Search Results (18)

The retinal pigment epithelium (RPE), a monolayer of pigmented cells, is critical for visual function through its interaction with the neural retina. In healthy eyes, RPE cells exhibit a uniform hexagonal arrangement, but under stress or disease, such as age-related macular degeneration (AMD), dysmorphic traits like cell enlargement and apparent multinucleation emerge. Multinucleation has been hypothesized to result from cellular fusion, a compensatory mechanism to maintain cell-to-cell contact and barrier function, as well as conserve resources in unhealthy tissue. However, traditional two-dimensional (2D) imaging using apical border markers alone may misrepresent multinucleation due to the lack of lateral markers. We present high-resolution confocal images enabling three-dimensional (3D) visualization of apical (ZO-1) and lateral (α-catenin) markers alongside nuclei. In two RPE damage models, we find that seemingly multinucleated cells are often single cells with displaced neighboring nuclei and lateral membranes. This emphasizes the need for 3D analyses to avoid misidentifying multinucleation and underlying fusion mechanisms. Lastly, images from the NaIO₃ oxidative damage model reveal variability in RPE damage, with elongated, dysmorphic cells showing increased ZsGreen reporter protein expression driven by EMT-linked CAG promoter activity, while more regular RPE cells displayed somewhat reduced green signal more typical of epithelial phenotypes. Full article

Epilepsy is a prevalent neurological condition, having a wide range of phenotypic traits, which complicate the diagnosis process. Next-generation sequencing (NGS) techniques have improved the diagnostics for unexplained epilepsies. Our goal was to evaluate the utility and impact of genetic testing in the clinical management of pediatric epilepsies. In addition, we aimed to identify clinical factors that could predict a genetic diagnosis. This was a retrospective study of 140 pediatric patients with epilepsy with or without other neurological conditions that underwent NGS testing (multigene panel, WES = whole exome sequencing and/or WGS = whole genome sequencing). A comparison between genetically diagnosed versus non-diagnosed children was performed based on different clinical features. Univariate and multivariate logistic regression analysis was performed to identify clinical predictors of a positive genetic diagnosis. Most children underwent gene panel testing, while 30 had exome sequencing and 3 had genome sequencing. The overall diagnostic yield of genetic testing was 28.6% (40/140) for more than 28 genes. The most frequently identified genes with causative variants were SCN1A (n = 4), SCN2A (n = 3), STXBP1 (n = 3), MECP2 (n = 2), KCNQ2 (n = 2), PRRT2 (n = 2), and NEXMIF (n = 2). Significant predictors from the logistic regression model were a younger age at seizure onset (p = 0.015), the presence of intellectual disability (p = 0.021), and facial dysmorphism (p = 0.049). A genetic diagnosis led to an impact on the choice or duration of medication in 85% (34/40) of the children, as well as the recommendation for screening of comorbidities or multidisciplinary referrals in 45% (18/40) of children. Epilepsy is a highly heterogeneous disorder, both genetically and phenotypically. Less than one third of patients had a genetic diagnosis identified using panels, exomes, and/or genomes. An early onset and syndromic features (including global developmental delay) were more likely to receive a diagnosis and benefit from optimized disease management. Full article

CSMD1 is a gene involved in various biological processes and is highly expressed in the central nervous system, where it plays a key role in complement activity, brain circuit development, and cognitive function. It has been implicated as a susceptibility gene for schizophrenia and a causative factor in developmental epileptic encephalopathy, neurodevelopmental disorders, and intellectual disability. However, no MIM phenotype number has been assigned to CSMD1 for a specific disorder. Here, we report an individual presenting with moderate intellectual disability, anxiety disorder, obsessive–compulsive personality traits, and facial dysmorphisms. Trio-based whole-exome sequencing (WES) identified two heterozygous CSMD1 variants, c.8095A>G and c.5315T>C, both classified as variants of uncertain significance (VUS) according to ACMG criteria. Computational analysis using the DOMINO tool supported an autosomal recessive inheritance model for CSMD1. This study contributes to the growing evidence linking CSMD1 to neurodevelopmental phenotypes, highlighting the need for further investigations to clarify its pathogenic role. Full article

Background: Interstitial deletions of chromosome 1q are rare, with about 30 cases reported in the literature. The phenotypical features of the affected subjects described so far include microcephaly, pre- and post-natal growth retardation, psychomotor delays, ear anomalies, brachydactyly, in addition to small hands and feet, and rarely a congenital diaphragmatic hernia (CDH). Case presentation: Here, we report on a neonate with CDH, dysmorphic features, and multiple midline anomalies including a cleft palate, in whom an array-comparative genomic hybridization (a-CGH) analysis allowed the identification of an interstitial deletion of the long arm of chromosome 1. Our patient underwent a surgical correction of CDH on the fourth day of life, while that of cleft palate has been planned to be performed at 12 months. Conclusions: The few subjects suffering such rearrangement reported to date, along with the clinical and genetic profile of the present newborn, show that 1q deletions should be considered within the context of the “interstitial 1q deletion syndrome”. Comparing our case with those described in previous studies, the involved genomic regions and the phenotypic traits are partially overlapping, although the clinical picture of the present patient is among the few ones including a congenital diaphragmatic hernia within the phenotypical spectrum. A more extensive comparative analysis of a larger number of patients with similar genetic profiles may allow for a more precise clinical and genomic characterization of this rare syndrome, and for genotype–phenotype correlations. Full article

Background/Objectives: Ischemic arterial stroke (AIS) is a cerebrovascular event that can occur acutely within the first hours or days of life, presenting as a neurological emergency. To date, clearly defined genetic risk factors for AIS have not been established, although certain genes involved in cerebrovascular regulation mechanisms are suspected to play a role. The Interferon Regulatory Factor 6 (IRF6) gene is a transcription factor involved in craniofacial and epidermal development. Recently, pathogenic variants of IRF6 have been implicated in the cytoprotective pathway of ischemic cerebrovascular disease. The aim of this manuscript is to further support the already-reported association between IRF6 and AIS. Materials and Methods: Genetic counseling and exome sequencing analysis were conducted for diagnostic purposes. Results: We report the case of a female newborn with palatoschisis, cleft palate, sensorineural deafness, facial dysmorphisms, and cutaneous defects who suffered an ischemic stroke in the territory of the left middle cerebral artery on day 1 of life. Family and pregnancy histories revealed no identifiable risk factors, and coagulation studies were normal. Exome sequencing identified a de novo c.1124T>C (p.Phe375Ser) variant in the IRF6 gene. The child developed right spastic hemiplegia and began motor rehabilitation therapy. Recently, a genome-wide association study (GWAS) using m6A-SNPs identified a statistical association between AIS and a single nucleotide polymorphism (SNP) that influences the expression of the IRF6 gene as an expression quantitative trait locus (eQTL). Conclusions: To our knowledge, this is the first report of neonatal ischemic stroke in a child carrying a de novo IRF6 pathogenic variant, further supporting its potential role as a genetic factor influencing cerebrovascular events. Further studies are needed to elucidate the precise relationship between IRF6 and AIS. Full article

Background: The characterization of facial sexual dimorphic patterns in healthy populations serves as valuable normative data to tailor functionally effective surgical treatments and predict their aesthetic outcomes and to identify dysmorphic facial traits related to hormonal disorders and genetic syndromes. Although the analysis of facial sexual differences in juveniles of different ages has already been investigated, few studies have approached this topic with three-dimensional (3D) geometric morphometric (GMM) analysis, whose interpretation may add important clinical insight to the current understanding. This study aims to investigate the location and extent of facial sexual variations in juveniles through a spatially dense GMM analysis. Methods: We investigated 3D stereophotogrammetric facial scans of 304 healthy Italians aged 3 to 18 years old (149 males, 155 females) and categorized into four different age groups: early childhood (3–6 years), late childhood (7–12 years), puberty (13–15 years), and adolescence (16–18 years). Geometric morphometric analyses of facial shape (allometry, general Procrustes analysis, Principal Component Analysis, Procrustes distance, and Partial Least Square Regression) were conducted to detail sexually dimorphic traits in each age group. Results: The findings confirmed that males have larger faces than females of the same age, and significant differences in facial shape between the two sexes exist in all age groups. Juveniles start to express sexual dimorphism from 3 years, even though biological sex becomes a predictor of facial soft tissue morphology from the 7th year of life, with males displaying more protrusive medial facial features and females showing more outwardly placed cheeks and eyes. Conclusions: We provided a detailed characterization of facial change trajectories in the two sexes along four age classes, and the provided data can be valuable for several clinical disciplines dealing with the craniofacial region. Our results may serve as comparative data in the early diagnosis of craniofacial abnormalities and alterations, as a reference in the planning of personalized surgical and orthodontic treatments and their outcomes evaluation, as well as in several forensic applications such as the prediction of the face of missing juveniles. Full article

Background: Houge-Janssens syndrome 1 is a condition with onset in early childhood caused by heterozygous pathogenic variants in the PPP2R5D gene, which encodes a B56 regulatory subunit of the serine/threonine protein phosphatase 2A (PP2A). There is evidence that the PP2A-PPP2R5D complex is involved in regulating the phosphatidylinositol 3-kinase (PI3K)/AKT signalling pathway, which is crucial for several cellular processes, including the pathogenesis and progression of haemangiomas. Case presentation: We report the first PPP2R5D-related neurodevelopmental disorder case from Sardinia, a child with transient hypoglycaemia, facial dysmorphisms, and multiple haemangiomas. Whole Exome Sequencing analysis confirmed the clinical suspicion, detecting the presence of the de novo missense variant c.592G>A in the PPP2R5D gene. Conclusions: Haemangiomas have never been linked to the syndromic phenotype of the PPP2R5D-associated disorder. The close correlation between the PP2A enzyme and the PI3K/AKT signalling pathway suggests the possible correlation between its dysfunction and activation of haemangiogenesis. Our report highlights a possible link between the PPP2R5D-related disorder and altered angiogenesis, characterizing diffuse haemangiomas as a possible novel phenotypic trait of this condition. Full article

Background/Objectives: Develop a clinical and genetic characterization, in a group of small-for-gestational-age (SGA) patients who did not experience catch-up growth Methods: In an ambispective cohort study with (SGA) patients. These patients received one treatment with growth hormone (GH) over 14 years. This study analyzes their response to treatment and conducts a genetic analysis in order to identify cases with specific phenotypic and auxological characteristics, defined as presenting two or more dysmorphic traits and/or a stature below −3 SDS (standard deviation score). Whole-exome sequencing (WES) was performed on selected patients. Results: Forty-four SGA patients were examined, with an average age of 6.4 (2.49) years and an initial size of −3.3 SDS. The pubertal growth was 24.1 (5.2) cm in boys and 14.7 (4.3) cm in girls. WES in 11 SGA patients revealed conclusive genetic variants in eight, including two pathogenic ACAN variants, one 15q26.2-q26.3 deletion, and four variants of uncertain significance in other genes. Conclusions: Treatment with GH in SGA patients was shown to be effective, with a similar response in the group with positive genetic results and in the group who did not undergo a genetic study. Genetic testing based on auxological and clinical criteria proved highly cost-effective. Full article

To date, only 13 studies have described patients with large overlapping deletions of 10p11.2-p12. These individuals shared a common phenotype characterized by intellectual disability, developmental delay, distinct facial dysmorphic features, abnormal behaviour, visual impairment, cardiac malformation, and cryptorchidism in males. Molecular cytogenetic analysis revealed that the deletion in this chromosomal region shares a common smallest region of overlap (SRO) of 80 kb, which contains only the WAC gene (WW-domain-containing adaptor with coiled coil). In this clinical case report, we report a 5-year-old girl, born from non-consanguineous parents, with a 10p11.22p11.21 microdeletion. She presents clinical features that overlap with other patients described in the literature, such as dysmorphic traits, speech delay, and behavioural abnormalities (hyperactivity), even though the WAC gene is not involved in the microdeletion. Our results are the first to highlight that the deletion described here represents a contiguous gene syndrome that is enough to explain the distinct phenotype but partially overlaps with the previous cases reported in the literature, even though the same genes are not involved. In particular, in this study, we speculate about the role of the WAC gene that seems to be associated with normal motor development. In fact, we found that our patient is the only one described in the literature with a large deletion in the 10p11.22p11.21 region without the involvement of the WAC gene deletion, and, interestingly, the patient did not have motor delay. Full article

Introduction: Moderate-late preterm infants constitute the largest segment of preterm births globally. While previously considered to have a low neurological risk, recent research has uncovered an elevated incidence of neurodevelopmental conditions in this group. This study aimed to assess the relationship between the general movement assessment and birth-related risk factor-based tools in moderate-late preterm infants. Methods: A prospective cohort study of 65 moderate-late preterm infants in a neonatal intensive care unit involved the evaluation of general movements, the Nursery Neurobiologic Risk Score, and the Perinatal Risk Inventory. Associations were analyzed using Fisher’s exact test, Spearman’s correlation was used for ordinal variables, and backward stepwise logistic regression was used to identify predictor variables for the assessments. Results: The findings indicated a high prevalence of normal (41%) and poor (52%) repertoire patterns during the writhing period. While no significant associations were found between the three assessments, a slight approximation emerged between dysmorphic traits and patterns (p = 0.053). Furthermore, an extended period of ventilation correlated with a higher likelihood of developing a cramped synchronized pattern and there was a correlation between both risk factor-based tools (p < 0.001). Conclusions: This research enhances our understanding of the early impact on general movement assessments in moderate-late preterm infants. While no clear relationship emerged between general movement assessment and risk factor-based tools, there was a subtle connection noted with dysmorphic traits. A longer ventilation duration was linked to a higher risk of developing cramped synchronized patterns. Full article

The NFIA (nuclear factor I/A) gene encodes for a transcription factor belonging to the nuclear factor I family and has key roles in various embryonic differentiation pathways. In humans, NFIA is the major contributor to the phenotypic traits of “Chromosome 1p32p31 deletion syndrome”. We report on two new cases with deletions involving NFIA without any other pathogenic protein-coding gene alterations. A cohort of 24 patients with NFIA haploinsufficiency as the sole anomaly was selected by reviewing the literature and public databases in order to analyze all clinical features reported and their relative frequencies. This process was useful because it provided an overall picture of the phenotypic outcome of NFIA haploinsufficiency and helped to define a cluster of phenotypic traits that can facilitate clinicians in identifying affected patients. NFIA haploinsufficiency can be suspected by a careful observation of the dysmorphisms (macrocephaly, craniofacial, and first-finger anomalies), and this potential diagnosis is strengthened by the presence of intellectual and developmental disabilities or other neurodevelopmental disorders. Further clues of NFIA haploinsufficiency can be provided by instrumental tests such as MRI and kidney urinary tract ultrasound and confirmed by genetic testing. Full article

KBG syndrome (KBGS; OMIM #148050) is a rare disease characterized by short stature, facial dysmorphism, macrodontia of the upper central incisors, skeletal anomalies, and neurodevelopmental disorder/intellectual disability. It is caused by a heterozygous variant or 16q24.3 microdeletions of the ANKRD11 gene (OMIM #611192), which plays a primary role in neuronal development. KBGS traits are variable, and mild expressions of the phenotype may complicate diagnosis. The present work aims at improving the characterization of KBGS in order to facilitate its recognition. A psychopathological evaluation of 17 subjects affected by KBGS found that 10 patients exhibited peculiar behavior related to “paper handling”. These children and adolescents performed repetitive activities with paper, reminiscent of the hoarding and ordering behaviors characteristic of obsessive compulsive disorder. Their activities were time consuming and carried out in solitary, and forced interruption could generate intense emotional reactions. Paper handling may thus be understood as a potential distinct KBGS symptom akin to an obsessive compulsive symptom. Further research is needed to verify this claim. Full article

(1) Background: we aimed to investigate the effects of physical activity on cognitive functions and deficits of healthy population and other needy groups. Secondly, we investigated the relation between healthy habits and psychopathological risks. Finally, we investigated the impact of COVID-19 pandemic on exercise addiction and possible associated disorders. (2) Methods: From April 2021 to October 2021, we conducted a review aimed at identifying the effects of physical exercise on mental health, from cognitive improvements to risk of addiction; we searched for relevant studies on PubMed, Web of Science, EMBASE, PsycINFO and CINHAL. (3) Results: For the first purpose, results indicated multiple effects such as better precision and response speed in information processing tasks on healthy populations; improvement of executive functions, cognitive flexibility and school performance in children; improvement of attention and executive functions and less hyperactivity and impulsiveness on children with attention deficit hyperactivity disorder (ADHD); improvement of executive and global functions on adults; improvement of overall cognitive functioning on patients with schizophrenic spectrum disorder or bipolar disorder. Data also demonstrated that exercise addiction seems to be related to low levels of education, low self-esteem, eating disorders and body dysmorphisms. Eventually, it was found that people with lower traits and intolerance of uncertainty show a strong association between COVID-19 anxiety and compulsive exercise and eating disorder. (4) Conclusions: these findings underline on one side the beneficial effects of physical activity on cognitive function in healthy individuals in a preventive and curative key, while on the other side the importance of an adequate evaluation of psychological distress and personality characteristics associated with exercise addiction. Full article

In this case report, we focus on Muenke syndrome (MS), a disease caused by the p.Pro250Arg variant in fibroblast growth factor receptor 3 (FGFR3) and characterized by uni- or bilateral coronal suture synostosis, macrocephaly without craniosynostosis, dysmorphic craniofacial features, and dental malocclusion. The clinical findings of MS are further complicated by variable expression of phenotypic traits and incomplete penetrance. As such, unraveling the mechanisms behind MS will require a comprehensive and systematic way of phenotyping patients to precisely identify the impact of the mutation variant on craniofacial development. To establish this framework, we quantitatively delineated the craniofacial phenotype of an individual with MS and compared this to his unaffected parents using three-dimensional cephalometric analysis of cone beam computed tomography scans and geometric morphometric analysis, in addition to an extensive clinical evaluation. Secondly, given the utility of human induced pluripotent stem cells (hiPSCs) as a patient-specific investigative tool, we also generated the first hiPSCs derived from a family trio, the proband and his unaffected parents as controls, with detailed characterization of all cell lines. This report provides a starting point for evaluating the mechanistic underpinning of the craniofacial development in MS with the goal of linking specific clinical manifestations to molecular insights gained from hiPSC-based disease modeling. Full article

Since 2011, eight males with an X-linked recessive disorder (Ogden syndrome, MIM #300855) associated with the same missense variant p.(Ser37Pro) in the NAA10 gene have been described. After the advent of whole exome sequencing, many NAA10 variants have been reported as causative of syndromic or non-syndromic intellectual disability in both males and females. The NAA10 gene lies in the Xq28 region and encodes the catalytic subunit of the major N-terminal acetyltransferase complex NatA, which acetylates almost half the human proteome. Here, we present a young female carrying a de novo NAA10 [NM_003491:c.247C > T, p.(Arg83Cys)] variant. The 18-year-old girl has severely delayed motor and language development, autistic traits, postnatal growth failure, facial dysmorphisms, interventricular septal defect, neuroimaging anomalies and epilepsy. Our attempt is to expand and compare genotype–phenotype correlation in females with NAA10-related syndrome. A detailed clinical description could have relevant consequences for the clinical management of known and newly identified individuals. Full article