Gökay Bozkurt

A Case of Ehlers-Danlos Syndrome Type VIA With a Novel PLOD1 Gene Mutation

BACKGROUND The kyphoscoliotic type of the Ehlers-Danlos syndrome is an autosomal recessive connective tissue disorder characterized by soft extensible skin, laxity of joints, severe muscle hypotonia at birth, and kyphoscoliosis. PATIENT We describe a 3-year-old girl with the kyphoscoliotic type of the Ehlers-Danlos syndrome whose parents were cousins. She was born with breech presentation by vaginal delivery at term after a normal pregnancy. At birth she manifested hypotonia and congenital kyphosis. On the second postnatal day, subdural and intraparenchymal hemorrhages were detected by magnetic resonance imaging. During follow-up at 18 months of age, strabismus, umbilical hernia, kyphoscoliosis, joint laxity, bilateral hip dislocation, muscular hypotonia, and motor developmental delay. RESULTS The cranial magnetic resonance imaging revealed periventricular leukomalacia and abnormal signal related to previous hemorrhage. Metabolic investigations and neuromuscular evaluation were normal, excluding other possible explanations of hypotonia. An analysis of urinary cross-links demonstrated an increase in the lysyl-pyridinoline to hydroxylysyl-pyridinoline ratio, suggesting the diagnosis of kyphoscoliotic type of the Ehlers-Danlos syndrome. Molecular analysis of the PLOD1 gene revealed that she had a novel homozygous p.Pro622Argfs*3 (c. 1863_1864dupCG) mutation in exon 17 that is expected to cause complete loss of the enzyme lysyl hydroxylase 1 and to cause kyphoscoliotic type of the Ehlers-Danlos syndrome. CONCLUSIONS We describe a child with the kyphoscoliotic type of the Ehlers-Danlos syndrome with a novel mutation of the PLOD1 gene. Our observations suggest that vascular lesions in the neonatal period may be a rare additional clinical feature of kyphoscoliotic type of the Ehlers-Danlos syndrome.

Frequency of mutations in Mediterranean fever gene, with gender and genotype-phenotype correlations in a Turkish population

Familial Mediterranean fever (FMF) is the most common hereditary inflammatory periodic disease, characterized by recurrent episodes of fever, abdominal pain, synovitis and pleurisy. The aim of this study was to determine the frequency and distribution of Mediterranean fever (MEFV) gene mutations and to investigate the clinical characteristics and genotype–phenotype correlation in patients with FMF in Aydın, a province in western Anatolia, Turkey. Therefore, we retrospectively analysed MEFVgene mutations in 383 patients with suspected FMF and the clinical features of 327 among them. The MEFV gene mutations were investigated using the reverse dot-blot hybridization technique. We detected 26 different genotypes and 11 different mutations. The most common mutations in our cohort were p.M694V (41.15%), p.E148Q (20.35%), p.M680I(G/C) (12.39%) and p.R761H (9.73%). Abdominal pain (86.2%), fever (80.7%), arthralgia (57.2%), vomiting (36.1%), arthritis (34.6%), fatigue (31.5%), anorexia (22.9%) and chest pain (19.0%) were the most prevalent clinical features in our patients. This is the first study from Aydın in which the distribution of MEFVgene mutations and clinical features were evaluated in patients with FMF. We found that the most common mutation was p.M694V in our region, while the frequency of the p.R761H mutation was higher compared to other regions of Turkey with respect to extracted data from previous similar studies. Presented results supported the clinical findings in the literature that the homozygous p.M694V and compound heterozygous genotype were associated with more severe courses in FMF patients.

Effects of sunitinib and bevacizumab on VEGF and miRNA levels on corneal neovascularization

Abstract Aim: To evaluate the effects of sunitinib (0.5 mg/ml) and bevacizumab (5 mg/ml) on VEGF-A, VEGFR-2 and microRNA (miRNA) levels on corneal neovascularization (CNV). Methods: In this study, CNV was induced by silver nitrate application to the cornea, and 40 Albino male rats were equally divided into four subgroups: Group 1 (sunitinib): After silver nitrate application to the cornea, 0.5 mg/ml sunitinib eyedrop was administered twice daily for two weeks (n = 10). Group 2 (bevacizumab): After silver nitrate application to the cornea, 5 mg/ml bevacizumab eyedrop was administered twice daily for two weeks (n = 10). Group 3 (control): After silver nitrate application to the cornea, normal saline eyedrop was administered twice daily for two weeks (n = 10). Group 4 (vehicle): After silver nitrate application to the cornea, 1% DMSO eyedrop was administered twice daily for two weeks (n = 10). After two weeks from the silver nitrate application, corneas were evaluated by hand-held biomicroscope for their vascularization status. Then, corneas were excised and the expression levels of VEGFR-2, VEGF-A and the common miRNA markers for neovascularization (miR-15 b, miR-16, miR-23a, miR-126, miR-188, miR-210, miR-221, miR-222, miR-410 and miR-423) were evaluated by real-time PCR. Results: It was seen that the CNV was decreased in sunitinib- and bevacizumab-administered groups compared to the control and DMSO groups. Also, in comparison with the control group; VEGF-A expression was downregulated by nearly 0.75 times in sunitinib group and nearly 0.52 times in bevacizumab group. VEGFR-2 expression was downregulated by 0.89 times in sunitinib group and 0.68 times in bevacizumab group, compared to the control group. miR-15 b, miR-16 and miR-126 levels were statistically lower in sunitinib and bevacizumab groups, but miR-188 and miR-410 levels were two-fold higher compared to the control group. The miR-210 level was found higher only in sunitinib group compared to the control group. There were no statistically significant changes in miR-23a, miR-221, miR-222 and miR-423 levels among the groups. Conclusion: Topical application of bevacizumab (5 mg/ml) and sunitinib (0.5 mg/ml) decreases the levels of VEGFR-2 and VEGF-A in CNV. Further studies are needed for detailed analysis of genes which are targeted by up- or downregulated miRNAs in this study.

The effects of topical everolimus and sunitinib on corneal neovascularization

Abstract Purpose: To evaluate the effects of topical everolimus and sunitinib on corneal neovascularization (CNV). Methods: CNV was induced by application of silver nitrate to the cornea for all groups. Rats were divided into four groups of 10 rats each, and two corneas were obtained from each rat. Group I received 1 mg/ml everolimus, Group II received 0.5 mg/ml sunitinib, Group IV received no treatment (control group) and Group IV received 1% Dimethylsulfoxide (DMSO). All treatments were administrated twice daily for 2 weeks. The right corneas were used for extracellular signal-regulated kinase 1/2 (ERK 1/2) protein analysis by western blot analysis and the left corneas were used for ERK 1/2 and vascular endothelial growth factor-receptor (VEGFR-2) gene expression analysis by quantitative real-time PCR. Results: VEGFR-2 mRNA expression levels (ΔCt, median, min-max) were reduced in the everolimus 1.0 (0.25–1.81) and sunitinib 1.06 (0.24–2.68) treated groups compared with the control 4.74 (1.02–14.74) and DMSO groups 7.41 (0.72–13.10). The expression of ERK 1/2 protein and mRNA levels were reduced in everolimus group compared with the control group (p < 0.05). These differences were not seen between the sunitinib and control groups. Conclusıon: Topical administration of both everolimus and sunitinib reduced VEGFR-2 levels and inhibited CNV. In additon, everolimus reduced ERK 1/2 levels and seems to be more effective than sunitinib on CNV.

Microarray analysis of the genes associated with osteitis in chronic rhinosinusitis.

Although numerous studies have examined epithelial remodeling in chronic rhinosinusitis (CRS), bone remodeling (osteitis) has only recently gained attention as a potential significant contributor to the pathophysiology of recalcitrant CRS. The purpose of this study was to compare gene expression profiles between osteitic bone and the adjacent diseased mucosa in patients with CRS to determine which genes affect mucosal and bony remodeling.

Screening Fabry’s disease in chronic kidney disease patients not on dialysis: a multicenter study

Abstract Objectives: Fabrys disease is an X-linked inherited, rare, progressive, lysosomal storage disorder, affecting multiple organs due to the deficient activity of α-galactosidase A (α-Gal A) enzyme. The prevalence has been reported to be 0.15–1% in hemodialysis patients; however, the information on the prevalence in chronic kidney disease not on dialysis is lacking. This study aimed to determine the prevalence of Fabry’s disease in chronic kidney disease. Methods: The patients older than 18 years, enclosing KDIGO 2012 chronic kidney disease definitions, not on dialysis, were enrolled. Dried blood spots on Guthrie papers were used to analyze α-Gal A enzyme and genetic analysis was performed in individuals with enzyme activity ≤1.2 μmol/L/h. Results: A total of 1453 chronic kidney disease patients not on dialysis from seven clinics in Turkey were screened. The mean age of the study population was 59.3 ± 15.9 years. 45.6% of patients were female. The creatinine clearance of 77.3% of patients was below 60 mL/min/1.73 m2, 8.4% had proteinuria, and 2.5% had isolated microscopic hematuria. The mean value of patients’ α-Gal A enzyme was detected as 2.93 ± 1.92 μmol/L/h. 152 patients had low levels of α-Gal A enzyme activity (≤1.2 μmol/L/h). In mutation analysis, A143T and D313Y variants were disclosed in three male patients. The prevalence of Fabry’s disease in chronic kidney disease not on dialysis was found to be 0.2% (0.4% in male, 0.0% in female). Conclusion: Fabry’s disease should be considered in the differential diagnosis of chronic kidney disease with unknown etiology even in the absence of symptoms and signs suggestive of Fabry’s disease.

Adrenal incidentaloma and the Janus Kinase 2 V617F mutation: A case-based review of the literature.

Adrenal incidentaloma was detected in an 81-year-old male patient and a 37-year-old female patient who had been diagnosed with essential thrombocytosis. Each patients Janus Kinase 2 (JAK2) V617F mutation was positive, and they were evaluated as having non-functional adrenal incidentaloma. The JAK2 activates the signal transducers and activators of transcription (STAT) proteins which then activate the phosphoinositol-3 kinases, Ras, mitogen-activated protein (MAP) kinases, and transcription. Constitutive activation causes cell proliferation and dysregulation of apoptosis. It is thought that STAT3 activation-mediated JAK family kinases have a central role in the solid tumor cell series. Permanent activation of STAT3 and STAT5 causes tumor cell proliferation, survival, metastasis, and an increase in tumor-mediated inflammation in solid and hematologic tumors. According to our literature screening, irregular JAK signaling, seen at the pathogenesis of many solid and hematologic tumors, has not been previously evaluated with regard to adrenal tumors. As a result, our cases are the first coexistence of JAK V617F mutation with adrenal incidentaloma in the literature. Because of this, we think that JAK2 mutation must be evaluated to clarify the etiology of adrenal incidentalomas.