Hereditary Predisposition Research Articles

Utilization of molecular genetic approaches for colorectal cancer screening

The feasibility of population screening for colorectal cancer has been demonstrated in several studies. Most of these studies have considered individual characteristics, diagnostic approaches, epidemiological data, and socioeconomic factors. In this article, we comment on an editorial by Metaxas et al published in the recent issue of the journal. The authors emphasized the need to raise public awareness through health education programs and the possibility of using easily accessible non-invasive screening methods. Here, we focus on non-invasive molecular genetic approaches that can aid in colorectal cancer screening. On the one hand, we highlighted the use of tumor DNA/RNA markers directly for screening and, on the other hand, underline the use of polygenic risk assessment and hereditary predisposition to select individuals for more thorough cancer screening.

Tp53 R217H and R242H mutant zebrafish exhibit dysfunctional p53 hallmarks and recapitulate Li-Fraumeni syndrome phenotypes

Li-Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome associated with a highly penetrant cancer spectrum characterized by germline TP53 mutations. We characterized the first LFS zebrafish hotspot mutants, tp53 R217H and R242H (human R248H and R273H), and found these mutants exhibit partial-to-no activation of p53 target genes, have defective cell-cycle checkpoints, and display partial-to-full resistance to apoptosis, although the R217H mutation has hypomorphic characteristics. Spontaneous tumor development histologically resembling human sarcomas was observed as early as 6 months. tp53 R242H mutants had a higher lifetime tumor incidence compared to tp53 null and R217H mutants, suggesting it is a more aggressive mutation. We observed mutation-specific tumor phenotypes across tp53 mutants with associated diverse transcriptomic and DNA methylome profiles in tp53 mutant larvae, impacting metabolism, cell signalling, and biomacromolecule synthesis and degradation. These tp53 zebrafish mutants demonstrate fidelity to their human counterparts and provide new insights into underlying tumorigenesis mechanisms and kinetics that suggest metabolic rewiring and cellular signalling changes occur prior to tumor initiation, which will guide targeted therapeutics for LFS.

Mutacje i ich konsekwencje w rozwoju raka trzustki

Pancreatic cancer is a common cancer with a very poor prognosis and aggressivecourse. The main reason for the highly unfavorable prognosis of patients withpancreatic cancer is its long-term asymptomatic development, which results in thediagnosis being made at a stage when the cancer process is significantly advanced.Despite extensive research in the field of effective diagnosis and treatment of thiscancer, patient survival rates are increasing slowly and insignificantly. Pancreaticcancer cells contain many mutations, the most frequently found of which concern theKRAS, TP53, CDKN2A, SMAD4, BRCA1 and BRCA2 genes. Each of these mutationsis associated with specific consequences at the molecular level and translates intofurther cell functioning, including uncontrolled cell division. The occurrence of specificmutations influences the planning of therapeutic procedures and patient prognosis.Many mutations are associated with a hereditary predisposition to cancer, includingpancreatic cancer.

A Comparative Study of Imipramine and Tolterodine for the Treatment of Children with Primary Nocturnal Enuresis

Background: Nocturnal enuresis (NE), or bed-wetting, affects children aged ≥5 years after ruling out organic causes. The ICCS defines NE as intermittent urinary incontinence during sleep, categorized into monosymptomatic (MNE) and non-monosymptomatic (NMNE) forms. NE is also classified by onset: primary (no dry period) and secondary (bed-wetting after a dry period). Contributing factors include sleep disorders, stress, hereditary predisposition, and delayed bladder development. Management involves behavioral and pharmacological treatments, with desmopressin and anticholinergic drugs being common options. Aim of the study: This study aims to find out an alternate effective and safe drug for the treatment of primary nocturnal enuresis. Methods: This study was conducted at the Department of Urology(outdoor), Shahid Sk. Abu Naser Specialized Hospital, Khulna, Bangladesh from January 2020 to December 2021. After excluding 12 patient’s pre-randomizations for non-cooperation, 60 patients were split into two groups: Group A received 25mg of imipramine before bedtime, while Group B took 1mg of tolterodine tartrate twice daily evaluated efficacy over 6 months, including a 2-week behavioral modification baseline and follow-ups at 3 and 6 months. Data were analyzed using SPSS 26, employing various statistical tests with significance set at p <0.05. Result: The study involved 60 children (mean age 10.0±3.1 years, 55% male), assessing bed-wetting patterns and treatment outcomes. The majority (80%) had unsatisfactory behavioral modifications, with 35% having a family history of enuresis. Both groups (A and B) showed no significant difference in bed-wetting episodes at baseline or after 3 months of treatment. Complications were more common in Group A, including dry mouth, nausea, and insomnia. Imipramine led to a higher proportion of patients with fewer than 50 dry nights after drug withdrawal, while Tolterodine showed better results at month 3 but a higher decrease in dry ...

Health Care Transition Programs for Adolescents and Young Adults With Hereditary Cancer Predisposition: A Scoping Review.

Adolescents and young adults (AYA) with increased risk for cancer due to hereditary predisposition, previous cancer treatment, or both are eligible for increased surveillance, chemoprevention, and prophylactic surgery that can improve early detection and prevention of cancers. One way to ensure continuity of cancer prevention care is to support adolescents through the transition from pediatric to adult health care. Yet, there are limited data on the impl ementation of health care transition (HCT) programs for AYA with increased risk for cancer. We conducted a scoping review of the literature on transition programs for AYA at increased risk of cancer due to known germline risk or prior cancer diagnosis, with a focus on implementation factors relevant to designing, implementing, and sustaining a new program. Data from 54 articles were extracted and analyzed using the RE-AIM implementation science framework. Few HCT programs have been implemented for AYA with hereditary cancer syndromes. Several groups have done preimplementation work for future hereditary cancer programs, but programs for cancer survivors are farther along the translational spectrum. We identified implementation factors along the five RE-AIM dimensions to assist preimplementation planning for HCT programs for AYA with increased risk for cancer.

Primary intracranial sarcoma associated with DICER1 mutant: a case report and preclinical investigation.

Primary intracranial sarcoma (PIS) is a rare and aggressive pediatric brain tumor, which is partially associated with DICER1 mutant. Although the molecular genetic characteristics of this tumor have previously been investigated, novel therapeutic targets remain unclear. Further, the lack of faithful preclinical models has hampered the development of novel therapeutic strategies. Herein, we describe a pediatric case of PIS with DICER1 mutant and describe the development of the first novel patient-derived xenograft (PDX) model of this rare tumor. Somatic genomic profiling of the tumor revealed mutations in DICER1, TP53, and ATRX. Germline analysis further revealed a pathogenic variant of DICER1, significant for the diagnosis and management of hereditary tumor predisposition syndrome. Overall, we demonstrated that the PDX model faithfully retained the phenotype and genotype of the patient's tumor, as well as the DNA methylation profile. Through high-throughput drug screening using PDX tumor cells, we found that activation of the retinoic acid receptor (RAR) signaling pathway reduced tumor cell viability. These findings indicate that the RAR signaling pathway is a potential therapeutic target for PIS in DICER1 mutant.

Validation of a guidelines-based digital tool to assess the need for germline cancer genetic testing

BackgroundEfficient and scalable solutions are needed to identify patients who qualify for germline cancer genetic testing. We evaluated the clinical validity of a brief, patient-administered hereditary cancer risk assessment digital tool programmed to assess if patients meet criteria for germline genetic testing, based on personal and family history, and in line with national guidelines.MethodsWe applied the tool to cases seen in a nationwide telehealth genetic counseling practice. Validity of the tool was evaluated by comparing the tool’s assessment to that of the genetic counselor who saw the patient. Patients’ histories were extracted from genetic counselor-collected pedigrees and input into the tool by the research team to model how a patient would complete the tool. We also validated the tool’s assessment of which specific aspects of the personal and family history met criteria for genetic testing. Descriptive statistics were used.ResultsOf the 152 cases (80% female, mean age 52.3), 56% had a personal history of cancer and 66% met genetic testing criteria. The tool and genetic counselor agreed in 96% of cases. Most disagreements (4/6; 67%) occurred because the genetic counselor’s assessment relied on details the tool was not programmed to collect since patients typically don’t have access to the relevant information (pathology details, risk models). We also found complete agreement between the tool and research team on which specific aspects of the patient’s history met criteria for genetic testing.ConclusionWe observed a high level of agreement with genetic counselor assessments, affirming the tool’s clinical validity in identifying individuals for hereditary cancer predisposition testing and its potential for increasing access to hereditary cancer risk assessment.

Oncologic outcomes of incidental serous tubal intraepithelial carcinoma and associated high-grade serous carcinoma in high-risk patients undergoing risk-reducing surgery

ObjectiveWe sought to describe the oncologic outcomes of isolated serous tubal intraepithelial carcinomas compared to an intraepithelial carcinoma found concurrently with microscopic high-grade serous carcinoma among patients with hereditary predisposition...

Bilateral Adrenal Tumors: A Visual Case Series

Adrenal incidentalomas are increasingly diagnosed with the widespread use of cross-sectional imaging modalities. Though these are often unilateral, bilateral adrenal masses uncommonly occur and can be of similar or different origins. While the majority of adrenal masses are benign, bilateral masses are more likely to be associated with hormonal disturbances. These range from syndromes of hormone excess, such as mild autonomous cortisol secretion, to primary adrenal insufficiency due to gland infiltration or destruction. Bilateral masses may herald the diagnosis of germline pathogenic variants, hereditary tumor predisposition syndromes, malignancy, or even infection. In many cases, imaging characteristics play an important role in making the diagnosis in addition to biochemical evaluation. Herein, we present various imaging findings of 10 patients with bilateral adrenal masses as evaluated with computed tomography, magnetic resonance imaging, and positron emission tomography scans.

Therapy-Related Myeloid Neoplasms: Complex Interactions among Cytotoxic Therapies, Genetic Factors, and Aberrant Microenvironment.

Therapy-related myeloid neoplasm (t-MN), characterized by its association with prior exposure to cytotoxic therapy, remains poorly understood and is a major impediment to long-term survival even in the era of novel targeted therapies due to its aggressive nature and treatment resistance. Previously, cytotoxic therapy-induced genomic changes in hematopoietic stem cells were considered sine qua non in pathogenesis; however, recent research demonstrates a complex interaction between acquired and hereditary genetic predispositions, along with a profoundly senescent bone marrow (BM) microenvironment. We review emerging data on t-MN risk factors and explore the intricate interplay among clonal hematopoiesis, genetic predisposition, and the abnormal BM microenvironment. Significance: t-MN represents a poorly understood blood cancer with extremely poor survival and no effective therapies. We provide a comprehensive review of recent preclinical research highlighting complex interaction among emerging therapies, hereditary and acquired genetic factors, and BM microenvironment. Understanding the risk factors associated with t-MN is crucial for clinicians, molecular pathologists, and cancer biologists to anticipate and potentially reduce its incidence in the future. Moreover, better understanding of the molecular pathogenesis of t-MN may enable preemptive screening and even intervention in high-risk patients.

Transcriptomic imputation identifies tissue-specific genes associated with cervical myelopathy

BACKGROUND CONTEXTDegenerative cervical myelopathy (DCM) is a progressive spinal condition that can lead to severe neurological dysfunction. Despite its degenerative pathophysiology, family history has shown to be a largely important factor in incidence and progression, suggesting that inherent genetic predisposition may play a role in pathophysiology. PURPOSETo determine the tissue-specific, functional genetic basis of hereditary predisposition to cervical myelopathy. STUDY DESIGNRetrospective case-control study using patient genetics and matched EHR from the Mount Sinai BioMe Biobank. METHODSIn a large, diverse, urban biobank of 32,031 individuals, with 558 individuals with cervical myopathy, we applied transcriptomic imputation to identify genetically regulated gene expression signatures associated with DCM. We performed drug-repurposing analysis using the CMAP database to identify candidate therapeutic interventions to reverse the cervical myelopathy-associated gene signature. RESULTSWe identified 16 genes significantly associated with DCM across 5 different tissues, suggesting tissue-specific manifestations of inherited genetic risk (upregulated: HES6, PI16, TMEM183A, BDH2, LINC00937, CLEC4D, USP43, SPATA1; downregulated: TTC12, CDK5, PAFAH1B2, RCSD1, KLHL29, PTPRG, RP11-620J15.3, C1RL). Drug repurposing identified 22 compounds with the potential to reverse the DCM-associated signature, suggesting points of therapeutic intervention. CONCLUSIONSThe inherited genetic risk for cervical myelopathy is functionally associated with genes involved in tissue-specific nociceptive and proliferative processes. These signatures may be reversed by candidate therapeutics with nociceptive, calcium channel modulating, and antiproliferative effects. CLINICAL SIGNIFICANCEUnderstanding the genetic basis of DCM provides critical insights into the hereditary factors contributing to the disease, allowing for more personalized and targeted therapeutic approaches. The identification of candidate drugs through transcriptomic imputation and drug repurposing analysis offers potential new treatments that could significantly improve patient outcomes and quality of life by addressing the underlying genetic mechanisms of DCM.

Telehealth in a Pediatric Patient with Nevoid Basal Cell Carcinoma Syndrome

During COVID19, telemedicine was adapted by many practices to serve patients with a variety of health conditions including those affected by cancer. Here we report an 11-year-old patient who went to her dentist where a routine panorama x-ray showed multiple jaw keratocysts. Because jaw keratocysts can be identified with a hereditary predisposition to basal cell cancer and other tumors, she was referred for genetics. She was seen in 2021 where telehealth was the primary modality for visits. The hospital’s secure video platform was used to gather medical history and counsel the mother on genetic testing for nevoid basal cell carcinoma syndrome(NBCCS). While in the past genetic testing was often thousands of dollars, the genetic testing company offered a patient pay option of $250. Two days later, the patient presented to the cancer center to have her blood drawn and a fifteen-minute physical exam was performed which identified macrocephaly, and palmar pits. Of note the mother asked about numerous pinpoint lesions around the patient’s ocular region. Genetic testing was positive for a pathogenic variant in PTCH1 c.454_455del. The patient was referred to pediatric dermatology where over fifty basal cells were diagnosed and started treatment with imiquimod and efudex. She also was referred to cardiology and gynecology given reports of individuals with cardiac fibromas and gynecologic ovarian tumors. The patient is now 14 going into her freshman year of high school and is doing well. This case highlights how telehealth offers a holistic approach to patient care.

Association between Clinical Features and Risk Factors for Breast Cancer through a Cross-Sectional Study

Introduction: Breast cancer was responsible for 685,000 deaths worldwide in 2020. Approximately half of all breast cancers arise in women who have no identifiable risk factors other than their gender and age. Objectives: The goal of this study was to determine the association between clinical features and breast cancer risk factors. Methods: This cross-sectional study was conducted among 50 histologically confirmed breast cancer patients included by purposive sampling technique in the Surgery Department of Rangpur Medical College, Rangpur. Results: The presence of breast lump was significantly associated with the residence of patients (p value<0.011). The significant association between nipple retraction and family history may indicate a hereditary predisposition that affects the course of the disease (p value<0.031). Conclusion: This research provides insights into vital aspects of breast cancer within a particular demographic, under scoring the necessity for focused approaches to public health to address the discrepancies in breast cancer presentation and outcomes. J Bangladesh Coll Phys Surg 2024; 42: 321-328

The serotonin 1A receptor promoter polymorphism, rs6295, is associated with morphofunctional features

Introduction. The tendency to weight gain is influenced by many genetic and environmental factors (nutrition, level of physical activity, social well-being, etc.), as well as complex interactions of these factors. Studying the genetic factors of obesity can help in developing individual strategies for the prevention and treatment of this common disease. One of the most important hereditary factors is the neurotransmitter systems gene polymorphism, (including the serotonin system gene polymorphism). The aim of the investigation is to study the associations of single nucleotide polymorphism of the rs6295 locus of the serotonin receptor gene 1A HTR1A with morphofunctional features and body weight gain. Material and methods. The study used the materials of a comprehensive anthropogenetic examination of 386 men and 418 women aged 17 to 30 years. More than 20 morphofunctional indicators were measured using the traditional anthropometric method. The material for genetic analysis was genomic DNA isolated from buccal epithelium. The reliability of intergroup differences was assessed using the Mann-Whitney criterion, while canonical discriminant analysis was used to study intergroup variability. Results. For the first time, a significant correlation was shown between the polymorphism of the serotonin receptor type 1 gene HTR1A and morphofunctional features: individuals with the G/G genotype with greater body weight have lower (compared to carriers of the C/C and C/G genotypes) values of the indicators of the level of metabolic processes and specific metabolism. Conclusion. The statistically significant obtained results may be used in the development of individual strategies for the prevention and treatment of obesity, and also allow us to supplement the information on the association of serotonin system gene polymorphism with morphofunctional features and contribute to expanding our understanding of the human physique features formation and their relationships with hereditary predisposition.

8657 Thymic Neoplasia In A Pediatric Patient With LI-Fraumeni Syndrome: A Case Report

Abstract Disclosure: M.A. Souza: None. W.M. Lins: None. D. di Matteo: None. J.L. Marcayata: None. A. Kuhn: None. H. Charcar: None. F. Ledesma: None. M.Q. Almeida: None. F. Jatene: None. B.B. Mendonca: None. M.C. Fragoso: None. Introduction: Li-Fraumeni Syndrome (LFS) is a rare autosomal dominant hereditary cancer predisposition syndrome primarily caused by pathogenic variants in the TP53 tumor suppressor gene. The individuals affected are typically young, with a cancer risk of approximately 90% in lifetime. Parents choosing to test their young children face the dilemma of when to disclose their own or the child's status and when to initiate cancer screening if LFS is detected. This process presents psychosocial challenges for both parents and affected children. Both providers and patients question whether the surveillance benefits outweigh the psychological burden of knowing LFS status and screening-related concerns, creating ambivalence toward genetic testing decisions.Case Report: We describe a 6-year-old male with Li-Fraumeni syndrome carrier of the germline pathogenic variant TP53 c.818G>A (p.R273H) in heterozygous (exon 8).In the family history, there are three relatives with advanced tumor cases, with the grandmother already deceased, the mother undergoing chemotherapy treatment, and the cousin being cancer-free for 10 years.The patient in question had no gestational complications. No consanguinity between parents. No signs or symptoms of hormonal hyperfunction. As proposed in the literature, Li-Fraumeni Syndrome patients should undergo frequent screening for early tumor detection, the patient began screening according to the Toronto protocol in 2018, at the age of 1 year and 7 months, through cranial and thoracic MRI, abdominal ultrasound, and annual hormonal assays. In the thoracic MRI conducted in February 2023, an enlarged and heterogeneously signaling thymus was identified, with a nodular formation (absent in previous exams), measuring about 2.5 cm. Facing suspicion of a thymoma, thymic carcinoma, or lymphoma, a biopsy guided by tomography in March 2023 was done. Histological examination was compatible with primary thymic neoplasia. During follow-up, a significant growth of the mass to 9 cm was observed. The patient underwent surgical treatment in August 2023 with resection of the mediastinal mass, and the anatomopathological examination revealed undifferentiated thymic carcinoma, followed in conjunction with the pediatric oncology team. The dilemma is about the adjuvant radiotherapy since the possibility to acquire a new tumor radio-induced such as sarcoma. We proposed to follow with MRI imaging each 3 months and if minimal signal of recurrence he will underwent radiotherapy. Conclusion: In addition to the intrinsic rarity of Li-Fraumeni Syndrome, this case draws attention to the possibility of a thymic tumor, an extremely rare neoplasm in syndrome carriers. In the literature, only scattered case reports show this association. Furthermore, this case reinforces the importance of systematic screening for investigating possible neoplasms in this susceptible population. Presentation: 6/1/2024

8657 Thymic Neoplasia in a Pediatric Patient With LI-Fraumeni Syndrome: A Case Report

Abstract Disclosure: M.A. Souza: None. W.M. Lins: None. D. di Matteo: None. J.L. Marcayata: None. A. Kuhn: None. H. Charcar: None. F. Ledesma: None. M.Q. Almeida: None. F. Jatene: None. B.B. Mendonca: None. M.C. Fragoso: None. Introduction: Li-Fraumeni Syndrome (LFS) is a rare autosomal dominant hereditary cancer predisposition syndrome primarily caused by pathogenic variants in the TP53 tumor suppressor gene. The individuals affected are typically young, with a cancer risk of approximately 90% in lifetime. Parents choosing to test their young children face the dilemma of when to disclose their own or the child's status and when to initiate cancer screening if LFS is detected. This process presents psychosocial challenges for both parents and affected children. Both providers and patients question whether the surveillance benefits outweigh the psychological burden of knowing LFS status and screening-related concerns, creating ambivalence toward genetic testing decisions.Case Report: We describe a 6-year-old male with Li-Fraumeni syndrome carrier of the germline pathogenic variant TP53 c.818G>A (p.R273H) in heterozygous (exon 8).In the family history, there are three relatives with advanced tumor cases, with the grandmother already deceased, the mother undergoing chemotherapy treatment, and the cousin being cancer-free for 10 years.The patient in question had no gestational complications. No consanguinity between parents. No signs or symptoms of hormonal hyperfunction. As proposed in the literature, Li-Fraumeni Syndrome patients should undergo frequent screening for early tumor detection, the patient began screening according to the Toronto protocol in 2018, at the age of 1 year and 7 months, through cranial and thoracic MRI, abdominal ultrasound, and annual hormonal assays. In the thoracic MRI conducted in February 2023, an enlarged and heterogeneously signaling thymus was identified, with a nodular formation (absent in previous exams), measuring about 2.5 cm. Facing suspicion of a thymoma, thymic carcinoma, or lymphoma, a biopsy guided by tomography in March 2023 was done. Histological examination was compatible with primary thymic neoplasia. During follow-up, a significant growth of the mass to 9 cm was observed. The patient underwent surgical treatment in August 2023 with resection of the mediastinal mass, and the anatomopathological examination revealed undifferentiated thymic carcinoma, followed in conjunction with the pediatric oncology team. The dilemma is about the adjuvant radiotherapy since the possibility to acquire a new tumor radio-induced such as sarcoma. We proposed to follow with MRI imaging each 3 months and if minimal signal of recurrence he will underwent radiotherapy. Conclusion: In addition to the intrinsic rarity of Li-Fraumeni Syndrome, this case draws attention to the possibility of a thymic tumor, an extremely rare neoplasm in syndrome carriers. In the literature, only scattered case reports show this association. Furthermore, this case reinforces the importance of systematic screening for investigating possible neoplasms in this susceptible population. Presentation: 6/1/2024

Reducing colorectal cancer mortality in South Africa: experiences and progress from the South African National Cancer Prevention Services

Aim The incidence rates of colorectal cancer are rapidly increasing in South Africa. Previous studies have shown that the prevalence of inherited colorectal cancer in South Africa is 3-5 times higher than in high-income countries. Targeted screening and surveillance programmes for individuals with known colorectal cancer-causing mutations have resulted in increased life expectancy. The South African National Cancer Prevention Services (SANCaPS), was established to implement national systems for identifying individuals with inherited cancers, improving their clinical management, and reducing the overall disease burden. Methods Using colorectal cancer as an example, SANCaPS aimed to extend surveillance and management practices from the Western Cape to a national level. The goals included improving the quality of pathology reporting, establishing counselling systems for at-risk individuals, developing cost-effective mutation detection protocols, identifying and counselling at-risk family members, providing mutation testing, organising endoscopic surveillance programmes for high-risk individuals, setting ethical frameworks for research, and extrapolating learnings from the inherited colorectal cancers surveillance programme to other cancers with known hereditary predispositions. Results SANCaPS initiated the standardisation of national pathology reporting for colorectal cancers. Currently, a minimum core pathology dataset collection is being piloted in the National Health Laboratory Service’s TrakCare system. Subsequently, SANCaPS aims for broader adoption through stakeholder engagements. This will help to identify patients with mismatch repair-deficient colorectal cancers, facilitate research, and improve reporting. Conclusions To improve patient outcomes, this consultative process and framework will be replicated to introduce standardised management workflows for other common cancers, including breast, prostate, uterine, and others.

Genetic Contribution of CFTR Mutations to Chronic Bronchitis in Children: A Case-Control Study

Background: Chronic bronchitis and bronchial asthma are significant respiratory conditions with complex etiologies influenced by genetic and environmental factors. Mutations in the CFTR gene have been implicated in severe respiratory diseases, underscoring the need to explore their association with these conditions. Methods: This study included 150 children with chronic bronchitis and bronchial asthma, alongside a control group of 60 healthy children. Clinical and genealogical analyses were conducted to evaluate hereditary predisposition. Molecular genetic studies focused on eight common CFTR mutations (F508del, W1282X, and N1303K) using RT-PCR with real-time detection. Statistical analyses, including Hardy-Weinberg equilibrium testing and odds ratio calculations, assessed genetic associations. Results: A hereditary predisposition was identified in 32.3% of parents of affected children. Among the patients, heterozygous CFTR mutations were detected, with F508del in 6.25%, W1282X in 2.1%, and N1303K in 2.1%. These findings suggest a strong genetic influence in the studied population. Conclusion: This study reinforces the role of CFTR mutations in chronic bronchitis and bronchial asthma, highlighting the genetic basis of these conditions. Future research should explore additional candidate genes and unidentified CFTR variants to enhance predictive medicine and personalized treatment strategies.

РОЛЬ КОНСТИТУЦИОНАЛЬНОЙ ПРИНАДЛЕЖНОСТИ В ГЕНЕЗЕ ОЖИРЕНИЯ У ДЕТЕЙ И ПОДРОСТКОВ 7-17 ЛЕТ

Obesity in children and adolescents is becoming a pressing issue that can be classified as a disease associated with the interaction of genetic and non-genetic factors. There are numerous causes of this disease. The most important ones are hereditary predisposition and the intake of a large number of calories along with reduced physical activity. In children of different somatotypes aged 7-17 years, there is a wave-like change in the growth of the bone, muscle and fat body components. There are periods when growth processes and hormonal changes lead to the maximum increase in the F, M, L components of body weight. Children of the MD, DM, and D body types are at risk of excess fat deposition. The natural age-related increase in the fat component accompanied by negative exogenous and endogenous factors can lead to hormonal failure and a substantial increase in fat mass.

Hereditary and clinical insights into paraganglioma and pheochromocytoma.

Approximately 30-40% of paragangliomas (PGLs) and pheochromocytomas (PCCs) harbor an underlying hereditary cause. Early identification of at-risk individuals is imperative given the early onset, aggressiveness of tumors, and other tumor/cancer risks associated with hereditary PGLs/PCCs. This study analyzes the clinical presentations and genetic histories of patients with PGL/PCC and/or hereditary risk to contribute to the expanding knowledge in this rare population. A retrospective chart review identified two cohorts of patients seen in cancer genetics clinics at an academic medical center and a safety-net hospital between August 2016 and December 2022. Cohort 1 consisted of patients with likely pathogenic variants (LPVs)/pathogenic variants (PVs) in hereditary PGL/PCC predisposition genes. Cohort 2 consisted of patients with a personal history of a PGL/PCC. Demographics, personal/family history, and genetic testing outcomes were analyzed. A total of 560 patients met the study criteria (Cohort 1, n = 364; Cohort 2, n = 269). In Cohort 1, 77 (21.1%) patients had an incidental LPV/PV in a PGL/PCC gene. Nearly half (n = 36, 46.8%) were in SDHx genes, with a majority in SDHA (n = 21). In Cohort 2, 86 patients tested positive for 87 LPV/PV in a hereditary cancer predisposition gene. The SDHx genes were most likely to have an LPV/PV identified (SDHB n = 24, SDHD n = 23). Multigene panels identify patients at risk for hereditary PGL/PCC, many of whom are incidentally found. While SDHA LPV/PVs were the most frequent incidental finding, they were less common in patients with PGL/PCC, indicating the need for longitudinal studies to better understand the prevalence and penetrance of these tumors.