Auswahl der wissenschaftlichen Literatur zum Thema „DS craniofacial dysmorphism“

Trisomy of human chromosome 21 in Down syndrome (DS) leads to several phenotypes, such as mild-to-severe intellectual disability, hypotonia, and craniofacial dysmorphisms. These are fundamental hallmarks of the disorder that affect the quality of life of most individuals with DS. Proper brain development involves meticulous regulation of various signaling pathways, and dysregulation may result in abnormal neurodevelopment. DS brain is characterized by an increased number of astrocytes with reduced number of neurons. In mouse models for DS, the pool of neural progenitor cells commits to glia rather than neuronal cell fate in the DS brain. However, the mechanism(s) and consequences of this slight neurogenic-to-gliogenic shift in DS brain are still poorly understood. To date, Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling has been proposed to be crucial in various developmental pathways, especially in promoting astrogliogenesis. Since both human and mouse models of DS brain exhibit less neurons and a higher percentage of cells with astrocytic phenotypes, understanding the role of JAK-STAT signaling in DS brain development will provide novel insight into its role in the pathogenesis of DS brain and may serve as a potential target for the development of effective therapy to improve DS cognition.

Donohue syndrome (DS) is a rare recessively inherited disorder characterized by severe insulin resistance caused by genetic defects affecting the insulin receptor. The classical clinical characteristics include severe intrauterine growth restriction, craniofacial dysmorphic features, body and skin features, and soft tissue overgrowth. Postnatal growth retardation, cardiac, gastrointestinal, and renal complications, and infection susceptibility develop within the first few months of life, leading to a short life expectancy (<2 years). The classical metabolic abnormalities vary from fasting hypoglycemia to postprandial hyperglycemia with severe hyperinsulinemia. We present the case of a 14-week-old infant with DS who developed cardiac, renal, hepatic, pancreatic, and gastrointestinal features, all of them previously reported in infants with DS. The gastrointestinal features started during the first week of life and included abdominal distension, feeding difficulties, intermittent vomiting, and two episodes of intestinal obstruction. The diagnosis of duodenogastric intussusception was made, and this previously unreported complication tragically resulted in mortality. We discuss how basic mechanisms of cross-talk between insulin and insulin-growth factor 1 receptors could be linked to hyperinsulinemia and its associated comorbidities.

BackgroundWeiss-Kruszka syndrome (WSKA) is an autosomal dominant congenital anomaly syndrome due to mutations in the ZNF462 gene and manifests with developmental delay and multiple craniofacial abnormalities with variable expressivity1. It is also characterized by cognitive impairment, whilst about a third of the affected individuals belong to the autism spectrum. Although the disease is inherited with the autosomal dominant manner, most of the described subjects (95%) had de novo variants with no affected family members1. WSKA has been recently described and only 26 (including our patient) affected individuals have been classified to date2. Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by the presence of autoantibodies and multi-organ inflammation. Genetic factors might play an important role in disease pathogenesis in patients with childhood-onset SLE.ObjectivesTo describe the case of a SLE patient who was found to have WSKA related to a novel pathogenic autosomal dominant (AD) variant in the ZNF462 gene, and inform clinicians of a possible association between the 2 conditions.MethodsA 25-year-old Caucasian female with a history of SLE, diagnosed at the age of 14, manifested with malar rash, Raynaud’s phenomenon, arthritis, thrombocytopenia, positive ANA, ds-DNA antibody and hypocomplementemia. At the age of 17, she developed renal dysfunction due to lupus nephritis class IV, and she was treated with glucocorticoids (GCs), cyclophosphamide and hydroxychloroquine. In Oct 2020, she was admitted to the hospital for thrombotic thrombocytopenic purpura due to lupus exacerbation. She was successfully treated with GCs, plasma exchange and rituximab. During her hospitalization, the presence of various clinical features raised the suspicion of a genetic syndrome. First, the patient exhibited dysmorphic features such as hypertelorism, prognathism, arched eyebrows, flattened nasal bridge, small upper lip, mild intellectual disability, and a history of childhood-onset SLE. Whole exome sequencing (WES) by NGS was used for the genetic investigation of the patient.Figure 1.ResultsThe patient underwent genetic evaluation with WES and the novel heterozygous AD pathogenic variant c.4142delT (p.lle1381ThrfsTer16) in ZNF462 gene was identified. Confirmation of the identified variant was also verified by sanger sequencing. Pathogenic variants in the ZNF462 gene were previously described in patients with the recently reported WSKA of which several characteristics are compatible with our patient’s features. The ZFN462 encodes a zinc-finger transcription factor that plays a role in embryonic development, transcriptional regulation, and chromatin remodelling. Given that chromatin remodelling has been implicated in the pathogenesis of SLE, the association of this novel ZNF462 variant in the development of SLE, needs to be determined3.ConclusionThis is the first report of a patient with coexisting SLE and WSKA due to a novel variant. It illustrates the need for further research in order to elucidate any possible pathophysiologic link among the 2 conditions.References[1]Weiss K, Wigby K, Fannemel M, Henderson LB, Beck N, Ghali N, Study DDD, Anderlid BM, Lundin J, Hamosh A, Jones MC, Ghedia S, Muenke M, Kruszka P. Haploinsufficiency of ZNF462 is associated with craniofacial anomalies, corpus callosum dysgenesis, ptosis, and developmental delay. Eur J Hum Genet. 2017 Aug;25(8):946-951. doi: 10.1038/ejhg.2017.86. Epub 2017 May 17. PMID: 28513610; PMCID: PMC5567153.[2]Park J, Ha DJ, Seo GH, Maeng S, Kang SM, Kim S, Lee JE. Empty Sella Syndrome Associated with Growth Hormone Deficiency: the First Case Report of Weiss-Kruszka Syndrome. J Korean Med Sci. 2021 May 10;36(18):e133. doi: 10.3346/jkms.2021.36.e133. PMID: 33975400; PMCID: PMC8111047.[3]Surace AEA, Hedrich CM. The Role of Epigenetics in Autoimmune/Inflammatory Disease. Front Immunol. 2019 Jul 4;10:1525. doi: 10.3389/fimmu.2019.01525. PMID: 31333659; PMCID: PMC6620790.Disclosure of InterestsNone declared

AbstractDown syndrome (DS) is characterised by several clinical features including intellectual disability (ID) and craniofacial dysmorphisms. In 1976, Jackson and coll. identified a checklist of signs for clinical diagnosis of DS; the utility of these checklists in improving the accuracy of clinical diagnosis has been recently reaffirmed, but they have rarely been revised. The purpose of this work is to reassess the characteristic phenotypic signs and their frequencies in 233 DS subjects, following Jackson's checklist. 63.77% of the subjects showed more than 12 signs while none showed less than 5, confirming the effectiveness of Jackson's checklist for the clinical diagnosis of DS. An association between three phenotypic signs emerged, allowing us to distinguish two sub-phenotypes: Brachycephaly, short and broad Hands, short Neck (BHN), which is more frequent, and "non-BHN". The strong association of these signs might be interpreted in the context of the growth defects observed in DS children suggesting decreased cell proliferation. Lastly, cognitive assessments were investigated for 114 subjects. The lack of association between the presence of a physical sign or the number of signs present in a subject and cognitive skills disproves the stereotype that physical characteristics are predictive of degree of ID.

Background: Down syndrome is the most common autosomal disorder in humans. And the most common genetic chromosomal disorder causing mental disability in children. It also cause other medical abnormalities including heart and gastrointestinal disorder. These children sharing common features and characteristic faces. Each individual with this syndrome will not have all the features, but they will have a unique combination. Objective: In our study we try to spot light on the craniofacial features of Down syndrome in our country: their percentage; to compare it with another study in other countries. We also focus on the craniofacial features accuracy in diagnosis. Karyotyping not always available. Also we study the risk factors where we found that the mother age is not the only risk factor, but also the father age play a big role in Down syndrome and this risk factor needs to be studied with large number of patients. Also we study the problems associated with Down syndrome and its percentages, and to compare it with other study done in our neighbor's countries, where we found many differences Setting and Design: Our study is a descriptive, case series retrospective study was conducted in Benghazi Libya's children hospital. This study includes 73 patients who were referred to our Genetic clinic from October 2016 to march 2017. The genetic clinic is the only clinic in Benghazi and the whole East of Libya. This clinic follows children with DS and children with dysmorphic features in Benghazi and the Libyan ‘east. Materials and Methods: We studied 73 children randomly from different age group, and different socioeconomic classes, who attend the genetic clinic, which is an outpatient clinic and the only clinic which follows children with DS and dysmorphic feature in a pediatric hospital in Benghazi- Libya. We took the history from the parent (the father and the Mother). The investigation done in our hospital. Father and mother age at pregnancy. Spontaneous or induced pregnancy. Drug history of the mothers and fathers. History of abortion and normal children. Any other baby with Down syndrome or other dysmorphic features. Echocardiography done for all children. Ultrasound abdomen and brain did for all children. Thyroid function test done for all children and repeated annually for all children. The diagnosis done mainly by clinical features. Some cases (40 cases) are proved by karyotype chromosomal analysis.

Les altérations les plus fréquentes et les plus caractéristiques du syndrome de Down (SD) sont les troubles de l'apprentissage et la dysmorphie crâniofaciale (CF). Le phénotype CF comprend des dimensions réduites de la tête, une brachycéphalie, une région orbitale médio-latérale réduite, une largeur bizygomatique réduite, un petit maxillaire, une petite mandibule et une variabilité individuelle accrue. Jusqu'à présent, les mécanismes cellulaires et moléculaires qui sous-tendent ce phénotype CF restent inconnus. Cette thèse, utilisant un nouveau panel de modèles de rats et de souris, a proposé de nouveaux gènes candidats pour le phénotype SD-CF. Nous avons confirmé le rôle de Dyrk1a dans la brachycéphalie du neurocrâne et identifié le surdosage du facteur de transcription Ripply3 pour le raccourcissement de la face médiane par la sous-régulation de Tbx1, un autre facteur de transcription impliqué dans des phénotypes similaires trouvés dans le syndrome de DiGeorge. Nous avons défini de nouveaux gènes sensibles au dosage responsables des malformations du SD-CF, et de nouveaux modèles ont été proposés pour sauver le phénotype SD-CF. Ces nouvelles connaissances pourraient également permettre de mieux comprendre les phénotypes cérébraux et cardiovasculaires spécifiques observés chez les mutants Tbx1 et les modèles de DS
The most frequent and distinctive alterations found in Down syndrome (DS) are learning disability and craniofacial (CF) dysmorphism. The CF phenotype includes reduced head dimensions, brachycephaly, reduced mediolateral orbital region, reduced bizygomatic breadth, small maxilla, small mandible, and increased individual variability. Until now, the cellular and molecular mechanisms underlying this CF phenotype remain unknown. This thesis, using a new panel of rats and mice models proposed new candidate genes for the DS-CF phenotype. We confirmed the role of Dyrk1a in neurocranium brachycephaly and identified the overdosage of the transcription factor Ripply3 for midface shortening through the downregulation of Tbx1, another transcription factor involved in similar phenotypes was found in Di George Syndrome. We defined new dosage-sensitive genes responsible for DS-CF malformations, and new models were proposed to rescue the DS-CF phenotype. This new knowledge may also lead to insights for specific brain and cardiovascular phenotypes observed in Tbx1 mutants and DS models