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Objective:Gender assignment in infants and children with disorders of sex development (DSD) is a stressful situation for both patient/families and medical professionals.Methods:The purpose of this study was to investigate the results of gender assignment recommendations in children with DSD in our clinic from 1999 through 2019.Results:The mean age of the 226 patients with DSD at the time of first admission were 3.05±4.70 years. 50.9% of patients were 46,XY DSD, 42.9% were 46,XX DSD and 6.2% were sex chromosome DSD. Congenital adrenal hyperplasia (majority of patients had 21-hydroxylase deficiency) was the most common etiological cause of 46,XX DSD. In 46,XX patients, 87 of 99 (89.7%) were recommended to be supported as a female, 6 as a male, and 4 were followed up. In 46,XY patients, 40 of 115 (34.8%) were recommended to be supported as a female, and 70 as male (60.9%), and 5 were followed up. In sex chromosome DSD patients, 3 of 14 were recommended to be supported as a female, 9 as a male. The greatest difficulty in making gender assignment recommendations were in the 46,XY DSD group.Conclusion:In DSD gender assignment recommendations, the etiologic diagnosis, psychiatric gender orientation, expectation of the family, phallus length and Prader stage were effective in the gender assignment in DSD cases, especially the first two criteria. It is important to share these experiences among the medical professionals who are routinely charged with this difficult task in multidisciplinary councils.

Tüm ekzom dizileme analizi genetik etiyolojisinde heterojenite gösteren hastalıkların tanısında etkili bir yöntemdir. Ancak, çok sık görülen ve klinik etkisi bilinmeyen varyantların analizi ileri düzeyde klinik yorumlama ve fenotip-genotip korelasyonu gerektirmektedir. Bu sunumda, klinik fenotiplemenin elde edilen veriler ile birlikte değerlendirilmesinin önemini vurgulamak amacıyla, birden fazla kliniğe neden olan gen mutasyonuna sahip 3 olgu sunulmaktadır.

Inactivating autosomal recessive mutations in fibroblast growth factor 23 (FGF23), klotho (KL) and polypeptide N-acetylgalactosaminotransferase 3 (GALNT3) genes lead to a rare disorder, hyperphosphatemic familial tumoral calcinosis (HFTC). Patients with HFTC present with hyperphosphatemia and tumor like soft tissue calcifications. Although 78% of patients develop their first symptoms between the ages of 2-13 years, diagnosis is usually delayed until adulthood. Some individuals with the same genetic defect develop a condition named hyperphosphatemic hyperostosis syndrome. Herein we report two siblings suffering from periarticular, warm, hard and tender subcutaneous masses. Subcutaneous calcifications were present on X-ray and biopsy results were consistent with calcinosis in both patients. Laboratory results showed marked hyperphosphatemia and elevated renal tubular phosphate reabsorption rates, normal renal function tests and normal serum 25-hydroxyvitamin D levels. Thus, we suspected HFTC and performed next generation sequencing for the GALNT3 gene, reported as the most frequent cause. A novel homozygote P85Rfs*6 (c.254_255delCT) mutation in GALNT3 was identified in both siblings. Our report adds two new patients to the literature about this rare genetic disease and suggests that small deletions in the GALNT3 gene may be related with HFTC phenotype.

Amaç: Çalışmamızda epilepsi ve anlıksal yetiyitimlerinde ilk basamak tanı testi olarak moleküler karyotipleme yapmayı ve bu hastalıklar ile ilişkisini ortaya koymayı amaçladık.Gereç ve Yöntem: Cukurova University Balcalı Hastanesi Tıbbi Genetik Polikliniği'ne başvuran ve geniş bir klinik problem yelpazesi sergileyen 580 hastaya Affymetrix CytoScan platform aracılı moleküler karyotipleme yapıldı.Bulgular: Moleküler karyotipleme sonucunda anlıksal yetiyitimi olan hastaların %41’inde mikrodelesyon, %32’sinde duplikasyon ve %50’sinde hem delesyon hem de duplikasyon tespit edildi. Epilepsi hastalarının %16’sında mikrodelesyon, %34’ünde duplikasyon ve %50’sinde delesyon ve duplikasyon; anlıksal yetiyitiminin eşlik ettiği epileptik hastalarda %33.3 mikrodelesyon, %44.4 duplikasyon ve %22.2 hem delesyonlar hem de duplikasyon bulundu. Ayrıca, bu çalışmada bir epileptik hastada uniparental dizomi ve 2 hastada marker kromozom saptandı. Sonuç: Elde edilen sonuçlar, moleküler karyotipleme tekniğinin klinik rutinde uygulanmasının ve elde edilen verilerin tıbbi genetik uzmanı tarafından yorumlanmasının kromozom düzeyindeki anomalilerin veya sendromların tanınmasında faydalı olduğunu göstermektedir. Özellikle epilepsi ve anlıksal yetiyitimi olan hastaların tanısında ilk basamak tanı testi olarak moleküler karyotipleme tercih edilebilir.

Öz Ağır kombine immün yetmezlik immün sistem hücrelerinin defektleri ile ilgili olan nadir görülen genetik bir hastalıktır. Bu hastalık T lenfosit, B lenfosit ve Doğal Öldürücü (NK) lenfosit gruplarının birinde veya birkaçında görülebilir. Çalışmamızda Türkiye’nin güneyinde yer alan ağır kombine immün yetmezlikli hastalarda IL7R gen polimorfizmlerinin tanımlanması ve hastaların immünfenotip sonuçları ile birlikte değerlendirilmesi amaçlandı. Çalışmamızda ağır kombine immün yetmezlik tanısı alan 30 hastanın sanger DNA dizi analizi yöntemi ile analizi yapıldı. Hastalardan taze kan örnekleri alınarak akım sitometri yöntemi ile hastalardaki IL7R gen polimorfizmlerinin fenotiplendirilmesi yapıldı. Çalışmanın sonunda ağır kombine immün yetmezlikli hastalardan birinde (%3,3; 1/30) heterozigot p.R140Q (c.419G>A) mutasyonu tespit edilirken, hastaların 26’sında (%86,7; 26/30) de heterozigot ve/veya homozigot IL7R polimorfizmleri (T166I, I138V, T244I ve I356V) saptandı. Ağır immün yetmezlikli hastalarda IL7R gen polimorfizmlerinin sık görülmesi, bu polimorfizm ile hastalık arasında ilişki olduğu görüşünü güçlendirmiştir. Abstract Severe combined immunodeficiencies are a group of rare inherited disorders with profound defects in immune cells. This genetic disorder might have effect on T lymphocytes, B lymphocytes and/or Natural Killer cells (NK). This study aimed at the identifying the polymorphisms in IL7R gene present in severe combined immunodeficies patients who located in southern part of Turkey. A total of 30 patients with severe combined immunodeficiencies were investigated for IL7R polymorphisms using Sanger sequencing and immune phenotyping by flow cytometric analysis. One heterozygote p.R140Q (c.419G>A) mutation was identified in 1 patient (n=1, %3,3) and 86.7% (n=26) of all patients had IL7R polymorphisms (T166I, I138V, T244I and I356V) whether heterozygote and/or homozygote. The frequent occurence of IL7R gene polymorphisms in patients with severe immunodeficiency has strengthened the view that there is a relationship between this polymorphism and disease.

Objective:Breast cancer (BC) is the most common cancer type in women and may be inherited, mostly in an autosomal dominant pattern. The clinical diagnosis of BC relies on the published diagnostic criteria, and analysis of two genes, BRCA1 and BRCA2, which are strongly associated with BC, are included in these criteria. The aim of this study was to compare BC index cases with non-BC individuals in terms of genotype and diagnostic features to investigate the genotype/demographic information association.Materials and Methods:Mutational analyses for the BRCA1/BRCA2 genes was performed in 2475 individuals between 2013-2022 from collaborative centers across Turkey, of whom 1444 with BC were designated as index cases.Results:Overall, mutations were identified in 17% (421/2475), while the percentage of mutation carriers in cases of BC was similar, 16.6% (239/1444). BRCA1/BRCA2 gene mutations were detected in 17.8% (131/737) of familial cases and 12% (78/549) of sporadic cases. Mutations in BRCA1 were found in 4.9%, whereas 12% were in BRCA2 (p

BRCA1/2 mutations play a significant role in cancer pathogenesis and predisposition particularly in breast, ovarian and prostate cancers. Thus, germline analysis of BRCA1 and BRCA2 is essential for clinical management strategies aiming at the identification of recurrent and novel mutations that could be used as a first screening approach. We analyzed germline variants of BRCA1/2 genes for 2168 individuals who had cancer diagnosis or high risk assessment due to BRCAs related cancers, referred to 10 health care centers distributed across 7 regions covering the Turkish landscape. Overall, 68 and 157 distinct mutations were identified in BRCA1 and BRCA2, respectively. Twenty-two novel variants were reported from both genes while BRCA2 showed higher mutational heterogeneity. We herein report the collective data as BRCA Turkish consortium that confirm the molecular heterogeneity in BRCAs among Turkish population, and also as the first study presenting the both geographical, demographical and gene based landscape of all recurrent and novel mutations which some might be a founder effect in comparison to global databases. This wider perspective leads to the most accurate variant interpretations which pave the way for the more precise and efficient management affecting the clinical and molecular aspects.

Abstract Next Generation Sequencing (NGS) has uncovered hundreds of common and rare genetic variants involved in complex and rare diseases including immune deficiencies in both an autosomal recessive and autosomal dominant pattern. These rare variants however, cannot be classified clinically, and common variants only marginally contribute to disease susceptibility. In this study, we evaluated the multi-gene panel results of Common Variable Immunodeficiency (CVID) patients and argue that rare variants located in different genes play a more prominent role in disease susceptibility and/or etiology. We performed NGS on DNA extracted from the peripheral blood leukocytes from 103 patients using a panel of 19 CVID-related genes: CARD11, CD19, CD81, ICOS, CTLA4, CXCR4, GATA2, CR2, IRF2BP2, MOGS, MS4A1, NFKB1, NFKB2, PLCG2, TNFRSF13B, TNFRSF13C, TNFSF12, TRNT1 and TTC37. Detected variants were evaluated and classified based on their impact, pathogenicity classification and population frequency as well as the frequency within our study group. NGS revealed 112 different (a total of 227) variants with under 10% population frequency in 103 patients of which 22(19.6%) were classified as benign, 29(25.9%) were classified as likely benign, 4(3.6%) were classified as likely pathogenic and 2(1.8%) were classified as pathogenic. Moreover, 55(49.1%) of the variants were classified as variants of uncertain significance. We also observed different variant frequencies when compared to population frequency databases. Case–control data is not sufficient to unravel the genetic etiology of immune deficiencies. Thus, it is important to understand the incidence of co-occurrence of two or more rare variants to aid in illuminating their potential roles in the pathogenesis of immune deficiencies.

Abstract Background This case series includes longitudinal clinical data of ten patients with Morquio A syndrome from south and southeastern parts of Turkey, which were retrospectively collected from medical records. All patients received enzyme replacement therapy (ERT). Clinical data collected included physical appearance, anthropometric data, neurological and psychological examinations, cardiovascular evaluation, pulmonary function tests, eye and ear-nose-throat examinations, endurance in the 6-min walk test and/or 3-min stair climb test, joint range of motion, and skeletal investigations (X-rays, bone mineral density). Results At the time of ERT initiation, two patients were infants (1.8 and 2.1 years), five were children (3.4–7.1 years), and three were adults (16.5–39.5 years). Patients had up to 4 years follow-up. Most patients had classical Morquio A, based on genotypic and phenotypic data. Endurance was considerably reduced in all patients, but remained relatively stable or increased over time in most cases after treatment initiation. Length/height fell below normal growth curves, except in the two infants who started ERT at ≤ 2.1 years of age. All patients had skeletal and/or joint abnormalities when ERT was started. Follow-up data did not suggest improvements in skeletal abnormalities, except in one of the younger infants. Nine patients had corneal clouding, which resolved after treatment initiation in the two infants, but not in the other patients. Hepatomegaly was reported in seven patients and resolved with treatment in five of them. Other frequent findings at treatment initiation were coarse facial features (N = 9), hearing loss (N = 6), and cardiac abnormalities (N = 6). Cardiac disease deteriorated over time in three patients, but did not progress in the others. Conclusions Overall, this case series with Morquio A patients confirms clinical trial data showing long-term stabilization of endurance after treatment initiation across ages and suggest that very early initiation of ERT optimizes growth outcomes.

Amaç: Bu çalışmada Henoch Shönlein purpurası (HSP) tanılı çocuklarda C2 gen polimorfizmlerinin semptomlar ve hastalık şiddeti üzerine etkilerinin incelenmesi amaçlanmıştır. Gereç ve Yöntem: Bu kesitsel çalışmaya kliniğimizde Temmuz 2016 ve Mart 2018 tarihleri arasında HSP tanısı almış ve en az 6 ay takip edilmiş olan 49 çocuk hasta dahil edilmiştir. Kompleman C2 gen polimorfizmlerini değerlendirmek amacı ile Sanger sekanslama tekniği kullanılmıştır. Hastalar C2 gen polimorfizm varlığına gruplara ayrılarak klinik ve laboratuvar verileri karşılaştırılmıştır. Bulgular: Çalışmamızda sadece 6 (%12,2) hastada C2 gen polimorfizmleri saptanmıştır. Bunlar; rs9332739 (n=3), rs36221133 (n=2), rs146054348 (n=1) olarak sıralanabilir. C2 gen polimorfizmleri varlığına göre hasta grupları arasında yaş, gastrointestinal ve eklem tutulumları, serum kompleman düzeyleri, böbrek tutulumu, sistemik steroid gereksinimi ve hastalık relaps oranları benzer bulunmuştur. C2 gen polimorfizmi olan hastalarda, olmayanlara göre istatistiksel anlamlı olarak daha yüksek serum IgM düzeyi ve daha düşük lökosit sayısı saptanmıştır. Sonuç: Konusunda ilk olan çalışmamızda her ne kadar C2 gen polimorfizmlerinin HSP’li hastalarda klinik bulgular ve hastalık seyri üzerine etkisi gösterilememiş olsa da, HSP tanılı hastalarda yüksek serum IgM düzeyi C2 gen polimorfizmi ile ilişkili olabilir.

The most common cancer-related cause of death worldwide is colorectal cancer. It is initiated with the formation of polyps, which further cause the development of colorectal cancer in multistep phases. Colorectal cancer mortality is high despite recent treatment breakthroughs and a greater understanding of its pathophysiology. Stress is one of the major causes of triggering different cellular signalling cascades inside the body and which might turn toward the development of cancer. Naturally occurring plant compounds or phytochemicals are being studied for medical purposes. Phytochemicals’ benefits are being analyzed for inflammatory illnesses, liver failure, metabolic disorders, neurodegenerative disorders, and nephropathies. Cancer treatment with fewer side effects and better outcomes has been achieved by combining phytochemicals with chemotherapy. Resveratrol, curcumin, and epigallocatechin-3-gallate have been studied for their chemotherapeutic and chemopreventive potentiality, but hydrophobicity, solubility, poor bioavailability, and target selectivity limit the clinical uses of these compounds. The therapeutic potential is maximized by utilizing nanocarriers such as liposomes, micelles, nanoemulsions, and nanoparticles to increase phytochemical bioavailability and target specificity. This updated literature review discusses the clinical limitations, increased sensitivity, chemopreventive and chemotherapeutic effects, and the clinical limitations of the phytochemicals.

Objective: The programmed cell death 1 (PD-1) receptor is an immune checkpoint receptor expressed by activated T cells. PD-1 inhibits the immune system by binding to its ligands expressed on tumor cells. Nivolumab and pembrolizumab are some of the monoclonal antibodies that inhibit the PD-1. We present our experience with eight cases which were treated with nivolumab for different malignant diseases in our clinic. Methodology: A total of eight patients (5 girls, 3 boys) aged between 4 and 16 years were treated with nivolumab at 3mg/kg/dose approximately twice a week in Erciyes University Pediatric Hematology clinic between 2019-2021. Nivolumab treatments of seven patients were given median 11 (4-32) doses and discontinued due to progression at a median 6 months (2-17 months). Results: Four patients were diagnosed with miss match repair syndrome in addition to their malignant disease. Non-Hodgkin lymphoma (two with T-cell and one with histiocyte-rich B-cell) in three patients, brain tumor (pons glioma, midline glioma, glioblastoma multiforme) in three patients, germ cell tumor (yolk salk, immature teratoma) in two patients, one patient had colon adenocarcinoma in addition to brain tumor. Except for nausea in a patient, no drug-related side effect was observed in patients. Conclusion: Nivolumab was well tolerated in patients with CMMRD syndrome with some transient partial responses. There is a risk of developing secondary cancer in patients with CMMRD syndrome. Further studies are needed due to the limited use in children.

Abstract The lack of awareness of patient risk factors, failure to obtain adequate family history, was discussed by clinical experience in prenatal testing of hypophosphatasia with a novel variant in the ALPL gene identified in the index case of the family.

Three prime repair exonuclease 1 (TREX1) degrades single- and double-stranded DNA with 3’-5’ exonuclease activity. TREX1 mutations are related to type 1 interferon-mediated autoinflammation owing to accumulated intracellular nucleic acids. Several cases of systemic lupus erythematosus, Aicardi–Goutieres syndrome (AGS), familial chilblain lupus (FCL), and retinal vasculopathy-cerebral leukodystrophy caused by TREX1 mutations have been reported, so far. In this report, we described five patients with TREX1 mutations from three families with three different disorders, which include AGS, FCL, and FCL with central nervous system vasculitis.

Neurodegeneration with brain iron accumulation (NBIA) is a group of genetic disorders with a progressive extrapyramidal syndrome and excessive iron deposition in the brain, particularly in the globus pallidus and substantia nigra. Mitochondrial membrane protein–associated neurodegeneration (MPAN), a subtype of NBIA, is caused by mutation in the orphan gene C19orf12. A slowly progressive gait disorder from generalized dystonia and spasticity and cognitive impairment constitute the main features of MPAN. The C19orf12 p.Thr11Met mutation is frequent among Turkish patients with MPAN. Here, we report the clinical manifestations and genetic study results of six Turkish patients with MPAN due to different mutations from previous.

Familial hypertrophic cardiomyopathy is a genetically heterogeneous disease with variable clinical features that is inherited as autosomal dominant with variable penetrance. Recent developments in genetics of hereditary cardiomyopathy have not only enlightened many points about pathogenesis, but have also provided great benefit to diagnostic approaches of clinicians. Heterozygous mutation of c3691-3692insTTCA in MYBPC3 gene was identified in a pediatric patient with diagnosis of hypertrophic cardiomyopathy at clinic. Hypertrophy was observed in sister and father of the patient in echocardiography screening, and it was subsequently determined that they also had same mutation. This mutation has not previously been defined and reported previously in the literature as cause of hypertrophic cardiomyopathy.

Background: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by multiple, large renal cysts and impaired kidney function. Although the reason for the development of kidney cysts is unknown, ADPKD is associated with cell cycle arrest and abundant apoptosis of renal tubular epithelial cells. Aims: We asked whether serum-soluble TNF-related apoptosis-inducing ligand (sTRAIL) might underlie ADPKD. Study Design: Case-control study. Methods: Serum sTRAIL levels were measured in 44 patients with ADPKD and 18 healthy volunteers. The human soluble TRAIL/Apo2L ELISA kit was used for the in vitro quantitative determination of sTRAIL in serum samples. Results: Mean serum sTRAIL levels were lower in patients with ADPKD as compared to the control group (446.9±103.1 and 875.9±349.6 pg/mL, p0.05). Conclusion: Our results show that ADPKD patients have depressed sTRAIL levels, indicating apoptosis unrelated to the stage of chronic renal failure.

Background. Allergic asthma is showed an increase in Th2-cytokine and IgE levels and an accumulation activation of Th2 cells, eosinophils and mast cells. However, recent studies focused on cell-based mechanisms for the pathogenesis of allergic asthma. Objectives. In this study, we compare the anti-IgE treatment modality in the dynamics of immune system cytokine levels in severe persistent asthma (SPA) patients who had no other any allergic disease, newly diagnosed allergic asthma patients and healthy volunteers. Study Design. The study population consisted of 14 SPA patients, 14 newly diagnosed allergic asthma patients and 14 healthy volunteers included as controls. Cytokine levels were measured. Total and specific IgE levels of anti-IgE monoclonal antibody treated patients, serum high-sensitivity C-reactive protein (hsCRP) levels, FEV1/FVC rates and asthma control test (ACT) were measured for the clinical follow-up. Results. We observed that SPA patients presented increasing levels of IL-8, IL-10, TGF-β and GCSF during the anti-IgE treatment in period of sampling times at 4 months and 18 months. However this increase was not correlated neither with serum hsCRP levels nor FEV1/FVC rates. Conclusions. Our study gives a different perspective for the SPA and anti-IgE immunotherapy efficacy at the cell cytokine-linked step.