Surveillance imaging with FDG-PET/CT in the post-operative follow-up of stage 3 melanoma.

Background: As early detection of recurrent melanoma maximizes treatment options, patients usually undergo post-operative imaging surveillance, increasingly with FDG-PET/CT (PET). To assess this, we evaluated stage 3 melanoma patients who underwent prospectively applied and sub-stage-specific schedules of PET surveillance. Patients and methods: From 2009, patients with stage 3 melanoma routinely underwent PET +/- MRI brain scans via defined schedules based on sub-stage-specific relapse probabilities. Data were collected regarding patient characteristics and outcomes. Contingency analyses were carried out of imaging outcomes. Results: One hundred and seventy patients (stage 3A: 34; 3B: 93; 3C: 43) underwent radiological surveillance. Relapses were identified in 65 (38%) patients, of which 45 (69%) were asymptomatic. False-positive imaging findings occurred in 7%, and 6% had treatable second (non-melanoma) malignancies. Positive predictive values (PPV) of individual scans were 56%-83%. Negative scans had predictive values of 89%-96% for true non-recurrence [negative predictive values (NPV)] until the next scan. A negative PET at 18 months had NPVs of 80%-84% for true non-recurrence at any time in the 47-month (median) follow-up period. Sensitivity and specificity of the overall approach of sub-stage-specific PET surveillance were 70% and 87%, respectively. Of relapsed patients, 33 (52%) underwent potentially curative resection and 10 (16%) remained disease-free after 24 months (median). Conclusions: Application of sub-stage-specific PET in stage 3 melanoma enables asymptomatic detection of most recurrences, has high NPVs that may provide patient reassurance, and is associated with a high rate of detection of resectable and potentially curable disease at relapse.

Parental perspective of the benefits of genetic testing in children with congenital deafness.

AIM: The aim of the study was to assess the perceived value of genetic testing for congenital deafness in families attending a clinical genetic outpatients department at a children's hospital. The major testing objective was to provide information regarding deafness etiology, although families were advised that changes in treatment as a result of the test were unlikely. Using a 'willingness-to-pay' approach in the form of a questionnaire developed by Ryan et al. [J Med Genet 2003;40:1-5], parents were surveyed for their attitudes and willingness to pay for genetic testing. RESULTS: Forty-nine families provided data for analysis, representing 56% of clinic attendances throughout the period. Most of the parents were themselves unaffected by hearing loss (93%) and none were deaf, although almost a quarter (22%) reported a family member born deaf. Parents considered the major benefit gained from testing was to better achieve clarity of understanding arising from discussion and the possible ascertainment of etiology. The average sum parents were willing to pay for genetic testing was 200 Australian dollars (AUD, 2007) or approximately 123 euros (EUR), ranging from 150 to 295 AUD according to ability to pay (as measured by gross income). However, the amount that even the highest income level were willing to pay underestimated the full economic cost of genetic testing. CONCLUSION: Genetic testing for deafness is highly valued by affected families despite the current limited overall expectation of definitive genetic diagnosis or changes in treatment. Parents considered the major benefits to be a better understanding of congenital deafness and the potential for assignment of causality.

Features of colorectal cancers with high-level microsatellite instability occurring in familial and sporadic settings: parallel pathways of tumorigenesis.

High-level microsatellite instability (MSI-H) is demonstrated in 10 to 15% of sporadic colorectal cancers and in most cancers presenting in the inherited condition hereditary nonpolyposis colorectal cancer (HNPCC). Distinction between these categories of MSI-H cancer is of clinical importance and the aim of this study was to assess clinical, pathological, and molecular features that might be discriminatory. One hundred and twelve MSI-H colorectal cancers from families fulfilling the Bethesda criteria were compared with 57 sporadic MSI-H colorectal cancers. HNPCC cancers presented at a lower age (P < 0.001) with no sporadic MSI-H cancer being diagnosed before the age of 57 years. MSI was less extensive in HNPCC cancers with 72% microsatellite markers showing band shifts compared with 87% in sporadic tumors (P < 0.001). Absent immunostaining for hMSH2 was only found in HNPCC tumors. Methylation of hMLH1 was observed in 87% of sporadic cancers but also in 55% of HNPCC tumors that showed loss of expression of hMLH1 (P = 0.02). HNPCC cancers were more frequently characterized by aberrant beta-catenin immunostaining as evidenced by nuclear positivity (P < 0.001). Aberrant p53 immunostaining was infrequent in both groups. There were no differences with respect to 5q loss of heterozygosity or codon 12 K-ras mutation, which were infrequent in both groups. Sporadic MSI-H cancers were more frequently heterogeneous (P < 0.001), poorly differentiated (P = 0.02), mucinous (P = 0.02), and proximally located (P = 0.04) than HNPCC tumors. In sporadic MSI-H cancers, contiguous adenomas were likely to be serrated whereas traditional adenomas were dominant in HNPCC. Lymphocytic infiltration was more pronounced in HNPCC but the results did not reach statistical significance. Overall, HNPCC cancers were more like common colorectal cancer in terms of morphology and expression of beta-catenin whereas sporadic MSI-H cancers displayed features consistent with a different morphogenesis. No individual feature was discriminatory for all HNPCC cancers. However, a model based on four features was able to classify 94.5% of tumors as sporadic or HNPCC. The finding of multiple differences between sporadic and familial MSI-H colorectal cancer with respect to both genotype and phenotype is consistent with tumorigenesis through parallel evolutionary pathways and emphasizes the importance of studying the two groups separately.

Population screening for cystic fibrosis in Western Australia: community response.

We measured acceptance of carrier testing for cystic fibrosis in the community when offered in a primary care setting, determined variables influencing acceptance, and assessed knowledge of cystic fibrosis 3-6 months later. A total of 5,102 individuals age 18-50 years attending general practices or a family planning clinic in Western Australia completed questionnaires about knowledge of cystic fibrosis and the State Anxiety Inventory. Testing for the delta F508 gene was offered. After 3-6 months, carriers, a sample of consenting participants who were not tested, and a sample of test-negative participants were sent a further questionnaire; 43.5% of participants chose to be tested for cystic fibrosis carrier status. Women, younger people, people with higher education, people without children, and people planning to have children were more likely to be tested. After 3-6 months, carriers gave correct responses to questions about cystic fibrosis more frequently than those who tested negative or were not tested; 82.2% of carriers knew that they were definitely a carrier and 31.1% of test-negative individuals believed they were definitely not carriers. Thus, population carrier screening for cystic fibrosis offered in a community setting in Western Australia was acceptable to almost half of those offered testing, particularly younger people and those planning to have children, for whom knowledge of carrier status could be useful in making reproductive decisions. There was evidence that tested individuals recalled information in a way that minimised their risk of being a carrier.

Genetic testing for Alzheimer's disease.

Genetic factors are important in the development of Alzheimer's disease (AD). Familial AD can result from rare mutations in some genes. Other genes, such as the apolipoprotein E gene (APOE), operate as risk factors for late-onset sporadic AD. On a background of advances in the genetics of AD we suggest a way in which genetic information may be used in the diagnosis of AD. If there is a positive family history of early-onset dementia and the clinical features suggest AD, patients may be tested for presenilin and amyloid precursor protein gene mutations with appropriate pretest and post-test counselling. Predictive testing should be performed under guidelines developed by the World Federation of Neurology and the Human Genetics Society of Australasia. The usefulness of APOE genotyping as an adjunct to conventional diagnostic tests is unknown; data suggest it has low sensitivity and specificity and may have little predictive value in an individual patient. APOE genotyping should not be performed in asymptomatic individuals, except as part of an ethically approved research project; this recommendation is supported by a number of international consensus statements. APOE testing should not be used as a diagnostic test without adequate pretest and post-test counselling, education and support. APOE testing should not be used as a sole diagnostic test in the work-up of patients with AD. Genetic risk factors other than APOE require validation and should not be used routinely, except as part of an ethically approved research protocol.

Expanding the phenotype of Filippi syndrome: a report of three cases.

This report is of two brothers and a male singleton with clinical characteristics of Filippi syndrome, born to young, healthy, non-consanguineous parents. Their features, which include borderline to milder developmental delay, particularly of speech and language, primary microdontia and previously unreported radiological findings are described to further delineate and expand the clinical spectrum of the condition.

Attitudes toward prophylactic oophorectomy and screening utilization in women at increased risk of developing hereditary breast/ovarian cancer.

OBJECTIVES: The aim of this study was to evaluate ovarian cancer screening uptake and attitudes toward prophylactic oophorectomy in women at risk of developing hereditary breast/ovarian cancer. STUDY METHODS: Ninety-five unaffected women, who approached 1 of 14 familial cancer clinics for advice about their breast/ovarian cancer risk and surveillance and prophylactic options, were assessed in a cross-sectional design when they attended the clinic. RESULTS: Among high-risk women ages 30 and over who had not had a prophylactic oophorectomy, 48% reported ever having had an ovarian ultrasound, and among women ages 50 and over 23% had had a serum CA 125 test. Twenty-three percent of women would consider, and 27% would not consider, a prophylactic oophorectomy should the genetic test indicate a germline mutation associated with hereditary breast/ovarian cancer, while 38% were unsure. Twelve percent had already undergone a prophylactic oophorectomy. Interest in prophylactic oophorectomy was associated with increased breast/ovarian cancer anxiety (chi(2) = 5.14, P = 0.023), but not objective cancer risk (chi(2) = 0.40, P = 0.53). CONCLUSION: Findings demonstrate that breast/ovarian cancer anxiety, rather than objective risk, is the major factor which determines women's attitude to prophylactic oophorectomy. Women are likely to benefit from interventions aimed at reducing breast/ovarian cancer anxiety. Research on the impact of prophylactic oophorectomy would be helpful in the development of educational strategies and decision aids to assist women who are trying to make a decision under conditions of uncertainty.

Syndrome of microcephaly, microphthalmia, cataracts, and intracranial calcification.

We present two sisters with microcephaly, developmental delay, marked microphthalmia, congenital cataracts, cerebral and cerebellar hypoplasia, and intracranial calcification. No evidence of intrauterine infection was found. There have been previous reports of microcephaly, intracranial calcification, and an intrauterine infection-like autosomal recessive condition, but the sibs in this report appear to represent a more severe form of such a condition or a previously undescribed entity.

Efficacy of gene testing for von Hippel-Lindau disease.

OBJECTIVE: To determine the efficacy of genetic testing of individuals presenting with features possibly indicative of von Hippel-Lindau (VHL) disease, regardless of other relevant family and clinical details. SETTING AND PARTICIPANTS: Between September 1994 and December 1997, 16 unrelated individuals were referred to Genetic Services of Western Australia by local clinicians and by similar genetic services in other States, for VHL gene mutation analysis because of clinical manifestations suggestive of the diagnosis. METHODS: The subjects were investigated by screening for mutations in the polymerase chain reaction products of the three VHL gene exons using single-stranded conformational polymorphism analysis (SSCP). If no mutations were detected the exons were sequenced, and if no variations were found DNA was examined by Southern analysis for germinal rearrangements. RESULTS: Mutations in the VHL gene were detected in eight of 16 individuals (50%), including 3 individuals with no family history suggestive of VHL disease. Five mutations were detected by SSCP, two by gene sequencing and one by Southern analysis. Each mutation occurred only in a single family and three had not been previously reported. CONCLUSION: Genetic screening of individuals presenting with clinical features suggestive of VHL facilitates confirmation of the diagnosis, accurate genetic counselling and surveillance of at-risk family members. The necessity for costly and time-consuming screening programs can be reduced and screening directed at those carrying the mutation. Our low stringency criteria are justified for screening for VHL mutations.

22q11 deletions in patients with conotruncal heart defects.

OBJECTIVE: To ascertain the frequency of 22q11 deletions in a representative population of conotruncal heart defects (CTD) and determine which children are at risk of having a deletion. METHODOLOGY: A clinical and laboratory evaluation of 90 children with CTD, including isolated and syndromic cases. RESULTS: Fifteen children (17%) were shown to have 22q11 deletions by fluorescence in situ hybridization (FISH) studies with the Oncor probe N25. Varying degrees of developmental delay/learning disabilities and facial dysmorphism were common in these children. None of the isolated cases without dysmorphism had a deletion. CONCLUSION: 22q11 deletions are a significant cause of a specific form of congenital heart disease, CTD. It is important to have a high index of suspicion of the 22q11 deletion disorders in children with CTD and other extracardiac manifestations so that the diagnosis can be made early and appropriate interventions implemented.

Variable penetrance of familial pheochromocytoma associated with the von Hipple Lindau gene mutation, S68W. Mutations in brief no. 150. Online.

Van Hippel-Lindau disease (VHL) is an autosomal dominantly inherited disorder, characterised by the development of clear cell renal carcinomas, CNS hemangioblastomas, retinal angiomas, pancreatic tumors, pheochromocytomas and hepatic cysts. Recently a number of families with dominant familial pheochromocytoma as the only clinical manifestation have been reported to carry mutations in the HVL gene. We describe a family in which a novel VHL S68W mutation was segregating and carrier individuals manifested with variable penetrance of isolated pheochromocytomas. Investigation of this kindred confirmed that a mutation in the VHL gene could produce isolated pheochromocytomas as the only clinical feature and was variably penetrant.

Evaluation of a project to enhance knowledge of hereditary diseases and management.

During 1992 and 1993, in a designated suburban area of Perth, Western Australia, information on hereditary disease was provided for health professionals and the general community. This information was in the form of posters, pamphlets, postal flyers and return letter cards, a static display, newspaper articles, advertisements and radio broadcasts, and professional seminars. The aim of this project was to evaluate the effectiveness of combined strategies to convey practical information about hereditary disease to the community and health professionals. Multiple measures of response evaluation were used, which included structured questionnaire surveys of health professionals and members of the community before and after the project. In the community surveys, respondents who were female, married, middle aged, and parents, and had a higher level of education or were born in Australia, New Zealand, or the United Kingdom were generally better informed about hereditary diseases. This intervention resulted in only meagre changes in community knowledge about hereditary disease, even though promotional materials were shown to be appropriate. General Practitioners (GPs) and Child Health Nurses (CHNs) were supportive of clinical genetic services and recognised a need for continuation of education in this field. There is a rapidly increasing need for community and health professional comprehension of the applications of the new genetic technology. This project indicates that routine educational and health promotion strategies will not be enough to achieve desired levels of knowledge and attitude change.

The clinical correlates of a 3' truncating mutation (codons 1982-1983) in the adenomatous polyposis coli gene.

Familial adenomatous polyposis (FAP) is caused by mutations in the adenomatous polyposis coli (APC) gene, and different mutations may produce different clinical pictures. Most mutations occur in the 5' half of the gene, and mutations toward the 3' end are rare. The aim of this study was to document the phenotypes in a family with a truncating mutation at codons 1982-1983, one of the most 3' mutations on record. Colonic polyps in this family were much less numerous, and their growth was delayed compared with the classical FAP picture, and malignant degeneration occurred considerably later. Two individuals had sparse colonic but profuse gastric fundic gland polyposis. Gardner's syndrome stigmata were variable, and a desmoid tumor was recorded in 1 person.

Dentofacial features of a family with Crouzon syndrome. Case reports.

Crouzon syndrome is an autosomal dominant condition characterized by craniosynostosis with associated dentofacial anomalies. This paper describes the variable clinical features in affected individuals over two generations of a family with particular reference to the dentofacial deformities and discussion of management strategies.

Genetic counselling and gene mutation analysis in familial adenomatous polyposis in Western Australia.

OBJECTIVE: To assess the provision of accurate pre-symptomatic genetic testing with DNA analysis and appropriate counselling for individuals and families known to be at high risk of developing familial adenomatous polyposis coli (FAP). PATIENTS AND METHODS: Thirty-one families with clinically and pathologically documented FAP were ascertained from the Western Australian Polyposis Registry. DNA was collected from over 200 individuals in these families to establish their genetic risk status for FAP, either by direct mutation analysis, or by linkage analysis. Individuals undergoing DNA testing were given intensive psychosocial support and counselling. RESULTS: In 19 families DNA-based counselling could not be offered because either the adenomatous polyposis coli (APC) gene mutation could not be detected or there were insufficient family members for linkage analysis. Gene testing yielded mutations of the APC gene in 87 individuals from 12 families; by gene tracking (or linkage analysis) in three families and by mutation analysis in the remaining nine (four of which had only one affected individual). DNA results conformed with a definite clinicopathological diagnosis in 27 FAP patients and, of the remaining 60 high-risk subjects tested, 14 had inherited the mutated APC gene. CONCLUSIONS: DNA analysis allowed accurate genetic counselling for 12 of 31 families affected by FAP, thus improving the medical and personal management in asymptomatic people who would otherwise be subjected to the uncertainty of long term surveillance and repeated colonic examinations. In future a superior biomolecular approach to gene mutation analysis, such as the protein truncation test, will facilitate management for most FAP individuals and families.