Familiärer Darmkrebs

Up to 5% of colorectal cancer cases are caused by a monogenic inherited disposition. Among these, hereditary nonpolyposis colorectal cancer (Lynch syndrome, HNPCC) accounts for 2–3% and adenomatous polyposis syndromes (familial adenomatous polyposis, FAP and MUTYH-associated polyposis, MAP) for about 1% of cases. Hamartomatous polyposis syndromes (juvenile polyposis syndrome, Peutz-Jeghers syndrome and Cowden syndrome) are rare disorders that are also associated with an increased colorectal cancer risk. The genetic basis is largely known for the tumour syndromes mentioned above. The identification of the causative germline mutation in the respective DNA repair genes (e.g. in HNPCC and MAP) or tumour suppressor genes (FAP or hamartomatous polyposis syndromes) allows confirmation of the diagnosis in affected individuals and provides predictive diagnostics for their healthy relatives. To achieve a targeted and useful molecular diagnostics, it is important that the clinician provides a detailed characterisation of the clinical picture; moreover, family history may also give a hint of the underlying gene defect. The screening of tumour tissue for the presence of a mismatch repair defect should precede mutation analysis in suspected cases of HNPCC, as it is difficult to differentiate between this condition and sporadic colorectal cancer. In contrast, mutation analysis can be directly performed in polyposis syndromes provided the syndrome has been correctly classified by the histology of polyps.     

Gastrointestinal polyposis syndromes

Colorectal cancer is one of the leading causes of cancer-related death in the Western society, and the incidence is rising. Rare hereditary gastrointestinal polyposis syndromes that predispose to colorectal cancer have provided a model for the investigation of cancer initiation and progression in the general population. Many insights in the molecular genetic basis of cancer have emerged from the study of these syndromes. This review discusses the genetics and clinical manifestations of the three most common syndromes with gastrointestinal polyposis and an increased risk of colorectal cancer: familial adenomatous polyposis (FAP), juvenile polyposis (JP) and Peutz-Jeghers syndrome (PJS).     

Klinik und Genetik des familiären Darmkrebses

Familial clustering of colorectal cancer (CRC) and early disease onset are indicators of an inherited tumour syndrome. Monogenic dispositions account for 3–5% of all CRC cases and are subdivided into hereditary non-polyposis colorectal cancer (HNPCC/Lynch syndrome) and various gastrointestinal polyposis syndromes. Many of these syndromes are characterised by a broad spectrum of extracolonic tumours. Early detection and accurate classification are essential in providing effective surveillance and treatment. Initial diagnosis is based on endoscopic and histological findings as well as on the presence of extracolonic manifestations and family history. Molecular genetic examination is important for the differential diagnosis, evaluation of recurrence risk, and predictive testing of asymptomatic at risk individuals; it is performed according to largely standardised algorithms. Diagnostic difficulties are common among the hamartomatous polyposes due to their broad phenotypic overlap and frequent uncertainties in histological evaluation, as well as among patients with few adenomas. Risk-adapted surveillance guidelines have been established for HNPCC and for the more frequently observed polyposis syndromes. Beyond established tumour syndromes, familial clustering of CRC (which is often of late onset) or the occurrence of few adenomas is likely to be based upon a multifactorial (complex) etiology. Although identification of the underlying genetic risk factors and biological pathways is still in the early stages, rapid progress is being made due to methodical developments such as genome-wide association studies and CNV analysis.     

先天性心脏病相关综合征的遗传学研究

先天性心脏病(congenitalheartdisease,CHD)是儿科常见的疾病,现已发现约有300多种临床综合征伴有CHD.对Alagille综合征、CHARGE联合征、Holt-Oram综合征、Noonan综合征、Turner综合征、VACTERL联合征、Williams综合征、22q11缺失综合征和13、18、21三体综合征与CHD相关流行病学、临床表型、遗传病因和诊断及其再发风险进行了综述,为产前和产后临床诊断,了解疾病预后和再发概率提供资料.     

Neuropathology of mitochondrial diseases

The term “mitochondrial diseases” (MD) refers to a group of disorders related to respiratory chain dysfunction. Clinical features are usually extremely heterogeneous because MD may involve several tissues with different degrees of severity. Muscle and brain are mostly affected, probably because of their high dependence on oxidative metabolism. Muscle can be the only affected tissue or involved as a part of a multi-system disease; ragged red fibers, accumulation of structurally altered mitochondria and cytochrome-c-oxidase (COX) negative fibers are the main pathological features. In mitochondrial encephalopathies, central nervous system (CNS) structures are affected according to different patterns of distribution and severity. Characteristic lesions are neuronal loss, vasculo-necrotic changes, gliosis, demyelination and spongy degeneration. In accordance with either grey matter or white matter involvement two main groups of diseases may be distinguished. Neuronal loss and vasculo-necrotic multifocal lesions are the common features of grey matter involvement; demyelination and spongy degeneration occur when white matter is affected, often associated with less severe lesions of the grey structures. Grey matter lesions are prevalent in MERRF, MELAS, Alpers and Leigh syndromes. White matter involvement is always seen in Kearns-Sayre syndrome and was recently described in mtDNA depletion syndrome linked to dGK mutations and in the rare conditions associated with complex I and II deficiency. In this review we describe the main histopathological features of muscle and CNS lesions in mitochondrial diseases.     

Congenital hypertrophy of retinal pigment epithelium: a sign of familial adenomatous polyposis.

Families of people known to have familial adenomatous polyposis are screened for signs of the disease by yearly examination of the bowel. Multiple areas of congenital hypertrophy of the retinal pigment epithelium have been described in patients with familial adenomatous polyposis. To assess the reliability of this marker 40 patients with familial adenomatous polyposis, representing all 25 pedigrees with living affected members in the Northern region''s polyposis registry, were examined for hypertrophy of the retinal pigment epithelium. All had multiple lesions, ranging in number from two to over 40. None of the 35 controls had more than two lesions. Ocular examination is valuable for detecting carriers of the gene for familial adenomatous polyposis before their symptoms develop.     

家族性腺瘤息肉病的遗传病因学研究进展

家族性腺瘤息肉病(FAP)是第二常见的遗传性结直肠癌综合征,多在青春期发病,发病率约1/10000,主要临床表现为大肠中多发的腺瘤性息肉,是一种结直肠癌的癌前病变,如果不予治疗,几乎100%的患者会发展成为结直肠癌。一直以来,FAP被认为是一种常染色体显性遗传疾病,发病由APC基因胚系突变引起。根据临床特点的不同,FAP患者可以分为经典型FAP(CFAP)和轻表型FAP(AFAP)。然而近年来,在一些无APC基因胚系突变的FAP患者中发现了Mut YH基因的双等位基因突变。这种由于Mut YH基因双等位基因突变而无APC生殖突变所引起的临床综合征定义为Mut YH基因相关性息肉病[2](MAP)。MAP为常染色体隐性遗传,是一种特殊类型的FAP。另外,很多研究表明,APC基因的突变位点与结肠腺瘤病的严重程度、癌变的风险程度和某些肠外表现相关。MAP的发现和对FAP基因型-表型相关性的研究,完善了对FAP遗传病因学的认识,对于FAP患者及高危亲属的合理防治和预后具有重要的意义。     

First reported patient with human ERCC1 deficiency has cerebro-oculo-facio-skeletal syndrome with a mild defect in nucleotide excision repair and severe developmental failure

Nucleotide excision repair (NER) is a genome caretaker mechanism responsible for removing helix-distorting DNA lesions, most notably ultraviolet photodimers. Inherited defects in NER result in profound photosensitivity and the cancer-prone syndrome xeroderma pigmentosum (XP) or two progeroid syndromes: Cockayne and trichothiodystrophy syndromes. The heterodimer ERCC1-XPF is one of two endonucleases required for NER. Mutations in XPF are associated with mild XP and rarely with progeria. Mutations in ERCC1 have not been reported. Here, we describe the first case of human inherited ERCC1 deficiency. Patient cells showed moderate hypersensitivity to ultraviolet rays and mitomycin C, yet the clinical features were very severe and, unexpectedly, were compatible with a diagnosis of cerebro-oculo-facio-skeletal syndrome. This discovery represents a novel complementation group of patients with defective NER. Further, the clinical severity, coupled with a relatively mild repair defect, suggests novel functions for ERCC1.     

Trait syndromes among North American trees are evolutionarily conserved and show adaptive value over broad geographic scales

Adaptive syndromes and their evolutionary constraints represent a powerful construct for understanding plant distributions. However, it is unclear how the species requirements to face multiple stressors promotes syndrome formation and to which abiotic stressors these syndromes show adaptive value over broad geographic scales. We combined local occurrence data from the U.S. Forest Inventory and Analysis (FIA) of 219 angiosperm and 85 gymnosperm species living across the conterminous US with phylogenies and trait data to identify tree syndromes, their evolutionary conservatism, and their adaptive value over broad scales. Factor analyses and evolutionary model selection revealed that trees possess functional trait syndromes that are strongly conserved. Major syndromes at the species level differed between angiosperms and gymnosperms. While the two main syndromes in angiosperms were related to cold and drought‐waterlogging tolerance, in gymnosperms a trade‐off between shade and drought tolerance was the main syndrome followed by a growth‐fire resistance syndrome. Additional RLQ and fourth‐corner approaches revealed that trait syndromes at the community level were broadly similar to those observed at the species level for angiosperms, although this was less clear for gymnosperms. This suggests that syndrome evolution has played an important role on angiosperm distributions, whereas additional ecological factors explain gymnosperm distributions. Importantly, syndromes show adaptive value, as they were geographically associated with several environmental variables showing structure from continental to local scales, being temperature the main abiotic stressor. Our results indicate that across the conterminous US tree species possess clear syndromes that are subjected to strong evolutionary constraints driving tree species and forest community distribution.     

The basal ganglia. A clinical and physiopathological approach (author's transl)

Clinical, anatomical and physiological observations reveal four principal syndromes in the pathology of the basal ganglia: a nigral or putamino-nigral syndrome, a caudate nucleus syndrome, a pallidal syndrome and a luysian syndrome. It seems necessary to make a distinction between those lesions of the neostriatum which are predominately of the putamen.     

Neuro-kardio-fazio-kutane Syndrome

Recently, neuro-cardio-facio-cutaneous (NCFC) syndromes were defined as a group of hereditary diseases with phenotypical overlap based on a similar pathogenetic mechanism. These syndromes are associated with increased signal transduction down the RAS-MAPK (RAS: rat sarcoma, MAPK: mitogen-activated protein kinase) pathway. Noonan, LEOPARD, cardio-facio-cutaneous, and Costello syndrome as well as neurofibromatosis type 1 and Legius syndrome belong to the NCFC diseases. Interdisciplinary health management is essential to determine and establish adequate medical diagnostics and treatment and to provide psychosocial support for affected patients and their families.     

Melanoma,Growth Factors,and Cutaneous Paraneoplastic Syndromes

Paraneoplastic syndromes are systemic reactions in patients with cancers that are unrelated to tumor size or location. Cutaneous paraneoplastic syndromes include proliferative, metabolic, and inflammatory skin disorders. Both systemic and cutaneous paraneoplastic reactions may occur in patients with malignant melanoma. Cancers, including melanoma, may produce growth factors, which may be responsible for proliferative cutaneous paraneoplastic syndromes. A patient with malignant melanoma we previously reported, who had the sudden onset of acanthosis nigricans, skin tags (acrochordons), and seborrheic keratoses provides a model for proliferative cutaneous paraneoplastic syndromes. High levels of α-TGF were found in the patient's urine prior to melanoma removal. The increased level of α-TGF declined after the melanoma was removed, and a corresponding clinical improvement in his acanthosis nigricans, skin tags, and seborrheic keratoses occurred. In the skin lesions, EGF receptors were abnormally present throughout all epidermal layers prior to melanoma removal, and returned to their normal distribution in the basal layers after surgery. Ectopic growth factor production by malignant melanomas and other epithelial neoplasms may cause rare, but distinctive cutaneous paraneoplastic lesions. The model of melanoma, cutaneous paraneoplastic syndromes, and growth factors may provide understanding of both cutaneous lesions associated with neoplasia, and benign cutaneous lesions.     

不同胃癌前病变中医证型PG、G-17、CEA和叶酸水平变化及相关性研究

目的:对不同胃癌前病变中医证型和血清胃蛋白酶原(pepsinogen,PG)、胃泌素-17(gastrin-17,G-17)、癌胚抗原(carcinoembryonic antigen,CEA)和叶酸水平变化的关系进行探讨,为胃癌前病变的诊断提供一定的依据。方法:以80例胃癌前病变(precancerous lesion of gastric cancer,PLGC)患者研究组,80例健康者为对照组,对研究组患者进行中医临床辨证分型,对两组研究对象的血清PG、G-17、CEA和叶酸进行测定比较。结果:研究组PLGC患者中医证型分布不均匀,差异显著(P<0.05),由多到少依次为湿热蕴胃并/兼脾胃虚寒证>胃络瘀阻并/兼气阴两虚证>痰湿中阻并/兼脾胃气虚证>肝胃气滞并/兼气阴两虚证>肝胃气滞并/兼脾胃虚寒证>湿热蕴胃并/兼胃阴不足证。PLGC不同中医证型患者血清PG I和PG II水平差异显著(P<0.05);与对照组比较,各证型PG I水平均显著降低,PG II水平均显著升高(P<0.05)。且湿热蕴胃并/兼脾胃虚寒证和胃络瘀阻并/兼气阴两虚证的PG I水平显著低于其他证候,血清PG II水平显著高于其他(P<0.05)。与对照组比较,研究组不同证候的G-17、CEA水平显著升高,叶酸水平显著降低(P<0.05);观察组中湿热蕴胃并/兼脾胃虚寒证和胃络瘀阻并/兼气阴两虚证G-17、CEA显著高于其他证候,叶酸水平显著低于其他证候(P<0.05)。结论:胃癌前病变不同中医证型血清PG、G-17、CEA和叶酸存在明显差异。     

Carney complex and lentiginosis

Initially described as the ‘complex of myxomas, spotty skin pigmentation and endocrine overactivity,’ Carney complex (CNC) is known as an autosomal dominant multiple neoplasia syndrome involving skin and cardiac myxomas, pigmented skin lesions and endocrine tumors. Pigmented cutaneous manifestations in CNC are important diagnostically because they can be used for the early detection of the disease and, thus, the prevention of life‐threatening complications of CNC related to heart myxomas and endocrine abnormalities. Specific for the disease skin lesions are present in more than half of the CNC patients. A major challenge is to distinguish pigmented skin lesions associated with CNC from other skin pathology, and thus accurately estimate the risk of cancer in affected patients; curiously, patients with CNC do not appear to have predisposition to skin cancers whereas this is not the case with other genetic syndromes associated with melanotic and other cutaneous lesions. In this paper, we review the current knowledge on cutaneous pathology associated with CNC and the most recent data on the molecular basis of the disease.     

Alternative splicing of the Drosophila PTEN gene.

Mutations in the human PTEN gene have been identified in a number of different tumour types, and in the hamartomatous polyposis syndromes Cowden disease and Bannayan-Zonana syndrome. The PTEN gene encodes a phosphatase that antagonises phosphoinositide 3-kinase (PI3K) signalling by removing the 3' phosphate from phosphatidylinositol 3, 4,5-trisphosphate (PtdIns (3,4,5)P(3)). Here we show that the PTEN gene is conserved in the invertebrate Drosophila melanogaster and demonstrate that the gene undergoes alternative splicing.     

The WNT7A G204S mutation is associated with both Al-Awadi–Raas Rothschild syndrome and Fuhrmann syndrome phenotypes

Two syndromes are known to be associated with WNT7A mutations: Al-Awadi–Raas-Rothschild syndrome (AARRS) and Fuhrmann syndrome. Woods et al. (2006) showed that there is complete and partial loss of WNT7A function in these two syndromes respectively. Therefore, both syndromes have similar clinical features but the phenotype in Fuhrmann syndrome is less severe. The G204S mutation was previously reported to result in AARRS phenotype in three Saudi families. In the current communication, we report on a different unrelated Saudi patient with the same mutation but the patient had Fuhrmann syndrome phenotype. We believe this case is important because it questions the presence of a phenotype–genotype correlation in WNT7A mutations and because it demonstrates that the G204S mutation may be associated with both AARRS and Fuhrmann phenotypes.     

Hereditary polyposis coli. III. Genetic and evolutionary fitness.

The numbers of progeny born to 355 patients with heritable polyposis of the colon and to 315 related, but normal, subjects, all old enough to have completed their families, are presented, as well as data on 432 subjects still young enough to have more children. Two main indices are used: mean family size ("genetic fitness") and the complement of the extinction probability of the line ("evolutionary fitness"), both of which suppose a steady state. Point- and interval-estimates (the latter derived by an extension of Stigler's method) are furnished. It is estimated that the probability a new mutant gene will persist is one in four for Gardner syndrome, one in 20 for familial polyposis coli, and 0 for Peutz-Jeghers syndrome. There is evidence of bimodality in family size, suggesting voluntary infertility in a proportion of subjects. The data confirm our provisional working assumption that most families are completed by the time women are in their mid-40's and men in their mid-50's.     

A study of small bowel tumors; with special emphasis on clinical aspects

Ninety-eight patients with 100 different tumors of the small bowel were studied. There were more malignant than benign tumors. Adenocarcinoma was the commonest lesion and the ileum the most frequent anatomical site of all tumors. Except for carcinoid tumors, the lesions were observed more often in male than in female patients. The average age of patients in this series was higher than that reported in most other series. Loss of weight, and abdominal pain were the most constant symptoms. Clinical syndromes of anemia and bleeding, small bowel obstruction, biliary obstruction, perforation with peritonitis, abdominal tumor, melanosis with small bowel polyposis, and cutaneous von Recklinghausen's disease with small bowel neurofibromatosis were encountered either alone or in combination. In the group operated upon, a resection of the involved segment with end-to-end anastomosis was done when feasible. None of the patients operated upon before 1946 lived as much as five years after operation. The most common causes of death were extension of the primary tumor and metastasis, peritonitis due to perforation, associated bronchopneumonia, and hemorrhage.     

La maladie de Parkinson et les syndromes parkinsoniens apparentés

Parkinson's disease represents the main cause of parkinsonian syndrome with precise clinical criteria and a prolonged sensitivity to the dopaminergic treatments. In a systematic way, in front of any parkinson's syndrome, an iatrogenic origin must be required (neuroleptic therapy). Other atypical degenerative parkinsonian syndromes include: multiple system atrophy and dementia with Lewy bodies within the group of synucleinopathy; progressive supranuclear palsy and corticobasal degeneration within the group of tauopathy. These diseases are distinguished in particular from the Parkinson's disease by the weak one, even the absence of reactivity with the dopaminergic treatment resulting in particular from postsynaptic lesions. The clinical and paraclinic characteristics of these various pathologies will be developed in this article like their therapeutic approach.