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BMJ Case Reports Jan 2021Patients with syndromic craniosynostosis are usually associated with the complexity of the malformation complex. We describe here detailed oculo-motility disorder and a...
Patients with syndromic craniosynostosis are usually associated with the complexity of the malformation complex. We describe here detailed oculo-motility disorder and a remarkable finding of hypoplastic bilateral media recti on imaging and its intraoperative absence in patients with phenotypic features resembling Shprintzen-Goldberg syndrome (SGS). SGS is a rare congenital disorder with craniosynostosis affecting multiple systems including mentation and having a considerable overlap of its phenotypic features with Marfan syndrome. Large A-pattern exotropia found in these patients may be related to the craniofacial features and their bearing on extraocular muscle development and function. In this paper, we aimed to sensitise ophthalmologists and strabismologists concerning the necessity to recognise syndromic associations of patients with craniosynostosis presenting with a large squint, be aware of the intraoperative surprises and consider the challenges in its management.
Topics: Arachnodactyly; Child; Craniosynostoses; Humans; Male; Marfan Syndrome; Oculomotor Muscles
PubMed: 33461988
DOI: 10.1136/bcr-2019-233557 -
ELife Jan 2021Shprintzen-Goldberg syndrome (SGS) is a multisystemic connective tissue disorder, with considerable clinical overlap with Marfan and Loeys-Dietz syndromes. These...
Shprintzen-Goldberg syndrome (SGS) is a multisystemic connective tissue disorder, with considerable clinical overlap with Marfan and Loeys-Dietz syndromes. These syndromes have commonly been associated with enhanced TGF-β signaling. In SGS patients, heterozygous point mutations have been mapped to the transcriptional co-repressor SKI, which is a negative regulator of TGF-β signaling that is rapidly degraded upon ligand stimulation. The molecular consequences of these mutations, however, are not understood. Here we use a combination of structural biology, genome editing, and biochemistry to show that SGS mutations in SKI abolish its binding to phosphorylated SMAD2 and SMAD3. This results in stabilization of SKI and consequently attenuation of TGF-β responses, both in knockin cells expressing an SGS mutation and in fibroblasts from SGS patients. Thus, we reveal that SGS is associated with an attenuation of TGF-β-induced transcriptional responses, and not enhancement, which has important implications for other Marfan-related syndromes.
Topics: Arachnodactyly; Craniosynostoses; DNA-Binding Proteins; Female; Humans; Male; Marfan Syndrome; Mutation; Proto-Oncogene Proteins; Signal Transduction; Transforming Growth Factor beta
PubMed: 33416497
DOI: 10.7554/eLife.63545 -
Ugeskrift For Laeger Nov 2020While psychotic symptoms may be the result of a primary psychiatric disorder, they can also be the presenting symptom of an underlying somatic disease. The organic...
While psychotic symptoms may be the result of a primary psychiatric disorder, they can also be the presenting symptom of an underlying somatic disease. The organic aetiology can vary from benign and transient to severe and enduring disorders. Early diagnosis and treatment can be crucial to the prognosis, though potentially challenging as well, given that several of the organic aetiologies are rare and therefore difficult to identify. This case report describes two pediatric patients with psychiatric manifestations as a result of 22q11.2 deletion syndrome and anti-N-methyl-D-aspartate receptor encephalitis.
Topics: Adolescent; Anti-N-Methyl-D-Aspartate Receptor Encephalitis; Arachnodactyly; Child; Craniosynostoses; Early Diagnosis; Humans; Psychotic Disorders
PubMed: 33215582
DOI: No ID Found -
JMIR Pediatrics and Parenting Oct 2020Young people with genetic conditions often face challenges coping with their health condition. It can be difficult for them to meet someone with a similar condition,...
BACKGROUND
Young people with genetic conditions often face challenges coping with their health condition. It can be difficult for them to meet someone with a similar condition, which is important for reinforcement of chronic illness management recommendations. Social media is used by 97% of young people in the United States and may provide those with these disorders a space for emotional expression and support. However, there is a scarcity of literature related to the use of social media among adolescents with genetic conditions as an indicator of their perception regarding their own condition.
OBJECTIVE
The purpose of this pilot study was to obtain preliminary data to assess and understand social media use by young people with connective tissue disorders and determine whether they use social media to connect with patients with similar conditions or whether they would be interested in doing so.
METHODS
We undertook a pilot study of selected connective tissue disorders occurring in young people between the ages of 11 and 25 years, including Marfan syndrome; Ehlers-Danlos syndrome subtypes classical, classical-like, cardiac-valvular, and vascular; Beals congenital contractual arachnodactyly; and Alport hereditary nephritis. The study took place within one pediatric clinical system. Patients were identified through electronic medical record search and International Classification of Diseases, Ninth Revision, coding at a Midwest university-based clinical system. Study subjects completed a short survey describing their experiences with their connective tissue disorders, their means of self-expression, their existing network of persons to communicate with, and their use of social media. Data analysis included nominal and bivariate regressions to compare social media use in relation to age.
RESULTS
Our 31 participants (42% response rate) were 55% female (17/31) and their average age was 18 years (SD 5). All participants used social media and there were no statistically significant differences between social media use and age. The majority of participants (25/30, 83%) reported that they never used social media to discuss their condition (P=.09), and only 17% (5/30) knew someone online with a similar condition (P=.50). Most participants (19/30, 63%) said they would communicate with someone with a similar disorder (P=.64).
CONCLUSIONS
We found that young individuals with connective tissue disorders use at least one type of social media. A majority did not use social media to discuss their condition or know someone online with a similar condition. However, many persons were interested in finding others similarly affected. Social media could serve as a platform for young people with connective tissue disorders to connect. Peer support is important in disease management and adolescent development. Future studies should aim at understanding social media use among young people with connective tissue disorders and helping them connect with other people who have similar conditions.
PubMed: 33124992
DOI: 10.2196/16367 -
The American Journal of Psychiatry Jul 2020
Topics: Arachnodactyly; DiGeorge Syndrome; Genetic Variation; Humans; Marfan Syndrome; Psychotic Disorders
PubMed: 32605438
DOI: 10.1176/appi.ajp.2020.20050598 -
Movement Disorders : Official Journal... Jul 2020
Topics: Arachnodactyly; Child; Chromosome Deletion; Craniosynostoses; DiGeorge Syndrome; Humans; Movement Disorders; Phenotype
PubMed: 32379361
DOI: 10.1002/mds.28078 -
Frontiers in Genetics 2020Congenital contractural arachnodactyly (CCA) is an extremely rare monogenic disorder in humans, and the prevalence of CCA is estimated to be less than 1 in 10,000...
Congenital contractural arachnodactyly (CCA) is an extremely rare monogenic disorder in humans, and the prevalence of CCA is estimated to be less than 1 in 10,000 worldwide. CCA is characterized by arachnodactyly, camptodactyly, the contracture of major joints, scoliosis, pectus deformities, and crumpled ears. Mutations in (which encodes fibrillin-2) are responsible for causing this disease. A family with CCA was investigated in this study, and a novel variant, c.3724+3A > C (also identified as IVS28+3A > C), in was found in nine patients from the family but was not found in seven unaffected relatives. Reverse transcription-PCR (RT-PCR) and complementary DNA (cDNA) sequencing data showed that exon 28 was skipped in the gene. The c.3724+3A > C variant led to an in-frame deletion during transcription, which eventually triggered CCA in the Chinese family.
PubMed: 32184806
DOI: 10.3389/fgene.2020.00143 -
Clinical Genetics Feb 2020Genome-scale high-throughput sequencing enables the detection of unprecedented numbers of sequence variants. Variant filtering and interpretation are facilitated by...
Genome-scale high-throughput sequencing enables the detection of unprecedented numbers of sequence variants. Variant filtering and interpretation are facilitated by mutation databases, in silico tools, and population-based reference datasets such as ExAC/gnomAD, while variants are classified using the ACMG/AMP guidelines. These methods, however, pose clinically relevant challenges. We queried the gnomAD dataset for (likely) pathogenic variants in genes causing autosomal-dominant disorders. Furthermore, focusing on the fibrillinopathies Marfan syndrome (MFS) and congenital contractural arachnodactyly (CCA), we screened 500 genomes of our patients for co-occurring variants in FBN1 and FBN2. In gnomAD, we detected 2653 (likely) pathogenic variants in 253 genes associated with autosomal-dominant disorders, enabling the estimation of variant-filtering thresholds and disease predisposition/prevalence rates. In our database, we discovered two families with hitherto unreported co-occurrence of FBN1/FBN2 variants causing phenotypes with mixed or modified MFS/CCA clinical features. We show that (likely) pathogenic gnomAD variants may be more frequent than expected and are challenging to classify according to the ACMG/AMP guidelines as well as that fibrillinopathies are likely underdiagnosed and may co-occur. Consequently, selection of appropriate frequency cutoffs, recognition of digenic variants, and variant classification represent considerable challenges in variant interpretation. Neglecting these challenges may lead to incomplete or missed diagnoses.
Topics: Adolescent; Adult; Aged; Alleles; Arachnodactyly; Child; Contracture; Databases, Genetic; Female; Fibrillin-1; Fibrillin-2; Frameshift Mutation; Genetic Association Studies; Genetic Variation; Genotype; Humans; INDEL Mutation; Male; Marfan Syndrome; Middle Aged; Pedigree; Phenotype; Whole Genome Sequencing
PubMed: 31506931
DOI: 10.1111/cge.13640 -
Genes Aug 2019The term linkeropathies (LKs) refers to a group of rare heritable connective tissue disorders, characterized by a variable degree of short stature, skeletal dysplasia,... (Review)
Review
The term linkeropathies (LKs) refers to a group of rare heritable connective tissue disorders, characterized by a variable degree of short stature, skeletal dysplasia, joint laxity, cutaneous anomalies, dysmorphism, heart malformation, and developmental delay. The LK genes encode for enzymes that add glycosaminoglycan chains onto proteoglycans via a common tetrasaccharide linker region. Biallelic variants in XYLT1 and XYLT2, encoding xylosyltransferases, are associated with Desbuquois dysplasia type 2 and spondylo-ocular syndrome, respectively. Defects in B4GALT7 and B3GALT6, encoding galactosyltransferases, lead to spondylodysplastic Ehlers-Danlos syndrome (spEDS). Mutations in B3GAT3, encoding a glucuronyltransferase, were described in 25 patients from 12 families with variable phenotypes resembling Larsen, Antley-Bixler, Shprintzen-Goldberg, and Geroderma osteodysplastica syndromes. Herein, we report on a 13-year-old girl with a clinical presentation suggestive of spEDS, according to the 2017 EDS nosology, in whom compound heterozygosity for two B3GAT3 likely pathogenic variants was identified. We review the spectrum of B3GAT3-related disorders and provide a comparison of all LK patients reported up to now, highlighting that LKs are a phenotypic continuum bridging EDS and skeletal disorders, hence offering future nosologic perspectives.
Topics: Adolescent; Antley-Bixler Syndrome Phenotype; Arachnodactyly; Bone Diseases; Craniosynostoses; Dwarfism; Female; Glucuronosyltransferase; Humans; Marfan Syndrome; Mutation; Osteochondrodysplasias; Phenotype; Skin Diseases, Genetic
PubMed: 31438591
DOI: 10.3390/genes10090631