Four cases of Chanarin-Dorfman syndrome presenting with different types of erythrokeratoderma.

Chanarin-Dorfman syndrome (CDS) is a multisystem autosomal recessive disorder due to variants of the ABHD5 gene, characterized by lipid vacuoles in the liver and leukocytes, and possible involvement of eyes, ears, skeletal muscle, and central nervous system. CDS may present with skin changes, most commonly congenital non- bullous ichthyosiform erythroderma, however erythrokeratoderma-like findings have been rarely reported in CDS patients. Herein, we report clinical, histopathological and genetic findings of four patients with CDS presenting with different clinical forms of erythrokeratoderma (three with progressive symmetric erythrokeratoderma-like features and one with erythrokeratoderma variabilis (EKV)-like features), including one patient with a novel mutation in ABHD5. Although the typical skin finding of CDS syndrome is reported as non-bullous congenital ichthyosiform erythroderma, CDS should also be in the differential diagnosis in patients with EKV-like lesions.

Prognostic and predictive role of liquid biopsy in lung cancer patients.

Introduction: Lung cancer (LC) is a leading cause of cancer-related mortality worldwide. Approximately 80% of LC cases are of the non-small cell lung cancer (NSCLC) type, and approximately two-thirds of these cases are diagnosed in advanced stages. Only systemic treatment methods can be applied to patients in the advanced stages when there is no chance of surgical treatment. Identification of mutations that cause LC is of vital importance in determining appropriate treatment methods. New noninvasive methods are needed to repeat and monitor these molecular analyses. In this regard, liquid biopsy (LB) is the most promising method. This study aimed to determine the effectiveness of LB in detecting EGFR executive gene mutations that cause LC. Methods: One hundred forty-six patients in stages IIIB and IV diagnosed with non-squamous cell non-small cell LC were included. Liquid biopsy was performed as a routine procedure in cases where no mutation was detected in solid tissue or in cases with progression after targeted therapy. Liquid biopsy samples were also obtained for the second time from 10 patients who showed progression under the applied treatment. Mutation analyses were performed using the Cobas® EGFR Test, a real-time PCR test designed to detect mutations in exons 18, 20, and 21 and changes in exon 19 of the EGFR gene. Results: Mutation positivity in paraffin blocks was 21.9%, whereas it was 32.2% in LB. Solids and LB were compatible in 16 patients. Additionally, while no mutation was found in solid tissue in the evaluation of 27 cases, it was detected in LB. It has been observed that new mutations can be detected not only at the time of diagnosis, but also in LB samples taken during the follow-up period, leading to the determination of targeted therapy. Discussion: The results showed that "liquid biopsy" is a successful and alternative non-invasive method for detecting cancer-causing executive mutations, given the limitations of conventional biopsies.

Evaluation of clinical findings and neurofibromatosis type 1 bright objects on brain magnetic resonance images of 60 Turkish patients with NF1 gene variants.

Neurofibromatosis type 1 (NF1) is caused by mutations in the NF1 gene. This retrospective study aims to evaluate the clinical manifestations and brain magnetic resonance images (MRI) analysis in 60 genetically confirmed NF1 patients. The results of next-generation sequencing (NGS), Sanger sequencing, and MLPA of NF1 gene were evaluated. A total of 54 different variants were identified. Fourteen out of them were novel variants (25.9%). Patients who complied with NIH criteria had most frequently frameshift variants (11/32 patients), and those with only CALMs had missense variants (9/28 patients). Neurofibromatosis type 1 bright objects (NBOs) on T2-weighted MRI were detected in 42 patients (42/56; 75%). These brain lesions were detected mostly in basal ganglia and in cerebellar vermis. NBOs were detected more in the patients who complied with NIH criteria (80.6%) compared to those who were only CALMs (68%). While frameshift variants (33.3%) were the most common type variants in the patients who had NBOs, the most common variants were splicing (35.7%) and missense (35.7%) variants in the patients whose MRIs were normal. Frameshift variants (11/28 patients; 39.3%) were the most common in the patients with more than one brain locus involvement. Therefore, we consider that frameshift variants may be associated with increased incidence of NBOs and involvement of more than one brain locus. In addition, NBOs may occur less frequently in the patients with splicing variants. To our knowledge, this is the first study evaluated the relationship between NF1 gene variants and NBOs. Future studies may help us understand the etiology of NBOs.

The relation between distant metastasis and genetic change type in stage IV lung adenocarcinoma patients at diagnosis.

INTRODUCTION: Brain metastasis prevalence is higher in patients with positive epidermal growth factor receptor (EGFR) mutation, anaplastic lymphoma kinase (ALK) and C-ROS oncogene 1 (ROS-1) fusion change in lung adenocarcinoma. OBJECTIVES: The purpose of our study is to investigate the relation between the genetic change type and the initial distant metastasis in stage IV lung adenocarcinoma patients with genetic changes. METHODS: The study was conducted between January 2007 and December 2018 in a retrospective fashion with patients who had lung cancer diagnosed as stage IV adenocarcinoma. The relation between genetic mutation change (EGFR, ALK or ROS-1) and distant metastasis was analysed. RESULTS: A total of 845 patients were included in the study. The median age was 62 (28-88). It was determined that lung and pleura metastases were more frequent at a significant level in patients with positive EGFR mutation (P = 0.032, P = 0.004, respectively). In patients with positive ALK fusion change, pleura metastasis was determined to be more frequent (P = 0.001). Multiple metastases were determined to be significantly more in patients with positive ALK fusion change than single metastasis (P = 0.02). CONCLUSION: In patients with EGFR mutant lung adenocarcinoma, lung and pleura metastasis is more frequent and pleura metastasis is more frequent in ALK positive adenocarcinoma. Additionally, multiple organ metastases are higher in ALK positive lung adenocarcinoma.

Evaluation of chromosomal abnormalities and Y-chromosome microdeletions in 1696 Turkish cases with primary male infertility: A single-center study.

OBJECTIVE: The aim of this study was to determine the frequencies of chromosomal abnormalities and Y-chromosome microdeletions in Turkish cases with primary male infertility in a single center. MATERIAL AND METHODS: Chromosomal abnormalities and Y-chromosome microdeletions were investigated in 1696 cases with primary male infertility between 2012 and 2017. Karyotype analyzes and Y-chromosome microdeletions analyzes [azoospermia factor (AZF) regions] were performed in all cases by using standard cytogenetic methods and the multiplex polymerase chain reaction method, respectively. RESULTS: Chromosomal abnormalities were found in 142 cases (8.4%; 142/1696). Y-chromosome microdeletions were detected in 46 cases (2.7%; 46/1696). Y-chromosome microdeletions in the AZFc region were found in 20 of 46 cases (43%). CONCLUSION: This study is one of the few were a large number of cases was studied in Turkey. It indicates that cytogenetic and Y-chromosome microdeletion studies should be conducted in cases with primary male infertility prior to selecting assisted reproductive techniques.

Could high levels of cell-free DNA in maternal blood be associated with maternal health and perinatal outcomes?

The aim of this study was to evaluate the maternal and foetal factors affect higher cell-free DNA (cfDNA) levels and to investigate a possible relationship between high cfDNA levels and adverse perinatal outcomes. From a total of 4594 women who underwent non-invasive prenatal testing from January 2016 to March 2018 in our hospital, 112 women had high levels of cfDNA, which was not appropriate for testing. Maternal characteristics and perinatal outcomes were compared between patients with high levels of cfDNA and normal levels of cfDNA. Patients with high levels of cfDNA had greater risks than patients with normal cfDNA levels of pregnancy complications but no statistically significant difference was found. Patients with high cfDNA levels had higher foetal death rates with a statistically significant difference (9.8% versus 1.8%, p = .024). An increase in foetal death could be expected in patients with increased cfDNA levels; therefore, these patients should be carefully followed up during pregnancy.IMPACT STATEMENTWhat's already known about this topic? Most studies about cfDNA levels are focussed on the foetal fraction. There are new arguments about maternal health and cfDNA. It is known that autoimmune diseases as systemic lupus erythematosus (SLE) and maternal obesity increase cell turnover. There are also clinical studies suggesting a relationship between low molecular weight heparin therapy and the amount of cfDNA.What do the results of this study add? This is the first study evaluating the maternal and foetal biological factors affecting cfDNA concentrations and investigating the possible relationship between high cfDNA levels and adverse perinatal outcomes in patients with high levels of cfDNA compared to patients with normal levels of cfDNA. In the present study, it was found that an increase in foetal death could be expected in patients with higher cfDNA levels.What are the implications of these findings for clinical practice and/or further research? If potential effects and underlying causes of increased cfDNA could be explained, cfDNA might be used as a biomarker for adverse perinatal outcomes.

First-Line Molecular Genetic Evaluation of Autosomal Recessive Non-Syndromic Hearing Loss.

OBJECTIVE: The aim of this study is to investigate the efficiency of a first-line molecular genetic evaluation approach, in children with deafness. METHODS: Patients who were found to have sensorineural hearing loss by age-appropriate audiological tests were selected for the molecular genetic evaluation. The molecular genetic evaluation was carried out with GJB2 gene sequence analysis and mtDNA m.1555A>G mutation Restriction Fragment Length Polymorphism (RFLP) analysis. Additionally, in a small group of patients, hearing loss Multiplex Ligation-dependent Probe Amplification (MLPA) analysis was done out to identify the possible role of copy number changes. RESULTS: In this Turkish cohort, which included 104 index patients and 78 relatives, 33 (31.7%) had Pathogenic/Likely Pathogenic variants. One or more GJB2 sequence variants were identified in 46 (44.1%) of the 104 index patients. The homozygous c.35delG mutation by itself explained the etiology in 24% of our ARSNHL group. In one (5%) of the 20 patients of MLPA group, a hemizygous deletion in POU3F4 gene was detected. CONCLUSION: In our Turkish cohort, we applied a first-line molecular genetic evaluation approach using GJB2 gene sequence analysis and mtDNA m.1555A>G RFLP analysis. This approach revealed the genetic etiology of 44.1% of our index patients. Additionaly, the results of hearing loss MLPA analysis revealed the limited role of copy number changes in this patient group. Furthermore, with a detailed genotype-phenotype association workup, 2 rare cases of Deafness with Palmoplantar Hyperkeratosis and Keratitis-Ichthyosis-Deafness syndrome were reported.

Chromosomal Microarray Analysis in Children with Unexplained Developmental Delay/Intellectual Disability.

Chromosomal microarray (CMA) analysis for discovery of copy number variants (CNVs) is now recommended as a first-line diagnostic tool in patients with unexplained developmental delay/intellectual disability (DD/ID) and autism spectrum disorders. In this study, we present the results of CMA analysis in patients with DD/ID. Of 210 patients, pathogenic CNVs were detected in 26 (12%) and variants of uncertain clinical significance in 36 (17%) children. The diagnosis of well-recognized genetic syndromes was achieved in 12 patients. CMA analysis revealed pathogenic de novo CNVs, such as 11p13 duplication with new clinical features. Our results support the utility of CMA as a routine diagnostic test for unexplained DD/ID.

A newborn with widespread skin lesions and extremity anomalies.

A variety of diseases can cause vesicular or pustular eruptions in newborns. A thorough clinical history and physical exam provide important clues for differential diagnosis. Goltz syndrome, also known as focal dermal hypoplasia, is a rare genodermatosis and generally diagnosed by the presence of the characteristic skin lesions. We present an infant with aplasia cutis, atrophic skin lesions, syndactyly and eye abnormalities who was diagnosed with Goltz syndrome soon after birth. Goltz syndrome should be considered in differential diagnosis of hypoplastic or aplastic skin lesions in neonates in the presence of skeletal or ophthalmic anomalies.

A case with proximal femoral focal deficiency (PFFD) and fibular A/hypoplasia (FA/H) associated with urogenital anomalies.

Malformations of the lower limbs are rare and heterogeneous anomalies. Some congenital anomalies involving face, gastrointestinal system, skeletal system, urogenital system, heart, lung and diaphragma associated with lower limb malformations have been described in the literature. Here, we report a case of left proximal femoral focal deficiency (PFFD) together with fibular aplasia associated with left undescended testis and hypospadias. The putative embryologic mechanisms of lower limb defects and their possible association with lower urogenital tract malformations are also discussed.