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Type 1 Chiari malformation (C1M) is characterized by cerebellar tonsillar herniation of 3–5 mm or more, the frequency of which is presumably much higher than one in 1000 births, as previously believed. Its etiology remains undefined, although a genetic basis is strongly supported by C1M presence in numerous genetic syndromes associated with different genes. Whole-exome sequencing (WES) in 51 between isolated and syndromic pediatric cases and their relatives was performed after confirmation of the defect by brain magnetic resonance image (MRI). Moreover, in all the cases showing an inherited candidate variant, brain MRI was performed in both parents and not only in the carrier one to investigate whether the defect segregated with the variant. More than half of the variants were Missense and belonged to the same chromatin-remodeling genes whose protein truncation variants are associated with severe neurodevelopmental syndromes. In the remaining cases, variants have been detected in genes with a role in cranial bone sutures, microcephaly, neural tube defects, and RASopathy. This study shows that the frequency of C1M is widely underestimated, in fact many of the variants, in particular those in the chromatin-remodeling genes, were inherited from a parent with C1M, either asymptomatic or with mild symptoms. In addition, C1M is a Mendelian trait, in most cases inherited as dominant. Finally, we demonstrate that modifications of the genes that regulate chromatin architecture can cause localized anatomical alterations, with symptoms of varying degrees.

Background COVID‐19 outbreak prompted health centres to reorganize their clinical and surgical activity. In this paper, we show how medical genetics department's activity, in our tertiary pediatric hospital, has changed due to pandemic. Methods We stratified all our scheduled visits, from March 9th through April 30th, and assessed case‐by‐case which genetic consultations should be maintained as face‐to‐face visit, or postponed/switched to telemedicine. Results Out of 288 scheduled appointments, 60 were prenatal consultations and 228 were postnatal visits. We performed most of prenatal consultations as face‐to‐face visits, as women would have been present in the hospital to perform other procedures in addition to our consult. As for postnatal care, we suspended all outpatient first visits and opted for telemedicine for selected follow‐up consultations: interestingly, 75% of our patients’ parents revealed that they would have cancelled the appointment themselves for the fear to contract an infection. Conclusions Spread of COVID‐19 in Italy forced us to change our working habits. Given the necessity to optimize healthcare resources and minimize the risk of in‐hospital infections, we experienced the benefits of telegenetics. Current pandemic made us familiar with telemedicine, laying the foundations for its application to deal with the increasing number of requests in clinical genetics. In this paper, we show how medical genetics department's activity, in our tertiary pediatric hospital, has changed due to COVID‐19 pandemic. Given the necessity to optimize healthcare resources and minimize the risk of in‐hospital infections, we experienced the benefits of telegenetics. Current pandemic made us familiar with telemedicine, laying the foundations for its application to deal with the increasing number of requests in clinical genetics.

Background Rare Eye Diseases (RED) are the leading cause of visual impairment and blindness for children and young adults in Europe. This heterogeneous group of conditions includes over 900 disorders ranging from relatively prevalent disorders such as retinitis pigmentosa to very rare entities such as developmental eye anomalies. A significant number of patients with RED have an underlying genetic etiology. One of the aims of the European Reference Network for Rare Eye Diseases (ERN–EYE) is to facilitate improvement in diagnosis of RED in European member states. Main body Technological advances have allowed genetic and genomic testing for RED. The outcome of genetic testing allows better understanding of the condition and allows reproductive and therapeutic options. The increase of the number of clinical trials for RED has provided urgency for genetic testing in RED. A survey of countries participating in ERN-EYE demonstrated that the majority are able to access some forms of genomic testing. However, there is significant variability, particularly regarding testing as part of clinical service. Some countries have a well-delineated rare disease pathway and have a national plan for rare diseases combined or not with a national plan for genomics in medicine. In other countries, there is a well-established organization of genetic centres that offer reimbursed genomic testing of RED and other rare diseases. Clinicians often rely upon research-funded laboratories or private companies. Notably, some member states rely on cross-border testing by way of an academic research project. Consequently, many clinicians are either unable to access testing or are confronted with long turnaround times. Overall, while the cost of sequencing has dropped, the cumulative cost of a genomic testing service for populations remains considerable. Importantly, the majority of countries reported healthcare budgets that limit testing. Short conclusion Despite technological advances, critical gaps in genomic testing remain in Europe, especially in smaller countries where no formal genomic testing pathways exist. Even within larger countries, the existing arrangements are insufficient to meet the demand and to ensure access. ERN-EYE promotes access to genetic testing in RED and emphasizes the clinical need and relevance of genetic testing in RED.

Abstract Disclosure: G. Del Medico: None. E. Andreucci: None. S. Bargiacchi: None. G. Gori: None. G. Mancano: None. G. Traficante: None. F. Girolami: None. S. Favilli: None. A. Peron: None. I. Olivotto: None. M. Tartaglia: None. S. Stagi: None. Background: Noonan syndrome (NS) is a congenital genetic condition with an estimated incidence of 1 in 1,000-2,500 live births. Typical clinical features include congenital heart defects, short stature, distinctive facial characteristics, chest anomalies, and varying degrees of cognitive impairment. NS is caused by pathogenic variants in genes involved in the RAS/MAPK signaling cascade, resulting in significant clinical and genetic variability. Aims: To analyze the prevalence of specific genetic mutations and their correlation to clinical features in NS. Methods: This retrospective observational study included 111 individuals with genetically confirmed NS. Data collected comprised genotype, cardiac abnormalities, and anthropometric measurements (birth weight, birth length, height, and weight at the latest clinical visit). Standard deviation (SD) scores were determined using Italian population growth references. Results: Complete data were available for 60 NS patients (38% male). The most prevalent mutations were identified in PTPN11 (60%) and SOS1 (10%), with additional variants detected in LZTR1, RAF1, RIT1, CBL, KRAS, SOS2, BRAF, and MAP2K1. Cardiovascular abnormalities were present in 62% of the cohort, with PTPN11 and RIT1 mutations predominantly linked to pulmonary valve stenosis, while RAF1 mutations were associated with hypertrophic cardiomyopathy. Less frequent heart defects, such as atrial and ventricular septal defects and abnormalities of the mitral or aortic valves, showed no clear genotype correlation. Small for gestational age (SGA) was identified in 5% of individuals, all carrying PTPN11 mutations. At an average age of 9.8 ± 5.9 years, mean height and weight were -1.8 ± 1.18 SD and -1.5 ± 1.40 SD, respectively. Short stature was present in 42% of patients, with an average height of -2.84 SD. Growth hormone treatment was administered to 37% of patients, the significant majority of whom carried PTPN11 mutations (74%, p<0.05). Among those born SGA, two-thirds developed short stature. Interestingly, individuals with CBL, SOS2, or MAP2K1 mutations did not exhibit short stature. In 28% of the cohort, both short stature and heart defects coexisted, though no significant genotype association was observed for this combination. Conclusion: This study underscores the high frequency of cardiac defects and short stature in NS, with distinct genotype-phenotype correlation for cardiovascular abnormalities. While being born SGA was relatively rare, it was strongly associated with the PTPN11 genotype. Conversely, genotype-growth correlations were less evident, though some mutations appeared to reduce the likelihood of short stature. These findings highlight the genetic and clinical variability of NS and emphasize the necessity for larger studies to enhance our understanding of genotype-phenotype correlations. Presentation: Saturday, July 12, 2025

Michelangelo's marble sculpture of David is one of the most admired works of art in the world. It is the most iconic symbol of the Florentine Renaissance, and a representation of the idealized human form in its perfection and proportion. The statue was examined in 2004 by two anatomists who observed the apparent absence of a single muscle. Our re-examination of the statue, from our perspective as clinical geneticists, shows unexpected and hitherto unpublished details of variations and disproportions within the overall context of exceptional harmony and beauty. This apparent contradiction raises the question as to what is considered to be morphologically \"normal\" and what \"is not\".

Background Agenesis of the internal carotid artery (ICA) is a rare congenital abnormality, sporadically reported to be associated with a combined congenital hypopituitarism. Nevertheless, only a few cases have been extensively described, and none of these have been characterized by an isolated growth hormone (GH) deficiency. Case presentation Here, we describe a 17-year old boy referred to our hospital for fatigue, decreased muscle strength and severe headache reported after the cessation of rhGH treatment for a GH deficiency diagnosed at the age of 2 years and 3 months. Magnetic resonance imaging (MRI) showed an adenohypophyseal hypoplasia with a lack of posterior pituitary hyperintensity, whereas MRI angiography indicated the absence of a normal flow void in the left ICA. Endocrinological tests confirmed the GH deficiency (GH peak after growth-hormone-releasing hormone (GHRH) + arginine: 2.42 ng/mL) with a very low IGF-I value (31 ng/mL) and normal function of other pituitary axes. Conclusion To the best of our knowledge this is the first confirmed case of an isolated GH deficiency in a patient with ICA agenesis. The presence of an isolated pituitary deficit is unlike to be considered only as an effect of hemodynamic mechanism, suggesting a role for genetic factor(s) as a common cause of these two rare birth defects. Further studies could clarify this issue and the underlying mechanisms to better understand the etiopathogenetic characteristics of this disorder.

Key Clinical Message This is the first reported case of fetal pericardial effusion in association with X‐linked adrenoleukodystrophy and hypocortisolism from a nonautoimmune cause. Our hypothesis is that in experienced hands and after accurate genetic counseling, isolated pericardial effusion can constitute an indication for a severe metabolic disease. This is the first reported case of fetal pericardial effusion in association with X‐linked adrenoleukodystrophy and hypocortisolism from a nonautoimmune cause. Our hypothesis is that in experienced hands and after accurate genetic counseling, isolated pericardial effusion can constitute an indication for a severe metabolic disease.

Many cell types release extracellular vesicles (EVs), including exosomes, microvesicles (MVs), and apoptotic bodies, which play a role in physiology and diseases. Presence and phenotype of circulating EVs in hematological malignancies (HMs) remain largely unexplored. The aim of this study was to characterize EVs in peripheral blood of HM patients compared to healthy subjects (controls). We isolated serum EVs from patients with chronic lymphocytic leukemia (CLL), non-Hodgkin’s lymphoma (NHL), Waldenstrom’s macroglobulinemia (WM), Hodgkin’s lymphoma (HL), multiple myeloma (MM), acute myeloid leukemia (AML), myeloproliferative neoplasms (MPNs), myelodysplastic syndromes (MDS), and controls. EVs were isolated from serum of peripheral blood by ultracentrifuge steps and analyzed by flow cytometry to define count, size, and immunophenotype. MV levels were significantly elevated in WM, HL, MM, AML, and some MPNs and, though at a lesser degree, in CLL and NHL as compared to healthy controls. HL, MM, and MPNs generated a population of MVs characterized by lower size (below 0.3 μm) when compared to controls. MVs from patients specifically expressed tumor-related antigens, such as CD19 in B cell neoplasms, CD38 in MM, CD13 in myeloid tumors, and CD30 in HL. Both total and antigen-specific count of MVs significantly correlated with different HM clinical features such as Rai stage in CLL, International Prognostic Scoring System in WM, International Staging System in MM, and clinical stage in HL. MVs may represent a novel biomarker in HMs.

Dickkopf-3 (Dkk3) is an atypical member of the Dkk family of Wnt inhibitors, which has been implicated in the pathophysiology of neurodegenerative disorders. However, the role of Dkk3 in mechanisms of cell degeneration and protection is unknown. We used Dkk3 knockout mice to examine how endogenous Dkk3 influences ischemic brain damage. In addition, we used primary cultures of astrocytes or mixed cultures of astrocytes and neurons to investigate the action of Dkk3 on cell damage and dissect the underlying molecular mechanisms. In a model of focal brain ischemia induced by permanent middle cerebral artery (MCA) occlusion (MCAO) Dkk3 mice showed a significantly greater infarct size with respect to their wild-type counterparts at all time points investigated (1, 3 and 7 days after MCAO). Immunohistochemical analysis showed that Dkk3 expression was enhanced at the borders of the ischemic focus, and was predominantly detected in astrocytes. This raised the possibility that Dkk3 produced by astrocytes acted as a protective molecule. We tested this hypothesis using either primary cultures of cortical astrocytes or mixed cortical cultures containing both neurons and astrocytes. Genetic deletion of Dkk3 was permissive to astrocyte damage induced by either oxidative stress or glucose deprivation. In addition, application of human recombinant Dkk3 (hrDkk3) was highly protective against oxidative stress in cultured astrocytes. We tested the hypothesis that the protective activity of Dkk3 was mediated byvascular endothelial growth factor (VEGF). Interestingly, glucose deprivation up-regulated both Dkk3 and VEGF in cultured astrocytes prepared from wild-type mice. VEGF induction was not observed in astrocytes lacking Dkk3 (i.e., in cultures prepared from Dkk3 mice). In mixed cultures of cortical cells, excitotoxic neuronal death induced by a brief pulse with -methyl-D-aspartate (NMDA) was significantly enhanced when Dkk3 was lacking in astrocytes, whereas post-NMDA addition of hrDkk3 was neuroprotective. Neuroprotection by hrDkk3 was significantly reduced by pharmacological blockade of type-2 VEGF receptors and was mimicked by hrVEGF. These data offer the first evidence that Dkk3 protects both neurons and astrocytes against a variety of toxic insults, and at least in culture, protection involves VEGF induction.

We have recently shown that pharmacological blockade of mGlu2 metabotropic glutamate receptors protects vulnerable neurons in the 4-vessel occlusion model of transient global ischemia, whereas receptor activation amplifies neuronal death. This raised the possibility that endogenous activation of mGlu2 receptors contributes to the pathophysiology of ischemic neuronal damage. Here, we examined this possibility using two models of transient focal ischemia: (i) the monofilament model of middle cerebral artery occlusion (MCAO) in mice, and (ii) the model based on intracerebral infusion of endothelin-1 (Et-1) in rats. Following transient MCAO, mGlu2 receptor knockout mice showed a significant reduction in infarct volume and an improved short-term behavioural outcome, as assessed by a neurological disability scale and the “grip test”. Following Et-1 infusion, Grm2 gene mutated Hannover Wistar rats lacking mGlu2 receptors did not show changes in the overall infarct volume as compared to their wild-type counterparts, although they showed a reduced infarct area in the agranular insular cortex. Interestingly, however, mGlu2 receptor-deficient rats performed better than wild-type rats in the adhesive tape test, in which these rats did not show the laterality preference typically observed after focal ischemia. These findings support the hypothesis that activation of mGlu2 receptors is detrimental in the post-ischemic phase, and support the use of mGlu2 receptor antagonists in the experimental treatment of brain ischemia.