Family History Data Research Articles

Mutation analysis of TGFBI and KRT12 in a case of concomitant keratoconus and granular corneal dystrophy.

This study is to summarize the concurrent keratoconus (KC) and granular corneal dystrophy (GCD) phenotype and identify the underlying genetic cause in a 23-year-old male patient. A detailed family history and clinical data from the patient and his parents were collected by ophthalmologic examination. The candidate genes were captured and sequenced by targeted next-generation sequencing, and the results were confirmed by Sanger sequencing. The proband was clinically diagnosed as a case of concurrent KC and GCD, which is a very rare presentation. His father and grandmother were diagnosed as GCD in both eyes. There was no character of KC in his father's and grandmother's eyes. A heterozygous TGFBI mutation in exon 4 (c.370G>A) was identified in the proband, which was predicted to generate a missense mutation (p.R124H). The mutation also existed in his father and grandmother. A heterozygous KRT12 mutation in exon 8 (c.1456-1457ins GTA) was identified in the proband, which was predicted to generate an insert mutation and created a premature termination codon. The mutation did not exist in his father and grandmother. The two mutations did not exist in his mother and 200 unrelated normal controls. KC can co-exist with GCD. The missense mutation (c.370G>A) in the TGFBI gene and insert mutation (c.1456-1457ins GAT) in the KRT12 gene were identified in a 23-year-old male patient with concurrent KC and GCD.

Next-generation sequencing for D47N mutation in Cx50 analysis associated with autosomal dominant congenital cataract in a six-generation Chinese family

BackgroundCongenital cataract is the most frequent cause of blindness during infancy or early childhood. To date, more than 40 loci associated with congenital cataract have been identified, including at least 26 genes on different chromosomes associated with inherited cataract. This present study aimed to identify the genetic mutation in a six-generation Chinese family affected with congenital cataract.MethodsA detailed six-generation Chinese cataract family history and clinical data of the family members were recorded. A total of 27 family members, including 14 affected and 13 unaffected individuals were recruited. Whole exome sequencing was performed to determine the disease-causing mutation. Sanger sequencing was used to confirm the results.ResultsA known missense mutation, c. 139G > A (p. D47N), in Cx50 was identified. This mutation co-segregated with all affected individuals and was not observed in the unaffected family members or in 100 unrelated controls. The homology modeling showed that the structure of the mutant protein was different with that wild-type Cx50.ConclusionsThe missense mutation c.139G > A in GJA8 gene is associated with autosomal dominant congenital cataract in a six-generation Chinese family. The result of this present study provides further evidence that the p. D47N mutation in CX50 is a hot-spot mutation.

Next generation sequencing is informing phenotype: a TP53 example.

The increased availability of next generation sequencing (NGS) and multi gene panel testing has resulted in more frequent TP53 testing of families that do not meet classic testing criteria. We investigated testing criteria, family history and result outcome in a cohort of Irish probands undergoing TP53 full sequencing. All TP53 test requests processed through the national genetic testing laboratory between 2012 and 2014 were retrospectively reviewed. Personal and family cancer histories were collected, including tumour type and age at diagnosis, from two adult cancer genetic services in Ireland. Association between Li Fraumeni syndrome (LFS) or Li Fraumeni like syndrome (LFL) criteria and test result was examined. One hundred and 35 TP53 test requests were identified. Family history data and test results were available on 123 of the TP53 test requests (118 female; 5 male). 59/123 (48%) did not meet classic LFS or LFL criteria. Two individuals from this group harboured pathogenic TP53 mutations, giving a 3% mutation detection rate in those not meeting testing criteria. Both were female and had a personal history of early onset bilateral breast cancer with no reported LFS cancers in the family. 64/123 (52%) met LFS or LFL criteria and were all TP53 negative. 37/64 (57.8%) met Chompret criteria, 19/64 (29.7%) met Eeles and 7/64 (10.9%) met Eeles and Chompret and 1/64 (1.6%) met Classic LFS criteria. Stringent testing criteria miss germline mutations in TP53. Broadening the criteria for TP53 testing may improve our understanding of the phenotype and penetrance in the association syndrome.

Abstract 336: Prevalence and Risk Factors for Idiopathic Venous Thromboembolism

Introduction: Venous thromboembolism (VTE) is a major cause of morbidity and mortality in the United States. Despite medical advances in diagnostics and thromboprophylaxis, the incidence of VTE has not substantially decreased over time. Furthermore, many patients are diagnosed with VTE without an identifiable cause. Objectives: We sought to investigate the prevalence of idiopathic VTE and risk factors associated with this diagnosis. Methods: Patients diagnosed with deep vein thrombosis (DVT) or pulmonary embolism (PE) were enrolled into a prospective venous thromboembolic center (VTEC) registry at a large tertiary medical center from 7/2015-12/2015. VTE events were considered to be idiopathic if none of the following criteria were met: current pregnancy; current use of hormonal therapy or oral contraceptives, active malignancy; diagnosed thrombophilia; major surgery within 90 days; bed rest, restricted mobility, cast or mold, or serious trauma within 30 days. Patient demographics, comorbidities, social history, family history, laboratory and clinical data were analyzed and compared between groups. Multivariable logistic regression analysis was used to estimate odds of idiopathic VTE. Results: Of 223 patients with VTE, 93 (41.7%) were determined to be idiopathic. Patients with idiopathic and non-idiopathic VTE were of similar age, race/ethnicity, level of education, type of insurance, and type of VTE (DVT or PE). Patients with idiopathic VTE were more frequently female (68.8% vs. 46.4%; p < 0.01), more likely to have a history of COPD (8.6% vs. 1.1%, p = 0.03), hyperlipidemia (33.6% vs. 18.3%, p = 0.02), and less likely to be on a statin at the time of diagnosis (17.2% vs. 29.3%, p = 0.05) than non-idiopathic VTE. After multivariable adjustment, female sex (OR: 2.47, 95% CI 1.35-4.64) and history of varicose veins (OR 2.67, 95% CI 1.15-6.37) were significantly associated with the prevalence of idiopathic VTE. Conclusions: In a large tertiary medical center, idiopathic VTE occurred in more than 40% of all VTEs. Female sex and history of varicose veins were independently associated with having an idiopathic VTE. These data provide a basis for future investigation into this high-risk population and for further development of prediction models.

Abstract 434: The Majority of Outpatients With Severe Hypercholesterolemia at an Academic Tertiary Centre Have Not Been Screened for FH

Background: National and International guidelines recommend, as a minimum, that individuals with LDL-C ≥190mg/dL are asked about a family history of ASCVD and hypercholesterolemia to screen for familial hypercholesterolemia (FH), a monogenic condition that carries considerable ASCVD risk. However, FH is grossly underdiagnosed and undertreated in the US. One reason for this may be failure to screen severely hypercholesterolemic individuals for FH. Hypothesis: We evaluated the hypothesis that poor identification of FH might be due to inadequate screening for FH among individuals with severe hypercholesterolemia. Methods: An EHR query was used to identify active adult patients in the University of Pennsylvania outpatient EHR database (N=310 802) with LDL-C≥220mg/dL, excluding secondary causes of hypercholesterolemia. The EHR was then systematically reviewed for structured notation of family history information. Result: The query identified 3,475 individuals with severely elevated LDL-C. Among them, only 47.9% (1666) had family history data relating to ASCVD (968), hypercholesterolemia (336) or both (362) in the EHR. The history was positive in 94.2% (1569) of these cases. Overall, patients with LDL-C ≥220mg/dL were more likely to be screened (OR 1.57; 95% CI 1.47-1.68) than those with LDL <220mg/dL. Within the former group, the odds of being screened were higher in Caucasians (OR 1.52; 95% CI 1.33-1.75), with more severe LDL-C elevation or a history of ASCVD (OR 1.36; 95% CI 1.10 - 1.67). Conversely, the presence of diabetes (OR 0.73; 95% CI 0.61-0.86) or hypertension (OR 0.82; 95% CI 0.72-0.94), made screening less likely to occur. Interestingly, the setting of clinical care was also important; individuals seen in secondary care (OR 1.68; 95% CI 1.41-2.26), general (OR 1.69, 95% CI 1.47-1.95) or preventative cardiology (OR 1.82; 95% CI 1.47-2.25) were more likely to be screened. Finally, statin prescription was more common in those screened (OR 1.39; 95% CI 1.16-1.88), but this did not affect LDL-C goal achievement. Conclusion: At a large academic centre, the majority of outpatients with severe hypercholesterolemia had no record of being screened for FH. This report sheds light on factors that might be relevant to the underdiagnosis of FH in the US.

Impact of family history of metabolic traits on severity of non‐alcoholic steatohepatitis related cirrhosis: A cross‐sectional study

Familial aggregation of metabolic traits with fatty liver disease is well documented. However, there is scarcity of data regarding such association with non-alcoholic steatohepatitis (NASH)-related cirrhosis. This study was aimed to explore the association of family history of metabolic traits with severity of cirrhosis. In a cross-sectional study, all consecutive patients with NASH-related cirrhosis presenting to our tertiary care centre were included. Family history, personal history, demographic characteristics, medical history, anthropometric measurements and laboratory data were recorded. Of the 1133 cirrhotics (68.1% males, age 51.4±10.9years); 779 (68.8%) had family history for metabolic traits. These patients had lower age at diagnosis (45.4±10.6 vs 49.6±11.2years), higher Child-Turcotte-Pugh (CTP) score (7.8±1.9 vs 6.6±1.5), higher model for end stage liver disease (MELD) score (12.9±6.1 vs 10.9±4.1) and more incidence of decompensation in the form of ascites (46.3% vs 25.7%), jaundice (12.1% vs 6.2%) and hepatic encephalopathy (26.1% vs 11.0%). Patients with family and personal history of metabolic traits, had an increased risk of an early diagnosis of cirrhosis at<45years of age (OR: 3.1, 95% CI 2.1-4.4), CTP≥10 (OR: 4.6, 95% CI 2.3-9.1), MELD>15 (OR: 6.6, 95% CI 3.8-11.5) with ≥1 features of decompensation (OR: 4.2, 95% CI 2.9-6.1). Family history of diabetes alone, also had higher risk of cirrhosis with MELD>15 (OR: 4.3, 95% CI 2.4-5.3, P<.001). Family and personal history of metabolic traits are associated with early age at diagnosis of cirrhosis with more severity and decompensation and so, has a prognostic importance in NASH-related cirrhotics.

Patients With Celiac Disease Reported Higher Consumption of Added Sugar and Total Fat Than Healthy Individuals.

The aim of the study was to compare the dietary pattern between subjects with celiac disease (CD) (cases) and subjects without (healthy controls) CD. A case-control design study was conducted. A total of 98 subjects with CD (age 10-23 years) were matched by age, sex, and body mass index with 98 nonceliac participants. A nonconsecutive 3-day food record was completed to assess energy, nutrient, and food intake and evaluate the participant's adherence to recommendations. Differences in energy, nutrients, food consumption, and compliance with general recommendations between cases and control groups were assessed by Student t test. Pearson chi-squared test was used to compare categorical variables. Sociodemographic, personal, and family history data were collected. Compared with the control group, the cases with CD reported a significantly higher consumption of added sugar (P < 0.001) and total fat (P < 0.017). Mean fiber consumption was below the nutritional recommendations in both groups. Participants with CD consumed significantly lower amounts of foods rich in starch (P < 0.001) and higher amounts of foods rich in protein such as meat, fish, and eggs (P = 0.007). Subjects with CD showed a significantly lower percentage of adherence to recommendations for folic acid (53.2 vs 70.5; P < 0.001), calcium (49.0 vs 56.3; P = 0.025), iron (57.4 vs 78.0; P < 0.001), and magnesium (50.0 vs 63.9; P < 0.001). The subjects with CD showed a more unbalanced diet than controls in terms of added sugars, total fat, and micronutrient consumption.

Natural selection and type 2 diabetes-associated mortality in an isolated indigenous community in the valley of Oaxaca, southern Mexico.

This study tests the hypothesis that natural selection is associated with type 2 diabetes (T2D)-associated mortality and fertility in a rural isolated Zapotec community in the Valley of Oaxaca, southern Mexico. Mortality data and related demographic and genealogic information were linked with data for fertility, prereproductive mortality and family history of mortality attributed to T2D. Physician verified T2D mortality (n = 27) between 1980 and 2009 and imputed T2D (n = 70) from cardiovascular mortality (68% random sample) and renal failure (44% random sample). Bootstrapping was used to obtain a robust variance estimate in survival analysis and multivariate analysis of variance. Estimated maximum natural selection by Crow's Index occurred circa 1930 and was relaxed after this time in the study population. Cox-regression survival analysis of T2D mortality with covariates (family history of T2D, cardiovascular disease, renal failure) indicated a significant hazard ratio (HR = 5.95, 95% CI: 1.38-25.67, p < .008) for the increase in T2D in 2000 to 2009. Survival analysis of imputed T2D resulted in a significant HR of 2.03 (95% CI: 1.08-3.85, p = .01) for the increase in T2D in the 2000 to 2009 cohort (reference group: 1980-1989). Mean number of live born offspring was lower among T2D (n = 27, 4.04 ± 3.85 SD) compared to non-T2D (n = 199, 5.30 ± 3.48) groups (p < .08). Mean number of live born offspring was lower (p = .003) among imputed T2D compared to non-T2D groups (4.10 ± 3.44 vs. 5.62 + 3.50). T2D-associated mortality increased in frequency as natural selection decreased, and favored offspring survival of non-T2D descedants. The results indicated statistically significant directional selection against T2D and imputed T2D to this population isolate.

Family History of Type 2 Diabetes: Does Having a Diabetic Parent Increase the Risk?

It is well established that there is an important genetic predisposition for type 2 diabetes mellitus (T2DM). To summarise available epidemiological data regarding T2DM transmission in various populations. Narrative review. The estimated risk for the diagnosis of T2DM increases approximately by 2-4 times, when father, mother or both have this condition. Conversely, many T2DM patients have family members with DM. Studies have suggested that the likelihood of T2DM in the next generation is higher in the event of a diabetic mother than father. Both genetic factors, such as mitochondrial DNA mutations, and environmental components, such as intra-uterine environment, have been implicated in the higher maternal transmission of T2DM. Despite the above findings, some studies in populations with high frequency of T2DM have not corroborated the predominantly maternal transmission. Such works have shown either an excess paternal or an equal transmission of T2DM. It appears that potential biases in reporting family history data, especially between the various racial groups, have contributed to the controversy over the existence of excess maternal transmission of DM.

Familial aggregation of Parkinson's disease may affect progression of motor symptoms and dementia.

Familial aggregation has been described in PD of both early and late onset, but has not been studied in a true population-based sample. Moreover, little is known about its association with disease progression and endophenotypes. The objectives of this work were to determine familial aggregation of idiopathic PD in a population-based cohort and study the association with clinical endophenotypes and disease progression. We examined family history data from the Norwegian ParkWest study, a well-characterized, population-based cohort of incident PD patients and age-matched healthy controls. Family data were collected at baseline with a simplified questionnaire (192 cases and 193 controls) and after 3 years of longitudinal follow-up using an extended questionnaire (172 cases and 171 controls). Compared to the controls, the PD patients had an increased relative risk of having a first-degree relative with PD when using the extended questionnaire (relative risk = 1.988; P = 0.036), but not when using the simplified questionnaire (relative risk = 1.453; P = 0.224). There was no significant difference in age of onset or motor subtype (P = 0.801). However, cases with a family history of PD had reduced progression over 7 years as measured by UPDRS II (P = 0.008) and smaller rate of decrease of MMSE (P = 0.046). Our findings confirm familial aggregation in a population-based cohort of idiopathic PD. Moreover, we show that positive family history of PD in patients is associated with a slower progression of PD symptoms and cognitive decline. © 2016 International Parkinson and Movement Disorder Society.

Improving Utilization of the Family History in the Electronic Health Record.

The purpose of this article is to provide an overview of Family History in the Electronic Health Record and to identify opportunities to advance the contributions of nurses in obtaining, updating and assessing family history in order to improve the health of all individuals and populations. The article presents an overview of the obstacles to charting Family History within the Electronic Health Record and recommendations for using specific Family History tools and core Family History data sets. Opportunities to advance nursing contributions in obtaining, updating, and assessing family history in order to improve the health of all individuals were identified. These opportunities are focused within the area of promoting the importance of communication within families and between healthcare providers to obtain, document, and update family histories. Nurses can increase awareness of existing resources that can guide collection of a comprehensive and accurate family history and facilitate family discussions. In this paper, opportunities to advance nursing contributions in obtaining, updating, and assessing family history in order to improve the health of all individuals were identified. Aligned with the clinical preparation of nurses, family health should be used routinely by nurses for risk assessment and to help inform patient and family members on screening, health promotion, and disease prevention. The quality of family health information is critical in order to leverage the use of genomic healthcare information and derive new knowledge about disease biology, treatment efficacy, and drug safety. These actionable steps need to be performed in the context of promoting evidence-based applications of family history that will be essential for implementing personalized genomic healthcare approaches and disease prevention efforts. Family health history is one of the most important tools for identifying the risk of developing rare and chronic conditions, including cardiovascular disease, cancer, and diabetes, and represents an integration of disease risk from genetic, environmental, and behavioral/lifestyle factors. In fact, family history has long been recognized as a strong independent risk factor for disease and is the current best practice used in clinical practice to guide risk assessment.

Val279Phe variant of Lp-PLA2 is a risk factor for a subpopulation of Indonesia patients with acute myocardial infarction

Lipoprotein-associated phospholipase A2 (Lp-PLA2), a member of the phospholipase A2 superfamily, is an enzyme that hydrolyses phospholipids, is found in blood circulation as a sign of inflammation, and takes a role in atherogenesis. There is an epidemiologic relation between increased Lp-PLA2 levels and coronary heart disease. Lp-PLA2 is an enzyme that is produced by macrophages and takes a role as an independent predictor of a coronary event. A genetic variant of Val279Phe on the Lp-PLA2 gene has been reported with various results in Japan, China, Korea, and Caucasian populations. This study aims to analyse the influence of the Val279Phe genetic variant on acute myocardial infarction (AMI) at Saiful Anwar Hospital, Indonesia. This study was conducted on 151 patients (111 AMI patients and 40 non-AMI patients). The genetic variant of Val279Phe was identified through a genotyping method. There were no significant differences in age, total cholesterol level, LDL-C (low-density lipoprotein cholesterol) level, and family history data between AMI and non-AMI patients. However, AMI patients had low HDL-C (high-density lipoprotein cholesterol), triglyceride levels, dyslipidaemia, and hypertension risk factors compared to non-AMI patients. The frequency of the GG genotype (279Val) was dominant in both AMI and non-AMI groups. Further analysis suggested that the GG genotype has a 2.9 times greater risk of AMI compared to the GT/TT genotype (279Phe). This study concluded that the Val279Phe genetic variant undoubtedly influenced AMI risk, which is a warrant for further development of early detection and improving strategy to prevent AMI in patients.

The Three-Generation Pedigree: A Critical Tool in Cancer Genetics Care.

The family history, a rather low-tech tool, is the backbone of genetic assessment and guides risk assessment and genetic testing decisions. The importance of the pedigree and its application to genetic practice is often overlooked and underestimated. Unfortunately, particularly with electronic health records, standard pedigrees are not routinely constructed. A clear understanding of how pedigrees are employed in clinical oncology practice may lead to improved collection and use of family history data. .

Factors Associated with Open-Angle Glaucoma among Iraqi Patients

Background: Glaucoma is the leading cause of blindness world wide and 22.5 million people are estimated to suffer from it. Open angle glaucoma is more prevalent form of glaucoma than closed angle glaucoma blindness can be avoided if glaucoma treated early. Objectives: There are many factors associated with open angle glaucoma this study is performed to assess The most important factors that associated with open angle glaucoma among Iraqi patients who had glaucoma attending AL-Yarmook teaching hospital Methods: Across sectional study was conducted at AL-Yarmook hospital in Baghdad from October 2013 till June 2014 one hundred fifty 150 glaucomatous patients age &gt;35 years both sexes were included in this study .open Angle glaucoma was diagnosed by ophthalmologist depending on the American Academy of Ophthalmology 2012 the data were obtained by using an interview questionnaire that was applied to patient with open angle glaucoma. The data include the age, sex. family history and clinical data which include intra ocular pressure ,Myopia, smoking, history of hypertension, diabetes and using systemic drugs as corticosteroid the data was analyzed by SPSS. Results: The study included 150 patients with open angle glaucoma. almost half of the patients were above 65 years, the rate of open angle glaucoma is more in those who have I.O.P.&gt;20 mm Hg (92%) ,myopia 65%family history72%, history of hypertension 63%, history of diabetes 53%,history of taking steroid 59% and smoking 52%. Open angle glaucoma was significantly associated with intra ocular pressure 0.0001, myopia P0.001, family history 0.0005, history of hypertension 0.001, and history of taking steroid 0.01. it show that there is no significant association with history of diabetes and smoking (P 0.1,0.2 ) respectively. Conclusion: This study show that old age, intra ocular pressure, Myopia, family history, history of hypertension and history of taking steroid are risk factors for open angle glaucoma. Recommendation: education of the people about risk factor associated with glaucoma and routine checking of I.O.P for old age and patients with hypertension and diabetic

Relative Risks for Lethal Prostate Cancer Based on Complete Family History of Prostate Cancer Death.

There are few published familial relative risks (RR) for lethal prostate cancer. This study estimates RRs for lethal prostate cancer based on comprehensive family history data, with the goal of improving identification of those men at highest risk of dying from prostate cancer. We used a population-based genealogical resource linked to a statewide electronic SEER cancer registry and death certificates to estimate relative risks (RR) for death from prostate cancer based upon family history. Over 600,000 male probands were analyzed, representing a variety of family history constellations of lethal prostate cancer. RR estimates were based on the ratio of the observed to the expected number of lethal prostate cancer cases using internal rates. RRs for lethal prostate cancer based on the number of affected first-degree relatives (FDR) ranged from 2.49 (95% CI: 2.27, 2.73) for exactly 1 FDR to 5.30 (2.13, 10.93) for ≥3 affected FDRs. In an absence of affected FDRs, increased risk was also significant for increasing numbers of affected second-degree or third degree relatives. Equivalent risks were observed for similar maternal and paternal family history. This study provides population-based estimates of lethal prostate cancer risk based on lethal prostate cancer family history. Many family history constellations associated with two to greater than five times increased risk for lethal prostate cancer were identified. These lethal prostate cancer risk estimates hold potential for use in identification, screening, early diagnosis, and treatment of men at high risk for death from prostate cancer. Prostate77:41-48, 2017. © 2016 Wiley Periodicals, Inc.

Abstract 4340: DNA repair genes aberrations in germline DNA in metastatic castration-resistant prostate cancer patients

Abstract INTRODUCTION: DNA repair defects are found in mCRPC and are therapeutically actionable; germline BRCA mutation-associated (gBRCA) prostate cancer has a poor prognosis. We hypothesized that metastatic castration resistant prostate cancer (mCRPC) is enriched for germline DNA repair mutations and that these may be relevant to patient outcome. METHODS: Targeted-sequencing for DNA repair genes was conducted in germline DNA from patients consenting to 3 clinical trials between 2013-2015. Germline DNA was extracted from saliva or buccal swabs using the Oragene kit; libraries were constructed using a customized Qiagen panel and sequenced using the Illumina MiSeq. Family history and clinical data were prospectively collected. For time to event analyses unadjusted Cox regression models were used and comparisons were made using log-rank tests. RESULTS: Germline samples from 154 mCRPC patients were available. Median age at diagnosis was 61years (y), median time to castration-resistance was 14.5 months (m) and median overall survival (OS) from initial diagnosis of prostate cancer was 106.8m; 69% (91/131; 24 N/A) of patients were initially diagnosed with Gleason≥8 tumors. 130/154 (84.4%) and 131/154 (85.0%) received Docetaxel and Abiraterone respectively. Of 154 patients, 4 were previously known to be gBRCA2 mutation carriers and were removed from the prevalence analysis but included in the clinical analyses; 22/150 (14.7%, 95%CI 9.4-21.4%) harboured a truncating or frameshift mutation in a DNA repair gene (9 BRCA2, 6%; 4 ATM, 2.7%; 2 PALB2, 1.3%, 1 each for CHEK2, FANCI, MRE11A, NBN, RAD51C, RAD51D and MSH6). Overall, patients with any germline DNA repair aberrations had a worse median OS (75.8 vs 106.8 m; log-rank p = 0.04). Time to resistance to primary hormonal ablation was shorter specifically for gBRCA2 mutations carriers (11.0 vs 14.8 m; log-rank p = 0.01) but not for non-BRCA2 repair aberrations. Age at diagnosis was similar in patients with or without DNA repair germline mutations (median 61.3 vs 61.7y, Mann-Whitney p = 0.41) as well as frequency of Gleason≥8 tumors (16/21 [76%] vs 75/109 [68%]; Mann-Whitney p = 0.23) Response rates to Docetaxel (14/18 [77.8%] vs 64/94 [68.1%]; Fisher exact p = 0.67) and Abiraterone (10/21 [47.6%] vs 44/94 [46.8%]; Fisher exact p = 0.73) were similar among individuals with and without mutations. Family cancer history was collected in 125/154 cases (81%). While having cases of ovarian/prostate/breast/pancreas cancers in these patients’ families associated with a higher likelihood of finding a germline mutation (Odds Ratio 3.36, p = 0.03), 5 of 68 (7.4%) men with no cases of ovarian/prostate/breast/pancreas cancers registered in their families carried a germline mutation in a DNA repair gene. CONCLUSIONS: mCRPC is enriched for patients with germline mutations in DNA repair genes (15%), with 6% having gBRCA2 mutation. Germline DNA repair aberrations are associated with a worse prognosis from mCRPC. Citation Format: JOAQUIN MATEO, Suzanne Carreira, Helen Mossop, Pasquale Rescigno, Michael Kolinsky, Elena Castro, Ada Balasopoulou, Jo Hunt, Desamparados Roda, Claudia Bertan, Jane Goodall, Susana Miranda, Penny Flohr, Nuria Porta, Zsofia Kote-Jarai, David Olmos, Christopher J. Lord, Emma Hall, Ros Eeles, Johann S. de Bono. DNA repair genes aberrations in germline DNA in metastatic castration-resistant prostate cancer patients. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4340.

Occurrence of renal cell carcinoma and hematologic malignancies (predominantly lymphoid) in individuals and in families.

The relationship between renal cell cancer (RCC) and hematologic malignancy (HM) in the same individual has been reported for more than 20years, and is noted in SEER database studies. Family histories suggest a familial association as well. This study evaluates the occurrence of renal cell cancer and hematologic malignancies in individual patients and families, and the occurrence of age-of-onset anticipation among generations. Family history data from our familial patient registry, including more than 700 pedigrees of familial hematologic malignancies, and 700 patients with renal cell cancer, were reviewed. Twenty-six patients with a personal history of both RCC and HM are reported. Seventy four patients with RCC are noted to have 95 family members with HM. Consistent with past reports, there was male predominance among the patients with both diseases (71%), and among the RCC patients' relatives with HM (57%). Also consistent was a predominance of lymphoid malignancies in those with both diseases (92%) and in the HMs among family members of RCC patients (79%). The majority (95%) of HM relatives were first or second degree relatives of the patient with RCC. Thirty of 34 parent/child pairs demonstrated age of onset anticipation in which the child developed either disease at a younger age than the parent. The co-occurrence of RCC and HM in the same patient has been shown to be significantly greater than expected. Families also appear to have an increased association. The appearance of anticipation suggests that genetic factors may be significant in this association of RCC and HM.

Clinical Characteristics and Risk Factors of Extensive Macular Atrophy with Pseudodrusen: The EMAP Case-Control National Clinical Trial

To assess the association of clinical and biological factors with extensive macular atrophy with pseudodrusen (EMAP) characterized by bilateral macular atrophy occurring in patients aged 50 to 60 years and a rapid progression to legal blindness within 5 to 10 years. A national matched case-control study. Participants were recruited in 10 French Departments of Ophthalmology and their associated clinical investigation centers. All 115 patients with EMAP had symptoms before the age of 55 years due to bilateral extensive macular atrophy with a larger vertical axis and diffuse pseudodrusen. Three controls without age-related macular degeneration (AMD) or retinal disease at fundus examination were matched for each patient with EMAP by gender, age, and geographic area (in total 415). Subjects and controls underwent an eye examination including color, red-free autofluorescent fundus photographs and spectral-domain optical coherence tomography with macular analysis. The interviews collected demographic, lifestyle, family and personal medical history, medications, and biological data. Associations of risk factors were estimated using conditional logistic regression. Extensive macular atrophy with pseudodrusen status (cases vs. controls). Extensive macular atrophy with pseudodrusen most frequently affected women (70 women, 45 men). After multivariate adjustment, family history of glaucoma or AMD was strongly associated with EMAP (odds ratio [OR], 2.3, P= 0.008 and OR, 1.5, P= 0.01, respectively). No association was found with cardiac diseases or their risk factors. Mild and moderate kidney disease and higher neutrophil rate were associated with a reduced risk of EMAP (OR, 0.58, P= 0.04; OR, 0.34, P= 0.01; and OR, 0.59, P= 0.003, respectively). On the contrary, eosinophilia (OR, 1.6; P= 0.0002), lymphocytosis (OR, 1.84; P= 0.0002), increased erythrocyte sedimentation rate (OR, 6.5; P= 0.0005), decreased CH50 (P= 0.001), and high plasma C3 level (P= 0.023) were significantly associated with a higher risk of EMAP. This study documents an association between EMAP and family history of AMD and glaucoma, a clear female predominance, and a systemic inflammatory profile. The reduced CH50 and increased C3 plasma values could reflect a more severe complement pathway dysfunction than in AMD, leading to early pseudodrusen and rapid development of geographic atrophy. There is no association of EMAP with AMD cardiac diseases or cardiac risks, including cigarette smoking.

Metopic Craniosynostosis: A Demographic Analysis Outside an Urban Environment.

Metopic craniosynostosis has traditionally been cited as the third most common type of isolated synostosis, after sagittal and coronal craniosynostosis. Recently, several urban institutions have observed an increase in the incidence of metopic synostosis. The authors sought to determine if similar demographic changes have occurred in a more suburban setting and if so, what specific variables were associated with this change. Patients who underwent operative correction of craniosynostosis between 1989 and 2014 were retrospectively reviewed. The type of craniosynostosis as well as sex, family history, birth history, and other demographic data were recorded. Kendall-Mann trend tests and multinomial logistic regressions were conducted, and marginal effects were calculated for all variables included in the model. Records of 493 patients were reviewed. Using Kendall-Mann trend tests, it was determined that metopic, sagittal, and lambdoid craniosynostoses all demonstrated an increase in incidence. Based on raw data, metopic synostosis was found to be the second most common type of craniosynostosis between 2004 and 2014. Male sex and multiple gestations were both associated with metopic craniosynostosis. This study demonstrated an increasing incidence of metopic craniosynostosis over time, which ascended to the second most common type of synostosis in an analysis outside of an urban environment. In our study, male sex and multiple gestation were positively associated with an increased risk of metopic craniosynostosis. Prospective studies are needed to further delineate the evolving characteristics of this patient population.

Evaluation of coagulation tests before newborn circumcision: is it necessary?

Evaluation of coagulation parameters prior to newborn circumcision is routinely performed in many countries. However, the value of this screening in predicting the bleeding risk is unknown. The aim of this study was to evaluate the correlation between the preoperative prolonged prothrombin time (PT), activated partial thromboplastin time (aPTT) and excessive bleeding after the circumcision in term, healthy newborns without family history of coagulopathy. The medical records of healthy, full term newborns born at VKV American Hospital, in Istanbul, Turkey, between 2009 and 2012 who were circumcised within the first week of life, were reviewed retrospectively. The data for family history of coagulopathy, clinical sign(s) of bleeding during and/or after delivery, preoperative PT, aPTT levels and the amount of bleeding after circumcision were gathered. The most recent medical records of the patients' were also reviewed for any possible, lately diagnosed bleeding disorder. A total of 450 newborns met the above criteria. None had a family history of bleeding disorder or clinical bleeding. A total of 158 (35%) newborns had an aPTT result greater than 54.5 s, 269 (59%) had PT result greater than 15.9 s and 72 (16%) had international normalized ratio result greater than 1.62. Neither of the patients with prolonged PT and/or aPTT had prolonged or excessive bleeding. The evaluation of PT and aPTT before elective newborn circumcision is not necessary in the absence of clinical bleeding or a family history of bleeding disorder. It is rather a habit in general practice and possibly a result of defensive medicine.