Unexpected Coexistence of a Derivative t(21;21) and Complementary Mosaic r(21) in a Female with Multiple Miscarriages.

The case presented here describes a female patient with recurrent miscarriages and a normal microarray analysis result. However, the coexistence of a robertsonian (21;21) translocation and complementary mosaic ring chromosome 21 was detected by karyotyping and FISH analysis. Partial trisomy 21 was found with QF-PCR and microarray analysis in one of the fetuses. The aim of this report was to emphasize the diagnostic importance of conventional cytogenetics.

Phenotypic spectrum of CHARGE syndrome based on clinical characteristics

Background/aim: CHARGE syndrome is a rare autosomal dominant disease with multiple congenital anomalies and cognitive impairment, which is caused by mutations in the CHD7 gene. This study aimed to disclose the mild end of the phenotypic spectrum of CHARGE syndrome, which has a highly variable expressivity. Materials and methods: Twenty-one patients who had at least one of the major symptoms of CHARGE syndrome (coloboma, choanal atresia, characteristic ear anomalies, semicircular canal hypoplasia, and cranial nerve anomalies) were included in the study. All patients were tested for karyotype analysis and CHD7 gene mutation/deletion. Results: In the study population, 6 different mutations were detected in 5 patients, and 2 different polymorphisms were detected in the CHD7 gene in 3 patients. MLPA analysis of all coding exons of the CHD7 gene revealed no pathogenic deletion/duplication. Conclusion: CHARGE syndrome should be considered as a differential diagnosis to detect the mild end of the spectrum, even if the patient does not fit the criteria.

Two Cases with Ring Chromosome 13 at either End of the Phenotypic Spectrum.

Ring chromosome 13 is a rare genetic condition with an incidence of 1/58,000 in live births. Major clinical features of patients with ring chromosome 13 include growth and developmental retardation, microcephaly, facial dysmorphism, ambiguous genitalia, anal atresia, eye malformations, retinoblastoma, and hand, foot, and toe abnormalities. The severity of the phenotype depends on the amount of genetic material lost during ring chromosome formation. Here, we report 2 cases with ring chromosome 13 at either end of the phenotypic spectrum.

Termination of pregnancy for fetal abnormalities: main arguments and a decision-tree model.

INTRODUCTION: By looking through our ethical committee cases, we demonstrate the main arguments we use for making a judgment in face of fetal abnormalities. Our decision making model is a simplified algorithm of the arguments and concepts we use in scientific-ethic discussion. MATERIALS AND METHODS: A retrospective analysis was conducted from single, tertiary referral center of patients evaluated for fetal abnormalities from 2004 to 2014. We hypothesized that all our judgments would fit into a decision-tree model. RESULTS: 553 fetal abnormality cases were discussed, 348 (63%) were given termination of pregnancy (TOP) proposal. When detected <24 weeks, fetuses with chromosomal abnormality/genetic disorders (n:100) and with mental retardation risk (n:93) ended up with TOP proposal. For incompatibility with life cases (n:111) and the multimorbidity cases (n:44) the committee suggest TOP, regardless of gestational age. The highest family approval ratios were in chromosomal abnormalities/genetic disorders group (93%), and the lowest figures were in mental retardation risk group (80%). DISCUSSION: Continuously changing literature on prenatal and postnatal therapy options and the long term outcome of various fetal abnormalities influence committee decisions. Theoretical high success rates and inconsistent data on long term prognosis of some anomaly groups resulted in heterogenous decisions and various approval ratios.

Prevalence of Prader-Willi syndrome among infants with hypotonia.

OBJECTIVE: To investigate the prevalence of Prader-Willi syndrome (PWS) in infants with hypotonia between the ages of 0 and 2 years. STUDY DESIGN: Karyotyping studies were performed in all infants with hypotonia. The study group was composed of infants with hypotonia for whom the karyotyping was found to be normal. Fluorescence in situ hybridization and methylation analysis were performed simultaneously in the study group. Molecular studies for uniparental disomy were undertaken in the patients without deletions with an abnormal methylation pattern. RESULTS: Sixty-five infants with hypotonia with a mean age of 8 months were enrolled. A deletion was detected in 6 patients by fluorescence in situ hybridization analysis. Only 1 patient had no deletion but had an abnormal methylation pattern. A maternal uniparental disomy was observed in this patient. PWS was diagnosed in 10.7 % (7/65) of the infants with hypotonia. CONCLUSION: The prevalence of PWS syndrome is high among infants with hypotonia. PWS should be considered by pediatricians and neonatologists in the differential diagnosis of all newborns with hypotonia. Early diagnosis of PWS is important for the management of these patients.

Lack of association of childhood partial epilepsy with brain derived neurotrophic factor gene.

Brain-derived factor (BDNF) is a member of neurotrophin family and is localized and upregulated in areas implicated in epileptogenesis. Several lines of evidence make the BDNF gene a plausible candidate gene for predisposition to epilepsy. In this study, we tested that BDNF might be involved in the etiology of childhood PE. To assess whether BDNF gene C270T polimorphism could be implicated in vulnerability to PE, we conducted a case-control association analysis (112 partial epileptic and 100 controls) in Turkish children. Epileptic children were divided into two groups: 1--idiopathic (n = 85) and 2--symptomathic epilepsy (n = 27). There was no significant difference in genotypic distribution and allelic frequencies of the BDNF gene C270T polimorphism between the PE and control groups. However, the BDNF gene TT genotype was more frequently seen in the epileptic children (15 versus 11 patients, resp.). Interestingly, in the epilepsy group, both two children with TT genotype have posttraumatic epilepsy. The data indicate a possible association with the 270T genotype of the BDNF gene with a posttraumatic epilepsy. To draw any conclusion, further studies using larger sample sizes should be carried out in various ethnic populations in childhood epilepsies.

Serum motilin levels and motilin gene polymorphisms in children with functional constipation.

BACKGROUND: Functional constipation is an important clinical problem among chidren all over the world. Its main cause is not completely understood. Motilin is a gastrointestinal hormone that increases intestinal motility. In this study, we aimed to investigate the serum motilin levels and its relationship with stool consistency and motilin gene polymorphisms in constipated children. METHODS: In this study we investigated 91 constipated patients (mean age 6.84±3.55 years) and 100 healthy controls (mean age 7.78±4.25 years). Serum motilin levels were assessed by sandwich enzyme-linked immunosorbent assay. rs2281820 (c.44 C>T) and rs2281818 (c.66 C>T) mutations were evaluated for motilin gene polymorphisms. RESULTS: Serum motilin levels were significantly lower in constipated children than healthy controls (6.20±7.86 vs. 11.54±17.89 pg/mL, respectively, P=0.008). Serum motilin levels were significantly correlated with Bristol stool scale rate (r=0.193, P=0.011) in whole study group, but in the constipation group there was no significant correlation (r=-0.072, P=0.528). There were no differences in terms of presence or distribution of the polymorphisms of rs2281820 (c.44 C>T) and rs2281818 (c.66 C>T) in both groups. There was not a significant difference between different polymorphism groups regarding serum motilin concentrations in whole study group and also in both of the study groups. CONCLUSIONS: This study indicated for the first time that serum motilin levels decreased in constipated children. Further studies are needed to clarify whether motilin or motilin gene polymorphisms has a role in pathogenesis of functional constipation.

Relationship between plasminogen activator inhibitor-1 gene alterations and fibrosis in peritoneal dialysis patients.

Peritoneal fibrosis (PF) is a pathological change that occurs mostly long-term peritoneal dialysis (PD) patients, as a result of triggering the inflammatory response. Plasminogen activator inhibitor-1 (PAI-1) is an important molecule featured in the development of fibrosis. It has been shown in literature that PAI-1 gene alterations are associated with fibrosis in many tissues and organs. However, PAI-1 gene alterations in long-term PD patients have not yet been investigated. In this study, PAI-1 4G/5G polymorphism was examined by reverse hybridization, and all coding exons of the PAI-1 gene were examined by sequence analysis to provide treatment modification in patients with predisposition before fibrosis develops. The patients were divided into two groups according to ultrafiltration failure test and duration of PD treatment: those with suspected PF or a high probability of developing PF (36%) and those with a low probability of developing PF (64%). There was no significant difference between the two groups in findings such as peritoneal equilibration test (PET), Kt/V, the content of the PD solution used, peritonitis, and PAI-1 4G/5G polymorphism (P > .05). A total of eight gene alterations (rs2227660, rs2227668, rs2854233, rs41281004, rs61553169, rs368413856, rs2227684) were detected by sequence analysis, one of which was exonic (rs6092). When the genotype distributions of these variants were examined, no significant difference was found between the two groups. PAI-1 gene changes were not detected in patients with the probability of developing PF. There is a need for further studies involving other molecules responsible for predisposing to PF with larger patient populations in patients undergoing long-term PD treatment.

Identification of PCDH19 Gene Mutations/Deletions in Patients with Early Onset Epilepsy.

BACKGROUND AND AIMS: PCDH19 gene, which encodes protocadherin 19, is associated with epilepsy and intellectual disability, mainly in affected females. The clinical manifestations are heterogeneous and the main features include early onset seizure, generalized or focal seizures sensitive to fever, and brief seizures occurring in clusters. The disorders exhibit a unique and unusual X-linked pattern of expression. We aimed to investigate PCDH19 mutations/deletions in patients with epilepsy and describe the clinical/molecular features. METHODS: PCDH19 gene was analyzed in 35 Turkish female patients from 34 families with early-onset epilepsy via direct sequencing and multiplex ligation-dependent probe amplification analysis. Additionally, array comparative genomic hybridization analysis was performed in patients with whole gene deletion. RESULTS: We identified 2 different heterozygous mutations in 2 unrelated probands (5. 7%) which were located in exon 1. Additionally, whole gene deletions were detected in dizygotic twin girls (5. 7%), who had distinct clinical features and the deletion was inherited from the unaffected father. The second twin suffered more severe clinical manifestations including autistic features, behavioral problems, mild-moderate mental retardation and seizures, which were under control with multidrug regimen when compared with the first twin. CONCLUSION: PCDH19 is a major causative gene in patients with epilepsy and further data is required to gain a better understanding of phenotype-genotype correlation. In addition to gene sequencing, deletion/duplication analysis will improve the molecular diagnosis in patients with clinical findings.

A toddler with a novel LEPR mutation.

There are numerous causes, such as environmental factors, medications, endocrine disorders, and genetic factors, that can lead to obesity. However, severe early-onset obesity with abnormal feeding behavior, mental retardation, dysmorphic features, organ-specific developmental abnormalities, and endocrine disorders suggest a genetic etiology. Mutations in genes related to the leptin-melanocortin pathway play a key role in genetic obesity. This pathway controls hypothalamic regulation of food intake. A few cases have been reported to have mutations in leptin (LEP) or leptin receptor (LEPR) genes. The cases had severe early-onset obesity, hyperphagia, and additional features, such as altered immune function, hypogonadism, and hypothyroidism. We present a 3-year-old male patient with severe early-onset obesity whose genetic analysis revealed a homozygous, novel, and pathogenic variant (c.1603+2T>C) in LEPR.

Role of apolipoprotein E in febrile convulsion.

Apolipoprotein E is consistently associated with the progression of some common human neurodegenerative diseases, e.g., epilepsy. We hypothesized that genetic variations in the apolipoprotein E gene have implications for susceptibility to, and prognoses in, febrile convulsion, which plays an apparent role in the development of epilepsy. We used the polymerase chain reaction and restriction enzyme digestion to characterize variations of the apolipoprotein E gene. Sixty-nine patients with febrile convulsion (simple/complex) and a corresponding cohort of healthy patients (n = 75) were used. There was no significant difference in genotypic distribution and allelic frequencies of the apolipoprotein E gene between the febrile convulsion and control groups. Comparing subpopulations of the febrile convulsion group (patients with simple and complex febrile convulsion), we noted that no patients with the epsilon3/epsilon4 genotype had complex febrile convulsions. The apolipoprotein E epsilon3/epsilon4 genotype was more frequently seen in the simple febrile than in the complicated febrile convulsion group (9 versus 0 patients, respectively). The data indicate an association with the epsilon3/epsilon4 genotype of the apolipoprotein E gene with a milder phenotype. Although apolipoprotein E4 is not a vulnerability factor regarding febrile convulsions, it seems effective in regard to prognoses.

Long-standing fever and Angelman syndrome: report of two cases.

An 8-month-old girl and a 20-month-old boy who presented with motor and developmental delay and long-standing fever are presented. The patients were diagnosed as Angelman syndrome with fluorescence in situ hybridization (FISH) analysis. Despite extensive clinical and laboratory examinations, no inflammatory or infectious origin for the fever was found. It was considered that the long-standing fever observed in these cases was due to hypothalamic dysfunction for thermoregulation.

Growth in familial mediterranean fever: effect of attack rate, genotype and colchicine treatment.

We evaluated the effect of attack frequency, homozygosity for the M694V mutation and colchicine treatment on growth in children with familial Mediterranean fever (FMF). Prepubertal patients with FMF (19 M, 14 F) were evaluated retrospectively for height SDS, weight SDS and body mass index (BMI) before and after 46.2 +/- 39.8 months of colchicine therapy. Pretreatment attack frequency and acute phase markers at diagnosis were also recorded. While acute phase markers were not correlated to anthropometric variables, attack rate was negatively, albeit insignificantly, correlated to height and weight SDS. Height SDS did not change, while BMI showed a slight but significant increase during colchicine therapy (16.2 +/- 2.6 to 17.3 +/- 3.1 kg/m2, p = 0.035). Homozygosity for M694V did not affect time from the onset of symptoms to diagnosis, anthropometric variables and acute phase markers. In conclusion, pre-treatment attack rate and anthropometric development correlated negatively. Colchicine therapy improved BMI slightly, but significantly. Homozygosity for M694V had no effect on anthropometric development.

Genetic Evaluation of Common Neurocutaneous Syndromes.

The neurocutaneous syndromes are a group of multisystem disorders that affect the skin and central nervous system. Neurofibromatosis 1, neurofibromatosis 2, tuberous sclerosis complex, and Sturge-Weber syndrome are the four major neurocutaneous disorders that mainly present in childhood. In this review, we discuss the clinical findings and genetic diagnosis, related genes/pathways and genotype-phenotype correlations of these four neurocutaneous syndromes.

The ASXL1 mutation p.Gly646Trpfs*12 found in a Turkish boy with Bohring-Opitz Syndrome.

In line with a recent study showing that ASXL1 mutations found in the common population cannot be ruled out as pathogenic, we have identified the ASXL1 p.Gly646Trpfs*12 mutation-present in 132 individuals in ExAC-as a very probable cause of the disease in a Bohring-Opitz syndrome patient.

A case of Wolf-Hirschhorn syndrome progressing to resistant epilepsy.

Wolf-Hirschhorn syndrome is defined by a collection of core characteristics that include mental retardation, epilepsy, growth delay, and craniofacial dysgenesis. The disorder is caused by subtelomeric deletions in the short arm of chromosome 4. The syndrome, as described in the literature, may have a progression to resistant seizures and status epilepticus, which may then exhibit specific electroencephalographic findings. This study investigates a 3-year-old girl presenting with the classic phenotype for Wolf-Hirschhorn syndrome, confirmed by fluorescence in situ hybridization. Here we describe and discuss this patient, who initially presented with myoclonic seizures but then had a progression toward resistant epilepsy, along with electroencephalographic findings specific to Wolf-Hirschhorn syndrome.

Expanding spectrum of SCN1A-related phenotype with novel mutations.

Mutations in the genes encoding voltage-gated sodium channels cause a variety of epilepsy syndromes, with most of the mutations occurring in SCN1A gene. It is one of the most well-researched epilepsy genes. The SCN1A gene, which seems to be a relevant regulator of excitability of the CNS, is implicated in various epilepsy phenotypes through various genetic mechanisms ranging from common variants to rare monogenic variants. It is known that SCN1A gene is tightly linked to severe myoclonic epilepsy of infancy (SMEI). However, its phenotypic spectrum is expanding. Here, we report clinical and genetic findings of 10 patients with SCN1A mutations where two of them were found to have novel mutations. Our findings support understanding and updating knowledge on the correlation between phenotype distribution and location and type of mutations in SCN1A-related disorders.

Identification of an AR mutation in Klinefelter syndrome during evaluation for penoscrotal hypospadias.

Genital anomalies, ranging from female genitalia to milder degrees of undervirilization, are rarely reported in Klinefelter syndrome, in which a male is classically expected to be born with male external genitalia. Though androgen insensitivity syndrome (AIS) is one of the possible pathogenic mechanisms also in Klinefelter syndrome with genital anomalies, to date the AR gene has not been analyzed in any of the published cases of Klinefelter syndrome of the milder phenotype, except for those patients presenting with a severe phenotype, such as female external genitalia.Lack of interest in considering androgen insensitivity in Klinefelter syndrome with a milder phenotype of genital anomalies may impede its identification through an accurate diagnosis. We present a 14-month-old boy with penoscrotal hypospadias, micropenis, and a ventral penile chordee abnormality who was observed to have both a 47,XXY karyotype and a known missense mutation in the ARgene that was inherited from his mother. Although it is recommended that Klinefelter syndrome be considered in the differential diagnosis of penoscrotal abnormalities, mutations in specific genes involved in androgen synthesis or responsiveness should also be investigated.

Diagnostic Approach to Genetic Causes of Early-Onset Epileptic Encephalopathy.

Epileptic encephalopathies are characterized by recurrent clinical seizures and prominent interictal epileptiform discharges seen during the early infantile period. Although epileptic encephalopathies are mostly associated with structural brain defects and inherited metabolic disorders, pathogenic gene mutations may also be involved in the development of epileptic encephalopathies even when no clear genetic inheritance patterns or consanguinity exist. The most common epileptic encephalopathies are Ohtahara syndrome, early myoclonic encephalopathy, epilepsy of infancy with migrating focal seizures, West syndrome and Dravet syndrome, which are usually unresponsive to traditional antiepileptic medication. Many of the diagnoses describe the phenotype of these electroclinical syndromes, but not the underlying causes. To date, approximately 265 genes have been defined in epilepsy and several genes including STXBP1, ARX, SLC25A22, KCNQ2, CDKL5, SCN1A, and PCDH19 have been found to be associated with early-onset epileptic encephalopathies. In this review, we aimed to present a diagnostic approach to primary genetic causes of early-onset epileptic encephalopathies.