Klotho gene G395A and C1818T polymorphisms in acromegaly: Association with clinical presentation and comorbidities.

BACKGROUND: Klotho is a new identified anti-ageing gene with tumour suppressor activities. Current data suggest that there is a tight relationship between Klotho protein and growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis. PURPOSE: This study aimed to investigate the possible association of Klotho gene polymorphisms with acromegaly and to assess whether these polymorphisms contribute to clinical characteristics, comorbidities and biochemical variables in these patients. METHODS: The study included 52 patients with acromegaly and 52 unrelated healthy subjects. The Klotho G395A and C1818T polymorphisms were assessed by Sanger sequencing. Serum levels of sKlotho were determined by ELISA method. RESULTS: Subjects carrying GA genotype of Klotho G395A polymorphism had 3.27 times higher risk of developing acromegaly [odds ratio (OR), 3.27; 95% confidence interval (CI): 1.37-7.81; p = .023]. The A allele of G395A was significantly associated with acromegaly risk (OR, 2.27; 95% CI: 1.1-4.72; p = .022). No association was observed between the studied polymorphisms and disease characteristics including age at acromegaly diagnosis, size of adenoma, baseline GH and IGF-1 concentrations, and final outcome. G395A polymorphism was associated with the presence of malignancy (OR, 2.24, 95% CI: 1.63-3.08; p = .019) and colorectal polyps (OR, 1.99; 95% CI: 1.02-3.88; p = .047) in patients with acromegaly. Serum sKlotho levels were significantly higher and correlated with GH and IGF-1 levels among acromegaly patients. There was no association between the studied polymorphisms and sKlotho levels. CONCLUSIONS: Klotho G395A polymorphism is associated with acromegaly susceptibility and increased risk of malignancy and colorectal polyps in these patients.

A novel mutation of keratin 5 in epidermolysis bullosa simplex with migratory circinate erythema.

Epidermolysis bullosa simplex migratory circinate erythema (EBS-Migr) is an uncommon subtype of EBS. We report a case of EBS-MIGR with a novel heterozygous pathogenic mutation in exon 9 (frameshift deletion c.1650delC) and likely benign heterozygous mutation in exon 2 (missense c.591C > A) of keratin 5. This novel pathogenic mutation in KRT5 expands the molecular spectrum of this rare subtype of EBS.

Clock gene PERIOD3 polymorphism is associated with susceptibility to Graves' disease but not to Hashimoto's thyroiditis.

Circadian disruption has been linked with immune-related morbidities including autoimmune diseases. PERIOD3 (PER3) clock gene is a key player in the mammalian circadian system. This study evaluated the possible association of PER3 rs2797685 (G/A) polymorphism and susceptibility of autoimmune thyroid diseases (AITD) and assessed if this SNP contributes to disease characteristics and serum levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). The PER3 rs2797685 (G/A) polymorphism was assessed in 125 patients with AITD [Graves' disease (GD), 69; Hashimoto's thyroiditis (HT), 56] and 115 unrelated healthy controls. Subjects carrying at least one variant allele of PER3 rs2797685 (GA+AA) had increased risk for GD (OR 1.9, 95% CI 1-3.61, p= .05). There were no differences in the frequencies of genotypes and alleles of the PER3 rs2797685 polymorphism between HT patients and control subjects. No association was observed between genotypes of the studied SNP and any of the disease characteristics in GD and HT patients. The GA+AA genotype of PER3 rs2797685 was associated with lower levels of IL-6 in patients with Graves' disease. There were no differences between genotypes of the studied SNP regarding TNF-α levels in GD, HT or control groups. In conclusion, this study provides the first evidence for a genetic association between GD and the PER3 gene, highlighting the possible relevance of polymorphisms in clock genes in the etiopathogenesis of AITD. However, functional studies to identify the underlying molecular mechanisms of this association are needed to translate these findings to clinical applications.

Clinical and molecular evaluation of 16 patients with Rett syndrome.

Zengin-Akkus P, Taskiran EZ, Kabaçam S, Simsek-Kiper PÖ, Haliloglu G, Boduroglu K, Utine GE. Clinical and molecular evaluation of 16 patients with Rett syndrome. Turk J Pediatr 2018; 60: 1-9. Rett syndrome is a neurodevelopmental disorder caused by mutations in MECP2. The disease is characterized by early neurological regression following a normal initial development. The diagnosis is a clinical one, based on major and minor diagnostic criteria. This study, in a group of patients from a single tertiary center, aimed to evaluate the efficiency of clinical diagnosis and to see if there was a diagnostic delay. A second aim was to investigate genotype-phenotype correlations, based on Pineda scores. In this study, sixteen patients with a median age of 6.5 years (2.5-22 years) were included, following molecular confirmation of clinical diagnosis. The median age at the onset of symptoms and the median age at clinical diagnosis was 1.5 years and 2.5 years, respectively, the difference being statistically significant. Considering the Rett syndrome diagnostic criteria, initially regulated in 2002 and revised in 2010, seven and two patients in our group, respectively, did not meet the main criteria. Pineda scores among mutation groups were statistically not different. To conclude, the present study revealed presence of a diagnostic delay. The challenge may be that the patients do not exhibit full-blown clinical picture initially. No genotype-phenotype correlations were detected in clinical severity, as measured by Pineda scores. Moreover, the diagnostic criteria revised in 2010 are more comprehensive as compared to the 2002 criteria; however, further revision may increase diagnostic sensitivity.

Epigenotype and phenotype correlations in patients with Beckwith-Wiedemann syndrome.

Bilgin B, Kabaçam S, Taskiran E, Simsek-Kiper PÖ, Alanay Y, Boduroglu K, Utine GE. Epigenotype and phenotype correlations in patients with Beckwith-Wiedemann syndrome. Turk J Pediatr 2018; 60: 506-513. Beckwith-Wiedemann Syndrome (BWS) is one of the most common overgrowth syndromes. Cancer predisposition is an important feature of this clinically heterogeneous syndrome. Patients may have fetal and early childhood overgrowth, hemihyperplasia, macroglossia, facial dysmorphic features, abdominal wall defects, visceromegaly, and anomalies of the heart and the kidneys. Various previous investigations showed that heterogeneous molecular etiology may contribute to clinical variability and that epigenotype-phenotype correlations exist in BWS. This study was performed to detect the molecular etiology in 28 patients with BWS, to search for epigenotype-phenotype correlations and to provide appropriate individualized multidisciplinary approach. Four different molecular etiology groups were determined based on testing for copy number analysis and methylation status at 11p15. Sequencing for CDKN1C mutations were also performed. Groups were compared for various clinical findings. Differences between groups were not statistically significant owing to the small number of patients in individual groups. Statistical studies for epigenotype-phenotype correlations showed significance for only anterior ear lobe creases, visceromegaly and embryonal tumors. Additionally, one interesting patient had a mesenchymal tumor. Anticipating follow-up is clinically important in BWS.

A novel missense mutation of the GRK1 gene in Oguchi disease.

Oguchi disease is a rare form of congenital stationary night blindness with an autosomal recessive inheritance pattern. The presence of S­antigen (SAG) and G­protein­dependent receptor kinase 1 (GRK1) mutations were investigated in the family members with Oguchi disease. All exons of the SAG and GRK1 genes were amplified by polymerase chain reaction and sequenced. The patients were shown to have characteristic clinical features of Oguchi disease. Gene analysis determined a novel GRK1 mutation c.923T>C, which caused Oguchi disease in all siblings. This mutation, was demonstrated by amino acid alignment analysis to be in a phylogenetically conserved region and resulted in an amino acid change from leucine to proline at position 308. Thus, the present study reports a novel missense mutation of GRK1 in the affected members of a consanguineous Turkish family. Homozygosity at position 308, which resides in the catalytic domain of the GRK1 gene, is the cause of Oguchi disease in this Turkish family.