First-degree Relatives Of Patients Research Articles

Prevalence, genetic and clinical characteristics in first-degree relatives of patients with familial cerebral cavernous malformations in China

ObjectiveThis study aims to investigate the prevalence of familial cerebral cavernous malformations (FCCMs) in first-degree relatives (FDRs) using familial screening, to describe the distribution of initial symptoms, lesion count on...

Current State of Application of Formal Thought Disorder Screening Methods in First-Degree Relatives of Patients With Schizophrenia: A Narrative Review

Abstract: Historically, formal thought disorder (FTD) has been considered one of the distinctive key symptoms of schizophrenia and is still regarded as an important early warning sign and a marker of illness severity with solid predictive value. Recent studies are able to found that the presence of FTD is predictive of the subsequent diagnosis of schizophrenia and often precedes the frank clinical picture by several months. Much effort has been put into developing scales that can reliably detect FTD and can be readily applied in routine clinical practice. This narrative review investigated the use of FTD as a screening tool to assess risk in first-degree relatives of patients with schizophrenia. The results show that the use of these scales in firstdegree relatives of schizophrenic individuals during clinical contact and counseling is still an exception, despite their uniquely heightened vulnerability profile. To our knowledge, this is the first time that the application of FTD screening methods in first-degree relatives of schizophrenic individuals has been reviewed in a structured way.

Cardiovascular Risk Factors Among First-Degree Relatives of Patients with Premature Cardiovascular Disease in Malta. Baseline Findings from the CRISO Project.

A family history of premature atherosclerotic cardiovascular disease (ASCVD) confers a greater risk of developing ASCVD. However, the prevalence of ASCVD risk factors among asymptomatic Maltese adults with parental or fraternal history of premature ASCVD is unknown. The study aimed to evaluate and compare their risk with the general population. Posters to market the project were distributed in cardiac rehabilitation areas. Patients with premature cardiovascular disease facilitated recruitment by informing their relatives about the project. Medical doctors and cardiac rehabilitation nurses referred first-degree relatives. Posters were put up in community pharmacies, and an explanatory video clip was shared on social media for interested individuals to contact researchers. Those eligible were enrolled in a preventive cardiology lifestyle intervention. Their data were compared with the risk in the general population. Many first-degree relatives had a suboptimal risk profile, with 60% (N = 89) having a total cholesterol level of >5.0 mmol/L; 54% having a low-density lipoprotein-cholesterol level of >3 mmol/L; 70.5% being overweight/obese, with 62% having a waist circumference greater than the recommended values; 34.8% having hypertension; 56.2% being inadequately adherent to the Mediterranean diet; 62% being underactive, with 18% being sedentary; and 25.8% being smokers. First-degree relatives had significantly higher proportions of underactive lifestyle (p = 0.00016), high body mass index (>25kg/m2) (p = 0.006), and systolic blood pressure (p = 0.001) than the general population, with 30% having metabolic syndrome. This study determined the prevalence of lifestyle, biochemical, physiological, and anthropometric cardiovascular risk factors among asymptomatic first-degree relatives of Maltese patients with premature ASCVD. First-degree relatives had considerable prevalences of an underactive lifestyle, hypertension, and obesity, suggesting better screening and early risk factor intervention are needed to modify their risk of ASCVD.

The landscape of rare genetic variants in familial Waldenström macroglobulinemia

AbstractWaldenström macroglobulinemia (WM) is a rare hematological malignancy. Risk for WM is elevated 20-fold among first-degree relatives of patients with WM. However, the list of variants and genes that cause WM remains incomplete. In this study we analyzed exomes from 64 WM pedigrees for evidence of genetic susceptibility for this malignancy. We determined the frequency of pathogenic (P) or likely pathogenic (LP) variants among patients with WM; performed variant- and gene-level association analyses with the set of 166 WM cases and 681 unaffected controls; and examined the segregation pattern of deleterious variants among affected members in each pedigree. We identified P variants in TREX1 and SAMHD1 (genes that function at the interface between innate immune response, genotoxic surveillance, and DNA repair) segregating in patients with WM from 2 pedigrees. There were additional P/LP variants in cancer-predisposing genes (eg, POT1, RECQL4, PTPN11, PMS2). In variant- and gene-level analyses, no associations were statistically significant after multiple testing correction. On a pathway level, we observed involvement of genes that play a role in telomere maintenance (q-value = 0.02), regulation of innate immune response (q-value = 0.05), and DNA repair (q-value = 0.08). Affected members of each pedigree shared multiple deleterious variants (median, n = 18) but the overlap between the families was modest. In summary, P/LP variants in highly penetrant genes constitute a modest proportion of the deleterious variants, each pedigree is largely unique in its genetic architecture, and multiple genes are likely involved in the etiology of WM.

Screening for colorectal cancer by full colonoscopy in first-degree relatives of colorectal cancer patients: a multicentric study by the Italian League for the Fight against Cancer.

Colorectal cancer currently presents the third-highest incidence of cancers worldwide, making secondary prevention through screening programs for colorectal cancer, usually by Fecal Occult Blood Testing, an essential preventive medicine intervention. First-degree relatives of colorectal cancer patients are a particularly at-risk group, with indications to consider direct screening by full colonoscopy. Colonoscopy is considered the gold standard for diagnosing colorectal cancer, as it has high sensitivity and specificity, and is both a diagnostic and therapeutic tool. However, it requires significant organizational and financial resources, and has a small but relatively higher risk of complications as opposed to fecal occult blood testing. The present study aimed to assess the appropriateness of a screening program without age restrictions of CRC by full colonoscopy in asymptomatic, first-degree adult relatives of patients with colorectal cancer, aiming both to actively increase screening coverage and to determine the detection rate of precancerous lesions and colorectal cancer in this population. Uncontrolled interventional study - colorectal cancer screening by full colonoscopy for at-risk population. The Italian League for the Fight against Cancer started a colorectal cancer screening program by full colonoscopy for first-degree relatives of colorectal cancer patients in 1998 in the province of Latina, Lazio Region, Italy. The program was expanded to the provinces of Rieti, Lazio Region, and Sassari, Sardinia Region, in 2014 and 2016 respectively, and was concluded in 2018. Subjects were actively and voluntarily recruited by the study's working group. Subjects that had already been subjected to a full colonoscopy in the preceding 5 years were excluded from this study. Identified neoplastic lesions were treated either directly or referred to the Day Hospital setting, and histologically diagnosed following World Health Organization guidelines. In total, 2,288 subjects (age range 15-88, mean 52.3 yrs, M/F = 946/1,204) were screened by colonoscopy, of which 103 (4.5%) were incomplete and 2,173 (95.0%) complete, with data on colonoscopy performance missing for 12 participants. Out of 468 positive outcomes on colonoscopy, diagnosis for 422 (204M/173F), 19.4% of total subjects, was adenomatous polyps and 46 (20M/20F), 2.1% of total subjects, was colorectal cancer. Female sex was a protective factor against a positive test outcome, with a 35% reduction compared to male sex, with OR=0.64 95%CI (0.52-0.80). On the other hand, being over 50 years of age was found to be a risk factor, making a positive outcome more than twice as likely, with OR=2.3 95%CI (1.8-2.9). Subjects over 50 also had significantly more instances of multiple adenomas being found, however the size distribution of found adenomas was not significantly different between subjects under and over 50, despite size being a predictor of risk of neoplastic progression. Given the high detection rate of precancerous lesions and colorectal cancer in the studied population, it is our opinion that guidelines should continue to recommend earlier and more frequent screening in first-degree relatives of patients with colorectal cancer, and, barring the introduction of more cost-effective and/or lower risk procedures with a similar efficacy profile, maintain the use of colonoscopy as the main screening option.

The frequency of colorectal lesions in the first-degree relatives of patients with colorectal lesions among PERSIAN Guilan Cohort Study population (PGCS)

BackgroundThis study aimed to investigate the frequency of colorectal lesions in the first-degree relatives of patients with colorectal lesions among the Prospective Epidemiological Research Studies in Iran (PERSIAN )Guilan Cohort Study (PGCS) population.MethodsIn this cross-sectional study, 162 first-degree relatives with a history of colorectal lesions were randomly selected from 52 participants in PGCS. All subjects underwent total colonoscopy by a gastroenterologist, and a pathologist evaluated colorectal biopsies. Also, individuals’ demographic information, clinical data, and dietary habits were recorded.ResultsThe mean age of the participants was 56.55 ± 7.04. Of 86 colon polyps, 52 neoplastic and 34 non-neoplastic polyps were observed in 56 patients (34.6%). Individuals with age > 60 years had 3.29-fold increased odds of developing colorectal polyps (OR = 3.29, 95% CI: 1.13–9.56, P = 0.029). The smokers were 2.73 times more susceptible to developing colorectal polyps than non-smokers (OR = 2.73, 95% CI: 1.24–6.02, P = 0.013). Moreover, consumption of vegetables more than three times per day was associated with decreased OR of colorectal polyp development (OR = 0.43, CI: 0.19–0.98, P = 0.045).ConclusionsConsidering the high prevalence of neoplastic colorectal polyps among the first-degree relatives of patients with colorectal lesions, early screening is recommended for individuals with a family history of colorectal lesions.

Risk of major adverse liver outcomes among first-degree relatives of individuals with MASLD.

Previous studies have suggested an increased risk of major adverse liver outcomes (MALO) in relatives of patients with metabolic dysfunction-associated steatotic liver disease (MASLD). However, granular and longitudinal evidence is lacking on the future risk of MALO among family members of individuals with MASLD. We identified 3526 first-degree relatives (FDRs) and 11 079 general population comparators to 1328 patients with MASLD diagnosed between 1974 and 2021, with detailed clinical data, including liver histology in 71% of patients. MALO was defined through diagnostic coding for cirrhosis or its complications. Cox regression models were used to estimate adjusted hazard ratios (aHRs) for MALO among FDRs compared to general population comparators. Cumulative incidence accounting for competing risks was calculated. During a median follow-up of 13.4 years, there were 65 (2%, 1.12/1000 person-years) and 225 (2%, 1.26/1000 person-years) MALO events in FDRs and general population comparators respectively. After adjusting for demographic factors and comorbidities, FDRs were at no increased risk of MALO (aHR = 0.99, 95% CI: 0.74-1.33). Increased relative rates of MALOs were, however, observed in some subgroups, including parents, although absolute risk estimates were low and comparable to the general population. FDRs of patients with MASLD did not have a higher rate of incident MALO than the general population. Since the absolute risk of MALO in relatives of patients with MASLD was low, these results do not support systematic screening of MASLD-related fibrosis in relatives of patients with MASLD.

Trajectory of reward-related abnormalities in unaffected relatives of patients with bipolar disorder – A longitudinal fMRI study

First-degree relatives of patients with bipolar disorder are at heightened risk of mood episodes, which may be attributed to the existence of endophenotypes i.e., heritable (neuro)biological changes present in patients and their unaffected relatives (UR). In this longitudinal MRI study, we aim to investigate the trajectories of aberrant reward-related functional changes identified in UR vs healthy controls (HC). Sixty-eight UR and 65 HC of similar age and gender distribution underwent MRI at baseline while performing a card guessing task. Of these, 29 UR and 36 HC were investigated with the same protocol following a 16-month period in average. We first identified brain regions showing group differences in the neural response to expected value (EV) and reward prediction error (PE) at baseline and analyzed how the reward-related response in these regions changed over time in UR vs HC. Relative to HC at baseline, UR showed lower EV signal in the right ventrolateral prefrontal cortex (vlPFC) and paracingulate gyrus and lower PE signal in the left vlPFC and dorsomedial PFC. The trajectories of these abnormalities in UR showed a normalization of the prefrontal EV signals, whereas the PE signals which correlated with depressive symptoms remained stable over time. While the UR showed both blunted EV and PE signals, none of these abnormalities increased over time, which is consistent with the observed stable mood symptoms.

The China Monoclonal Gammopathy Screening Project in First-Degree Relatives of Patients with Multiple Myeloma (CHAPERONE) –a Multicenter Screening Study

Background and Significance: Multiple myeloma (MM) evolves from the precursor state monoclonal gammopathy of undetermined significance (MGUS). According to previous reports, the incidence of MM and its precancerous state MGUS was lower in Asian populations than in Western populations. However, with the aging of the population, we found that the incidence of MM in China has been on the rise in recent years, and the medical burden has continued to increase. Therefore, early recognition of MM and its precursor condition is even more critical. Our previous research has confirmed that monoclonal gammopathy (M-protein) screening and close follow-up of MGUS can increase the early diagnosis rate of MM and improve the prognosis of MM patients[1]. M-protein screening in healthy people at high risk for MM is a rational strategy. The risk of MM in the first-degree relatives of myeloma patients is 2-4 times that of the general population, constituting a high-risk group for MM. Although the screening of M-protein in high-risk populations has been explored in the US (the PROMISE study), little was known about the incidence, clinical features, and prognosis of MGUS in high-risk groups in China. Here, we describe the first prospective screening project to assess the potential benefits of M-protein screening and the prevalence and outcomes of MGUS in first-degree relatives of patients with multiple myeloma in the China population (NCT05965115). Study Design and Methods: The CHAPERONE study is a prospective, multicenter screening study for MGUS in first-degree relatives of MM patients, including a risk-stratified follow-up strategy(Figure). Clinical trial registry number: NCT05965115, actively recruiting. This study aims to assess the clinical significance of screening for monoclonal gammopathy in first-degree relatives of patients with multiple myeloma in China. The primary objective is to determine the prevalence and incidence rate of MGUS, the time to disease progression (TTP), and its influencing factors in first-degree relatives of MM patients in China. The secondary and exploratory study objective is to explore the clinical/genomic features, survival, and quality of life of the screened MGUS cases. The expected screening size is 10,000 healthy persons. To be eligible, participants must be over 18, with one or more first-degree relatives (including parents, children, and biological siblings) having multiple myeloma diagnosed by the International Myeloma Working Group (IMWG) Myeloma Diagnostic Criteria. Participants with a known diagnosis of plasma cell diseases, such as MGUS, smoldering myeloma (SMM), or MM, will be excluded. All eligible participants will receive M-protein screening by serum electrophoresis. Individuals with detected M-protein will undergo further diagnostic tests, including peripheral blood tests (immunofixation electrophoresis, serum free light chain, immunoglobulin quantification, blood routine, liver and kidney function, and blood calcium level) and X-ray bone assays. Patients with suspecting MM features will undergo further bone marrow surveys to ascertain the diagnosis. Patients with MGUS will be carefully assessed and stratified by the risk of progression to MM according to the IMWG MGUS consensus. Low-risk MGUS will be followed-up annually, while intermediate/high-risk MGUS will be biannual. Participants who progress to MM will be offered early treatment. Conclusions and Future Directions: One path to making MM a preventable cancer is better understanding its precursor condition (MGUS). This trial is positioned to provide epidemiology, clinical, and potential mechanistic data on MGUS at a high-risk group in China population that has yet to be thoroughly studied. Reference: [1] Li J, Wang Y, Liu P. The impact on early diagnosis and survival outcome of M-protein screening-driven diagnostic approach to multiple myeloma in China: a cohort study[J]. J Cancer, 2019, 10(20): 4807-4813.

The prevalence and risk factors of kidney disease in first degree relatives of patients with ESRD treatment – single center study

Objective: To determine the prevalence and risk factors of kidney disease in first degree relatives of patients undergoing treatment for end-stage renal disease. Method: The prospective, cross-sectional study was conducted at the Sindh Institute of Urology and Transplantation, Karachi, from May 1 to July 31, 2021, and comprised patients undergoing treatment for end-stage renal disease at the pre-transplant out-patients clinic, and their first degree relatives. Risk factors of chronic kidney disease, including age, gender, body mass index, hypertension, diabetes mellitus, and the causes of index cases were investigated alongside proteinuria, haematuria and estimated glomerular filtration rate. Diagnosis was made according to the criteria of the National Kidney Foundation-Kidney Disease Outcomes Quality Initiative. The participants were divided chronic kidney disease group 1, and healthy group 2. The risk factors were compared between the groups. Data was analysed using SPSS 22. Results: Of the 1,406 subjects assessed, 266(19%) were ESRD patients; 175(65.8%) males and 91(34.2%) females with mean age 34.04±11.19 years. 1,140(81%) first degree relatives of these 266 ESRD patient were assessed; 595(52.2%) males and 545(47.8%) females with mean age 36.78±13.76 years. Among the relatives, 146(12.8%) had chronic kidney disease out of which 54 (4.7%) were already aware of their underlying disease. Older age, hypertension and diabetes mellitus were among the risk factors for chronic kidney disease (p<0.05), while gender was not significantly different between groups 1 and 2 (p>0.05). The relatives of index cases with underlying stone disease were at higher risk of haematuria 39(22.4%), whereas the relatives of index cases with chronic glomerulonephritis were at higher risk of proteinuria 67(28.03%) compared to index cases of other kinds (p<0.05). Conclusion: Screening in the high-risk population might help to identify early chronic kidney disease patients for making suitable interventions to prevent disease progression. Key Words: ESRD, First degree relatives, CKD.

Cardiovascular Disease Risk Profiling among First-Degree Relatives of Premature Coronary Artery Disease Patients

Background and Aims: First-degree relatives of patients with premature coronary artery disease are at heightened risk of cardiovascular events due to the synergy of genetic and environmental factors. The aim of this study was to assess the cardiovascular disease (CVD) risk factors and to estimate cardiovascular risk in first-degree relatives of patients with premature CAD. Methods: The study was conducted among first-degree relatives of patients with coronary artery disease in a tertiary care hospital in Kathmandu. A total of 144 first-degree relatives aged 18 years or older participated in this study. Age and gender matched subjects with no clinical evidence of CAD and no history of premature CAD in frst degree relatives were recruited as controls. The cardiovascular risk of study participants was assessed using the American Heart Association (AHA) Cardiovascular Risk Assessment Tool. Result: The study age group was between 18 to 59 years. The mean age of the subjects was 35.54 ± 10.57 years and 63.19% of subjects were men. A statistically significant number of first-degree relatives of premature CAD were found to be hypertensive and had metabolic syndrome. CVD risk factors like physical inactivity, smoking, diabetes, and dyslipidemia were found in 46.5%, 47.22%, 13.2%, and 52.01%, of the study participants, respectively. Conclusion: The study highlights the widespread presence of risk factors and underlying medical conditions among young study participants both with and without a family history of premature CAD. Appropriate direction based on opportunistic screening programs and risk stratifcation should be initiated which can play an important role in the primary prevention of early CAD.

Screening uptake of colonoscopy versus fecal immunochemical testing in first-degree relatives of patients with non-syndromic colorectal cancer: A multicenter, open-label, parallel-group, randomized trial (ParCoFit study).

Colonoscopy screening is underused by first-degree relatives (FDRs) of patients with non-syndromic colorectal cancer (CRC) with screening completion rates below 50%. Studies conducted in FDR referred for screening suggest that fecal immunochemical testing (FIT) was not inferior to colonoscopy in terms of diagnostic yield and tumor staging, but screening uptake of FIT has not yet been tested in this population. In this study, we investigated whether the uptake of FIT screening is superior to the uptake of colonoscopy screening in the familial-risk population, with an equivalent effect on CRC detection. This open-label, parallel-group, randomized trial was conducted in 12 Spanish centers between February 2016 and December 2021. Eligible individuals included asymptomatic FDR of index cases <60 years, siblings or ≥2 FDR with CRC. The primary outcome was to compare screening uptake between colonoscopy and FIT. The secondary outcome was to determine the efficacy of each strategy to detect advanced colorectal neoplasia (adenoma or serrated polyps ≥10 mm, polyps with tubulovillous architecture, high-grade dysplasia, and/or CRC). Screening-naïve FDR were randomized (1:1) to one-time colonoscopy versus annual FIT during 3 consecutive years followed by a work-up colonoscopy in the case of a positive test. Randomization was performed before signing the informed consent using computer-generated allocation algorithm based on stratified block randomization. Multivariable regression analysis was performed by intention-to-screen. On December 31, 2019, when 81% of the estimated sample size was reached, the trial was terminated prematurely after an interim analysis for futility. Study outcomes were further analyzed through 2-year follow-up. The main limitation of this study was the impossibility of collecting information on eligible individuals who declined to participate. A total of 1,790 FDR of 460 index cases were evaluated for inclusion, of whom 870 were assigned to undergo one-time colonoscopy (n = 431) or FIT (n = 439). Of them, 383 (44.0%) attended the appointment and signed the informed consent: 147/431 (34.1%) FDR received colonoscopy-based screening and 158/439 (35.9%) underwent FIT-based screening (odds ratio [OR] 1.08; 95% confidence intervals [CI] [0.82, 1.44], p = 0.564). The detection rate of advanced colorectal neoplasia was significantly higher in the colonoscopy group than in the FIT group (OR 3.64, 95% CI [1.55, 8.53], p = 0.003). Study outcomes did not change throughout follow-up. In this study, compared to colonoscopy, FIT screening did not improve screening uptake by individuals at high risk of CRC, resulting in less detection of advanced colorectal neoplasia. Further studies are needed to assess how screening uptake could be improved in this high-risk group, including by inclusion in population-based screening programs. This trial was registered with ClinicalTrials.gov (NCT02567045).

Assessment of risk of ALS conferred by the GGGGCC hexanucleotide repeat expansion in C9orf72 among first-degree relatives of patients with ALS carrying the repeat expansion

Objectives We aimed to estimate the age-related risk of ALS in first-degree relatives of patients with ALS carrying the C9orf72 repeat expansion. Methods We included all patients with ALS carrying a C9orf72 repeat expansion in The Netherlands. Using structured questionnaires, we determined the number of first-degree relatives, their age at death due to ALS or another cause, or age at time of questionnaire. The cumulative incidence of ALS among first-degree relatives was estimated, while accounting for death from other causes. Variability in ALS risk between families was evaluated using a random effects hazards model. We used a second, distinct approach to estimate the risk of ALS and FTD in the general population, using previously published data. Results In total, 214 of the 2,486 (9.2%) patients with ALS carried the C9orf72 repeat expansion. The mean risk of ALS at age 80 for first-degree relatives carrying the repeat expansion was 24.1%, but ranged between individual families from 16.0 to 60.6%. Using the second approach, we found the risk of ALS and FTD combined was 28.7% (95% CI 17.8%–54.3%) for carriers in the general population. Conclusions On average, our estimated risk of ALS in the C9orf72 repeat expansion was lower compared to historical estimates. We showed, however, that the risk of ALS likely varies between families and one overall penetrance estimate may not be sufficient to describe ALS risk. This warrants a tailor-made, patient-specific approach in testing. Further studies are needed to assess the risk of FTD in the C9orf72 repeat expansion.

Empowering Family Glaucoma Risk Communication Using QR-Code-Mediated Online Intervention

Attempts at engaging relatives of glaucoma patients in education and screening have had limited success. This study explores the feasibility of an electronic intervention to facilitate direct yet reliable glaucoma risk communication between open-angle glaucoma patients (probands) and their first-degree relatives (FDRs). Prospective survey and assessment of intervention. Fifty adult probands, engaging 140 FDRs. Phase I was an iterative process involving creating a customized website and Quick Response (QR)-code-based intervention designed with input from probands, FDRs of patients, community members, and researchers. In phase II, the intervention was deployed in a clinical setting; this involved recruiting probands who had a smartphone and were willing to use the QR-code to message their FDRs a standard message, including a website link about glaucoma risk in FDRs and the importance of getting examined. Follow-up interviews were conducted with probands 1 to 2 weeks after their clinic visit to assess the impact of the intervention. Demographic data, website analytics, and participant feedback were collected and analyzed. Increased awareness of glaucoma risk among FDRs and enhanced discussions. At the time of the first interview, probands reported that 70% of the FDRs were aware of the probands' glaucoma diagnosis, but only 26% had undergone glaucoma screening. Ninety percent of probands had no issues using the QR-codes. Website analytics recorded 73 visits from 51 distinct internet protocol addresses (IPs). After receiving the standard message, 95% of FDRs followed up with the probands, actively discussing glaucoma. Of the probands, 84% completed the follow-up interview 1 to 2 weeks after enrollment. Fifty-nine percent of the FDRs were reported to have scheduled screening appointments. The collected feedback revealed that 96% of probands found the intervention helpful, fostering glaucoma discussions with their FDRs and improving probands' comfort level in discussing health issues with FDRs from baseline (very comfortable: 88%, comfortable: 8%, neutral: 2%, and very uncomfortable: 2%) to the follow-up interview (very comfortable: 98% and comfortable: 2%). This innovative online method of communicating the risk of glaucoma to FDRs of probands prompted and increased the comfort level of familial discussions of glaucoma. More than half of FDRs reported making an appointment to get screened for glaucoma. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

FRI686 Phenotypic Profiling And Molecular Mechanisms In Hyperparathyroidism-jaw Tumor Syndrome

Abstract Disclosure: R. Tora: None. J. Welch: None. J. Sun: None. S.K. Agarwal: None. D.A. Bell: None. M. Merino: None. L.S. Weinstein: None. W.F. Simonds: None. S. Jha: None. Background: Hyperparathyroidism-Jaw Tumor (HPT-JT) syndrome is a heritable form of primary hyperparathyroidism (PHPT) that is associated with tumors in the parathyroid, jaw, kidney, and uterus. We previously presented on the clinical characteristics of primary hyperparathyroidism in our cohort. Methods: We now expand on the report through review of uterine tumors, immunohistochemical staining for parafibromin, sequencing of parathyroid and kidney tumor tissue, and RNA-seq of parathyroid tumors. Results: We identified 68 patients (36 males, 32 females) from 29 kindreds with HPT-JT with median age at last follow-up of 39 [29-53] years. Of these, 7 patients were unaffected (2 males, 5 females). Among females, 12/32 (38%) developed uterine tumors with multiple adenomyomatous polyps, an unusual form of endometrial polyps seen in 10/24 tumors (42%). Given that these types of lesions are very rare in the general population, it is likely that such epithelial-mesenchymal uterine proliferations are a characteristic feature of HPT-JT syndrome.Solid kidney tumors were seen in 4/61 patients (7%). Three had surgery for the tumors - 2/3 were female and had mixed epithelial stromal tumor, while the third patient, a 6-year old male, had metastatic Wilm’s tumor as his initial disease-related manifestation. Among these, two had a germline CDC73 variant at the p.M1 residue while the third patient had the germline variant p.L95P; however, sequencing of his tumor tissue showed a “second hit” at the p.M1 residue resulting in loss of heterozygosity in the tumor. The fourth patient, a female with p.Y55S variant, is being conservatively managed with no kidney surgery yet. All three women with kidney tumors also had a history of uterine tumors. Parafibromin staining of 19 available CDC73 related parathyroid tumors (13 adenomas and 6 carcinoma) did not correlate with histology or genotype. Pathway analysis of 21 parathyroid tumors (8 HPT-JT-related adenomas, 6 HPT-JT-related carcinomas and 7 sporadic parathyroid carcinoma with wild-type CDC73) showed a significant association of HPT-JT-related parathyroid carcinoma with growth, transmembrane receptor protein tyrosine kinase signaling and mesodermal commitment pathways. Conclusion: Multiple, recurrent atypical adenomyomatous uterine polyps appear to be characteristic of HPT-JT syndrome. Our findings support germline testing at a young age in first-degree relatives of patients with HPT-JT given onset of manifestations as early as 6 years. Variants at M1 residue appear to predispose to genitourinary tumors. At present, there are no therapeutic approaches to compensate for CDC73 inactivation. Future research to identify standards of care and therapeutics targets are warranted for this rare disease. Presentation: Friday, June 16, 2023

OC 72.4 Risk of Venous Thromboembolism (VTE) in First-Degree Relatives of Patients with VTE Compared with General Population VTE Risk

OC 72.4 Risk of Venous Thromboembolism (VTE) in First-Degree Relatives of Patients with VTE Compared with General Population VTE Risk

Cognitive impairment in 'non-user' first-degree relatives of persons with cannabis dependence syndrome: A pilot, endophenotype study.

Cannabis use disorders are global emerging problem nowadays, with high prevalence and morbidity. Cognitive impairments, and also corresponding genetic vulnerability, has been fairly replicated in individuals with cannabis dependence. However, there are few studies that assess cognitive functioning as an endophenotype or a trait marker for cannabis dependence. While the primary objective of this study was to assess the endophenotype pattern of cognitive dysfunction in cannabis dependence, assessing the association between the degree of cognitive functioning, and their socio-demographicand clinical variables in the cannabis dependence patients and their first-degree relatives was the secondary objective. We compared cognitive functioning across three groups- patients with cannabis dependence syndrome, their 'non-user' first-degree relatives and healthy controls, with 30 participants in each group. Five cognitive domains- attention and concentration, verbal fluency, memory, visuospatial ability and executive functions were assessed. We assessed for endophenotype pattern of statistical significance in pairwise analyses of Kruskal-Wallis test, which was corrected for multiple comparisons. Subsequently, correlation analysis to assess association of cognitive impairment with socio-demographic and clinical variables was conducted. Although impairment in attention and executive functions also was seen in patients with cannabis dependence, endophenotype pattern of statistical significance in pairwise analyses, with impairment in first-degree relatives too, was seen in all sub-scores of verbal fluency and verbal memory. None of the correlations were significant. 'Non-user' first-degree relatives of patients with cannabis dependence too show significant cognitive impairment. Verbal fluency and verbal memory are possible endophenotypes or trait markers for cannabis dependence syndrome.

Atypical manifestation of celiac disease in carriers of HLA mutant gene

Annotation. Celiac disease is an autoimmune disease, which is manifested by enteropathy of the small intestine and is caused by the consumption of gluten-containing foods. According to statistics, the number of patients suffering from this disease has increased by 7.5% recently, which may be due to epigenetic factors and improvements in diagnostic methods of gluten intolerance. Human Leukocyte Antigen (HLA) gene plays a major role in the pathophysiological development of celiac disease. The function of HLA is an autoimmune response to endogenous and exogenous proteins. The pathogenesis of organ damage is based on an autoimmune reaction that occurs as a result of the entry of gliadin – the main component of gluten – into the organism. The influence of circulating immune complexes (CIC) leads to the appearance of typical and numerous atypical manifestations of the disease. This, in turn, significantly complicates the diagnosis and prescription of the correct treatment, which can ensure the restoration of the structure of the affected organs and improve the quality of life for patients. Atypical manifestations of gluten enteropathy are diverse, including chronic fatigue syndrome, damage to joints, bones, liver, male and female infertility, thyroid gland dysfunction, dermatitis, and tooth enamel structure disorders. Taking into account the importance of this issue, we conducted a systematic review and analysis of sources related to this question. The search was conducted in the scientometric databases PubMed, Google Scholar, Web of Science, Scopus, mostly over the last three years. In particular, it was found that screening for the specific HLA gene in first-degree relatives of patients with gluten enteropathy allows for an explanation of the exact etiology of possible atypical symptoms - manifestations of celiac disease, and subsequently prescribing a gluten-free diet that leads to the involution of the negative impact of the immune system on target organs. Moreover, this screening will be useful for identifying risk groups because manifestations of celiac disease could be in different ages and have different symptoms.

Analysis of MCP-1 Levels and TNF-alfa /Il-10 Ratio in First Degree Relatives (FDR) Type 2 Diabetes Mellitus Subjects with High Fat Diet Treatment

Type 2 diabetes mellitus is a chronic metabolic disease, which involves a variety of pathogenic processes. Overall these processes result in loss of mass and/or function of pancreatic-cells which is manifested as hyperglycemia. The influence of familial factors appears to be involved in the initiation and development of T2DM through both genetic and non-genetic factors. In the same family environment as patients with diabetes, first-degree relatives of patients with diabetes show a 30-70% increased risk of developing diabetes. Insulin resistance and cell dysfunction have been identified in individuals with a family history of diabetes, even before the onset of T2DM symptoms. Monocyte chemoattractant protein-1 (MCP-1) is a CC-chemokine with an attractant effect on monocytes, memory T cells and basophils. Expression of adipose tissue MCP-1 and circulating levels were positively correlated with adiposity. Larger adipocytes are associated with insulin resistance. This study aims to determine the changes in MCP-1 expression on monocytes before and after treatment with a high-fat diet for five days. The results showed that there was a change in inflammatory activity which was indicated by a high ratio of TNF-alfa/IL – 10 in the FDR group so that it could increase MCP-1 activity. However, there was no relationship between serum MCP-1 levels and the percentage of CD14+CD16+ monocytes in both groups.

Macular Pigment Optical Density in First Degree Relatives of Age-Related Macular Degeneration Patients

Purpose To measure the macular pigment optical density in first-degree relatives of patients with age-related macular degeneration and compare it with a healthy control group. Methods One hundred and twenty-eight healthy subjects who were first-degree relatives of age-related macular degeneration patients were included in the study (Group 1). As the control group, 74 healthy subjects were included in the study (Group 2). The right eyes of all cases were included in the study. Macular pigment optical density was measured with a commercially available device (MPSII®, Elektron Technology, Switzerland) using technology based on heterochromatic flicker photometry. Central foveal thickness and subfoveal choroidal thickness were measured with spectral-domain optical coherence tomography. Values were compared between the two groups. Results There were 54 males and 74 females in Group 1 and 32 males and 42 females in Group 2. The mean ± SD ages of Group 1 and Group 2 were 49.0 ± 7.6 and 41.8 ± 8.6, respectively. Mean ± SD macular pigment optical density values of Group 1 and Group 2 were 0.43 ± 0.09 and 0.47 ± 0.12 (p = 0.048), mean ± SD central foveal thickness were 208 ± 19 and 216 ± 8 µm (p = 0.014), and mean ± SD subfoveal choroidal thickness were 232 ± 29 and 250 ± 21 µm (p = 0.002), respectively. Conclusion The macular pigment optical density values were significantly lower in the first-degree relatives of patients with age-related macular degeneration than in the control group. Macular pigment optical density may be a marker for the development of age-related macular degeneration in the future in the first-degree relatives of age-related macular degeneration patients. Further prospective studies with a larger number of participants will be needed to confirm our results moreover, to clarify its benefit as an early diagnostic biomarker.