Anna Křepelová

DYT 6--a novel THAP1 mutation with excellent effect on pallidal DBS.

DYT6 is an early-onset dystonia caused by variable mutations of the gene encoding the thanatos-associated protein (THAP1).1 It usually starts in the cranial region or on the upper extremities with subsequent generalization. It has been reported that deep brain stimulation of the internal globus pallidus (GPi-DBS) has moderate or unsatisfactory effects in these patients.2,3 We describe a novel mutation of the THAP1 gene in 2 siblings (a boy and a girl) with a rapid generalization into a life-threatening status dystonicus (SD) in the boy. Unlike in the 7 previously reported patients,2,3 in his case, we observed excellent long-term effects from bilateral GPi-DBS.

Expression of the hMLH1 and hMSH2 proteins in normal tissues: relationship to cancer predisposition in hereditary non-polyposis colon cancer.

The majority of tumours in patients with hereditary non-polyposis colon cancer (HNPCC) occur in large intestine and endometrium; also, other tissues are at increased risk. We studied expression of hMLH1 and hMSH2 proteins in 148 normal samples of various tissues from non-HNPCC patients and in 14 normal colon tissues from HNPCC patients. Immunohistochemical technique was used. Intensity of nuclear staining, percentage of stained cells and H-scores were calculated. Tissues were divided into groups. Groups A, B and C included tissues with increased risk of cancer in HNPCC A) stomach, small and large bowel; (B) endometrium; (C) ovary, ureter, urinary bladder, kidney and liver. Group D tissues were without increased risk. Expression of the proteins was significantly higher in groups A, B and C compared with group D (P<0.0001, P=0.0004 for hMSH2 in C versus D). The expression was highest in testis. In colons of HNPCC patients, expression of the mutated gene product was significantly lower than in non-HNPCC patients. In conclusion, hMLH1/hMSH2 protein expression is constitutively higher in certain cell types of certain tissues, including the majority of tissues that are at increased risk of cancer in HNPCC. However, association of strong hMLH1/hMSH2 expression with cancer risk is not strictly valid.

Elejalde syndrome—A case report

Elejalde syndrome (McKusick 200995), also known as acrocephalopolydactylous dysplasia, is a rare condition. We describe a sixth patient with this syndrome which is characterized by craniosynostosis and hyperproliferation of fibroblasts in many tissues including skin, liver, kidney, and pancreas. The cause of the syndrome is the homozygous state of an autosomal recessive mutation. We present a hypothesis that Elejalde syndrome might be associated with an inactivating FGFR gene mutation.

Mutations in STK11 gene in Czech Peutz-Jeghers patients

BackgroundPeutz-Jeghers syndrome (PJS) is an autosomal dominant hereditary disease characterized by mucocutaneous pigmentation and gastrointestinal hamartomatous polyposis. The germline mutations in the serine/threonine kinase 11 (STK11) gene have been shown to be associated with the disease. Individuals with PJS are at increased risk for development of various neoplasms. The aim of the present study was to characterize the genotype and phenotype of Czech patients with PJS.MethodsWe examined genomic DNA of 8 individuals from five Czech families by sequencing analysis of STK11 gene, covering its promotor region, the entire coding region and the splice-site boundaries, and by multiplex ligation-dependent probe amplification (MLPA) assay designed for the identification of large exonic deletions or duplications of STK11 gene.ResultsWe found pathogenic mutations in STK11 gene in two families fulfilling the diagnostic criteria of PJS and in one of three sporadic cases not complying with the criteria. The patient with the frameshift mutation in STK11 gene developed aggressive gastric cancer. No other studied proband has developed a carcinoma so far.ConclusionOur results showed that a germline mutation of STK11 gene can be found not only in probands fulfilling the PJS diagnostic criteria, but also in some sporadic cases not complying with the criteria. Moreover, we observed a new case of aggressive gastric cancer in a young patient with a frameshift mutation of STK11 gene.

Multiple primary malignancies and subtle mucocutaneous lesions associated with a novel PTEN gene mutation in a patient with Cowden syndrome: case report.

BackgroundCowden syndrome (CS) is a cancer predisposition syndrome associated with increased risk of breast, thyroid, and endometrial cancers, and is characterized by development of benign mucocutaneous lesions.Case presentationHere we report on a 58-year-old woman with multiple primary malignancies and subtle mucocutaneous lesions such as small polyps and wart-like papulas. Over a period of 23 years, she developed various malignant neoplasms including thyroid, ovarian, stomach, and colon carcinomas, and a benign meningioma. Direct sequencing analysis of the PTEN gene revealed a novel germline mutation (c.438delT, p.Leu146X).ConclusionThis case demonstrates that Cowden syndrome is a multi-system disease that can result in the development of multiple malignant and benign tumors.

Paraganglioma in a 13-year-old girl: a novel SDHB gene mutation in the family?

Paraganglioma (PGL) is a rare tumor that may be found in the abdomen, the thorax, or the head and neck region. Succinate dehydrogenase (SDH, or succinate-coenzyme Q reductase) was recognized as one of the key molecules playing a role in the pathogenesis of the tumor [1]. An enzyme complex bound to the inner mitochondrial membrane, SDH is the only enzyme that participates in both the citric acid cycle and the mitochondrial electron transport chain. It is a heterotetramer divided into three domains: SDHA, the catalytic domain, SDHB, the electron transfer subunit; and SDHC and SDHD, the anchor subunits. Germline mutations in the genes encoding the B, D, and C subunits have recently been recognized as associated with paraganglioma syndromes. These three genes are mapped to 1p36.1wp35 (SDHB), 11q23 (SDHD), and 1q21 (SDHC ). Thus, familial PGL syndromes can be classified according to the mutations in individual SDH subunit genes. PGL type 1 is associated with germline mutations in the SDHD gene; the tumors are more likely multifocal and rarely malignant than in the other types. The locus for PGL type 2, reported in a large Dutch family, has recently been identified as SDH5, on 11q13.1 [2]. The very rare PGL type 3 is associated with mutations in SDHC, encoding subunit C of the SDH complex. PGL type 4 is associated with mutations in the SDHB gene, and these patients are at high risk for malignant disease [3e5]. Individuals with germline mutations in SDHB and SDHD may develop tumors along the whole paraganglia distribution area, and they may also be susceptible to pheochromocytoma (PHE) (i.e., intra-adrenal paraganglioma) [6]. The proband, a 13-year-old girl of Czech origin, demonstrated clinical indicators of PGL. She had refractory hypertension, sweating and headaches, and elevated catecholamine concentrations in plasma and urine (namely, norepinephrine). Computed tomography revealed an expansive mass, 35 30 35 mm) of uncertain etiology in the left para-aortic region (or inside the left suprarenal gland), and an extending mass, 38 45 50 mm, in the left superior posterior mediastinum region. At surgery, the para-aortic mass was excised and paraganglioma revealed by histology. One month after the first operation, a biopsy of the mediastinal tumor was made and the diagnosis of paraganglioma confirmed. Postoperative computed tomography, positron emission tomography, and magnetic resonance imaging demonstrated voluminous tumor

Epidermal growth factor receptor expression in colorectal tumors with and without microsatellite instability

Dear Editor, epidermal growth factor receptor (EGFR) is expressed in a proportion of colon cancers. High grades of EGFR expression have been described to be associated with worsened survival [1, 4]. We have studied EGFR expression in colon cancer specimens with respect to their status of microsatellite stability or instability. Included in the study were 31 specimens with high-frequency microsatellite instability (MSI-H) and 39 specimens with stable microsatellites (MSS). Of the specimens, 20 MSI-H cancers were from patients with a germline mutation in the hMLH1 or hMSH2 genes; 11 were sporadic MSI-H cancers. EGFR expression was detected via indirect immunohistochemistry [4] using mouse monoclonal antiEGFR antibody (NeoMarkers, CA, USA). Antigen retrieval with trypsin was used. Membrane and/or cytoplasmic expression of EGFR was evaluated semiquantitatively as 0, negative; 1+, slight; 2+, moderate; and 3+, intense [1]. A sample of lung cancer with 3+ intensity was used as a positive control. Nerve fibers served as an internal positive control. Results were statistically analyzed using chisquare test. The EGFR protein was expressed in 5 of 31 MSI-H (16.1%) cancers [4 at 1+ level (12.9%) and 1 at 2+ level (3.2%)] and in 17 of 39 MSS (43.6%) cancers [11 at 1+ level (28.2%), 4 at 2+ level (10.3%), 2 at 3+ level (5.1%)]. The difference was statistically significant (P= 0.014), using chi-square test. EGFR expression did not correlate with age, grade and localization of the tumor. EGFR expression was usually not observed in adjacent normal colonic mucosa. In a few specimens, EGFR was expressed in enterocytes of superficial parts of colon mucosa. The percentage of EGFR-positive MSS tumors is in accord with two studies that reported 49% and 46% of EGFR-positive colorectal tumors, respectively [3, 4]. Goldstein and Armin found EGFR reactivity in 75.5% of cases [1]. The pathogeneses of MSS and MSI-H colorectal cancers are different. For instance, aneuploidy, 18q loss of heterozygosity and p53 mutations are predominantly present in MSS tumors [5]. Tumors with microsatellite instability are associated with unique pathological attri-butes [5] and better prognosis [2]. The significantly lower EGFR expression might correspond to the less aggressive behavior of MSI-H tumors.