Genotypic and Phenotypic Characteristics of Hereditary Colorectal Cancer

The genomic causes and clinical manifestations of hereditary colorectal cancer (HCRC) might be stratified into 2 groups, namely, familial (FCRC) and a limited sense of HCRC, respectively. Otherwise, FCRC is canonically classified into 2 major categories; Lynch syndrome (LS) or associated spectra and inherited polyposis syndrome. By contrast, despite an increasing body of genotypic and phenotypic traits, some FCRC cannot be clearly differentiated as definitively single type, and the situation has become more complex as additional causative genes have been discovered. This review provides an overview of HCRC, including 6 LS or associated spectra and 8 inherited polyposis syndromes, according to molecular pathogenesis. Variants and newly-identified FCRC are particularly emphasized, including MUTYH (or MYH)-associated polyposis, Muir-Torre syndrome, constitutional mismatch repair deficiency, EPCAM-associated LS, polymerase proofreading-associated polyposis, RNF43- or NTHL1-associated serrated polyposis syndrome, PTEN hamartoma tumor syndrome, and hereditary mixed polyposis syndrome. We also comment on the clinical utility of multigene panel tests, focusing on comprehensive cancer panels that include HCRC. Finally, HCRC surveillance strategies are recommended, based on revised or notable concepts underpinned by competent validation and clinical implications, and favoring major guidelines. As hereditary syndromes are mainly attributable to genomic constitutions of distinctive ancestral groups, an integrative national HCRC registry and guideline is an urgent priority.

What Are the Place and Modalities of Surgical Management for Pancreatic Neuroendocrine Neoplasms? A Narrative Review

Pancreatic neuroendocrine neoplasms (panNENs) are a heterogeneous group of tumors derived from cells with neuroendocrine differentiation. They are considered malignant by default. However, their outcomes are variable depending on their presentation in the onset of hereditary syndromes, hormonal secretion, grading, and extension. Therefore, although surgical treatment has long been suggested as the only treatment of pancreatic neuroendocrine neoplasms, its modalities are an evolving landscape. For selected patients (small, localized, non-functional panNENs), a “wait and see” strategy is suggested, as it is in the setting of multiple neuroendocrine neoplasia type 1, but the accurate size cut-off remains to be established. Parenchyma-sparring pancreatectomy, aiming to limit pancreatic insufficiency, are also emerging procedures, which place beyond the treatment of insulinomas and small non-functional panNENs (in association with lymph node picking) remains to be clarified. Furthermore, giving the fact that the liver is generally the only metastatic site, surgery keeps a place of choice alongside medical therapies in the treatment of metastatic disease, but its modalities and extensions are still a matter of debate. This narrative review aims to describe the current recommended surgical management for pancreatic NENs and controversies in light of the actual recommendations and recent literature.

The Second Allele: A Key to Understanding the Timing of Sporadic and Hereditary Colorectal Tumorigenesis

Our understanding of the molecular basis of colorectal neoplasia is derived from Mendelian genetics, with tumor suppressor genes contributing more to the deregulation of growth than oncogenes. In patients with hereditary syndromes, expression of one allele of a key tumor suppressor gene is absent at birth. The loss of the expression of the second allele precipitates tumorigenesis. However, there are multiple ways in which the expression of the second allele of a tumor suppressor gene is lost. Here, we review these ways and their possible effect on phenotype.

Ontology of Variants of the Structure and Malformations of the Skull. Part II. Hereditary Syndromes

Congenital abnormalities occur in 2-3% of all children and about 1% have hereditary syndromes or multiple malformations. About 30% of all cases have a cleft lip or palate. Genetic factors such as chromosomal abnormalities and gene mutations cause about 15% of congenital abnormalities; exogenous environmental factors cause about 10% of defects; a combination of genetic and environmental factors (multifactorial inheritance) cause 20-25%; multiple pregnancy causes 0.5-1% of congenital abnormalities. Craniofacial anomalies represent an important pediatric problem. They are among the leading causes of infant mortality and morbidity. Craniofacial anomalies mainly affect the development of the skull and facial bones. These defects range from mild to severe, which can be life-threatening and require immediate surgical intervention. Examination of patients with congenital cranial pathology is of particular importance, since a correct diagnosis can often be established only by taking into consideration all stigmas and malformations. The onset of pathology occurs during ontogenesis: normal embryonic development is disturbed under the influence of exogenous and endogenous factors, to which the body is particularly sensitive during critical periods. The consequences of various endogenous and exogenous factors are disruption of growth and development of the organism and occurrence of congenital malformations as an independent unit or occurrence of hereditary syndromes as a set of certain symptoms. Craniofacial syndromes can be divided into several groups. They are most often accompanied by premature fusion of cranial sutures (craniosynostosis) and syndromes with cleft formation. The most frequent syndromes in this group are: Crouzon syndrome, suture synostosis, microsomia, cerebral anomalies and midface clefts. These developmental disorders can lead to a variety of health consequences, namely affecting these patients’ respiratory health, appearance, brain development, hearing, vision, bite, speech, and mental development. Congenital malformations of the skull bones can be related to genetic mutations and environmental factors. Conclusion. Based on the analysis of the literature, a brief clinical characterization of the most common hereditary syndromes accompanied by cerebral and facial skull deformities is given, the type of inheritance and the gene mutation that causes these disorders are indicated

Hair: more than just an appendage

<p class="abstract">Hypotrichosis is a relatively common feature of a number of complex hereditary syndromes. However, the isolated variant, called hereditary hypotrichosis simplex (HHS), is uncommon. We present a 4 years old child and his father who presented to us with features suggestive of HHS. No other associated ectodermal and systemic abnormalities were noted.</p>

A Direct Comparison of Patients With Hereditary and Sporadic Pancreatic Neuroendocrine Tumors: Evaluation of Clinical Course, Prognostic Factors and Genotype–Phenotype Correlations

IntroductionPancreatic neuroendocrine tumors (PNETs) in hereditary syndromes pose a significant challenge to clinicians. The rarity of these syndromes and PNETs itself make it difficult to directly compare them with sporadic PNETs. Despite research suggesting differences between these two entities, the same approach is used in hereditary and sporadic PNETs.MethodsWe included 63 patients with hereditary PNET (GpNET) and 145 with sporadic PNET (SpNET) in a retrospective observational study. Clinical and genetic data were collected in two Polish endocrine departments from January 2004 to February 2020. Only patients with confirmed germline mutations were included in the GpNET cohort. We attempted to establish prognostic factors of metastases and overall survival in both groups and genotype–phenotype correlations in the GpNET group.ResultsPatients with GpNET were younger and diagnosed earlier, whereas their tumors were smaller and more frequently multifocal compared with patients with SpNET. Metastases occurred more frequently in the SpNET group, and their appearance was associated with tumor size in both groups. GpNET patients had longer overall survival (OS). OS was affected by age, age at diagnosis, sex, grade, stage, tumor diameter, occurrence and localization of metastases, type of treatment, and comorbidities. In the MEN1 group, carriers of frameshift with STOP codon, splice site, and missense mutations tended to have less advanced disease, while patients with mutations in exon 2 tended to have metastases more frequently.ConclusionsDirect comparisons of GpNET and SpNET demonstrate significant differences in the clinical courses of both entities, which should force different approaches. A larger group of patients with GpNET should be assessed to confirm genotype–phenotype correlations.

Genetic aspects of Ebstein anomaly and related heart diseases

Ebstein anomaly is a congenital heart disease, which is characterized by the presence of atrialized portion of the right ventricle, formed as a result of displacement of the tricuspid valve leaflets into the right ventricle and their partial adherence to the underlying myocardium. Atrialized portion in the right ventricle occupies the space between the fibrous annulus of the right atrioventricular orifice and the functional annulus of tricuspid valve, which represents a zone of closure of free (non-adherent to the underlying myocardium) edges of its leaflets. Ebstein anomaly is very rarely isolated, and can be combined with a number of heart diseases and be an integral part of hereditary syndromes. Currently, the role of genetic research in the investigation of the etiology of human diseases as well as understanding of the relationship between different diseases is increasing. The review presents literature data on the combination of Ebstein anomaly with other heart diseases (congenital heart diseases, Wolf-Parkinson-White syndrome, cardiomyopathies, including left ventricular noncompaction), inter alia, within the scope of hereditary syndromes (Noonan syndrome, 8p deletion syndrome, 18q deletion syndrome, 1p36 deletion syndrome, Pierre Robin syndrome). Genetic factors (gene and chromosomal mutations) lying at the core of Ebstein anomaly, as well as heart diseases combined with it, are highlighted. The analysis of published data suggests that Ebstein anomaly is a monogenic disease, and is characterized by allelic and locus genetic heterogeneity. The combination of Ebstein anomaly with other heart diseases is based on their genetic linkage.

Malignant Phyllodes Tumor of the Breast: A Practice Review

Introduction: Phyllodes tumor (PT) of the breast, particularly malignant phyllodes tumor (mPT), is a rare fibroepithelial neoplasm. A complex diagnosis is based on pathologic, radiologic, and clinical findings, with controversies about what is the best therapeutic strategy. Objective: Our objective was to provide an overview of the clinical, pathologic, and therapeutic aspects of this rare tumor. Conclusions: mPT is a rare presentation of breast cancer and a challenge in clinical practice. A multidisciplinary approach should take into account some aspects like pathogenic mutations and hereditary syndromes. Oncologic surgery is the fundamental approach, and the use of adjuvant therapies is still controversial due to the lack of clinical trials. Treatment recommendations should be individualized according to patient risk and preferences. Prospective studies are fundamental to clarifying the best treatment for these tumors.