Second international guidelines for the diagnosis and management of hereditary hemorrhagic telangiectasia

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease with an estimated prevalence of 1 in 5000 that is characterized by the presence of vascular malformations (VMs). These result in chronic bleeding, acute hemorrhage, and complications from shunting through VMs. The goal of the Second International HHT Guidelines process was to develop evidence-based consensus guidelines for the management and prevention of HHT-related symptoms and complications. The guidelines were developed using the AGREE II (Appraisal of Guidelines for Research and Evaluation II) framework and GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology. The guidelines expert panel included expert physicians (clinical and genetic) in HHT from 15 countries, guidelines methodologists, health care workers, health care administrators, patient advocacy representatives, and persons with HHT. During the preconference process, the expert panel generated clinically relevant questions in 6 priority topic areas. A systematic literature search was done in June 2019, and articles meeting a priori criteria were included to generate evidence tables, which were used as the basis for recommendation development. The expert panel subsequently convened during a guidelines conference to conduct a structured consensus process, during which recommendations reaching at least 80% consensus were discussed and approved. The expert panel generated and approved 6 new recommendations for each of the following 6 priority topic areas: epistaxis, gastrointestinal bleeding, anemia and iron deficiency, liver VMs, pediatric care, and pregnancy and delivery (36 total). The recommendations highlight new evidence in existing topics from the first International HHT Guidelines and provide guidance in 3 new areas: anemia, pediatrics, and pregnancy and delivery. These recommendations should facilitate implementation of key components of HHT care into clinical practice.

International guidelines for the diagnosis and management of hereditary haemorrhagic telangiectasia.

BACKGROUND: HHT is an autosomal dominant disease with an estimated prevalence of at least 1/5000 which can frequently be complicated by the presence of clinically significant arteriovenous malformations in the brain, lung, gastrointestinal tract and liver. HHT is under-diagnosed and families may be unaware of the available screening and treatment, leading to unnecessary stroke and life-threatening hemorrhage in children and adults. OBJECTIVE: The goal of this international HHT guidelines process was to develop evidence-informed consensus guidelines regarding the diagnosis of HHT and the prevention of HHT-related complications and treatment of symptomatic disease. METHODS: The overall guidelines process was developed using the AGREE framework, using a systematic search strategy and literature retrieval with incorporation of expert evidence in a structured consensus process where published literature was lacking. The Guidelines Working Group included experts (clinical and genetic) from eleven countries, in all aspects of HHT, guidelines methodologists, health care workers, health care administrators, HHT clinic staff, medical trainees, patient advocacy representatives and patients with HHT. The Working Group determined clinically relevant questions during the pre-conference process. The literature search was conducted using the OVID MEDLINE database, from 1966 to October 2006. The Working Group subsequently convened at the Guidelines Conference to partake in a structured consensus process using the evidence tables generated from the systematic searches. RESULTS: The outcome of the conference was the generation of 33 recommendations for the diagnosis and management of HHT, with at least 80% agreement amongst the expert panel for 30 of the 33 recommendations.

Life expectancy and death from cardiomyopathy amongst carriers of Duchenne and Becker muscular dystrophy in Scotland.

OBJECTIVES: To assess life expectancy and cardiovascular mortality in carriers of Duchenne and Becker muscular dystrophy. DESIGN: Family pedigrees of individuals affected with these conditions, held by the four genetics centres in Scotland, were examined to identify a cohort of definite carriers. Electronic death registration data, held by the General Register Office for Scotland, were used to identify death certificates of carriers who had died, to obtain age at death and cause of death. Survival and mortality data were obtained for the general population for comparison. PATIENTS: 397 definite carriers in 202 pedigrees were identified from which 94 deaths were identified by record linkage to death certificates. MAIN OUTCOME MEASURES: Observed numbers surviving to certain ages and numbers dying of cardiac causes were compared with expected numbers calculated from general population data. RESULTS: There were no significant differences between observed and expected numbers surviving to ages 40-90. The standardised mortality ratio for the 371 carriers alive in 1974 was 0.53 (95% confidence interval 0.32 to 0.82). CONCLUSIONS: Whereas female carriers may have clinical features of cardiomyopathy, this study does not suggest that this is associated with reduced life expectancy or increased risk of cardiac death. Routine cardiac surveillance of obligate carriers is therefore probably unnecessary.

Prevalence of family history of colorectal cancer in the general population.

BACKGROUND: Robust estimates of the prevalence of a family history of colorectal cancer in the general population are essential to inform planning of provision for colonoscopic surveillance and for clinical genetics services. However, there is a paucity of high-quality data. METHODS: Computerized record linkage was used to assess systematically the family history of 160 cancer-free community subjects and thereby provide prevalence data that are independent of participant recall. The data set comprised 2664 first- and second-degree relatives of study subjects, with 148 068 years at risk. RESULTS: Of people in the 30-70 years age range, 9.4 (95 per cent confidence interval (c.i.) 5.8 to 14.9) per cent had a first-degree relative affected by colorectal cancer, and 28.8 (95 per cent c.i. 22.3 to 36.2) per cent had an affected first- or second-degree relative. Between 0 and 3.1 per cent of study subjects merited colonic surveillance, depending on the stringency of the guidelines used. CONCLUSION: An appreciable proportion of the general population has a relative affected by colorectal cancer, sufficient to merit screening under certain criteria. In the absence of good-quality evidence supporting colonoscopic surveillance in groups at moderate risk, these data directly inform the planning of services for people with a family history of colorectal cancer. However, the clinical risk and financial implications of screening should be taken into account.

A cross-sectional survey to estimate the prevalence of family history of colorectal, breast and ovarian cancer in a Scottish general practice population.

A cross-sectional survey of all patients aged 30-65 in four general practices within one Local Health Care Co-operative in Fife, Scotland was undertaken to measure the prevalence of family history of colorectal, breast and ovarian cancer. A total of 7619 patients aged 30-65 responded to a postal questionnaire (response rate 59%). In all, 17% of respondents (1324, 95% Cl 16-18%) reported a relative affected by colorectal, breast or ovarian cancer. Of those, 6% (78, 95% CI 5-7%) met the Scottish guidelines for referral for genetics counselling. In all, 2% (24, 95% CI 1-3%) of all individuals with an affected relative had received genetic counselling and risk assessment. Of these, 25% (6, 95% CI 8-42%) met the moderate- or high-risk criteria for developing a cancer. In conclusion, the number of patients who are at a significantly increased risk of cancer on the basis of a family history is small (approximately 10 per General Practitioner (GP) list). It is therefore unrealistic to expect GPs to develop expertise in genetic risk estimation. A simple family history chart or pedigree is one way that a GP can, within the constraints of a GP consultation, determine which patients should be reassured and which referred to the local cancer genetic clinic.

Accuracy of reporting of family history of colorectal cancer.

BACKGROUND AND AIMS: Family history is used extensively to estimate the risk of colorectal cancer but there is considerable potential for recall bias and inaccuracy. Hence we systematically assessed the accuracy of family history reported at interview compared with actual cancer experience in relatives. METHODS: Using face to face interviews, we recorded family history from 199 colorectal cancer cases and 133 community controls, totalling 5637 first and second degree relatives (FDRs/SDRs). We linked computerised cancer registry data to interview information to determine the accuracy of family history reporting. RESULTS: Cases substantially underreported colorectal cancer arising both in FDRs (sensitivity 0.566 (95% confidence interval (CI) 0.433, 0.690); specificity 0.990 (95% CI 0.983, 0.994)) and SDRs (sensitivity 0.271 (95% CI 0.166, 0.410); specificity 0.996 (95% CI 0.992, 0.998)). There was no observable difference in accuracy of reporting family history between case and control interviewees. Control subjects similarly underreported colorectal cancer in FDRs (sensitivity 0.529 (95% CI 0.310, 0.738); specificity 0.995 (95% CI 0.989, 0.998)) and SDRs (sensitivity 0.333 (95% CI 0.192, 0.512); specificity 0.995 (95% CI 0.991, 0.995)). To determine practical implications of inaccurate family history, we applied family history criteria before and after record linkage. Only two of five families reported at interview to meet surveillance criteria did so after validation, whereas only two of six families that actually merited surveillance were identified by interview. CONCLUSIONS: This study has quantified the inaccuracy of interview in identifying people at risk of colorectal cancer due to a family history. Colorectal cancer was substantially underreported and so family history information should be interpreted with caution. These findings have considerable relevance to identifying patients who merit surveillance colonoscopy and to epidemiological studies.

Colonoscopy surveillance of individuals at risk of familial colorectal cancer.

BACKGROUND: Individuals with first degree relatives affected with colorectal cancer (CRC) at a young age, or more than one relative affected but who do not fulfil the Amsterdam criteria for a diagnosis of hereditary non-polyposis colon cancer (HNPCC), are believed to be at an increased risk of CRC. However, there is a paucity of prospective data on the potential benefit of colonoscopic surveillance in such groups categorised by empiric family history criteria. We report a prospective study of 448 individuals seeking counselling about their perceived family history of CRC. PATIENTS AND METHODS: Following pedigree tracing, verification, and risk assignment by genetic counsellors, colonoscopy was undertaken for those at a moderate or high risk (HNPCC). Those classified as low risk were reassured and discharged without surveillance. Here we report our findings at the prevalence screen in the 176 patients of the 448 assessed who underwent colonoscopy. RESULTS: Fifty three individuals had a family history that met Amsterdam criteria (median age 43 years) and 123 individuals were classed as moderate risk (median age 43 years). No cancers were detected at colonoscopy in any group. Four individuals (8% (95% confidence limits (CL) 0.4-15%)) in the high risk group had an adenoma detected at a median age of 46 years and all four were less than 50 years of age. Five (4% (95% CL 0.6- 8%)) of the moderate risk individuals had an adenoma at a median age of 54 years, two of whom were less than 50 years of age. CONCLUSIONS: These findings indicate that the prevalence of significant neoplasia in groups defined by family history is low, particularly in younger age groups. These prospective data call into question the value of colonoscopy before the age of 50 years in moderate risk individuals.

Food aversion and facial dysmorphism--a newly described syndrome?

We report three children with food aversion and characteristic facial dysmorphism, long digits and genitourinary abnormality. Interrogation of the London Dysmorphology Database suggests that this is a previously unreported syndrome.