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PubMed1999

Clinical impact of molecular genetic diagnosis, genetic counseling, and management of hereditary cancer. Part II: Hereditary nonpolyposis colorectal carcinoma as a model.

Hereditary nonpolyposis colorectal carcinoma (HNPCC) is the most common hereditary form of colorectal carcinoma (CRC) and may account for 5-10% of the total CRC burden. The discovery of DNA mismatch repair (MMR) genes, inclusive of hMSH2, hMLH1, hPMS2, and hMSH6, has enabled the identification of who has and who does not have inordinately increased susceptibility to CRC as well as a litany of extracolonic cancers. Mutation testing has focused on hMSH2 and hMLH1, the most common mutations in HNPCC. The protocol for DNA testing and DNA-based genetic counseling is described in Part I of this study. One hundred ninety-nine bloodline relatives were tested and counseled from five hMLH1 and two hMSH2 families. Their major reason for seeking genetic counseling and DNA testing was to inform their children and other loved ones of their mutation status. Those who sought counseling overestimated their risk for inheriting the mutation and showed a high rate of interest in prophylactic surgery, and many were greatly concerned about insurance discrimination. Knowledge about HNPCC, its molecular genetic diagnosis, surveillance and management opportunities, and genetic counseling implications are still emerging, all in the face of a greater need for physician education regarding all facets of hereditary cancer.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Carrier risk status changes resulting from mutation testing in hereditary non-polyposis colorectal cancer and hereditary breast-ovarian cancer.

CONTEXT: In hereditary cancer syndrome families with an identified cancer associated mutation, mutation testing changes the carrier risk status of the tested person and may change the carrier risk status of relatives. OBJECTIVE: This study aimed to describe the change in the distribution of carrier risk status resulting from testing in hereditary breast-ovarian cancer (HBOC) and hereditary non-polyposis colorectal cancer (HNPCC) families. DESIGN: This was an observational cohort study. PATIENTS: The cohort included members of 75 HBOC and 47 HNPCC families. Of the 10 910 cohort members, 1408 were tested for a mutation and learned their test results. OUTCOME MEASURE: Carrier risk for all cohort members was assessed before and after mutation testing. RESULTS: There was a change in carrier risk status in 2906 subjects after testing of 1408 family members. The most common type of carrier risk change, from at risk to non-carrier status, accounted for 77% of the risk changes; 12% were a change to known carrier status from a lower risk. Sixty percent of persons with a carrier risk status change were not themselves tested; their risk status changed because of a relative's test result. CONCLUSIONS: Carrier risk status changes from uncertainty to certainty (that is, to carrier or to non-carrier) account for 89% of risk changes resulting from testing. These risk changes affect cancer prevention recommendations, most commonly reducing their burden. Current practices do not ensure that untested family members are informed about changes in their carrier risk status which result from mutation testing of their relatives.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Hereditary polyposis syndromes and hereditary non-polyposis colorectal cancer.

Colorectal cancer due to hereditary syndromes comprises approximately 5% of the overall colorectal cancer burden. Conditions fall into two distinct categories, the polyposis syndromes and hereditary non-polyposis colorectal cancer. It is important for the clinician to have a working knowledge of both as screening and surveillance recommendations differ significantly from those applicable to the general population. The polyposis syndromes include familial adenomatous polyposis, Peutz-Jeghers syndrome, juvenile polyposis, and Cowden syndrome. For each condition, a review of both the intestinal and extra-intestinal clinical findings is presented as well as the genetic basis, genetic testing, screening, surveillance and treatment options. As genetic testing for several of these conditions has recently become both commercially available and standard practice, special attention is given to indications and strategies for genetic testing in hereditary colorectal cancer syndromes.

Adenomatous Polyposis Coli↗
PubMed2000

Combined analysis of hereditary prostate cancer linkage to 1q24-25: results from 772 hereditary prostate cancer families from the International Consortium for Prostate Cancer Genetics.

A previous linkage study provided evidence for a prostate cancer-susceptibility locus at 1q24-25. Subsequent reports in additional collections of families have yielded conflicting results. In addition, evidence for locus heterogeneity has been provided by the identification of other putative hereditary prostate cancer loci on Xq27-28, 1q42-43, and 1p36. The present study describes a combined analysis for six markers in the 1q24-25 region in 772 families affected by hereditary prostate cancer and ascertained by the members of the International Consortium for Prostate Cancer Genetics (ICPCG) from North America, Australia, Finland, Norway, Sweden, and the United Kingdom. Overall, there was some evidence for linkage, with a peak parametric multipoint LOD score assuming heterogeneity (HLOD) of 1.40 (P=.01) at D1S212. The estimated proportion of families (alpha) linked to the locus was.06 (1-LOD support interval.01-.12). This evidence was not observed by a nonparametric approach, presumably because of the extensive heterogeneity. Further parametric analysis revealed a significant effect of the presence of male-to-male disease transmission within the families. In the subset of 491 such families, the peak HLOD was 2.56 (P=.0006) and alpha =.11 (1-LOD support interval.04-.19), compared with HLODs of 0 in the remaining 281 families. Within the families with male-to-male disease transmission, alpha increased with the early mean age at diagnosis (<65 years, alpha =.19, with 1-LOD support interval.06-.34) and the number of affected family members (five or more family members, alpha =.15, with 1-LOD support interval.04-.28). The highest value of alpha was observed for the 48 families that met all three criteria (peak HLOD = 2.25, P=.001, alpha=.29, with 1-LOD support interval.08-.53). These results support the finding of a prostate cancer-susceptibility gene linked to 1q24-25, albeit in a defined subset of prostate cancer families. Although HPC1 accounts for only a small proportion of all families affected by hereditary prostate cancer, it appears to play a more prominent role in the subset of families with several members affected at an early age and with male-to-male disease transmission.

Age of Onset↗
PubMed1995

Spectrum of germline mutations in the RB1 gene: a study of 232 patients with hereditary and non hereditary retinoblastoma.

Germline mutations in the RB1 gene confer hereditary predisposition to retinoblastoma. We have performed a mutation survey of the RB1 gene in 232 patients with hereditary or non hereditary retinoblastoma. We systematically explored all 27 exons and flanking sequences as well as the promotor. All types of point mutations are represented and are found unequally distributed along the RB1 gene sequence. In the population we studied, exons 3, 8, 18 and 19 are preferentially altered. The range of frequency of detection of germline mutations is about 20%, indicating that other mechanisms of inactivation of RB1 should be involved. The spectrum of mutations presented here should help to improve the clinical management of retinoblastoma and to understand the molecular mechanisms leading to tumorigenesis.

Base Sequence↗
PubMed2004

Absence of PRSS1 mutations and association of SPINK1 trypsin inhibitor mutations in hereditary and non-hereditary chronic pancreatitis.

BACKGROUND AND AIMS: Mutations in the cationic trypsinogen (protease, serine, 1 (trypsin 1); PRSS1) gene are causally associated with recurrent acute and chronic pancreatitis. We investigated whether mutations in the PRSS1 gene are associated with hereditary and non-hereditary pancreatitis. As a modifier role has been proposed for trypsin inhibitor (serine protease inhibitor, Kazal type I; SPINK1) mutations, the role of SPINK1 mutations in these patients was also analysed. SUBJECTS AND METHODS: The coding regions of PRSS1 and SPINK1 genes were sequenced in 290 controls and 198 patients, of whom 120 were diagnosed as idiopathic (ICP), 41 as alcoholic (ACP), and 37 as hereditary pancreatitis (HP). Twenty four unaffected relatives of HP probands were also analysed and genotype-phenotype correlations and statistical analyses were performed. RESULTS: No mutations in the PRSS1 gene were detected in any of the patients, including HP patients, while the N34S mutation was observed in the SPINK1 gene in the majority of HP patients (73%). Similarly, 26.8% of ACP (11 of 41) and 32.5% (39 of 120) of ICP patients also had SPINK1 mutations. The N34S mutation was observed in both homozygous and heterozygous conditions. In comparison, only 2.76% of the control population had the N34S allele (p<0.001). The P55S mutation was observed in one ICP and one ACP patient, and in three normal individuals. Genotype-phenotype correlations did not suggest any significant difference in the age of onset, severity of disease, or pancreatic endocrine insufficiency in patients with or without mutated SPINK1 and irrespective of the allelic status of N34S SPINK1. CONCLUSIONS: Irrespective of the aetiology, mutations in the PRSS1 gene are not associated with chronic pancreatitis, including HP. In contrast, the N34S mutation in the SPINK1 gene shows a significant correlation in these patients. A comparable phenotype in terms of age of onset, diabetes mellitus, and other phenotypic features in patients with or without SPINK1 mutations and N34S homozygotes and heterozygotes suggests that there may still be involvement of other genetic or environmental factors.

Adult↗
PubMed2003

Hereditary hyperferritinaemia-cataract syndrome and differential diagnosis of hereditary haemochromatosis.

Hereditary hyperferritinaemia-cataract syndrome (HHCS) is a rare differential diagnosis of hereditary haemochromatosis. It should be suspected in patients with raised ferritin levels, but no evidence of iron overload, and in the absence of mutations in the HFE gene. Awareness of this condition prevents unnecessary liver biopsies and allows accurate genetic counselling since HHCS is an autosomal dominant disorder. The danger of treating these patients by phlebotomy in the same manner as those with hereditary haemochromatosis is highlighted.

Adult↗
PubMed1999

Familial pseudohyperkalemia maps to the same locus as dehydrated hereditary stomatocytosis (hereditary xerocytosis).

Familial pseudohyperkalemia is a "leaky red blood cell" condition in which the cells show a temperature-dependent loss of potassium (K) from red blood cells when stored at room temperature, manifesting as apparent hyperkalemia. The red blood cells show a reduced lifespan in vivo but there is no frank hemolysis. Studies of cation content and transport show a marginal increase in permeability at 37 degrees C and a degree of cellular dehydration, qualitatively similar to the changes seen in dehydrated hereditary stomatocytosis (hereditary xerocytosis). Physiological studies have shown that the passive leak to K has an abnormal temperature dependence, such that the leak is less sensitive to temperature than that in normal cells. We performed genetic mapping on the original family and found that the condition in this kindred maps to the same locus (16q23-ter) that we have previously identified for an Irish family with dehydrated hereditary stomatocytosis, which does not show the same temperature effects.

Anemia, Hemolytic, Congenital↗
PubMed1986

Mode of inheritance of Samoyed hereditary glomerulopathy: an animal model for hereditary nephritis in humans.

The pedigree of a line of Samoyed dogs with Samoyed hereditary glomerulopathy (SHG) was investigated to determine the mode of inheritance. Sixty percent of males were affected with severe renal disease that progressed to renal failure before 15 months of age. In contrast, female carriers showed less severe involvement and their disease did not progress to renal failure. This pattern is consistent with the inheritance of an X-linked dominant gene. A similar mode of inheritance has been postulated in some families with hereditary nephritis. Further similarities between SHG in dogs and hereditary nephritis in humans have been demonstrated previously in clinical and renal morphologic studies. The present study supports the view that this line of Samoyed dogs would be an appropriate model for studying the human disease.

Animals↗
PubMed1985

[An autopsy case of hereditary ataxia (hereditary spastic ataxia)].

An autopsy case of hereditary spastic ataxia is reported. There are four family members with similar symptomatology through three generations. A 36-year-old man developed atactic gait at the age of 22 years, with following dysarthria, scanning speech, pyramidal signs, dysmetria, dysdiadochokinesia, nystagmus and mild sensory disturbance. The clinical course was steadily progressive and terminated about 14 years after the onset. The gross examination showed smallness of the brain stem and spinal cord with marked symmetrical atrophy of the anterior and lateral columns, especially at thoracic level. Histologically, pronounced degeneration was found in the anterior and posterior spino-cerebellar tracts, spino-thalamic tracts, and spinal ganglia. The olivary nuclei, pons and cerebellum were spared. The dentate nuclei showed considerable loss of neurons with degeneration, however there were no clinical signs related to this pathology. This case is considered to fall in the group of hereditary spastic ataxia according to Greenfield's classification, however, there was no report on degeneration of the dentate nucleus in this disease for the present. Hereditary spastic ataxia is very rare disease and only four cases have well been documented in our country to the best of our knowledge. The presence of nystagmus and superficial sensory disturbance, and sparing of the posterior column of the spinal cord seems to be common clinico-pathology in Japanese cases, differing from those of foreign cases. The fact that reactive astrogliosis was immunohistochemistry demonstrated in the degenerative regions of the spinal cord and where is no discrepancy between degenerative and reparative processes as reported before is stressed.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

[Modification of hereditary and non-hereditary variations by antimutagens].

A new approach has been worked out to access negative effects of environmental pollution on the genetic system based both on hereditary (mutational) and non-hereditary (modification) changes, as reflected by generational and regulatory disorder of a genome. The results of the authors' own experiments on different plants and Drosophila, studying the influence of mutagenic and antimutagenic factors on the extent of chromosomal aberrations, gene mutation, and variable asymmetry (the latter as a non-hereditary variation) have been presented. A rationale has been provided for that there are possibilities of concurrent antimutagenic inhibition of mutations and modifications induced by chemical mutagens (alkylating agents). The findings open up a new perspective for antimutagenic correction of both generational and regulatory genetic disorders caused by environmental pollutants.

Air Pollutants↗
PubMed1998

Major impacts of gonadal mosaicism on hereditary risk estimation, origin of hereditary diseases, and evolution.

The specific-locus test in mice is by far the most extensively applied method for precisely defining gene mutation frequencies in mammals. Computer simulations of control experiments involving 57.4 million offspring, based on vast amounts of historical data, show that because of gonadal mosaicism, the total frequency of spontaneous mutations per generation is much higher than has been thought. The estimated combined spontaneous mutation frequency for both sexes for the seven genes tested in specific-locus experiments is 39.6 x 10(-5) mutation/gamete. Division of this frequency by the combined induced mutation frequencies in parents of both results in an estimate of the doubling-dose (DD) of from 5.4 to 7.7 Gy. For decades, the DD has been thought to be about 1 Gy. As the DD increases, estimates of hereditary risk that are based upon it decrease. Thus, one important ramification of this new understanding is that estimates of the hereditary risk to humans from radiation, commonly made by the doubling-dose (DD) approach, are probably at least five times too high. It also appears that gonadal mosaicism is likely to play a much more important role both in evolution and the origin of hereditary diseases than has been appreciated in the past.

Animals↗
PubMed1990

Hereditary motor and sensory neuropathies and hereditary spastic paraplegia: a magnetic stimulation study.

Central motor conduction to the small hand muscles was investigated in 59 patients with peroneal muscular atrophy and hereditary spastic paraplegia (HSP) by using transcranial magnetic brain stimulation. These comprised 20 patients with type I hereditary motor and sensory neuropathy (HMSN I), 15 with type II (HMSN II), 4 with HMSN I and 10 with HMSN II with associated pyramidal features, and 10 with the "pure" form of HSP. Central motor conduction was usually normal in HMSN I, HMSN II, and HSP. In HMSN I with pyramidal signs, central motor conduction time was greatly prolonged bilaterally. This result may reflect an associated involvement of the central motor pathways in these patients. In HMSN II with accompanying pyramidal features, 6 of the 10 patients had abnormal central motor conduction, although conduction times were only slightly prolonged, suggesting a different pathophysiological pattern.

Adolescent↗
PubMed2005

Association of hereditary hemorrhagic telangiectasia and hereditary nonpolyposis colorectal cancer in the same kindred.

Endoglin (CD105) is a proliferation-associated protein that is strongly expressed in endothelial tissue and has a role in tumor angiogenesis. Mutations in endoglin are also linked to Hereditary Hemorrhagic Telangiectasia type 1 (HHT1), an autosomal dominant disease associated with aberrant angiogenesis. We report an unusual association of HHT1 and Hereditary Nonpolyposis Colorectal Cancer (HNPCC) in the same kindred. Genetic analysis indicates that these 2 syndromes are genetically unrelated and separately segregated within the family. The mutation in the endoglin gene leads to a truncated protein. The mutation in the mismatch repair gene MLH1 causes a splicing defect, giving synthesis to an unstable mRNA from this mutated allele. The potential protective role of an endoglin mutation in patients with HNPCC is discussed.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Central motor conduction in hereditary motor and sensory neuropathy and hereditary spastic paraplegia.

Conduction of the central motor pathways (CMCT) by magnetic stimulation of the motor cortex (TMS) was performed in 17 patients with hereditary motor sensory neuropathy (HMSN) and 2 siblings with hereditary spastic paraplegia (HSP). CMCT was prolonged in two patients with HMSN I with associated pyramidal features and in two subjects with HMSN II without clinical pyramidal signs. CMCT may be abnormal in HMSN due to central motor pathways involvement or altered spinal excitability with increased synaptic delay. CMCT was normal in the upper limbs in patients with HSP but increased in the legs. Diagnostic yield of TMS increased in less disabled cases with HSP when selective conduction at the spinal level (C7-S1) was calculated. Abnormal spinal conduction in HSP is consistent with degeneration of the crossed corticospinal tracts at the thoracic level found in neuropathologic observations.

Adolescent↗
PubMed2004

[Molecular pathology in hereditary colorectal cancer. Recommendations of the Collaborative German Study Group on hereditary colorectal cancer funded by the German Cancer Aid (Deutsche Krebshilfe)].

Although twin studies indicate that inherited genetic factors contribute to about 35% of colorectal cancers (CRC), the exact genetic background has currently been elucidated in only 5-10% of cases. These comprise several hereditary cancer predisposition syndromes that present with a high number of syn- or metachronous neoplasms within an affected person and/or family. Many of these tumors exhibit typical histopathological changes. In general, one should discriminate between cancer syndromes associated with adenomatous and non-adenomatous (i.e., hamartomatous) polyps, the latter being quite rare. The patient's age often serves as a substantial hint to hereditary cancer. The next step of diagnostic work-up includes analysis of microsatellite instability (MSI) together with immunohistochemical detection of a loss of expression in one of the most frequently affected mismatch repair genes (MSH2, MSH6; MLH1, PMS2). Finally, the molecular demonstration of a gene mutation in the blood or germline is the most expensive and tedious procedure. This requires a signed informed consent from the patient after appropriate genetic counseling.

Colonic Neoplasms↗
PubMed1992

Hereditary spastic dystonia with Leber's hereditary optic neuropathy: neuropathological findings.

Neuropathological findings in a 59-year-old male case of hereditary spastic dystonia with Leber's hereditary optic atrophy included: marked depletion of myelinated nerve fibres in the posterior funiculi, corticopontine tracts and striatum; practically complete neuronal depletion in the putamen and lateral part of the caudate, and mild cell loss in the substantia nigra. The putamina had changed into a spongy fibrillary scar, the pallidal fibres and laminae were practically all degenerated. Moreover, there was generalised mild fibre degeneration of the white matter. The optic nerve showed marked, predominantly central, loss of nerve fibres with demyelination.

Brain↗
PubMed1978

Clinical differentiation of recessive congenital hereditary endothelial dystrophy and dominant hereditary endothelial dystrophy.

Our review of previously published reports and familial cases revealed that corneal clouding in autosomal recessive congenital hereditary endothelial dystrophy was present at birth or within the neonatal period. Further, corneal changes with time were minimal, nystagmus was often present, and there were no other signs or symptoms. Patients with autosomal dominant endothelial dystrophy usually had clear corneas early in life; corneal opacification was slowly progressive, nystagmus was infrequent, and photophobia, as well as epiphora, may have been the first indications of the dystrophy. As there is usually little or no congenital evidence of the dominant type, "infantile" or "autosomal dominant" hereditary endothelial dystrophy would be more appropriate names for the dominant variant.

Chromosome Aberrations↗