MECP2 DUPLICATION SYNDROME WITH ADDITIONAL FINDINGS.

Rett syndrome (RTT) and Angelman syndrome (AS) are devastating neurological disorders that participate in overlapping clinical features with autism spectrum disorders (ASDs). It has been reported that in addition to common mutations or deletions, individuals with chromosomal duplications including either the MECP2 or UBE3A loci show clinical features related to those of MECP2 duplication syndrome, AS, or ASDs. Here we report a 10-year--10-months old male patient having overlapping clinical features of MECP2 duplication syndrome, AS and ASDs. He had mental retardation, lack of speech and developmental delay, and also dysmorphic features such as plagiocephaly, retrognathia, hyperextensible joints in fingers and elbows, broad great toe and three different sizes of cafe au laits. The X-ray revealed compound craniosynostosis and the cranial MRI at 10 years showed delayed myclination. Due to his clinical features, we performed molecular karyotyping and found numerous genomic alterations. Two of these genomic alterations including duplications of chromosome Xq28 and 15qll.2ql3.l1 were found to be compatible with his clinical findings. According to methylation analysis, duplicated UBE3A gene found to be not methylated. The present case study may contribute to a better definition and an improved comprehension of the overlapping pathways of MECP2 and UBE3A.

The evaluation of long-term effects of ionizing radiation through measurement of current sister chromatid exchange (SCE) rates in radiology technologists, compared with previous SCE values.

Ionizing radiation is a strong physical mutagen, causing breakage of phosphodiester bonds in DNA at any stage of the mitotic cycle. Analysis of sister chromatid exchange (SCE) has come into use as a sensitive DNA-damage indicator. We investigated the SCE rates in radiology technologists who are occupationally and chronically exposed to ionizing radiation. The study included 39 radiology technologists and 35 sex- and age-matched healthy controls. There was a statistically significant difference in the SCE frequency between radiology technologists and controls (p<0.0001). Additionally, previous SCE data of 10 radiology technologists were compared with current results regarding radiation exposure time. There was statistically significant difference between previous and current SCE values (p=0.005). The significant increase in the frequency of SCE in radiology technologists emphasizes the importance of radiation-protection procedures in order to minimize radiation exposure and avoid possible genotoxic effects. Comparison of two studies that measured SCE values of radiology technologists after 8 years also suggests that the genotoxic effect is reversible. In conclusion, radiation is still an important mutagenic agent despite improvements in daily working hours and conditions.

Lack of an effect of CYP3A4 and MDR1 gene polymorphisms on colchicine pharmacogenetics in the treatment of Familial Mediterranean fever.

The P-gp/MDR1 multidrug transporter mediates detoxification of numerous drugs, including colchicine, and CYP3A4 is key to the biotransformation of colchicine. We investigated the effects of CYP3A4 and P-gp/MDR1 polymorphisms on bioavailability of colchicine in patients with Familial Mediterranean fever (FMF). Forty-eight Turkish patients with FMF treated with colchicine were genotyped for 3435C>T, (-)1A>G, 61A>G, 1199G>A, 1236C>T, 2677G>A, 2677G>T polymorphisms in the P-gp/MDR1 gene and 3435C>T, 1B(-392A>G), 2(15713T>C), 3(23171T>C), 12(21896C>T), 17(15615T>C) polymorphisms in the CYP3A4 gene. Doses of colchicine administered to patients did not differ with respect to P-gp/MDR1 or CYP3A4 gene polymorphism. We also determined the genotype distributions of CYP3A4 and P-gp/MDR1 genes among FMF patients. There was no significant gender difference in the P-gp/MDR1 polymorphism, whereas there were significant gender differences in the frequencies of 15713T>C and 15615T>C polymorphisms in the CYP3A4 gene. No significant relationship was found between colchicine doses that would introduce optimal clinical response and affect the therapeutic dose and CYP3A4 and P-gp/MDR1 gene polymorphisms in these FMF patients.

Thrombophilia gene mutations in oculoauriculovertebral spectrum.

Oculoauriculovertebral spectrum or Goldenhar syndrome is a phenotypically and probably genetically heterogeneous disorder characterized by hemifacial microsomia (unilateral ear abnormalities and ipsilateral mandibular hypoplasia) as well as vertebral anomalies and epibulbar dermoid/lipodermoids. Although most cases of the Goldenhar syndrome are sporadic, both autosomal recessive and dominant inheritance have been reported so far. In this report, we describe the clinical aspects of two familial cases with evidence of autosomal dominant inheritance and a non-familial case, and compare them with the reports in the literature. One of our familial cases was a ten day old female infant of a mother with left hemifacial microsomia. She had multiple bilateral preauricular tags and a "fleshy masse" on her right cheek. The other familial case was a two months old male infant whose father had hemifacial asymmetry. He had unilateral microtia, and abnormal antihelix, a skin tag in the contralateral ear associated with bilateral sensorineural hearing loss. The third case was a sporadic case who was 2 years old boy with preauricular skin tag, right hemifacial microsomia and limbal dermoid at the temporal limbus of the right eye. As there were no other associated defects, the cases we presented here were thought to be mild variations of the Goldenhar spectrum. The most commonly encountered mutations of thrombophilia genes were studied. We believe that the interfamilial and intrafamilial clinical variabilities observed in these cases reinforce the necessity of a careful examination for the whole family with regards to the stigmata of Goldenhar syndrome.

A patient with 9q subtelomeric deletion syndrome with additional findings.

We describe a one-year old girl, with a de novo segmental aneusomy due to the subtelomeric deletion of the long arm of chromosome 9, determined via fluorescence in situ hybridization technique. Common clinical findings of the 9q subtelomeric deletion syndrome are developmental delay, hypotonia, microcephaly and dysmorphic facial features especially including midface hypoplasia and low set ears. Sensorineural deafness, as a rare condition of the syndrome is also announced. Presented case with sensorineural deafness has most of the common clinical findings of the syndrome, except brachycephaly, downslanting palpebral fissures, synophrys, epicanthus and low set ears, and has also additional findings like microtia, asymmetric and simple ears, long curly eyelashes and fetal finger pads which are not reported previously.

The Impact of the D727E Polymorphism has no Significant Role in Multi Nodular Goiter.

Interactions between individual genetic and environmental factors determine the onset of the multi nodular goiter (MNG). The thyroid-stimulating hormone receptor (TSHR) gene is a convincing candidate gene in the pathogenesis of certain thyroid diseases including MNG. We investigated the codon 727 polymorphism (p.Asp727Glu, p.D727E) of the human TSHR gene using the polymerase chain reaction-restriction fragment length polymorphim (PCR-RFLP) methods in 31 Turkish patients with MNG and in 30 control subjects, aiming to evaluate the relationship between this polymorphism and MNG. After genomic DNA isolation, PCR amplification was performed using a pair of primers in exon 10 of the TSHR gene that contains the p.D727E polymorphism and digested by theNlaIII (Hin1II) restriction enzyme. We found the CC and CG genotype incidence for the patient group to be 0.71 and 0.29, respectively, and for the control group to be 0.8 and 0.2, respectively. No statistically significant difference was found between the genotype and allele distribution of both groups (p = 0.417 and p = 0.449, respectively). However, the polymorphism is significantly correlated with the low serum level of the TSH (p = 0.047). These results suggest that the p.D727E polymorphism of the TSHR gene may not contribute to the pathogenesis of nontoxic MNG diseases.

Linkage analysis and a novel COL4A5 mutation in a large Turkish family with Alport syndrome.

BACKGROUND: Alport syndrome (AS) is a renal disease that is characterized by proteinuria and progressive renal failure, and often accompanied by sensorineural hearing loss and ocular changes. Mutations in the genes encoding for three members of the type IV collagen protein family have been found to be the cause of the disease. We describe a large Turkish family with X-linked AS. We performed linkage analysis in this family and sequencing to identify the mutation in the proband whose disease was confirmed by renal biopsy. METHODS: After genomic DNAs extracted, linkage to the COL4A5 locus was examined using the 2B6 and 2B20, DXS1106, DXS1105 and COL4A5 markers. In addition, COL4A5 gene sequence analysis was performed in the proband. RESULTS: Genetic linkage analysis demonstrated co-segregation of the disease. Haplotype analysis showed that the same haplotype was carried by all affected males and obligatory carrier females. Mutation analysis of the proband has revealed a novel nonsense mutation (c.1135C>T; Gln379X) in exon 19 of the COL4A5 gene which may lead to a more severe phenotype in affected family members carrying this mutation. According to GenBank data base, this mutation has not been reported previously. CONCLUSION: Genetic testing identified a previously undescribed COL4A5 mutation as the cause of the disease.

A Turkish patient with large 17p11.2 deletion presenting with Smith Magenis syndrome.

Smith-Magenis syndrome (SMS), which occurs as a result of an interstitial deletion within chromosome 17p11.2-p12, is a disorder that presents itself with minor dysmorphic features, brachydactyly, short stature, hypotonia, delayed speech, cognitive deficits and neurobehavioral problems including sleep disturbances and maladaptive repetitive and self-injurious behavior. We present a girl with full SMS phenotype. G-banding cytogenetic analysis showed normal 46,XX karyotype. Whole-genome array comparative genomic hybridization (CGH) was performed due to the severity of the phenotype and the unusual features present in the patient. An interstitial deletion in 17p11.2-p12, approximately 4.73 Mb in size was determined. Characteristic physical and behavioral phenotype strongly suggested SMS. This, to the best of our knowledge is the first patient with SMS reported in Turkey. We emphasize the need for whole genome analysis in multiple congenital abnormalities/mental retardation disorders with unusual and severe phenotypes.

A Turkish patient of typical Loeys-Dietz syndrome with a TGFBR2 mutation.

We describe a 2-year-old male patient with skeletal, neurological, cardiovascular, and connective tissue anomalies. Skeletal anomalies included pectus excavatum, hammer toes and hallux valgus and camptodactyly. The characteristic craniofacial findings of hypertelorism, down slanting palpebral fissures, strabismus, ptosis of eyelids, bifid uvula, high-arched palate and retrognathia were present. The proband has been operated on twice for bilateral inguinal hernia and several times for his foot deformities. Psychomotor development was retarded. At present, echocardiographic findings show aortic root dilation. The patient has important characteristics of Loeys-Dietz syndrome (LDS). Direct sequencing analysis of the transforming growth factor beta receptor I and II (TGFBR1 and 2) genes was performed and was demonstrated heterozygous missense mutation of the TGFBR2 gene in the patient, which confirms the diagnosis of LDS. This is the first Turkish patient with typical clinical signs of LDS. This report also illustrates that LDS and Shprintzen-Goldberg syndrome (SGS) have some common clinical characteristics.

Relationship between the IL-12B promoter polymorphism and allergic rhinitis, familial asthma, serum total IgE, and eosinophil level in asthma patients.

BACKGROUND: IL-12B is a strong candidate gene for asthma. OBJECTIVES: We investigated the relationship between IL-12B and asthma, allergic rhinitis, familial asthma, and levels of eosinophils and total immunoglobulin (Ig) E in the serum of asthma patients. METHODS: The study group consisted of 53 asthma patients and 60 control patients. Serum total IgE levels, eosinophil count, and the presence of allergic rhinitis and familial asthma were determined, and the IL-12B polymorphism was analyzed. Both patients and controls were divided into 3 groups based on their genotypes-homozygous for allele 1 (Al), homozygous for allele 2 (A2), and heterozygous patients, ie, alleles 1 and 2 (A1A2). Each genotype was compared with the other genotypes and the control genotypes. RESULTS: The rates for genotypes A1, A1A2, and A2 were 17%, 40%, and 43%, respectively. Male and female total IgE levels were not different between the groups (P>.05), but they were higher than in the controls (P > .05). The frequencies of allergic rhinitis and familial asthma were not different between the groups (P > .05), although allergic rhinitis in the A1A2 genotype and familial asthma in the A2 genotype were higher than in the controls (P < .05). CONCLUSIONS: Our comparison of asthma patients and controls showed that familial susceptibility to asthma may be related to the A2 genotype, whereas coexistence of asthma and allergic rhinitis may be related to the A1A2 genotype. In asthmatic patients, the effects of the IL-12B polymorphism on asthma, allergic rhinitis, familial asthma, eosinophilia and total IgE levels, are controversial. We think that there is a need to investigate this hypothesis in larger series.

Effects of long-term inhaled steroid use on bone mineral density in asthma patients.

UNLABELLED: Asthma is a chronic inflammatory disease of the airways. Inhaled corticosteroids are the most effective and most frequently used antiinflammatory drugs in the treatment of asthma. It is well known that long-term systemic steroid therapy causes osteoporosis, whereas it is thought that inhaled forms do not cause this side effect. Despite the recent disagreeing reports, it has been suggested that the use of inhaled steroids are associated with findings of biochemical bone changes. Therefore, we measured the bone mineral densities (BMD) of 18 patients (15 female, 3 male) with bronchial asthma receiving long-term inhaled steroids by X-ray absorptiometry technique and compared the results with those of 14 healthy control subjects (12 female, 2 male) who had been matched according to age, sex, menopausal state, and body mass index (BMI). RESULTS: There were no detectable significant difference between the BMD levels of left hip (trochanter major, neck of femur, Ward's triangle) and lumbar area of the spine (L2-L4) (p > 0.05).