Presymptomatic Screening Research Articles

Lynch syndrome: still not a familiar picture

BackgroundGerm line mutations in mismatch repair genes underlie Lynch syndrome and predispose carriers for colorectal carcinoma and malignancies in many other organ systems.Case presentationA large Lynch syndrome family with 15 affected family members and involvement in 7 organs is reported. It illustrates a lack of awareness and knowledge about this hereditary tumor syndrome among doctors as well as patients. None of the described family members underwent presymptomatic screening on the basis of the family history.ConclusionHereditary features, like young age at diagnosis, multiple tumors in multiple organs and a positive family history, should lead to timely referral of suspected cases for genetic counseling and diagnostics. For Lynch syndrome, these features can be found in the Amsterdam and Bethesda criteria. Subsequently, early identification of mutation carriers might have diminished, at least in part, the high and early morbidity and mortality observed in this family.

Familial multiple myeloma: report on two families and discussion of screening options.

Multiple myeloma (MM) is a relatively rare haematological malignancy seen in older persons. It has an unknown aetiology and usually occurs incidentally within a family. However, several families have been reported with multiple cases of MM, so that the existence of hereditary MM has been postulated although no causative germline mutations have been detected so far. First-degree relatives of MM patients have been reported to have a relative risk between two and four times higher than normal of developing MM and we presume the risks are higher for relatives in the case of familial MM. Here we report on two families with MM who requested presymptomatic screening of healthy relatives. Although risk estimates for asymptomatic relatives in these types of families are not available, a clinically significant risk of developing MM cannot be excluded. We suggest that, in a research setting, screening for MM could be offered to individuals with more than one first-degree affected relative, or to those with one first-degree and at least one second-degree relative with MM. We propose a screening programme of annual protein electrophoresis of blood and urine, starting at age 40 (or earlier if a family member presented with MM at a younger age).

Colorectal cancer screening awareness among physicians in Greece

BackgroundData comparison between SEER and EUROCARE database provided evidence that colorectal cancer survival in USA is higher than in European countries. Since adjustment for stage at diagnosis markedly reduces the survival differences, a screening bias was hypothesized. Considering the important role of primary care in screening activities, the purpose of the study was to investigate the colorectal cancer screening awareness among Hellenic physicians.Methods211 primary care physicians were surveyed by mean of a self-reported prescription-habits questionnaire. Both physicians' colorectal cancer screening behaviors and colorectal cancer screening recommendations during usual check-up visits were analyzed.ResultsOnly 50% of physicians were found to recommend screening for colorectal cancer during usual check-up visits, and only 25% prescribed cost-effective procedures. The percentage of physicians recommending stool occult blood test and sigmoidoscopy was 24% and 4% respectively. Only 48% and 23% of physicians recognized a cancer screening value for stool occult blood test and sigmoidoscopy. Colorectal screening recommendations were statistically lower among physicians aged 30 or less (p = 0.012). No differences were found when gender, level and type of specialization were analyzed, even though specialists in general practice showed a trend for better prescription (p = 0.054).ConclusionContemporary recommendations for colorectal cancer screening are not followed by implementation in primary care setting. Education on presymptomatic control and screening practice monitoring are required if primary care is to make a major impact on colorectal cancer mortality.

Retrospective determination of ceruloplasmin in newborn screening blood spots of patients with Wilson disease

Wilson disease is an autosomal recessive disorder of copper transport, caused by the reduced or absent function of the Wilson disease gene ATP7B on chromosome 13. The disease is characterized by reduced incorporation of copper into the ceruloplasmin protein and reduced excretion of copper into the bile. Wilson disease is effectively treated if detected early. Our study goals were to determine the feasibility of a population screening for Wilson disease using dried blood spots and to characterize the base-line ceruloplasmin concentration in newborn blood spots of patients with Wilson disease. Ceruloplasmin was analyzed in dried blood spots obtained from 353 Mayo Clinic pediatric volunteers aged from 3 months to 18 years and from 1045 anonymous newborn screening specimens using a sandwich enzyme-linked immunosorbent assay. The original newborn screening blood spots were retrieved from two patients with Wilson disease along with age-matched controls for ceruloplasmin determination. The mean (±SD) concentration of ceruloplasmin in the pediatric blood spots was 40.0 ± 14.4 mg/dL (range 13.1 to >60 mg/dL) and newborn blood spots was 47.2 ± 15.5 mg/dL (range 6.5 to >60 mg/dL). Ceruloplasmin in the newborn blood spots from two Wilson disease patients were 2.6 and 2.8 mg/dL, respectively. The newborns affected with Wilson disease had significantly lower ceruloplasmin levels in blood spots than unaffected newborns. These findings support that presymptomatic screening for Wilson disease using dried blood spots could be possible, even in the newborn period.

Emergency presentation and mortality from colorectal cancer in the elderly.

We have assessed the influence of age on the mode of presentation and perioperative mortality in 1033 patients with colorectal cancer. There were 522 patients (51 per cent) over 70 years (group I) and 511 patients (49 per cent) under 70 (group II). In group I, 301 patients (58 per cent) were admitted as emergencies compared with only 222 (43 per cent) in group II (P less than 0.001). Perioperative mortality was especially high in the elderly emergencies, 38 per cent, compared with 18 per cent for elective operations. Of the patients presenting as emergencies in either age group 66 per cent had localized "potentially curable' disease. The incidence of colorectal cancer is highest in the elderly. A larger number of these elderly patients present as emergencies and die from the consequences of complications of localized disease. Earlier diagnosis by pre-symptomatic screening is therefore especially desirable in these old patients.

Developing the use of mismatch binding proteins for discovering rare somatic mutations

A method for detecting rare, unknown, somatic mutations could allow presymptomatic cancer screening from human fluids. Immobilized mismatch binding protein can bind DNA heteroduplexes while allowing homoduplexes to be washed away, thus enriching for rare mutations. We examined the potential use, for mutation enrichment, of a fusion protein of maltose binding protein and the mismatch binding protein TaqMutS (MBP-MutS). Unlabeled and fluorescent-labeled oligonucleotides, either perfectly complementary or with single nucleotide mismatches or deletions, were combined to form homo- or heteroduplexes that were then mixed at low ratios of hetero- to homoduplexes and enriched for heteroduplexes. Enrichment was observed using a capillary DNA sequencer. A single base deletion oligonucleotide was enriched by a factor of 29, and a mismatch oligonucleotide was enriched by a factor of 2. N-1 oligonucleotide synthesis fragments were enriched more than were mismatches, suggesting that these deletion fragments may compete for MutS and impede enrichment of mismatches. Purification of oligonucleotides by high pressure liquid chromatography or polyacrylamide gel electrophoresis failed to remove n-1 fragments, thus overcoming this obstacle to enrichment of mismatch mutations may require alternative strategies, such as developing new purification methods or avoiding the use of synthetic oligonucleotides before enrichment.

Presymptomatic diagnosis using a deletion of a single codon in families with hereditary non-polyposis colorectal cancer

The diagnosis of hereditary non-polyposis colorectal cancer (HNPCC) is often confirmed by a mutation in one of several mismatch-repair genes, in particular MLH1, MSH2 and MSH6. Presymptomatic diagnosis requires the identification of a mutation causing the disease. Three different deletions of a single amino acid codon have previously been published as assumed pathogenic. The objective of this study was to determine if an MSH2 3 base pair in-frame deletion (N596del) could be used in presymptomatic screening of at-risk individuals. We report on five HNPCC families with the N596del mutation, identified after mutation screening of MSH2 and MLH1. All patients in the families were haplotyped using markers flanking the MSH2 gene. The haplotypes revealed that the five families with high probability descended from only two founders. The N596del segregated with the HNPCC phenotype with lod scores of 3.2 and 2.0 at the recombination fraction of 0.0 in the two founder families. Sequencing of MSH2 and MLH1 did not reveal other pathogenic mutations, and N596del was not identified in 50 healthy controls. The mutation has previously been found expressed in mRNA, and is located in a conserved domain. The results support the hypothesis that N596del is the disease causing mutation and not a clinically silent variation. On this basis, the application of the MSH2 N596del mutation, in presymptomatic screening of HNPCC families, is recommended.

Follow-up of intracranial aneurysms in autosomal-dominant polycystic kidney disease

Approximately 8% of autosomal-dominant polycystic kidney disease (ADPKD) patients have intracranial aneurysms. The risk of growth and rupture of those discovered by presymptomatic screening is key to the feasibility and success of a screening program. This study was initiated to ascertain this risk. ADPKD patients were offered screening with magnetic resonance (MR) imaging that included three-dimensional time-of-flight MR angiographic and three-dimensional phase-contrast sequences. Patients with aneurysms were recommended periodic surveillance, initially at 6 months and yearly, and less frequently after demonstration of their stability. Twenty-two saccular and one fusiform aneurysms were detected at the initial screening in 21 patients from 19 families (seven men and 14 women, 47.9 +/- 10.6 years old). All the saccular aneurysms were small (mean diameter 3.5 mm, range 2.0 to 6.5 mm) and the majority (77%) in the anterior circulation. Two patients died from unrelated causes without further follow-up. One patient was lost to follow-up. A new 2 mm middle cerebral artery aneurysm developed in one patient. One aneurysm increased from a size of 4 mm to 5 mm after a follow-up of 105 months. No aneurysmal development or growth occurred in the remaining 16 patients. No aneurysmal rupture occurred during a mean imaging follow-up of 81 months and a mean clinical follow-up of 92 months. During the period of the study, two additional ADPKD patients, with three intracranial aneurysms detected elsewhere by presymptomatic MR angiographic screening, were referred for surgical treatment. The larger size of these aneurysms (10, 8, and 8 mm) probably reflects referral bias. Most intracranial aneurysms detected by presymptomatic screening in ADPKD patients are small and in the anterior circulation. The follow-up results do not suggest an increased risk for growth and rupture, compared to those of intracranial aneurysms in the general population. These data do not support widespread screening for intracranial aneurysms in the ADPKD population.

Prophylactic thyroidectomy in multiple endocrine neoplasia: the impact of molecular mechanisms of RET proto-oncogene.

Multiple endocrine neoplasia (MEN) type 2, a cancer syndrome inherited in the dominant fashion, is defined by the occurrence of medullary thyroid carcinoma (MTC), either as a singular lesion (familial medullary thyroid carcinoma, FMTC) or with the variable expression of pheochromocytoma, hyperparathyroidism (MEN 2A), ganglioneuromas, buccal neuromas and Marfanoid-like phenotype (MEN 2B). Germline mutations of the RET proto-oncogene, localized on chromosome 10q11.2, have been identified as the underlying genetic cause of the disorder. In the majority of patients with MEN 2A/FMTC missense mutations at exon 10 or exon 11 are identifiable. Cysteine to arginine exchange at codon 634 is the mutation most frequently found. In MEN 2B approximately 95% of patients present with a mutation at codon 918 (exon 16). Additionally, less frequent mutations in other codons have been found in both syndromes. The DNA-based genotype analysis enables the identification of gene carriers at risk of developing MTC and offer them prophylactic thyroidectomy prior to development of any thyroid pathologies. Prophylactic surgery is generally recommended for MEN 2A/FMTC gene carriers at the age of 4-6 years. Due to the aggressiveness of the MEN 2B syndrome gene carriers should be operated by the age of 1 year. Presumably some less virulent mutations allow postponement of the prophylactic treatment to the second to fourth decade of life. Compared to standard presymptomatic biochemical screening, genetic testing and consecutive prophylactic treatment contribute to better outcome of individuals at risk for MTC.

The genetics of cerebrovascular malformations

Certain rare familial or congenital syndromes include cerebrovascular malformations among their constellations of abnormalities. In addition, recognition of familial clustering in a subset of patients with cerebrovascular malformations has led to studies investigating the underlying genetic basis for these lesions. Genetic defects have been identified that cause familial cerebral cavernous malformations and hereditary hemorrhagic telangiectasia, a syndrome that features cerebral arteriovenous malformations. In addition to enhancing presymptomatic screening, identification of the responsible genes may result in a better understanding of the pathogenesis of these lesions, and ultimately, in novel treatments.

The genetics of cerebrovascular malformations

Certain rare familial or congenital syndromes include cerebrovascular malformations among their constellations of abnormalities. In addition, recognition of familial clustering in a subset of patients with cerebrovascular malformations has led to studies investigating the underlying genetic basic for these lesions. Genetic defects have been identified that cause familial cerebral cavernous malformations and hereditary hemorrhagic telangiectasia, a syndrome that features cerebral arteriovenous malformations. In addition to enhancing presymptomatic screening, identification of the responsible genes may result in a better understanding of the pathogenesis of these lesions, and ultimately, in novel treatments.

Early Onset of Medullary Thyroid Carcinoma in a Kindred with Multiple Endocrine Neoplasia Type IIA Associated with Cutaneous Lichen Amyloidosis

To describe the molecular characterization of a kindred affected by the rare variant of multiple endocrine neoplasia type IIA (MEN IIA) associated with cutaneous lichen amyloidosis and to discuss the clinical implications in the management of this syndrome. A kindred with four affected family members was identified, and DNA analysis was performed by sequencing exon 11 of the RET proto-oncogene. Presymptomatic genetic screening was offered to all first-degree relatives. Sequencing analysis of the RET proto-oncogene revealed a Cys634Trp (TGC->TGG) mutation in all clinically affected family members and in an asymptomatic 5-year-old child who, after thyroidectomy, was found to have multicentric medullary thyroid carcinoma and C-cell hyperplasia. A Gly691Ser (GGT->AGT) polymorphism was also detected in this family but did not segregate with the disease. To our knowledge, this is the earliest detection of medullary thyroid carcinoma reported thus far in a kindred with MEN IIA associated with cutaneous lichen amyloidosis, and this finding suggests that prophylactic thyroidectomy, in kindreds with this variant, should be performed before the age of 5 years.

A frameshift mutation in exon 28 of the OPA1 gene explains the high prevalence of dominant optic atrophy in the Danish population: evidence for a founder effect.

Dominant optic atrophy (DOA) is a hereditary optic neuropathy characterised by decreased visual acuity, colour vision deficits, centro-coecal scotoma and optic nerve pallor. The gene OPA1, encoding a dynamin-related GTPase, has recently been identified within the genetic linkage interval for the major locus for DOA on chromosome 3q28 and shown to harbour genetic aberrations segregating with disease in DOA families. The prevalence of the disorder in Denmark is reported to be the highest of any geographical location, suggestive of a founder effect. In order to establish the genetic basis of disease in a sample of 33 apparently unrelated Danish families, we screened DNA from affected members for OPA1 gene mutations by heteroduplex analysis and direct sequencing. A novel identical mutation in exon 28 (2826delT) was associated with DOA in 14 pedigrees and led to a frameshift and abnormal OPA1 protein -COOH terminus. Haplotype analysis of a region of approximately 1 Mb flanking the OPA1 gene using eight polymorphic markers revealed a common haplotype shared by all 14 patients; this haplotype was markedly over-represented compared with ethnically matched controls. Statistical analysis confirmed significant linkage disequilibrium with DOA over approximately 600 kb encompassing the disease mutation. We have therefore demonstrated that the relatively high frequency of DOA in Denmark is attributable to a founder mutation responsible for approximately 42% of the examined families and suggest that presymptomatic screening for the (2826delT) mutation may facilitate diagnosis and genetic counselling in a significant proportion of DOA patients of Danish ancestry.

Presymptomatic screening for schizophrenia: a geneticist's perspective.

To examine whether the experience gained in offering various genetic tests may be of help in the planning for screening in schools for a personality profile that may identify those destined to develop schizophrenia. To examine the outcomes in offering genetic testing: (i) to individuals at risk of developing Huntington's disease; (ii) to school pupils for carrier status for cystic fibrosis; and (iii) to the intellectually handicapped in schools to identify those with the fragile X syndrome. All programs however carefully planned, encounter the unexpected and unforeseen. It is essential to know the specificity and sensitivity of your screening test; to ensure that all have adequate knowledge before consenting to the testing; to ensure the confidentiality of the test results to the individual being tested and their families; and to ensure that funding is adequate and ongoing to provide continuing support and therapy to the families identified when research converts to service.

Presymptomatic screening for schizophrenia: a geneticist's perspective

Presymptomatic screening for schizophrenia: a geneticist's perspective

Two common endoglin mutations in families with hereditary hemorrhagic telangiectasia in the Netherlands Antilles: evidence for a founder effect.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant bleeding disorder characterized by localized angiodysplasia. Mutations in either of two genes, endoglin or ALK-1, can cause HHT. Both genes encode putative receptors for the transforming growth factor-beta superfamily of ligands. Many mutations in each gene have been identified in HHT kindreds from around the world, and with few exceptions mutations are unique and family specific. The prevalence of HHT in the Leeward Islands of the Netherlands Antilles is possibly the highest of any geographical location. We wished to establish whether this high prevalence is due to a genetic founder effect or to multiple mutational events. HHT kindreds from the Netherlands Antilles and The Netherlands were screened for mutations in the two genes associated with HHT. Haplotype analysis of a 5-cM region on chromosome 9 flanking the endoglin gene revealed three distinct disease haplotypes in the ten Antillean families studied. Seven of these families share a splice-site mutation in exon 1 of endoglin. Two other Antillean families share a missense mutation in exon 9a of endoglin. This mutation was also found in a Dutch family that shares the same disease haplotype as the Antillean families with this mutation. Thus it appears that HHT in the Netherlands Antilles is due to a limited number of ancestral mutations in the endoglin gene, and that one of these mutations was introduced into the African slave population by a Dutch colonist. The limited scope of mutations suggests that a presymptomatic screening program for HHT would be feasible in this population.

Presymptomatic Screening for Schizophrenia: A Geneticist's Perspective

Objective To examine whether the experience gained in offering various genetic tests may be of help in the planning for screening in schools for a personality profile that may identify those destined to develop schizophrenia. Method To examine the outcomes in offering genetic testing: (i) to individuals at risk of developing Huntington's disease; (ii) to school pupils for carrier status for cystic fibrosis; and (iii) to the intellectually handicapped in schools to identify those with the fragile X syndrome. Results All programs however carefully planned, encounter the unexpected and unforeseen. Conclusions It is essential to know the specificity and sensitivity of your screening test; to ensure that all have adequate knowledge before consenting to the testing; to ensure the confidentiality of the test results to the individual being tested and their families; and to ensure that funding is adequate and ongoing to provide continuing support and therapy to the families identified when research converts to service.

Utility of RET mutation analysis in multiple endocrine neoplasia type 2.

To review the role of RET mutation analysis in the diagnosis of multiple endocrine neoplasia type 2 (MEN 2) and in presymptomatic screening for this disorder. Review of the medical literature and current clinical practice. RET mutation analysis is a sensitive and specific test for MEN 2. It plays a pivotal role in the diagnosis and management of patients and families with MEN 2 and in the individual who presents with an apparently sporadic medullary thyroid carcinoma or pheochromocytoma. These disorders may first come to the attention of either the anatomic or clinical pathologist, who has the opportunity to see that appropriate testing is done. As with any familial disease, professional genetic counseling is an important part of the care of these patients.

The new biology enters the generalist pediatrician's office: lessons from the Human Genome Project.

1. Edward R.B. McCabe, MD, PhD* 1. 2. *Physician-in-Chief, Mattel Children’s Hospital at UCLA; Professor and Executive Chair, Department of Pediatrics, UCLA School of Medicine, Los Angeles, CA. Birth defects are the leading cause of infant mortality in the United States, representing more than 20% of all infant deaths. This infant mortality rate from birth defects exceeds that from sudden infant death syndrome, low-birthweight/short gestation, respiratory distress syndrome, and maternal complications. In addition, birth defects and genetic diseases represent major sources of morbidity for those who survive. As our ability increases to care effectively for those who have infectious diseases and other acute illnesses, individuals who have chronic illnesses due to genetic etiologies represent an increasing proportion of patients seen in the general pediatrician”s office. The Human Genome Project was initiated on October 1, 1990, and has a projected funding period of 15 years. The goal is to sequence the entire human genome, representing three billion base pairs that contain the coding sequences for approximately 75,000 genes. During the latter half of this century, investigations into the genetics of disease gathered increasing momentum. In addition to fundamental investigations into human genetics, technologic tools were developed that permitted large-scale genomic sequencing. These tools included the polymerase chain reaction (PCR), which permits amplification of hundreds of thousands or even millions of copies of DNA and requires only limited sequence data for its success; automated DNA sequencing, which allows increased sequence processing and decreased cost compared with manual methods; and improved information systems, which permit sophisticated analysis and assembly of the three billion base pairs of DNA in the human genome. Thus, the Human Genome Project represents the current chapter in our understanding, but it is neither the first nor the final chapter in this story. Once we know the sequences of all of the human genes, we must learn their functional roles in human development and disease pathogenesis. The Human Genome Project has been referred to as the “moon shot …

Molecular genetics and the assessment of human cancers.

The past 20 years have seen rapid advances in the understanding of the biology of human cancers, and a large body of evidence now supports the idea that accumulated genetic changes underlie the development of neoplasia. In this article, we have reviewed the current research into the genetic bases of cancer and discussed the potential clinical applications of recent advances, with particular reference to the possibility of using molecular genetic tests for pre-symptomatic screening, clinical diagnosis and clinical staging. The possibility that the genetic profile of a tumour, its 'molecular fingerprint', will improve the ability of oncologists to predict tumour behaviour and thus help to determine optimum treatment has also been considered. Although the potential for the application of molecular genetic technologies is enormous, these technologies have yet to be subjected to rigorous evaluation in a clinical setting, and much work needs to be done before they are adopted for use in routine clinical care.