Purpose To date, many genes have been associated with congenital hypothyroidism (CH). Our aim was to identify the mutational spectrum of 23 causative genes in Turkish patients with permanent CH, including thyroid dysgenesis (TD) and dyshormonogenesis (TDH) cases. Methods A total of 134 patients with permanent CH (130 primary, 4 central) were included. To identify the genetic etiology, we screened 23 candidate genes associated with CH by next-generation sequencing. For confirmation and to detect the status of the specific familial variant in relatives, Sanger sequencing was also performed. Results Possible pathogenic variants were found in 5.2% of patients with TD and in 64.0% of the patients with normal-sized thyroid or goiter. In all patients, variants were most frequently found in TSHR, followed by TPO and TG. The same homozygous TSHB variant (c.162 + 5G > A) was identified in four patients with central CH. In addition, we detected novel variants in the TSHR, TG, SLC26A7, FOXE1, and DUOX2. Conclusion Genetic causes were determined in the majority of CH patients with TDH, however, despite advances in genetics, we were unable to identify the genetic etiology of most CH patients with TD, suggesting the effect of unknown genes or environmental factors. The previous studies and our findings suggest that TSHR and TPO mutations is the main genetic defect of CH in the Turkish population.

Objective: Hemophagocytic lymphohistiocytosis (HLH) is a rare disorder which develops as a result of cytokine storm syndrome due to uncontrolled hemophagocytosis. Fever, splenomegaly, hyperferritinemia and cytopenias are well-known clinical manifestations of the disease. Hemophagocytic lymphohistiocytosis is classified as familial (primary/genetic) and secondary (acquired) where an underlying disease is present. Among acquired causes infections, malignancies, autoimmune disorders and some metabolic disorders may be enumerated. The basis of treatment for HLH is immunosuppression and apoptotic chemotherapy. The curative treatment alternative for familial or non-familial persistent HLH is stem cell transplantation.& para;& para;Methods: We retrospectively analyzed 46 HLH cases diagnosed and treated in our clinic in terms of diagnostic criteria and treatment plans.& para;& para;Results: We identified the most frequently recorded diagnostic criteria as fever, hemophagocytosis and hyperferritinemia. We found that 46% of the cases needed treatment consisting of dexamethasone, cyclosporine (CsA) and etoposide according to HLH-2004 treatment guideline.& para;& para;Conclusion: As a result, we think that search for HLH in children who presented with hectic-persistent fever is important for the early diagnosis and treatment of HLH.

Limb-girdle muscular dystrophy type 2E (LGMD-2E) is caused by autosomal recessive defects in the beta sarcoglycan ( SGCB ) gene located on chromosome 4q12. In this case report, the clinical findings, histopathological features and molecular genetic data in a boy with β sarcoglycanopathy are presented. An 18-month-old boy had a very high serum creatinine phosphokinase (CPK) level that was accidentally determined. The results of molecular analyses for the dystrophin gene was found to be normal. He underwent a muscle biopsy which showed dystrophic features. Immunohistochemistry showed that there was a total loss of sarcolemmal sarcoglycan complex. DNA analysis revealed a large homozygous deletion in the SCGB gene. During 4 years of follow-up, there was no evidence to predict a severe clinical course except the muscle enzyme elevation and myopathic electromyography (EMG) finding. The presented milder phenotype of LGMD-2E with a large deletion in the SGCB gene provided additional support for the clinical heterogeneity and pathogenic complexity of the disease.

Chronic neutropenia (CN) is defined as neutropenia that persists for >3 months; it is caused by a heterogeneous group of diseases in children. The aim of the present study was to evaluate the significance and clinical manifestations of CN in children at a single children's hospital. Between October 2004 and April 2014, CN patient data were evaluated retrospectively. Thirty-one patients were assessed in this study. Thirteen of them (41.9%) were younger than 12 months of age at initial diagnosis. There was no difference in the absolute number of neutrophils at diagnosis between the children aged younger than 12 months and those aged 12 months and older at CN onset. Twenty-two of the patients (70.9%) were diagnosed during treatment for acute infections. A total of 11 patients (35.5%) were hospitalized because of recurrent infections. Most of the recurrent infections occurred in the lungs (81.8%). Congenital neutropenia (CoN) was identified in 14 patients (45.1%). Eight of 14 patients (57.1%) required granulocyte-colony stimulating factor treatment, and none of them experienced adverse effects from this treatment. Fifteen patients (48.3%) were diagnosed with idiopathic neutropenia. Comparison between the idiopathic and CoN groups revealed no differences in age, the absolute number of neutrophils, or the presence of infection at diagnosis; however, differences were detected in sex and the rate of spontaneous recovery from neutropenia. Ten of the patients (32.2%) experienced spontaneous recovery from neutropenia during a follow-up period of 7 to 52 months. In current study, we found a higher CoN ratio in the CN patients compared with previous reports, which may be due to the high rate of consanguineous marriages in our country. However, the finding of CN requires several laboratory investigations, prolonged follow-up, and advanced molecular analysis, and its etiology can remain idiopathic.

Williams Syndrome is a microdeletion syndrome characterized by a number of developmental and physical abnormalities. The aim of the present study was to evaluate the oral abnormalities and dental management of patients with Williams Syndrome. Fifteen patients with Williams Syndrome aged between 3-20 years old were evaluated in this study. Oro-facial findings, dental plaque index and DMFT/dmft scores were recorded in each patient. Panoramic radiographs and extraoral, intraoral photographs were taken from all patients. According to the results of this study, the mean DMFT and dmft scores were 0.39 ± 0.12 and 1.81 ± 0.39, respectively. The most common oro-facial findings were detected as high palate (87%), diastema (60%), failure to thrive (60%), feeding difficulties (60%), vomiting (47%), macroglossi (47%), microdontia (40%) and frenulum hyperplasia (40%). All decayed teeth were restored with compomer and composite restorations. In conclusion, dentists play a significant role for improving the quality of life of the patients with Williams Syndrome to minimize or prevent dental abnormalities.

Limb-girdle muscular dystrophy type 2D (LGMD-2D) is caused by autosomal recessive defects in the alpha-sarcoglycan gene located on chromosome 17q21. In this study, we present a child with alpha-sarcoglycanopathy and describe a novel deletion in the alpha-sarcoglycan gene. A 5-year-old boy had a very high serum creatinine phosphokinase level, which was determined incidentally, and a negative molecular test for the dystrophin gene. Muscle biopsy showed dystrophic features. Immunohistochemistry showed that there was diminished expression of alpha- and gamma-sarcoglycans. DNA analysis revealed a novel 7 bp homozygous deletion in exon 3 of the alpha-sarcoglycan gene. His parents were consanguineous heterozygous carriers of the same deletion. We believe this is the first confirmed case of primary alpha-sarcoglycanopathy with a novel deletion in Turkey. In addition, this study demonstrated that both muscle biopsy and DNA analysis remain important methods for the differential diagnosis of muscular dystrophies because dystrophinopathies and sarcoglycanopathies are so similar.

In this study, it was aimed to describe the clinical, histopathological and genetic features of 35 patients with sarcoglycanopathies confirmed by muscle biopsies and genetic analysis. We retrospectively reviewed 35 patients who underwent muscle biopsy examination between 2007 and 2013 at pathology laboratory of Izmir Neuromuscular Diseases’ Centre. All patients clinically diagnosed as muscular dystrophy and biopsies were collected from 5 different centers of neurological disorders. All DNAs were extracted from muscle tissues or blood of patients and genetic tests (mutation analyses and deletion-duplication analyses for all 4 sarcoglycan genes) were performed at Ankara Duzen Laboratory. The mean age of patients was 7.61 years (0–21 years). Only one case (2.85%) was older than 14 years. The mean CPK level was 10,545 U/L (between 700 and 35,000). There were 6 siblings in these series. Expression defects of alpha, beta or gamma sarcoglycans were determined in (male: 23/34.2% and female: 12/66.8%) all patients with muscle biopsy. Gamma sarcoglycanopathies were the most (n = 25) and alpha sarcoglycanopathies were the second common (n = 7) muscular dystrophy in this series. Although focal delta sarcoglycan staining defects were determined in some patients by muscle biopsy, any genetic defects were found in them. The present study demonstrated that, both muscle biopsy and DNA analysis remain important methods for diagnosis of muscular dystrophies. Because differential diagnosis of sarcoglycanopathies and distrophinopathies, is impossible to achieve on clinical grounds alone; therefore immunohistochemical straining on muscle biopsy and molecular genetic analysis are mandatory for correct diagnosis. In this study, it was aimed to describe the clinical, histopathological and genetic features of 35 patients with sarcoglycanopathies confirmed by muscle biopsies and genetic analysis. We retrospectively reviewed 35 patients who underwent muscle biopsy examination between 2007 and 2013 at pathology laboratory of Izmir Neuromuscular Diseases’ Centre. All patients clinically diagnosed as muscular dystrophy and biopsies were collected from 5 different centers of neurological disorders. All DNAs were extracted from muscle tissues or blood of patients and genetic tests (mutation analyses and deletion-duplication analyses for all 4 sarcoglycan genes) were performed at Ankara Duzen Laboratory. The mean age of patients was 7.61 years (0–21 years). Only one case (2.85%) was older than 14 years. The mean CPK level was 10,545 U/L (between 700 and 35,000). There were 6 siblings in these series. Expression defects of alpha, beta or gamma sarcoglycans were determined in (male: 23/34.2% and female: 12/66.8%) all patients with muscle biopsy. Gamma sarcoglycanopathies were the most (n = 25) and alpha sarcoglycanopathies were the second common (n = 7) muscular dystrophy in this series. Although focal delta sarcoglycan staining defects were determined in some patients by muscle biopsy, any genetic defects were found in them. The present study demonstrated that, both muscle biopsy and DNA analysis remain important methods for diagnosis of muscular dystrophies. Because differential diagnosis of sarcoglycanopathies and distrophinopathies, is impossible to achieve on clinical grounds alone; therefore immunohistochemical straining on muscle biopsy and molecular genetic analysis are mandatory for correct diagnosis.

Limb-girdle muscular dystrophy type 2E (LGMD-2E) is caused by autosomal recessive defects in the beta-sarcoglycan gene located on chromosome 4q12. In this study, the clinical findings, histopathological features and molecular genetic data in a boy with beta-sarcoglycanopathy are presented. An eighteen-month-old boy had a very high serum creatinine phosphokinase level, which was determined incidentally. He had consanguineous parents. The result of molecular analyses for dystrophin gene was found normal. He underwent a muscle biopsy which showed dystrophic features. Immunohistochemistry showed that, there was a total loss of sarcolemmal sarcoglycan complex (alpha, beta, delta and gamma sarcoglycans) while sarcolemmal dystrophin expression was normal. DNA analysis revealed a huge deletion in the beta-sarcoglycan gene. The deletion was homozygous and occurred from exon 1 to 6. This study demonstrated that the total absence or abnormal expressions of all 4 sarcoglycans are more likely to indicate a primary defect in the beta sarcoglycan gene.

Cardio-facio-cutaneous syndrome (CFCS) is a multiple congenital anomaly disorder characterized by craniofacial features, cardiac defects, ectodermal anomalies and neurocognitive delay. Clinical findings of patients with CFCS show similarities to those of patients with Costello Syndrome (CS). CFCS and CS are caused by mutations in genes encoding proteins of the RAS-MAPK signaling pathway. Musculoskeletal findings including tight Achilles tendons and contractures of elbows, shoulders or hips have been reported in CS patients. However, limited extension of joints were observed in some patients with CFCS. According to the literature, no tight Achilles tendons have been reported in CFCS patients so far. In this case report, we present a male CFCS patient with tight Achilles tendons with a de-novo heterozygote N581D mutation in the BRAF gene detected by DNA sequence analysis.

Crouzon Syndrome (CS) is an autosomal dominant hereditary disease, which is characterized by clinical triad of cranium deformity, facial anomalies and exophthalmia. Craniofacial features of CS include acrocephaly, exophthalmos, and maxillary hypoplasia with "parrotbeak" nose, short upper lip, high narrow palate, narrowly spaced teeth, and prognathism (4). This syndrome is caused by the mutations in FGFR2 gene. FGFR2 mutations are also observed in Apert, Pfeiffer and Jackson-Weiss syndromes as well. Cardiac anomalies are occurring in 10 % of the patients with Apert Syndrome. To date, cardiac anomalies have been reported in only three patients with CS but there is no report on cardiac anomalies, neither in patients with Pfeiffer nor the ones with Jackson- Weiss syndrome.The female patient was referred to us for genetic evaluation because of severe developmental delay and dysmorphic features at the age of 10. She was the first child of healthy, non-consanguineous Turkish parents. Her father and her brother were healthy. Her mother had facial dysmorphic features and mild mental retardation. The patient was born at term after an uneventful pregnancy. Her birth weight was 2200 g (At the age of 10, her height was 132 cm (10-25th centile) his weight was 29 kg (25-50th centile) and head circumference was 48 cm (%250 SD). On physical examination hypertelorism, proptosis, parrot-like nose, thin upper lip, high palate, prognathism, pectus excavatum were detected (Fig. 1). Laboratory tests including complete blood count, electrolytes, liver enzymes, urea, creatinine, thyroid hormones, urine and blood amino acid chromatography were normal. An additional eye abnormality was not detected by ophthalmological examination. A Chiari type I malformation and the shallow orbits were detected by cranial Magnetic resonance imaging (MRI). Cervical spinal MRI confirmed the Chiari type I malformation. 3D computed tomography (CT) of the skull showed bilateral sagittal and coronal craniosynostosis. A perimembranous ventricular septal defect (3 mm) was detected by echocardiography. Abdominal ultrasonography, X-ray of vertebral column and extremities were normal. A hearing test revealed normal hearing. Her karyotype was 46,XX. A heterozygous c.868G>C mutation which lead to Trp290Arg (W290R) substitution was detected by DNA sequence analysis of the FGFR2 gene.The patient's mother was 47 years old and had similar dysmorphic features including hypertelorism, proptosis, parrot-like nose, thin upper lip, high palate, prognathism and mild mental retardation (Fig 2). Neurological examination was normal as well as ophthalmological examination. Cranial MRI, 3D-CT and echocardiography were revealed normal. DNA sequencing analysis revealed a heterozygous Trp290Arg (W290R) mutation in the FGFR2 gene. The maternal grandparents were not available for DNA analysis.CS and the other craniosynostosis syndromes including AS, PS and JWS are autosomal dominant inheritance and related to the FGFR2 gene mutations (5, 6). Heterozygous mutations of the FGFR2 gene were first described in patients with CS in 1914 (8, 4). More than 40 mutations in the FGFR2 gene have been reported in CS (7). Trp290 is a major hotspot in the FGFR2 gene. While the presence of arginine and glycine instead of tryptophan in 290th position, is related to CS, presence of cysteine in the same position caused a severe form of PS (5). Trp290Arg (W290R) mutation was detected in the proband and her mother both with typical CS phenotypical findings, and this is also consistent with the literature.Among the craniosynostosis syndromes caused by mutations in the FGFR2 gene, congenital cardiac defects have been reported commonly in AS patients (10%) (2). Ventricular septal defect (VSD) and dextroposition of the aorta (DA) are the most frequently reported cardiac defects (3). …