Heterogeneous Clinical Phenotypes Research Articles

Clinical and genetic analysis of ten Chinese pedigrees affected with 7q11.23 duplication syndrome

To analyze the clinical and genetic characteristics of ten Chinese pedigrees affected with 7q11.23 duplication syndrome. From December 2017 to January 2022, ten pedigrees diagnosed with 7q11.23 duplication syndrome at the First Affiliated Hospital of Zhengzhou University were enrolled as the study subjects. Clinical data of all subjects were collected, and some had subjected to copy number variation sequencing or single nucleotide polymorphism array to analyze the pattern of inheritance. The probands had included six fetuses and four adolescents. Four of the six prenatal cases showed abnormal ultrasound indicators, including three with soft indicators and one with abnormal fetal structural development. The clinical phenotype of the four adolescent cases had included mental retardation, delayed language development, and attention deficit hyperactivity disorder. The size of the copy number variations had ranged from 1.31 to 1.42 Mb, involving the classic region of 7q11.23 duplication syndrome. Of these, five cases had undergone parental origin testing, three cases were de novo, and two were hereditary. Individuals with 7q11.23 duplication syndrome may show substantial clinical phenotypic heterogeneity, hence the affected families should be provided with pre-pregnancy consultation and reproductive guidance.

Abstract B061: Discovering co-driver genes and pathways of mutant TP53 in breast cancer by CRISPR screening and multi-omics approaches

Abstract Triple-Negative Breast Cancer (TNBC) is the most aggressive and highly heterogeneous molecular subtype of breast cancer lacking the progesterone, HER2 and estrogen receptors. The heterogeneity of these receptors makes it difficult to target and treat. The TP53 gene which encodes the p53 protein is mutated in 80% of TNBC cases. We hypothesized that, in addition to the neo-morphic activities of different p53 mutants themselves, the heterogeneity in clinical phenotypes observed in TNBC is due to functional interactions of the p53 driver mutants with other functionally important co-existing mutations called ‘co-drivers’. To identify co-driver mutations, our lab performed a genome-wide screening by using lentiviral CRISPR libraries on a cell line over-expressing p53-R273C (a prevalent mutant form of p53), and MYC (an oncogene). Upon injection of the library-transduced cells into mice, large tumor was formed, which was extracted and subjected to targeted PCR and whole exome sequencing. This identified truncation mutations in the EVC2 (EvC Ciliary Complex Subunit 2) and the NR1D1 (Nuclear Receptor 1D1) genes. This suggested that they are tumor suppressors in their wild type functions, and loss of this native function would co-drive the formation of tumors implicated with mutant p53-R273C to promote tumor formation in vivo. EVC2 positively modulates the Hedgehog signaling pathway. Interestingly, a majority of mutations in NR1D1 were an in-frame deletion of a tyrosine residue, which may be a critical regulatory residue of NR1D1. It is known to modulate the JAK/STAT3 pathway and, just like p53, NR1D1 can inhibit the circadian clock genes. We are testing whether deleting EVC2 and NR1D1 genes by CRISPR or expressing the mutant forms in the presence of p53-R273C increase invasion and/or other cancer hallmark phenotypes and also whether the amino acid, tyrosine is critical to the regulation of NR1D1, with the goal of understanding their contributions to the development of various hallmarks of cancer and the underlying mechanisms which will identify how these mutations contribute to the progression of TNBC and could potentially provide molecularly targeted therapies for TNBC. In parallel, our lab previously carried out RNA-Seq on cell lines expressing 10 different mutant p53 proteins, where pathway analysis identified the Hippo pathway, a tumor suppressor pathway, highly associated with aggressive cellular phenotypes in the mutant p53 contexts. In cancer, it is known that, upon suppression of the upstream Hippo pathway, unphosphorylated TAZ (or WWTR1) localizes in the nucleus binds to TEAD, leading to the activation of a series of genes to promote cancer hallmark phenotypes. We are investigating the molecular mechanisms of actions through which Hippo pathway drives the progression of TNBC and assess the pathway as the target for potential therapy for TNBC with specific TP53 mutations. This study will reveal how different mutant p53 proteins regulate Hippo pathway, TAZ activation/localization, and TEAD-mediated transcription to promote invasiveness. Citation Format: Lilian Nwekwo, Anasuya Pal, Yining Zheng, Lydia Sakala, Laura Gonzalez-Malerva, Dustin Grief, Dustin Lord, Jin Park, Joshua LaBaer. Discovering co-driver genes and pathways of mutant TP53 in breast cancer by CRISPR screening and multi-omics approaches [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B061.

Emerging Role of Precision Medicine in Diagnosis and Treatment of Chronic Respiratory Disease

Precision medicine is the current approach to managing chronic respiratory diseases, especially asthma and chronic obstructive pulmonary disease (COPD). It involves the evaluation of genetic, environmental, and lifestyle variations for each patient. It requires valid and specific biomarkers obtained through genetic studies, biomolecular technology, and omics-based technology to determine targeted therapies. Asthma and COPD have heterogeneous clinical phenotype variations, and giving one standard treatment for asthma and COPD may not necessarily provide the same effectiveness to other patients. The endotype, a specific molecular mechanism in disease pathogenesis, is essential in phenotype variation. The role of precision medicine in asthma and COPD is to determine endotypes through specific biomarkers and to provide specific targeted therapy for achieving personalized treatment in each patient. The application of precision medicine not only provides precise diagnosis and treatment but also enables early detection in individuals at risk and prevention of progression and exacerbation in asthma and COPD.

P804 Does Crohn's disease extent and behavior have an impact on ustekinumab effectiveness? A real-world multicenter retrospective study

Abstract Background Crohn's disease (CD) presents heterogeneity in clinical phenotypes. Progression of disease and response to therapy have been associated, among other factors, with the extent and behavior of the disease. Real-world data on long term effectiveness of ustekinumab (UST) in CD based on disease characteristics are limited and conflicting1,2. The aim of this study is to describe real-world UST persistence according to disease distribution and perianal involvement in patients with CD. Methods This was a retrospective multicenter study involving adult patients with CD who received, at least, one dose of UST until August 2023, at 5 major hospitals in Athens, Greece. UST effectiveness based on treatment persistence was evaluated using Kaplan Meier curves for survival free of treatment discontinuation among patients with different disease extent and behavior. Log-rank test was used for statistical significance. Results A total of 147 adult CD patients who received biological treatment with UST for a median of 34 months (IQR 17-48) were included in the study. Patient baseline characteristics are shown in Table 1. UST treatment persistence rates were 93% (95% CI: 89-98) at 12 months and 87% (95% CI: 81-94) at 36 months. The persistence rate of UST differed significantly between patients with or without perianal disease (p=0.036) (Figure 1), while there was no significant difference based on disease extent (p=0.59) or behavior (p=0.31). Conclusion Our study showed that UST treatment persistence is similar in adult patients with CD, regardless of disease localization or behavior. Nonetheless, perianal disease involvement is associated with reduced treatment persistence.

"Deficiency in ELF4, X-Linked": a Monogenic Disease Entity Resembling Behçet's Syndrome and Inflammatory Bowel Disease.

Defining monogenic drivers of autoinflammatory syndromes elucidates mechanisms of disease in patients with these inborn errors of immunity and can facilitate targeted therapeutic interventions. Here, we describe a cohort of patients with a Behçet's- and inflammatory bowel disease (IBD)-like disorder termed "deficiency in ELF4, X-linked" (DEX) affecting males with loss-of-function variants in the ELF4 transcription factor gene located on the X chromosome. An international cohort of fourteen DEX patients was assessed to identify unifying clinical manifestations and diagnostic criteria as well as collate findings informing therapeutic responses. DEX patients exhibit a heterogeneous clinical phenotype including weight loss, oral and gastrointestinal aphthous ulcers, fevers, skin inflammation, gastrointestinal symptoms, arthritis, arthralgia, and myalgia, with findings of increased inflammatory markers, anemia, neutrophilic leukocytosis, thrombocytosis, intermittently low natural killer and class-switched memory B cells, and increased inflammatory cytokines in the serum. Patients have been predominantly treated with anti-inflammatory agents, with the majority of DEX patients treated with biologics targeting TNFα.

Ten Rules for the Management of Antiphospholipid Syndrome

2023 ACR/EULAR APS classification criteria started a new era for doctors to comprehensively understand this disease. According to current research evidence and clinical practice experiences, we summarize 10 rules for management of APS as followed: Rule 1: APS is a systemic autoimmune disease with multi-systemic involvement and heterogeneity of clinical phenotypes. Rule 2: Each APS related thrombotic event requires a comprehensive assessment of “risk factors”. Rule 3: APS arterial n venous events w/ different mechanisms require separate predict models of recurrency. Rule 4: APS-related arterial thrombosis are not only “thromboembolic” but also “vasculopathic”. Rule 5: Microangiopathy is an unawareness and underestimated but pivotal phenotype of APS. Rule 6: Effective screening & timely diagnosis of APS-valvular heart diseases are crucial for prevention and prognosis improvement. Rule 7: APS-related hematological involvement includes thrombocytopenia & autoimmune hemolytic anemia. Rule 8: Significant heterogeneity of OAPS indicates different mechanisms and the necessity of stratification before Treatment. Rule 9: APLs is one of major contributing factors related irreversible organ damage in SLE Rule 10: Treatment of APS requires individualized precision stratification strategies including immunomodulators.

Genetic landscape of inherited retinal dystrophies in a Welsh Tertiary Referral Centre

Aims/Purpose: Inherited retinal dystrophies (IRD) are a group of predominantly monogenic disorders which have genetically heterogeneous origins and display wide clinical phenotypic heterogeneity. The current study aims to describe the clinical diagnoses, demographics, and genetic aetiology of patients in an adult cohort of Welsh patients to provide insight into the rates of genetic diagnosis of IRD. This will help inform patient prognosis and counselling in future clinical encounters.Methods: A comprehensive database of patients attending the tertiary referral clinic from 2011 to 2022 was compiled contemporaneously. Demographic data were collated from patients' clinical records. Subjects underwent genetic screening, including targeted gene sequencing, next‐generation sequencing‐based gene panel, or whole exome sequencing, to investigate the causative mutations.Results: A total of 365 probands (191 men and 174 women). The median age at which the patients developed visual symptoms related to IRD was 42 ± 17.7 years (range, 1–86 years). Retinitis pigmentosa (176; 48.2%), Macular Dystrophy (49; 13.4%), and Cone Rod Dystrophy (41; 11.2%) were the most common clinical diagnoses in this cohort. Among all the subjects, a genetic mutation was identified in 193 (52.9%) patients and the genetic aetiology of diseases was confirmed in 147 (40.3%) patients. Pathogenic mutations were identified in 48 retinal genes with the most commonly affected genes being ABCA4, USH2A and GUCY2D with 78, 44 and 13 mutations identified overall.Conclusions: The establishment of a molecular genetic diagnosis in this group of patients serves as a basis for genetic counselling and will allow patients to enrol in current and future gene‐based clinical trials, and benefit from any future gene‐based treatments.

Clinical and molecular heterogeneity of VPS13D-related neurodevelopmental and movement disorders

BackgroundThe VPS13 family of proteins has been implicated in lipid transport and trafficking between endoplasmic reticulum and organelles, to maintain homeostasis of subcellular membranes. Recently, pathogenic variants in each human VPS13S gene, have been linked to distinct human neurodevelopmental or neurodegenerative disorders. Within the VPS13 family of genes, VPS13D is known to be implicated in mitochondria homeostasis and function. MethodsWe investigated a Pakistani sibship affected with neurodevelopmental impairment and severe hyperkinetic (choreoathetoid) movements. Whole exome sequencing (WES) and Sanger sequencing were performed to identify potential candidate variants segregating in the family. We described clinical phenotypes and natural history of the disease during a 3-year clinical follow-up and summarized literature data related to previously identified patients with VPS13D-related neurological disorders. ResultsWe identified by WES an homozygous non-synonymous variant in VPS13D (c.5723 T > C; p.Ile1908Thr) as the potential underlying cause of the disease in our family. Two young siblings developed an early-onset neurological impairment characterized by global developmental delay, with impaired speech and motor milestones, associated to hyperkinetic movement disorders as well as progressive and non-progressive neurological abnormalities. ConclusionIn this study we delineated the heterogeneity of VPS13D-related clinical phenotypes and described a novel VPS13D homozygous variant associated with severe neurological impairment. Further studies will be pivotal to understand the exact VPS13D function and its impact on mitochondria homeostasis, brain development and regulation of movements, to further clarify genotype-phenotype correlations and provide crucial prognostic information and potential therapeutic implications.

Emerging Therapeutic Options for Refractory Pulmonary Sarcoidosis: The Evidence and Proposed Mechanisms of Action.

Sarcoidosis is a systemic disease with heterogenous clinical phenotypes characterized by non-necrotizing granuloma formation in affected organs. Most disease either remits spontaneously or responds to corticosteroids and second-line disease-modifying therapies. These medications are associated with numerous toxicities that can significantly impact patient quality-of-life and often limit their long-term use. Additionally, a minority of patients experience chronic, progressive disease that proves refractory to standard treatments. To date, there are limited data to guide the selection of alternative third-line medications for these patients. This review will outline the pathobiological rationale behind current and emerging therapeutic agents for refractory or drug-intolerant sarcoidosis and summarize the existing clinical evidence in support of their use.

Prenatal diagnosis of mosaic chromosomal aneuploidy and uniparental disomy and clinical outcomes evaluation of four fetuses

BackgroundFew co-occurrence cases of mosaic aneuploidy and uniparental disomy (UPD) chromosomes have been reported in prenatal periods. It is a big challenge for us to predict fetal clinical outcomes with these chromosome abnormalities because of their highly heterogeneous clinical manifestations and limited phenotype attainable by ultrasound.MethodsAmniotic fluid samples were collected from four cases. Karyotype, chromosome microarray analysis, short tandem repeats, and whole exome sequencing were adopted to analyze fetal chromosomal aneuploidy, UPD, and gene variation. Meanwhile, CNVseq analysis proceeded for cultured and uncultured amniocytes in case 2 and case 4 and MS-MLPA for chr11 and chr15 in case 3.ResultsAll four fetuses showed mosaic chromosomal aneuploidy and UPD simultaneously. The results were: Case 1: T2(7%) and UPD(2)mat(12%). Case 2: T15(60%) and UPD(15)mat(40%). Case 3: 45,X(13%) and genome-wide paternal UPD(20%). Case 4: <10% of T20 and > 90% UPD(20)mat in uncultured amniocyte. By analyzing their formation mechanism of mosaic chromosomal aneuploidy and UPD, at least two adverse genetic events happened during their meiosis and mitosis. The fetus of case 1 presented a benign with a normal intrauterine phenotype, consistent with a low proportion of trisomy cells. However, the other three fetuses had adverse pregnancy outcomes, resulting from the UPD chromosomes with imprinted regions involved or a higher level of mosaic aneuploidy.ConclusionUPD is often present with mosaic aneuploidy. It is necessary to analyze them simultaneously using a whole battery of analyses for these cases when their chromosomes with imprinted regions are involved or known carriers of a recessive allele. Fetal clinical outcomes were related to the affected chromosomes aneuploidy and UPD, mosaic levels and tissues, methylation status, and homozygous variation of recessive genes on the UPD chromosome. Genetic counseling for pregnant women with such fetuses is crucial to make informed choices.

PIGW-related glycosylphosphatidylinositol deficiency: A case report and literature review.

PIGW-related glycosylphosphatidylinositol deficiency is a rare disease that manifests heterogeneous clinical phenotypes. We describe a patient with PIGW deficiency and summarize the clinical characteristics of the case. In addition, we conducted a literature review of previously reported patients with pathogenic variants of PIGW. A Chinese girl presented with refractoryepilepsy, severe intellectual disability, recurrent respiratory infections, and hyperphosphatasia. Seizures worsened during fever and infections, making her more susceptible to epileptic status. She was found to carry a heterozygous variant of PIGW and a deletion of chromosome 17q12 containing PIGW. Only six patients with homozygous or compound heterozygous pathogenic variants of PIGW have been identified in the literature thus far. Epileptic seizures were reported in all patients, and the most common types of seizures were epileptic spasms. Distinctive facial and physical features and recurrent respiratory infections are common in these patients with developmental delays. Serum alkaline phosphatase (ALP) levels were elevated in four of the six patients. PIGW-related glycosylphosphatidylinositol deficiency is characterized by developmental delay, epilepsy, distinctive facial features, and multiple organ anomalies. Genetic testing is an important method for diagnosing this disease, and flow cytometry and serum ALP level detection are crucial complements for genetic testing.

Subcortical deformation is uniquely related to cortical thickness among FTLD mutation carriers

AbstractBackgroundFrontotemporal lobar degeneration (FTLD) due to familial mutations results in heterogenous clinical phenotypes for which there are no specific biomarkers. Here, we test whether subcortical deformation differs in FTLD genetic mutation carriers, and if deformation was uniquely related to cortical thickness.Method317 participants from ALLFTD with familial FTLD (C9orf72 (n = 139), GRN (n = 77), and MAPT (n = 101)) and 27 controls without mutations (NCC) were evaluated. MRI data underwent FreeSurfer processing to estimate cortical thickness (CT). High‐dimensional, large‐deformation diffeomorphic metric mapping was used to model surfaces of the caudate and putamen. Regression analyses investigated the effect of mutation on CT and subcortical surface deformation, after controlling for age, sex, and education. Finally, linear models were constructed in each mutation group to explore the association between areas of significant surface deformity and CT, corrected for age and multiple comparisons.ResultFigure 1 shows significant (corrected p&lt;.05) T‐scores where mutation carrier groups differ in CT from NCC (red = greater atrophy in mutation). Figure 2 shows greater outward local deformation in the caudate body among C9 and MAPT compared to NCC. Significant relationships between deformation and CT (corrected p&lt;.05) were observed in bilateral temporoparietal, frontal and cingulate cortex in both C9 and MAPT carriers. C9 and MAPT mutation carriers have greater outward deformation in postero‐lateral putamen. Deformation was associated with CT in C9 within the left temporal and prefrontal lobes, and in the right temporoparietal, occipital and cingulate cortices for MAPT (Figure 3). No significant deformation was observed in GRN compared to NCC.ConclusionFamilial FTLD mutations are associated with subtle subcortical shape variations that show unique relationships to cortical atrophy.

Subcortical deformation is uniquely related to cortical thickness among FTLD mutation carriers

AbstractBackgroundFrontotemporal lobar degeneration (FTLD) due to familial mutations results in heterogenous clinical phenotypes for which there are no specific biomarkers. Here, we test whether subcortical deformation differs in FTLD genetic mutation carriers, and if deformation was uniquely related to cortical thickness.Method317 participants from ALLFTD with familial FTLD (C9orf72 (n = 139), GRN (n = 77), and MAPT (n = 101)) and 27 controls without mutations (NCC) were evaluated. MRI data underwent FreeSurfer processing to estimate cortical thickness (CT). High‐dimensional, large‐deformation diffeomorphic metric mapping was used to model surfaces of the caudate and putamen. Regression analyses investigated the effect of mutation on CT and subcortical surface deformation, after controlling for age, sex, and education. Finally, linear models were constructed in each mutation group to explore the association between areas of significant surface deformity and CT, corrected for age and multiple comparisons.ResultFigure 1 shows significant (corrected p&lt;.05) T‐scores where mutation carrier groups differ in CT from NCC (red = greater atrophy in mutation). Figure 2 shows greater outward local deformation in the caudate body among C9 and MAPT compared to NCC. Significant relationships between deformation and CT (corrected p&lt;.05) were observed in bilateral temporoparietal, frontal and cingulate cortex in both C9 and MAPT carriers. C9 and MAPT mutation carriers have greater outward deformation in postero‐lateral putamen. Deformation was associated with CT in C9 within the left temporal and prefrontal lobes, and in the right temporoparietal, occipital and cingulate cortices for MAPT (Figure 3). No significant deformation was observed in GRN compared to NCC.ConclusionFamilial FTLD mutations are associated with subtle subcortical shape variations that show unique relationships to cortical atrophy.

Comprehensive phenotyping of fetuses with trisomy 18: a perinatal center experience.

Trisomy 18 is the second most common aneuploidy after trisomy 21. It presents with varying degrees of heterogeneous clinical phenotypes involving multiple organ systems, with a high mortality rate. Clinical assessment of fetal trisomy 18 is always challenging. In this study, we describe the phenotypes of the fetuses with trisomy 18 from a perinatal cohort. We reviewed fetuses with trisomy 18 in referrals for perinatal autopsy over the period of 15 years. A detailed phenotyping of the fetuses with trisomy 18 was executed by perinatal autopsy. Appropriate fetal tissues were obtained to perform genomic testing. We observed trisomy 18 in 16 fetuses (2%) in our cohort of 784 fetal/neonatal losses and a perinatal autopsy was performed on all of them. Abnormal facial profile was the most frequent anomaly (10/16, 62%) followed by anomalies of the extremities (9/16, 56%), and cardiac defects (6/16, 37%). We also observed esophageal atresia, diaphragmatic hernia, and neural tube defect. The study represents one of the largest cohorts of trisomy 18 from a perinatal center from a developing country and highlights the clinical heterogeneity attributed to trisomy 18. We also report a recurrence of trisomy 18 in a family.

Wolfram syndrome type 1: a case series

BackgroundWolfram syndrome (WS) is a rare autosomal recessive multisystem neurodegenerative disease characterized by non-autoimmune insulin-dependent diabetes mellitus, optic atrophy, sensorineural deafness, and diabetes as the main features. Owing to clinical phenotypic heterogeneity, the misdiagnosis rate is high. However, early accurate diagnosis and comprehensive management are key to improving quality of life and prolonging life.ResultsEleven patients from seven WS pedigrees with 10 mutation sites (c.1314_1317delCTTT, c.C529T, c.C529A, c.G2105A, c.C1885T, c.1859_1860del, c.G2020A, c.C529A, c.G2105A, and c.G1393C) in the WFS1 gene were included. We conducted further expert department analysis to clarify the diagnosis and analyze the correlation between genes and phenotypes.ConclusionsThe genotypes of these patients were closely associated with their phenotypes. The clinical data of the patients were analyzed to provide a basis for the diagnosis and clinical management of the disease.

Biologics in the Management of Sever Atopic Dermatitis

Atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases, it is presented with heterogeneous clinical phenotypes that can alter by severity, age, and ethnic background. The chronic nature of AD necessitates safer, and newer treatment that is effective in improving quality of life [1]. A new era of therapeutics is in innovation phase including Biologic treatment and it is essential to provide a comprehensive understanding of this modality of treatment. Hence, this review presents an overview of up to date biologics that are approved or are in development for the treatment of AD.

Regional differences and coronary microvascular dysfunction in heart failure with preserved ejection fraction.

In heart failure with preserved ejection fraction (HFpEF), regional heterogeneity of clinical phenotypes is increasingly recognized, with coronary microvascular dysfunction (CMD) potentially being a common shared feature. We sought to determine the regional differences in clinical characteristics and prevalence of CMD in HFpEF. We analysed clinical characteristics and CMD in 202 patients with stable HFpEF (left ventricular ejection fraction ≥40%) in Finland, Singapore, Sweden, and United States in the multicentre PROMIS-HFpEF study. Patients with unrevascularized macrovascular coronary artery disease were excluded. CMD was assessed using Doppler echocardiography and defined as coronary flow reserve (adenosine-induced vs. resting flow)<2.5. Patients from Singapore had the lowest body mass index yet highest prevalence of hypertension, dyslipidaemia, and diabetes; patients from Finland and Sweden were oldest, with the most atrial fibrillation, chronic kidney disease, and high smoking rates; and those from United States were youngest and most obese. The prevalence of CMD was 88% in Finland, 80% in Singapore, 77% in Sweden, and 59% in the United States; however, non-significant after adjustment for age, sex, N-terminal pro-brain natriuretic peptide, smoking, left atrial reservoir strain, and atrial fibrillation. Associations between CMD and clinical characteristics did not differ based on region (interaction analysis). Despite regional differences in clinical characteristics, CMD was present in the majority of patients with HFpEF across different regions of the world with the lowest prevalence in the United States. This difference was explained by differences in patient characteristics. CMD could be a common therapeutic target across regions.

Excessive generalized and visceral adiposity is associated with a higher prevalence of diabetic retinopathy in Caucasian patients with type 2 diabetes

Background and aimsType 2 Diabetes Mellitus (T2D) has heterogeneous clinical phenotypes related to different risk of developing diabetes complications. We investigated the correlation between generalized and abdominal adiposity and the prevalence of both micro- and macrovascular complications in Caucasian patients with T2D. Methods and resultsWe evaluated 769 individuals with T2D consecutively referred to our diabetes center. Body mass index (BMI), waist circumference (WC), waist to hip (W/H) ratio, glycated hemoglobin (HbA1c), systolic and diastolic blood pressure, lipid profile, smoking habit, diabetes therapy, and micro- and macrovascular complications were recorded. Patients were divided into three groups based on BMI and WC: non-obese with normal WC (nWC, n = 220), non-obese with excess of abdominal fat (AF, n = 260) and obese (Ob, n = 289). We found that nWC, compared with AF and Ob individuals, were predominantly males (p<0.01), had lower HbA1c (p<0.01), diastolic blood pressure (p<0.01), triglycerides (p<0.01), and showed a significantly lower prevalence of diabetic retinopathy (DR) (p = 0.01). The rate of proliferative DR was significantly higher in Ob (13.2 %) compared to the other groups (p = 0.03). Multivariate analyses showed a significantly decreased prevalence of DR in nWC compared to both AF (OR 0.58, 95 CI 0.34–0.96; p = 0.03) and Ob (OR 0.57, 95 CI 0.33–0.98; p = 0.04) individuals. Conversely, DR was associated, mainly in women, to higher WC and W/H ratio. The prevalence of the other diabetes-related complications was similar among the studied groups. ConclusionsIn our population, nWC subjects showed a lower prevalence of DR. An increased generalized and abdominal adiposity was associated to a higher prevalence of DR, especially among females.

Behçet's syndrome: recent advances to aid diagnosis.

Behçet's syndrome is a recurring inflammatory multiorgan disorder affecting the skin, mucosa, eyes, joints, stomach, and central nervous system. Behçet's syndrome epidemiology varies greatly among populations (0.64-420/100,000), and Behçet's syndrome has gained increasing international acclaim in the recent 50years due to raising awareness of the syndrome, although it is rare in most population. In addition to the unclear etiology of the syndrome, the diagnosis of Behçet's syndrome is complicated by a vague clinical presentation, phenotypic heterogeneity and/or incomplete representation, and the lack of any specific laboratory, radiographic, or histological findings. There exists a dire need to elucidate factors that contribute to disease pathogenesis and/or are associated with clinical features of Behçet's syndrome and the classification of different forms of the syndrome. The identification of such molecular, cellular, and/or clinical factors are crucial for timely diagnosis and efficacious management of Behçet's syndrome. We discuss recent advances in the clinical diagnosis of Behçet's syndrome and related contributions of genetics, epigenetics, microbiome, inflammasomes, and autoantibodies to the improved diagnosis, management, and understanding of Behçet's syndrome.

Discrepancies in Patient and Caregiver Ratings of Personality Change in Alzheimer's Disease and Related Dementias.

Personality change in Alzheimer's disease and related dementias (ADRD) is complicated by the patient and informant factors that confound accurate reporting of personality traits. We assessed the impact of caregiver burden on informant report of Big Five personality traits (extraversion, agreeableness, conscientiousness, neuroticism, and openness) and investigated the regional cortical volumes associated with larger discrepancies in the patient and informant report of the Big Five personality traits. Sixty-four ADRD participants with heterogeneous neurodegenerative clinical phenotypes and their informants completed the Big Five Inventory (BFI). Caregiver burden was measured using the Zarit Burden Interview. Discrepancy scores were computed as the difference between patient and informant ratings for the BFI. Regional gray matter volumes from T1-weighted 3T MRI were normalized to intracranial volume and related to global Big Five discrepancy scores using linear regression. Higher levels of caregiver burden were associated with higher informant ratings of patient neuroticism (ß = 0.08, p =.012) and with lower informant ratings of patient agreeableness (ß = 0.11, p =.021) and conscientiousness (ß = 0.04, p =.034) independent of disease severity. Patients with greater Big Five discrepancy scores showed smaller cortical volumes in the right medial prefrontal cortex (β = -5.24, p =.045) and right superior temporal gyrus (β = -7.91, p =.028). Informant ratings of personality traits in ADRD can be confounded by the caregiver burden, highlighting the need for more objective measures of personality and behavior in dementia samples. Discrepancies between informant and patient ratings of personality may additionally reflect loss of insight secondary to cortical atrophy in the frontal and temporal structures.