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The pediatric cervical spine is structurally and biomechanically unique in comparison to adults. Guidelines to assess for cervical spine instability and standard of care treatments in the pediatric population have yet to be delineated. This is due to the rarity of the condition and the lack of multicenter data published on the topic. Our review explores the biomechanics of the pediatric cervical spine and highlights evolving concepts/research over the last several decades, with special attention to the Down syndrome and complex Chiari malformation cohorts. [ABSTRACT FROM AUTHOR]

Bi-allelic disruptive variants (nonsense, frameshift, and splicing variants) in KDM5B have been identified as causative for autosomal recessive intellectual developmental disorder type 65. In contrast, dominant variants, usually disruptive as well, have been more difficult to implicate in a specific phenotype, since some of them have been found in unaffected controls or relatives. Here, we describe individuals with likely pathogenic variants in KDM5B, including eight individuals with dominant missense variants. This study is a retrospective case series of 21 individuals with variants in KDM5B. We performed deep phenotyping and collected the clinical information and molecular data of these individuals' family members. We compared the phenotypes according to variant type and to those previously described in the literature. The most common features were developmental delay, impaired intellectual development, behavioral problems, autistic behaviors, sleep disorders, facial dysmorphism, and overgrowth. DD, ASD behaviors, and sleep disorders were more common in individuals with dominant disruptive KDM5B variants, while individuals with dominant missense variants presented more frequently with renal and skin anomalies. This study extends our understanding of the KDM5B-related neurodevelopmental disorder and suggests the pathogenicity of certain dominant KDM5B missense variants. [ABSTRACT FROM AUTHOR]

Background: Children with genetic conditions are at increased risk for mental health and neurodevelopmental problems, often accompanied by significant parental distress. Genetic and family factors can impact children and parents' mental health. Early parenting interventions, like the Incredible Years® programs, have demonstrated to improve parental distress and children's mental health. The recent version for young children with language delays or autism spectrum disorder (IY-ASLD®) has shown to be feasible and effective to support parents in their children's developmental trajectories. The effectiveness of treatments for children with genetic conditions and neurodevelopmental problems is largely unexplored, leaving significant gaps in evidence-based options. Clinicians lack guidance, especially when patients exhibit language or social communication impairments but do not meet diagnostic criteria for a full-blown autism spectrum disorder (ASD). We aim to fill this gap, providing evidence on the feasibility and effectiveness of the IY-ASLD® intervention for such patients. Methods: We designed a prospective multicenter pragmatic randomized controlled trial including approximately 68 children aged 3 to 7 years, recruited from three tertiary care reference hospitals. Inclusion criteria will necessitate genetic confirmation of a neurodevelopmental disorder along with language, communication, or socialization difficulties. Individuals with an ASD diagnosis will be excluded. All subjects are included in a territorial register for rare conditions (ReMin, Registre de Malalties Minoritàries de Catalunya). Families will randomly be assigned to the intervention or the control group. The intervention will be held online by clinical psychologists and child and adolescent psychiatrists. Discussion: Our group has recently piloted the online implementation of the IY-ASLD® intervention for the first time in Spain, for parents of children with language delays, socialization difficulties, or ASD, but not genetically determined. Our multicenter research consortium is well-positioned to recruit patients with rare conditions and implement efficient treatment pathways within the National Health System. Given the geographical dispersion of families affected by rare conditions, the online format offers logistical advantages and improved therapy access, enhancing homogeneity across all patients. The results of this study will inform clinicians and policymakers about evidence-based treatment options for this vulnerable and overlooked group of young children. Trial registration: ClinicalTrials.gov NCT06125093. Date of registration: first submitted 2023–10-23; first posted 2023–11-09. URL of trial registry record. [ABSTRACT FROM AUTHOR]

Background: Congenital anomalies of the kidney and urinary tract (CAKUT) represent 20–30% of all birth defects and are often associated with extra-renal malformations. We investigated the frequency of brain/spine malformations and neurological features in children with CAKUT. Methods: We reviewed the clinico-radiological and genetic data of 199 out of 1,165 children with CAKUT evaluated from 2006 to 2023 (99 males, mean age at MRI 6.4 years) who underwent brain and/or spine MRI. Patients were grouped according to the type of CAKUT (CAKUT-K involving the kidney and CAKUT-H involving the inferior urinary tract). Group comparisons were performed using χ2 and Fisher exact tests. Results: Brain/spine malformations were observed in 101/199 subjects (50.7%), 8.6% (101/1165) of our CAKUT population, including midbrain-hindbrain anomalies (40/158, 25.3%), commissural malformations (36/158, 22.7%), malformation of cortical development (23/158, 14.5%), Chiari I anomaly (12/199, 6%), cranio-cervical junction malformations (12/199, 6%), vertebral defects (46/94, 48.9%), caudal regression syndrome (29/94, 30.8%), and other spinal dysraphisms (13/94, 13.8%). Brain/spine malformations were more frequent in the CAKUT-K group (62.4%, p < 0.001). Sixty-two subjects (62/199, 31.2%) had developmental delay/intellectual disability. Neurological examination was abnormal in 40/199 (20.1%). Seizures and/or electroencephalographic anomalies were reported in 28/199 (14%) and behavior problems in 19/199 subjects (9%). Developmental delay/intellectual disability was more frequent in kidney dysplasia (65.2%) and agenesis (40.7%) (p = 0.001). Conclusions: We report a relative high frequency of brain/spine malformations and neurodevelopmental disorders in children with CAKUT who underwent MRI examinations in a tertiary referral center, widening the spectrum of anomalies associated with this condition. [ABSTRACT FROM AUTHOR]

Introduction: A plethora of biological molecules regulate chondrogenesis in the epiphyseal growth plate. Disruptions of the quantity and function of these molecules can manifest clinically as stature abnormalities of various etiologies. Traditionally, the growth hormone/insulin-like growth factor 1 (IGF1) axis represents the etiological centre of final stature attainment. Of note, little is known about the molecular events that dominate the growth of the craniofacial complex and its correlation with somatic stature. Aim: Given the paucity of relevant data, this review discusses available information regarding potential applications of lateral cephalometric radiography as a potential clinical indicator of genetic short stature in children. Materials and Methods: A literature search was conducted in the PubMed electronic database using the keywords: cephalometric analysis and short stature; cephalometric analysis and achondroplasia; cephalometric analysis and hypochondroplasia; cephalometric analysis and skeletal abnormalities; cephalometr* and SHOX; cephalometr* and CNP; cephalometr* and ACAN; cephalometr* and CNVs; cephalometr* and IHH; cephalometr* and FGFR3; cephalometr* and Noonan syndrome; cephalometr* and "Turner syndrome"; cephalometr* and achondroplasia. Results: In individuals with genetic syndromes causing short stature, linear growth of the craniofacial complex is confined, following the pattern of somatic short stature regardless of its aetiology. The angular and linear cephalometric measurements differ from the measurements of the average normal individuals and are suggestive of a posterior placement of the jaws and a vertical growth pattern of the face. Conclusions: The greater part of the existing literature regarding cephalometric measurements in short-statured children with genetic syndromes provides qualitative data. Furthermore, cephalometric data for individuals affected with specific rare genetic conditions causing short stature should be the focus of future studies. These quantitative data are required to potentially establish cut-off values for reference for genetic testing based on craniofacial phenotypes. [ABSTRACT FROM AUTHOR]

Abstract Background Children with genetic conditions are at increased risk for mental health and neurodevelopmental problems, often accompanied by significant parental distress. Genetic and family factors can impact children and parents’ mental health. Early parenting interventions, like the Incredible Years® programs, have demonstrated to improve parental distress and children’s mental health. The recent version for young children with language delays or autism spectrum disorder (IY-ASLD®) has shown to be feasible and effective to support parents in their children’s developmental trajectories. The effectiveness of treatments for children with genetic conditions and neurodevelopmental problems is largely unexplored, leaving significant gaps in evidence-based options. Clinicians lack guidance, especially when patients exhibit language or social communication impairments but do not meet diagnostic criteria for a full-blown autism spectrum disorder (ASD). We aim to fill this gap, providing evidence on the feasibility and effectiveness of the IY-ASLD® intervention for such patients. Methods We designed a prospective multicenter pragmatic randomized controlled trial including approximately 68 children aged 3 to 7 years, recruited from three tertiary care reference hospitals. Inclusion criteria will necessitate genetic confirmation of a neurodevelopmental disorder along with language, communication, or socialization difficulties. Individuals with an ASD diagnosis will be excluded. All subjects are included in a territorial register for rare conditions (ReMin, Registre de Malalties Minoritàries de Catalunya). Families will randomly be assigned to the intervention or the control group. The intervention will be held online by clinical psychologists and child and adolescent psychiatrists. Discussion Our group has recently piloted the online implementation of the IY-ASLD® intervention for the first time in Spain, for parents of children with language delays, socialization difficulties, or ASD, but not genetically determined. Our multicenter research consortium is well-positioned to recruit patients with rare conditions and implement efficient treatment pathways within the National Health System. Given the geographical dispersion of families affected by rare conditions, the online format offers logistical advantages and improved therapy access, enhancing homogeneity across all patients. The results of this study will inform clinicians and policymakers about evidence-based treatment options for this vulnerable and overlooked group of young children. Trial registration ClinicalTrials.gov NCT06125093 . Date of registration: first submitted 2023–10-23; first posted 2023–11-09. URL of trial registry record.

Cardiac tumours can occur in association with genetic syndromes. Rhabdomyomas have been reported in association with tuberous sclerosis, myxomas with Carney's complex, cardiac fibromas with Gorlin syndrome, and paragangliomas with multiple endocrine neoplasm syndrome. The presentation and prognosis of cardiac tumours associated with genetic syndromes differ compared with sporadic cases. Knowledge about the associated syndromes' genetic features and extracardiac manifestations is essential for the diagnosis, prognosis, and management of cardiac neoplasms. Moreover, identifying genetic mutations in benign and malignant cardiac tumours is needed to personalise management and improve treatment outcomes. Thus, this review discusses the genetic abnormalities associated with cardiac tumours, the current genetic screening recommendations, and the effect of those genetic mutations on the outcomes. [ABSTRACT FROM AUTHOR]

Gene therapy holds promise as a life-changing option for individuals with genetic variants that give rise to disease. FDA-approved gene therapies for Spinal Muscular Atrophy (SMA), cerebral adrenoleukodystrophy, β-Thalassemia, hemophilia A/B, retinal dystrophy, and Duchenne Muscular Dystrophy have generated buzz around the ability to change the course of genetic syndromes. However, this excitement risks over-expansion into areas of genetic disease that may not fit the current state of gene therapy. While in situ (targeted to an area) and ex vivo (removal of cells, delivery, and administration of cells) approaches show promise, they have a limited target ability. Broader in vivo gene therapy trials have shown various continued challenges, including immune response, use of immune suppressants correlating to secondary infections, unknown outcomes of overexpression, and challenges in driving tissue-specific corrections. Viral delivery systems can be associated with adverse outcomes such as hepatotoxicity and lethality if uncontrolled. In some cases, these risks are far outweighed by the potentially lethal syndromes for which these systems are being developed. Therefore, it is critical to evaluate the field of genetic diseases to perform cost–benefit analyses for gene therapy. In this work, we present the current state while setting forth tools and resources to guide informed directions to avoid foreseeable issues in gene therapy that could prevent the field from continued success. [ABSTRACT FROM AUTHOR]

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Several studies have suggested an inverse relationship between lower socioeconomic status (SES) and the incidence of congenital heart disease (CHD) among live births. We sought to examine this relationship further in a Canada-wide population study, exploring CHD subtypes, trends, and associated noncardiac abnormalities. Infants born in Canada (less Quebec) from 2008 to 2018 with CHD requiring intervention in the first year were identified using ICD-10 codes through the Canadian Institute for Health Information Discharge Abstract Database. Births of CHD patients were stratified by SES (census-based income quintiles) and compared against national birth proportions using X2 tests. Proportions with extracardiac defects (ED) and nonlethal genetic syndromes (GS) were also explored. From 2008 to 2018, 7711 infants born with CHD were included. The proportions of major CHD distributed across SES quintiles were 27.1%, 20.1%, 19.2%, 18.6%, and 15.0% from lowest to highest, with significant differences relative to national birth proportions (22.0%, 20.0%, 20.6%, 20.7%, and 16.7% from lowest (1) to highest (5)) (p < 0.0001). No temporal trends in the CHD proportions across SES categories were observed over the study period. The distribution across SES quintiles was different only for specific CHD subtypes (double-outlet right ventricle (n = 485, p = 0.03), hypoplastic left heart syndrome (n = 547, p = 0.006), heterotaxy (n = 224, p = 0.03), tetralogy of Fallot (n = 1007, p = 0.008), truncus arteriosus (n = 126, p < 0.0001), and ventricular septal defect (n = 1916, p < 0.0001)), with highest proportions observed in the lowest quintile. The proportion of the total population with ED but not GS was highest in lower SES quintiles (< 0.0001) commensurate with increased proportion of CHD. Our study suggests a negative association between SES and certain CHD lesions and ED. [ABSTRACT FROM AUTHOR]

Abstract Background Relatively little is known about social cognition in people with intellectual disability (ID), and how this may support understanding of co-occurring autism. A limitation of previous research is that traditional social-cognitive tasks place a demand on domain-general cognition and language abilities. These tasks are not suitable for people with ID and lack the sensitivity to detect subtle social-cognitive processes. In autism research, eye-tracking technology has offered an effective method of evaluating social cognition—indicating associations between visual social attention and autism characteristics. The present systematic review synthesised research which has used eye-tracking technology to study social cognition in ID. A meta-analysis was used to explore whether visual attention on socially salient regions (SSRs) of stimuli during these tasks correlated with degree of autism characteristics presented on clinical assessment tools. Method Searches were conducted using four databases, research mailing lists, and citation tracking. Following in-depth screening and exclusion of studies with low methodological quality, 49 articles were included in the review. A correlational meta-analysis was run on Pearson’s r values obtained from twelve studies, reporting the relationship between visual attention on SSRs and autism characteristics. Results and conclusions Eye-tracking technology was used to measure different social-cognitive abilities across a range of syndromic and non-syndromic ID groups. Restricted scan paths and eye-region avoidance appeared to impact people’s ability to make explicit inferences about mental states and social cues. Readiness to attend to social stimuli also varied depending on social content and degree of familiarity. A meta-analysis using a random effects model revealed a significant negative correlation (r = −.28, [95% CI −.47, −.08]) between visual attention on SSRs and autism characteristics across ID groups. Together, these findings highlight how eye-tracking can be used as an accessible tool to measure more subtle social-cognitive processes, which appear to reflect variability in observable behaviour. Further research is needed to be able to explore additional covariates (e.g. ID severity, ADHD, anxiety) which may be related to visual attention on SSRs, to different degrees within syndromic and non-syndromic ID groups, in order to determine the specificity of the association with autism characteristics.

Bi-allelic disruptive variants (nonsense, frameshift, and splicing variants) in KDM5B have been identified as causative for autosomal recessive intellectual developmental disorder type 65. In contrast, dominant variants, usually disruptive as well, have been more difficult to implicate in a specific phenotype, since some of them have been found in unaffected controls or relatives. Here, we describe individuals with likely pathogenic variants in KDM5B, including eight individuals with dominant missense variants. This study is a retrospective case series of 21 individuals with variants in KDM5B. We performed deep phenotyping and collected the clinical information and molecular data of these individuals’ family members. We compared the phenotypes according to variant type and to those previously described in the literature. The most common features were developmental delay, impaired intellectual development, behavioral problems, autistic behaviors, sleep disorders, facial dysmorphism, and overgrowth. DD, ASD behaviors, and sleep disorders were more common in individuals with dominant disruptive KDM5B variants, while individuals with dominant missense variants presented more frequently with renal and skin anomalies. This study extends our understanding of the KDM5B-related neurodevelopmental disorder and suggests the pathogenicity of certain dominant KDM5B missense variants.

Background: Relatively little is known about social cognition in people with intellectual disability (ID), and how this may support understanding of co-occurring autism. A limitation of previous research is that traditional social-cognitive tasks place a demand on domain-general cognition and language abilities. These tasks are not suitable for people with ID and lack the sensitivity to detect subtle social-cognitive processes. In autism research, eye-tracking technology has offered an effective method of evaluating social cognition—indicating associations between visual social attention and autism characteristics. The present systematic review synthesised research which has used eye-tracking technology to study social cognition in ID. A meta-analysis was used to explore whether visual attention on socially salient regions (SSRs) of stimuli during these tasks correlated with degree of autism characteristics presented on clinical assessment tools. Method: Searches were conducted using four databases, research mailing lists, and citation tracking. Following in-depth screening and exclusion of studies with low methodological quality, 49 articles were included in the review. A correlational meta-analysis was run on Pearson's r values obtained from twelve studies, reporting the relationship between visual attention on SSRs and autism characteristics. Results and conclusions: Eye-tracking technology was used to measure different social-cognitive abilities across a range of syndromic and non-syndromic ID groups. Restricted scan paths and eye-region avoidance appeared to impact people's ability to make explicit inferences about mental states and social cues. Readiness to attend to social stimuli also varied depending on social content and degree of familiarity. A meta-analysis using a random effects model revealed a significant negative correlation (r = −.28, [95% CI −.47, −.08]) between visual attention on SSRs and autism characteristics across ID groups. Together, these findings highlight how eye-tracking can be used as an accessible tool to measure more subtle social-cognitive processes, which appear to reflect variability in observable behaviour. Further research is needed to be able to explore additional covariates (e.g. ID severity, ADHD, anxiety) which may be related to visual attention on SSRs, to different degrees within syndromic and non-syndromic ID groups, in order to determine the specificity of the association with autism characteristics. [ABSTRACT FROM AUTHOR]

This review initiates by outlining the clinical relevance of IA, underlining the pressing need to comprehend its foundational elements. We delve into the assorted risk factors tied to IA, spotlighting both environmental and genetic influences. Additionally, we illuminate distinct genetic syndromes linked to a pronounced prevalence of intracranial aneurysms, underscoring the pivotal nature of genetics in this ailment's susceptibility. A detailed scrutiny of genome-wide association studies allows us to identify key genomic changes and locations associated with IA risk. We further detail the molecular and physiopathological dynamics instrumental in IA's evolution and escalation, with a focus on inflammation's role in affecting the vascular landscape. Wrapping up, we offer a glimpse into upcoming research directions and the promising horizons of personalized therapeutic strategies in IA intervention, emphasizing the central role of genetic insights. This thorough review solidifies genetics' cardinal role in IA, positioning it as a cornerstone resource for professionals in the realms of neurology and genomics. [ABSTRACT FROM AUTHOR]

Background Individuals with genetic syndromes can manifest both congenital heart disease (CHD) and cancer attributable to possible common underlying pathways. To date, reliable risk estimates of hematopoietic cancer (HC) among children with CHD based on large population‐based data remain scant. This study sought to quantify the risk of HC by the presence of genetic syndrome among children with CHD. Methods and Results Data sources were the Canadian CHD database, a nationwide database on CHD (1999–2017), and the CCR (Canadian Cancer Registry). Standardized incidence ratios were calculated for comparing HC incidences in children with CHD with the general pediatric population. A modified Kaplan‐Meier curve was used to estimate the cumulative incidence of HC with death as a competing risk. A total of 143 794 children (aged 0–17 years) with CHD were followed up from birth to age 18 years for 1 314 603 person‐years. Of them, 8.6% had genetic syndromes, and 898 HC cases were observed. Children with known syndromes had a substantially higher risk of incident HC than the general pediatric population (standardized incidence ratio, 13.4 [95% CI, 11.7–15.1]). The cumulative incidence of HC was 2.44% (95% CI, 2.11–2.76) among children with a syndrome and 0.79% (95% CI, 0.72–0.87) among children without a syndrome. Acute myeloid leukemia had a higher cumulative incidence during early childhood than acute lymphoblastic leukemia. Conclusions This is the first large population‐based analysis documenting that known genetic syndromes in children with CHD are a significant predictor of HC. The finding could be essential in informing risk‐stratified policy recommendations for cancer surveillance in children with CHD.

BackgroundAdequate sleep is important for proper neurodevelopment and positive health outcomes. Sleep disturbances are more prevalent in children with genetically determined neurodevelopmental syndromes compared with typically developing counterparts. We characterize sleep behavior in Rett (RTT), Angelman (AS), and Prader-Willi (PWS) syndromes to identify effective approaches for treating sleep problems in these populations. We compared sleep-related symptoms across individuals with these different syndromes with each other, and with typically developing controls.MethodsChildren were recruited from the Rare Diseases Clinical Research Network consortium registries; unaffected siblings were enrolled as related controls. For each participant, a parent completed multiple sleep questionnaires including Pediatric Sleep Questionnaire (Sleep-Disordered Breathing), Children's Sleep Habits Questionnaire (CSHQ), and Pediatric Daytime Sleepiness Scale.ResultsSleep data were analyzed from 714 participants, aged two to 18 years. Young children with AS had more reported sleep problems than children with RTT or PWS. Older children with RTT had more reported daytime sleepiness than those with AS or PWS. Finally, all individuals with RTT had more evidence of sleep-disordered breathing when compared with individuals with PWS. Notably, typically developing siblings were also reported to have sleep problems, except for sleep-related breathing disturbances, which were associated with each of the genetic syndromes.ConclusionsIndividuals with RTT, AS, and PWS frequently experience sleep problems, including sleep-disordered breathing. Screening for sleep problems in individuals with these and other neurogenetic disorders should be included in clinical assessment and managements. These data may also be useful in developing treatment strategies and in clinical trials.

Introduction: A plethora of biological molecules regulate chondrogenesis in the epiphyseal growth plate. Disruptions of the quantity and function of these molecules can manifest clinically as stature abnormalities of various etiologies. Traditionally, the growth hormone/insulin-like growth factor 1 (IGF1) axis represents the etiological centre of final stature attainment. Of note, little is known about the molecular events that dominate the growth of the craniofacial complex and its correlation with somatic stature. Aim: Given the paucity of relevant data, this review discusses available information regarding potential applications of lateral cephalometric radiography as a potential clinical indicator of genetic short stature in children. Materials and Methods: A literature search was conducted in the PubMed electronic database using the keywords: cephalometric analysis and short stature; cephalometric analysis and achondroplasia; cephalometric analysis and hypochondroplasia; cephalometric analysis and skeletal abnormalities; cephalometr* and SHOX; cephalometr* and CNP; cephalometr* and ACAN; cephalometr* and CNVs; cephalometr* and IHH; cephalometr* and FGFR3; cephalometr* and Noonan syndrome; cephalometr* and “Turner syndrome”; cephalometr* and achondroplasia. Results: In individuals with genetic syndromes causing short stature, linear growth of the craniofacial complex is confined, following the pattern of somatic short stature regardless of its aetiology. The angular and linear cephalometric measurements differ from the measurements of the average normal individuals and are suggestive of a posterior placement of the jaws and a vertical growth pattern of the face. Conclusions: The greater part of the existing literature regarding cephalometric measurements in short-statured children with genetic syndromes provides qualitative data. Furthermore, cephalometric data for individuals affected with specific rare genetic conditions causing short stature should be the focus of future studies. These quantitative data are required to potentially establish cut-off values for reference for genetic testing based on craniofacial phenotypes.

Abstract Background Genomic conditions can be associated with developmental delay, intellectual disability, autism spectrum disorder, and physical and mental health symptoms. They are individually rare and highly variable in presentation, which limits the use of standard clinical guidelines for diagnosis and treatment. A simple screening tool to identify young people with genomic conditions associated with neurodevelopmental disorders (ND-GCs) who could benefit from further support would be of considerable value. We used machine learning approaches to address this question. Method A total of 493 individuals were included: 389 with a ND-GC, mean age = 9.01, 66% male) and 104 siblings without known genomic conditions (controls, mean age = 10.23, 53% male). Primary carers completed assessments of behavioural, neurodevelopmental and psychiatric symptoms and physical health and development. Machine learning techniques (penalised logistic regression, random forests, support vector machines and artificial neural networks) were used to develop classifiers of ND-GC status and identified limited sets of variables that gave the best classification performance. Exploratory graph analysis was used to understand associations within the final variable set. Results All machine learning methods identified variable sets giving high classification accuracy (AUROC between 0.883 and 0.915). We identified a subset of 30 variables best discriminating between individuals with ND-GCs and controls which formed 5 dimensions: conduct, separation anxiety, situational anxiety, communication and motor development. Limitations This study used cross-sectional data from a cohort study which was imbalanced with respect to ND-GC status. Our model requires validation in independent datasets and with longitudinal follow-up data for validation before clinical application. Conclusions In this study, we developed models that identified a compact set of psychiatric and physical health measures that differentiate individuals with a ND-GC from controls and highlight higher-order structure within these measures. This work is a step towards developing a screening instrument to identify young people with ND-GCs who might benefit from further specialist assessment.

Purpose of Review: Congenital cervical stenosis (CCS) is a phenomenon in which an individual has a narrow canal due to abnormal anatomy which can present with earlier degenerative symptoms due to a reduced sagittal diameter. The diagnosis of CCS is important to individual treatment and preventative measures. Often, athletes are warned against sport participation that may cause damage to the cervical spine. There may be a predisposition in certain populations, but lack of data limits conclusions. The current review investigates recent literature on the definition, pathoanatomy, clinical presentation, and management of CCS. It specifically interrogates potential populations predisposed to this condition. Recent Findings: The current literature reveals a potential predisposition for CCS in the black population when compared to the white population; however, many studies do not report race when discussing CCS patients. The lack of data limits a consensus on specific populations with a congenitally narrow canal. Summary: CCS may be more prevalent in specific populations. With knowledge of populations more at risk for this condition, physicians and teams can be alert when evaluating players and young adults. Furthermore, this may provide insight into risk for symptoms with degenerative disease. These findings introduce an avenue for further research into CCS. [ABSTRACT FROM AUTHOR]

Sotos syndrome (Sotos) and Tatton-Brown–Rahman Syndrome (TBRS) are two of the most common overgrowth disorders associated with intellectual disability. Individuals with these syndromes tend to have similar cognitive profiles and high likelihood of autism symptomatology. However, whether and how sensory processing is affected is currently unknown. Parents/caregivers of 36 children with Sotos and 20 children with TBRS completed the Child Sensory Profile-2 (CSP-2) and the Sensory Behavior Questionnaire (SBQ) along with other standardized questionnaires assessing autistic traits (Social Responsiveness Scale, Second Edition, SRS-2), attention deficit hyperactivity disorder (ADHD) traits (Conners 3), anxiety (Spence Children's Anxiety Scale, Parent Version, SCAS-P), and adaptive behavior (Vineland Adaptive Behavior Scales Third Edition). Sensory processing differences were clearly evident in both syndromes, though there was significant variation in both cohorts. SBQ data indicated that both the frequency and impact of sensory behavior were more severe when compared to neurotypicals, with levels of sensory behavior impact and frequency being similar to autistic children. CSP-2 data indicated 77% of children with Sotos and 85% children with TBRS displayed clear differences in sensory Registration (missing sensory input). Clear differences relating to Body Position (proprioceptive response to joint and muscle position; 79% Sotos; 90% TBRS) and Touch (somatosensory response to touch on skin; 56% Sotos; 60% TBRS) were also particularly prevalent. Correlation analyses demonstrated that in both syndromes sensory processing differences tend to be associated with difficulties relating to autistic traits, anxiety, and some domains of ADHD. In Sotos, sensory processing differences were also associated with lower adaptive behavior skills. This first detailed assessment of sensory processing, alongside other clinical features, in relatively large cohorts of children with Sotos and TBRS, demonstrates that sensory processing differences have a profound impact on everyday life. General Scientific Summary: This study found that children with Sotos Syndrome and Tatton-Brown–Rahman Syndrome were likely to experience sensory differences, although the level of differences varied. Common differences in both syndromes were missing sensory input and differences in the processing of body position and touch information. [ABSTRACT FROM AUTHOR]

Background: Disorders of immunity are poorly recognised in some rare multisystem genetic conditions. We aim to describe syndromic features and immunological defects in children with syndromic primary immunodeficiencies (sPIDs). Methods: This is a retrospective descriptive study of children aged 0–18 years with sPIDs under the care of the paediatric immunology service at the Bristol Royal Hospital for Children, United Kingdom, from January 2006 to September 2021. Results: sPIDs were identified in 36 patients. Genetic diagnoses which are not commonly associated with PIDs and not included in the International Union of Immunological Societies classification were present in 7/36 (19%): Trisomy 22, Arboleda-Tham syndrome, 2p16.3 deletion syndrome, supernumerary ring chromosome 20 syndrome, Myhre syndrome, Noonan syndrome, and trichothiodystrophy/Cockayne syndrome complex. Recurrent and/or severe infections were the most common clinical features (n = 33, 92%). Approximately half had combined immunodeficiency or antibody deficiency. The most common extra-immunological manifestations include dysmorphism (72%), disorders of nervous (78%), musculoskeletal (69%), haematology/lymphatic (58%), and gastrointestinal, hepatic/pancreatic (58%) systems. Conclusions: Patients with sPIDs often have multiorgan involvement and some are non-immunologically mediated. There should be a low threshold to clinically assess and investigate for disorders of immunity in any patients with syndromic features especially when they present with recurrent/severe/opportunistic infections, features of immune dysregulation, autoinflammation or lymphoproliferation. [ABSTRACT FROM AUTHOR]

Li Fraumeni syndrome (LFS) is an inherited cancer predisposition syndrome due to TP53 gene mutation. There is sparse literature on LFS in the Indian population. We conducted a retrospective study of patients diagnosed with LFS and their family members, registered at our Medical Oncology Department between September 2015 and 2022. 9 LFS families consisted of 29 patients diagnosed currently or historically with malignancies including 9 index cases and 20 first or second-degree relatives. Of these 29 patients, 7 (24.1%) patients developed their first malignancy before the age of 18 years, 15 (51.7%) were diagnosed between 18and and 60 years, and 7 (24.1%) were diagnosed at age more than 60 years. A total of 31 cancers occurred among the families, including 2 index cases who had metachronous malignancies. Each family had a median of three cancers (range 2-5); sarcoma (n = 12, 38.7% of total cancers) and breast cancer (n = 6, 19.3% of total cancers) being the commonest malignancies. Germline TP53 mutations were documented among 11 patients with cancers and 6 asymptomatic carriers. Of these nine mutations, the most common types were missense (n = 6, 66.6%) and nonsense (n = 2, 22.2%), and the commonest aberration was replacement of arginine with histidine (n = 4, 44.4%). Eight (88.8%) families met either classical or Chompret's diagnostic criteria and two (22.2%) satisfied both. Two (22.2%) families fit the diagnostic criteria prior to onset of malignancy in the index cases but were untested till the index cases presented to us. Four mutation carriers from three families are undergoing screening as per the Toronto protocol. No new malignancies have been detected so far during the mean surveillance duration of 14 months. The diagnosis of LFS has socio-economic implications for patients and their families. Delay in genetic testing misses out a crucial window wherein asymptomatic carriers could initiate surveillance in a timely fashion. Greater awareness on LFS and genetic testing in Indian patients is warranted for better management of this hereditary condition. [ABSTRACT FROM AUTHOR]

Abstract Background Phenotypic studies have identified distinct patterns of autistic characteristics in genetic syndromes associated with intellectual disability (ID), leading to diagnostic uncertainty and compromised access to autism-related support. Previous research has tended to include small samples and diverse measures, which limits the generalisability of findings. In this study, we generated detailed profiles of autistic characteristics in a large sample of > 1500 individuals with rare genetic syndromes. Methods Profiles of autistic characteristics based on the Social Communication Questionnaire (SCQ) scores were generated for thirteen genetic syndrome groups (Angelman n = 154, Cri du Chat n = 75, Cornelia de Lange n = 199, fragile X n = 297, Prader–Willi n = 278, Lowe n = 89, Smith–Magenis n = 54, Down n = 135, Sotos n = 40, Rubinstein–Taybi n = 102, 1p36 deletion n = 41, tuberous sclerosis complex n = 83 and Phelan–McDermid n = 35 syndromes). It was hypothesised that each syndrome group would evidence a degree of specificity in autistic characteristics. To test this hypothesis, a classification algorithm via support vector machine (SVM) learning was applied to scores from over 1500 individuals diagnosed with one of the thirteen genetic syndromes and autistic individuals who did not have a known genetic syndrome (ASD; n = 254). Self-help skills were included as an additional predictor. Results Genetic syndromes were associated with different but overlapping autism-related profiles, indicated by the substantial accuracy of the entire, multiclass SVM model (55% correctly classified individuals). Syndrome groups such as Angelman, fragile X, Prader–Willi, Rubinstein–Taybi and Cornelia de Lange showed greater phenotypic specificity than groups such as Cri du Chat, Lowe, Smith–Magenis, tuberous sclerosis complex, Sotos and Phelan-McDermid. The inclusion of the ASD reference group and self-help skills did not change the model accuracy. Limitations The key limitations of our study include a cross-sectional design, reliance on a screening tool which focuses primarily on social communication skills and imbalanced sample size across syndrome groups. Conclusions These findings replicate and extend previous work, demonstrating syndrome-specific profiles of autistic characteristics in people with genetic syndromes compared to autistic individuals without a genetic syndrome. This work calls for greater precision of assessment of autistic characteristics in individuals with genetic syndromes associated with ID.

Gene therapy holds promise as a life-changing option for individuals with genetic variants that give rise to disease. FDA-approved gene therapies for Spinal Muscular Atrophy (SMA), cerebral adrenoleukodystrophy, β-Thalassemia, hemophilia A/B, retinal dystrophy, and Duchenne Muscular Dystrophy have generated buzz around the ability to change the course of genetic syndromes. However, this excitement risks over-expansion into areas of genetic disease that may not fit the current state of gene therapy. While in situ (targeted to an area) and ex vivo (removal of cells, delivery, and administration of cells) approaches show promise, they have a limited target ability. Broader in vivo gene therapy trials have shown various continued challenges, including immune response, use of immune suppressants correlating to secondary infections, unknown outcomes of overexpression, and challenges in driving tissue-specific corrections. Viral delivery systems can be associated with adverse outcomes such as hepatotoxicity and lethality if uncontrolled. In some cases, these risks are far outweighed by the potentially lethal syndromes for which these systems are being developed. Therefore, it is critical to evaluate the field of genetic diseases to perform cost–benefit analyses for gene therapy. In this work, we present the current state while setting forth tools and resources to guide informed directions to avoid foreseeable issues in gene therapy that could prevent the field from continued success.

Prostate cancer is one of the most significant causes of morbidity and mortality in male patients. The incidence increases with age, and it is higher among African Americans. The occurrence of prostate cancer is associated with many risk factors, including genetic and hereditary predisposition. The most common genetic syndromes associated with prostate cancer risk are BRCA-associated hereditary breast and ovarian cancer (HBOC) and Lynch syndrome. Local-regional therapy, i.e., surgery is beneficial in early-stage prostate cancer management. Advanced and metastatic prostate cancers require systemic therapies, including hormonal inhibition, chemotherapy, and targeted agents. Most prostate cancers can be treated by targeting the androgen-receptor pathway and decreasing androgen production or binding to androgen receptors (AR). Castration-resistant prostate cancer (CRPC) usually involves the PI3K/AKT/mTOR pathway and requires targeted therapy. Specific molecular therapy can target mutated cell lines in which DNA defect repair is altered, caused by mutations of BRCA2, partner and localizer of BRCA2 (PALB2), and phosphatase and tensin homolog (PTEN) or the transmembrane protease serine 2-ERG (TMPRSS2-ERG) fusion. Most benefits were demonstrated in cyclin dependent-kinase 12 (CDK12) mutated cell lines when treated with anti-programmed cell death protein 1 (PD1) therapy. Therapies targeting p53 and AKT are the subject of ongoing clinical trials. Many genetic defects are listed as diagnostic, prognostic, and clinically actionable markers in prostate cancer. Androgen receptor splice variant 7 (AR-V7) is an important oncogenic driver and an early diagnostic and prognostic marker, as well as a therapeutic target in hormone-resistant CRPC. This review summarizes the pathophysiological mechanisms and available targeted therapies for prostate cancer.

Background: Genomic conditions can be associated with developmental delay, intellectual disability, autism spectrum disorder, and physical and mental health symptoms. They are individually rare and highly variable in presentation, which limits the use of standard clinical guidelines for diagnosis and treatment. A simple screening tool to identify young people with genomic conditions associated with neurodevelopmental disorders (ND-GCs) who could benefit from further support would be of considerable value. We used machine learning approaches to address this question. Method: A total of 493 individuals were included: 389 with a ND-GC, mean age = 9.01, 66% male) and 104 siblings without known genomic conditions (controls, mean age = 10.23, 53% male). Primary carers completed assessments of behavioural, neurodevelopmental and psychiatric symptoms and physical health and development. Machine learning techniques (penalised logistic regression, random forests, support vector machines and artificial neural networks) were used to develop classifiers of ND-GC status and identified limited sets of variables that gave the best classification performance. Exploratory graph analysis was used to understand associations within the final variable set. Results: All machine learning methods identified variable sets giving high classification accuracy (AUROC between 0.883 and 0.915). We identified a subset of 30 variables best discriminating between individuals with ND-GCs and controls which formed 5 dimensions: conduct, separation anxiety, situational anxiety, communication and motor development. Limitations: This study used cross-sectional data from a cohort study which was imbalanced with respect to ND-GC status. Our model requires validation in independent datasets and with longitudinal follow-up data for validation before clinical application. Conclusions: In this study, we developed models that identified a compact set of psychiatric and physical health measures that differentiate individuals with a ND-GC from controls and highlight higher-order structure within these measures. This work is a step towards developing a screening instrument to identify young people with ND-GCs who might benefit from further specialist assessment. [ABSTRACT FROM AUTHOR]

The frequency of genetic diseases is estimated at approximately 1 in 40 live newborns, including both minor and major disorders. The medico-psycho-social impact of diseases with genetic determinism is important. Although taken individually, genetic diseases are considered rare, cumulatively, they represent such a frequent pathology, that one can rightfully consider genetic anomalies the basis of the majority of currently diagnosable and treatable conditions. This is the hypothesis that underlies the orientation of contemporary medicine towards individualized therapy. Congenital heart malformations associate a high morbidity and mortality potential even as an isolated disease, even more so if they appear in the context of a genetic syndrome. For these reasons, it is particularly important for today's practitioner to know the small clues that should raise a reasonable suspicion for the presence of a genetic syndrome in a patient diagnosed with a congenital heart disease. Dysmorphology is the youngest genetic branch, studying the structural anomalies commonly reffered to as birth defects. It has proven to be an important tool for the modern practitioner when dealing with complex congenital anomalies.

Abstract Background Anxiety symptomatology is common in individuals with intellectual disability (ID). Symptomatology includes both traditional Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) anxiety disorders and autism spectrum disorder (ASD)-related anxiety traits. Some genetic disorders such as Cornelia de Lange (CdLS) and fragile X syndromes (FXS) are at very high risk of anxiety and afford the opportunity to examine prevalence, profiles and associated person characteristics. However, prevalence and associated characteristics of anxiety in these high-risk groups remain poorly described and understood. The aim of the current study was to examine the prevalence and profile of DSM-5 and ASD-related anxiety symptomatology in individuals with CdLS and FXS and associated behavioural and cognitive characteristics. Methods Questionnaires and interviews assessing DSM-5 and ASD-related anxiety were conducted with caregivers of individuals with CdLS (n = 49) and FXS (n = 36). Results DSM-5 anxiety symptomatology was present in both groups with high co-morbidity across anxiety diagnoses. ASD-related anxiety was also prevalent with specific difficulties related to intolerance of uncertainty identified in both groups. Symptomatology was persistent over the lifespan for both groups. Anxiety type was partially associated with repetitive behaviour but not measures of overall ASD phenomenology in CdLS. Conclusions DSM-5 and ASD-related anxiety are common in these high-risk syndromes associated with ID. Prospective syndrome specific presentations and associations, which may implicate specific underlying mechanisms, are discussed. Clinicians should be aware of the risk and difficulties involved in assessment of anxiety in individuals with ID, including atypical types, to ensure these individuals do not “miss” diagnoses and support in general clinical practice.

Le développement lexical est un des domaines langagiers les moins abordés dans le cadre de la déficience intellectuelle. Les banques de données PubMed et Scopus permettent de recenser environ 13 000 publications scientifiques revues par les pairs consacrées au développement langagier en général des personnes présentant une déficience intellectuelle pour 20 fois moins de résultats sur le thème du développement lexical. Les études analysées dans cet article renvoient à deux champs de recherches distincts : (1) l'étude comparative des trajectoires développementales des enfants présentant une déficience syndromique et des enfants neurotypiques et (2) la description du contenu référentiel du lexique et du processus d'apprentissage lexical. Le premier axe de recherche a permis de décrire l'allure générale de la trajectoire d'acquisition lexicale des enfants présentant une déficience intellectuelle ; trajectoire marquée par une explosion lexicale plus tardive et moins importante que chez l'enfant neurotypique. L'influence respective de l'âge mental et de l'âge chronologique (ou l'expérience de vie) dans le développemental lexical y est également discutée ; le premier étant impliqué dans le développement du versant tant expressif que réceptif du vocabulaire et le second impactant uniquement le versant réceptif. Le second axe de recherche a permis d'avancer des éléments d'explication au problème relevé dans la maîtrise de certains domaines du lexique (mots abstraits ou lexique relationnel) ; une interprétation de ces difficultés en termes de déficit des connaissances conceptuelles et donc de l'accès à la mémoire sémantique est généralement avancée. Cet axe de recherche reprend également les travaux sur l'utilisation des contraintes et des principes lexicaux chez les enfants présentant une déficience intellectuelle. Les conclusions de ces études soulignent des capacités de généralisation des nouveaux mots appris à de nouveaux exemplaires comparables à celles observées chez les enfants neurotypiques. La variabilité intersyndromique, et plus particulièrement une description détaillée des profils lexicaux spécifiques des personnes présentant une trisomie 21 et de celles porteuses d'un syndrome de Williams, traverse les deux axes de recherche cités et permet de dégager ce qui est propre à la déficience intellectuelle en général de ce qui est spécifique à un syndrome particulier. Beaucoup de questions restent cependant encore en suspens. Lexical development of children with intellectual disability has received poor attention in the scientific literature compared to general language development. PubMed and Scopus databases identify around 13,000 peer-reviewed scientific publications on general language development of people with intellectual disabilities and 20 times fewer results on lexical development. The studies analyzed in this article refer to two distinct fields of research: (1) the comparative study of children with disabilities and neurotypical children's developmental trajectories and (2) the description of the referential content of the lexicon and of the learning process. The first line of research describes the general shape of the lexical acquisition trajectory of children with intellectual disabilities; trajectory marked by a later and less important lexical explosion than the one observed in neurotypical children. It is also marked by the highlighting of the respective influence of mental age and chronological age (or life experience) in lexical development; the first being involved in the development of both the expressive and receptive side of the vocabulary and the second impacting only the receptive side. The second line of research gives elements of explanation for the problem identified in the mastery of complex areas of the lexicon (abstract words or relational vocabulary). These difficulties are often interpreted in terms of a deficit of conceptual knowledge and therefore of access to semantic memory. This line of research also describes the use of lexical constraints and principles in children with intellectual disabilities. The conclusions of these studies highlight abilities to generalize new words to new examples comparable to those observed in neurotypical children. The intersyndromic variability, more particularly the specific lexical profiles of people with trisomy 21 and those with Williams syndrome, crosses the two lines of research and makes it possible to identify what is specific to intellectual disability from what is specific to a particular syndrome. However, many questions still remain unanswered. [ABSTRACT FROM AUTHOR]

Background: Phenotypic studies have identified distinct patterns of autistic characteristics in genetic syndromes associated with intellectual disability (ID), leading to diagnostic uncertainty and compromised access to autism-related support. Previous research has tended to include small samples and diverse measures, which limits the generalisability of findings. In this study, we generated detailed profiles of autistic characteristics in a large sample of > 1500 individuals with rare genetic syndromes. Methods: Profiles of autistic characteristics based on the Social Communication Questionnaire (SCQ) scores were generated for thirteen genetic syndrome groups (Angelman n = 154, Cri du Chat n = 75, Cornelia de Lange n = 199, fragile X n = 297, Prader–Willi n = 278, Lowe n = 89, Smith–Magenis n = 54, Down n = 135, Sotos n = 40, Rubinstein–Taybi n = 102, 1p36 deletion n = 41, tuberous sclerosis complex n = 83 and Phelan–McDermid n = 35 syndromes). It was hypothesised that each syndrome group would evidence a degree of specificity in autistic characteristics. To test this hypothesis, a classification algorithm via support vector machine (SVM) learning was applied to scores from over 1500 individuals diagnosed with one of the thirteen genetic syndromes and autistic individuals who did not have a known genetic syndrome (ASD; n = 254). Self-help skills were included as an additional predictor. Results: Genetic syndromes were associated with different but overlapping autism-related profiles, indicated by the substantial accuracy of the entire, multiclass SVM model (55% correctly classified individuals). Syndrome groups such as Angelman, fragile X, Prader–Willi, Rubinstein–Taybi and Cornelia de Lange showed greater phenotypic specificity than groups such as Cri du Chat, Lowe, Smith–Magenis, tuberous sclerosis complex, Sotos and Phelan-McDermid. The inclusion of the ASD reference group and self-help skills did not change the model accuracy. Limitations: The key limitations of our study include a cross-sectional design, reliance on a screening tool which focuses primarily on social communication skills and imbalanced sample size across syndrome groups. Conclusions: These findings replicate and extend previous work, demonstrating syndrome-specific profiles of autistic characteristics in people with genetic syndromes compared to autistic individuals without a genetic syndrome. This work calls for greater precision of assessment of autistic characteristics in individuals with genetic syndromes associated with ID. [ABSTRACT FROM AUTHOR]

In this study, we focus on Rubinstein-Taybi syndrome (RTS) to explore the associations between executive function deficits and repetitive behaviors. Thirty individuals with RTS completed direct assessments of inhibition, working memory and set-shifting. Informants completed repetitive behavior and executive function questionnaires. Repetitive questions were associated with poorer inhibition and working memory. Stereotypy was associated with poorer inhibition. Adherence to routines was associated with poorer set-shifting, but only on the parental report measure. No other associations were evident. There is evidence of an association between specific repetitive behaviors and executive functioning in RTS, suggesting executive dysfunction may underpin behavioral difference in RTS. The findings point towards specific associations that are of interest for further research across populations in which repetitive behaviors are present. [ABSTRACT FROM AUTHOR]

This review initiates by outlining the clinical relevance of IA, underlining the pressing need to comprehend its foundational elements. We delve into the assorted risk factors tied to IA, spotlighting both environmental and genetic influences. Additionally, we illuminate distinct genetic syndromes linked to a pronounced prevalence of intracranial aneurysms, underscoring the pivotal nature of genetics in this ailment’s susceptibility. A detailed scrutiny of genome-wide association studies allows us to identify key genomic changes and locations associated with IA risk. We further detail the molecular and physiopathological dynamics instrumental in IA’s evolution and escalation, with a focus on inflammation’s role in affecting the vascular landscape. Wrapping up, we offer a glimpse into upcoming research directions and the promising horizons of personalized therapeutic strategies in IA intervention, emphasizing the central role of genetic insights. This thorough review solidifies genetics’ cardinal role in IA, positioning it as a cornerstone resource for professionals in the realms of neurology and genomics.

Simple Summary: A review of the molecular and cellular features of the major cancer syndromes associated with radiosensitivity revealed the importance of the ATM protein, either as an impaired kinase in the nucleus or as a complex in the cytoplasm, with the mutated protein responsible for the syndrome. There are a number of genetic syndromes associated with both high cancer risk and clinical radiosensitivity. However, the link between these two notions remains unknown. Particularly, some cancer syndromes are caused by mutations in genes involved in DNA damage signaling and repair. How are the DNA sequence errors propagated and amplified to cause cell transformation? Conversely, some cancer syndromes are caused by mutations in genes involved in cell cycle checkpoint control. How is misrepaired DNA damage produced? Lastly, certain genes, considered as tumor suppressors, are not involved in DNA damage signaling and repair or in cell cycle checkpoint control. The mechanistic model based on radiation-induced nucleoshuttling of the ATM kinase (RIANS), a major actor of the response to ionizing radiation, may help in providing a unified explanation of the link between cancer proneness and radiosensitivity. In the frame of this model, a given protein may ensure its own specific function but may also play additional biological role(s) as an ATM phosphorylation substrate in cytoplasm. It appears that the mutated proteins that cause the major cancer and radiosensitivity syndromes are all ATM phosphorylation substrates, and they generally localize in the cytoplasm when mutated. The relevance of the RIANS model is discussed by considering different categories of the cancer syndromes. [ABSTRACT FROM AUTHOR]

Wolfram syndrome (WFS) is a rare neurodegenerative disease. Clinical diagnosis is made when nonautoimmune insulin-dependent diabetes is found to be associated with bilateral optic atrophy in a patient early in life. Frequent associations include diabetes insipidus, diabetes mellitus, optic atrophy and deafness. Many other multisystemic associations have been described including menstrual irregularities in female and hypogonadism in male patients. We present a first case of WFS associated with hypergonadotropic hypogonadism in a female adolescent diagnosed with WFS both clinically and genetically. Other causes of premature ovarian insufficiency (POI) have been excluded. This case report shows the importance of gonadal function assessment and follow-up in time for both genders. [ABSTRACT FROM AUTHOR]

The frequency of genetic diseases is estimated at approximately 1 in 40 live newborns, including both minor and major disorders. The medico-psycho-social impact of diseases with genetic determinism is important. Although taken individually, genetic diseases are considered rare, cumulatively, they represent such a frequent pathology, that one can rightfully consider genetic anomalies the basis of the majority of currently diagnosable and treatable conditions. This is the hypothesis that underlies the orientation of contemporary medicine towards individualized therapy. Congenital heart malformations associate a high morbidity and mortality potential even as an isolated disease, even more so if they appear in the context of a genetic syndrome. For these reasons, it is particularly important for today's practitioner to know the small clues that should raise a reasonable suspicion for the presence of a genetic syndrome in a patient diagnosed with a congenital heart disease. Dysmorphology is the youngest genetic branch, studying the structural anomalies commonly reffered to as birth defects. It has proven to be an important tool for the modern practitioner when dealing with complex congenital anomalies. [ABSTRACT FROM AUTHOR]

Background: Anxiety symptomatology is common in individuals with intellectual disability (ID). Symptomatology includes both traditional Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) anxiety disorders and autism spectrum disorder (ASD)-related anxiety traits. Some genetic disorders such as Cornelia de Lange (CdLS) and fragile X syndromes (FXS) are at very high risk of anxiety and afford the opportunity to examine prevalence, profiles and associated person characteristics. However, prevalence and associated characteristics of anxiety in these high-risk groups remain poorly described and understood. The aim of the current study was to examine the prevalence and profile of DSM-5 and ASD-related anxiety symptomatology in individuals with CdLS and FXS and associated behavioural and cognitive characteristics. Methods: Questionnaires and interviews assessing DSM-5 and ASD-related anxiety were conducted with caregivers of individuals with CdLS (n = 49) and FXS (n = 36). Results: DSM-5 anxiety symptomatology was present in both groups with high co-morbidity across anxiety diagnoses. ASD-related anxiety was also prevalent with specific difficulties related to intolerance of uncertainty identified in both groups. Symptomatology was persistent over the lifespan for both groups. Anxiety type was partially associated with repetitive behaviour but not measures of overall ASD phenomenology in CdLS. Conclusions: DSM-5 and ASD-related anxiety are common in these high-risk syndromes associated with ID. Prospective syndrome specific presentations and associations, which may implicate specific underlying mechanisms, are discussed. Clinicians should be aware of the risk and difficulties involved in assessment of anxiety in individuals with ID, including atypical types, to ensure these individuals do not "miss" diagnoses and support in general clinical practice. [ABSTRACT FROM AUTHOR]

Many patients with genetic syndromes have special facial features, which boast significant potential value for clinical diagnosis. Deep learning and computer vision technology can be employed to diagnose genetic diseases by analyzing facial features of patients. As a matter of fact, the application of deep learning technology in the area of genetic diseases is confined owing to the difficulties of patient data acquisition. This study develops BioFace, a deep learning framework that can recognize multiple genetic diseases facial attributes based on limited datasets. BioFace is a deep neural network architecture designed premised on Resnet. To increase the weight of effective features and weaken the weight of invalid or unobvious features during extraction of facial features, we add Squeeze-and-Excitation (SE) blocks in the network. In combination with this network architecture, we designed a cross-loss training method based on transfer learning. This method can transfer the ability learned from the task of face identification to the task of recognition of genetic diseases facial attribute, and improve the inter-class distance of different genetic diseases and the intra-class distance of similar genetic diseases simultaneously. These render it possible for deep learning to be applied to recognition of multiple genetic diseases facial attribute with very small amount of data. In this research, we tested 10 syndromes with our framework and the Top-1 accuracy was 93.5%, which is the state-of-the-art in multiple genetic syndromes recognition research. In practical clinical applications, our framework and methods can be extended to the disease identification of more small datasets, potentially offering valuable assistance for the auxiliary clinical application of genetic diagnosis and other related genetic research.

Background: Disorders of immunity are poorly recognised in some rare multisystem genetic conditions. We aim to describe syndromic features and immunological defects in children with syndromic primary immunodeficiencies (sPIDs). Methods: This is a retrospective descriptive study of children aged 0–18 years with sPIDs under the care of the paediatric immunology service at the Bristol Royal Hospital for Children, United Kingdom, from January 2006 to September 2021. Results: sPIDs were identified in 36 patients. Genetic diagnoses which are not commonly associated with PIDs and not included in the International Union of Immunological Societies classification were present in 7/36 (19%): Trisomy 22, Arboleda-Tham syndrome, 2p16.3 deletion syndrome, supernumerary ring chromosome 20 syndrome, Myhre syndrome, Noonan syndrome, and trichothiodystrophy/Cockayne syndrome complex. Recurrent and/or severe infections were the most common clinical features (n = 33, 92%). Approximately half had combined immunodeficiency or antibody deficiency. The most common extra-immunological manifestations include dysmorphism (72%), disorders of nervous (78%), musculoskeletal (69%), haematology/lymphatic (58%), and gastrointestinal, hepatic/pancreatic (58%) systems. Conclusions: Patients with sPIDs often have multiorgan involvement and some are non-immunologically mediated. There should be a low threshold to clinically assess and investigate for disorders of immunity in any patients with syndromic features especially when they present with recurrent/severe/opportunistic infections, features of immune dysregulation, autoinflammation or lymphoproliferation.

Background: Human telomerase reverse transcriptase (hTERT)-mRNA was shown to be elevated in exosomes derived from the sera of a variety of hematological and solid cancer patients. We aimed to evaluate its role as a diagnostic marker in patients with newly diagnosed colon cancer and in hereditary syndromes with predisposition to colon cancer. Methods: hTERT -mRNA levels were determined in serum-derived exosomes from 88 patients with colon cancer, 71 Lynch-syndrome carriers with unknown active malignancies and 50 healthy controls. Data, including demographics, background diseases, clinical data regarding tumor characteristics and genetic data, were retrieved data from medical files. Results: Patients with colon cancer had both higher exosomal hTERT mRNA levels and a higher proportion of patients with positive exosomal hTERT mRNA than controls (29.5% vs. 4%, respectively, P values < 0.001). Within the cancer group, patients with a metastatic disease had higher levels of telomerase mRNA than non-metastatic disease patients, and these levels correlated with CEA levels. Likewise, Lynch syndrome carriers had a higher proportion of positive exosomal hTERT mRNA than controls (21.1% vs. 4%, respectively, P value 0.008) but only a trend towards higher exosomal hTERT mRNA levels. Higher telomerase mRNA levels were not correlated with the mutated gene. Conclusions: Exosomal serum hTERT -mRNA levels are associated with metastatic colon cancer and were also demonstrated in a subset of Lynch syndrome carriers. Its significance as a biomarker for developing malignancy should be elucidated. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by core deficits in social communication and restricted and repetitive behaviors and interests. Recent advances in clinical genetics have improved our understanding of genetic syndromes associated with ASD, which has helped clarify distinct etiologies of ASD and document syndrome-specific profiles of neurocognitive strengths and weaknesses. Pediatric neuropsychologists have the potential to be impactful members of the care team for children with genetic syndromes and their families. We provide a critical review of the current literature related to the neuropsychological profiles of children with four genetic syndromes associated with ASD, including Tuberous Sclerosis Complex (TSC), fragile X syndrome (FXS), 22q11.2 deletion syndrome, and Angelman syndrome. Recommendations for assessment, intervention, and future directions are provided. There is vast heterogeneity in terms of the cognitive, language, and developmental abilities of these populations. The within- and across-syndrome variability characteristic of genetic syndromes should be carefully considered during clinical evaluations, including possible measurement limitations, presence of intellectual disability, and important qualitative differences in the ASD-phenotypes across groups. Individuals with genetic disorders pose challenging diagnostic and assessment questions. Pediatric neuropsychologists with expertise in neurodevelopmental processes are well suited to address these questions and identify profiles of neurocognitive strengths and weaknesses, tailor individualized recommendations, and provide diagnostic clarification. [ABSTRACT FROM AUTHOR]