Impact of national guidelines on family history breast cancer surveillance.

The breast cancer risk of women already under family history surveillance was accurately assessed according to national guidelines in an attempt to rationalize the service. Women attending two breast units in Glasgow between November 2003 and February 2005 were included. One thousand and five women under annual surveillance were assessed and had their relatives diagnoses verified. Four hundred and ninety-seven women were at significantly increased risk and eligible for follow-up. Five hundred and eight (50%) women attending were not eligible for family history surveillance, and 498 (98%) of these women accepted discharge. In conclusion, national guidelines have helped to more clearly define women who should undergo surveillance. This avoids unnecessary and potentially harmful routine investigations, and the service has been improved.

Mutation update for the CSB/ERCC6 and CSA/ERCC8 genes involved in Cockayne syndrome.

Cockayne syndrome is an autosomal recessive multisystem disorder characterized principally by neurological and sensory impairment, cachectic dwarfism, and photosensitivity. This rare disease is linked to mutations in the CSB/ERCC6 and CSA/ERCC8 genes encoding proteins involved in the transcription-coupled DNA repair pathway. The clinical spectrum of Cockayne syndrome encompasses a wide range of severity from severe prenatal forms to mild and late-onset presentations. We have reviewed the 45 published mutations in CSA and CSB to date and we report 43 new mutations in these genes together with the corresponding clinical data. Among the 84 reported kindreds, 52 (62%) have mutations in the CSB gene. Many types of mutations are scattered along the whole coding sequence of both genes, but clusters of missense mutations can be recognized and highlight the role of particular motifs in the proteins. Genotype-phenotype correlation hypotheses are considered with regard to these new molecular and clinical data. Additional cases of molecular prenatal diagnosis are reported and the strategy for prenatal testing is discussed. Two web-based locus-specific databases have been created to list all identified variants and to allow the inclusion of future reports (www.umd.be/CSA/ and www.umd.be/CSB/).

Prospective surveillance of women with a family history of breast cancer: auditing the risk threshold.

To evaluate current guidelines criteria for inclusion of women in special 'breast cancer family history' surveillance programmes, records were reviewed of women referred to Scottish breast cancer family clinics between January 1994 and December 2003 but discharged as at 'less than 'moderate' familial risk'. The Scottish Cancer Registry was then interrogated to determine subsequent age-specific incidence of breast cancer in this cohort and corresponding Scottish population figures. Among 2074 women, with an average follow-up of 4.0 years, 28 invasive breast cancers were recorded up to December 2003, where 14.4 were expected, a relative risk (RR) of 1.94. Eleven further breast cancers were recorded between January 2004 and February 2006 (ascertainment incomplete for this period). The overall RR for women in the study cohort exceeded the accepted 'cutoff' level (RR=1.7) for provision of special counselling and surveillance. The highest RR was found for the age group 45-59 years and this group also generated the majority of breast cancers. The National Institute for Clinical Excellence ('NICE') guidelines appear to be more accurate than those of the Scottish Intercollegiate Guidelines Network ('SIGN') in defining 'moderate' familial risk, and longer follow-up of this cohort could generate an evidence base for further modification of familial breast cancer services.

Mutations in FAM20C are associated with lethal osteosclerotic bone dysplasia (Raine syndrome), highlighting a crucial molecule in bone development.

The generation and homeostasis of bone tissue throughout development and maturity is controlled by the carefully balanced processes of bone formation and resorption. Disruption of this balance can give rise to a broad range of skeletal pathologies. Lethal osteosclerotic bone dysplasia (or, Raine syndrome) is an autosomal recessive disorder characterized by generalized osteosclerosis with periosteal bone formation and a distinctive facial phenotype. Affected individuals survive only days or weeks. We have identified and defined a chromosome 7 uniparental isodisomy and a 7p telomeric microdeletion in an affected subject. The extent of the deleted region at the 7p telomere was established by genotyping microsatellite markers across the telomeric region. The region is delimited by marker D7S2563 and contains five transcriptional units. Sequence analysis of FAM20C, located within the deleted region, in six additional affected subjects revealed four homozygous mutations and two compound heterozygotes. The identified mutations include four nonsynonymous base changes, all affecting evolutionarily conserved residues, and four splice-site changes that are predicted to have a detrimental effect on splicing. FAM20C is a member of the FAM20 family of secreted proteins, and its mouse orthologue (DMP4) has demonstrated calcium-binding properties; we also show by in situ hybridization its expression profile in mineralizing tissues during development. This study defines the causative role of FAM20C in this lethal osteosclerotic disorder and its crucial role in normal bone development.

Biliary hypoplasia in Williams syndrome.

Neonatal hepatitis and biliary hypoplasia are not recognised features of Williams syndrome. A case of Williams syndrome, presenting with neonatal conjugated hyperbilirubinaemia leading to an initial misdiagnosis is reported.

Exonic STK11 deletions are not a rare cause of Peutz-Jeghers syndrome.

BACKGROUND: Peutz-Jeghers syndrome (PJS) is a rare, autosomal dominant cancer predisposition syndrome characterised by oro-facial pigmentation and hamartomatous polyposis of the gastrointestinal tract. A causal germline mutation in STK11 can be identified in 30% to 80% of PJS patients. METHODS: Here we report the comprehensive mutational analysis of STK11 in 38 PJS probands applying conventional PCR based mutation detection methods and the recently introduced MLPA (multiplex ligation dependent probe amplification) technique developed for the identification of exonic deletions/duplications. RESULTS: Nineteen of 38 probands (50%) had detectable point mutations or small scale deletions/insertions and six probands (16%) had genomic deletions encompassing one or more STK11 exons. CONCLUSIONS: These findings demonstrate that exonic STK11 deletions are a common cause of PJS and provide a strong rationale for conducting a primary screen for such mutations in patients.

Confirmation of CHD7 as a cause of CHARGE association identified by mapping a balanced chromosome translocation in affected monozygotic twins.

BACKGROUND: CHARGE syndrome has an estimated prevalence of 1/10,000. Most cases are sporadic which led to hypotheses of a non-genetic aetiology. However, there was also evidence for a genetic cause with reports of multiplex families with presumed autosomal dominant, possible autosomal recessive inheritance and concordant twin pairs. We identified a monozygotic twin pair with CHARGE syndrome and a de novo balanced chromosome rearrangement t(8;13)(q11.2;q22). METHODS: Fluorescence in situ hybridisation was performed with BAC and PAC probes to characterise the translocation breakpoints. The breakpoint on chromosome 8 was further refined using 10 kb probes we designed and produced using sequence data for clone RP11 33I11, the Primer3 website, and a long range PCR kit. RESULTS: BAC and PAC probe hybridisation redefined the breakpoints to 8q12.2 and 13q31.1. Probe RP11 33I11 spanned the breakpoint on chromosome 8. Using our 10 kb probes we demonstrated that the chromodomain gene CHD7 was disrupted by the translocation between exons 3 and 8. DISCUSSION: Identifying that the translocation breakpoint in our patients occurred between exons 3 and 8 of CHD7 suggests that disruption of this gene is the cause of CHARGE syndrome in the twins and independently confirms the role of CHD7 in CHARGE syndrome.

Genetic predisposition to cancer: the consequences of a delayed diagnosis of Gorlin syndrome.

This report outlines a case of Gorlin syndrome, the diagnosis of which was delayed for many years, and raises a number of important issues. These are the spectrum of late radiotherapy effects, particularly after treatment for benign disease, and the importance of considering the possibility of the presence of a genetic syndrome predisposing to cancer in all individuals before starting any treatment. As our knowledge of genetic syndromes expands, this will become increasingly important. Finally, if a genetic predisposition to cancer is suspected, consideration should be given to obtaining a blood sample from the affected patient for DNA storage, particularly if their prognosis is limited. Currently, genetic testing can only be instituted in most families by first obtaining DNA from an individual affected by cancer, as most genetic mutations are unique to a family. If all relatives with cancer have died, then, at this time, genetic testing cannot usually be attempted, unless such samples have previously been stored.

Does genetic counseling have any impact on management of breast cancer risk?

Despite there being an increasing literature on the impact of cancer genetic counseling on risk perception and mental health, there is a lack of data describing impact on risk management. Genetic counseling and testing for cancer predisposition genes aims to improve the future health of those at high risk through appropriate surveillance and screening. However, management of breast cancer risk in women with a family history of this disease is an area of controversy. Counseling services may recommend specific risk management options to women, who then rely on their local screening service to make provision. This study investigated the impact of genetic counseling on management of breast cancer risk in women attending Cancer Family Clinics. A total of 293 women attending four genetic clinics were enrolled. Rates of breast self-examination, clinical breast examination, mammography, biopsy, detected cancers, and other screenings were documented. Participants' perceived benefits and barriers to mammography were assessed along with cancer worry. Results show that rates of mammography, clinical breast examination, and breast self-examination were increased following clinic attendance (p < 0.001). Women in the under 35 age-group had limited access to screening. Rates for biopsy and detected cancers were low. Women reported positive attitudes to mammography, with few reported barriers. Contrary to previous studies, there was no evidence that anxiety about breast cancer impedes uptake of health surveillance methods. Genetic counseling had a positive impact on management of breast cancer risk. Whether this translates into future health gains remains to be established.

A randomised comparison of UK genetic risk counselling services for familial cancer: psychosocial outcomes.

The aim of the study was to compare psychosocial outcomes for 50 new clinic attendees, referred for cancer genetic counselling to five UK centres. The centres represented England, Scotland and Wales, and were randomly selected from groups ranked by different levels of clinical activity in cancer genetics practice. Questionnaires assessed demographic data, risk perception, mental health and use of health services pre-consultation and at 1 and 12 months follow-up. Satisfaction was measured for attendees and referring doctors at follow-up. A total of 256 unaffected adults fulfilled the study criteria. The five centres varied widely with respect to service organisation and activity, but all had a greater proportion of unaffected attendees with a breast cancer risk (61-91%) than either a bowel cancer risk (0-33%) or ovarian cancer risk (3-25%). There were no significant differences in the psychosocial data between centres pre-counselling. No significant change over time occurred for any of the centres for risk perception or general psychological distress. There were significant differences between centres in reduction of cancer worry from baseline to 12 months and with the number of women who were recommended to have mammographic surveillance who had not received this. Overall, one-third of women for whom mammography had been recommended had not been screened within 1 year of follow-up. Subsequent attendance at the GP, but not at a hospital, was associated with risk level, but differences between centres could not be analysed. Satisfaction differed significantly between centres for 4 : 14 aspects of service provision and with 3 : 17 items concerning communication; satisfaction was high overall. Over 90% of referring doctors were moderately/very satisfied with the service, but 23% were dissatisfied with waiting times and 19% with access to preventive treatment. Results differed significantly between centres for doctor's satisfaction with the provision of referral criteria and prescribing information. In conclusion, there were relatively few significant differences in psychosocial outcomes between centres, considering the wide variation in service organisation and activity. These significant differences were not consistent across the centres, therefore, differences could not be linked to specific aspects of service provision.

Further observations on LKB1/STK11 status and cancer risk in Peutz-Jeghers syndrome.

Germline mutations in the LKB1/STK11 tumour suppressor gene cause Peutz-Jeghers syndrome (PJS), a rare dominant disorder. In addition to typical hamartomatous gastrointestinal polyps and pigmented perioral lesions, PJS is associated with an increased risk of tumours at multiple sites. Follow-up information on carriers is limited and genetic heterogeneity makes counselling and management in PJS difficult. Here we report the analysis of the LKB1/STK11 locus in a series of 33 PJS families, and estimation of cancer risks in carriers and noncarriers. Germline mutations of LKB1/STK11 were identified in 52% of cases. This observation reinforces the hypothesis of a second PJS locus. In carriers of LKB1/STK11 mutations, the risk of cancer was markedly elevated. The risk of developing any cancer in carriers by age 65 years was 47% (95% CI: 27-73%) with elevated risks of both gastrointestinal and breast cancer. PJS with germline mutations in LKB1/STK11 are at a very high relative and absolute risk of multiple gastrointestinal and nongastrointestinal cancers. To obtain precise estimates of risk associated with PJS requires further studies of genotype-phenotype especially with respect to LKB1/STK11 negative cases, as this group is likely to be heterogeneous.

An ancestral Ashkenazi haplotype at the HMPS/CRAC1 locus on 15q13-q14 is associated with hereditary mixed polyposis syndrome.

The putative locus for hereditary mixed polyposis syndrome (HMPS) in a large family of Ashkenazi descent (SM96) was previously reported to map to chromosome sub-bands 6q16-q21. However, new clinical data, together with molecular data from additional family members, have shown 6q linkage to be incorrect. A high-density genomewide screen for the HMPS gene was therefore performed on SM96, using stringent criteria for assignment of affection status to minimize phenocopy rates. Significant evidence of linkage was found only on a region on chromosome 15q13-q14. Since this region encompassed CRAC1, a locus involved in inherited susceptibility to colorectal adenomas and carcinomas in another Ashkenazi family (SM1311), we determined whether HMPS and CRAC1 might be the same. We found that affected individuals from both families shared a haplotype between D15S1031 and D15S118; the haplotype was rare in the general Ashkenazi population. A third informative family, SM2952, showed linkage of disease to HMPS/CRAC1 and shared the putative ancestral haplotype, as did a further two families, SMU and RF. Although there are probably multiple causes of the multiple colorectal adenoma and cancer phenotype in Ashkenazim, an important one is the HMPS/CRAC1 locus on 15q13-q14.

Balancing autonomy and responsibility: the ethics of generating and disclosing genetic information.

Using data obtained during a retrospective interview study of 30 women who had undergone genetic testing-BRCA1/2 mutation searching-this paper describes how women, previously diagnosed with breast/ovarian cancer, perceive their role in generating genetic information about themselves and their families. It observes that when describing their motivations for undergoing DNA testing and their experiences of disclosing genetic information within the family these women provide care based ethical justifications for their actions. Finally, it argues that generating genetic information and disclosing this information to kin raise different types of ethical issues. The implications of these findings for ethical debates about informed choice in the context of genetic testing are discussed.

Genetic testing for women previously diagnosed with breast/ovarian cancer: examining the impact of BRCA1 and BRCA2 mutation searching.

This study sought to investigate the impact of BRCA1 and BRCA2 mutation searching on women previously diagnosed with breast or ovarian cancer. In-depth interviews were undertaken with 30 women who had undergone a BRCA1 and BRCA2 mutation search within the clinical setting. The main reasons reported for undergoing mutation searching were: to provide genetic information for other family members, general altruism, curiosity about the aetiology of cancer, and to provide information to facilitate risk management decisions. In the main, the process of undergoing genetic testing was not experienced as anxiety provoking. The benefit of receiving a result confirming the presence of a genetic mutation was seen as an end to uncertainty, whereas the costs included difficulties in disclosing information to kin and potentially increased anxiety about one's own or others' cancer risks. Women receiving an inconclusive test result reported a range of emotional reactions. There was evidence that some women misunderstood the meaning of this result, interpreting it as definitive confirmation that a cancer-predisposing mutation was not present within the family. It is concluded that women with cancer who participate in BRCA1 and BRCA2 testing need to receive clear information about the meaning and implications of the different types of test results. Some recommendations for clinical practice are discussed.

Analysis of the phenotypic abnormalities in lymphoedema-distichiasis syndrome in 74 patients with FOXC2 mutations or linkage to 16q24.

INTRODUCTION: Lymphoedema-distichiasis syndrome (LD) (OMIM 153400) is a rare, primary lymphoedema of pubertal onset, associated with distichiasis. Causative mutations have now been described in FOXC2, a forkhead transcription factor gene. Numerous clinical associations have been reported with this condition, including congenital heart disease, ptosis, varicose veins, cleft palate, and spinal extradural cysts. SUBJECTS: We report clinical findings in 74 affected subjects from 18 families and six isolated cases. All of them were shown to have mutations in FOXC2 with the exception of one family who had two affected subjects with lymphoedema and distichiasis and linkage consistent with the 16q24 locus. RESULTS: The presence of lymphoedema was highly penetrant. Males had an earlier onset of lymphoedema and a significantly increased risk of complications. Lymphatic imaging confirmed the earlier suggestion that LD is associated with a normal or increased number of lymphatic vessels rather than the hypoplasia or aplasia seen in other forms of primary lymphoedema. Distichiasis was 94.2% penetrant, but not always symptomatic. Associated findings included ptosis (31%), congenital heart disease (6.8%), and cleft palate (4%). Other than distichiasis, the most commonly occurring anomaly was varicose veins of early onset (49%). This has not been previously reported and suggests a possible developmental role for FOXC2 in both venous and lymphatic systems. This is the first gene that has been implicated in the aetiology of varicose veins. CONCLUSION: Unlike previous publications, the thorough clinical characterisation of our patients permits more accurate prediction of various phenotypic abnormalities likely to manifest in subjects with FOXC2 mutations.

Colonoscopy in asymptomatic individuals with a family history of colorectal cancer.

BACKGROUND: This study was performed to evaluate the use of total colonoscopy as the optimal screening test in asymptomatic individuals with a family history of colorectal cancer (CRC). METHODS: Colonoscopy was performed in 249 asymptomatic individuals who had one or two first-degree relatives (FDRs) with CRC; individuals with three or more FDRs with CRC were excluded. RESULTS: Eighty-six colonic lesions were found in 51 individuals (51 of 249; 20.5%). Among these 51 subjects, 27 had neoplastic polyps (n = 38) and 29 had metaplastic polyps (n = 44). Although no invasive cancer was detected, in 14 individuals the lesions had a high malignancy potential because of their size and histopathology. We did not confirm a statistically significant difference in the incidence of neoplastic polyps according to the number of affected FDRs. Finally, the presence of metaplastic polyps was a very strong indication for the concomitant presence of metaplastic polyps (P <.0001). CONCLUSIONS: Total colonoscopy is the optimal screening procedure for the examination of asymptomatic individuals with a family history of CRC.

Analysis of lymphoedema-distichiasis families for FOXC2 mutations reveals small insertions and deletions throughout the gene.

Lymphoedema-distichiasis (LD) is a dominantly inherited form of primary lymphoedema with onset of lower limb swelling at puberty or later. There is variable penetrance of this disorder, but the most consistently inherited feature is distichiasis, viz. fine hairs arising inappropriately from the meibomian glands. We established linkage of this disorder to 16q24.3 and the gene has recently been identified as the forkhead transcription factor FOXC2. We report the mutational analysis of 14 families with LD. All but one of these pedigrees have small insertions or deletions in the gene, which seem likely to produce haploinsufficiency. The mutation sites are scattered throughout the gene. There is one family with a mis-sense mutation in the forkhead domain of the protein. This base alteration is not a common polymorphism, is co-inherited with the disease and produces a non-conservative amino acid change.