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Abstract Cancer predisposition syndromes are recognized in about 10% of pediatric malignancies with several genes specifically involved in a subset of pediatric tumors such as DICER1, in pleuropulmonary blastoma, cystic nephroma, and brain sarcomas. By contrast, the role of BRCA1/2 in pediatric cancer predisposition is still under investigation. We present two cases of young first-degree cousins, both carrying a germline BRCA2 variant and developing tumors characterized by somatic DICER1 mutations. Patient 1 presented with a cystic nephroma harboring a somatic DICER1 variant (p.Asp1810Tyr), while patient 2 had a primary intracranial DICER1-mutated sarcoma showing a distinct somatic DICER1 variant (p.Asp1709Glu) as well as biallelic inactivation of TP53 (p.Val173Leu, VAF 91%) and APC (p.Ile1307Lys, VAF 95%) and a pathogenic variant in KRAS (p.Gln61His). Both patients carried the same germline BRCA2 variant (p.Arg2842Cys) of unknown significance. The same variant was found in the mother of patient 2 and in the father of patient 1, who are siblings. A homologous recombination deficiency signature was not identified in any of the two tumors, possibly suggesting a reduction of BRCA2 activity. The association of BRCA2 and DICER1 variants in our cases hints at a potential cooperative role in cancer pathogenesis. Further studies are warranted to elucidate the interplay between BRCA1/2 and DICER1 variants and their implications for cancer predisposition and treatment in pediatric patients.

IntroductionCACNA1A-related Hemiplegic Migraine (HM) is a rare neurological disorder distinguished by paroxysmal episodes of hemiparesis/hemiplegia with and without headache. Clinical features have been widely characterized, yet the impacts of the paroxysmal events on the patient and caregiver have not been thoroughly explored. Disease concept models are formal frameworks used to describe the lived experiences of patients and their families, offering a source for surrogate endpoints for clinical trials.MethodsWe completed 13 semi-structured interviews with caregivers of 12 individuals diagnosed with CACNA1A-related HM. We methodically coded themes, grouping concepts into three domains. We measured the occurrence of concepts throughout all interviews and subgroups stratified by age categories.ResultsOver 11 h of interviews yielded 2,018 references to 27 distinct concepts. Established symptoms such as seizures (87 references; including status epilepticus 27 references), hemiparesis/hemiplegia (24 references), and unconsciousness (17 references) were referenced, as well as previously underreported symptoms such as apneic episodes (32 references), lost ability to eat (13 references), and vascular access challenges (10 references). The symptom impacts were largely medical (294 references), followed by health (101 references), emotional (36 references), daily living (28 references), and social (26 references). Caregiver impacts were the most referenced domain (995 references), with the pivotal effects seen in caregiver requirements (355 references), emotional (245 references), HM treatments (179 references), daily living (148 references), and health support (135 references).DiscussionCACNA1A-related HM is a complex disorder defined by serious paroxysmal events that affects a broad range of social and clinical domains. We systematically classified symptoms and impacts from HM episodes, creating a disease concept model to help develop surrogate endpoints for future clinical trials, and identified two opportunities to improve patient management, including a written emergency protocol and a transition plan for adolescents approaching adulthood.

Abstract Background Anorexia nervosa has one of the highest mortality rates of all mental illnesses. For those who survive, less than 70% fully recover, with many going on to develop a more severe and enduring phenotype. Research now suggests that genetics plays a role in the development and persistence of anorexia nervosa. Inclusion of participants with more severe and enduring illness in genetics studies of anorexia nervosa is critical. Objective The primary goal of this review was to assess the inclusion of participants meeting the criteria for the severe enduring anorexia nervosa phenotype in genetics research by (1) identifying the most widely used defining criteria for severe enduring anorexia nervosa and (2) performing a review of the genetics literature to assess the inclusion of participants meeting the identified criteria. Methods Searches of the genetics literature from 2012 to 2023 were performed in the PubMed, PsycINFO, and Web of Science databases. Publications were selected per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR). The criteria used to define the severe and enduring anorexia nervosa phenotype were derived by how often they were used in the literature since 2017. The publications identified through the literature search were then assessed for inclusion of participants meeting these criteria. Results most prevalent criteria used to define severe enduring anorexia nervosa in the literature were an illness duration of ≥ 7 years, lack of positive response to at least two previous evidence-based treatments, a body mass index meeting the Diagnostic and Statistical Manual of Mental Disorders-5 for extreme anorexia nervosa, and an assessment of psychological and/or behavioral severity indicating a significant impact on quality of life. There was a lack of consistent identification and inclusion of those meeting the criteria for severe enduring anorexia nervosa in the genetics literature. Discussion This lack of consistent identification and inclusion of patients with severe enduring anorexia nervosa in genetics research has the potential to hamper the isolation of risk loci and the development of new, more effective treatment options for patients with anorexia nervosa.

Background:. Hidradenitis suppurativa (HS) is a chronic inflammatory disease characterized by deep-seated, painful lesions most frequently occurring in intertriginous areas of the skin. HS leads to poor quality of life in affected individuals and is difficult to diagnose and treat. Objective:. Understanding the genetics associated with familial inheritance may lead to a better understanding of the pathogenesis of this debilitating disease. Methods:. Articles published until March 9, 2023, were identified in PubMed using the following search terms: hidradenitis suppurativa and gene* or acne inversa and gene*. Results:. The rate of monogenic mutations associated with HS is less than 7%, with the most common genetic mutations reported in sporadic and familial HS cases being in NCSTN and less frequently in PSENEN. Individuals with mutations in the gamma-secretase complex tended to have more severe HS and an early age of onset. Limitations:. This study was limited to the case studies available in PubMed, the majority of which used targeted gene panels to detect genetic mutations. Conclusion:. Approximately 30% of individuals diagnosed with HS report having a positive family history; however, very few studies demonstrate monogenic familial transmission of HS. The case studies of syndromic HS reported a variety of genetic mutations associated with HS, some of which were familial, while others were sporadic, suggesting that other pathways may be involved in the pathogenesis of HS and other potential mutations that have yet to be evaluated. More research is needed to understand the genetic mutations in HS.

Background: Inflammatory bowel disease (IBD) is characterized by persistent inflammation and is often associated with metabolic dysfunction-associated steatotic liver disease (MASLD). IBD patients are at risk of developing MASLD due to shared risk factors such as gut dysbiosis and systemic inflammation. The new MASLD nomenclature emphasizes the link between liver steatosis and cardiometabolic comorbidities. However, the prevalence of MASLD in IBD patients remains poorly explored. The main aim of this cross-sectional study is to assess the prevalence of ultrasound (US) and the clinical features of MASLD in patients with IBDs. Materials and Methods: We conducted a retrospective study enrolling 272 Italian IBD patients attending Renato Dulbecco Teaching Hospital in a period between 1 January 2021 and 31 December 2023. MASLD was diagnosed based on the presence of liver steatosis with cardiometabolic risk factors, using established guidelines. Demographic, clinical, and laboratory data were collected and analyzed. Statistical significance was determined at a p-value < 0.05. Results: Of the 272 IBD patients, 6% had non-alcoholic fatty liver disease (NAFLD), while 18% had MASLD. Patients with IBD-MASLD were significantly older, had higher body mass index, waist circumference, and triglyceride levels, and were more likely to have type 2 diabetes mellitus and hypertension compared to those with IBD-NAFLD. IBD-MASLD patients also showed higher disease activity scores and required more frequent surgical interventions. Bivariate logistic regression revealed triglyceride levels as a significant predictor of MASLD in IBD patients. Conclusions: MASLD is more prevalent in IBD patients, highlighting the importance of early detection of liver steatosis in this at-risk population. The association between MASLD and cardiometabolic risk factors underscores the need for a multidisciplinary approach to manage these patients effectively. Further studies in larger cohorts are necessary to confirm these findings and explore the pathophysiological mechanisms involved.

Effective communication of genetic testing results between healthcare providers and patients remains essential, but the concept generally lacks a precise definition. Since clinical genetic testing has increased dramatically in recent years, it is crucial to clarify the concept of effective communication as it pertains to patient-provider communication in healthcare genetics. The Walker and Avant methodology of concept analysis was used to operationalize the effective communication definition, along with the identification of associated characteristics and illustrative examples of the concept’s application. This refined definition informs communication in healthcare genetics practice and supports the development of future research methodologies for assessing the effectiveness of communication approaches in clinical genetics.

Abstract Background Familial pancreatic cancer touches families through a genetic susceptibility to developing this neoplasia. Genetic susceptibility is assessed via family history, genetic testing, or both. Individuals with two or more first-degree relatives or three or more relatives of any degree diagnosed with pancreatic cancer are considered at elevated risk. Following a diagnosis of familial pancreatic cancer, patients and families face uncertainty and anxiety about the future. Psychosocial effects of a pancreatic cancer diagnosis on families include fear, concerns about personal health, and how lifestyle may impact the risk of developing pancreatic cancer. Case presentation A 66-year-old male was diagnosed with pancreatic ductal adenocarcinoma stage IIB, T3, N1, M0. A genetic referral was made due to a history of multiple cases of pancreatic cancer within the patient’s family. Genetic testing revealed the patient had a pathogenic variant in the ATM gene that is associated with an increased risk for pancreatic cancer development. The patient’s one adult child was offered testing due to the autosomal dominant pattern of inheritance for this variant. The adult child was found to have the same pathogenic variant. She expressed fear for her future and her child’s future health and longevity. Discussing a case study allows us to capture the multi-faceted relationship between the disease, the affected individuals, and their families. Examining the psychosocial stresses and concerns when there is a pancreatic cancer diagnosis in the family is essential to provide holistic care to patients and families. Conclusions The psychosocial effects of FPC may be overwhelming for patients and families. Healthcare providers can offer education, support, and referrals to appropriate services to help families cope through stages of evaluation, diagnosis, and treatment of FPC.

Acquired immunodeficiency syndrome (AIDS) has transitioned from a progressive, fatal disease to a chronic, manageable disease thanks to better defining of antiretroviral therapy, contributing to increased life expectancy. In parallel, a growing number of subjects without clinical signs of disease but living with chronic HIV infection (also indicated as PLWHs, i.e., People Living With HIV) are experiencing early cardiovascular disease, and the risk increases with age. However, a progressive increase in the prevalence of multiple comorbidity diseases has been reported as these patients age, including cardiovascular disease (CVD). Cardiovascular mortality can be related to viral infection, a progressive reduction in response to antiretroviral therapy, chronic inflammation, and lifestyle. Cardiovascular ageing represents a relevant issue in the management of HIV-infected patients. Although the exact pathophysiological mechanism that leads PLWHs to develop cardiovascular disease is not entirely understood, there is substantial evidence that they accumulate age-related conditions earlier than the general population. Furthermore, since the proportion of PLWHs growing older than 50 years has progressively increased, this results in a complex interaction between disease-related pathophysiology and the exposition of a growing burden of cardiovascular risk factors. We performed a study to relate the effect ageing gas on genes associated with HIV and cardiovascular diseases. We performed a systematic review of the genes most frequently associated with ageing in HIV-infected subjects, followed by a bioinformatic analysis to explore the biological impact of the ageing-related genes.

The family of the neurotrophic tyrosine kinase receptor (NTRK) gene encodes for members of the tropomyosin receptor kinase (TRK) family. Rearrangements involving NTRK1/2/3 are rare oncogenic factors reported with variable frequencies in an extensive range of cancers in pediatrics and adult populations, although they are more common in the former than in the latter. The alterations in these genes are causative of the constitutive activation of TRKs that drive carcinogenesis. In 2017, first-generation TRK inhibitor (TRKi) larotrectinib was granted accelerated approval from the FDA, having demonstrated histologic-agnostic activity against NTRKs fusions tumors. Since this new era has begun, resistance to first-generation TRKi has been described and has opened the development of second-generation molecules, such as selitrectinib and repotrectinib. In this review, we provide a brief overview of the studies on NTRK alterations found in pediatric central nervous system tumors and first and second-generation TRKi useful in clinical practice.

Autism spectrum disorder (ASD) is a heterogeneous group of neurodevelopmental disorders (NDDs) with a high unmet medical need. The diagnosis of ASD is currently based on behavior criteria, which overlooks the diversity of genetic, neurophysiological, and clinical manifestations. Failure to acknowledge such heterogeneity has hindered the development of efficient drug treatments for ASD and other NDDs. DEPI® (Databased Endophenotyping Patient Identification) is a systems biology, multi-omics, and machine learning-driven platform enabling the identification of subgroups of patients with NDDs and the development of patient-tailored treatments. In this study, we provide evidence for the validation of a first clinically and biologically defined subgroup of patients with ASD identified by DEPI, ASD Phenotype 1 (ASD-Phen1). Among 313 screened patients with idiopathic ASD, the prevalence of ASD-Phen1 was observed to be ~24% in 84 patients who qualified to be enrolled in the study. Metabolic and transcriptomic alterations differentiating patients with ASD-Phen1 were consistent with an over-activation of NF-κB and NRF2 transcription factors, as predicted by DEPI. Finally, the suitability of STP1 combination treatment to revert such observed molecular alterations in patients with ASD-Phen1 was determined. Overall, our results support the development of precision medicine-based treatments for patients diagnosed with ASD.

Alcoholic liver disease (ALD) is a major cause of chronic liver disease. This term covers a broad spectrum of liver lesions, from simple steatosis to alcoholic hepatitis and cirrhosis. The pathogenesis of ALD is multifactorial and not fully elucidated due to complex mechanisms related to direct ethanol toxicity with subsequent hepatic and systemic inflammation. The accumulation of pro-inflammatory cytokines and the reduction of anti-inflammatory cytokines promote the development and progression of ALD. To date, there are no targeted therapies to counter the progression of chronic alcohol-related liver disease and prevent acute liver failure. Corticosteroids reduce mortality by acting on the hepatic-systemic inflammation. On the other hand, several studies analyzed the effect of inhibiting pro-inflammatory cytokines and stimulating anti-inflammatory cytokines as potential therapeutic targets in ALD. This narrative review aims to clarify the role of the main cytokines involved in the pathogenesis and treatment of ALD.

Alagille syndrome (ALGS) is a genetic-driven condition of chronic cholestasis, involving the intrahepatic bile ducts, heart, vessels, kidneys, skeletal tissues, eyes, and nervous system. Pathological mechanisms are still not defined. JAG1 and NOTCH2 gene mutations are responsible for most cases (96–97%). Diagnosis is based on clinical and laboratory findings—especially the presence of chronic cholestasis—and on genetic assessment. Bone abnormalities, deficiency of liposoluble vitamins, heart issues, and pruritus are the most prominent features of ALGS. Diagnostic imaging, such as ultrasonography, magnetic resonance imaging, and bone mass density assessment, is useful to study hepatic disease progression, estimate the risk of bone fracture, and rule out malignities. Therapy is based on ursodeoxycholic acid, rifampicin, cholestyramine, and supplementation of liposoluble vitamins. New therapeutic approaches are under investigation. Here, we describe a case of an individual with ALGS presenting with congenital chronic cholestasis and a long clinical history, in which pruritus is the main symptom.

Phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome (PHTS) is a cancer predisposition syndrome characterized by an increased risk of developing benign and malignant tumors, caused by germline pathogenic variants of the PTEN tumour suppressor gene. PTEN gene variants often present in childhood with macrocephaly, developmental delay, and/or autism spectrum disorder while tumors and intestinal polyps are commonly detected in adults. PHTS is rarely associated with childhood brain tumors with only two reported cases of medulloblastoma (MB). We report the exceptional case of an infant carrying a germline and somatic pathogenic variant of PTEN and a germline and somatic pathogenic variant of CHEK2 who developed a MB SHH in addition to intestinal polyposis.

In the past decade significant advancements have been made in the discovery of targetable lesions in pediatric low-grade gliomas (pLGGs). These tumors account for 30-50% of all pediatric brain tumors with generally a favorable prognosis. The latest 2021 WHO classification of pLGGs places a strong emphasis on molecular characterization for significant implications on prognosis, diagnosis, management, and the potential target treatment. With the technological advances and new applications in molecular diagnostics, the molecular characterization of pLGGs has revealed that tumors that appear similar under a microscope can have different genetic and molecular characteristics. Therefore, the new classification system divides pLGGs into several distinct subtypes based on these characteristics, enabling a more accurate strategy for diagnosis and personalized therapy based on the specific genetic and molecular abnormalities present in each tumor. This approach holds great promise for improving outcomes for patients with pLGGs, highlighting the importance of the recent breakthroughs in the discovery of targetable lesions.