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American Journal of Human Genetics Jul 2013SHORT syndrome is a rare, multisystem disease characterized by short stature, anterior-chamber eye anomalies, characteristic facial features, lipodystrophy, hernias,...
SHORT syndrome is a rare, multisystem disease characterized by short stature, anterior-chamber eye anomalies, characteristic facial features, lipodystrophy, hernias, hyperextensibility, and delayed dentition. As part of the FORGE (Finding of Rare Disease Genes) Canada Consortium, we studied individuals with clinical features of SHORT syndrome to identify the genetic etiology of this rare disease. Whole-exome sequencing in a family trio of an affected child and unaffected parents identified a de novo frameshift insertion, c.1906_1907insC (p.Asn636Thrfs*18), in exon 14 of PIK3R1. Heterozygous mutations in exon 14 of PIK3R1 were subsequently identified by Sanger sequencing in three additional affected individuals and two affected family members. One of these mutations, c.1945C>T (p.Arg649Trp), was confirmed to be a de novo mutation in one affected individual and was also identified and shown to segregate with the phenotype in an unrelated family. The other mutation, a de novo truncating mutation (c.1971T>G [p.Tyr657*]), was identified in another affected individual. PIK3R1 is involved in the phosphatidylinositol 3 kinase (PI3K) signaling cascade and, as such, plays an important role in cell growth, proliferation, and survival. Functional studies on lymphoblastoid cells with the PIK3R1 c.1906_1907insC mutation showed decreased phosphorylation of the downstream S6 target of the PI3K-AKT-mTOR pathway. Our findings show that PIK3R1 mutations are the major cause of SHORT syndrome and suggest that the molecular mechanism of disease might involve downregulation of the PI3K-AKT-mTOR pathway.
Topics: Adolescent; Child; Child, Preschool; Class Ia Phosphatidylinositol 3-Kinase; DNA Mutational Analysis; Exome; Exons; Female; Frameshift Mutation; Genetic Carrier Screening; Growth Disorders; Heterozygote; Humans; Hypercalcemia; Infant, Newborn; Male; Metabolic Diseases; Nephrocalcinosis; Pedigree; Phenotype; Phosphorylation; Signal Transduction
PubMed: 23810382
DOI: 10.1016/j.ajhg.2013.06.005 -
CMAJ : Canadian Medical Association... Aug 2016Rare diseases often present in the first days and weeks of life and may require complex management in the setting of a neonatal intensive care unit (NICU). Exhaustive...
BACKGROUND
Rare diseases often present in the first days and weeks of life and may require complex management in the setting of a neonatal intensive care unit (NICU). Exhaustive consultations and traditional genetic or metabolic investigations are costly and often fail to arrive at a final diagnosis when no recognizable syndrome is suspected. For this pilot project, we assessed the feasibility of next-generation sequencing as a tool to improve the diagnosis of rare diseases in newborns in the NICU.
METHODS
We retrospectively identified and prospectively recruited newborns and infants admitted to the NICU of the Children's Hospital of Eastern Ontario and the Ottawa Hospital, General Campus, who had been referred to the medical genetics or metabolics inpatient consult service and had features suggesting an underlying genetic or metabolic condition. DNA from the newborns and parents was enriched for a panel of clinically relevant genes and sequenced on a MiSeq sequencing platform (Illumina Inc.). The data were interpreted with a standard informatics pipeline and reported to care providers, who assessed the importance of genotype-phenotype correlations.
RESULTS
Of 20 newborns studied, 8 received a diagnosis on the basis of next-generation sequencing (diagnostic rate 40%). The diagnoses were renal tubular dysgenesis, SCN1A-related encephalopathy syndrome, myotubular myopathy, FTO deficiency syndrome, cranioectodermal dysplasia, congenital myasthenic syndrome, autosomal dominant intellectual disability syndrome type 7 and Denys-Drash syndrome.
INTERPRETATION
This pilot study highlighted the potential of next-generation sequencing to deliver molecular diagnoses rapidly with a high success rate. With broader use, this approach has the potential to alter health care delivery in the NICU.
Topics: Female; Genetic Association Studies; Genetic Testing; High-Throughput Nucleotide Sequencing; Humans; Infant, Newborn; Intensive Care Units, Neonatal; Male; Mutation; Ontario; Pilot Projects; Prospective Studies; Rare Diseases; Retrospective Studies
PubMed: 27241786
DOI: 10.1503/cmaj.150823 -
Journal of Medical Case Reports Nov 2021Over-the-counter medication overdose is a difficult diagnostic challenge for many physicians as common drug screening assays cannot detect these substances. We present a...
BACKGROUND
Over-the-counter medication overdose is a difficult diagnostic challenge for many physicians as common drug screening assays cannot detect these substances. We present a case of acute psychosis, serotonin syndrome, and anticholinergic overdose-like properties in the setting of Coricidin HBP Cough & Cold tablets, known by their street name Triple-C. This is the first case report we are aware of involving a patient presenting with these symptoms and requiring critical-care-level support.
CASE PRESENTATION
A 31-year-old African American female with a past medical history of anxiety, childhood asthma, previous methamphetamine abuse, and coronavirus disease 2019 infection in August 2020 was brought to the emergency department by the local police department with altered mental status. Initial blood work, including extended drug screens, were unremarkable for a definitive diagnosis. This patient required critical-care-level support and high sedation because of her symptoms. Collateral history revealed the patient regularly consumed Triple-C daily for the 6 weeks prior to admission. A trial off sedation was attempted after 24 hours with no complications. The patient admitted to regular Triple-C consumption and auditory hallucinations since adolescence. She was discharged safely after 48 hours back into the community. She was lost to follow-up with psychiatry and internal medicine; however, she was evaluated in the emergency room 1 month later with a similar psychiatric presentation.
CONCLUSION
Overdose of Triple-C should be kept in the differential diagnosis of patients presenting with a triad of psychosis, serotonin syndrome, and anticholinergic overdose, in the setting of unknown substance ingestion.
Topics: Adolescent; Adult; COVID-19; Child; Drug Overdose; Female; Humans; Psychotic Disorders; SARS-CoV-2; Serotonin Syndrome
PubMed: 34732250
DOI: 10.1186/s13256-021-03163-z -
Endokrynologia Polska 2013We present revised Polish guidelines regarding the management of patients harbouring neuroendocrine neoplasms (NENs) of the small intestine and appendix. The small...
We present revised Polish guidelines regarding the management of patients harbouring neuroendocrine neoplasms (NENs) of the small intestine and appendix. The small intestine, especially the ileum, is the most common origin of these neoplasms. Most of them are well differentiated with slow growth. Rarely, they are less differentiated, growing fast with a poor prognosis. Since symptoms can be atypical, the diagnosis is often accidental. Typical symptoms of carcinoid syndrome occur in less than 10% of patients. The most useful laboratory marker is chromogranin A; 5-hydroxyindoleacetic acid is helpful in the monitoring of carcinoid syndrome. Ultrasound, computed tomography, magnetic resonance imaging, colonoscopy, video capsule endoscopy, balloon enteroscopy and somatostatin receptors scintigraphy are used in the visualisation. A histological report is crucial for the proper diagnostics and therapy of NENs, and it has been extensively described. The treatment of choice is surgery, either radical or palliative. Somatostatin analogues are crucial in the pharmacological treatment of the hormonally active and non-active small intestine NENs and NENs of the appendix. Radioisotope therapy is possible in patients with a good expression of somatostatin receptors. Chemotherapy is not effective in general. Everolimus therapy can be applied in patients with generalised NENs of the small intestine in progression and where there has been a failure or an inability to use other treatment options. Finally, we make recommendations regarding the monitoring of patients with NENs of the small intestine and appendix.
Topics: Appendiceal Neoplasms; Clinical Competence; Endocrinology; Humans; Intestinal Neoplasms; Medical Oncology; Neuroendocrine Tumors; Physical Examination; Poland; Practice Guidelines as Topic; Quality Assurance, Health Care
PubMed: 24431119
DOI: 10.5603/EP.2013.0029 -
Journal of Cell Science Mar 2023The primary cilium is a sensory organelle, receiving signals from the external environment and relaying them into the cell. Mutations in proteins required for transport...
The primary cilium is a sensory organelle, receiving signals from the external environment and relaying them into the cell. Mutations in proteins required for transport in the primary cilium result in ciliopathies, a group of genetic disorders that commonly lead to the malformation of organs such as the kidney, liver and eyes and skeletal dysplasias. The motor proteins dynein-2 and kinesin-2 mediate retrograde and anterograde transport, respectively, in the cilium. WDR34 (also known as DYNC2I2), a dynein-2 intermediate chain, is required for the maintenance of cilia function. Here, we investigated WDR34 mutations identified in Jeune syndrome, short-rib polydactyly syndrome and asphyxiating thoracic dysplasia patients. There is a poor correlation between genotype and phenotype in these cases, making diagnosis and treatment highly complex. We set out to define the biological impacts on cilia formation and function of WDR34 mutations by stably expressing the mutant proteins in WDR34-knockout cells. WDR34 mutations led to different spectrums of phenotypes. Quantitative proteomics demonstrated changes in dynein-2 assembly, whereas initiation and extension of the axoneme, localization of intraflagellar transport complex-B proteins, transition zone integrity and Hedgehog signalling were also affected.
Topics: Humans; Dyneins; Carrier Proteins; Hedgehog Proteins; Ellis-Van Creveld Syndrome; Cilia; Mutation
PubMed: 36268591
DOI: 10.1242/jcs.260073 -
Cell Cycle (Georgetown, Tex.) 2015Short-rib polydactyly syndromes (SRPS) arise from mutations in genes involved in retrograde intraflagellar transport (IFT) and basal body homeostasis, which are critical...
Short-rib polydactyly syndromes (SRPS) arise from mutations in genes involved in retrograde intraflagellar transport (IFT) and basal body homeostasis, which are critical for cilia assembly and function. Recently, mutations in WDR34 or WDR60 (candidate dynein intermediate chains) were identified in SRPS. We have identified and characterized Tctex1d2, which associates with Wdr34, Wdr60 and other dynein complex 1 and 2 subunits. Tctex1d2 and Wdr60 localize to the base of the cilium and their depletion causes defects in ciliogenesis. We propose that Tctex1d2 is a novel dynein light chain important for trafficking to the cilium and potentially retrograde IFT and is a new molecular link to understanding SRPS pathology.
Topics: Adaptor Proteins, Signal Transducing; Carrier Proteins; Cilia; Cytoskeletal Proteins; Dyneins; HEK293 Cells; HeLa Cells; Humans; Microtubule-Organizing Center; Mutation; Protein Transport; Short Rib-Polydactyly Syndrome
PubMed: 25830415
DOI: 10.4161/15384101.2014.985066 -
BMC Medical Genomics Mar 2022Short-rib thoracic dysplasia 3 with or without polydactyly (SRTD3, OMIM: 613091) is an autosomal recessive disorder. SRTD3 presents clinically with a narrow thorax,...
BACKGROUND
Short-rib thoracic dysplasia 3 with or without polydactyly (SRTD3, OMIM: 613091) is an autosomal recessive disorder. SRTD3 presents clinically with a narrow thorax, short ribs, shortened tubular bones, and acetabular roof abnormalities. Clinical signs of SRTD3 vary among individuals. Pathogenic variants of DYNC2H1 (OMIM: 603297) have been reported to cause SRTD3.
METHODS
We performed a detailed clinical prenatal sonographic characterization of a foetus with SRTD3. Trio whole-exome sequencing was used to identify causative variants in the family. The identified variants in the families were validated by Sanger sequencing and mass spectrometry. Multiple computational tools were used to predict the harmfulness of the two variants. A minigene splicing assay was carried out to evaluate the impact of the splice-site variant.
RESULTS
We evaluated prenatal sonographic images of the foetus with SRTD3, including abnormal rib curvature, narrow thorax, bilateral hypoplastic lungs, bilateral polydactyly, syndactyly, and foetal visceral situs inversus with mirror-image dextrocardia. We revealed novel compound variants of DYNC2H1 (NM_001377.3:c.11483T > G (p.Ile3828Arg) and c.2106 + 3A > T). Various statistical methods predicted that the variants would cause harmful effects on genes or gene products. The minigene assay findings suggested that c.2106 + 3A > T caused the skipping over exon 14, producing an exon 14 loss in the protein.
CONCLUSION
This study identified a foetus with SRTD3 with situs inversus totalis with mirror-image dextrocardia in a Chinese family, revealing two novel compound heterozygous dynein cytoplasmic 2 heavy chain 1 (DYNC2H1) variants, expanding the phenotypic spectrum of SRTD3. The minigene study of c.2106 + 3A > T was predicted to cause an inframe exclusion of exon 14, which was predicted to have important molecular functions. Our findings strongly supported the use of WES in prenatal diagnosis and helped to understand the correlation of genotype and phenotypes of DYNC2H1. The specific sonographic findings and the molecular diagnosis helped add experience to further our expertise in prenatal counselling for SRTD3.
Topics: Cytoplasmic Dyneins; Dextrocardia; Female; Fetus; Humans; Polydactyly; Pregnancy; Short Rib-Polydactyly Syndrome; Situs Inversus
PubMed: 35277174
DOI: 10.1186/s12920-022-01205-z -
Ultrasound in Obstetrics & Gynecology :... Apr 2008We report the sonographic and autopsy findings in two sibling fetuses with autosomal recessive orofaciodigital syndrome (OFDS) Type IV (Mohr-Majewski) diagnosed at 11-13...
We report the sonographic and autopsy findings in two sibling fetuses with autosomal recessive orofaciodigital syndrome (OFDS) Type IV (Mohr-Majewski) diagnosed at 11-13 weeks' gestation. The first-trimester anomaly scan showed a markedly increased nuchal translucency (NT) thickness in both fetuses (4.7 mm and 5.1 mm). Both fetuses had multiple anomalies involving the brain, cranium, heart and skeletal system and their karyotypes were normal. The pregnancies were terminated and the autopsies showed findings consistent with Mohr-Majewski syndrome. These cases show the overlap between OFDS Type II (Mohr) and lethal short-rib-polydactyly syndrome Type II (Majewski) and confirm both the autosomal recessive inheritance of the condition and our ability to diagnose it early in pregnancy using detailed fetal ultrasonography.
Topics: Abortion, Therapeutic; Adult; Early Diagnosis; Female; Humans; Male; Nuchal Translucency Measurement; Orofaciodigital Syndromes; Pregnancy; Pregnancy Trimester, First
PubMed: 18383484
DOI: 10.1002/uog.5285 -
Taiwanese Journal of Obstetrics &... Dec 2012To present the perinatal findings and first-trimester molecular and transabdominal ultrasound diagnosis of a fetus with Ellis-van Creveld (EvC) syndrome.
OBJECTIVE
To present the perinatal findings and first-trimester molecular and transabdominal ultrasound diagnosis of a fetus with Ellis-van Creveld (EvC) syndrome.
CASE REPORT
A 35-year-old woman was referred for genetic counseling at 13 weeks of gestation because of a family history of skeletal dysplasia. She had experienced one spontaneous abortion, and delivered one male fetus and one female fetus with EvC syndrome. During this pregnancy, a prenatal transabdominal ultrasound at 13(+4) weeks of gestation revealed a nuchal translucency (NT) thickness of 2.0 mm, an endocardial cushion defect, postaxial polydactyly of bilateral hands, and mesomelic dysplasia of the long bones. Amniocentesis was performed at 13(+5) weeks of gestation. Results of a cytogenetic analysis revealed a karyotype of 46,XX and that of a molecular analysis revealed compound heterozygous mutations of c.1195C>T and c.871-2_894del26 in the EVC2 gene. Prenatal ultrasound at 16 weeks of gestation showed a fetus with short limbs, an endocardial cushion defect, and postaxial polydactyly of bilateral hands. The parents decided to terminate the pregnancy, and a 116-g female fetus was delivered with a narrow thorax, shortening limbs, and postaxial polydactyly of the hands.
CONCLUSION
Prenatal diagnosis of an endocardial cushion defect with postaxial polydactyly should include a differential diagnosis of EvC syndrome in addition to short rib-polydactyly syndrome, Bardet-Biedl syndrome, orofaciodigital syndrome, Smith-Lemli-Opitz syndrome, and hydrolethalus syndrome.
Topics: Abortion, Eugenic; Adult; Amniocentesis; Ellis-Van Creveld Syndrome; Female; Fetal Diseases; Humans; Intercellular Signaling Peptides and Proteins; Karyotype; Nuchal Translucency Measurement; Pregnancy; Pregnancy Trimester, First; Proteins
PubMed: 23276573
DOI: 10.1016/j.tjog.2012.10.001 -
Journal of Medical Genetics Mar 1990We present a male infant with hypertelorism, median pseudo-cleft of the upper lip and cleft palate, lobulated tongue, hypoplastic larynx and epiglottis, mesomelic...
We present a male infant with hypertelorism, median pseudo-cleft of the upper lip and cleft palate, lobulated tongue, hypoplastic larynx and epiglottis, mesomelic shortening of limbs with particularly short and broad tibiae, polydactyly of the upper limbs, severely hypoplastic external genitalia with anorchidism, anal atresia, severe congenital heart defect, and renal agenesis. These features show considerable overlap with severe Majewski type short rib-polydactyly syndrome and so expand the known spectrum of anomalies in orofaciodigital syndrome type IV.
Topics: Abnormalities, Multiple; Humans; Infant, Newborn; Male; Orofaciodigital Syndromes; Prenatal Diagnosis; Radiography, Thoracic
PubMed: 2325097
DOI: 10.1136/jmg.27.3.200