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Post-zygotic mosaicism is a well-known biological phenomenon characterized by the presence of genetically distinct lineages of cells in the same individual due to post-zygotic de novo mutational events. It has been identified in about 13% of Cornelia de Lange (CdLS) syndrome patients with a molecular diagnosis, an unusual high frequency. Here, we report the case of a patient affected by classic CdLS harboring post-zygotic mosaicism for two different likely pathogenic variants at the same nucleotide position in NIPBL. Double somatic mosaicism has never been reported in CdLS and only rarely recognized in human diseases. Possible pathogenetic mechanisms are discussed.
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Síndrome de Cornélia de Lange , Humanos , Síndrome de Cornélia de Lange/diagnóstico , Síndrome de Cornélia de Lange/genética , Proteínas de Ciclo Celular/genética , Mosaicismo , FenótipoRESUMO
PURPOSE: To evaluate safety and efficacy of the novel percutaneous interspinous device (PID) for the treatment of symptomatic degenerative lumbar spinal stenosis (DLSS) in 3 different centers. METHODS: From November 2016 to March 2020, 255 patients (male 125, mean age 71.2 years old range 49-91 years old) with neurogenic claudication, confirmed by electromyography, related to mono or bi-segmental lumbar central canal and/or foraminal stenosis were enrolled in the study. Magnetic resonance (MR) and/or computer tomography (CT), physical exam, and Visual Analogue Scale (VAS) and Zurich Claudication Questionnaire (ZCQ) were performed before and 6 months after the procedure. All treatments were performed under fluoroscopic guidance with local anesthesia and mild sedation. Technical success was defined as correct placement of the Lobster® (Demetrios Medical, Firenze, Italy) PID as demonstrated by computer tomography (CT) performed immediately after treatment; spinoplasty was performed in selected patients. RESULTS: PID placement was accomplished with a 99.6% success rate (257/258). The one device that was not implanted was due to a spinous process fracture. In 28 patients, more than 1 device was implanted in the same session (max 3 PIDs); 6 patients required a second implant in different session. A total of 172 prophylactic spinoplasties were performed (59.3%). No major complications occurred; 3 device misplacements were successfully treated with percutaneous retrieval and new device deployment. 99.6% of patients experienced clinical improvement. CONCLUSION: Lobster PID is an effective and safe minimally invasive decompression method for central canal and neural foraminal stenosis when patients are correctly selected.
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Estudos de Viabilidade , Estenose Espinal , Humanos , Masculino , Idoso , Feminino , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Estudos Retrospectivos , Estenose Espinal/cirurgia , Estenose Espinal/diagnóstico por imagem , Vértebras Lombares/cirurgia , Vértebras Lombares/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Próteses e Implantes , Descompressão Cirúrgica/métodosRESUMO
Vertebral augmentation has been used to treat painful vertebral compression fractures and metastatic lesions in millions of patients around the world. An international group of subject matter experts have considered the evidence, including but not limited to mortality. These considerations led them to ask whether it is appropriate to allow the subjective measure of pain to so dominate the clinical decision of whether to proceed with augmentation. The discussions that ensued are related below.
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Fraturas por Compressão , Fraturas da Coluna Vertebral , Acidente Vascular Cerebral , Vertebroplastia , Humanos , Fraturas por Compressão/cirurgia , Fraturas da Coluna Vertebral/cirurgia , Dor , Resultado do TratamentoRESUMO
A comprehensive description of the literature regarding interspinous process devices (IPD) mainly focused on comparison with conservative treatment and surgical decompression for the treatment of degenerative lumbar spinal stenosis. Recent meta-analysis and articles are listed in the present article in order to establish IPD pros and cons.
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Próteses e Implantes/normas , Estenose Espinal/cirurgia , Tratamento Conservador/normas , Tratamento Conservador/estatística & dados numéricos , Humanos , Degeneração do Disco Intervertebral/complicações , Degeneração do Disco Intervertebral/cirurgia , Próteses e Implantes/estatística & dados numéricos , Resultado do TratamentoAssuntos
Analgésicos/efeitos adversos , Injeções Espinhais/efeitos adversos , Deslocamento do Disco Intervertebral/tratamento farmacológico , Dor Lombar/tratamento farmacológico , Ozônio/efeitos adversos , Pneumocefalia/induzido quimicamente , Adulto , Analgésicos/administração & dosagem , Feminino , Humanos , Ozônio/administração & dosagemRESUMO
Thanks to a long-read sequencing (LRS) approach, in this study, we have reported a molecularly solved case of a proband with a clinical diagnosis of Cornelia de Lange syndrome (CDLS), which is a multisystemic disorder whose causative molecular defects involve cohesin complex genes, with NIPBL located at 5p13.2 accounting for approximately 50%-60% of CDLS cases. The first-tier tests revealed an abnormal karyotype 46,XY,t(5;15)(p13;q25)dn and a preserved NIPBL sequencing. Copy number variants (CNVs) at the translocation breakpoints, in disease genes, or in probably pathogenic loci were excluded by a-CGH analysis. Through fluorescence in situ hybridization (FISH) analysis on derivative chromosome 5, the breakpoint was relocated 3 Mb far from NIPBL 5'UTR, which seemed fully maintained as FISH-probe mapping to the gene showed no split signals. Moreover, tri-color FISH revealed an apparently balanced paracentric inversion including NIPBL on derivative 5. Based on the strong clinical suspicion, we evaluated the NIPBL transcript by RT-qPCR that revealed a normal amount of transcript till exon 22 and a halved amount of the transcript from exon 23 to 3'UTR, indicating the expression of a truncated transcript probably leading to a defective protein. Despite RT-qPCR confirmed the patient's CDLS clinical diagnosis, the molecular mechanism underlying this event remained to be an unsolved challenge for years. The LRS approach with nanopore technologies was able to fill the gap in this complex scenario and highlighted a chromothripsis event marked out at 5p13.2 by 36 breaks clustered in a 7.3-Mb region. The NIPBL gene was disrupted by 16 breaks and the resulting fragments were relocated in different positions and orientations. LRS confirmed the previous findings, and it has been proven to be crucial to define the complex chromosomal rearrangement in this patient which escaped current diagnostic investigations. Its application in the clinical practice will contribute to solve the unsolved.
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BACKGROUND: The recent guidelines suggest the use of genome-wide analyses, such as whole exome sequencing (WES), at the beginning of the diagnostic approach for cases with suspected genetic conditions. However, in many realities it still provides for the execution of a multi-step pathway, thus requiring several genetic tests to end the so-called 'diagnostic odyssey'. METHODS: We reported the results of GENE Project (Genomic analysis Evaluation NEtwork): a multicentre prospective cohort study on 125 paediatric outpatients with a suspected genetic disease in which we performed first-tier trio-WES, including exome-based copy number variation analysis, in parallel to a 'traditional approach' of two/three sequential genetic tests. RESULTS: First-tier trio-WES detected a conclusive diagnosis in 41.6% of patients, way above what was found with routine genetic testing (25%), with a time-to-result of about 50 days. Notably, the study showed that 44% of WES-reached diagnoses would be missed with the traditional approach. The diagnostic rate (DR) of the two approaches varied in relation to the phenotypic class of referral and to the proportion of cases with a defined diagnostic suspect, proving the major difference for neurodevelopmental disorders. Moreover, trio-WES analysis detected variants in candidate genes of unknown significance (EPHA4, DTNA, SYNCRIP, NCOR1, TFDP1, SPRED3, EDA2R, PHF12, PPP1R12A, WDR91, CDC42BPG, CSNK1D, EIF3H, TMEM63B, RIPPLY3) in 19.4% of undiagnosed cases. CONCLUSION: Our findings represent real-practice evidence of how first-tier genome-wide sequencing tests significantly improve the DR for paediatric outpatients with a suspected underlying genetic aetiology, thereby allowing a time-saving setting of the correct management, follow-up and family planning.
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Variações do Número de Cópias de DNA , Pacientes Ambulatoriais , Humanos , Criança , Estudos Prospectivos , Sequenciamento do Exoma , Estudo de Associação Genômica Ampla , ItáliaRESUMO
[This corrects the article DOI: 10.3389/fneur.2022.1072256.].
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Hipertrofia/etiologia , Músculo Esquelético/diagnóstico por imagem , Doenças Musculares/etiologia , Radiculopatia/complicações , Idoso , Humanos , Hipertrofia/diagnóstico por imagem , Imageamento por Ressonância Magnética , Masculino , Doenças Musculares/diagnóstico por imagem , Radiculopatia/diagnóstico por imagemRESUMO
Objective: The aim of this study is to explain the technique used for removing and replacing a novel percutaneous interspinous device (PID).Procedure: Three male patients, with a mean age of 66 years (range 62-72), were included in the study due to displacement (N = 2) or misplacement (N = 1) of the novel PID. This occurred after a mean of 23.3 ± 10.5 days from the initial placement (range 13-34) at the L4-L5 level (N = 1) and L3-L4 level (N = 2). Following the removal of the PID, four new devices were implanted.Conclusion: The novel PID can be safely removed either immediately after its placement during the procedure or after a certain period of days or months from its implantation. The removal procedure can be performed percutaneously under imaging guidance, by closing the four retractable wings, using the same instrumentation as utilized during the initial implantation.
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Pathogenic variants impacting upon assembly of mitochondrial respiratory chain Complex IV (Cytochrome c Oxidase or COX) predominantly result in early onset mitochondrial disorders often leading to CNS, skeletal and cardiac muscle manifestations. The aim of this study is to describe a molecular defect in the COX assembly factor gene COX18 as the likely cause of a neonatal form of mitochondrial encephalo-cardio-myopathy and axonal sensory neuropathy. The proband is a 19-months old female displaying hypertrophic cardiomyopathy at birth and myopathy with axonal sensory neuropathy and failure to thrive developing in the first months of life. Serum lactate was consistently increased. Whole exome sequencing allowed the prioritization of the unreported homozygous substitution NM_001297732.2:c.667 G > C p.(Asp223His) in COX18. Patient's muscle biopsy revealed severe and diffuse COX deficiency and striking mitochondrial abnormalities. Biochemical and enzymatic studies in patient's myoblasts and in HEK293 cells after COX18 silencing showed a severe impairment of both COX activity and assembly. The biochemical defect was partially rescued by delivery of wild-type COX18 cDNA into patient's myoblasts. Our study identifies a novel defect of COX assembly and expands the number of nuclear genes involved in a mitochondrial disorder due to isolated COX deficiency.
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Deficiência de Citocromo-c Oxidase , Doenças Musculares , Feminino , Humanos , Lactente , Deficiência de Citocromo-c Oxidase/genética , Complexo IV da Cadeia de Transporte de Elétrons/genética , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Células HEK293 , Proteínas Mitocondriais/genética , MutaçãoRESUMO
In the last few years, trio-Whole Exome Sequencing (WES) analysis has revolutionized the diagnostic process for patients with rare genetic syndromes, demonstrating its potential even in non-specific clinical pictures and in atypical presentations of known diseases. Multiple disorders in a single patient have been estimated to occur in approximately 2-7.5% of diagnosed cases, with higher frequency in consanguineous families. Here, we report the clinical and molecular characterisation of eight illustrative patients for whom trio-WES allowed for identifing more than one genetic condition. Double homozygosity represented the causal mechanism in only half of them, whereas the other half showed peculiar multilocus combinations. The paper takes into consideration difficulties and learned lessons from our experience and therefore supports the powerful role of wide analyses for ascertaining multiple genetic diseases in complex patients, especially when a clinical suspicion could account for the majority of clinical signs. It finally makes clear how a patient's "deep phenotyping" might not be sufficient to suggest the presence of multiple genetic diagnoses but remains essential to validate an unexpected multilocus result from genetic tests.
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Exoma , Testes Genéticos , Família , Homozigoto , FenótipoRESUMO
Introduction: X-linked adrenoleukodystrophy (X-ALD) is the most common inherited peroxisomal disorder caused by variants in the ABCD1 gene. The main phenotypes observed in men with X-ALD are primary adrenal insufficiency, adrenomyeloneuropathy, and cerebral ALD (cALD). Cerebral ALD consists of a demyelinating progressive cerebral white matter (WM) disease associated with rapid clinical decline and is fatal if left untreated. Hematopoietic stem cell transplantation is the standard treatment for cALD as it stabilizes WM degeneration when performed early in the disease. For this reason, early diagnosis is crucial, and several countries have already implemented their newborn screening programs (NBS) with the assessment of C26:0-lysophosphatidylcholine (C26:0-LPC) values as screening for X-ALD. Methods: In June 2021, an Italian group in Lombardy launched a pilot study for the implementation of X-ALD in the Italian NBS program. A three-tiered approach was adopted, and it involved quantifying the values of C26:0-LPC and other metabolites in dried blood spots with FIA-MS/MS first, followed by the more specific ultra-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) technique and, finally, the genetic confirmation via focused NGS. Discussion: Genetically confirmed patients are set to undergo a follow-up protocol and are periodically evaluated to promptly start a specific treatment if and when the first signs of brain damage appear, as suggested by international guidelines. A specific disease monitoring protocol has been created based on literature data and personal direct experience. Conclusion: The primary aim of this study was to develop a model able to improve the early diagnosis and subsequent follow-up and timely treatment of X-ALD. Ethics: The study was approved by the local ethics committee. The research was conducted in the absence of any commercial or financial relationship that could be construed as a potential conflict of interest.
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Whole-exome sequencing (WES) is a powerful and comprehensive tool for the genetic diagnosis of rare diseases, but few reports describe its timely application and clinical impact on infantile cardiomyopathies (CM). We conducted a retrospective analysis of patients with infantile CMs who had trio (proband and parents)-WES to determine whether results contributed to clinical management in urgent and non-urgent settings. Twenty-nine out of 42 enrolled patients (69.0%) received a definitive molecular diagnosis. The mean time-to-diagnosis was 9.7 days in urgent settings, and 17 out of 24 patients (70.8%) obtained an etiological classification. In non-urgent settings, the mean time-to-diagnosis was 225 days, and 12 out of 18 patients (66.7%) had a molecular diagnosis. In 37 out of 42 patients (88.1%), the genetic findings contributed to clinical management, including heart transplantation, palliative care, or medical treatment, independent of the patient's critical condition. All 29 patients and families with a definitive diagnosis received specific counseling about recurrence risk, and in seven (24.1%) cases, the result facilitated diagnosis in parents or siblings. In conclusion, genetic diagnosis significantly contributes to patients' clinical and family management, and trio-WES should be performed promptly to be an essential part of care in infantile cardiomyopathy, maximizing its clinical utility.
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Spindle cell lipoma is a rare and distinct variant of soft tissue tumour characterised by spindle cells in which the fat content may be scarce or absent. Most spindle cell lipomas arise as a subcutaneous mass of the neck, shoulders or back. Rarely, they can also be found in unusual sites, such as the oral cavity, larynx, bronchus, breast, and extremities. Localisation of spindle cell lipoma in the orbit has been described in a few cases. We report here on a case of an orbital mass surgically excised in an adult male and discuss the differential diagnosis with other soft tissue tumours with a lipomatous component, such as lipomatous haemangiopericytoma, a rare variant of haemangiopericytoma.
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Lipoma/patologia , Lipoma/cirurgia , Neoplasias Orbitárias/diagnóstico , Neoplasias Orbitárias/cirurgia , Neoplasias de Tecidos Moles/diagnóstico , Neoplasias de Tecidos Moles/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Orbitárias/patologia , Neoplasias de Tecidos Moles/patologia , Resultado do TratamentoRESUMO
PURPOSE: To retrospectively assess safety and potential effectiveness of percutaneous intervertebral disc coagulation therapy (PDCT) using plasma thermal reaction for the treatment of lumbar and cervical disc hernias resistant to medical therapy. MATERIALS AND METHODS: Forty-four patients (age range 18-87 years, mean 52.7) with contained and extruded symptomatic lumbar (N = 48) and cervical (N = 6) disc hernias in the absence of free fragments causing radiculopathy without improvement after 6-week conservative therapy were enrolled. Pretreatment discography has been performed in every patient. Spine MRI was performed before the procedure and 4 months later, in order to check post-PDCT changes. Technical success was defined as correct placement of PDCT fiber; clinical outcomes were evaluated using visual analog scale (VAS) and the Oswestry Disability Index (ODI) before the procedure and after 4 months. RESULTS: A total of 54 levels have been treated with 98% technical success; in 12 patients (27%), the treatment was performed in two levels at the same time. All patients well tolerated the procedure; most patients (N = 39; 89%) had significant improvement in symptoms, with ODI score reduction from 47.61 ± 8.7 to 13.38 ± 9.4 (p < 0.001). The mean pre-PDCT VAS score was 7.47 ± 0.8. VAS score was decreased down to 1.36 ± 1.6 at final follow-up (p < 0.001). There were no cases of infection, nerve damage, or bleeding. CONCLUSIONS: PDCT can be an effective and safe for minimally invasive indirect decompression for cervical and lumbar hernia resistant to conservative treatment, particularly when patients are correctly selected.
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Discotomia Percutânea/métodos , Deslocamento do Disco Intervertebral/cirurgia , Fotocoagulação a Laser/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Europa (Continente) , Feminino , Humanos , Disco Intervertebral/diagnóstico por imagem , Disco Intervertebral/cirurgia , Deslocamento do Disco Intervertebral/diagnóstico por imagem , Vértebras Lombares/diagnóstico por imagem , Vértebras Lombares/cirurgia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Dados Preliminares , Estudos Retrospectivos , Resultado do Tratamento , Adulto JovemRESUMO
Occipital neuralgia may be related to traumatic, compressive, or inflammatory injury to the occipital nerve or C2 radicular level and cervical spinal cord lesions. We report a series of 3 patients with definite relapsing-remitting multiple sclerosis (MS) who experienced sudden occipital neuralgiform pain with or without diminished sensation in the cervical region and associated with magnetic resonance imaging (MRI) evidence of a new active or new T2-weighted demyelinating C2 cervical lesion. We suggest that sudden paroxysmal occipital pain may signal relapse of MS and cervical MRI with gadolinium should be considered; these patients show good clinical response to high-dose intravenous corticosteroids.
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Esclerose Múltipla Recidivante-Remitente/complicações , Esclerose Múltipla Recidivante-Remitente/patologia , Neuralgia/etiologia , Osso Occipital/inervação , Medula Espinal/patologia , Adulto , Idoso , Vértebras Cervicais , Feminino , Humanos , Imageamento por Ressonância Magnética , Metilprednisolona/uso terapêutico , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Neuralgia/tratamento farmacológico , Neuralgia/patologia , Fármacos Neuroprotetores/uso terapêuticoRESUMO
Low back pain, radicular leg pain, and lumbar spinal stenosis are the most common of all chronic pain disorders. Discogenic pain is related to distress of annular fibers and tears, whereas spinal stenosis is related to reduction of the spinal canal dimensions and compression of the neural elements; radicular pain is mainly related to disc herniation and is initially managed conservatively. The percutaneous minimally invasive approach in discogenic and radicular pain is designed to reduce the volume of the nucleus pulposus in patients with failure of medical and physical treatment prolonged for at least 6 weeks.