aminoglycoside Exposure and Ototoxicity in Children with Cystic Fibrosis.

INTRODUCTION: Pulmonary exacerbations increase the requirement of aminoglycoside (AG) antibiotics in people with cystic fibrosis (pwCF). Several studies have shown that AGs have a cumulative effect on ototoxicity. We aimed to investigate the relationship between AG exposure and ototoxicity by using 3 different methods in patients with CF. MATERIALS/METHODS: The multicenter study included 121 pwCF aged between 5 and 18 years with a history of parenteral AG exposure. Standard pure-tone audiometry, extended high-frequency pure-tone audiometry (EHF-PTA), and distortion-product otoacoustic emissions (DPOAE) tests were performed. Mitochondrial mutation analysis for m1555G>A was performed in 61 patients. RESULTS: Median age was 12.85 years and 52.1% (n = 63) were male. 18.2% (n = 22) of the patients had received parenteral AGs more than 5 courses/lifetime. Ototoxicity was detected in at least one of the tests in 56.2% (n = 68) of the patients. Only 10.7% (n = 13) of the patients had reported a symptom indicating ototoxicity. 30.3% (n = 30) of the patients had ototoxicity in the low exposure group, while it was 45.5% (n = 10) in the high exposure group according to EHF-PTA (p > 0.05). Median number of parenteral amikacin courses was significantly higher in the ototoxic group (2 [1.25-5.75] vs. 2 [1-3]; p = 0.045). No m1555A>G mutation was detected in 61 patients who screened for mitochondrial mutation analysis. CONCLUSION: As AG ototoxicity occurs primarily at high frequencies, EHF-PTA is important in early detecting ototoxicity. EHF-PTA and DPOAE detected ototoxicity in some patients with normal PTA results. All pwCF with a history of AG exposure should be evaluated for hearing loss since symptoms may only be noticed in the late period.

Clinical and genetic characterization of children with cubilin variants.

BACKGROUND: Cubilin is one of the receptor proteins responsible for reabsorption of albumin in proximal tubules and is encoded by the CUBN gene. We aimed to evaluate clinical and genetic characterization of six patients with proteinuria who had CUBN mutations. METHODS: Patients' characteristics, serum creatinine, albumin, vitamin B12 levels, urine analysis, spot urine protein/creatinine, microalbumin/creatinine, beta-2 microglobulin/creatinine ratios, estimated glomerular filtration rates (eGFR), treatments, kidney biopsies, and genetic analyses were evaluated. RESULTS: Six patients (2 female, 4 male) with an incidental finding of proteinuria were evaluated. Mean admission age and follow-up time were 7.3 ± 2.9 and 6.5 ± 5.6 years, respectively. Serum albumin, creatinine, and eGFR were normal; urine analysis revealed no hematuria, and C3, C4, ANA, and anti-DNA were negative; kidney ultrasonography was normal for all patients. Urine protein/creatinine was 0.9 ± 0.3 mg/mg, and microalbumin was high in all patients. Serum vitamin B12 was low in two patients and normal in four. Kidney biopsy was performed in four patients, three demonstrated normal light microscopy, and there was one focal segmental glomerulosclerosis (FSGS). Genetic tests revealed four homozygous and two compound heterozygous mutations in the C-terminal part of cubilin. All patients had normal eGFR and still had non-nephrotic range proteinuria at last visit. CONCLUSIONS: CUBN gene mutations should be considered in patients with isolated non-nephrotic range proteinuria and normal kidney function. Diagnosing these patients, who are thought to have a better prognosis, is important in terms of avoiding unnecessary treatment and predicting prognosis. CUBN gene mutations may also present as FSGS which extends the spectrum of renal manifestation of these patients. A higher resolution version of the Graphical abstract is available as Supplementary information.

Analysis of ACE2 and TMPRSS2 coding variants as a risk factor for SARS-CoV-2 from 946 whole-exome sequencing data in the Turkish population.

Heterogeneity in symptoms associated with COVID-19 in infected patients remains unclear. ACE2 and TMPRSS2 gene variants are considered possible risk factors for COVID-19. In this study, a retrospective comparative genome analysis of the ACE2 and TMPRSS2 variants from 946 whole-exome sequencing data was conducted. Allele frequencies of all variants were calculated and filtered to remove variants with allele frequencies lower than 0.003 and to prioritize functional coding variants. The majority of detected variants were intronic, only two ACE2 and three TMPRSS2 nonsynonymous variants were detected in the analyzed cohort. The main ACE2 variants that putatively have a protective or susceptibility effect on SARS-CoV-2 have not yet been determined in the Turkish population. The Turkish genetic makeup likely lacks any ACE2 variant that increases susceptibility to SARS-CoV-2 infection. TMPRSS2 rs75603675 and rs12329760 variants that were previously defined as common variants that have different allele frequencies among populations and may have a role in SARS-CoV-2 attachment to host cells were determined in the population. Overall, these data will contribute to the formation of a national variation database and may also contribute to further studies of ACE2 and TMPRSS2 in the Turkish population and differences in SARS-CoV-2 infection among other populations.

Effects of vitamin D receptor gene polymorphisms on the prognosis of COVID-19.

PURPOSE: Vitamin D deficiency has emerged as another potential risk factor for coronavirus disease (COVID-19) due to the immunomodulatory effects of 25 hydroxyvitamin D [25 (OH)D]. Vitamin D receptor (VDR) gene polymorphisms such as Fok I, Bsm I, Apa I, and Taq I are also associated with different courses of viral infections. This study aimed to evaluate the association between the VDR gene polymorphism at Fok I, Taq I, Bsm I, and Apa I genotypes and the prognosis of COVID-19 in respect to vitamin D deficiency. METHODS: Two-hundred ninety-seven patients with COVID-19 were enrolled. Serum 25 (OH)D levels were measured. Four variant regions of the VDR gene, FokI, BsmI, ApaI, and TaqI were determined. RESULTS: Eighty-three percent of subjects had vitamin D deficiency, and 40.7% of the whole group had severe deficiency. Median 25 (OH)D level was 11.97 ng/ml. Vitamin D levels were not related to inflammatory markers, disease severity, admission to intensive care unit (ICU), and mortality. While disease severity was related to Fok I Ff genotype, it was Taq TT genotype for ICU admission. Moreover, the ApaI aa genotype was common among the patients who were died. None of the deceased subjects had the Fok I FF genotype. CONCLUSION: 25 (OH)D levels were not related to the severity and mortality of COVID-19. VDR gene polymorphisms are independently associated with the severity of COVID-19 and the survival of patients.

Whole-exome sequencing reveals new potential genes and variants in patients with premature ovarian insufficiency.

PURPOSE: Premature ovarian insufficiency (POI) is a heterogeneous disorder characterized by the cessation of menstrual cycles before the age of 40 years due to the depletion or dysfunction of the ovarian follicles. POI is a highly heterogeneous disease in terms of etiology. The aim of this study is to reveal the genetic etiology in POI patients. METHODS: A total of 35 patients (mean age: 27.2 years) from 28 different families diagnosed with POI were included in the study. Karyotype, FMR1 premutation analysis, single nucleotide polymorphism (SNP) array, and whole-exome sequencing (WES) were conducted to determine the genetic etiology of patients. RESULTS: A total of 35 patients with POI were first evaluated by karyotype analysis, and chromosomal anomaly was detected in three (8.5%) and FMR1 premutation was detected in six patients (17%) from two different families. A total of 29 patients without FMR1 premutation were included in the SNP array analysis, and one patient had a 337-kb deletion in the chromosome 6q26 region including PARK2 gene, which was thought to be associated with POI. Twenty-nine cases included in SNP array analysis were evaluated simultaneously with WES analysis, and genetic variant was detected in 55.1% (16/29). CONCLUSION: In the present study, rare novel variants were identified in genes known to be associated with POI, which contribute to the mutation spectrum. The effects of detected novel genes and variations on different pathways such as gonadal development, meiosis and DNA repair, or metabolism need to be investigated by experimental studies. Molecular etiology allows accurate genetic counseling to the patient and family as well as fertility planning.

Secondary findings in 622 Turkish clinical exome sequencing data.

CES (Clinical Exome Sequencing) is a method that we use to diagnose rare diseases with nonspesific clinical features. Besides primary indication for testing genetic information may be detected about diseases which have not yet emerged. ACMG guidelines recommend to report pathogenic variations in medically actionable 59 genes. In this study we evaluated CES data of 622 cases which were tested for various indications. According to ACMG recommendations 59 genes were screened for reportable variations. The detected variations were reviewed using distinct databases and ACMG variation classification guidelines. Among 622 cases 13 (2.1%) had reportable variations including oncogenetic, cardiogenetic disorders, and malignant hyperthermia susceptibility-related genes. In 15 cases (2.4%) heterozygous pathogenic and likely pathogenic variations were detected in genes showing autosomal recessive inheritance. Ten novel variations causing truncated protein or splicing defect were reported. We detected 11 variations having conflicting interpretations in databases and 30 novel variations, predicted as likely pathogenic via insilico analysis tools which further evaluations are needed. As to our knowledge this is the first study investigating secondary findings in Turkish population. To extract the information that may lead to prevent severe morbidities and mortalities from big data is a valuable and lifesaving effort. Results of this study will contrbute to existing knowledge about secondary findings in exome sequencing and will be a pioneer for studies in Turkish population.

Does Genotype-Phenotype Correlation Exist in Vitamin D-Dependent Rickets Type IA: Report of 13 New Cases and Review of the Literature.

Vitamin D-dependent rickets type IA (VDDR-IA) is caused by biallelic mutations in CYP27B1. Data regarding genotype-phenotype correlation in VDDR-IA are scarce. Here, we aimed to investigate clinical/genotypic features and long-term follow-up of 13 new cases with VDDR-IA and genotype-phenotype correlation of reported cases in the literature. Thirteen patients with VDDR-IA were evaluated. Eight patients had reached their final height at the time of the study and, for whom, long-term outcome data were analyzed. Further, all VDDR-IA patients in the literature (n:183) were analyzed and clinical-genetic features were recorded. The median age of diagnosis was 2.55 ± 1.13 (1.0-12) years. Initial diagnoses before referral to our clinic were nutritional rickets (n:7), hypophosphatemic rickets (n:2), and pseudohypoparathyroidism (n:1). All had biochemical evidence suggestive of VDDR-IA; except one with elevated 1,25(OH)2D3 and another with hyperphosphatemia, in whom pseudohypoparathyroidism was excluded with molecular tests. Combined analyses of our cohort and other series in the literature demonstrated that three most common CYP27B1 mutations are p.F443Pfs*24, c.195 + 2T > G, and p.V88Wfs*71. In Turkish population, p.K192E mutation along with the former two is the most common mutations. Comparison of clinical features demonstrated that c.195 + 2T > G mutation causes the most severe and p.K192E mutation causes the least severe phenotype with respect to age and height at presentation and calcitriol requirement. We found a clear genotype-phenotype correlation in VDDR-IA, notably CYP27B1 intronic c.195 + 2T > G mutation causes a more severe phenotype with lower height SDS at presentation and, higher calcitriol requirement, while less severe phenotype occurs in p.K192E mutation.

A Rare Cause of Hypophosphatemia: Raine Syndrome Changing Clinical Features with Age.

Raine Syndrome (RS) is caused by biallelic loss-of-function mutations in FAM20C gene and characterized by hypophosphatemia, typical facial and skeletal features. Subperiosteal bone formation and generalized osteosclerosis are the most common radiological findings. Here we present a new case with RS. A 9-month-old male patient on a home-type ventilator was referred for hypophosphatemia. He was born with a weight of 3800 g to non-consanguineous parents. Prenatal ultrasound had demonstrated nasal bone agenesis. A large anterior fontanel, frontal bossing, exophthalmos, hypoplastic nose, high arched palate, low set ears, triangular mouth, and corneal opacification were detected on physical examination. Serial skeletal X-rays revealed diffuse osteosclerosis at birth which was gradually decreased by the age of 5 months with subperiosteal undermineralized bone formation and medullary space of long bone could be distinguishable with bone-within-a-bone appearance. At 9 months of age, hand X-ray revealed cupping of the ulna with loose radial bone margin with minimal fraying and osteopenia. Cranial computed tomography scan showed bilateral periventricular calcification and hydrocephalus in progress. The clinical, laboratory, and radiological examinations were consistent with RS. Molecular analyses revealed a compound heterozygous mutation in FAM20C gene (a known pathogenic mutation, c.1645C > T, p.Arg549Trp; and a novel c.863 + 5 G > C variant). The patient died due to respiratory failure at 17 months of age. This case allowed us to demonstrate natural progression of skeletal features in RS. Furthermore, we have described a novel FAM20C variant causing RS. Previous literature on RS is also reviewed.

Fibrodysplasia ossificans progressiva: lessons learned from a rare disease.

PURPOSE OF REVIEW: Fibrodysplasia ossificans progressiva (FOP) is an extremely rare and severely disabling autosomal dominant disease that is yet to be clearly understood. The purpose of this review is to present recent literature on pathophysiology, clinical features, diagnosis and treatment of FOP. RECENT FINDINGS: FOP is characterized by congenital great toe deformity and progressive heterotopic ossifications in connective tissue. Heterotopic ossifications occur after painful flare-ups that can arise spontaneously or can be triggered by minor trauma. Each flare-up ultimately causes restriction of related-joint, and along with the others eventually leads to immobility. Death is usually caused by pulmonary complications because of chest wall involvement. The causative gene of FOP is activin A receptor type 1 (ACVR1), a bone morphogenetic protein-signalling component, which normally acts to inhibit osteoblastogenesis. The treatment of FOP is still preventive and supportive. SUMMARY: Although there are still gaps in the underlying mechanism of FOP, effective treatment options, such as potential pharmacologic targets and cell-based therapies are promising for the future. Some of these were tested without a clinical trial setting, and are currently in the process of evidence-based research.

Challenges in the treatment of fibrodysplasia ossificans progressiva.

Fibrodysplasia ossificans progressiva (FOP), is a rare autosomal dominant connective tissue disease with a prevalence of 1 in 2 million. It is characterized by congenital foot deformities and multiple heterotopic ossifications in fibrous tissue. It usually starts with painful soft tissue swellings occurring with attacks at the ages of three or four. The attacks develop spontaneously or after minor trauma, and gradually turn into heterotopic ossifications that cause joint limitations, growth defects, skeletal deformities and chronic pain. The average life expectancy is forthy, and most of the patients are lost due to pulmonary complications. FOP is often misdiagnosed as fibromatosis, desmoid tumour or cancer, bunion, myositis, arthritis and rheumatic diseases. After clinical suspicion, confirmatory genetic analysis should be used for the diagnosis. The treatment of FOP is currently supportive. An effective, proven method has not yet been established. Herein, we present an 18-year-old female patient with FOP who underwent different treatment modalities in a 5-year period. This case-based review reveals all available treatment approaches with at least 6-month follow-up for FOP in the literature.

Association between occurrence of ossicular chain defect and osteoprotegerin gene expression in patients with chronic otitis media.

OBJECTIVE: Chronic otitis media (COM) is an important debilitating public problem causing hearing loss due to irreversible resorption of the ossicular chain. Activation of osteoprotegerin (OPG) during an acute attack of COM prevents bone resorption.The aim of the study was to investigate the role of OPG gene expression level on ossicular chain resorption in chronic otitis media. MATERIALS AND METHODS: Fifty operated COM patients were included in the study. While 20 patients underwent ossiculoplasty, 30 patients underwent type 1 tympanoplasty. For RNA isolation and OPG gene expression analysis, middle ear swabs were taken from nasopharynx in the ostium of the Eustachian tube. RNA was isolated with mRNA easy kit and kept at - 85 °C till the cDNA and expression analysis. Expression levels were analyzed with real-time quantitative PCR in comparison with PDGB gene expression level as an internal control. RESULTS: Sample Cq measurements of type 1 tympanoplasty group were higher than Cq measurements of the internal control group (p = 0.027; p < 0.05). In contrast, there was no statistically significant difference between sample Cq measurements of ossiculoplasty group and Cq measurements of the internal control group (p = 0.293; p > 0.05). CONCLUSION: Since OPG gene expression level was significantly higher in type 1 tympanoplasty group, OPG gene regulation system may have an effect on ossicular chain destruction in COM.

Expanding the Clinical Features of Schimke Immuno-Osseous Dysplasia: A New Patient with a Novel Variant and Novel Clinical Findings.

Schimke Immuno-Osseous Dysplasia (SIOD) (MIM:242900) is an ultra-rare autosomal recessive pan-ethnic pleiotropic disease. Typical findings of this syndrome are steroid-resistant nephrotic syndrome, cellular immunodeficiency and spondyloepiphyseal dysplasia and facial dysmorphism. Biallelic variants in the SMARCAL1 gene cause SIOD. The five-and-half-year-old female patient was evaluated because of short stature, dysmorphism, hypercalcemia, hypophosphatemia and elevated FSH levels. Karyotype analysis and array-CGH testing were normal. Clinical Exome Sequencing was performed via next-generation sequencing to analyze genes associated with hypophosphatemia. No pathogenic variant was detected. The subsequent detection of proteinuria during her follow-up for cross-fused ectopic left kidney ultimately facilitated the diagnosis of SIOD, although no obvious spondyloepiphyseal dysplasia was detected. Re-analysis of CES revealed a novel homozygous c.2422_2427+9delinsA pathogenic variant in the SMARCAL1. One hundred twenty-five SIOD cases from 38 literature reporting SMARCAL1 gene pathogenic variants were reviewed to investigate whether hypercalcemia, hypophosphatemia and elevated FSH levels had been previously reported in SIOD patients. This review revealed that this was the first time these findings had been reported in a SIOD patient. This report expands not only the phenotypic but also genotypic spectrum of SIOD.

Exploring Turkey's mosaic of novel variants and complex alleles in cystic fibrosis genetics.

BACKGROUNDS: Genetic variants in CF transmembrane conductance regulator (CFTR) gene causes cystic fibrosis (CF), a prevalent autosomal recessive disorder. More than 2000 variants in CFTR have been described as disease causative. This study aims to delineate the genotypic and phenotypic landscape of CF among people with CF (pwCF) followed at the largest CF center in Turkey. METHODS: We conducted a descriptive and retrospective analysis of 481 patients registered with the European CF Society Patient Registry and followed at Marmara University Selim Çöremen CF Center from 2015 onwards. Comprehensive CFTR analysis was utilized for genetic diagnosis. Besides the whole cohort, novel variants and complex alleles were also described. RESULTS: Our cohort exhibited a broad spectrum of CFTR variants, with 136 different variants detected, indicating substantial genetic diversity. The F508del variant was less prevalent in our cohort compared to US and European averages, which could reflect unique genetic and demographic characteristics of the Turkish population. Additionally, we identified nine novel variants in 12 alleles, which enhances the understanding of CF's genetic complexity in this region, and complex alleles in 32 pwCF. CONCLUSION: Our research underscores the heterogeneity of CFTR variants in Turkey and highlights the necessity for extensive genetic profiling particularly for diverse populations to provide effective personalized treatment strategies. It is crucial to understand the full spectrum of CFTR variants with the advent of CFTR modulators.

Beyond the 10%: Unraveling the genetic diversity in Turkish cystic fibrosis patients not eligible for CFTR modulators.

BACKGROUND: Cystic fibrosis (CF) is an autosomal recessive disease caused by variants of CFTR gene. Over 2000 variants have been identified, and new drugs called CFTR modulators have been developed to target specific defects in the CFTR protein. However, these drugs are only suitable for patients with certain variants of CFTR, and eligibility rates vary depending on race and geographical region. This study aimed to reveal the detailed genotype and clinical characteristics of people with CF (pwCF) at our center in Turkey, a developing country, who are not eligible for CFTR modulators. METHODS: A total of 445 pwCF followed up at Marmara University were reviewed retrospectively. Variants of the patients ineligible to CFTR modulators were classified based on American College of Medical Genetics guidelines, CFTR classification, the change in the encoded protein, and the variant type. RESULTS: The study revealed that 139 (31.2%) patients weren't eligible for CFTR modulators. There were 60 different variants in the 276 alleles, as two were missing. The majority of patients had missense or nonsense variants, and that the most common variant was c.1545_1546del, which can be said unique to this geography. CONCLUSION: The study highlights the importance of detecting the variants of ineligible patients in detail to guide future approaches for more targeted and effective interventions in CF care. Testing the effectiveness of CFTR modulators for rare or newly occurring variants is crucial to ensure equal access for pwCF to these therapies from different racial backgrounds and ethnic minorities.

Association of COL1A1 polymorphism in Turkish patients with otosclerosis.

OBJECTIVE: To evaluate the role of COL1A1 gene polymorphism in the etiology of otosclerosis. MATERIAL AND METHODS: Peripheric blood samples are obtained from 28 patients diagnosed with otosclerosis and 50 control subjects. DNA's of all samples are isolated and amplified by using the PCR technique. The products are restricted by appropriate enzymes and the allele distributions were compared. RESULTS: SS (homozygous normal), Ss (heterozygous mutant) and ss (homozygous mutant) alleles of the otosclerotic and control subjects were significantly different from each other. CONCLUSION: Otosclerosis is a disease with progressive hearing loss. There are viral, hormonal, immunologic and genetic hypothesis of etiology. In this study, we concluded that the polymorphism seen in the COL1A1 gene resulting in production of excessive type 1 collagen, could play a role in the pathogenesis of otosclerosis.

Angiotensin-Converting Enzyme (ACE) level, but not ACE gene polymorphism, is associated with prognosis of COVID-19 infection: Implications for diabetes and hypertension.

BACKGROUND: The renin-angiotensin-aldosterone system was shown to be activated in severe COVID-19 infection. We aimed to investigate the relationship between angiotensin converting enzyme (ACE) levels, ACE gene polymorphism, type 2 diabetes (T2DM), and hypertension (HT) and the prognosis of COVID-19 infection. METHODS: This cross-sectional study analyzed the clinical features of adult patients with SARS-CoV-2 infection. ACE gene analysis and ACE level measurements were performed. The patients were grouped according to ACE gene polymorphism (DD, ID or II), disease severity (mild, moderate, or severe), and the use of dipeptidyl peptidase-4 enzyme inhibitor (DPP4i), ACE-inhibitor (ACEi) or angiotensin receptor blocker (ARB). Intensive care unit (ICU) admissions and mortality were also recorded. RESULTS: A total of 266 patients were enrolled. Gene analysis detected DD polymorphism in the ACE 1 gene in 32.7% (n = 87), ID in 51.5% (n = 137), and II in 15.8% (n = 42) of the patients. ACE gene polymorphisms were not associated with disease severity, ICU admission, or mortality. ACE levels were higher in patients who died (p = 0.004) or were admitted to the ICU (p<0.001) and in those with severe disease compared to cases with mild (p = 0.023) or moderate (p<0.001) disease. HT, T2DM, and ACEi/ARB or DPP4i use were not associated with mortality or ICU admission. ACE levels were similar in patients with or without HT (p = 0.374) and with HT using or not using ACEi/ARB (p = 0.999). They were also similar in patients with and without T2DM (p = 0.062) and in those with and without DPP4i treatment (p = 0.427). ACE level was a weak predictor of mortality but an important predictor of ICU admission. It predicted ICU admission in total (cutoff value >37.092 ng/mL, AUC: 0.775, p<0.001). CONCLUSION: Our findings suggest that higher ACE levels, but not ACE gene polymorphism, ACEi/ARB or DPP4i use, were associated with the prognosis of COVID-19 infection. The presence of HT and T2DM and ACEi/ARB or DPP4i use were not associated with mortality or ICU admission.

First Patient Diagnosed as Feingold Syndrome Type 2 with Alport Syndrome and Review of the Current Literature.

Introduction: Feingold syndrome type 2 (FGLDS2) is an ultra-rare genetic disorder characterized by short stature, microcephaly, digital abnormalities, and intellectual disability. Until now, 22 patients have been reported in the literature. FGLDS2 is caused by a germline heterozygous deletion of 13q resulting in haploinsufficiency of the MIR17HG gene. Case report: In the present study, we evaluated clinical, radiological, and genetic analyses of a 10-year-old Turkish-origin girl with short stature, brachydactyly, intellectual disability, hematuria, and proteinuria. Conclusion/Discussion: In the array-CGH analysis, a 15.7-Mb deletion, arr[hg19] 13q22q31.3(78,241,132_93,967,288)×1, was detected, and this alteration was evaluated to be pathogenic. The deletion of this region covering the MIR17HG gene is a potential cause of FGLDS2. Also, at her clinical exome sequencing study, a heterozygous c.2023G>A p.(Gly675Ser) variation was detected in the COL4A5 gene (NM_000495.4) that was likely pathogenic in up-to-date databases. As a result, we report on a patient who has FGLDS2 and Alport syndrome. This is the first report of a Turkish-origin FGLDS2 patient. Reporting new cases expands the range of phenotypes, plays a crucial role in understanding the FGLDS2 pathogenesis, and is important in terms of screening at-risk family members for giving appropriate genetic counseling and preimplantation genetic diagnosis opportunities.

A New Biomarker on Bone Resorption in Chronic Otitis Media: Osteoprotegerin and NLRP3 Inflammasome Gene Polymorphisms.

Chronic Otitis Media (COM) is a chronic inflammation of the middle ear and mastoid with persistent membrane perforation and hearing loss. Osteoprotegerin (OPG) and NOD like receptor protein 3 (NLRP3) play an important role in bone metabolism. The aim of the study was to investigate the role of OPG and NLRP3 gene polymorphism on ossicular chain resorption in COM. Fourty COM patients and 20 healhty control group were included in the study. While 20 patients underwent ossiculoplasty, 20 patients underwent type 1 tympanoplasty. DNA was isolated from peripheral blood using the DNA kit. OPG gene c.226A > C (p.Thr76Pro) and NLRP3 gene c.592G > A (p. Val198Met) polymorphisms were genotyped using melting curve analysis technique. NLRP3 gene polymorphism were determined in 6 of 20 patients (30%) in ossiculoplasty group, 4 of 20 patients (20%) in type 1 tympanoplasty group and 3 of 20 patients (15%) in control group. OPG gene polymorphism were determined in 5 of 20 patients (25%) in ossiculoplasty group, 3 of 20 patients (15%) in type 1 tympanoplasty group and 1 of 20 patients (5%) in control group, respectively. There was no statistically significant difference between groups regarding to results. Although the difference was not significant NLRP3 and OPG gene polymorphisms were higher in the ossiculoplasty group. Since NLRP3 and OPG gene polymorphisms were determined to be higher numerically in the ossiculoplasty group, OPG and NLRP3 gene regulation system may have an effect on ossicular chain destruction in COM.

Intraoperative Tissue-Immunosuppressive Therapy Reduces Rejection Episodes in Heart Transplant Recipients.

OBJECTIVES: Our study was conducted to determine the effects of intraoperative antithymocyte globulin administration on donor hearts procured after cardiocirculatory death. We evaluated the impact of antithymocyte globulin on graft function and related parameters during isothermic blood cardioplegia. MATERIALS AND METHODS: In this prospective and randomized single center study, 30 patients with orthotropic heart transplant were divided into 2 groups: group 1 included 15 patients who received retrograde antithymocyte globulin infusion via coronary sinus intraoperatively and immediately after organ procurement and group 2 included 15 patients who received traditional antithymocyte globulin infusion after implantation. RESULTS: Study patients had a mean age of 33.8 years (range, 15-56 y). All patients had panel reactive antibody less than 10% except for 3 patients. The cluster of differentiation 3-positive cell count decrease was more than 20%. The inotropic therapy dose required and the myocardial pressure (stiffness) were less for group 1 patients. These patients had less acute rejection episodes than group 2 (0% vs 13.3%; P < .05). CONCLUSIONS: Favorable clinical outcomes were observed in terms of less acute rejection episodes and better graft function at least during the early posttransplant period. Intraoperative antithymocyte globulin treatment may have a preventive effect for acute cellular rejection in heart transplant patients.

Molecular Aspects of Distal Kidney Tubular Acidosis in Children, Its Long-Term Outcome, and Relationship with Hyperammonemia.

OBJECTIVE: We aimed to present the characteristics, genetic analysis results, long-term progno- sis of our patients with distal kidney tubular acidosis, and the relationship between hyperam- monemia and distal kidney tubular acidosis. MATERIALS AND METHODS: Biochemical, clinical, and imaging findings were collected at presen- tation and the last clinic visit, and results of the genetic analysis were recorded. RESULTS: Our study included 9 patients (3 female, 33%). The median age at diagnosis was 3 months, and the median follow-up period was 111 months. Height standard deviation scores were less than -2 in 4 (44%) patients at presentation and in 3 (33%) at the last clinic visit. The median estimated glomerular filtration rate was 98 mL/min/1.73 m2 at presentation and 126 mL/min/1.73 m2 at the last clinic visit. We have found 8 different types of mutations of 2 genes, including 6 in the ATP6V0A4 gene, 2 in the SLCA4A1 gene, and 2 of them were novel. At the time of presentation, nephrocalcinosis and hypercalciuria were present in all our patients, but at the last visit, only 1 patient had hypercalciuria. Sensorineural hearing loss was found in 4 of our patients with a mutation in the ATP6V0A4 gene. Serum ammonia levels were found to be high in 3 patients with mutations in the ATP6V0A4 gene. CONCLUSION: Adequate metabolic control is essential for optimal growth and preserved kidney function in distal kidney tubular acidosis patients. Distal kidney tubular acidosis may be associ- ated with hyperammonemia. We recommend keeping potassium levels at high-normal levels to reduce ammonia levels, especially in the absence of acidosis.