Publications by authors named "Atil Bisgin"

65 Publications

The impact of rare and low-frequency genetic variants in common variable immunodeficiency (CVID).

Sci Rep 2021 Apr 15;11(1):8308. Epub 2021 Apr 15.

Division of Pediatric Allergy and Immunology, Faculty of Medicine, Balcali Hospital and Clinics, Cukurova University, Adana, Turkey.

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.
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http://dx.doi.org/10.1038/s41598-021-87898-1DOI Listing
April 2021

Current update on SARS-CoV-2 vaccine development with a special emphasis on gene therapy viral vector design and construction for vaccination.

Hum Gene Ther 2021 Apr 15. Epub 2021 Apr 15.

Akdeniz University Medical School, 64032, The Department of Gene and Cell Therapy, Antalya, Turkey;

Severe acute respiratory syndrome (SARS) is a newly emerging infectious disease (COVID-19) caused by the novel coronavirus SARS-CoV-2. To combat the devastating spread of SARS-CoV-2, extraordinary efforts from numerous laboratories have focused on the development of effective and safe vaccines. Traditional live-attenuated or inactivated viral vaccines are not recommended for immunocompromised patients as the attenuated virus can still cause disease via phenotypic or genotypic reversion. Subunit vaccines require repeated dosing and adjuvant use to be effective, and DNA vaccines exhibit lower immune responses. mRNA vaccines can be highly unstable under physiological conditions. On the other hand, naturally antigenic viral vectors with well-characterized structure and safety profile serve as among the most effective gene carriers to provoke immune response via heterologous gene transfer. Viral vector-based vaccines induce both an effective cellular immune response and a humoral immune response owing to their natural adjuvant properties via transduction of immune cells. Consequently, viral vectored vaccines carrying the SARS-CoV-2 spike protein have recently been generated and successfully used to activate cytotoxic T cells and develop a neutralizing antibody response. Recent progress in SARS-CoV-2 vaccines, with an emphasis on gene therapy viral vector-based vaccine development, is discussed in this review.
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http://dx.doi.org/10.1089/hum.2021.052DOI Listing
April 2021

Experience with the targeted next-generation sequencing in the diagnosis of hereditary hypophosphatemic rickets.

J Pediatr Endocrinol Metab 2021 Apr 12. Epub 2021 Apr 12.

Department of Pediatrics, Division of Pediatric Endocrinology, Cukurova University Faculty of Medicine, Adana, Turkey.

Objectives: Hereditary Hypophosphatemic Rickets (HHR) is a heterogeneous group of disorders characterized by hypophosphatemia. Although the X-linked dominant HHR is the most common form, the genetic etiology of HHR is variable. Recently, developed next-generation sequencing techniques may provide opportunities for making HHR diagnosis in a timely and efficient way.

Methods: We investigated clinical and genetic features for 18 consecutive probands and their 17 affected family members with HHR. All patient's clinical and biochemical data were collected. We first analyzed a single gene with Next-generation sequencing if the patients have a strong clue for an individual gene. For the remaining cases, a Hypophosphatemic Rickets gene panel, including all known HHR genes by Next-generation sequencing, was employed.

Results: We were able to diagnosis all of the consecutive 35 patients in our tertiary care center. We detected nine novel and 10 previously described variants in (9; 50%), (3; 17%), (3; 17%), (1; 5%), (1; 5%), and (1; 5%).

Conclusions: To delineate the etiology of HHR cases in a cost and time-efficient manner, we propose single gene analysis by next-generation sequencing if findings of patients indicate a strong clue for an individual gene. If that analysis is negative or for all other cases, a Next-generation Sequence gene panel, which includes all known HHR genes, should be employed.
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http://dx.doi.org/10.1515/jpem-2020-0624DOI Listing
April 2021

The cumulative effects of MEFV gene polymorphisms and mutations in patients with inflammatory bowel diseases.

J Pak Med Assoc 2021 02;71(2(A)):479-483

Department of Pediatric Gastroenterology, Hepatology and Nutrition, Cukurova University, Turkey.

Objective: To determine the cumulative effects of Mediterranean fever gene polymorphisms and mutations in patients with ınflammatory bowel diseases.

Methods: The case-control study was conducted from January, 2012, to January, 2016,at Cukurova University, Turkey, and comprised patients diagnosed with inflammatory bowel diseases and followed up at the Children Gastroenterology Department. By using molecular methods, 12 Mediterranean fevergene variants most frequently observed in the country were examined in all the diagnosed cases. The results were compared with age-matched healthy population data from the Genetic Diseases Diagnosis and Treatment Centre. Data was analysed using Graph Pad Prism.

Results: Of the 151 subjects, 46(30.4%) were cases and 105(69.5%) were controls. Among the cases, there were 23(50%) subjects with a mean age of 14.8±3 years who had ulcerative colitis, and 23(50%) with mean age 14.5±3.2 years who had Crohn's disease. The mean age of the controls was 16.4±3.2 years (p=0.716). Patients with ulcerative colitishad high frequencies of C allele in D102D T>C variant, G allele in G138G A>G variant, A allele in A165A C>A variant and A allele in R202Q G>A variant. Those with Crohn's disease frequently had wild type of R202Q G>A variant. Also, D102D T>C / R314R C>T haplotype was common at a certain level in the UC group.

Conclusions: Mediterranean fever gene variant was more frequently found in cases with ulcerative colitis compared to the controls.
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http://dx.doi.org/10.47391/JPMA.762DOI Listing
February 2021

Morquio A syndrome and effect of enzyme replacement therapy in different age groups of Turkish patients: a case series.

Orphanet J Rare Dis 2021 Mar 22;16(1):144. Epub 2021 Mar 22.

Division of Pediatric Metabolism and Nutrition, Department of Pediatrics, Faculty of Medicine, Çukurova University, 01130, Sarıçam, Adana, Turkey.

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.
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http://dx.doi.org/10.1186/s13023-021-01761-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983100PMC
March 2021

Mitochondrial Membrane Protein-Associated Neurodegeneration: A Case Series of Six Children.

Ann Indian Acad Neurol 2020 Nov-Dec;23(6):802-804. Epub 2019 Sep 17.

Department of Medical Genetics, AGENTEM, Cukurova University Faculty of Medicine, Adana, Turkey.

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 . A slowly progressive gait disorder from generalized dystonia and spasticity and cognitive impairment constitute the main features of MPAN. The 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.
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http://dx.doi.org/10.4103/aian.AIAN_268_19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7900730PMC
September 2019

The emerging clinical relevance of genomic profiling in neuroendocrine tumours.

BMC Cancer 2021 Mar 6;21(1):234. Epub 2021 Mar 6.

Cukurova University AGENTEM & Cukurova University Faculty of Medicine Medical Genetics Department of Balcali Hospital and Clinics, Adana, Turkey.

Background: Neuroendocrine tumours (NETs) arise from hormone-producing or nervous system cells and can develop from anywhere in the body. They have heterogeneous origins from skin to gastrointestinal track and a complicated histology. Thus, there is an inevitable need for genomic profiling to determine the exact genetics of each tumour for prognosis and treatment strategies to overcome the disease's complexity. For this purpose, next-generation-sequencing (NGS) is the most reliable methodology for both germ-line and somatic studies to make a clinical diagnosis. In this study, we analyse liquid biopsies, formalin fixed paraffin embedded (FFPE) tissues, and peripheral blood samples for their ability to provide information for actionability.

Methods: A customized multi-gene panel comprised of Succinate Dehydrogenase Complex Iron Sulfur Subunit B (SDHB), Succinate Dehydrogenase Complex Subunit C (SDHC), Cell Division Cycle 73(CDC73), Calcium Sensing Receptor (CASR), Platelet Derived Growth Factor Receptor Alpha (PDGFRA), Succinate Dehydrogenase Complex Flavoprotein Subunit A (SDHA), Ret Proto-Oncogene (RET), Succinate Dehydrogenase Complex Assembly Factor 2(SDHAF2), Menin 1(MEN1), Succinate Dehydrogenase Complex Subunit D (SDHD), MYC Associated Factor X (MAX) and Protein Kinase CAMP-Dependent Type I Regulatory Subunit Alpha (PRKAR1A) genes was constructed to assess multiple specimen types including: 3 liquid biopsies, 6 FFPE tissues, and 26 peripheral blood samples from 35 unique NET patients. Quality-control and bioinformatics analyses were performed using QCI-Analyze and QCI-Interpret.

Results: The three liquid biopsies and the 6 FFPE tissue samples were evaluated for somatic mutations; while the 26 peripheral blood samples were analysed using the germ-line pipeline. Five (55.6%) of the nine patients that were studied for somatic changes carried actionable mutations related to therapy sensitivities. Through the germ-line studies, we observed a 50% positivity rate for disease predisposition with 16 variants classified according to ACMG (American College of Medical Genetics) Standards and Guidelines.

Conclusions: Genomic profiling medicine is an emerging area of clinical oncology and has become crucial for disease and patient management by providing a precision approach; this is especially true for rare diseases including rare cancers such as NETs. Notably, this study emphasized the relevance of multiple distinctive biological sample types for use in the genetic testing of cancers to help with the choice of therapy to maximize the likelihood of a positive clinical outcome.
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http://dx.doi.org/10.1186/s12885-021-07961-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937236PMC
March 2021

Different Clinical Manifestations of Three Prime Repair Exonuclease 1 Mutation: A Case Series.

Ann Indian Acad Neurol 2020 Sep-Oct;23(5):699-703. Epub 2020 Dec 8.

Department of Pediatric Immunology, AGENTEM, Cukurova University Faculty of Medicine, Adana, Turkey.

Three prime repair exonuclease 1 () degrades single- and double-stranded DNA with 3'-5' exonuclease activity. 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 mutations have been reported, so far. In this report, we described five patients with mutations from three families with three different disorders, which include AGS, FCL, and FCL with central nervous system vasculitis.
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http://dx.doi.org/10.4103/aian.AIAN_469_18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887468PMC
December 2020

Current Status of Genetic Diagnosis Laboratories and Frequency of Genetic Variants Associated with Cystic Fibrosis through a Newborn-Screening Program in Turkey.

Genes (Basel) 2021 Jan 31;12(2). Epub 2021 Jan 31.

Medical Genetics Department, Faculty of Medicine, Cukurova University, Adana 01250, Turkey.

Background: Cystic fibrosis (CF) is the most common worldwide, life-shortening multisystem hereditary disease, with an autosomal recessive inheritance pattern caused by mutations in the cystic fibrosis transmembrane conductance regulator () gene. The national newborn screening (NBS) program for CF has been initiated in Turkey since 2015. If the immunoreactive trypsinogen (IRT) is elevated (higher than 70 μg/L in the second control) and confirmed by sweat test or clinical findings, genetic testing is performed. The aims of this study are to emphasize the effect of NBS on the status of genetic diagnosis centers with the increasing numbers of molecular testing methods, and to determine the numbers and types of mutations in Turkey.

Methods: The next-generation sequencing (NGS) and multiplex ligation-dependent probe amplification (MLPA) results of 1595 newborns, who were referred to Cukurova University Adana Genetic Diseases Diagnosis and Treatment Center (AGENTEM) for molecular genetic testing, were evaluated with positive CF NBS program results since 2017.

Results: According to the results; 560 (35.1%) of the 1595 patients carried at least 1 (one) CF-related variant, while 1035 patients (64.9%) had no mutation. Compound heterozygosity for two mutations was the most common in patients, while two detected variants were homozygote in 14 patients. A total of 161 variants were detected in 561 patients with mutations. Fifteen novel variants that have not been previously reported were found. Moreover, p.L997F was identified as the most frequent pathogenic mutation that might affect the IRT measurements used for the NBS. The distribution of mutation frequencies in our study showed a difference from those previously reported; for example, the well-known p.F508del was the third most common ( = 42 alleles), rather than the first. The most striking finding is that 313 cases had a pathogenic variant together with the V470M variant, which might have a cumulative effect on CF perpetuation.

Conclusion: This study is the first to determine the mutational spectrum of CFTR in correlation with the NBS program in the Turkish population. NBS for CF raises issues regarding screening in diverse populations, both medical and non-medical benefits, and carrier identification. Through the lens of NBS, we focused on the integrated diagnostic algorithms and their effect on the results of genetic testing.
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http://dx.doi.org/10.3390/genes12020206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910984PMC
January 2021

A Novel Intronic Mutation Reduces HAX1 Level and is Associated With Severe Congenital Neutropenia.

J Pediatr Hematol Oncol 2021 Feb 3. Epub 2021 Feb 3.

Departments of Pediatrics, Division of Pediatric Allergy and Immunology Medical Biology Pediatrics, Division of Pediatric Hematology-Oncology & Pediatric HSCT Unit, Faculty of Medicine, Erciyes University Pediatric Allergy and Immunology Clinic, Kayseri City Hospital, Health Science University Betül-Ziya Eren Genome and Stem Cell Center (GENKOK), Kayseri Adana Genetic Diseases Diagnosis and Treatment Center (AGENTEM) Department of Medical Genetics, Faculty of Medicine, Cukurova University, Adana, Turkey Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-Universität München, Munich, Germany.

Severe congenital neutropenia (SCN) is a rare disease. Autosomal recessive forms of SCN are more frequent in countries where consanguineous marriages are common. In this report, we describe a 54-day-old female with neutropenia who presented with ecthyma gangrenosum. Clinical exome sequencing was used to identify the mutation. HAX1 messenger RNA and isoforms were examined by real-time quantitative and conventional polymerase chain reaction. Bone marrow aspiration was stained by hematoxylin and eosin. Granulocytes were tested for apoptosis upon H2O2 exposure. T-cell proliferation was tested by flow cytometry. Clinical exome sequencing revealed a novel homozygous acceptor splice site mutation in intron 3 of HAX1 (c.505-1G>C), which reduced both isoforms A and B of HAX1 messenger RNA. The Western blot studies showed a complete absence of neutrophils from the patient showed increased apoptosis upon H2O2 exposure, whereas T-cell proliferative responses to various stimuli were intact. The patient was treated with combined antibiotics, filgrastim, and placed on antibiotics prophylaxis. To the best of our knowledge, our data provide the first experimental evidence for HAX1 deficiency because of a splice site mutation. Although 3 other splice site variants have been deposited in databases, functional studies were missing. This novel variant of HAX1 may explain the SCN and secondary infections in our patients.
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http://dx.doi.org/10.1097/MPH.0000000000002071DOI Listing
February 2021

Evaluation of The Results of Patients who Applied to the Cukurova University Medical Genetics Department for Prenatal Diagnosis and Determination of Genetic Counseling Principles.

Turk J Med Sci 2020 Nov 16. Epub 2020 Nov 16.

Introduction: The aim of this study was to summarize the experiences of a single medical center for genetic diagnosis and treatment of prenatal patients.

Materials And Methods: This study includes a retrospective data analysis of 2843 prenatally investigated cases using invasive methods during a 6-year period (2013-2019) at a single tertiary care center.

Results: Chromosomal abnormalities were detected in 80 out of 1221 amniotic fluid samples; 178 out of 1608 chorionic villus samples; and 1 out of 14 cordocentesis samples. The most common chromosomal abnormality was trisomy 21. At least one mutation was detected in 63 of the 152 molecular tests performed on fetuses.

Conclusion: Clinical procedures such as ultrasounds and genetic tests are able to provide a better clinical follow-up for pregnant women about the possible congenital anomalies or any genetic condition, with proper genetic counseling and testing methodology.
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http://dx.doi.org/10.3906/sag-2004-298DOI Listing
November 2020

Identification of a novel homozygous variant in the alkaline phosphate () gene associated with hypophosphatasia.

Clin Case Rep 2020 Sep 21;8(9):1719-1721. Epub 2020 Jun 21.

Perinatology Unit Obstetrics And Gynecology Department of Balcali Clinics and Hospital Faculty of Medicine Cukurova University Adana Turkey.

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.
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http://dx.doi.org/10.1002/ccr3.2962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7495770PMC
September 2020

Primary melanoma of the urinary tract; Clinicopathologic and molecular review of a case series.

Pathol Res Pract 2020 Sep 29;216(9):153095. Epub 2020 Jun 29.

Cukurova University Medical School, Department of Pathology, 01260, Saricam, Adana, Turkey.

Primary melanoma of the urinary tract is a very rare and aggressive cancer. It accounts for less than 1% of all the melanoma cases, making it difficult to histopathologically diagnose and manage. We present a retrospective case series of eight primary urinary tract melanoma with clinical, pathological, and molecular findings to add more insight to this challenging disease. These cases were evaluated for histopathological, immunohistochemical, and molecular features of melanoma that were most commonly found in the urethra, followed by those in the bladder and ureter. Identification of nested growth patterns and in situ melanocytic components at cell edges are helpful in the histopathological diagnosis of amelanotic or hypomelanotic tumors. Our results indicate that urinary tract melanoma has several molecular traits, such as gene expression patterns. Genetic mutations may be related to metastasis, as well as provide targets for the management programs.
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http://dx.doi.org/10.1016/j.prp.2020.153095DOI Listing
September 2020

From infancy to adulthood: challenges in congenital nephrogenic diabetes insipidus.

J Pediatr Endocrinol Metab 2020 Jul 4. Epub 2020 Jul 4.

Department of Pediatric Nephrology, Cukurova Univsersity Faculty of Medicine, Adana, Turkey.

Objectives Congenital nephrogenic diabetes insipidus (NDI) is a rare hereditary disorder which is characterized by unresponsiveness to arginine vasopressin (AVP) in collecting ducts and leads to polyuria and polydipsia. The wide clinical spectrum of congenital NDI can cause difficulties in early diagnosis. We aimed to evaluate clinical prognosis of children with congenital NDI in long-term period. Methods Nineteen children with congenital NDI followed up in Pediatric Nephrology Department were enrolled to the study. This study is a single-center retrospective study, which reports clinical follow-up and genetic results of children with congenital NDI. Results Presenting symptoms of patients were mostly dehydration and fever due to polyuria and polydipsia. Four male patients had bilateral nonobstructive hydroureteronephrosis (HUN) and neurogenic bladder which requires clean intermittent catheterization (CIC). One patient had intracranial calcification which is a rarely seen complication in congenital NDI due to recurrent hypernatremic dehydration and severe brain dehydration. The causative mutations were identified in all patients. The identified mutations in six of them (31.6%) were hemizygous mutations in AVPR2 gene and homozygous mutations of AQP2 gene in the rest 13 cases (68.4%). More than that, four of these mutations (two in AVPR2 and two in AQP2) were novel mutations. Noncompliance with the treatments is associated with high risk of morbidity due to neurogenic bladder and chronic kidney disease (CKD). Conclusions The prognosis of congenital NDI is good when diagnosis can be made early and treatment is started immediately. Genetic counseling and prenatal testing for hereditary diseases are recommended especially in regions with relatively higher rates of consanguineous marriages.
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http://dx.doi.org/10.1515/jpem-2019-0529DOI Listing
July 2020

Evaluation of phenotypic and genotypic features of children with distal kidney tubular acidosis.

Pediatr Nephrol 2020 12 1;35(12):2297-2306. Epub 2020 Jul 1.

Department of Pediatric Nephrology, Cukurova University Faculty of Medicine, Adana, Turkey.

Background: The present study aimed to assess genotype-phenotype correlations with long-term prognosis in children with distal kidney tubular acidosis (dKTA). The kidney function of children with dKTA could be impaired in the long-term.

Methods: Thirty-one children with dKTA from 23 families were included in the present study. Demographic features, growth parameters, clinical manifestations, follow-up results, and genetic analysis results of the patients were recorded.

Results: Eighteen children (58.1%) were male. The median age at diagnosis was 3 months. The median follow-up period was 77 months and the longest was 23.5 years. Eight (28.8%) patients had chronic kidney disease (CKD) stage 2 or 3. Three patients aged 24, 23, and 19 years had CKD stage 3 with an estimated glomerular filtration rate of 54, 57, and 48 mL/min/1.73 m, respectively. Thirteen patients had mutations in the ATP6V0A4 gene, eight had mutations in the ATP6V1B1 gene, and three had mutations in the SLC4A1 gene. There was no significant correlation between molecular diagnosis and CKD. Growth retardation with a height below a standard deviation (SD) score of - 2 was found in 14 patients (45.1%) at the time of diagnosis. The mean height SD score at the last visit was significantly higher in patients who had adequate metabolic control at > 75% of all visits as compared with that in patients who did not.

Conclusion: Patients with dKTA usually have a good clinical prognosis in childhood with appropriate treatment; however, dRTA is characterized by deterioration of kidney function in adulthood, particularly after puberty.
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http://dx.doi.org/10.1007/s00467-020-04685-2DOI Listing
December 2020

The contribution of diet preference to the disease course in children with familial Mediterranean fever: a cross-sectional study.

Reumatologia 2020 30;58(2):81-86. Epub 2020 Apr 30.

Department of Pediatric Gastroenterology, Cukurova University Faculty of Medicine, Adana, Turkey.

Objectives: Familial Mediterranean fever (FMF) is characterized by recurrent, self-limiting attacks of fever and serositis. Nutrition is very important in the management of chronic diseases. Previous studies suggested that salty and fatty diet cause inflammation, therefore we aimed to investigate the effects of dietary self-efficacy and behavior about low-salt or low-fat diet on disease course in children with FMF.

Material And Methods: This cross-sectional study included patients aged between 10-18 years, diagnosed in our department and admitted between June 2019 and September 2019. Demographic and clinical properties were obtained from the medical files of the patients. Children's Dietary Self-Efficacy Scale (CDSS) and Health Behavior Questionnaire (HBQ) - Diet Behavior Scale (DBS) were performed for dietary self-efficacy and behavior about preferring low-salt or low-fat diet. Clinical features were compared between patients, which were grouped according to the sum of these two scales, with a cut-off score of 5.

Results: The mean age of 74 FMF patients (44 females, 34 males), included in the study, was 14.6 ±2.82 years. Median CDSS and DBS scores of the patients were 5 (minimum -6, maximum 14) and 0 (minimum -10, maximum 12), respectively. According to the sum of these two scales, 39 (52.7%) patients who had scored at least 5, had a statistically higher rate of complete response to colchicine. The remaining clinical parameters were similar between these two groups.

Conclusions: Low-salt or low-fat diet may be an adjuvant modification in the management of children with FMF. Further studies are needed to clarify the role of low-salt or low-fat diet in FMF pathogenesis.
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http://dx.doi.org/10.5114/reum.2020.95361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7249529PMC
April 2020

Integration of Liquid Biopsies into Clinical Laboratory Applications via NGS in Cancer Diagnostics.

Clin Lab 2020 May;66(5)

Background: Next Generation Sequencing is one of the latest advances in molecular testing and clinical laboratory applications. Next Generation Sequencing techniques involving liquid biopsies are emerging as important tools in cancer diagnostics and prognostics. Thus, integration of liquid biopsy studies into clinical laboratory applications has become a necessity. By virtue of liquid biopsies, determining potential treatment targets through metastasis and primary tumor sites in the right clinical context can result in a more comprehensive treatment. This also helps to overcome re-sampling difficulties which require an invasive procedure with the problem of tumor heterogeneity. As the literature involving liquid biopsies and next generation sequencing increases, the rate of laboratories with competencies and experience in this novel technology remains limited.

Methods: Next generation sequencing was performed via a comprehensive multi-gene cancer panel (Actionable In-sight Solid Tumor Panel, Qiagen) consisting of 12 solid tumor related genes (EGFR, ALK, KRAS, PIK3CA, NRAS, PDGFRA, KIT, ERBB2, ERBB3, ESR1, BRAF and RAF1) from lung cancer patients who applied or were referred to CU AGENTEM (Cukurova University Adana Genetic Diseases Diagnosis and Treatment Center) for routine genetic testing.

Results: A modified next generation sequencing workflow was performed with a multi-gene solid tumor panel using liquid biopsies in comparison with formalin fixed paraffin embedded samples to integrate this technique into the routine clinical laboratory applications and bioinformatics. In this study, next generation sequencing of liquid biopsies in cancer patients was integrated into cancer diagnostics.

Conclusions: Liquid biopsy studies provide numerous advantages when integrated with next generation sequencing through a well-optimized workflow.
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http://dx.doi.org/10.7754/Clin.Lab.2019.190836DOI Listing
May 2020

Recurrent macroscopic hematuria in a pediatric patient: is it early to diagnose as having type I hereditary C2 deficiency?

CEN Case Rep 2020 11 5;9(4):344-346. Epub 2020 May 5.

Department of Pediatric Rheumatology, Faculty of Medicine, Cukurova University, Saricam, Adana, 01331, Turkey.

Hereditary C2 deficiency is the most common early complement deficiency and characterized by recurrent infections and autoimmunity despite most patients are also asymptomatic. Type I hereditary C2 deficiency is caused by a heterozygous deletion in C2 gene resulting in early stop codon and lack of C2 production. Clinical spectrum may vary and pure nephrological involvement without the presence of recurrent infections is scarce in hereditary C2 deficiency.We report here a previously healthy 14-year-old boy presenting recurrent self-limited macroscopic hematuria and persistently low serum C4 levels, diagnosed as having type I hereditary C2 deficiency with confirming a novel heterozygote deletion (c.1567 + 22_1567 + 43del) in C2 gene. He has been remained asymptomatic for the next 18 months. Since the diagnosis of C2 deficiency was made in the absence of organ-threatening involvement such as immune complex-mediated glomerulonephritis, we think that early diagnosis and optimal follow-up may improve life-span of the patients with hereditary early complement deficiencies.
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http://dx.doi.org/10.1007/s13730-020-00487-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502104PMC
November 2020

A homozygote frameshift mutation in OCLN gene result in Pseudo-TORCH syndrome type I: A case report extending the phenotype with central diabetes insipidus and renal dysfunction.

Eur J Med Genet 2020 Jun 30;63(6):103923. Epub 2020 Mar 30.

Department of Medical Genetics, Cukurova University Faculty of Medicine, Adana, Turkey. Electronic address:

Intrauterine infections with the pathogens, including toxoplasmosis, other (syphilis, varicella, mumps, parvovirus, and HIV), rubella, cytomegalovirus, and herpes simplex (TORCH) in susceptible individuals during pregnancy, result in microcephaly, white matter disease, cerebral atrophy, and calcifications in the fetus. Pseudo-TORCH syndrome is an umbrella term, consisting of several syndromes, resultant from different genetic alterations and pathogenetic mechanisms. Band-like calcification with simplified gyration and polymicrogyria (BLC-PMG) is one of these conditions, resultant from biallelic mutations in the OCLN gene, located in the chromosome 5q13.2. OCLN gene encodes occludin, a tight junction protein, which is expressed in the endothelia. The absence of occludin in the developing brain subsequently results in abnormal blood-brain barrier, thus immune-cell mediated tissue damage and cortical malformation. Herein, we present a pediatric patient who had progressive microcephaly, spasticity, multi-drug resistant epilepsy, PMG and intracranial band-type calcifications, accompanied by central diabetes insipidus and renal dysfunction. Whole exome sequencing revealed a homozygote W58Ffs*10 (c.173_194del) frameshift mutation in the OCLN gene. Of 34 BLC-PMG cases with demonstrable OCLN mutations, only three had renal manifestations, which is responsible for the majority of the demises. This is the first case diagnosed as having central diabetes insipidus and responded to desmopressin treatment to the best of our knowledge, however, this clinical improvement could not prevent the patient from renal dysfunction. The patient deceased at four years of age from sepsis, therefore early diagnosis, optimal follow-up for renal involvement and infection prevention measures are necessary for the patients with BLC-PMG.
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http://dx.doi.org/10.1016/j.ejmg.2020.103923DOI Listing
June 2020

Gender Identity and Assignment Recommendations in Disorders of Sex Development Patients: 20 Years’ Experience and Challenges

J Clin Res Pediatr Endocrinol 2020 11 26;12(4):347-357. Epub 2020 Mar 26.

Çukurova University Faculty of Medicine, Department of Pediatric Endocrinology, Adana, Turkey

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.
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http://dx.doi.org/10.4274/jcrpe.galenos.2020.2020.0009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7711639PMC
November 2020

Bi-allelic JAM2 Variants Lead to Early-Onset Recessive Primary Familial Brain Calcification.

Am J Hum Genet 2020 03;106(3):412-421

Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, Queen Square, WC1N3BG London, UK; The National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK; Neurogenetics Laboratory and Clinical Service, The National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK. Electronic address:

Primary familial brain calcification (PFBC) is a rare neurodegenerative disorder characterized by a combination of neurological, psychiatric, and cognitive decline associated with calcium deposition on brain imaging. To date, mutations in five genes have been linked to PFBC. However, more than 50% of individuals affected by PFBC have no molecular diagnosis. We report four unrelated families presenting with initial learning difficulties and seizures and later psychiatric symptoms, cerebellar ataxia, extrapyramidal signs, and extensive calcifications on brain imaging. Through a combination of homozygosity mapping and exome sequencing, we mapped this phenotype to chromosome 21q21.3 and identified bi-allelic variants in JAM2. JAM2 encodes for the junctional-adhesion-molecule-2, a key tight-junction protein in blood-brain-barrier permeability. We show that JAM2 variants lead to reduction of JAM2 mRNA expression and absence of JAM2 protein in patient's fibroblasts, consistent with a loss-of-function mechanism. We show that the human phenotype is replicated in the jam2 complete knockout mouse (jam2 KO). Furthermore, neuropathology of jam2 KO mouse showed prominent vacuolation in the cerebral cortex, thalamus, and cerebellum and particularly widespread vacuolation in the midbrain with reactive astrogliosis and neuronal density reduction. The regions of the human brain affected on neuroimaging are similar to the affected brain areas in the myorg PFBC null mouse. Along with JAM3 and OCLN, JAM2 is the third tight-junction gene in which bi-allelic variants are associated with brain calcification, suggesting that defective cell-to-cell adhesion and dysfunction of the movement of solutes through the paracellular spaces in the neurovascular unit is a key mechanism in CNS calcification.
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http://dx.doi.org/10.1016/j.ajhg.2020.02.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058839PMC
March 2020

Altered expression of apoptosis-related, circulating cell-free miRNAs in children with familial Mediterranean fever: a cross-sectional study.

Rheumatol Int 2021 Jan 5;41(1):103-111. Epub 2020 Mar 5.

Department of Pediatric Rheumatology, Faculty of Medicine, Cukurova University, Adana, Turkey.

Objectives: Familial Mediterranean Fever (FMF) is the most common hereditary autoinflammatory disorder characterized by recurrent fever and serositis episodes. Identification of low penetrant or heterozygous MEFV mutations in clinically diagnosed FMF patients did raise a concern on whether epigenetic or environmental factors play an additional role in FMF pathogenesis. We aimed to investigate the expression profile of apoptosis-related miRNAs in FMF and their influence on clinical manifestations in the present study.

Method: 191 pediatric FMF patients and 31 healthy children included in the study. Expressions of 33 apoptosis-related, circulating cell-free miRNAs were evaluated by a quantitative polymerase chain reaction, statistically calculated within ΔΔCt values and fold changes were evaluated by Welch T test, in which p < 0.05 were considered to be significant.

Results: Nineteen miRNAs, including let-7a-5p, let-7c, let-7 g-5p, miR-15b-5p, miR-16-5p, miR-17-5p, miR-23a-3p, miR-24-3p, miR-25-3p, miR-26a-5p, miR-26b-5p, miR-27a-3p, miR-29c-3p, miR-30a-5p, miR-30d-5p, miR-30e-5p, miR-106b-5p, miR-146a-5p, and miR-195-5p, were found down-regulated; miR-15a-5p, miR-29b-3p, miR-181a-5p, miR-181b-5p, miR-181c-5p, miR-214-3p, and miR-365a-3p were up-regulated in FMF patients. In detail, these miRNAs were similar among FMF patients in terms of genotype, colchicine response, and having an inflammatory attack during analysis.

Conclusion: We found that 26 apoptosis-related circulating miRNAs were deregulated in children with FMF. Thus, we speculate that these miRNAs have a role in FMF pathogenesis via apoptotic mechanisms.
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http://dx.doi.org/10.1007/s00296-020-04541-4DOI Listing
January 2021

Two years of newborn screening for cystic fibrosis in Turkey: Çukurova experience.

Turk J Pediatr 2019 ;61(4):505-512

Departments of Pediatric Allergy and Immunology, Çukurova University Faculty of Medicine, Adana, Turkey.

Şaşihüseyinoğlu AŞ, Altıntaş DU, Bişgin A, Doğruel D, Yılmaz M, Serbes M. Two years of newborn screening for cystic fibrosis in Turkey: Çukurova experience. Turk J Pediatr 2019; 61: 505-512. The severity of cystic fibrosis (CF) depends on the type of cystic fibrosis transmembrane conductance regulator (CFTR) mutation. The primary goal of newborn screening (NBS) is to decrease morbidity, mortality and associated disabilities. The National NBS for CF programme was initiated in Turkey since 01.01.2015. The aim of this study was to present two years of experience of our CF center which is located in the south of Turkey. The study population comprised of infants who were born in Adana between 1 January 2015 - 31 December 2016, referred to our CF center as part of NBS for CF and performed CFTR gene analysis. The infants were divided into three groups according to laboratory tests and symptoms as CF, CRMS (cystic fibrosis transmembrane conductance regulator-related metabolic syndrome) and false positive NBS. Between January 1, 2015 and December 31, 2016, NBS was performed in 77,437 newborns in Adana. Two hundred seven (0.26%) newborns screened were positive for CF. A total of 184 infants were included to the study. We reported 12 babies as CF with an incidence of 1:6,452. The babies diagnosed as CF constituted 6.5% of positive CF NBS. Rest of study group diagnosed with CRMS/CFSPID (54/184, 29.5%) and false positive (118/184, 64%). Positive predictive value (PPV) of NBS was 6.5%. The most common CFTR mutations were 508del, p.F1052L and p.L997 F. The implementation of CF-NBS program has been successful in Turkey. But it is too early to determine the specificity and sensitivity of the program.
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http://dx.doi.org/10.24953/turkjped.2019.04.006DOI Listing
May 2020

Renal features of Bardet Biedl syndrome: A single center experience.

Turk J Pediatr 2019 ;61(2):186-192

Departments of Pediatric Nephrology, Çukurova University Faculty of Medicine, Adana, Turkey.

Atmış B, Karabay-Bayazıt A, Melek E, Bişgin A, Anarat A. Renal features of Bardet Biedl syndrome: A single center experience. Turk J Pediatr 2019; 61: 186-192. Bardet Biedl syndrome (BBS), is a multisystemic disorder which is described as a ciliopathy. BBS is a rare autosomal recessive disorder and 21 different BBS genes have been defined to date. BBS is characterized with dysmorphic extremities, retinitis pigmentosa, obesity, hypogenitalism, intellectual disabilility and renal structural abnormalities. Renal symptoms in patients with BBS, are nonspecific and often undetected until end-stage renal disease. Here, we were reported 23 children with BBS (12 females, 11 males) with renal abnormalities from a single center and defined their features. Age at diagnosis were very variable (2 days-16 years). Median age at diagnosis was 84 months. Mean follow-up period was 42 months. All 23 children had urinary tract abnormalities on renal ultrasonography. These abnormalities were polycysts (34.8%), hyperechogenic kidneys (34.8%), fetal lobulation (21.7%), hypoplasia on at least one kidney (21.7%) and hydronephrosis in at least one kidney (17.4%). Vesicoureteral reflux and neurogenic bladder detected 11.1% and 22.2% of patients who recieved a voiding cystourethrogram, respectively. Proteinuria was found in 39 % of patients. Hypertension was defined in 21.7% of patients. Six of 23 children (26%) in our cohort had proven mutations in BBS genes. Five of them (83.3%) had homozygous mutations in BBS10 gene and one of them had homozygous mutation in BBS2 gene. All of 23 children had retinitis pigmentosa, twenty two of them (95.6%) had learning disabilities/cognitive impairment and seventeen of them (82.6%) had obesity. Renal involvement is now accepted as a cardinal feature and the most important factor causing mortality in BBS.
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http://dx.doi.org/10.24953/turkjped.2019.02.006DOI Listing
August 2020

Concomitance of Familial Mediterranean Fever and Gitelman syndrome in an adolescent.

Turk J Pediatr 2019 ;61(3):444-448

Departments of Pediatric Nephrology, Çukurova University Faculty of Medicine, Adana, Turkey.

Atmış B, Kışla-Ekinci RM, Melek E, Bişgin A, Yılmaz M, Anarat A, Karabay-Bayazıt A. Concomitance of Familial Mediterranean Fever and Gitelman syndrome in an adolescent. Turk J Pediatr 2019; 61: 444-448. Gitelman syndrome is a renal tubular salt-wasting disorder characterized by hypokalemic metabolic alkalosis with hypomagnesemia and hypocalciuria. Patients occasionally have symptoms in childhood, while diagnosis is often in adulthood. It is inherited by an autosomal recessive manner through SLC12A3 gene mutations. Familial Mediterranean Fever (FMF) is the most common autoinflammatory disorder, inherited by an autosomal recessive manner and characterized by recurrent fever and pleuritis, peritonitis, and synovitis. Mutations in MEditerrenean FeVer (MEFV) gene, coding pyrin protein are responsible for FMF. Both MEFV and SCL12A3 genes were located on chromosome 16. A 9-year-old boy was admitted to our department because of recurrent abdominal pain, fever, joint pain and swelling since he was three years old. He was diagnosed as FMF and MEFV gene sequencing revealed homozygous M694V (c.2080A > G) mutation. At the age of 14 years, polyuria, polydipsia, hypokalemia and mild hypomagnesemia had occurred. Patient was successfully treated with oral supplementation of potassium and magnesium along with colchicine. Molecular genetic analysis including SCL12A3 gene sequencing revealed homozygote IVS4-16G > A (c.602-16G > A) intronic splicing site mutation.
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http://dx.doi.org/10.24953/turkjped.2019.03.021DOI Listing
July 2020

Congenital myasthenic syndrome in Turkey: clinical and genetic features in the long-term follow-up of patients.

Acta Neurol Belg 2021 Apr 26;121(2):529-534. Epub 2019 Nov 26.

Intergen Genetic Laboratory, Ankara, Turkey.

Congenital Myasthenic Syndromes (CMS) are rare disorders that occur as a result of defects in the structure and in the function of neuromuscular junctions. Molecular genetic diagnosis is important to select the most suitable therapeutic option and treatment. Eight patients with congenital myasthenic syndromes who presented to the Çukurova University Pediatric Neurology Department Outpatient Clinic between June 2015 and May 2018 were reviewed. Mutations in the acetylcholine receptor (subunits in epsilon) (CHRNE) in three and mutations in the collagenic tail of endplate acetylcholinesterase (COLQ) gene in five patients were identified; p.W148 mutation was detected to be homozygous in four, c.1169A > G novel mutation in COLQ gene was homozygous in one, c452_454delAGG mutation was homozygous in the other patient, IVS7 + 2T > C(c.802 + 2T > C) mutation was homozygous in a patient and compound heterozygous mutations of c.865C > T(p.Leu289Phe) and c.872C > G(p.A2916)(p.Arg291Gly) in the CHRNE gene in the last patient. The parents of all the evaluated patients were consanguineous. Ptosis, ophthalmoplegia, generalized hypotonia, bulbar weakness, and respiratory crisis were the main findings at the time of presentation. Pyridostigmine is the first-line drug therapy in primary AChR deficiency. Beta adrenergic agonists, ephedrine, and albuterol are the other treatment options for CMS subtypes caused by mutations in COLQ. This study points out the genetic and phenotypic features of CMS patients in the Turkish population and it also reports previously unreported mutations in the literature. CHRNE and COLQ gene mutations are common in the Turkish population. Patients can get serious benefits and recover after the treatment. The treatment should be planned according to genetic tests and clinical findings.
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http://dx.doi.org/10.1007/s13760-019-01246-9DOI Listing
April 2021

Phenotypic variability in two patients with tumor necrosis factor receptor associated periodic fever syndrome emphasizes a rare manifestation: Immunoglobulin A nephropathy.

Eur J Med Genet 2020 Apr 3;63(4):103780. Epub 2019 Oct 3.

Department of Pediatric Rheumatology, Cukurova University Faculty of Medicine, Adana, Turkey. Electronic address:

Tumor necrosis factor receptor associated periodic fever syndrome (TRAPS) is caused by heterozygote mutations in TNFRSF1A, characterized by recurrent inflammatory attacks. In this report, we described two patients with different heterozygote mutations in TNFRSF1A. Patient 1, a 15-year-old male, had suffered from recurrent fever attacks accompanied by abdominal pain, eye manifestations, and myalgia with increased acute phase reactants since the age of 6-month. He had been unsuccessfully treated with colchicine for having familial Mediterranean fever without an identifiable MEFV mutation since the age of 4-year. At the age of 15 years, he was diagnosed with immunoglobulin (Ig) A nephropathy due to massive proteinuria and renal biopsy findings. Next generation sequencing revealed NM_001065.3: c.236C>T; p. (Thr79Met); T50M heterozygote mutation in TNFRFS1A. He was treated with methylprednisolone and cyclosporine for IgA nephropathy, thereafter with canakinumab for TRAPS. Patient 2, a 17-year-old female, had recurrent arthritis attacks accompanied by increased acute phase reactants for the last two months. She had neither fever attacks nor rashes or myalgia. Her physical examination was normal between attacks. Magnetic resonance imaging of both knees and ankles showed no signs of chronic arthritis. MEFV analyzes showed no mutation. Next generation sequencing revealed NM_001065.3: c.362G>A; p.(Arg121Gln); R92Q heterozygote mutation in TNFRFS1A. Arthritis attacks were treated successfully with ibuprofen thereafter. In conclusion, we wish to emphasize the diversity of the clinical manifestations between these two patients with distinct sequence variants in TNFRSF1A. Moreover, we presented a rare manifestation of TRAPS, IgA nephropathy.
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http://dx.doi.org/10.1016/j.ejmg.2019.103780DOI Listing
April 2020

A homozygote novel L451W mutation in CECR1 gene causes deficiency of adenosine deaminase 2 in a pediatric patient representing with chronic lymphoproliferation and cytopenia.

Pediatr Hematol Oncol 2019 Sep 14;36(6):376-381. Epub 2019 Sep 14.

Department of Pediatric Rheumatology, Cukurova University Faculty of Medicine , Adana , Turkey.

Deficiency of Adenosine Deaminase 2 (DADA2) is a monogenic autoinflammatory disorder characterized by livedo reticularis, skin ulcers, subcutaneous rash, aphthous ulcers, and leukocytoclastic vasculitis, neurological signs such as early onset stroke and polyneuropathy. A minority of DADA2 patients suffer from severe cytopenia and lymphoproliferation. Herein, we report an adolescent patient, followed up as having a hematological disorder for many years, eventually diagnosed as having DADA2. In view of the presence of elevated acute phase reactants, hepatosplenomegaly, low IgM level, lymphopenia, anemia, and neutropenia, and a subtle neurological involvement we considered DADA2 diagnosis. The diagnosis was confirmed by identification of a novel L451W mutation in CECR1 gene. The patient has been successfully treated with etanercept, monthly intravenous immunoglobulin replacement, and low-dose methylprednisolone. In conclusion, although the absence of skin and neurological findings, low IgM levels, and persistent lymphopenia should lead the physicians to consider DADA2 in patients with particularly complicated hematological abnormalities.
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http://dx.doi.org/10.1080/08880018.2019.1621973DOI Listing
September 2019