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Medicine Feb 2020KIAA0586 variants have been associated to short-rib thoracic dysplasia, an autosomal recessive skeletal ciliopathy characterized by a narrow thorax, short limbs, and...
INTRODUCTION
KIAA0586 variants have been associated to short-rib thoracic dysplasia, an autosomal recessive skeletal ciliopathy characterized by a narrow thorax, short limbs, and radiological skeletal abnormalities.
PATIENT CONCERNS
Patients 1 and 2 were two Roma Gypsy siblings presenting thoracic dysplasia and a combination of oral cavity anomalies.
DIAGNOSIS
A custom NGS gene panel, including genes associated to skeletal ciliopathies, identified the homozygous KIAA0586 splicing variant c.1815G>A (p.Gln605Gln) in both siblings, confirming the clinical diagnosis of short-rib-polydactyly.
INTERVENTION
Patients were transferred to neonatal intensive care unit and received life-support treatment.
OUTCOMES
Patients 1 and 2 died after few hours and 1 month of birth, respectively, because of respiratory failure related with the disease.
CONCLUSION
We report two patients affected by short-rib polydactyly syndrome and overlapping phenotype with oral-facial-digital syndrome associated with the c.1815G>A variant in KIAA0586, suggesting a quite peculiar genotype-phenotype correlation.
Topics: Cell Cycle Proteins; Ciliopathies; Humans; Infant, Newborn; Italy; Male; Orofaciodigital Syndromes; Phenotype; Roma; Short Rib-Polydactyly Syndrome; Siblings
PubMed: 32080096
DOI: 10.1097/MD.0000000000019169 -
Japanese Journal of Radiology Mar 2020Ciliopathy encompasses a diverse group of autosomal recessive genetic disorders caused by mutations in genes coding for components of the primary cilia. Skeletal... (Review)
Review
Ciliopathy encompasses a diverse group of autosomal recessive genetic disorders caused by mutations in genes coding for components of the primary cilia. Skeletal ciliopathy forms a subset of ciliopathies characterized by distinctive skeletal changes. Common skeletal ciliopathies include Jeune asphyxiating thoracic dysplasia, Ellis-van Creveld syndrome, Sensenbrenner syndrome, and short-rib polydactyly syndromes. These disorders share common clinical and radiological features. The clinical hallmarks comprise thoracic hypoplasia with respiratory failure, body disproportion with a normal trunk length and short limbs, and severely short digits occasionally accompanied by polydactyly. Reflecting the clinical features, the radiological hallmarks consist of a narrow thorax caused by extremely short ribs, normal or only mildly affected spine, shortening of the tubular bones, and severe brachydactyly with or without polydactyly. Other radiological clues include trident ilia/pelvis and cone-shaped epiphysis. Skeletal ciliopathies are commonly associated with extraskeletal anomalies, such as progressive renal degeneration, liver disease, retinopathy, cardiac anomalies, and cerebellar abnormalities. In this article, we discuss the radiological pattern recognition approach to skeletal ciliopathies. We also describe the clinical and genetic features of skeletal ciliopathies that the radiologists should know for them to play an appropriate role in multidisciplinary care and scientific advancement of these complicated disorders.
Topics: Bone and Bones; Ciliopathies; Craniosynostoses; Dwarfism; Ectodermal Dysplasia; Ellis-Van Creveld Syndrome; Female; Humans; Image Interpretation, Computer-Assisted; Male; Osteochondrodysplasias; Radiography
PubMed: 31965514
DOI: 10.1007/s11604-020-00920-w -
Health Physics Jul 2020Concern about the threat of a terrorist attack with a Radiological Dispersal Device has increased considerably over the last few years, and this comes along with an...
Concern about the threat of a terrorist attack with a Radiological Dispersal Device has increased considerably over the last few years, and this comes along with an immense challenge, especially regarding medical treatment of combined injuries with incorporated radioactive fragments. In such scenarios, the identification and surgical exploration of radioactive fragments is a major issue to prevent further radiation-induced effects like wound healing disorders, onset of acute radiation syndrome, and as a late-effect cancer. However, in a usual emergency setting, it is unclear how this task can be achieved. Within this study, we evaluated the feasibility of different radiological methods to identify and locate an incorporated radioactive fragment. We placed two different Cs sources and several non-radioactive fragments representing sham control samples within a human spine phantom. Standard emergency imaging procedures were performed, including plane radiography and different CT scans (64 row, 384 row dual energy, 320 row without iterative metal artifact reduction), respectively. Eight radiologists were blinded toward the results and asked to identify the radioactive fragments within the provided images. For both sources, correct identification was rather low (15.63%). Furthermore, none of the questioned radiologists (N = 0) stated that they were able to identify the radioactive shrapnel distinctly. Positive predictive value was accordingly low (15.63%). Most participants recommended a scintigraphy-based technique for identification (26.67%) rather than radiographic procedures (6.67%). Identification and location of incorporated small radioactive fragments with low energies by standard radiological procedures prior to surgical exploration is not promising. Nevertheless, procedures that can achieve this aim are needed direly in the case of a terrorist attack with a radiological dispersal device and should be available in an emergency department.
Topics: Decontamination; Emergency Medical Services; Humans; Image Processing, Computer-Assisted; Phantoms, Imaging; Radiation Dosage; Radiation Injuries; Radiation Monitoring; Radiation Protection; Radioactivity; Radiography; Radiometry; Radionuclide Imaging
PubMed: 31913860
DOI: 10.1097/HP.0000000000001203 -
Tremor and Other Hyperkinetic Movements... 2019Detection of defective deep brain stimulation (DBS) contacts/electrodes is sometimes challenging.
BACKGROUND
Detection of defective deep brain stimulation (DBS) contacts/electrodes is sometimes challenging.
CASE REPORT
We report a patient with Tourette syndrome (TS), who presented with abrupt tic increase and mild generalized headache 9 years after DBS implantation. On the suspicion of a hardware defect, a fracture of the DBS electrode and extension lead was ruled out by radiography and standard implantable pulse generator readouts. Further investigation revealed position-dependent modifiable therapeutic impedances, suggesting an impaired contact of the extension lead/adaptor. After replacement normal impedances were recorded, and the patient fully recovered.
DISCUSSION
In DBS dysfunction with inconspicuous hardware check, position-dependent defects might be suspected.
Topics: Adult; Deep Brain Stimulation; Electrodes, Implanted; Humans; Male; Postoperative Complications; Tourette Syndrome
PubMed: 31709126
DOI: 10.7916/tohm.v0.713 -
Journal of Obstetrics and Gynaecology :... Aug 2020
Topics: Abortion, Eugenic; Cytoplasmic Dyneins; Female; Humans; Nuchal Translucency Measurement; Pedigree; Pregnancy; Pregnancy Trimester, First; Short Rib-Polydactyly Syndrome; Exome Sequencing
PubMed: 31609148
DOI: 10.1080/01443615.2019.1655722 -
Molecular Genetics & Genomic Medicine Jan 2020This study reports the genetic features of four Caucasian males from the Saguenay-Lac-St-Jean region affected by partial agenesis of the corpus callosum (ACC) with...
BACKGROUND
This study reports the genetic features of four Caucasian males from the Saguenay-Lac-St-Jean region affected by partial agenesis of the corpus callosum (ACC) with hypotonia, epilepsy, developmental delay, microcephaly, hypoplasia, and autistic behavior.
METHODS
We performed whole exome sequencing (WES) to identify new genes involved in this pathological phenotype. The regions of interest were subsequently sequenced for family members.
RESULTS
Single-nucleotide variations (SNVs) and insertions or deletions were detected in genes potentially implicated in brain defects observed in these patients. One patient did not have mutations in genes related to ACC, but carried a de novo pathogenic mutation in Mucolipin-1 (MCOLN1) and was diagnosed with mucolipidosis type IV. Among the other probands, missense SNVs were observed in DCLK2 (Doublecortin Like Kinase 2), HERC2 (HECT And RLD Domain Containing E3 Ubiquitin Protein Ligase 2), and KCNH3 (Potassium channel, voltage-gated, subfamily H, member 3). One patient also carried a non-frameshift insertion in CACNA1A (Cav2.1(P/Q-type) calcium channels).
CONCLUSION
Although no common genetic defect was observed in this study, we provide evidence for new avenues of investigation for ACC, such as molecular pathways involving HERC2, CACNA1A, KCNH3, and more importantly DCLK2. We also allowed to diagnose an individual with mucolipidosis type IV.
Topics: Adolescent; Adult; Agenesis of Corpus Callosum; Calcium Channels; Developmental Disabilities; Doublecortin-Like Kinases; Epilepsy; Ether-A-Go-Go Potassium Channels; Exome; Humans; Male; Microcephaly; Nerve Tissue Proteins; Polymorphism, Single Nucleotide; Protein Serine-Threonine Kinases; Syndrome; Transient Receptor Potential Channels; Ubiquitin-Protein Ligases
PubMed: 31578829
DOI: 10.1002/mgg3.992 -
Nature Sep 2019Enzymes that catalyse CpG methylation in DNA, including the DNA methyltransferases 1 (DNMT1), 3A (DNMT3A) and 3B (DNMT3B), are indispensable for mammalian tissue...
Enzymes that catalyse CpG methylation in DNA, including the DNA methyltransferases 1 (DNMT1), 3A (DNMT3A) and 3B (DNMT3B), are indispensable for mammalian tissue development and homeostasis. They are also implicated in human developmental disorders and cancers, supporting the critical role of DNA methylation in the specification and maintenance of cell fate. Previous studies have suggested that post-translational modifications of histones are involved in specifying patterns of DNA methyltransferase localization and DNA methylation at promoters and actively transcribed gene bodies. However, the mechanisms that control the establishment and maintenance of intergenic DNA methylation remain poorly understood. Tatton-Brown-Rahman syndrome (TBRS) is a childhood overgrowth disorder that is defined by germline mutations in DNMT3A. TBRS shares clinical features with Sotos syndrome (which is caused by haploinsufficiency of NSD1, a histone methyltransferase that catalyses the dimethylation of histone H3 at K36 (H3K36me2)), which suggests that there is a mechanistic link between these two diseases. Here we report that NSD1-mediated H3K36me2 is required for the recruitment of DNMT3A and maintenance of DNA methylation at intergenic regions. Genome-wide analysis shows that the binding and activity of DNMT3A colocalize with H3K36me2 at non-coding regions of euchromatin. Genetic ablation of Nsd1 and its paralogue Nsd2 in mouse cells results in a redistribution of DNMT3A to H3K36me3-modified gene bodies and a reduction in the methylation of intergenic DNA. Blood samples from patients with Sotos syndrome and NSD1-mutant tumours also exhibit hypomethylation of intergenic DNA. The PWWP domain of DNMT3A shows dual recognition of H3K36me2 and H3K36me3 in vitro, with a higher binding affinity towards H3K36me2 that is abrogated by TBRS-derived missense mutations. Together, our study reveals a trans-chromatin regulatory pathway that connects aberrant intergenic CpG methylation to human neoplastic and developmental overgrowth.
Topics: Animals; Cell Line; DNA (Cytosine-5-)-Methyltransferases; DNA Methylation; DNA Methyltransferase 3A; DNA, Intergenic; Genome-Wide Association Study; Growth Disorders; Histones; Humans; Mice; Protein Binding; Protein Domains; Protein Transport; Sotos Syndrome
PubMed: 31485078
DOI: 10.1038/s41586-019-1534-3 -
American Journal of Medical Genetics.... Oct 2019Lenz-Majewski syndrome (LMS) is an extremely rare type of cutis laxa caused by dominant mutations in PTDSS1 gene. We report an Egyptian patient who presented with cutis...
Lenz-Majewski syndrome (LMS) is an extremely rare type of cutis laxa caused by dominant mutations in PTDSS1 gene. We report an Egyptian patient who presented with cutis laxa, brachydactyly, and progeroid features. LMS syndrome was suspected and a previously reported de novo heterozygous missense mutation (c.284G > T, p.R95L) in PTDSS1 was identified. To the best of our knowledge, nine molecularly proven patients with LMS from different ethnicities have been reported. Our patient is the first report from the Middle East and the tenth molecularly proven patient reported to date. His clinical features were in accordance with LMS syndrome. In addition, his hands X-ray images showed hypoplastic or absent middle and proximal phalanges but sparing the thumbs. This hand patterning was similarly observed before. Further, he had relatively large and convex fingernails. Our report highlights this unique hand patterning and suggests these signs should be considered among the diagnostic criteria of LMS. Further reports of patients with PTDSS1 mutations are necessary to further elucidate the detailed clinical features of LMS syndrome.
Topics: Abnormalities, Multiple; Bone Diseases, Developmental; Egypt; Exons; Humans; Infant; Intellectual Disability; Introns; Male; Nitrogenous Group Transferases; Syndrome
PubMed: 31403251
DOI: 10.1002/ajmg.a.61327 -
Kardiologia Polska Sep 2019
Anomalous origin of the right coronary artery from the left Valsalva sinus in a patient presenting with syncope, ventricular tachycardia, and electrocardiographic early repolarization pattern.
Topics: Coronary Angiography; Coronary Vessel Anomalies; Electrocardiography; Humans; Middle Aged; Sinus of Valsalva; Syncope; Syndrome; Tachycardia, Ventricular
PubMed: 31354160
DOI: 10.33963/KP.14909 -
Radiation Protection Dosimetry Dec 2019The relation of radiation exposure (dose) with acute radiation syndrome (ARS) depends on many factors. In this overview, we reconsider (1) radiation exposure...
The relation of radiation exposure (dose) with acute radiation syndrome (ARS) depends on many factors. In this overview, we reconsider (1) radiation exposure characteristics (e.g. radiation quality, fractionation, dose rate, partial/total body irradiation) and (2) biological processes (e.g. radiosensitivity, cell cycle dependency, oxygenation) affecting acute health effects after exposure. Furthermore we include evidence from recently published work that examined the relationship of absorbed dose and risk of clinically relevant ARS in persons exposed after a radiation accident. We introduce the concept of radiation-related bioindicators for effect prediction. Bioindicators are considered here to be factors that integrate multiple radiation exposure characteristics and cell- and molecular-based processes to improve clinical prediction in persons with ARS.
Topics: Acute Radiation Syndrome; Biomarkers; Cytogenetic Analysis; Humans; Occupational Exposure; Radiation Dosage; Radiation Exposure; Radioactive Hazard Release; Radiometry; Risk Assessment; Whole-Body Irradiation
PubMed: 31330030
DOI: 10.1093/rpd/ncz058