Atypical presentations of DYT1 dystonia with acute craniocervical onset.

DYT1 gene mutations lead to early-onset dystonia that begins with focal limb onset and spreads to other body regions within 5 years, with typical sparing of the oromandibular muscles. In the present study, we describe two patients with an unusual presentation of the disease.

Molecular genetic analysis in 14 Czech Kabuki syndrome patients is confirming the utility of phenotypic scoring.

Kabuki syndrome (KS) is a dominantly inherited disorder mainly due to de novo pathogenic variation in KMT2D or KDM6A genes. Initially, a representative cohort of 14 Czech cases with clinical features suggestive of KS was analyzed by experienced clinical geneticists in collaboration with other specialties, and observed disease features were evaluated according to the 'MLL2-Kabuki score' defined by Makrythanasis et al. Subsequently, the aforementioned genes were Sanger sequenced and copy number variation analysis was performed by MLPA, followed by genome-wide array CGH testing. Pathogenic variants in KMT2D resulting in protein truncation in 43% (6/14; of which 3 are novel) of all cases were detected, while analysis of KDM6A was negative. MLPA analysis was negative in all instances. One female patient bears a 6.6 Mb duplication of the Xp21.2-Xp21.3 region that is probably disease causing. Subjective KS phenotyping identified predictive clinical features associated with the presence of a pathogenic variant in KMT2D. We provide additional evidence that this scoring approach fosters prioritization of patients prior to KMT2D sequencing. We conclude that KMT2D sequencing followed by array CGH is a diagnostic strategy with the highest diagnostic yield.

[Hepatoblastoma, Etiology, Case Reports]. / Hepatoblastom, etiologie, kazuistiky.

Hepatoblastoma is an uncommon malignant neoplasm in general, yet, it is the most common liver malignancy in children with the incidence about one per milion children. This type of liver tumor usually occurs before the age of three years. The etiology of hepatoblastoma remains unknown. However, there are some genetic conditions known to be associated with an increased risk of developing hepatoblastoma such as Beckwith-Wiedemann syndrome, hemihypertrophy, APC-associated polyposis, α-1-antitrypsin defficiency and some metabolic disorders including tyrosinemia, galactosemia and glycogen storage disease type 1. There is a higher risk of hepatoblastoma in children with very low birthweight, children who acquire hepatitis B at an early age and children with congenital biliary atresia.

[Fanconi Anemia, Complementation Group D1 Caused by Biallelic Mutations of BRCA2 Gene--Case Report]. / Fanconiho anémie, komplementacní skupina D1 v dusledku bialelické mutace genu BRCA2--kazuistika.

Fanconi anemia is a rare autosomal recessive disorder, clinically and genetically heterogeneous, characterized by typical clinical features, such as short stature, microcephaly, skeletal abnormalities, abnormal skin pigmentations, developmental delay and congenital heart, kidney anomalies etc. Pancytopenia leading to bone marrow failure occurs in the first decade. Patients with Fanconi anemia have a high risk of hematologic malignancies and solid tumors. The diagnosis of Fanconi anemia is based on cytogenetic testing for increased rates of spontaneous chromosomal breakage and increased sensitivity to diepoxybutane or mitomycin C. Fanconi anemia is a heterogeneous disorder, at least 15 complementation groups are described, and 15 genes in which mutations are responsible for all of the 15 Fanconi anemia complementation groups have been identified. Unlike other Fanconi anemia complementation groups, for complementation group D1 (FANCD1), the bone marrow failure is not a typical feature, but early-onset leukemia and specific solid tumors, most often medulloblastoma and Wilms tumor, are typical for this complementation group.

TET1 is a tumour suppressor that inhibits colon cancer growth by derepressing inhibitors of the WNT pathway.

Ten eleven translocation (TET) enzymes catalyse the oxidative reactions of 5-methylcytosine (5mC) to promote the demethylation process. The reaction intermediate 5-hydroxymethylcytosine (5hmC) has been shown to be abundant in embryonic stem cells and tissues but strongly depleted in human cancers. Genetic mutations of TET2 gene were associated with leukaemia, whereas TET1 downregulation has been shown to promote malignancy in breast cancer. Here we report that TET1 is downregulated in colon tumours from the initial stage. TET1 silencing in primary epithelial colon cells increase their cellular proliferation while its re-expression in colon cancer cells inhibits their proliferation and the growth of tumour xenografts even at later stages. We found that TET1 binds to the promoter of the DKK gene inhibitors of the WNT signalling to maintain them hypomethylated. Downregulation of TET1 during colon cancer initiation leads to repression, by DNA methylation, the promoters of the inhibitors of the WNT pathway resulting in a constitutive activation of the WNT pathway. Thus the DNA hydroxymethylation mediated by TET1 controlling the WNT signalling is a key player of tumour growth. These results provide new insights for understanding how tumours escape cellular controls.

[Prenatal diagnosis of skeletal dysplasia in first trimester of pregnancy X-linked dominant chondrodysplasia punctata]. / Prenatální diagnóza skeletální dysplazie v prvním trimestru tehotenství X-vázaná dominantní chondrodysplasia punctata.

Case report describes successful prenatal diagnosis of skeletal dysplasia in the first trimester of pregnancy in a female patient affected with X-linked dominat chondrodysplasia punctata (CDPX2). Her first pregnancy was terminated in the second trimester due to skeletal dysplasia of the foetus. The diagnosis in the following pregnancy was finished in the first trimester - before the end of the 13th gestational week. The diagnosis was established on the basis of ultrasonographic (US) examination and mutation analysis of the EBP gene in the material of chorionic villus sampling (CVS).

[Pregnancy and delivery in a patient with pure 46,XY karyotype. Summary of actual knowledge about XY women]. / Tehotenství a porod u pacientky s cistým karyotypem 46,XY Souhrn dosavadních poznatku o XY zenách.

TYPE OF STUDY: Summary review and a case report. SETTINGS: GEST IVF, Centre of Reproductive Medicine, Prague. INTRODUCTION: In scientific literature there two syndrome have been described in the presence of pure 46,XY karyotype when an individual is phenotypically and psychosexually identified as a woman. Androgen insensitivity syndrome (AIS) and pure gonadal dysgenesis XY (GD XY, Swyer syndrome). Thanks to the presence of a uterus in Swyer syndrome we can treat this type of sterility with donated oocytes. METHOD: The paper describes both syndromes from prenatal, genetical, endocrinological, oncological, reproductive and perinatological points of view. A case study concerning a patient with pure gonadal dysgenesis XY, who successfully became pregnant through a donated oocytes programme, is also described. The pregnancy progressed physiologically, and a healthy boy, 3820g/52cm, was delivered in term by ceasarean section. DISCUSSION: In world scientific literature at least fifteen successful pregnancies with pure gonadal dysgenesis XY have been described. In spite of the expectation of diminished uterine capacity, children are born to term with a normal delivery weight. CONCLUSION: This article should be considered as a summary of all actual knowledge about these patients. This article should be available and usefull for clinicians who come across XY females. The case study provides evidence that even an individual with male genetic gender can be pregnant and deliver a healthy child.

[Birt-Hogg-Dubé syndrome]. / Syndrom Birt-Hogg-Dubé

Birt-Hogg-Dubé syndrome (BHDS, MIM 135150) is an autosomal dominant condition characterized by presence of skin fibrofolliculomas, lung cysts, spontaneous pneumothorax and renal cancer. The disease is caused by germ-line mutations of the FLCN gene, which encodes protein folliculin. BHDS is a rare condition with high penetrance and variable expression. Clinical recommendations include increased care during general anesthesia due to a higher risk of pneumothorax, and long-term follow-up due to an elevated risk of renal cancer. Diagnostic and predictive DNA tests are available; prenatal and preimplantation diagnosis is possible.

[Juvenile polyposis syndrome]. / Juvenilný polypózny syndróm.

Juvenile polyposis syndrome (JPS) is an autosomal dominant disorder characterized by the occurrence of juvenile polyps and predisposition to cancer of the gastrointestinal tract (GIT). Characteristic feature of juvenile polyps are irregular cystic glands filled with mucus not observed in other colorectal cancer syndromes. Germline mutations in the SMAD4 and BMPR1A genes are found in 40% of the JP individuals. Hereditary hemorrhagic telangiectasia (HHT) and higher frequency of gastric polyposis are associated mostly with SMAD4 mutations.

[Rhabdoid tumours]. / Rhabdoidné nádory.

Rhabdoid tumors (RT) are rare highly malignant tumors. They are part of the embryonic types of tumors and therefore occur in early childhood (between ages of 0-2 years). The most common locations are brain and kidney, but RTs arising usually from soft tissues have been reported widely at most anatomical sites in the body. These tumors are composed of rhabdoid cells alone or as a mixture with primitive neuroectodermal cells, mesenchymal cells and/or epithelial cells, commonly denoted as atypical teratoid/rhabdoid tumours (AT/RT). Based on extremely rare incidence and usually non-specific histological picture, molecular genetic studies are extremely helpful in confirming diagnosis of RT. Biallelic inactivation mutation of the SMARCB1 gene plays a crucial role in the pathogenesis of most RT. One third of mutations are germline mutations leading to the designation of the so-called rhabdoid predisposition syndrome. Molecular genetic analysis of the SMARCB1 gene might be beneficial in the establishment of correct diagnosis, genetic counselling and for epidemiologic studies.

[Hereditary diffuse gastric cancer]. / Hereditární difuzní karcinom zaludku.

Hereditary diffuse gastric cancer is an autosomal dominant syndrome with a high lifetime risk of diffuse gastric cancer and also a high risk of lobular breast carcinoma. Hereditary diffuse gastric cancer (HDGC) is characterized by late presentation and a poor prognosis. The average age of onset of HDGC is 38 years, with a range of 14-69 years. The estimated lifetime risk of developing gastric cancer by age 80 is 67% for men and 83% for women. Many families with HDGC have germline mutations in the E-cadherin (CDH1) gene. We describe indication for genetic testing of germline mutations in CDH1 gene, possibilities of predictive testing, preventive care, prophylactic gastrectomy and preimplantation diagnosis.

[Li-Fraumeni syndrome - a proposal of complex prevention care for carriers of TP53 mutation with total-body MRI]. / Li-Fraumeni syndrom - návrh komplexní preventivní péce o nosice TP53 mutace s pouzitím celotelové magnetické rezonance.

Li-Fraumeni syndrome (LFS) is one of the most serious hereditary cancer syndromes with high risk of malignancy already in childhood. Adrenocortical carcinoma, brain tumor, leukemia, sarcoma are the most frequent malignancies in children. Early breast cancer, brain tumor, sarcoma, skin cancer, gastrointestinal, lung, gynecological, hematological and other malignancies can be seen in adults. Predictive testing in families with detected LFS and TP53 mutation is offered from the age of 18 for various reasons. One of the most important reasons is a very limited effectivity of prevention especially in children, also the possible risk of psychological harm to the child and his family caused by the diagnosis of this syndrome. Progress in diagnostic methods, especially total body MRI, enables to propose preventive care for early cancer diagnoses for children and adults. Biochemical tests, ultrasound, MRI may improve survival of these high risk individuals and support the possibility of predictive testing in children.

Unique mutational profile associated with a loss of TDG expression in the rectal cancer of a patient with a constitutional PMS2 deficiency.

Cells with DNA repair defects have increased genomic instability and are more likely to acquire secondary mutations that bring about cellular transformation. We describe the frequency and spectrum of somatic mutations involving several tumor suppressor genes in the rectal carcinoma of a 13-year-old girl harboring biallelic, germline mutations in the DNA mismatch repair gene PMS2. Apart from microsatellite instability, the tumor DNA contained a number of C:G→T:A or G:C→A:T transitions in CpG dinucleotides, which often result through spontaneous deamination of cytosine or 5-methylcytosine. Four DNA glycosylases, UNG2, SMUG1, MBD4 and TDG, are involved in the repair of these deamination events. We identified a heterozygous missense mutation in TDG, which was associated with TDG protein loss in the tumor. The CpGs mutated in this patient's tumor are generally methylated in normal colonic mucosa. Thus, it is highly likely that loss of TDG contributed to the supermutator phenotype and that most of the point mutations were caused by deamination of 5-methylcytosine to thymine, which remained uncorrected owing to the TDG deficiency. This case provides the first in vivo evidence of the key role of TDG in protecting the human genome against the deleterious effects of 5-methylcytosine deamination.

An in situ cell to study phase transitions in individual aerosol particles on a substrate using scanning transmission x-ray microspectroscopy.

A new in situ cell to study phase transitions and chemical processes on individual aerosol particles in the x-ray transmission microscope at the PolLux beamline of the Swiss light source has been built. The cell is machined from stainless steel and aluminum components and is designed to be used in the standard mount of the microscope without need of complicated rearrangements of the microscope. The cell consists of two parts, a back part which contains connections for the gas supply, heating, cooling devices, and temperature measurement. The second part is a removable clip, which hosts the sample. This clip can be easily exchanged and brought into a sampling unit for aerosol particles. Currently, the cell can be operated at temperatures ranging from -40 to +50 °C. The function of the cell is demonstrated using two systems of submicron size: inorganic sodium bromide aerosols and soot originating from a diesel passenger car. For the sodium bromide we demonstrate how phase transitions can be studied in these systems and that O1s spectra from aqueous sodium bromide solution can be taken from submicron sized particles. For the case of soot, we demonstrate that the uptake of water onto individual soot particles can be studied.

[Our experience with analysis of the PTEN gene in patients suspected of having Cowden syndrome]. / Nase skúsenosti s analýzou génu PTEN u pacientov s podozrenim na Cowdenovej syndróm.

BACKGROUNDS: Cowden syndrome (CS) is a rare autosomal dominant disorder with an increased risk of breast, thyroid and uterine cancer development. The International Cowden Consortium has defined strict diagnostic criteria for individuals and families suspected of having CS. PATIENTS AND METHODS: We analyzed the genomic DNA of 16 patients by sequencing analysis and MLPA (multiplex ligation-dependent probe amplification) method. RESULTS: We found germline mutations, c.825_840del, resp. c.438delT, in 2 patients. Both patients fulfilled strict diagnostic criteria. The other patients, except one, who did not fulfil the criteria, did not harbour any pathogenic mutation. Patients not fulfilling strict diagnostic criteria were included in the study according to major CS criteria but not pathogenic. CONCLUSION: Our results and information from relevant articles show that strict international criteria are well established and analysis of "CS-like" patients has no significant prognostic meaning.

Germline variants of the promyelocytic leukemia tumor suppressor gene in patients with familial cancer.

The promyelocytic leukemia (PML) gene is an important tumor suppressor gene. We tested the hypothesis that germline disruption of the PML gene may be associated with a cancer predisposition syndrome. Mutation analysis of the PML gene was performed in 111 patients with familial adult cancer or young age-onset adult cancer. These were mostly breast and colon cancer, or colon polyposis patients in whom mutation analyses of the BRCA1, BRCA2, MLH1, MSH2, APC or TP53 genes did not detect a pathogenic germline mutation. Heteroduplex analysis and direct sequencing were used for mutation screening. Mutation-specific methods were designed for frequency determination of novel variants in the general population. No deleterious nonsense or frameshift germline mutations were detected. Several missense single-nucleotide substitutions were found, including two novel missense variants, c.83C>T (p.Thr28Ile) in exon 1 in a 42-year-old breast cancer patient and c.1558C>T (p.Pro520Ser) in exon 6 in a 32-year-old colon cancer patient, that were not detected in 100 and 214 non-cancer persons, respectively. Frequency of the c.2260G>C (p.Ala754Pro) variant in isoform IV of the PML gene was higher in patients with colon polyposis and cancer than in the control group (P = 0.029). In conclusion, germline disruption of the PML gene is probably not associated with a highly penetrant susceptibility to adult-onset breast and colon cancer. Pathogenicity of c.83C>T and c.1558C>T variants in the PML gene is uncertain. Carriers of the c.2260 G>C variant in PMLIV isoform may be at an increased risk of colon polyposis and cancer.