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Simple Summary: Lynch syndrome (LS) is a genetic condition predisposing to a variety of tumors, including endometrial (EC) and ovarian cancers (OC), with cancer lifetime risk depending on the specific LS-mutation involved. Universal Screening is the standard for LS detection. Prophylactic surgery is a risk-reducing option that may be considered, and the age at hysterectomy and recommendation for bilateral oophorectomy depend on the mutated variant and offspring desire. Besides surgery, chemoprevention via contraceptives combination or progestin-alone is a viable option, and vaccination with tumor-specific antigens has shown promising results in mouse models. LS patients requiring adjuvant radiotherapy or systemic treatment for EC or OC are managed according to international standard of care. However, when conservative treatment for EC is considered, worse oncologic and obstetric outcomes are reported for patients with mismatch repair deficiency or LS. Moreover, LS-related tumors are characterized by a highly immunogenic tumor-environment that can be targeted by specific immune checkpoint inhibitors. This review provides a comprehensive update on recent evidence regarding gynecologic tumors associated with Lynch Syndrome (LS). Endometrial cancer (EC) and ovarian cancer (OC) are the first and second most common gynecologic malignancies in developed countries, respectively, and LS is estimated to be the hereditary cause in 3% of both EC and OC. Despite the increasing evidence on LS-related tumors, few studies have analyzed the outcomes of LS-related EC and OC stratified by mutational variant. This review aims to provide a comprehensive overview of the literature and comparison between updated international guidelines, to help outline a shared pathway for the diagnosis, prevention, and management of LS. Through the widespread adoption of the immunohistochemistry-based Universal Screening, LS diagnosis and identification of mutational variants could be standardized and recognized by international guidelines as a feasible, reproducible, and cost-effective method. Furthermore, the development of a better understanding of LS and its mutational variants will support our ability to better tailor EC and OC management in terms of prophylactic surgery and systemic treatment in the light of the promising results shown by immunotherapy. [ABSTRACT FROM AUTHOR]

Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant disorder caused, in more than 80% of cases, by mutations of either the endoglin (ENG) or the activin A receptor-like type 1 (ACVRL1) gene. Several hundred variants have been identified in these HHT-causing genes, including deletions, missense and nonsense mutations, splice defects, duplications, and insertions. In this study, we have analyzed retrospectively collected images of magnetic resonance angiographies (MRA) of the brain of HHT patients, followed at the HHT Center of our University Hospital, and looked for the distribution of cerebrovascular phenotypes according to specific gene variants. We found that cerebrovascular malformations were heterogeneous among HHT patients, with phenotypes that ranged from classical arteriovenous malformations (AVM) to intracranial aneurysms (IA), developmental venous anomalies (DVA), and cavernous angiomas (CA). There was also wide heterogeneity among the variants of the ENG and ACVRL1 genes, which included known pathogenic variants, variants of unknown significance, variants pending classification, and variants which had not been previously reported. The percentage of patients with cerebrovascular malformations was significantly higher among subjects with ENG variants than ACVRL1 variants (25.0% vs. 13.1%, p < 0.05). The prevalence of neurovascular anomalies was different among subjects with different gene variants, with an incidence that ranged from 3.3% among subjects with the c.1231C > T, c.200G > A, or c.1120C > T missense mutations of the ACVRL1 gene, to 75.0% among subjects with the c.1435C > T missense mutation of the ACVRL1 gene. Further studies and larger sample sizes are required to confirm these findings. [ABSTRACT FROM AUTHOR]

Keywords: BRCA1/2; founder mutation; HBOC; novel mutations EN BRCA1/2 founder mutation HBOC novel mutations e95 e98 4 02/06/21 20210301 NES 210301 To the Editor, Inherited pathogenic variants (PVs) in cancer susceptibility genes account for approximately 5%-10% of all breast (BC) and ovarian cancers (OvCa), with a large proportion of mutations found in families with several affected patients over multiple generations [[1]], [[2]], [[3]]. Graph: Figure 1: Family pedigree by cancer gene software BRCAPRO v6.The proband is indicated with an arrow. [Extracted from the article]

Lynch syndrome (LS) is an autosomal dominant condition caused by pathogenic variants in mismatch repair (MMR) genes that predispose individuals to different malignancies, such as colorectal cancer (CRC) and endometrial cancer. Current guidelines recommended testing for LS in individuals with newly diagnosed CRC to reduce cancer morbidity and mortality in relatives. Economic evaluations in support of such approach, however, are not available in Italy. We developed a decision-analytic model to analyze the cost-effectiveness of LS screening from the perspective of the Italian National Health System. Three testing strategies: the sequencing of all MMR genes without prior tumor analysis (Strategy 1), a sequential IHC and MS-MLPA analysis (Strategy 2), and an age-targeted strategy with a revised Bethesda criteria assessment before IHC and methylation-specific MLPA for patients ≥ than 70 years old (Strategy 3) were analyzed and compared to the "no testing" strategy. Quality Adjusted Life Years (QALYs) in relatives after colonoscopy, aspirin prophylaxis and an intensive gynecological surveillance were estimated through a Markov model. Assuming a CRC incidence rate of 0.09% and a share of patients affected by LS equal to 2.81%, the number of detected pathogenic variants among CRC cases ranges, in a given year, between 910 and 1167 depending on the testing strategy employed. The testing strategies investigated, provided one-time to the entire eligible population (CRC patients), were associated with an overall cost ranging between €1,753,059.93-€10,388,000.00. The incremental cost-effectiveness ratios of the Markov model ranged from €941.24 /QALY to €1,681.93 /QALY, thus supporting that "universal testing" versus "no testing" is cost-effective, but not necessarily in comparison with age-targeted strategies. This is the first economic evaluation on different testing strategies for LS in Italy. The results might support the introduction of cost-effective recommendations for LS screening in Italy. [ABSTRACT FROM AUTHOR]

Muir–Torre syndrome (MTS) is clinically characterized by the occurrence of skin, usually sebaceous, and visceral tumors in the same individual. The most common underlying mechanism is a constitutional defect of the mismatch repair (MMR) genes that cause Lynch syndrome (LS). Herewithin we report on a 76 years-old male patient heterozygous for a pathogenic MSH2 missense substitution who presented with a striking cutaneous phenotype in the absence of typical LS visceral tumors. The patient developed 20 skin tumors, including sebaceous adenomas/carcinomas and keratoacanthomas. Two skin tumors showed immunohistochemical loss of MSH2 and MSH6 expression. There was no apparent family history of neoplasia. Based on the variable involvement of the skin and internal organs, we suggest that the definition of tumor associations that are often observed as variants of inherited tumor syndromes, such as MTS, should be guided by the underlying molecular bases. In addition, the presence of multiple sebaceous tumors, especially if showing MMR deficiency, appears to be a very strong indicator of a constitutional MMR gene defect. The reasons underlying the high phenotypic variability of cutaneous phenotypes associated with constitutional MMR defects are yet to be determined. [ABSTRACT FROM AUTHOR]

Purpose. Desmoid-type fibromatosis is a benign fibrous neoplasia originating from connective tissue, fascial planes, and musculoaponeurotic structures of the muscles. Currently, there is no evidence-based treatment approach available for desmoid fibromatosis. In this article, a case of a patient in the pediatric age affected by desmoid fibromatosis localized in the orbit is presented. The aim of the article is to describe this unusual and rare location for the desmoid fibromatosis and outline the principle phases in the decision-making process and the therapeutic alternatives for a patient affected by desmoid fibromatosis. Methods. The protocol of this review included study objectives, search strategy, and selection criteria. The primary end point of this study was to analyze the head and neck desmoid fibromatosis. The secondary end point was to identify the available therapies and assess their specific indications. Results. The mean age of patients was 18.9 years ranging from 0 to 66, and 52% were female. A bimodal age distribution was observed, and two age peaks were identified: 0–14 years (57%) and 28–42 years (18%). The most common involved areas were the mandible (25%) followed by the neck (21%). In 86% of the cases, the treatment was the surgical resection of the disease, and only in 5% of the cases, the surgical resection was followed by adjuvant radiotherapy. Conclusion. The orbital location is extremely rare, especially in the pediatric population. The management of desmoid fibromatosis is based on the function preservation and the maintenance of a good quality of life, but in case of symptomatic patients or aggressive course of the disease or risk of functional damages, the surgical approach may be considered. Therapeutic alternatives to surgical resection are radiotherapy and systemic therapy. [ABSTRACT FROM AUTHOR]

Familial adenomatous polyposis has been the first form of inherited intestinal polyposis to be recognized. For a long time it has been considered the main polyposis syndrome, associated with an easily recognizable phenotype, with a marginal role attributed to a few very rare hamartomatous conditions. More recently, it has been gradually demonstrated that the intestinal polyposes encompass a range of conditions within a wide spectrum of disease severity, polyp histology, and extraintestinal manifestations. A growing number of genes and phenotypes has been identified, and heterogeneity of somatic molecular pathways underlying epithelial transformation in different syndromes and associated tumors has been documented. Increasing knowledge on the molecular bases and more widespread use of genetic tests has shown phenotypic overlaps between conditions that were previously considered distinct, highlighting diagnostic difficulties. With the advent of next generation sequencing, the diagnosis and the classification of these syndromes will be progressively based more on genetic testing results. However, the phenotypic variability documented among patients with mutations in the same genes cannot be fully explained by different expressivity, indicating a role for as yet unknown modifying factors. Until the latter will be identified, the management of patients with polyposis syndromes should be guided by both clinical and genetic findings. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Anterior pituitary aplasia (APA) is a very rare cause of congenital-onset multiple pituitary hormone deficiency (CO-MPHD). We report on molecular analysis and clinical follow-up of three previously reported cases of APA [Scommegna et al., 2004], who share a characteristic physical and neuropsychological profile. Mutation analysis of genes encoding transcription factors involved in pituitary development ( PROP1, POUF1, HESX1, LHX3, and LHX4) did not demonstrate a any mutation. In order to identify the genetic cause underlying the phenotypes we performed an array-based comparative genomic hybridization (array-CGH), which showed a cryptic interstitial deletion of 9p (200 kb), including the TEK and MOBKL2B, in one patient. Although an apparently identical deletion was carried by the clinically normal father, we assumed that the patient's phenotype might be due to a recessive mutation in the other allele. However, sequence analysis of exons and splice junctions of these genes did not detect pathogenic or predisposing variants in the three patients. We suggest that the constellation of clinical signs in these patients constitutes a previously undescribed syndrome, whose genetic cause has yet to be identified. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Head and neck paragangliomas (HNPGLs) are neural crest-derived tumors. In comparison with paragangliomas located in the abdomen and the chest, which are generally catecholamine secreting (sPGLs) and sympathetic in origin, HNPGLs are, in fact, parasympathetic in origin and are generally nonsecreting. Overall, 79 consecutive patients with HNPGL were examined for mutations in SDHA, SDHB, SDHC, SDHD, SDHAF2, VHL, MAX, and TMEM127 genes by PCR/sequencing. According to a detailed family history (FH) and clinical, laboratory (including metanephrines), and instrumental examinations, patients were divided into three groups: a) patients with a positive FH for HNPGL (index cases only), b) patients with a negative FH and multiple HNPGLs (synchronous or metachronous) or HNPGL associated with an sPGL, and c) patients with negative FH and single HNPGL. The ten patients in group a) proved to be SDHD mutation carriers. The 16 patients in group b) proved to be SDHD mutation carriers. Among the 53 patients in group c), ten presented with germ-line mutations (three SDHB, three SDHD, two VHL, and two SDHAF2). An sPGL was found at diagnosis or followed up in five patients (6.3%), all were SDHD mutation carriers. No SDHC, SDHA, MAX, and TMEM127 mutations were found. In SDHD mutation carriers, none of the patients affected by HNPGL associated with sPGL presented missense mutations. In conclusion, a positive FH or the presence of multiple HNPGLs is a strong predictor for germ-line mutations, which are also present in 18.8% of patients carefully classified as sporadic. The most frequently mutated gene so far is SDHD but others, including SDHB, SDHAF2, and VHL, may also be affected. [ABSTRACT FROM AUTHOR]

Objective. A unique mutation of the MLH1 gene was recently reported in six families living in a small area of Northern Italy. The mutation consists in the insertion of a T base between nucleotides 2269 and 2270 (2269-2270insT), causing the synthesis of an unstable polypeptide. The mutation was not reported by other investigators or outside this small geographic area, thus suggesting a possible founder effect. The main purpose of this investigation was to investigate whether patients (and families) with the 2260-2270insT mutation show relevant clinical differences when compared with individuals with other MLH1 or MSH2 gene alterations. Material and methods. We identified hereditary non-polyposis colorectal cancer (HNPCC) families through the specialized colorectal cancer registry following a previously described multistep approach. In all, 58 HNPCC families were identified; of these, 38 were detected through the registry, and 20 were referred from other areas in Italy. Results. Small differences were found in the main clinical and pathologic features; however, tumour burden per family tended to be higher in kindred sharing the founder mutation; in addition, multiple primaries (four or five different tumours in some subjects) were significantly more frequent in patients with the 2269-2270insT than in individuals with MSH2, MLH1 gene mutations or sporadic colorectal neoplasms. No significant difference in prognosis was found between patients with the founder mutation and those with other MLH1 or MSH2 mutations. Regardless of the type of mutation, neoplasms of the colon-rectum, stomach and endometrium represented nearly 80% of the tumour burden in families with HNPCC. Conclusions. A proclivity to multiple tumours arising in the same subject and a higher tumour burden per family were the most relevant findings observed in affected patients with the founder mutation compared with other MLH1 or MSH2 mutations. In general, the results of the study underline the difficulty in discriminating between Lynch I and Lynch II syndromes on the basis of specific molecular changes. [ABSTRACT FROM AUTHOR]

The International Registry of Werner syndrome () has been providing molecular diagnosis of the Werner syndrome (WS) for the past decade. The present communication summarizes, from among 99 WS subjects, the spectrum of 50 distinct mutations discovered by our group and by others since the WRN gene (also called RECQL2 or REQ3) was first cloned in 1996; 25 of these have not previously been published. All WRN mutations reported thus far have resulted in the elimination of the nuclear localization signal at the C-terminus of the protein, precluding functional interactions in the nucleus; thus, all could be classified as null mutations. We now report two new mutations in the N-terminus that result in instability of the WRN protein. Clinical data confirm that the most penetrant phenotype is bilateral ocular cataracts. Other cardinal signs were seen in more than 95% of the cases. The median age of death, previously reported to be in the range of 46-48 years, is 54 years. Lymphoblastoid cell lines (LCLs) have been cryopreserved from the majority of our index cases, including material from nuclear pedigrees. These, as well as inducible and complemented hTERT (catalytic subunit of human telomerase) immortalized skin fibroblast cell lines are available to qualified investigators. Hum Mutat 27(6), 558-567, 2006. Published 2006 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Missense changes constitute approximately 1/3 and 1/5 of all rare sequence constitutional variations identified in the MLH1 and MSH2 genes by mutation screening. They represent a challenge for the clinician and for the genetic counselor, who often cannot use them for the management of Lynch syndrome families. Several parameters can be evaluated to gain insight into the significance of such unclassified variants (UVs). These include analysis of microsatellite instability (MSI), immunohistochemistry of mismatch repair (MMR) proteins, segregation data, frequency of the variants in control samples, presence of other pathogenic mutations, and functional and mRNA analyses. While none of these variables can be used alone to predict the significance of UVs in a single case, combined evaluation can lead to clinically useful conclusions. This review reports available information on a sample of MLH1 and MSH2 missense UVs, for which MSI and immunohistochemical data could be retrieved from the literature. Currently, since MSI analysis is routinely performed as a diagnostic test for Lynch syndrome, tumor MSI status represents the most important factor for determining the pathogenicity of UVs in MMR genes. [ABSTRACT FROM AUTHOR]

Mutations of the mismatch repair (MMR) genes MLH1 and MSH2 are associated with hereditary nonpolyposis colorectal cancer (HNPCC), a highly penetrant autosomal dominant condition characterized by hypermutability of short tandemly repeated sequences in tumor DNA. Mutations of another MMR gene, MSH6, seem to be less common than MLH1 and MSH2 defects, and have been mostly observed in atypical HNPCC families, characterized by a weaker tumor family history, higher age at disease onset, and low degrees of microsatellite instability (MSI), predominantly involving mononucleotide runs. We have investigated the MSH6 gene sequence in the peripheral blood of 4 HNPCC and 20 atypical HNPCC probands. Two frameshift mutations within exon 4 were detected in 2 patients. One mutation was found in a proband from a typical HNPCC family, who had developed a colorectal cancer (CRC), a gastric cancer and a rectal adenoma. The CRC and the adenoma showed mild MSI limited to mononucleotide tracts, while the gastric carcinoma was microsatellite stable. The other mutation was detected in an atypical HNPCC proband, whose CRC showed widespread MSI involving both mono- and dinucleotide repeats. The phenotypic variability associated with MSH6 constitutional mutations represents a complicating factor for the optimization of strategies aimed at identifying candidates to MSH6 genetic testing. [ABSTRACT FROM AUTHOR]