The Aggressive Diabetic Kidney Disease in Youth-Onset Type 2 Diabetes: Pathogenetic Mechanisms and Potential Therapies

Youth-onset Type 2 Diabetes Mellitus (T2DM) represents a major burden worldwide. In the last decades, the prevalence of T2DM became higher than that of Type 1 Diabetes Mellitus (T1DM), helped by the increasing rate of childhood obesity. The highest prevalence rates of youth-onset T2DM are recorded in China (520 cases/100,000) and in the United States (212 cases/100,000), and the numbers are still increasing. T2DM young people present a strong hereditary component, often unmasked by social and environmental risk factors. These patients are affected by multiple coexisting risk factors, including obesity, hyperglycemia, dyslipidemia, insulin resistance, hypertension, and inflammation. Juvenile T2DM nephropathy occurs earlier in life compared to T1DM-related nephropathy in children or T2DM-related nephropathy in adult. Diabetic kidney disease (DKD) is T2DM major long term microvascular complication. This review summarizes the main mechanisms involved in the pathogenesis of the DKD in young population and the recent evolution of treatment, in order to reduce the risk of DKD progression.

Angiomyolipoma with Intraluminal Tumor Thrombus into the Inferior Vena Cava: Insights and Treatment Alternatives

Angiomyolipoma (AML) is a frequent benign renal tumor, corresponding to 0.3-3% of all renal masses. Eighty percent of AML occur sporadically; however, 10% have a hereditary component. We describe the case of a 41-year-old female patient with left abdominal pain associated with emesis, diarrheal stools, and dysuria. Upon admission, a computed tomography scan showed a left renal mass with tumor thrombus extending into the left renal vein and inferior vena cava (IVC). The patient underwent an open left radical nephrectomy plus thrombectomy. At 6months of follow-up, the patient is without tumor recurrence and asymptomatic.

Cancer Susceptibility Mutations in Patients With Urothelial Malignancies

PURPOSE Urothelial cancers (UCs) have a substantial hereditary component, but, other than their association with Lynch syndrome, the contribution of genetic risk factors to UC pathogenesis has not been systematically defined. We sought to determine the prevalence of pathogenic/likely pathogenic (P/LP) germline variants in patients with UC and identify associated clinical factors. PATIENTS AND METHODS Overall, 586 patients with UC underwent prospective, matched tumor-normal DNA sequencing. Seventy-seven genes associated with cancer predisposition were analyzed; allele frequencies were compared with publicly available database. RESULTS P/LP germline variants were identified in 80 (14%) of 586 individuals with UC. The most common P/LP variants in high- or moderate-penetrance genes were BRCA2 (n = 9; 1.5%), MSH2 (n = 8; 1.4%), BRCA1 (n = 8; 1.4%), CHEK2 (n = 6; 1.0%), ERCC3 (n = 4; 0.7%), and NBN and RAD50 (n = 3; 0.5% each). Sixty-six patients (83%) had germline P/LP variants in DNA-damage repair (DDR) genes, of which 28 (42%) had biallelic inactivation. Patients with P/LP variants were more commonly diagnosed at an early age (22% v 6% in those without variants; P = .01). BRCA2 and MSH2 were significantly associated with an increased risk for UC (odds ratio, 3.7 [ P = .004] and 4.6 [ P = .001], respectively). Current clinical guidelines for referral for genetic testing failed to identify 6 (26%) patients with high-penetrance variants. CONCLUSION Clinically significant P/LP germline variants in DDR genes frequently are present in patients with advanced UC. The presence of DDR germline variants could guide cancer screening for patients and their families and serve as predictive biomarkers of response to targeted or immunotherapies. Family history–based criteria to identify patients with hereditary UC susceptibility are insensitive. Broader germline testing in UC, particularly in those of young ages, should be considered.

Recurrent melanoma development in a Caucasian female with CDKN2A+ mutation and FAMMM syndrome: A case report

Melanoma is a form of skin cancer originating from melanocytes that has an increasing incidence over the past few decades. From 1992 to 2010, the overall incidence of melanoma was 12.29 cases per 100,000 person-years in Canada. Approximately 10% of cases are attributed to a hereditary component, with one of the most common being familial atypical multiple mole melanoma syndrome. In this case report, we highlight the atypical case of a middle-aged Caucasian female with familial atypical multiple mole melanoma syndrome, who has developed dozens of primary melanomas over the past decade. We highlight the management of her case, as well as the importance of monitoring by multiple other subspecialists given the propensity for the development of alternate malignancies.

A novel ribosomal protein S20 variant in a family with unexplained colorectal cancer and polyposis

ABSTRACTColorectal cancer (CRC) has a large hereditary component, which is only partially explained by known genetic causes. Recently, variants in ribosomal protein S20 (RPS20, [OMIM: 603682]) were identified in a family with familial CRC type X and in a CRC cancer case-control screen. This study describes a novel splice donor variant in RPS20, NM_001023.3:c.177+1G>A. It segregates with CRC [OMIM: 114500] and polyposis [HP: 0200063] within the proband’s family. Reverse transcription-polymerase chain reaction (RT-PCR) confirms the variant results in two aberrantly-spliced transcripts that are absent in controls. The location of the novel RPS20 variant is near two previously-reported truncating RPS20 variants associated with CRC. DNA from colon adenocarcinoma showed no evidence of loss-of-heterozygosity, supporting a haploinsufficiency or dominant negative disease mechanism. These findings support designation of RPS20 as a CRC predisposition gene, and expand the phenotypic spectrum of RPS20 truncating variants to include polyposis.

Associative connection of molecular genetic and biochemical markers with the character of chronic fl uoride intoxication in aluminum industry workers

Introduction.Th e aluminum industry belongs to the industry with a high status of occupational pathology. The study of metabolic bases and hygienic aspects of fl uorosis is a priority section of modern occupational health. Organ failure occurs in a separate group of workers, despite the equivalent conditions of production and may be due to biochemical polymorphism.The aimof the study was to explore the associative relationship of molecular genetic, biochemical markers with the nature of chronic fl uoride intoxication in workers of the aluminum industry.Materials and methods. Th e complex of clinical and genetic parameters of workers of Novokuznetsk aluminum plant with the determination of the content of harmful impurities in the air of the working areas was evaluated. Statistical analysis was carried out using IBM SPSS Statistics 22.Results. Over 25 years of observation, the maximum risk of intoxication was observed in the workplaces of electrolyzers, anodes against the background of metabolic disorders. Th e associative relationship of CYP, GST, SOD genes with the nature of fl uoride intoxication was determined.Conclusions.Th e development of fl uorosis is predetermined by the hereditary component. Markers associated with the dynamics of metabolic maladaptation allow to predict the course of the disease.

The Role of Genetic Polymorphism in the Formation of Arterial Hypertension, Type 2 Diabetes and their Comorbidity

Background: Hereditary component plays a significant role in the formation of insulin resistance (IR) - one of the pathogenetic links of arterial hypertension (AH) and type 2 diabetes mellitus (DM2). However, the genetic predisposition to IR can not be realized and does not manifest itself clinically in the absence of appropriate factors of the environment (excessive nutrition, low physical activity, etc.). Objective: The review summarizes the results of studies which describe the contribution of genetic polymorphism to the formation and progression of AH, DM2 and their comorbidity in various populations. Results: In many studies, it has been established that genetic polymorphism of candidate genes is influenced by the formation, course and complication of AH and DM2. According to research data, the modulating effect of polymorphism of some genetic markers of AH and DM2 on metabolism and hemodynamics has been established. The results of numerous studies have shown a higher frequency of occurrence of AH and DM2, as well as their more severe course with adverse genetic polymorphisms. At the same time, the role of genetic polymorphism in the formation of AH and DM2 differs in different populations. Conclusion: Contradictory data on the influence of gene polymorphisms on the formation of AH and DM2 in different populations, as well as a small number of studies on the combined effects of several polymorphisms on the formation of comorbidity, determine the continuation of research in this direction.

DIAGNOSIS AND MANAGEMENT OF PAGET'S DISEASE OF BONE - SERIES OF 8 CASES

ABSTRACT Paget's disease of bone is a chronic condition characterized by focal abnormalities of absorption and formation of bone, and it may lead to anatomical deformities, pain, fractures, and malignant transformation. It is common in the UK, Australia, New Zealand, and North America and has a strong hereditary component, affecting first- to third-degree relatives. The etiology remains unclear and treatment is based on control of the disease with bisphosphonates, with the aim of relieving symptoms and correcting laboratory abnormalities. Surgical treatment may also be necessary to correct deformities or treat pathological fractures. This study evaluated the management and course of 8 patients with Paget's disease of bone, followed in the Orthopedic Clinic of this hospital. Among these patients, 1 had concomitant advanced prostate carcinoma, highlighting the association between Paget's disease and secondary bone diseases that can affect the differential diagnosis. Level of evidence IV, Study type: Case Series.

Genetic Testing Practices of Genetic Counselors, Geneticists, and Pediatric Neurologists With Regard to Childhood-Onset Neurogenetic Conditions

Identifying genetic diagnoses for neurologic conditions with a considerable hereditary component, such as autism spectrum disorder, intellectual disability, and epilepsy, is critical to providing proper medical management for patients and their families. However, many patients with these conditions are not tested appropriately or receive no genetic testing at all. The current study was designed to characterize the genetic testing practices of the providers most likely to evaluate or order genetic testing for these patients: pediatric neurologists, geneticists, and genetic counselors. Significant variance was present between testing strategies selected by pediatric neurologists and those by geneticists and genetic counselors, supporting the need for updated genetic testing guidelines that are consistent across specialties. Pediatric neurologists also report lower confidence in ordering genetic testing and desire further education regarding genetic testing. Together, these results propose that continued integration of genetics providers, such as genetic counselors, into pediatric neurology clinics may improve utilization of genetic testing while reducing the burden on pediatric neurologists.