Pre-attentive and Attentive Auditory Event-related Potentials in Children With Attention-Deficit Hyperactivity Disorder and Autism.

Abnormalities in auditory processing are believed to play a major role in autism and attention-deficit hyperactivity disorder (ADHD). Both conditions often co-occur in children, causing difficulties in deciding the most promising intervention. Event-related potentials (ERPs) have been investigated and are showing promise to act as potential biomarkers for both conditions. This study investigated mismatch negativity (MMN) using a passive listening task and P3b in an active auditory go/no-go discrimination task. Recordings were available from 103 children (24 females): 35 with ADHD, 27 autistic, 15 autistic children with co-occurring ADHD, and 26 neurotypical (NT) children. The age range considered was between 4 and 17 years, but varied between groups. The results revealed increases in the MMN and P3b amplitudes with age. Older children with ADHD exhibited smaller P3b amplitudes, while younger autistic children showed reduced MMN amplitudes in response to phoneme changes compared to their NT counterparts. Notably, children diagnosed with autism and ADHD did not follow this pattern; instead, they exhibited more similarities to NT children. The reduced amplitudes of phonetically elicited MMN in children with autism and reduced P3b in children with ADHD suggest that the two respective ERPs can act as potential biomarkers for each condition. However, optimisation and standardisation of the testing protocol, as well as longitudinal studies are required in order to translate these findings into clinical practice.

Biosynthesis of photostable CdS quantum dots by UV-resistant psychrotolerant bacteria isolated from Union Glacier, Antarctica.

BACKGROUND: Quantum Dots (QDs) are fluorescent nanoparticles with exceptional optical and optoelectronic properties, finding widespread utility in diverse industrial applications. Presently, chemically synthesized QDs are employed in solar cells, bioimaging, and various technological domains. However, many applications demand QDs with prolonged lifespans under conditions of high-energy radiation. Over the past decade, microbial biosynthesis of nanomaterials has emerged as a sustainable and cost-effective process. In this context, the utilization of extremophile microorganisms for synthesizing QDs with unique properties has recently been reported. RESULTS: In this study, UV-resistant bacteria were isolated from one of the most extreme environments in Antarctica, Union Glacier at the Ellsworth Mountains. Bacterial isolates, identified through 16 S sequencing, belong to the genera Rhodococcus, Pseudarthrobacter, and Arthrobacter. Notably, Rhodococcus sp. (EXRC-4 A-4), Pseudarthrobacter sp. (RC-2-3), and Arthrobacter sp. (EH-1B-1) tolerate UV-C radiation doses ≥ 120 J/m². Isolated UV-resistant bacteria biosynthesized CdS QDs with fluorescence intensities 4 to 8 times higher than those biosynthesized by E. coli, a mesophilic organism tolerating low doses of UV radiation. Transmission electron microscopy (TEM) analysis determined QD sizes ranging from 6 to 23 nm, and Fourier-transform infrared (FTIR) analysis demonstrated the presence of biomolecules. QDs produced by UV-resistant Antarctic bacteria exhibit high photostability after exposure to UV-B radiation, particularly in comparison to those biosynthesized by E. coli. Interestingly, red fluorescence-emitting QDs biosynthesized by Rhodococcus sp. (EXRC-4 A-4) and Arthrobacter sp. (EH-1B-1) increased their fluorescence emission after irradiation. Analysis of methylene blue degradation after exposure to irradiated QDs biosynthesized by UV-resistant bacteria, indicates that the QDs transfer their electrons to O2 for the formation of reactive oxygen species (ROS) at different levels. CONCLUSIONS: UV-resistant Antarctic bacteria represent a novel alternative for the sustainable generation of nanostructures with increased radiation tolerance-two characteristics favoring their potential application in technologies requiring continuous exposure to high-energy radiation.

Elevated Prostaglandin E2 Synthesis Is Associated with Clinical and Radiological Disease Severity in Cystic Fibrosis.

Background: Previous studies found high but very variable levels of tetranor-PGEM and PGDM (urine metabolites of prostaglandin (PG) E2 and PGD2, respectively) in persons with cystic fibrosis (pwCF). This study aims to assess the role of cyclooxygenase COX-1 and COX-2 genetic polymorphisms in PG production and of PG metabolites as potential markers of symptoms' severity and imaging findings. Methods: A total of 30 healthy subjects and 103 pwCF were included in this study. Clinical and radiological CF severity was evaluated using clinical scoring methods and chest computed tomography (CT), respectively. Urine metabolites were measured using liquid chromatography/tandem mass spectrometry. Variants in the COX-1 gene (PTGS1 639 C>A, PTGS1 762+14delA and COX-2 gene: PTGS2-899G>C (-765G>C) and PTGS2 (8473T>C) were also analyzed. Results: PGE-M and PGD-M urine concentrations were significantly higher in pwCF than in controls. There were also statistically significant differences between clinically mild and moderate disease and severe disease. Patients with bronchiectasis and/or air trapping had higher PGE-M levels than patients without these complications. The four polymorphisms did not associate with clinical severity, air trapping, bronchiectasis, or urinary PG levels. Conclusions: These results suggest that urinary PG level testing can be used as a biomarker of CF severity. COX genetic polymorphisms are not involved in the variability of PG production.

Influence of the HLA-Cw6 Allele and IFIH1/MDA5 Gene Variants on the Cardiometabolic Risk Profile of Patients with Psoriatic Disease.

BACKGROUND: Cardiovascular comorbidity is a common companion of psoriasis and psoriatic arthritis (PsA). Recently, a significant link has been found between the HLA-Cw6 allele and a better cardiometabolic profile in these patients. We aimed to check this finding in our setting. METHODS: A cross-sectional observational study (n: 572 psoriasis patients, 30% with PsA) was conducted. Different study variables were collected in detail, as well as classic cardiometabolic risk factors. The distribution of the HLA-Cw6 allele and the IFIH1/MDA5 gene variants previously linked to disease risk were determined in the study cohort and stratified according to the cardiometabolic comorbidity. Linear and logistic regression models were constructed to analyze these associations. RESULTS: The study cohort included 309 men and 263 women, with a mean age of 46.7 years (SD 14.5) and a mean disease duration of 19.4 years (SD 14.8). We confirmed the known association between HLA-Cw6 and type I psoriasis (familial, severe, and early onset). Psoriasis severity (OR: 2.14), female sex (OR: 1.63), and the IFIH1/MDA5 rs1990760 TT genotype (OR: 1.62) were significantly related to PsA, while HLA-Cw6 was protective (OR: 0.65). HLA-Cw6 carriers showed a lower waist perimeter, lower BMI, and lower risk of both hypertension (OR: 0.52, p < 0.001) and diabetes (OR: 0.36, p < 0.001), but these findings were no longer apparent upon adjusting the regression models. No IFIH1/MDA5 gene variant was associated with any cardiometabolic risk factor. CONCLUSIONS: The influence of HLA-Cw6 on the cardiometabolic risk profile of psoriatic patients seems to be explained by other factors (age, sex, duration of the disease or arthritis) and not by this biomarker itself.

Shrinking body size of European anchovy in the Bay of Biscay.

Decreased body size is often cited as a major response to ocean warming. Available evidence, however, questions the actual emergence of shrinking trends and the prevalence of temperature-driven changes in size over alternative drivers. In marine fish, changes in food availability or fluctuations in abundance, including those due to size-selective fishing, provide compelling mechanisms to explain changes in body size. Here, based on three decades of scientific survey data (1990-2021), we report a decline in the average body size-length and weight-of anchovy, Engraulis encrasicolus L., in the Bay of Biscay. Shrinking was evident in all age classes, from juveniles to adults. Allometric adjustment indicated slightly more pronounced declines in weight than in total length, which is consistent with a change toward a slender body shape. Trends in adult weight were nonlinear, with rates accelerating to an average decline of up to 25% decade-1 during the last two decades. We found a strong association between higher anchovy abundance and reduced juvenile size. The effect of density dependence was less clear later in life, and temperature became the best predictor of declines in adult size. Theoretical analyses based on a strategic model further suggested that observed patterns are consistent with a simultaneous, opposing effect of rising temperatures on accelerating early growth and decreasing adult size as predicted by the temperature-size rule. Macroecological assessment of ecogeographical-Bergmann's and James'-rules in anchovy size suggested that the observed decline largely exceeds intraspecific variation and might be the result of selection. Limitations inherent in the observational nature of the study recommend caution and a continued assessment and exploration of alternative drivers. Additional evidence of a climate-driven regime shift in the region suggests, however, that shrinking anchovy sizes may signal a long-lasting change in the structure and functioning of the Bay of Biscay ecosystem.

Patient with adrenal insufficiency due to a de novo mutation in the NR0B1 gene.

Objectives: Congenital X-linked adrenal hypoplasia is a rare disease with a known genetic basis characterized by adrenal insufficiency, hypogonadotropic hypogonadism, and a wide variety of clinical manifestations. Case presentation: We present the case of a 26-day old male newborn with symptoms consistent with adrenal insufficiency, hyponatremia, and hyperkalemia. Following NaCl and fludrocortisone supplementation, the patient remained clinically stable. 17-OH-progesterone testing excluded congenital adrenal hyperplasia. The rest of hormones were within normal limits, except for adrenocorticotropic hormone (ACTH), which was significantly elevated, and aldosterone, which was below the reference value. Further testing included very long chain fatty acids to exclude adrenoleukodystrophy, the CYP11B2 gene (aldosterone synthase), and an MRI to screen for other morphological abnormalities. All tests yielded normal results. Finally, after cortisol deficiency was detected, expanded genetic testing revealed a mutation in the NR0B1 gene, which led to a diagnosis of congenital adrenal hypoplasia. Conclusions: Diagnosis of congenital adrenal hypoplasia is challenging due to the heterogeneity of both clinical manifestations and laboratory abnormalities. As a result, diagnosis requires close monitoring and genetic testing.

Preliminary experience of the use of self-expanding nititol stent in refractory variceal bleeding: a real-world study.

BACKGROUND AND AIMS: The fully-covered self-expanding metal stent (SEMS) has a role in the management of refractory acute variceal haemorrhage. The aim of this study was to evaluate its effectiveness and complications in real-world practice. PATIENTS AND METHODS: An observational, descriptive, multicenter study was carried out. Eight patients with clinically significant portal hypertension who underwent a SEMS were included. RESULTS: SEMS placement controlled acute bleeding in 7 patients with technical success. Stents were removed after a median of 8 days. Rescue transjugular intrahepatic portosystemic shunt was performed around 48 hours after SEMS placement. Four patients survived after successful SEMS removal. The most common adverse event was stent loop in 2 patients. CONCLUSIONS: In our experience, SEMS was highly effective in controlling acute refractory variceal bleeding. Bleeding-related mortality rate was probably due to impossibility of TIPS implantation. Stent loop was a common limiting factor.

Epidemiological measures: application and interpretation in real-life scenarios according to epidemiological study designs

Frequency, association and impact measures are key concepts in clinical epidemiology; however, it has been found that a considerable proportion of health students and professionals have no knowledge of how to use or interpret them when reading a scientific paper or conducting research. This article aims to explain the main epidemiological measures, how they are used, derived and interpreted. They are approached from the perspective of each of the most frequently used types of primary quantitative research studies (randomized clinical trials, cohort studies, case-control estudies and cross-sectional studies) in order to provide the reader with the context in which they are used. Moreover, the process for calculating and interpreting each result in a real setting is explained using clinical examples for a better understanding of these concepts and in order to prevent their use from becoming just a mechanical or repetitive exercise.

Las medidas de frecuencia, asociación e impacto son conceptos fundamentales de la epidemiología clínica; sin embargo, se ha encontrado que una parte considerable de los estudiantes y de los profesionales en el área de la salud no sabe cómo usarlas ni cómo interpretarlas al leer un texto científico o al hacer una investigación. Este artículo busca explicar las principales medidas epidemiológicas, cuándo se usan, cómo se obtienen y cómo se interpretan. Se abordan desde cada tipo de estudios primarios más frecuentemente utilizados cuando se realizan investigaciones cuantitativas (ensayos clínicos aleatorizados, estudios de cohorte, casos y controles y estudios de corte transversal), con el fin de darle al lector el contexto en el cual se usan. Además, mediante ejemplos clínicos, se explica el proceso para calcular e interpretar cada resultado en un escenario real, con el fin de lograr una mayor comprensión de estos conceptos y de que su uso no sea un ejercicio mecánico o de repetición.

Topical delivery systems containing clotrimazole for the management of candidiasis: Effect of different excipients and enhanced antifungal activity of nanovesicles.

WHO classified Candida albicans as one of the four critical priority fungi for public health worldwide in 2022. Conventional topical formulations commercially available for the treatment of cutaneous candidiasis are associated with low drug bioavailability at the infection site and the lack of a sustained therapeutic effect. The main objectives of this work were to develop new topical administration systems of clotrimazole (CLT) and study the influence of surfactants on the antifungal inhibitory efficacy. Therefore, the minimum concentration of CLT required to inhibit 50 % of growth (MIC50) was determined, obtaining a value of approximately 15 ng/mL. A non-ionic emulsion type 1, Beeler base cream, hydrogel and liposomes containing CLT were designed, prepared, characterized and their antifungal activity against C. albicans was tested. CLT loaded liposomes were small in size (102 nm), homogeneous (polydispersity index = 0.3) and uncharged (+0.07 mV), showing higher antifungal activity against C. albicans than that of the commercially available cream Canesten®. Furthermore, the antifungal activity of CLT was reduced in combination with surfactants such as Tween-80/Span-80 or Brij-S10. Sodium lauryl sulphate showed a fungicidal effect that disappeared when formulated as part of the Beeler base cream.

Dynamic Changes in Non-Invasive Markers of Liver Fibrosis Are Predictors of Liver Events after SVR in HCV Patients.

Objectives: The course of progressive liver damage after achieving sustained virological response (SVR) with direct-acting antivirals (DAAs) remains undetermined. We aimed to determine risk factors associated with the development of liver-related events (LREs) after SVR, focusing on the utility of non-invasive markers. Methods: An observational, retrospective study that included patients with advanced chronic liver disease (ACLD) caused by hepatitis C virus (HCV), who achieved SVR with DAAs between 2014 and 2017. Patients were followed-up until December 2020. LREs were defined as the development of portal hypertension decompensation and the occurrence of hepatocellular carcinoma (HCC). Serological markers of fibrosis were calculated before treatment and one and two years after SVR. Results: The study included 321 patients, with a median follow-up of 48 months. LREs occurred in 13.7% of patients (10% portal hypertension decompensation and 3.7% HCC). Child-Pugh [HR 4.13 (CI 95% 1.74; 9.81)], baseline FIB-4 [HR 1.12 (CI 95% 1.03; 1.21)], FIB-4 one year post-SVR [HR 1.31 (CI 95% 1.15; 1.48)] and FIB-4 two years post-SVR [HR 1.42 (CI 95% 1.23; 1.64)] were associated with portal hypertension decompensation. Older age, genotype 3, diabetes mellitus and FIB-4 before and after SVR were associated with the development of HCC. FIB-4 cut-off values one and two years post-SVR to predict portal hypertension decompensation were 2.03 and 2.21, respectively, and to predict HCC were 2.42 and 2.70, respectively. Conclusions: HCV patients with ACLD remain at risk of developing liver complications after having achieved SVR. FIB-4 evaluation before and after SVR may help to predict this risk, selecting patients who will benefit from surveillance.

Situación Nutricional de embarazadas y lactantes haitianos atendidos en el CESFAM "Los Castaños" de la comuna de La Florida, Región Metropolitana, Chile

En Chile, al 31 de diciembre del 2020 un 12,5% de los extranjeros eran de nacionalidad haitiana. Se desconoce el estado nutricional (EN) en embarazadas y lactantes; así como también la prevalencia de lactancia materna exclusiva (LME) de la población haitiana en Chile. Los objetivos de este trabajo fueron comparar: (i) el EN de embarazadas haitianas y chilenas, (ii) el EN de lactantes y (iii) la duración de la LME en hijos de madres haitianas y chilenas. Para esto se analizó la base de datos de la población haitiana y chilena atendidos entre los años 2016-2019 en el Centro de Salud Familiar (CESFAM) "Los Castaños" ubicado en la comuna de La Florida. En la etapa pre-gestacional, las embarazadas haitianas presentaron mayor prevalencia de bajo peso en comparación a embarazadas chilenas (p= 0,0003), mientras que al término del embarazo presentaron una mayor prevalencia de estado nutricional normal (p= 0,0001) y menor prevalencia de obesidad (p= 0,0001). Respecto al estado nutricional de los lactantes, sólo se observaron diferencias en el primer mes de vida, donde un 82% de los lactantes haitianos tenían un EN normopeso en comparación al 24% en los lactantes chilenos (p= 0,0001). No se observaron diferencias significativas en la prevalencia de LME hasta los 6 meses entre lactantes haitianos y chilenos (35,3% vs 30%, respectivamente). Es importante mencionar que ninguno de los dos grupos de lactantes cumplió con la meta establecida por la Organización Mundial de la Salud (OMS) que propone LME en los primeros seis meses de vida hasta al menos 50%. En conclusión, se evidencian diferencias en el EN de las embarazadas y lactantes de ambos países, mientras que la prevalencia de LME en ambos grupos fue similar.

In Chile, until December 31st, 2020, 12.5% of foreign residents were from Haiti. The nutritional status (NS) in pregnant women and infants is unknown; as well as the prevalence of exclusive breastfeeding (EBF) of the Haitian population residing in Chile. This study aimed to compare: (i) the NS of Haitian and Chilean pregnant women, (ii) the NS of infants, and (iii) the duration of EBF in children of Haitian and Chilean mothers. We analyzed the database of the Haitian and Chilean population attended between the years 2016-2019 at the Primary Care Health Center (CESFAM) "Los Castaños" located in the commune of La Florida. During the pregestational stage, the Haitian pregnant women had a higher prevalence of low weight compared to the Chilean pregnant women (p= 0,0003), whereas, at the end of the pregnancy, they had a higher prevalence of normal nutritional status (p= 0,0001) and a lower prevalence of obesity and a tendency at the end of pregnancy. Whereas at the end of the pregnancy, Chilean women had a higher prevalence of obesity. Regarding the nutritional status of the infants, differences were only observed in the first month of life, where 82% of Haitian infants had a normal weight compared to 24% of Chilean infants (p= 0.0001). No significant differences were observed in the prevalence of EBF up to 6 months between Haitian and Chilean infants (35.3% vs. 30%, respectively). It is important to mention that neither of the two groups of infants met the goal established by the World Health Organization (WHO) that proposes EBF for the first six months of life up to at least 50%. In conclusion, there are differences in the NE of pregnant and lactating women in both countries, while the prevalence of EBF in both groups was similar.

CERT1 mutations perturb human development by disrupting sphingolipid homeostasis.

Neural differentiation, synaptic transmission, and action potential propagation depend on membrane sphingolipids, whose metabolism is tightly regulated. Mutations in the ceramide transporter CERT (CERT1), which is involved in sphingolipid biosynthesis, are associated with intellectual disability, but the pathogenic mechanism remains obscure. Here, we characterize 31 individuals with de novo missense variants in CERT1. Several variants fall into a previously uncharacterized dimeric helical domain that enables CERT homeostatic inactivation, without which sphingolipid production goes unchecked. The clinical severity reflects the degree to which CERT autoregulation is disrupted, and inhibiting CERT pharmacologically corrects morphological and motor abnormalities in a Drosophila model of the disease, which we call ceramide transporter (CerTra) syndrome. These findings uncover a central role for CERT autoregulation in the control of sphingolipid biosynthetic flux, provide unexpected insight into the structural organization of CERT, and suggest a possible therapeutic approach for patients with CerTra syndrome.

RFC1 repeat expansions and cerebellar ataxia, neuropathy and vestibular areflexia syndrome: Experience and perspectives from a neuromuscular disorders unit.

INTRODUCTION: Pathogenic expansions in RFC1 have been described as a cause of a spectrum of disorders including late-onset ataxia, chronic cough, and cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS). Sensory neuronopathy/neuropathy appears to be a major symptom of RFC1-disorder, and RFC1 expansions are common in patients with sensory chronic idiopathic axonal neuropathy or sensory ganglionopathy. We aimed to investigate RFC1 expansions in patients with suspected RFC1-related disease followed-up in a Neuromuscular Diseases Unit, with a particular interest in the involvement of the peripheral nervous system. METHODS: We recruited twenty consecutive patients based on the presence of at least two of the following features: progressive ataxia, sensory neuropathy/neuronopathy, vestibulopathy and chronic cough. Medical records were retrospectively reviewed for a detailed clinical description. More extensive phenotyping of the RFC1-positive patients and clinical comparison between RFC1 positive and negative patients were performed. RESULTS: Biallelic AAGGG repeat expansions were identified in 13 patients (65%). The most frequent symptoms were chronic cough and sensory disturbances in the lower extremities (12/13). Only 4 patients (31%) had complete CANVAS. The phenotypes were sensory ataxia and sensory symptoms in extremities in 4/13; sensory ataxia, sensory symptoms, and vestibulopathy in 3/13; sensory symptoms plus chronic cough in 2/13. Chronic cough and isolated sensory neuronopathy were significantly more prevalent in RFC1-positive patients. CONCLUSION: Pathogenic RFC1 expansions are a common cause of sensory neuropathy/neuronopathy and should be considered in the approach to these patients. Identification of key symptoms or detailed interpretation of nerve conduction studies may improve patient selection for genetic testing.

Experience using singleton exome sequencing of probands as an approach to preconception carrier screening in consanguineous couples.

BACKGROUND: Consanguineous couples have an increased risk of severe diseases in offspring due to autosomal recessive disorders. Exome sequencing (ES) offers the possibility of extensive preconception carrier screening (PCS) in consanguineous couples who may be at risk of rare genetic disorders. METHODS: We retrospectively analysed ES data from 65 probands affected with rare genetic disorders born from consanguineous couples. We explored diagnostic yield and carrier status for recessive disorders. RESULTS: The overall diagnostic yield in a singleton approach was 53.8%, mostly recessive variants. In a hypothetical exome-based PCS, only 11.7% of these causative rare variants would have been missed in the filtering process. Carrier screening for recessive conditions allowed the identification of at least one additional pathogenic or likely pathogenic variant in 85.7% of the probands, being the majority with a gene carrier frequency <1 in 200. In addition, considering only clinically actionable conditions, we estimated that 12.3% of our close consanguineous couples may be at risk for an additional recessive disease. CONCLUSIONS: Our results demonstrate that ES outperforms panel-based screening in a PCS context in consanguineous couples and could potentially increase their reproductive autonomy and facilitate informed decision-making.

An spanish study of secondary findings in families affected with mendelian disorders: choices, prevalence and family history.

Clinical exome sequencing has the potential to identify pathogenic variants unrelated to the purpose of the study (secondary findings, SFs). Data describing actual choices of SFs in participants in a clinical setting and factors influencing their decision are virtually non-existant in Europe. In this work, we report the acceptance rate of SFs, calculate their prevalence and study factors associated with the decision in a cohort of patients affected with a rare genetic disorder in a Spanish Hospital. Finally, we re-examine the presence of previously non reported family history in positive cases. We retrospectively reviewed informed consent choices and SF results from 824 unrelated probands affected with rare genetic disorders who underwent whole-genome or exome sequencing. Ninety percent of families (740/824) affected with rare disorders wished to be informed of SFs. Declining SFs was associated with a prenatal setting (30% vs. 8.7%, p = 0.025), consanguinity (19% vs. 8.7%, p = 0.013), male gender (10.6% vs. 1.5%, p = 0.00865) and the proband being a minor (10.6% vs. 1.5%, p = 0.014). Overall, 27 pathogenic or likely pathogenic variants were identified in 27 individuals, with an SF prevalence of 3.6%. Disclosure of SFs increased the percentage of positive family histories and resulted in early diagnosis or changes in the management of 10 individuals from five families. We show that the acceptance of SFs in Spain is high and the disclosure of SFs leads to a clinically meaningful change in the medical management of individuals.

Prolyl Endopeptidase-like Deficiency Associated with Growth Hormone Deficiency

Prolyl endopeptidase-like (PREPL) deficiency (MIM#616224) is a rare congenital disorder characterised by neonatal hypotonia and feeding difficulties, growth hormone (GH) deficiency and hypergonadotropic hypogonadism. This syndrome is an autosomal recessive disease resulting from mutations in the PREPL gene (MIM#609557). Herein we report a 7-year-old female patient with biallelic mutations in PREPL (c.1528C>T in one allele and whole gene deletion in the other) with early growth impairment in infancy. GH deficiency was confirmed at 20 months of life. Recombinant GH treatment was introduced with a good response. Her clinical features were similar to those of previously reported cases. The description of new patients with PREPL deficiency syndrome is essential to better delineate the phenotypic and genotypic spectrum of the disease.

Multimodal Imaging in Iris Vascular Tumors: A Case Series.

Iris vascular tumors are very unusual and tend to affect middle-aged and older adults. We report a case series of four adult patients with vascular alterations of the iris. Two patients were diagnosed with simple iris arteriovenous malformation (IAVM) and two with iris microhemangiomatosis (IM). Although the diagnosis is typically clinic, multimodal imaging techniques, especially anterior segment fluorescein angiography (AS-FA), anterior segment optical coherence tomography (AS-OCT), and optical coherence tomography angiography (OCT-A), improve the accuracy and delimitation of their attributes and extension. Differential diagnosis with angle or iris neovascularization, melanoma, and other iris vascular tumors is essential to avoid unnecessary tests and treatments.

The genetic diagnosis of rare endocrine disorders of sex development and maturation: a survey among Endo-ERN centres.

Differences of sex development and maturation (SDM) represent a heterogeneous puzzle of rare conditions with a large genetic component whose management and treatment could be improved by an accurate classification of underlying molecular conditions, and next-generation sequencing (NGS) should represent the most appropriate approach. Therefore, we conducted a survey dedicated to the use and potential outcomes of NGS for SDM disorders diagnosis among the 53 health care providers (HCP) of the European Reference Network for rare endocrine conditions. The response rate was 49% with a total of 26 HCPs from 13 countries. All HCPs, except 1, performed NGS investigations for SDM disorders on 6720 patients, 3764 (56%) with differences of sex development (DSD), including 811 unexplained primary ovarian insufficiency, and 2956 (44%) with congenital hypogonadotropic hypogonadism (CHH). The approaches varied from targeted analysis of custom gene panels (range: 11-490 genes) in 81.5% of cases or whole exome sequencing with the extraction of a virtual panel in the remaining cases. These analyses were performed for diagnostic purposes in 21 HCPs, supported by the National Health Systems in 16 cases. The likelihood of finding a variant ranged between 7 and 60%, mainly depending upon the number of analysed genes or criteria used for reporting, most HCPs also reporting variants of uncertain significance. These data illustrate the status of genetic diagnosis of DSD and CHH across Europe. In most countries, these analyses are performed for diagnostic purposes, yielding highly variable results, thus suggesting the need for harmonization and general improvements of NGS approaches.

De novo missense variants in the E3 ubiquitin ligase adaptor KLHL20 cause a developmental disorder with intellectual disability, epilepsy, and autism spectrum disorder.

PURPOSE: KLHL20 is part of a CUL3-RING E3 ubiquitin ligase involved in protein ubiquitination. KLHL20 functions as the substrate adaptor that recognizes substrates and mediates the transfer of ubiquitin to the substrates. Although KLHL20 regulates neurite outgrowth and synaptic development in animal models, a role in human neurodevelopment has not yet been described. We report on a neurodevelopmental disorder caused by de novo missense variants in KLHL20. METHODS: Patients were ascertained by the investigators through Matchmaker Exchange. Phenotyping of patients with de novo missense variants in KLHL20 was performed. RESULTS: We studied 14 patients with de novo missense variants in KLHL20, delineating a genetic syndrome with patients having mild to severe intellectual disability, febrile seizures or epilepsy, autism spectrum disorder, hyperactivity, and subtle dysmorphic facial features. We observed a recurrent de novo missense variant in 11 patients (NM_014458.4:c.1069G>A p.[Gly357Arg]). The recurrent missense and the 3 other missense variants all clustered in the Kelch-type ß-propeller domain of the KLHL20 protein, which shapes the substrate binding surface. CONCLUSION: Our findings implicate KLHL20 in a neurodevelopmental disorder characterized by intellectual disability, febrile seizures or epilepsy, autism spectrum disorder, and hyperactivity.