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Objectives: To present a case series of novel CHD2 variants in patients presenting with genetic epileptic and developmental encephalopathy. Background: CHD2 gene encodes an ATP-dependent enzyme, chromodomain helicase DNA-binding protein 2, involved in chromatin remodeling. Pathogenic variants in CHD2 are linked to early-onset conditions such as developmental and epileptic encephalopathy, drug-resistant epilepsies, and neurodevelopmental disorders. Approximately 225 diagnosed patients from 28 countries exhibit various allelic variants in CHD2, including small intragenic deletions/insertions and missense, nonsense, and splice site variants. Results: We present the molecular and clinical characteristics of 17 unreported individuals from 17 families with novel pathogenic or likely pathogenic variants in CHD2. All individuals presented with severe global developmental delay, childhood-onset myoclonic epilepsy, and additional neuropsychiatric features, such as behavioral including autism, ADHD, and hyperactivity. Additional findings include abnormal reflexes, hypotonia and hypertonia, motor impairment, gastrointestinal problems, and kyphoscoliosis. Neuroimaging features included hippocampal signal alterations (4/10), with additional volume loss in 2 cases, inferior vermis hypoplasia (7/10), mild cerebellar atrophy (4/10), and cerebral atrophy (1/10). Discussion: Our study broadens the geographic scope of CHD2-related phenotypes, providing valuable insights into the prevalence and clinical characteristics of this genetic disorder in previously underrepresented populations.
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Deubiquitination is crucial for the proper functioning of numerous biological pathways, such as DNA repair, cell cycle progression, transcription, signal transduction and autophagy. Accordingly, pathogenic variants in deubiquitinating enzymes (DUBs) have been implicated in neurodevelopmental disorders and congenital abnormalities. ATXN7L3 is a component of the DUB module of the Spt-Ada-Gcn5 acetyltransferase (SAGA) complex and two other related DUB modules, and it serves as an obligate adaptor protein of three ubiquitin-specific proteases (USP22, USP27X or USP51). Through exome sequencing and by using GeneMatcher, we identified nine individuals with heterozygous variants in ATXN7L3. The core phenotype included global motor and language developmental delay, hypotonia and distinctive facial characteristics, including hypertelorism, epicanthal folds, blepharoptosis, a small nose and mouth, and low-set, posteriorly rotated ears. To assess pathogenicity, we investigated the effects of a recurrent nonsense variant [c.340C>T; p.(Arg114Ter)] in fibroblasts of an affected individual. ATXN7L3 protein levels were reduced, and deubiquitylation was impaired, as indicated by an increase in histone H2Bub1 levels. This is consistent with the previous observation of increased H2Bub1 levels in Atxn7l3-null mouse embryos, which have developmental delay and embryonic lethality. In conclusion, we present clinical information and biochemical characterization supporting ATXN7L3 variants in the pathogenesis of a rare syndromic neurodevelopmental disorder.
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Discapacidades del Desarrollo , Hipotonía Muscular , Humanos , Hipotonía Muscular/genética , Discapacidades del Desarrollo/genética , Femenino , Masculino , Preescolar , Niño , Fenotipo , Animales , Adolescente , Secuenciación del Exoma , Cara/anomalías , Lactante , Factores de TranscripciónRESUMEN
To date 11 patients with Coffin-Siris syndrome type 7 (OMIM 618027) have been described since the first literature report. All reported patients carried de novo variants with presumed dominant negative effect, which localized in the PHD1/PHD2 domains of DPF2. Here we report on the first familial case of Coffin-Siris syndrome type 7. The index patient presented during the 1st year of life with failure to thrive and ectodermal anomalies. The genetic analysis using whole exome sequencing showed a likely pathogenic missense variant in the PHD1 region. The family analysis showed that the mother as well as the older brother of the index patient also carried the detected DPF2 variant in heterozygous state. The mother had a history of school difficulties but no history of failure to thrive and was overall mildly affected. The brother showed developmental delay with autistic features, ectodermal anomalies and overlapping morphologic features but did not have a history of growth failure problems. To our knowledge this is the first report of an inherited likely pathogenic variant in DPF2, underlining the variability of the associated phenotype as well as the importance of considering inherited DPF2 variants during the variant filtering strategy of whole exome data.
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Anomalías Múltiples , Cara , Deformidades Congénitas de la Mano , Discapacidad Intelectual , Micrognatismo , Cuello , Linaje , Factores de Transcripción , Adulto , Femenino , Humanos , Lactante , Masculino , Anomalías Múltiples/genética , Anomalías Múltiples/patología , Proteínas de Unión al ADN/genética , Cara/anomalías , Cara/patología , Deformidades Congénitas de la Mano/genética , Deformidades Congénitas de la Mano/patología , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Micrognatismo/genética , Micrognatismo/patología , Mutación Missense , Cuello/anomalías , Cuello/patología , Fenotipo , Factores de Transcripción/genéticaRESUMEN
In a conventional fattening farm in southern Germany, up to 100 % of the livers of individual slaughter groups were condemned due to parasitic lesions during 2022. Intensification of antiparasitic metaphylaxis with fenbendazole to control Ascaris suum in the herd was unsuccessful. A pathomorphologic examination of 6 livers from two slaughter groups revealed oligofocal fibrotic inflammation. Histologically, chronic granulomatous hepatitis with massive involvement of eosinophilic granulocytes and central parasitic structures of a helminth were detected. Examination of the liver lesions by PCR revealed evidence of Echinococcus (E.) multilocularis. To determine the source of introduction into the herd, fecal samples were collected from semi-feral domestic cats near the feed mixer and in the corridor of the barn. Parasitologically, cestode eggs were detected in the fecal samples. Genome fragments of E. multilocularis could not be amplified by PCR. In the present case, domestic cats were suspected as the most likely source of entry into the herd. Control measures were aimed at preventing parasite entry by therapy of the domestic cats with antiparasitics. Differentially, no other possible pathogens could be detected by PCR and bacteriological examination.
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Enfermedades de los Gatos , Equinococosis , Enfermedades de los Porcinos , Animales , Porcinos , Gatos , Vivienda para Animales , Equinococosis/veterinaria , Equinococosis/parasitología , Hígado/parasitología , Fenbendazol , Enfermedades de los Gatos/tratamiento farmacológico , Enfermedades de los Porcinos/diagnósticoRESUMEN
AIM: Investigation of the perspectives of paediatric health care professionals (PHCPs) in Switzerland regarding factors that influence participation in physical activity programs for children and adolescents with disabilities or chronic conditions (CADCCs). Evaluation of self-reported exercise counselling behavior of those professionals. METHOD: A cross-sectional survey was used to collect the opinions of 171 PHCPs working with CADCCs using a structured questionnaire. The information obtained was evaluated by performing a combined quantitative and qualitative statistical analysis. RESULTS: PHCPs in Switzerland think that CADCC do not get enough physical activity and see the underlying reasons in lacking information/knowledge and organizational factors. We found that the level of knowledge about disability sports opportunities among PHCPs has a positive influence on their exercise counselling behaviour. CONCLUSIONS: We propose three approaches to increase the level of physical activity in CADCC: Establishing personalized exercise counseling, intensifying information about disability sports programmes towards PHCPs, and improving inclusion and integration in PE lessons or regular sports clubs.
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Niños con Discapacidad , Adolescente , Humanos , Niño , Niños con Discapacidad/psicología , Estudios Transversales , Suiza , Ejercicio Físico/psicología , Personal de Salud/psicologíaRESUMEN
Costello syndrome is a clinically recognizable, severe neurodevelopmental disorder caused by heterozygous activating variants in HRAS. The vast majority of affected patients share recurring variants affecting HRAS codons 12 and 13 and a relatively uniform phenotype. Here, we report the unique and attenuated phenotype of six individuals of an extended family affected by the HRAS variant c.176C>T p.(Ala59Gly), which, to our knowledge, has never been reported as a germline variant in patients so far. HRAS Alanine 59 has been previously functionally investigated as an oncogenic hotspot and the p.Ala59Gly substitution was shown to impair intrinsic GTP hydrolysis. All six individuals we report share a phenotype of ectodermal anomalies and mild features suggestive of a RASopathy, reminiscent of patients with Noonan syndrome-like disorder with loose anagen hair. All six are of normal intelligence, none have a history of failure to thrive or malignancy, and they have no known cardiac or neurologic pathologies. Our report adds to the previous reports of patients with rare variants affecting amino acids located in the SWITCH II/G3 region of HRAS and suggests a consistent, attenuated phenotype distinct from classical Costello syndrome. We propose the definition of a new distinct HRAS-related RASopathy for patients carrying HRAS variants affecting codons 58, 59, 60.
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Síndrome de Costello , Síndrome de Noonan , Humanos , Síndrome de Costello/genética , Síndrome de Costello/patología , Fenotipo , Síndrome de Noonan/genética , Síndrome de Noonan/patología , Insuficiencia de Crecimiento/genética , Insuficiencia de Crecimiento/patología , Mutación de Línea Germinal , Proteínas Proto-Oncogénicas p21(ras)/genéticaRESUMEN
BACKGROUND: By modulating the levels of sex steroid hormones and sex hormone-binding globulin (SHBG), caffeine could be a factor in the development of several conditions in men, including prostate cancer. The aim of this study was to evaluate if caffeine consumption is associated with concentrations of sex steroid hormones and SHBG in men. METHODS: 1,410 men aged 20 + years who attended the morning examination session of the Third National Health and Nutrition Examination Survey (1988-1991) were included in the analysis. Coffee and soft drink consumption was assessed using a food frequency questionnaire. Daily caffeine intake was estimated by multiplying caffeine content per cup times the daily frequency of coffee, tea, or soft drink consumption. Serum levels of hormones and SHBG were measured by immunoassay. Associations of frequency of beverage consumption or estimated caffeine intake with hormone levels were examined using multivariable linear regression. RESULTS: Coffee consumption was positively associated with SHBG concentration (p = 0.045) taking lifestyle factors into account, but mutually adjusting for testosterone and estradiol attenuated the association; no association with SHBG was observed for soft drink consumption or caffeine intake. No associations between caffeinated beverage consumption and androgen or estrogen concentrations were observed. CONCLUSION: Men who drink coffee more frequently may have higher circulating SHBG concentration, but there were no consistent associations for soft drinks or caffeine intake.