Uncertainty management for individuals with Lynch Syndrome: Identifying and responding to healthcare barriers

ObjectiveExamine the uncertainty management process of individuals with Lynch syndrome (LS).Methods19 phone interviews were conducted with individuals with LS. The interview guide included questions on family communication, risk perceptions, and uncertainty management. Data were analyzed using the constant comparison method to code for emergent themes.ResultsQualitative analysis found individuals with LS tried to manage their uncertainty through preventive care, but were often confounded by healthcare barriers. Healthcare barriers included cost and insurance issues, absence of coordinated care, insufficient provider knowledge, and lack of patient-centered communication. Participants reported increased uncertainty and anxiety due to these barriers and used alternative uncertainty management strategies such as advocating for themselves with providers, seeking information online, and communicating with family for emotional support.ConclusionHealthcare barriers identified in this study exacerbated uncertainty and anxiety for individuals with LS and challenged their ability to engage in preventive care. In response, participants used alternative uncertainty management strategies to reduce their uncertainty, which may have unintended negative consequences.Practice implicationsFindings support the need for providers to partner with specialists in genetics and/or LS to better care for individuals with LS. Findings highlight opportunities for interventions in healthcare to better support individuals with LS.     

A potpourri of pathogenetic pathways in endometrial carcinoma with a focus on Lynch Syndrome

Endometrial carcinoma is the most frequently occurring female genital tract malignancy in developed nations, with a rising annual incidence. Endometrioid endometrial carcinoma (EEC), the most common histological variant, differs in morphologic and molecular characteristics from serous carcinomas but morphological distinction of high-grade EECs from serous carcinomas may prove difficult. Thus, molecular categorization of tumors may allow for better tumor classification with greater insight into the underlying biology of endometrial carcinomas with new therapeutic options.Microsatellite instability (MSI) is a commonly occurring molecular aberration in EECs and has been identified in most Lynch Syndrome (LS) associated tumors. This tumor syndrome predisposes afflicted individuals to a myriad of tumors including endometrial carcinoma. Herein, the molecular signature of endometrial tumors as well as LS, and its clinical manifestations are reviewed. Understanding of the pathogenetic pathways allows for greater comprehension of occurrences at a molecular level which are then appreciated at a cellular and tissue level, by the histopathologist.The molecular classification of endometrial tumors allows for further targeted therapeutic options for affected patients. Screening tests for patients with suspected LS enables surveillance of other tumors in the affected patient and her family with the potential to decrease morbidity and mortality. It is envisioned that this overview will allow for enhanced comprehension of genetic pathways by practicing pathologists, oncologists, gynecologists and other members of the multidisciplinary team, all of whom are involved in the management of the patient with an endometrial malignancy.     

A New Overgrowth Syndrome is due to Mutations in RNF125

Overgrowth syndromes (OGS) are a group of disorders in which all parameters of growth and physical development are above the mean for age and sex. We evaluated a series of 270 families from the Spanish Overgrowth Syndrome Registry with no known OGS. We identified one de novo deletion and three missense mutations in RNF125 in six patients from four families with overgrowth, macrocephaly, intellectual disability, mild hydrocephaly, hypoglycemia, and inflammatory diseases resembling Sjögren syndrome. RNF125 encodes an E3 ubiquitin ligase and is a novel gene of OGS. Our studies of the RNF125 pathway point to upregulation of RIG‐I‐IPS1‐MDA5 and/or disruption of the PI3K‐AKT and interferon signaling pathways as the putative final effectors.     

Munchausen Syndrome: A Review and New Conceptualization

For more than 40 years, the literature on Munchausen syndrome has primarily focused on presenting cases describing the often intriguing and tragic experiences of individuals who have presented to hospitals with self-inflicted illnesses. Due to the nature of this disorder, many patients are never seen by psychological or psychiatric personnel, and thus, assessment results and preferred treatment options are understandably limited. Despite the paucity of research conducted with patients diagnosed with Munchausen syndrome, etio-logical models for this disorder have been proposed, notably object relations and psychodynamic theories. Although both models present rationales for the development of this disorder, the two theories fail to account for several aspects of the disorder. In this article, an overview of Munchausen syndrome and existing theories is presented. In addition, a diathesis-stress model of Munchausen syndrome is proposed with future directions for research.     

A novel germline MLH1 mutation causing Lynch Syndrome in patients from the Republic of Macedonia

Aim

To implement molecular analysis in the clinical diagnosis and management of Lynch syndrome (LS).

Methods

We analyzed the mutations in MLH1 and MSH2 in the selected LS families from the Republic of Macedonia.

Results

We performed the very first genetic identification of LS families and characterized a novel mutation. The novel nonsense germline point mutation c.392C>G in the codon 131 of MLH1(S131X) was identified as the underlying genetic cause of LS in three families. The haplotype analysis suggested a founder effect of this mutation in our population.

Conclusion

We expect to detect the mutation in other LS patients from the region, and recommend cost-effective screening for this mutation by restriction fragment length polymorphism-polymerase chain reaction or DNA sequencing of MLH1 Exon5 prior to full genetic testing in all LS suspects of Macedonian ancestry.Lynch syndrome (LS), formerly known as hereditary non-polyposis colorectal cancer (HNPCC), is considered the most common form of hereditary colorectal cancer (1). It is an autosomal dominantly inherited predisposition to early development of colorectal cancers (CRC), as well as malignancies affecting the endometrium, ovaries, stomach, small intestine, hepatobiliary, and urinary tracts. The genetic foundation of this syndrome in 50%-70% of cases are germline mutations in the mismatch repair (MMR) genes, leading to microsatellite instability (MSI) in the affected tissue as a molecular hallmark of the disease. Germline mutations in MLH1 and MSH2 account for 90% of these mutations, but there is evidence for the involvement of PMS2 and MSH6 (2-8).The risk of colon cancer development in a patient with LS before the age of 70 is 52%-82%, ie, 9.5-15 times higher than in the general population (9). Genetic identification of a patient with LS alerts relatives to cancer risk and enables subsequent genetic testing, with a great benefit in terms of timing, expense, and effectiveness of surveillance (10), early detection of polyps, and reduction of cancer mortality. Furthermore, it spares the “healthy” relatives from unnecessary fear and intensified surveillance. Therefore, the evaluation of inherited susceptibility to colorectal cancer is becoming a very common diagnostic and even prognostic tool in colorectal cancer management. Up to now, there have been no official published data on the Lynch Syndrome and genetic testing for familial colorectal cancer predisposition in the Republic of Macedonia. In this regard, our aim was to implement molecular analyses in the clinical diagnosis and management of the LS in the country.     

一种新的颗粒白细胞粘弹性模型的理论和实验探讨

提出了描述颗粒白细胞粘弹性的三参数粘膜模型,采用用微管吸吮实验技术,将此模型用于大鼠单个颗粒白细胞粘弹研究,结果表明用三参数粘性模型能较好地描述颗粒白细胞发生小变形的粘弹性特征,克服了惯用的标准固体模型描述颗粒白细胞发生小变形时初始变形为弹性响应的假设。     

基于模糊覆盖集的糖尿病中医辩证模型研究

目的 针对中医诊断糖尿病中症状描述的模糊性和不完备性,提出了一种基于模糊覆盖集的糖尿病中医分类算法,建立了一种糖尿病中医辩证模型.实验结果表明,使用本法得出的辅助诊断结果能较好的覆盖医生诊断结果,缩小了证候的范围.从而使诊断结果自动化、客观化,减轻中医医师诊断病人的工作量.     

Understanding the Pathogenicity of Noncoding Mismatch Repair Gene Promoter Variants in Lynch Syndrome

Lynch syndrome is the most common familial cancer condition that mainly predisposes to tumors of the colon and endometrium. Cancer susceptibility is caused by the autosomal dominant inheritance of a loss‐of‐function mutation or epimutation in one of the DNA mismatch repair (MMR) genes. Cancer risk assessment is often possible with nonsynonymous coding region mutations, but in many cases patients present with DNA sequence changes within noncoding regions, including the promoters, of MMR genes. The pathogenic role of promoter variants, and hence clinical significance, is unclear and this hinders the clinical management of carriers. In this review, we provide an overview of the classification of MMR gene variants, outline the laboratory assays and online resources that can be used to assess the causality of promoter variants in Lynch syndrome, and highlight some of the practical challenges of demonstrating the pathogenicity of these variants. In conclusion, we propose a guide that could be integrated into the current InSiGHT classification scheme to help determine if a MMR gene promoter variant is pathogenic.     

A Genetic Model for the Inheritance of the P,P1 and Pk Antigens

A new genetic model of the P blood group system is presented. The system is controlled by two chromosomal loci. The first locus has three allelic genes. The P^k gene codes for an $aL galactosyl transferase that converts ceramide dihexoside to ceramide trihexoside (or the P^k antigen). The second allele, the P₁^k gene, codes for an $aL galactosyl transferase that converts both ceramide dihexoside to ceramide trihexoside (or the P^k antigen) and paragloboside to the P₁ antigen. The third allele does not produce an active product. The second locus has two allelic genes. The P₂ gene codes for a β N-acetyl galactosaminyl transferase that converts ceramide trihexoside to globoside (or the P antigen). The second allele does not produce an active product. The predictions of the model are in agreement with family studies and fibroblast fusion studies. The current model and previous genetic models, however, predict different possible phenotypes from rare P₂ x p or P₂^k x p matings or fibroblast fusions.     

A Genetic Model for the Inheritance of the P, P1 and Pk Antigens

A new genetic model of the P blood group system is presented. The system is controlled by two chromosomal loci. The first locus has three allelic genes. The P^k gene codes for an $aL galactosyl transferase that converts ceramide dihexoside to ceramide trihexoside (or the P^k antigen). The second allele, the P₁^k gene, codes for an $aL galactosyl transferase that converts both ceramide dihexoside to ceramide trihexoside (or the P^k antigen) and paragloboside to the P₁ antigen. The third allele does not produce an active product. The second locus has two allelic genes. The P₂ gene codes for a β N-acetyl galactosaminyl transferase that converts ceramide trihexoside to globoside (or the P antigen). The second allele does not produce an active product. The predictions of the model are in agreement with family studies and fibroblast fusion studies. The current model and previous genetic models, however, predict different possible phenotypes from rare P₂ x p or P₂^k x p matings or fibroblast fusions.     

A hypothesis: Sudden Infant Death Syndrome is a disorder of entrainment

A hypothesis is presented that explains Sudden Infant Death Syndrome (SIDS) as a disorder of entrainment. This hypothesis fits the known characteristics of SIDS i.e., age at death, sleep-related, natural death and absence of a lethal lesion. The spectrum from reversible hypoxia (near-miss SIDS) to irreversible hypoxia (SIDS) can be explained by the presence or absence of brainstem lesions in infants with a disorder of entrainment.     

A framework to build capacity for a reflex-testing program for Lynch syndrome

PurposeLynch syndrome (LS) is the most common inherited cause of colorectal cancer. Although testing all colorectal tumors for LS is recommended, the uptake of reflex-testing programs within health systems has been limited. This multipronged study describes the design of a provincial program for reflex testing in Ontario, Canada.MethodsWe recruited key stakeholders to participate in qualitative interviews to explore the barriers and facilitators to the implementation of a reflex-testing program. Data were analyzed in an iterative manner, key themes identified, and a framework for a proposed program developed.ResultsTwenty-six key informants participated in our interviews, and several themes were identified. These included providing education for stakeholders (patients, primary care providers, surgeons); challenges with sustaining various resources (laboratory costs, increased workload for pathologists); ensuring consistency of reporting test results; and developing a plan to measure program success. Using these themes, a framework for the reflex-testing program was developed. At a subsequent stakeholder meeting, the framework was refined, and recommendations were identified.ConclusionsThis study identifies factors to ensure the effective implementation of a population-level program for reflex LS testing. The final product is a prototype that can be utilized in other jurisdictions, taking into account local environmental considerations.     

A Tragic Inheritance: The Irresolvable Conflict for Children of Perpetrators

How do you live with the knowledge that your father ordered the death of thousands of innocent people? Children of parents who have committed or been involved in atrocities have to live with the guilt of their parents’ deeds, even when guilt is acknowledged by the parents. Because of their family history, these children often become ‘lightning conductors’ for social guilt, tainted with the mark of evil. Drawing on clinical material and interviews with children of Nazi SS officers, this paper examines the personal psychological repercussions and conflicts that children of perpetrators face in their lives. These conflicts live on not only within the children who have inherited their parents’ crimes but within the larger society in the form of memory, denial and guilt. The psychological dilemma for children of perpetrators provides a prism through which we can better understand the impact of past atrocities on the collective.