Importance of Myc-related microRNAs in induced pluripotency.

Pluripotent stem cells (PSCs) have the capacity to differentiate into any cell type of the body. Therefore, induced pluripotent stem cells (iPSCs) are seen as a promising solution for patient-specific cell therapies. However, the safety is major issue for in vitro methods that are used in induction of pluripotency and also in differentiation of PSCs toward specific cell types. In pioneer studies of iPSC generation, the role of c-Myc has been highlighted as a possible master regulator of pluripotency, but direct c-Myc overexpression is known to prompt drawbacks, especially in human cells. In recent studies, the role of non-protein coding RNA molecules such as microRNAs (miRNAs) has been shown in enhanced reprogramming efficiency. In addition, new reprogramming methods have been ultimately improved by adding miRNAs, in the absence of previous factors. Cross interaction between miRNAs and c-Myc has been also found in differentiation of iPSCs, as well as in reprogramming and self-renewing the pluripotent state. Thence, miRNAs are promising solution for efficiency and safety of iPSC derivation and differentiation methods. The purpose of the present review is to evaluate interaction mechanisms of miRNAs with c-Myc and in iPSC technology.

Gorlin-Chaudhry-Moss syndrome revisited: expanding the phenotype.

Gorlin-Chaudhry-Moss syndrome (OMIM 233500) is a rare congenital malformation syndrome with the cardinal manifestations of craniofacial dysostosis, hypertrichosis, underdeveloped genitalia, ocular, and dental anomalies. Since 1960, only six affected individuals have been reported. We report a 4-year and 6-month-old female patient with this phenotype and review the clinical presentation of all patients known so far. Previously unreported malformations of the extremities, larynx, and nose are also described, expanding the phenotype of this rare syndrome. Array-CGH analysis did not show pathological deletions or duplications.

Methylation of SOCS3 in Myeloproliferative Neoplasms and Secondary Erythrocytosis/Thrombocythemia.

OBJECTIVE: Myeloproliferative neoplasms (MPNs) like essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF) are acquired clonal hematopoietic stem cell disorders and originate from a multipotent hematopoietic stem cell. The SOCS1 and SOCS3 genes are negative regulators of the JAK/STAT signal pathway. In this study we investigate the promoter methylation of these genes in the pathogenesis of MPNs and secondary erythrocytosis/thrombocythemia. MATERIALS AND METHODS: Promoter methylation of SOCS1 and SOCS3 genes was analyzed with methylation-specific PCR. PCR products were analyzed by agarose gel electrophoresis. RESULTS: No disease-specific CpG island methylation of SOCS1 was observed. Hypermethylation of the SOCS3 promoter was identified in 5 out of 19 (26.3%) PV cases, 2 out of 21 (9.5%) ET cases, 1 out of 5 (20%) PMF cases, and 9 out of 42 (21.4%) cases of secondary erythrocytosis/thrombocythemia. CONCLUSION: The results revealed that promoter methylation of the SOCS3 gene suggests a possible role for SOCS3 methylation in the pathogenesis of MPNs and secondary erythrocytosis/thrombocythemia. CONFLICT OF INTEREST: None declared.

Genomic large rearrangement screening of BRCA1 and BRCA2 genes in high-risk Turkish breast/ovarian cancer patients by using multiplex ligation-dependent probe amplification assay.

In this study, MLPA assay was performed for detection of large rearrangements of BRCA1 and BRCA2 genes in 16 familial, 29 early onset, 3 male breast cancer, and 2 bilateral breast/ovarian cancer high risk Turkish index cases. MLPA assay for all exons of both genes and for 1100delC variant of CHEK2 gene were performed. Analyses, revealed no large genomic rearrangements in both genes, and, no 1100del variant in CHEK2 gene. Our data which represents the first results for Turkish patients, suggest that, the frequency of BRCA1 and BRCA2 genes' large rearrangements is very low.

A case with oto-spondylo-mega-epiphyseal-dysplasia (OSMED): the clinical recognition and differential diagnosis.

The oto-spondylo-mega-epiphyseal-dysplasia (OSMED) phenotype is an autosomal recessive trait that is a skeletal dysplasia with the hallmark findings of limb shortening, multiple skeletal and radiological abnormalities, mid-face hypoplasia with a flat nasal bridge, small upturned nasal tip, and sensorineural hearing loss. A 3.5-year-old girl born to consanguineous Turkish parents had characteristic facial features at birth: mid-face hypoplasia, mild hypertelorism, upslanting palpebral fissures, prominent supraorbital ridges, depressed nasal bridge, small upturned nasal tip, long philtrum, and micrognathia. Radiological examination at three years of age revealed large flaring metaphyses and wide flat epiphyses. The humerus and femur showed the characteristic dumbbell shape. She had bilateral hearing loss with no ophthalmologic findings. There is continuing debate over the clinical overlap and differential diagnosis of OSMED syndrome. The patient was examined considering Weissenbacher-Zweymuller, Stickler type 3, Marshall syndrome, and Kniest dysplasia as possible differential diagnoses. We believe that the presented patient clinically manifested features of OSMED syndrome. We would like to point out that the management of OSMED calls for a coordinated multidisciplinary approach.

Familial multiple myeloma associated with disorders of chronic inflammation: first report from Turkey.

Multiple myeloma (MM) is a malignancy arising from mature plasma cells in the bone marrow and usually presents with bone destruction, hypercalcemia, anemia, renal damage, and increased susceptibility to infection. The etiology of MM is unknown, with no established lifestyle, occupational, or environmental risk factors. Because MM is an uncommon disease, etiologic assessments can be difficult. It has been reported to be in association with sarcoidosis, and in a few cases, rheumatoid arthritis. Familial type of MM with an autosomal dominant heredity pattern has also been reported. The genetic loci affected in these cases are still unknown. Herein we present a family with 3 affected cases in an autosomal dominant inheritance pattern. The first case was a man diagnosed to have immunoglobulin (Ig)A-type myeloma at the age of 50. The history revealed 2 more cases in the family: an uncle diagnosed to have unsecretory-type myeloma at the age of 76 and a cousin (the daughter of the affected uncle) who was diagnosed at the age of 48 years to have IgG-type myeloma and did not respond to therapy. This patient also had a history of sarcoidosis preceding the diagnosis of myeloma. All other affected family members had been treated for dental-oral infection (including chronic gingivitis) for 3 and 4 years before the diagnosis of myeloma. Karyotype analysis revealed pseudohypodiploidy and deletion of chromosome 13q in only the patient with coexisting sarcoidosis. To our knowledge, this is the first report on familial myeloma from Turkey. This family enhances the role of hereditary factors and chronic inflammation in the etiology of MM.

Persistent mullerian duct syndrome with transverse testicular ectopia.

A 15-month-old boy was discovered to have internal female genitalia during an operation for bilateral inguinal hernia. The biopsies showed normal testicular tissue and the karyotyping result was 46XY, so the diagnosis of persistent mullerian duct syndrome (PMDS) was made. At the second operation, the uterine fundus and fallopian tubes were excised. Then, he underwent bilateral orchiopexy. We discuss a rare presentation of this disorder, its management, and genetic implications together with a review of the literature.

A case of neurofibromatosis and breast cancer: loss of heterozygosity of NF1 in breast cancer.

Only a few cases with breast cancer and neurofibromatosis type 1 (NF1) have been reported in the literature. Here, we present a family with a history of neurofibromatosis and breast cancer. No hereditary NF1 mutation was observed in this case. Loss of heterozygosity (LOH) analyses of the breast tumor revealed LOH in the NF1 region. In this family, the proband and her mother had breast cancer. The proband was diagnosed with breast cancer at the age of 23 years. No BRCA1 or BRCA2 mutations were observed in the proband's peripheral blood DNA nor were such mutations observed in the immunohistochemically analyzed paraffin block of the tumor DNA. Neurofibromin, encoded by the NF1 gene region, was reported as nearly absent in human breast cancer-MDA-MP-231 cells. Neurofibromin is similar in function to the GTPase activating protein (GAP), p120 GAP. It also accelerates the inactivation of the RAS oncogene. Molecular alterations in NF1 gene region cause neurofibromatosis. LOH in the tumor tissue of our case supports the role of the NF1 gene in the etiology of some cases of breast cancer.

Hereditary breast cancer syndromes in a Turkish population. Results of molecular germline analysis.

Breast cancer is the most common malignancy which affects women. In 5-10% of all cases, breast cancer presents as a hereditary cancer syndrome. Since 1996, 68 families with suspicion of familial breast cancer have been referred to our department. In 5 of the 68 families (7.4%), the clinical diagnosis was hereditary breast ovarian cancer syndrome. In 17 families (25%), two or more breast cancer cases were present. Mutation screening of BRCA1 and BRCA2 in these families revealed a BRCA1 mutation (185delAG) in one family. Three families (4.4%) had a diagnosis of Li-Fraumeni syndrome and germline mutations in TP53 (Lys292Ile, Pro278Ser and Pro278Thr). Breast cancer occurred in a family with hereditary nonpolyposis colon carcinoma (HNPCC; Lynch syndrome) carrying an MLH1 mutation (IVS17-3G>C). Most of our families (41 families; 60.2%) had only one case with breast cancer or cystic adenoma (or both) and did not need counseling and DNA testing. In summary, in 10 of the 68 families in our series (14.7%), a germline mutation in a breast cancer predisposing gene was detected. Our data show the importance of detailed examination of clinical data, pedigree analyses, and molecular germline diagnostics for the counseling of breast cancer cases.

Periodontal status in two siblings with severe congenital neutropenia: diagnosis and mutational analysis of the cases.

BACKGROUND: Severe congenital neutropenia (SCN), also known as Kostmann syndrome, was originally reported as an autosomal recessive disease of neutrophil production. The disease is characterized by a maturation arrest of neutrophil precursors at the promyelocytic stage of differentiation and by extremely low levels of mature neutrophils in peripheral blood. METHODS: A 6-year-old male presented with a complaint of gingival swelling and bleeding, and swelling at the left side of his face. Upon clinical examination, severe inflammation of all gingival tissues was apparent, and a periapical abscess with mobility was noted on the left mandibular second molar. Medical and dental histories revealed numerous recurrent bacterial infections associated with oral and non-oral tissues. His medical history with recurrent infections led us to evaluate his 3-year-old sister to determine the status of her oral health. Inflammation of her oral tissues and recurrent bacterial infections were apparent. Their consanguineous parents were in good health. To assist in identifying possible systemic diseases underlying the inflammatory situation in the siblings, consultations were requested from the Pediatric Hematology Department at Selcuk University and Pediatric Oncology Department at Gulhane Military Medical Academy. RESULTS: Based on absolute neutrophil count (< or =200/mm(3)) and bone marrow aspiration findings consistent with early maturation arrest in myelopoiesis, the cases were diagnosed as SCN. No chromosomal abnormality was detected upon cytogenetic examination. Sequencing analysis also revealed no mutation in the neutrophil elastase or growth factor independent-1 (GFI-1) genes in these patients. Severe periodontal disease, attachment loss, and mobility for over 50% of the deciduous teeth were noted. Within 6 months, the male sibling lost all of his deciduous teeth due to periapical and periodontal infections. His sister presented with tooth mobility for all mandibular incisors. Monthly visits, including scaling, polishing, and 0.2% chlorhexidine digluconate irrigation were performed to support their oral hygiene and to avoid recurrent oral infections. We have been able to stabilize these patients' periodontal conditions during a 2-year follow-up period. CONCLUSION: This case report emphasizes the role of periodontists and pediatric dentists in the diagnosis of diseases linked with neutrophil and other systemic disorders and highlights the need to optimize the health of oral tissues with regular appointments.

Development of squamous cell carcinoma of the tongue during induction chemotherapy for acute myeloid leukemia.

Immunosuppression is a well-recognized cause of skin tumors, in particular squamous cell carcinomas (SCC). In patients with hematological malignancies undergoing chemotherapy, SCC has been reported late in the course of the disease or many years after completion of treatment. Here we report a patient with acute myeloid leukemia who developed a SCC of the tongue while receiving the third course of induction chemotherapy. This is the second such case in the medical literature. The role of immunosuppression, chemotherapy, the malignancy itself and possible genetic predisposition is discussed and the literature on this topic is reviewed.

Germline mutations of BRCA1 and BRCA2 genes in Turkish breast, ovarian, and prostate cancer patients.

Distribution and prevalence of germline mutations in BRCA1 and BRCA2 differ among different populations. For the Turkish population, several studies have addressed high-risk breast cancer and ovarian cancer (BC-OC) patients. In most studies, both genes were analyzed in part, and a quite heterogeneous mutation spectrum was observed. For high-risk Turkish prostate cancer (PCa) patients, however, there are no data available about mutations of germline BRCA genes. To accurately determine the contribution of germline mutations in BRCA1 and BRCA2 in Turkish BC, OC, and PCa high-risk patients, 106 high-risk BC-OC patients, 50 high-risk PCa patients, and 50 control subjects were recruited. The study represents the only full screening, to date, of a large series of Turkish high-risk BC-OC patients and the only study in Turkish high-risk PCa patients. Mutation screenings were performed on coding exons of both genes with either denaturing gradient gel electrophoresis or denaturing high performance liquid chromatography, or with both techniques. Three deleterious mutations in BRCA1 and three deleterious mutations in BRCA2 were detected in different BC-OC patients, and one truncating mutation was detected in a high-risk PCa patient. In addition, 28 different unclassified and mostly novel variants were detected in both genes, as well as several silent polymorphisms. These findings reflect the genetic heterogeneity of the Turkish population and are relevant to genetic counseling and clinical management.

A new syndrome associated with absence of lower lid lacrimal punctum, ptosis, elevation deficiency of both eyes and mild facial dysmorphism.

A considerable volume of literature has been published on the association of lacrimal outflow dysgenesis with developmental anomalies or systemic syndromes. We report three affected individuals in a consanguineous family those are associated with bilateral ptosis, upper ocular movement limitation, and absence of the lacrimal punctum. T our knowledge, this is the first article reporting the association of bilateral ptosis, facial dysmorphism, upper ocular movement limitation, and absence of the lacrimal punctum in a hereditary form. As a sole example, these findings may be accepted as a new syndrome with autosomal recessive pattern because of consanguinity.

Donor cell leukemia in a patient developing 11 months after an allogeneic bone marrow transplantation for chronic myeloid leukemia.

A 38-year-old female with chronic myeloid leukemia underwent an allogeneic bone marrow transplantation from her full-matched brother. Eleven months later, she readmitted with an acute leukemia that was shown to be of donor origin. The patient never achieved a remission even after chemotherapies with cytarabine and mitoxantrone, donor lymphocyte infusion, and second allogeneic peripheral blood stem cell transplantation. Donor cell leukemia (DCL) is sometimes misdiagnosed as relapse by clinicians and the real incidence may be higher than expected. Cytogenetic and molecular techniques may be helpful to clarify the issue of the leukemia. The current case is another case of DCL reported in the literature after an allogeneic transplant for a kind of leukemia.