Fılız Hazan

Izmir University

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Semra Gürsoy

Dokuz Eylül University

BÖ

Behzat Özkan

Dr. Behçet Uz Çocuk Hastalıkları Hastanesi

ÖN

Özlem Nalbantoğlu

Dr. Behçet Uz Çocuk Hastalıkları Hastanesi

FÖ

Ferda Özkınay

Ege University

Hüseyin Anıl Korkmaz

Dr. Behçet Uz Çocuk Hastalıkları Hastanesi

Ajlan Tükün

Ankara University

Korcan Demir

Istanbul Medeniyet University

AÜ

Aycan Ünalp

Sağlık Bilimleri Üniversitesi

Sezer Acar

Dokuz Eylül University

Ayça Aykut

Ege University

Cooperative Institutions

Dr. Behçet Uz Çocuk Hastalıkları Hastanesi

100

Sağlık Bilimleri Üniversitesi

Izmir University

Ege University

Izmir Tepecik Eğitim ve Araştırma Hastanesi

Dokuz Eylül University

University of Health Science

Children's Hospital

Boston Children's Hospital

Pediatrics and Genetics

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Detection of <i>SHOX</i> Gene Variations in Patients with Skeletal Abnormalities with or without Short Stature

Journal of Clinical Research in Pediatric Endocrinology (2020)

Semra Gürsoy Fılız Hazan Ayça Aykut Özlem Nalbantoğlu Hüseyin Anıl Korkmaz

Objective: SHOX gene mutations constitute one of the genetic causes of short stature.The clinical phenotype includes variable degrees of growth impairment, such as Langer mesomelic dysplasia (LMD), Léri-Weill dyschondrosteosis (LWD) or idiopathic short stature (ISS).The aim of this study was to describe the clinical features and molecular results of SHOX deficiency in a group of Turkish patients who had skeletal findings with and without short stature.Methods: Forty-six patients with ISS, disproportionate short stature or skeletal findings without short stature from 35 different families were included.SHOX gene analysis was performed using Sanger sequencing and multiplex ligation-dependent probe amplification analysis.Results: Three different point mutations (two nonsense, one frameshift) and one whole SHOX gene deletion were detected in 15 patients from four different families.While 4/15 patients had LMD, the remaining patients had clinical features compatible with LWD.Madelung's deformity, cubitus valgus, muscular hypertrophy and short forearm were the most common phenotypic features, as well as short stature.Additionally, hearing loss was detected in two patients with LMD. Conclusion:This study has presented the clinical spectrum and molecular findings of 15 patients with SHOX gene mutations or deletions.SHOX deficiency should be especially considered in patients who have disproportionate short stature or forearm anomalies with or without short stature.Although most of the patients had partial or whole gene deletions, SHOX gene sequencing should be performed in suspected cases.Furthermore, conductive hearing loss may rarely accompany these clinical manifestations.

Idiopathic short stature

10.4274/jcrpe.galenos.2020.2019.0001

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Early Onset Monogenic Obesity: Two Cases with Homozygous Mutation in Lepr Gene

58th Annual ESPE Meeting (ESPE 2019) (2019)

Özlem Nalbantoğlu Sezer Acar Özge Köprülü Gülçin Arslan Beyhan Özkaya

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A Null Mutation of TNFRSF11A Causes Dysosteosclerosis, Not Osteopetrosis

Frontiers in Genetics (2022)

Tarık Kırkgöz Behzat Özkan Fılız Hazan Sezer Acar Özlem Nalbantoğlu

Dysosteosclerosis (DOS) is a rare sclerosing bone dysplasia characterized by unique osteosclerosis of the long tubular bones and platyspondyly. DOS is inherited in an autosomal recessive manner and is genetically and clinically heterogeneous. To date, four individuals with DOS who have five different TNFRSF11A mutations have been reported. Based on their data, it is hypothesized that mutations producing aberrant mutant RANK proteins (missense or truncated or elongated) cause DOS, while null mutations lead to osteopetrosis, autosomal recessive 7 (OPTB7). Herein, we present the fifth case of TNFRSF11A-associated DOS with a novel homozygous frame-shift mutation (c.19_31del; p.[Arg7CysfsTer172]). The mutation is predicted to cause nonsense mutation-mediated mRNA decay (NMD) in all RANK isoform transcripts, resulting in totally null allele. Our findings suggest genotype-phenotype relationship in TNFRSF11A-associated OPTB7 and DOS remains unclear, and that the deficiency of TNFRSF11A functions might cause DOS, rather than osteopetrosis. More data are necessary to understand the phenotypic spectrum caused by TNFRSF11A mutations.

Osteopetrosis

Osteosclerosis

Null allele

10.3389/fgene.2022.938814

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Compound Heterozygosity of Low-Frequency Promoter Deletions and Rare Loss-of-Function Mutations in TXNL4A Causes Burn-McKeown Syndrome

The American Journal of Human Genetics (2014)

Dagmar Wieczorek William G. Newman Thomas Wieland Tea Berulava Maria Kaffe

Loss function

Compound heterozygosity

10.1016/j.ajhg.2014.10.014

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Evaluation of the Clinical and Laboratory Findings of Patients with Chromosome 22q11.2 Deletion Syndrome

Turkiye Klinikleri Journal of Pediatrics (2021)

Fılız Hazan Özlem Nalbantoğlu Semra Gürsoy Selime Özen Murat Muhtar Yılmazer

Amaç: Bu çalışmada; kromozom 22q11.2 Delesyon Sendromu (22q11.2DS) tanısı konulan hastaların, genetik polikliniğine başvuru nedenleri ile birlikte, klinik ve laboratuvar bulgularının ayrıntılı olarak değerlendirilmesi amaçlandı. Ayrıca bu sendroma özgü fizik muayene bulgularına dikkat çekilerek, erken tanı ve izlemdeki önemleri vurgulandı. Gereç ve Yöntemler: Ocak 2014 ve Nisan 2018 tarihleri arasında 'Floresan in Situ Hibridizasyon Analizi' ile 22q11.2DS tanısı konulan 13 hasta çalışma kapsamına alındı. Hastaların başvuru yakınmaları, fizik ve dismorfik muayene bulguları, tanı alma yaşları, laboratuvar ve görüntüleme sonuçları, dosyalarından geriye dönük olarak incelenerek değerlendirildi. Bulgular: Hastaların, genetik polikliniğine en sık başvuru nedenleri; atipik yüz görünümü ve kardiyak anomali olarak saptandı. Hastalar, klinik bulgularına göre değerlendirildiğinde en sık bulgular; öğrenme geriliği (13 hasta; %100), doğumsal kalp anomalileri (12 hasta; %92,3) dismorfik yüz bulguları (11 hasta; %84,6) ve hipernazal konuşma (10 hasta; %76,9) idi. Dört (%30,9) hastada, yarık damak tespit edildi. Boy kısalığı 3 hastada görülürken, büyüme hormon eksikliği hiçbir hastada saptanmadı. Üç (%23) hastaya hipoparatiroidizm, 5 (%38,4) hastaya hipokalsemi ve 4 (%30,7) hastaya hipotiroidi tanısı konuldu. İki (%15,4) hastada ise timus hipoplazisi vardı. İskelet sistemi değerlendirilmesinde; 2 (%15,4) hastada skolyoz, 1 (%7,6) hastada platibazi ve 1 (%7,6) hastada pes ekinovarus deformitesi saptandı. Bağ dokusu problemi olarak; 3 (%23,1) hastada umblikal herni ve 1 (%7,6) hastada ise inguinal herni tespit edildi. Sonuç: 22q11.2DS'li hastalarda, majör klinik bulguların yanında, diğer sistemik bulguların varlığı da mutlaka araştırılmalıdır. Hastaları değerlendirirken özellikle; skolyoz, platibazi, umblikal ve inguinal herni gibi iskelet sistemi ve bağ dokusu anomalileri açısından da dikkatli olunmalıdır.

Hasta

10.5336/pediatr.2021-81283

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Genetic Approach to the Patient and the Family: A Rett Syndrome Case with R270X Mutation in MECP2 Gene

Turkish Journal of Biochemistry (2013)

Fılız Hazan Orkide Güzel Mehmet Çeleğen Ajlan Tükün Ajlan Tükün

Rett syndrome is an X-linked dominant neurodevelopmental disorder which is primarily seen in girls. Mutations in the MECP2 gene are responsible for 80% of affected patients. The most common mutations are found in exons 3, 4 of this gene. Most MECP2 alterations are de novo and the recurrence risk is low. Approximately 1% of all affected patients are thought to be familial and clinically unaffected carrier mothers have been reported. Here, we present 3 year old girl patient who had all of the diagnostic criteria for typical Rett syndrome. The de novo, heterozygous c.808C>T mutation was detected by sequence analysis of exon 3 in the MECP2 gene. We report this patient to emphasize the importance of the steps followed in the molecular analysis in Rett syndrome. Hovewer, when the mutation was detected in a patient, the molecular analysis of the mother is extremely important for correct genetic counseling.

Rett Syndrome

MeCP2

10.5505/tjb.2013.07742

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Novel Ocular and Inner Ear Anomalies in a Patient with Myhre Syndrome

Molecular Syndromology (2019)

Semra Gürsoy Fılız Hazan Tülay Öztürk Halil Ateş

Myhre syndrome is a rare autosomal dominant multisystemic disorder. Typical features of this disorder include distinctive facial appearance, deafness, intellectual disability, cardiovascular abnormalities, short stature, brachydactyly, and skeletal anomalies. Gain-of-function mutations in the SMAD4 gene are responsible for this syndrome. Herein, we present a 9.6-year-old Turkish girl with molecularly confirmed Myhre syndrome who had novel findings including bilateral Axenfield Rieger anomaly with secondary glaucoma and bilateral enlarged vestibular aqueducts.

10.1159/000504829

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Evaluation of Eeg Pattern and Seizure Types of Genetic Dysmorphic Syndromes: Report of 50 Patients and Review of the Literature

Advanced Biomedicine (2021)

Gürkan Gürbüz Fılız Hazan Selvinaz Edizer Bahar Toklu Baysal Ünsal Yılmaz

Many chromosomal anomalies manifest with epilepsy. Only few typical EEG and seizure type have been identified in genetic syndromes. Identification of typical seizure and EEG findings of certain genetic syndromes may serve as a guide for genetic analysis. This study aims to find typical EEG paterns of spesific genetic syndromes. The study enrolled 50 patients aged 0-16 years with a diagnosis of epilepsy and genetic syndrome in between 2014-2017 at the Dr. Behçet UZ Children’s Hospital Pediatric Neurology and Medical Genetics departments. Patients' characteristics and dysmorphic features were retrieved from Medical Genetic outpatient clinic patient files, while seizure type, epileptic syndromic classification, EEG and brain MRI findings, age at onset and frequency of seizure were determined from pediatric neurology follow-ups. Fifty patients (29 girls) with a mean age of 6.52 ±3.67 years (max=16, min=1) were enrolled. Twenty-two patients had microdeletion-duplication (44%), 12 had chromosomal anomalies (24%) and 16 had monogenic syndrome (32%). Pathology was present in the EEGs of 40 patients (80%). Focal epileptic disorder was determined in 28 subjects (56%), epileptic encephalopathy in 7 (14%), and generalized epileptic disorder in 5 (10%) Identification of seizure type and EEG pattern specific to each genetic dysmorphic syndrome may give clues to clinicians in recognizing these syndromes. However, in order to detect other specific EEG patterns, there is a need for multicentre studies with more patients.

Seizure types

Epilepsy syndromes

Genetic syndromes

Genetic disorder

Outpatient clinic

10.54730/abm.2021.030405

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Ventricular septal defect in Crouzon Syndrome: case report.

PubMed (2012)

Fılız Hazan Ayça Aykut Aycan Ünalp Timur Meşe N. Ünal

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). …

Hypertelorism

Frontal Bossing

Crouzon syndrome

Maxillary hypoplasia

Pectus carinatum

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Attempted suicide with levothyroxine in an adolescent girl

Journal of Pediatric Endocrinology and Metabolism (2012)

Hüseyin Anıl Korkmaz Ceyhun Dizdarer Fılız Hazan Utku Karaarslan

Attempted suicide with levothyroxine is very rare and has been described only in a few case reports. Although acute accidental or intentional overdoses of thyroid hormones can lead to marked elevations in serum T4 levels, many children who take as much as 5–10 mg of levothyroxine as a single dose have few or no symptoms of thyrotoxicosis. We report an adolescent girl who attempted suicide by ingesting levothyroxine. She responded well to β-adrenergic blockade.

Levothyroxine

Girl

Accidental

10.1515/jpem-2012-0247

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