Functional analysis of MMR gene VUS from potential Lynch syndrome patients.

Lynch syndrome is caused by inactivating variants in DNA mismatch repair genes, namely MLH1, MSH2, MSH6 and PMS2. We have investigated five MLH1 and one MSH2 variants that we have identified in Turkish and Tunisian colorectal cancer patients. These variants comprised two small deletions causing frameshifts resulting in premature stops which could be classified pathogenic (MLH1 p.(His727Profs*57) and MSH2 p.(Thr788Asnfs*11)), but also two missense variants (MLH1 p.(Asn338Ser) and p.(Gly181Ser)) and two small, in-frame deletion variants (p.(Val647-Leu650del) and p.(Lys678_Cys680del)). For such small coding genetic variants, it is unclear if they are inactivating or not. We here provide clinical description of the variant carriers and their families, and we performed biochemical laboratory testing on the variant proteins to test if their stability or their MMR activity are compromised. Subsequently, we compared the results to in-silico predictions on structure and conservation. We demonstrate that neither missense alteration affected function, while both deletion variants caused a dramatic instability of the MLH1 protein, resulting in MMR deficiency. These results were consistent with the structural analyses that were performed. The study shows that knowledge of protein function may provide molecular explanations of results obtained with functional biochemical testing and can thereby, in conjunction with clinical information, elevate the evidential value and facilitate clinical management in affected families.

The Impact of Total Tumor Diameter on Lymph Node Metastasis and Tumor Recurrence in Papillary Thyroid Carcinomas.

(1) Introduction: The impact of multifocality/bilaterality on the prognosis of papillary thyroid carcinoma (PTC) is a matter of debate. In order to clarify this debate, several studies have attempted to identify additional parameters associated with poor prognosis, including total tumor diameter (TTD), in the context of multifocal PTCs. In this context, this study was carried out to investigate the impact of TTD on tumor recurrence and lymph node metastasis (LNM) in PTCs. (2) Materials and Methods: The sample of this single-center retrospective study consisted of 706 patients diagnosed with PTC. TTD was calculated as the sum of the largest diameters of tumor foci in multifocal tumors. The resulting TTDs were grouped into TTDs ≤ 10 mm, TTDs > 10 mm, TTDs ≤ 20 mm, and TTDs > 20 mm, using 10 mm and 20 mm as cutoff values. (3) Results: There was no significant difference between multifocal papillary microcarcinomas (PTMCs) with a TTD of >10 mm and unifocal PTCs with a primary tumor diameter (PTD) of >10 mm except for advanced age and lymphovascular invasion (LVI). In addition, perineural invasion (PNI) and TTD > 10 mm were found to be significant risk factors for LNM, and PNI, TTD > 10 mm, TTD > 20 mm, and bilaterality were found to be significant risk factors for recurrence. LVI, and TTD > 10 mm were found to be independent significant predictors for recurrence, and LVI and extrathyroidal extension (ETE) were found to be independent significant predictors for LNM. (4) Conclusions: Considering TTD > 10 mm in recurrence risk categorization models and adopting a clinical approach that takes into account multifocal PTMCs with TTD > 10 mm along with unifocal PTCs with PTD > 10 mm may be more useful in terms of clinical management of the disease.

A Genetics Study in the Foreskin of Boys with Hypospadias.

Introduction: Hypospadias is a malformation of the genitourinary system in males, characterized by the placement of the urethral opening in the ventral surface of the penis. Although controversies continue about etiology, endocrine disrupting chemicals that disrupt normal endocrine signaling at the receptor or signal transduction level are thought to play an essential role in etiology. This study aimed to investigate the receptor gene expressions of the sex hormones and FGFR2, HOXA13, and TGFB1, which are considered to play an essential role in developing hypospadias. Methods: The samples from the foreskin of 26 patients with hypospadias and 26 healthy children who underwent circumcision operations were collected. ESR1, AR, FGFR2, HOXA13, and TGFB gene expressions were investigated by real-time PCR in samples obtained during surgery. Results: In the hypospadias group, ESR1 expression was increased (p = 0.013), and AR and FGFR2 expressions were decreased, which were found to be statistically significant (p = 0.027 and p = 0.003, respectively). There was no statistically significant difference between hypospadias and control groups in TGFBand HOXA13expression levels (p > 0.05). Discussion: The results suggest that sex hormone receptors and FGFR2 may play an essential role in developing male external genital structures at the gene level. The defects in the expression of these genes can contribute to understanding the development of hypospadias.

Investigation of Relationship Between Small Noncoding RNA (sncRNA) Expression Levels and Serum Iron, Copper, and Zinc Levels in Clinical Diagnosed Multiple Sclerosis Patients.

In our study, we aimed to investigate the relationship between microRNA (miRNA) expression levels and serum iron (Fe), copper (Cu), and zinc (Zn) levels in Multiple sclerosis (MS) patients. Total RNA was isolated from peripheral venous blood containing ethylenediaminetetraacetic acid (EDTA) of MS patients and controls. Total RNA was labeled with Cy3-CTP fluorescent dye. Hybridization of samples was performed on microarray slides and arrays were scanned. Data argument and bioinformatics analysis were performed. Atomic absorption spectrophotometer method was used to measure serum Fe, Cu, and Zn levels. In our study, in bioinformatics analysis, although differently expressed miRNAs were not detected between 16 MS patients and 16 controls, hsa-miR-744-5p upregulation was detected between 4 MS patients and 4 controls. This may be stem from the patient group consisting of MS patients who have never had an attack for 1 year. Serum iron levels were detected significantly higher in the 16 MS patients compared to the 16 controls. This may be stem from the increase in iron accumulation based on inflammation in MS disease. According to the findings in our study, hsa-miR-744-5p upregulation has been determined as an early diagnostic biomarker for the development together of insulin resistance, diabetes mellitus associated with insulin signaling, and Alzheimer's diseases. Therefore, hsa-miR-744-5p is recommended as an important biomarker for the development together of diabetes mellitus, Alzheimer's disease, and MS disease. In addition, increased serum Fe levels may be suggested as an important biomarker for neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, and MS disease.

A Case of Diabetes Mellitus Type MODY5 as a feature of 17q12 Deletion Syndrome.

Maturity onset diabetes of the young (MODY) is characterized by noninsulin-dependent diabetes diagnosed at a young age (<25 years) with an autosomal dominant inheritence. Rare mutations in the hepatocyte nuclear factor-1-beta (HNF1B) gene produce a syndrome that resemble MODY and about half of patients diagnosed with MODY5 (HNF1B mutation) have a a whole gene deletion, called as 17q12 deletion syndrome, is a rare chromosomal anomaly and is typified by deletion of the more than 15 genes including HNF1B resulting in kidney abnormalities and renal cysts and diabetes syndrome and neurodevelepmental or neuropsychiatric disorders. A 12-year-old girl was referred to our clinic, after high blood sugar was detected in the hospital where she suffered with the complaints of poliuria and polydipsia for the last 1 month. Her serum magnessium level was low (1.5 mg/dl) (normal value 1.6-2.6) and HbA1c level was 14% (normal value 3.6-5.8) and c-peptide level was 1.54 ng/ml (normal value 0.8-4). MODY5 was suspected and followed NGS gene panel (ABCC8, BLK, CEL, GCK, HNF1A, HNF1B, HNF4A, INS, KCNJ11, KLF11, NEURODD1, PAX4, PDX1, RFX6, ZFP57, GLIS3, FOXP3, NEUROG3, G6PC2) analysis revealed that there was no any mutation. On follow-up period, her serum magnessium level was low (1.2 mg/dl) and her urinary magnessium excretion was high at 172.5 mg/day. HNF1B gene mutation was considered in the patient with chronic hypomagnesemia with increased basal C peptide level. Abdominal CT and MR imagings revealed that there was a 43 mm diameter cystic lesion in the head of the pancreas, and agenesis of the pancreatic neck, trunk and tail as well. Because of there is no mutation in HBF1B gene in NGS panel, microarray analysis was performed, heterozygous deletion at 17q12 including HNF1B was detected. The HNF1B mutation is difficult to diagnose and has a large phenotypic variation . In case of clinical suspicion,further genetic examination (MLPA, array CGH) may be required since deletions and duplications can not be detected even if mutations in the HNF1B gene are not detected with NGS.

The evaluation of risk factors leading to early deaths in patients with acute promyelocytic leukemia: a retrospective study.

Acute promyelocytic leukemia (APL) differs from other forms of acute myeloid leukemia (AML), including coagulopathy, hemorrhage, disseminated intravascular coagulation (DIC), and treatment success with all-trans retinoic acid (ATRA). Despite ATRA, early deaths (ED) are still common in APL. Here, we evaluated factors associated with ED and applicability of scoring systems used to diagnose DIC. Ninety-one APL patients (55 females, 36 males, and median age 40 years) were included. ED was defined as deaths attributable to any cause between day of diagnosis and following 30th day. DIC was assessed based on DIC scoring system released by the International Society of Thrombosis and Hemostasis (ISTH) and Chinese Diagnostic Scoring System (CDSS). Patients' median follow-up time was 49.2 months, and ED developed in 14 (15.4% of) cases. Patients succumbing to ED had higher levels of the Eastern Cooperative Oncology Group Performance Status (ECOG PS), lactate dehydrogenase (LDH), and ISTH DIC, and lower fibrinogen levels (p <0.05). In multivariate Cox regression analysis, age >55 and ECOG PS ≥2 rates were revealed to be associated with ED. Based on ISTH and CDSS scores, DIC was reported in 47.3 and 58.2% of the patients, respectively. Despite advances in APL, ED is still a major obstacle. Besides the prompt recognition and correction of coagulopathy, those at high ED risk are recommended to be detected rapidly. Implementation of local treatment plans and creating awareness should be achieved in hematological centers. Common utilization of ATRA and arsenic trioxide (ATO) may be beneficial to overcome ED and coagulopathy in APL patients.

Comprehensive Genetic Analysis Results of TSC1/TSC2 Genes in Patients with Clinical Suspicion of Tuberous Sclerosis Complex and Definition of 3 Novel Variants.

BACKGROUND: Tuberous Sclerosis Complex is an autosomal dominant multi-system disorder with an incidence of about 1 in 6000 live births. Defects in either TSC1 (* 605284) or TSC2 (* 191092) genes encoding the components of the Tuberous Sclerosis Complex are responsible for the disease. Therefore, consideration of TSC1/TSC2 pathogenic variations is recommended in the updated diagnostic criteria of Tuberous Sclerosis Complex. AIMS: To present the TSC1/TSC2 screening results of a mixed patient population as well as possible new variants in 23 cases from 20 different families who were referred to our Genetic Diseases Diagnosis Center with the signs and symptoms of Tuberous Sclerosis Complex. STUDY DESIGN: Retrospective, cross-sectional study. METHODS: Germline TSC1/TSC2 variants were screened in DNA samples extracted from peripheral blood samples of 23 patients from 20 unrelated families using targeted high-throughput sequencing and multiplex ligation-dependent probe amplification methods. The variants identified were classified according to ACMG 2015 guidelines. RESULTS: In total, 5 different pathogenic/likely pathogenic changes have been defined. All these pathogenic/likely pathogenic variants were located in the TSC2 gene. Three of the pathogenic/likely pathogenic variants were novel. Two patients who are twin sisters were found to have TSC2/PKD1 contiguous deletion syndrome. One of the 3 novel variants was a mosaic in-frame deletion. We did not identify any pathogenic variants of the TSC1 gene. CONCLUSION: The novelty of most of the variants found, including a mosaic likely pathogenic variant, and the presence of a large genomic rearrangement, supports the importance of a comprehensive approach in analyzing TSC1/TSC2 genes. Genetic diagnosis should be performed with caution, considering the possibility of mosaic variants with low allelic fractions.

Targeted massively parallel sequencing in the management of cytogenetically normal lymphoid malignancies.

The variations in clinical and biological background of lymphoid malignancies trigger researchers to try to find out novel therapeutic targets. A typical treatment includes multiagent chemotherapy and/or targeted therapy in the light of driver mutations. Next generation sequencing (NGS) plays a pivotal role during the identification of genetic alterations in lymphoid malignancies. A total of 52 patients [30 men (58%) and 22 women (42%)] having normal cytogenetic and FISH results were enrolled in this study. Usage of NGS based targeted sequencing could confirm or support a particularly preferred diagnosis (41/52, 78%) or make a differential diagnosis in cases of interference. Notably, in 11 out of these 52 cases (21%), the initial suspect diagnosis was not supported by the NGS result and thereby had to be reconsidered. In this study, we highlight the importance of targeted NGS panel testing for diagnosis, prognosis and treatment decision in highly selected instances of lymphoid malignancies and lymphoproliferative disorders in which histopathology and more conventional molecular analyses remain inconclusive.

Germline Pathogenic Variants Identified by Targeted Next-Generation Sequencing of Susceptibility Genes in Pheochromocytoma and Paraganglioma.

The aim of this study was to evaluate germline variant frequencies of pheochromocytoma and paraganglioma targeted susceptibility genes with next-generation sequencing method. Germline DNA from 75 cases were evaluated with targeted next-generation sequencing on an Illumina NextSeq550 instrument. KIF1B, RET, SDHB, SDHD, TMEM127, and VHL genes were included in the study, and Sanger sequencing was used for verifying the variants. The pathogenic/likely pathogenic variants were in the VHL, RET, SDHB, and SDHD genes, and the diagnosis rate was 24% in this study. Three different novel pathogenic variants were determined in five cases. This is the first study from Turkey, evaluating germline susceptibility genes of pheochromocytoma and paraganglioma with a detection rate of 24% and three novel variants. All patients with pheochromocytoma and paraganglioma need clinical genetic testing with expanded targeted gene panels for higher diagnosis rates.

An unknown chromosomal aberration in a patient with chronic lymphocytic leukemia: Extra isochromosome 4q.

The genetic characterization of chronic lymphocytic leukemia (CLL) has made significant progress over the past few years. Chromosomal abnormalities are detected in up to 80% of patients. Determination of new chromosomal disorders is important in the pathogenesis and treatment facilities. A patient was diagnosed with CLL Stage 2 on 2012 and followed since then by hematology clinic. She was 63 years old. Mature, small lymphocytes, and smudge cell was found in the patient's peripheral blood smear. Bone marrow (BM) biopsy made and hypercellularity showing infiltration of atypical cells with CD5+, CD20+, and CD23+ were determined. Hypoplasia is detected in myeloid/erythroid series, and Stage 2 reticular fibers proliferation were detected. The patient was followed up without medication. While follow-up of patient's white blood cell: 57300, hemoglobin: 5.36, and PLT: 99700 are determined in May 2014. According to the patient's flow results, CD5+, CD23+, and FMC7+ were detected. Mature, small lymphocytes and smudge cell was found in the patient's peripheral blood smear. In ultrasonography imaging, multiple laps were found in the abdomen and multiple neck lymph nodes were detected. The patient BM aspiration was performed in 2014, and hypercellularity was found to contain 54% of atypical lymphocytes in the BM. Fluorescence in situ hybridization (FISH) analysis made two times in 2014. At first, FISH analysis patient's rate of 18% in RB1/13q14.2/13qter revealed a deletion of the gene regions. Patient's FISH result was reported as normal (for RB1/13q14.2/13qter) after 5 months at second analysis. Cytogenetic analysis is made from the patient's BM at the same time. According to the results of karyotyping and FISH, 47, XX, isochromosome 4q (+i4q) is determined. According to literature, extra isochromosome 4q is reported by our case for the first time in CLL. She was diagnosed with Stage 4 CLL and FISH treatment was initiated. Our patient showed disease progression compared to previous results. Hence, we offer that this evidence can be considered regarding triggering the disease's progression or as a result of disease progression i4q was occurred.

The Importance of Targeted Next-Generation Sequencing Usage in Cytogenetically Normal Myeloid Malignancies.

Advanced diagnostic methods give an advantage for the identification of abnormalities in myeloid malignancies. Various researchers have shown the potential importance of genetic tests before the disease's onset and in remission. Large testing panels prevent false-negative results in myeloid malignancies. However, the critical question is how the results of conventional cytogenetic and molecular cytogenetic techniques can be merged with NGS technologies. In this paper, we drew an algorithm for the evaluation of myeloid malignancies. To evaluate genetic abnormalities, we performed cytogenetics, molecular cytogenetics, and NGS testing in myeloid malignancies. In this study, we analyzed 100 patients admitted to the Medical Genetics Laboratory with different myeloid malignancies. We highlighted the possible diagnostic algorithm for cytogenetically normal cases. We applied NGS 141 gene panel for cytogenetically normal patients, and we detected two or more pathogenic variations in 61 out of 100 patients (61%). NGS's pathogenic variation detection rate varies in disease groups: they were present in 85% of A.M.L. and 23% of M.D.S. Here, we identified 24 novel variations out of total pathogenic variations in myeloid malignancies. A total of 18 novel variations were identified in A.M.L., and 6 novel variations were identified in M.D.S. Despite long turnaround times, conventional techniques are still a golden standard for myeloid malignancies but sometimes cryptic gene fusions or complex abnormalities cannot be easily identified by conventional techniques. In these conditions, advanced technologies like NGS are highly recommended.

A Pilot Study of Identification Genetic Background of Craniosynostosis Cases.

ABSTRACT: The early fusion of the cranial sutures was described as a craniosynostosis. The early diagnosis and management of craniosynostosis is very important. Environmental factors and genetic abnormalities plays a key role during the development of craniosynostosis. Syndromic craniosynostosis cases are related with autosomal dominant disorders but nearly half of the affected cases carry a new mutation. In this study, in order to identify the genetic etiology of craniosynostosis the authors analyzed 20 craniosynostosis patients by using conventional karyotype, aCGH, sanger sequencing, next generation sequencing (NGS) and Multiplex ligation-dependent probe amplification (MLPA) techniques. The authors identified mutations on FGFR2 and FGFR3 genes which were associated with Muenke syndrome, Crouzon syndrome and skeletal dysplasia syndromes. NGS applied all of the cases and 7 clinical variations in 5 different gene were detected in %20 of cases. In addition to these abnormalities; del(11)(q14.1q22.2), del(17)(q21.31), dup(22)(q13.31) and t(2;16)(q37;p13) have been identified in our cohort which are not previously detected in craniosynostosis cases. Our study demonstrates the importance of detailed genetic analysis for the diagnosis, progression and management of the craniosynostosis.

Genetic screening results of individuals with high risk BRCA-related breast/ovarian cancer in Trakya region of Turkey.

PURPOSE: Pathogenic/likely pathogenic (P/LP) germline variations in BRCA1 and BRCA2 genes are responsible for the majority of hereditary breast and ovarian cancers. This study presents the BRCA1/BRCA2 sequencing and deletion duplication analyses results of of 493 participants (485 women, 8 men) selected based on the National Comprehensive Cancer Network (NCCN) guidelines. METHODS: Next generation sequencing (NGS) and multiplex ligation-dependent probe amplification methods (MLPA) were used to define germline BRCA1/BRCA2 positivity. RESULTS: Overall, the P/LP frequency of the participants was 17.8%. Five of the likely pathogenic variants were novel. The 5266dupC pathogenic variation, which is a founder mutation in the Ashkenazi Jewish population, was the most common variation among the patients, with a frequency of 5.47%. The pathogenic/likely pathogenic variation frequency was significantly higher (p=0.01) among clinically diagnosed familial cancer patisents than those participants without personal history of cancer but enrolled for BRCA1 testing due to familial risk. BRCA1/BRCA mutation positivity was significantly higher (p=0.000) among those who had at least one first- or second-degree relative with breast/ovarian cancer from patients who had no family history. BRCA1/BRCA2 mutation positivity was 69.23% between the patients who had personal history of both breast and ovarian cancer. CONCLUSION: Based on our findings, we suggest that sequencing all of the coding regions of the BRCA1/BRCA2 genes using NGS is a feasible approach for individuals who are at risk of developing BRCA-related cancer according to NCCN guidelines. The 5266dupC pathogenic variation, as the most common pathogenic variation in the Trakya region of Turkey, should be included if a targeted mutatin screening is planned.

Targeted next-generation sequencing as a diagnostic tool in gastrointestinal system cancer/polyposis patients.

BACKGROUND: Recent advances in next-generation sequencing (NGS) technology have enabled multigene testing and changed the diagnostic approach to hereditary gastrointestinal cancer/polyposis syndromes. The aim of this study was to analyze different cancer predisposition genes in hereditary/sporadic gastrointestinal cancer/polyposis. METHODS: Cancer predisposition genes were analyzed with an Illumina MiSeq NGS system in 80 patients with gastrointestinal cancer/polyposis who were examined between the years 2016 and 2019. Deletion/duplication analysis of MLH1, MSH2, and EPCAM genes was performed by using the multiplex ligation-dependent probe amplification method. RESULTS: Germline testing of hereditary cancer-related genes was performed in 80 patients with gastrointestinal cancer/polyposis. A total of 30 variants in 30 cases (37.5%) were assessed as pathogenic/likely pathogenic. A total of 19 heterozygous variants were assessed as variants of uncertain clinical significance in 17 cases (21.25%) and 18 (22.5%) novel variations (9 pathogenic/likely pathogenic, 9 variants of uncertain significance) were determined. In 4 (5%) cases, multiplex ligation-dependent probe amplification detected deletions in MLH1, MSH2, and EPCAM genes. CONCLUSION: The accumulation of analyses with multigene testing will increase the available data for cancer predisposition genes in hereditary gastrointestinal cancer/polyposis. Educational campaigns for prevention, efficient screening programs, and more personalized care based on the profile of individual patients are necessary.

Concepts of Double Hit and Triple Hit Disease in Multiple Myeloma, Entity and Prognostic Significance.

Risk assessment in newly diagnosed multiple myeloma patients (NDMM) is the first and the most crucial determinant of treatment. With the utilization of FISH analysis as a part of routine practice, high risk Multiple Myeloma (MM) is defined as having at least one of the mutations related with poor prognosis including; t(4;14) t(14;16), t(14;20), del 17p, p53 mutation, gain 1q and del 1p. M-Smart MM risk stratification guideline by Mayo Clinic has proposed a concept similar to high grade lymphomas. Having two of the high risk genetic abnormalities were defined as double hit MM and having any three as triple hit MM. Based on these definitions which may bring a much more clinically relatable understanding in MM prognosis, we aimed to assess our database regarding these two concepts and their probable significance in terms of outcome and prognosis. We retrospectively evaluated 159 newly diagnosed multiple myeloma patients and their clinical course. Among these patients; twenty-four patients have one high risk determinant and also seven and two patients were classified as double hit MM and triple hit MM respectively. Overall survival (OS) of the patients with double hit MM was 6 months, 32.0 months for patients with single high risk abnormality and 57.0 months for patients with no high risk abnormality. Univariate analysis showed that Double Hit and Triple Hit MM is a predictive of low OS. Hazard Ratio of patients with one high risk abnormality was 1.42, double-hit MM patients was 5.55, and triple-hit MM patients was 7.3. Despite the development of novel drugs and their effects of prolonging survival, the treatment has not been individualized. Understanding the biology of each patient as a unique process will be the success of the treatment. As it is known that some MM patients harbor high risk genetic abnormalities according to FISH analysis, we can continue the argument that some patients bring an even higher risk and that can be defined as double or triple hit MM.

The relation between BRAFV600E mutation and clinicopathological characteristics of papillary thyroid cancer.

Aim BRAF mutation inhibits many tumour suppressor genes, increases pro-angiogenic molecules and reduces radioactive iodine uptake of tumour in papillary thyroid cancer (PTC), giving it more aggressive clinical characteristics. In this study, we aimed to evaluate the effect of BRAF V600E mutation on the clinicopathological features in patients with PTC. Methods The laboratory and clinical findings of 256 PTC patients who were referred to our clinic between 2007 and 2017 were assessed. Subjects involved in the study were divided into two groups depending on the presence of BRAF V600E mutation. Results BRAF V600E mutation testing gave positive results for 65 (25.4%) out of 256 patients. No significant correlation between BRAF V600E mutation, age and gender was detected. There was no difference between the groups in terms of tumour variant, tumour localization, tumour focality, and perineural invasion. In terms of histopathologic characteristics, presence of tumour capsular invasion (p=0.027), extrathyroidal extension (ETE) (p=0.002), absence of pathologically detected lymphocytic thyroiditis (p=0.006) and radio iodine I-131 treatment (p=0.001) were significantly higher in BRAF V600E (+) patients. During a followup period, four patients with BRAF V600E (+) and two patients with BRAF V600E (-) status underwent lateral neck dissection due to lymph node metastasis (p=0.01). Conclusion The presence of BRAF V600E mutation was proved to be a poor prognostic factor. However, in order to further assess the prognostic effect of BRAF V600E mutation in this group of patients and particularly its effect on mortality, long term followup results must be evaluated.

Chronic myeloid leukaemia after chemoradiotherapy for solid malignancies.

Haematological malignancies associated with chemoradiotherapy (CRT) are often acute myeloid leukaemias and myelodysplastic syndromes. Chronic myeloid leukaemia (CML) has been reported rarely in these situations. Cytogenetics of CRT-associated CML is not different from de novo CML, and there are not enough data about its prognosis. We report two patients who had CRT because of lung cancer and squamous cell carcinoma of head and neck, who subsequently developed CML.

Schizencephaly accompanied by occipital encephalocele and deletion of chromosome 22q13.32: a case report.

Background: Schizencephaly is a neuronal migration anomaly characterized by presence of a cleft between ependymal layer of the ventricle and pia mater of the cerebral cortex. It may be associated with additional cerebral abnormalities, including polymicrogyria, pachygyria, gray matter heterotopy, ventriculomegaly and corpus callosum agenesis. Case Report: We present a female fetus with schizencephaly accompanied by occipital encephalocele, polymicrogyria, agenesis of the corpus callosum, dysmorphic facies and cardiac muscular ventricular septal defect. Array comparative genomic hybridization (array-cGH) analysis revealed a deletion of chromosome 22q13.32 including FAM19A5 gene that is a member of TAFA family. Conclusions: Schizencephaly may be accompanied by unexpected structural and genetic anomalies as in our case with occipital encephalocele, dysmorphic facies, cardiac ventricular septal defect and chromosome 22q13.32 deletion.